| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Department of Medicine, Division of Endocrinology (G.F.L., A.C., A.G.), Department of Physiology (A.G.), and Department of Laboratory Medicine and Pathobiology (K.A.), University of Toronto, Toronto, Canada M5G 2C4
Correspondence: Address all correspondence and requests for reprints to: Dr. Gary Lewis, Toronto General Hospital, 200 Elizabeth Street, Room EN11-229, Toronto, Ontario, Canada M5G 2C4. E-mail: gary.lewis{at}uhn.on.ca
 |
Abstract |
|---|
I. Introduction
II. Abnormalities of FFA Metabolism in Obesity, Insulin Resistance, and Type 2 Diabetes
A. Hormone-sensitive lipase (HSL) and insulin suppression of lipolysis
B. Adipose tissue uptake and intracellular esterification of fatty acids
C. Total fat mass and regional fat depots
D. Fat diversion from adipose to nonadipose tissue
E. Abnormal fatty acid metabolism in skeletal muscle
F. Potential abnormalities of intestinal fatty acid uptake
G. Protective role of leptin and adiponectin against lipotoxicity
H.Summary of the abnormalities of FFA metabolism in obesity, IRS, and type 2 diabetes
III. Dyslipidemia and Fatty Liver Infiltration in IRS and Type 2 Diabetes
A. The contribution of de novo lipogenesis to elevated VLDL production
B. Contribution of hepatic cytosolic triglyceride stores to VLDL overproduction and fatty liver infiltration (nonalcoholic steatohepatitis)
C. Hepatic lipoprotein remnant uptake also contributes to VLDL production
D. The role of resistance to insulin action in the hepatocyte and chronic hyperinsulinemia per se in facilitating VLDL synthesis and secretion
E. Summary of the mechanisms of VLDL overproduction in relation to fat maldistribution between adipose and nonadipose tissue
IV. Effects of FFA on Muscle Glucose Metabolism
A. Effects of the Randle cycle on muscle glucose metabolism
B. Effects of long-chain fatty acid acyl-CoA (LCFA-CoA) and PKC activation on muscle glucose metabolism
C. Effects of FFAs on the hexosamine pathway and oxidative stress in muscle
D. Effects of FFAs on the gene expression of enzymes involved in muscle glucose metabolism
V. Effects of FFA on Hepatic Glucose Metabolism
A. Controversial role of FFA in the regulation of hepatic glucose production in vivo
B. Effects of FFA oxidation on hepatic glucose metabolism
C. Other effects of FFA on hepatic glucose metabolism
D. Effects of FFA on insulin resistance: concluding remarks
VI. Effect of FFA on Hepatic Insulin Extraction
VII. Effects of FFA and Islet Triglyceride Stores on Pancreatic ß-Cells
A. Acute effects of FFA on insulin secretion
B. Chronic effects of FFA on insulin secretion
C. Effect of chronically elevated FFAs on insulin secretion in vivo
D. Summary of the effects of FFAs on insulin secretion
VIII. Inhibition of Fatty Acid Flux from Adipose Tissue: Is it Effective in Ameliorating the Manifestations of IRS and Type 2 Diabetes?
IX. Summary
|
I. Introduction |
|---|
|
II. Abnormalities of FFA Metabolism in Obesity, Insulin Resistance, and Type 2 Diabetes |
|---|
Plasma FFA concentration reflects a balance between release (from the intravascular lipolysis of triglyceride-rich lipoproteins and lipolysis of adipose tissue triglyceride stores) and uptake (predominantly re-esterified in adipose tissue and liver and oxidized in muscle, heart, liver, and other tissues). In the postabsorptive state, the systemic FFA concentration is determined largely by the rate of FFA entry into the circulation, but postprandially, the rate of uptake, particularly by adipose tissue, is also a critical determinant of plasma FFA concentration.
A. Hormone-sensitive lipase (HSL) and insulin suppression of lipolysis
Because insulin has a potent suppressive effect on HSL, the enzyme which is the principal regulator of FFA release from adipose tissue, there has been an intense focus on determining whether resistance of HSL to insulin in IRS and type 2 diabetes is the predominant abnormality accounting for increased flux of FFAs from adipose tissue in these conditions.
A number of in vitro studies have failed to demonstrate increased HSL and basal lipolytic rate in adipose tissue from obese individuals (16) or resistance to insulin’s suppressive effect on HSL (Refs. 16 and 17 and reviewed in Ref. 18). There has been some confusion in the literature because of differences in the denominator used to ascertain the true lipolysis rate (i.e., in relation to fat cell number, per unit lipid weight or cell surface area; reviewed in Ref. 18). Some studies have actually shown that the sensitivity or maximum insulin-induced inhibition of adipose tissue lipolysis was greater in obese subjects than in normal weight controls (17, 19).
In vivo, the rate of FFA turnover per unit of lean body weight does appear to be elevated in obese individuals (20, 21, 22, 23, 24, 25, 26, 27, 28). A number of studies have shown a diminished suppressive effect of insulin on FFA rate of appearance in obese and nonobese insulin-resistant humans (20, 21, 29) and in those with type 2 diabetes (25, 30). Resistance to insulin’s suppressive effect on HSL also appears to be present postprandially in IRS and type 2 diabetes (6). Confusion regarding whether HSL activity in individual adipocytes is actually resistant to the suppressive effect of insulin arises because, when normalized per total body fat, lipolysis appears in fact to be normal or reduced in obese individuals (20, 28, 31, 32). In other words, the diminished whole-body insulin-suppressive effect on FFA rate of appearance seen in obese individuals may be largely due to a mass effect of the overall expansion of body fat depots.
A reduction in insulin-mediated suppression of fasting lipolysis vs. control subjects of the same age and weight has been found in most (13, 33, 34), but not in all (34), studies performed in glucose-tolerant first-degree relatives of patients with type 2 diabetes. This suggests that abnormal insulin-mediated suppression of plasma FFA appearance rate is a very early defect in those genetically predisposed to develop type 2 diabetes.
B. Adipose tissue uptake and intracellular esterification of fatty acids (see Fig. 1
)
Although insulin plays an important role in the suppression of HSL, an additional major mechanism of insulin action is in stimulating postprandial glucose uptake and FFA esterification (2, 6, 20, 35, 36, 37, 38, 39, 40, 41, 42). Riemens et al. (36) recently challenged the notion that the elevated FFA transport rate during fasting in patients with type 2 diabetes is due to impaired insulin-mediated suppression of HSL activity and suggested that the main abnormality is rather an elevated rate of escape of FFA from esterification in adipose tissue. We have shown previously that postprandial fatty acids become markedly elevated in type 1 diabetic subjects after ingestion of a high-fat meal when insulin is underreplaced in the periprandial period, emphasizing the important role that insulin plays in postprandial fatty acid disposal (43). Although the adipose tissue in lean individuals can switch from a negative to a positive FFA balance during the transition from fasting to the postprandial state, the adipose tissue FFA balance remains negative postprandially in insulin-resistant obese individuals, despite the presence of hyperinsulinemia (41). Lean, glucose-tolerant first-degree relatives of patients with type 2 diabetes have an increase in postprandial glucose and triglyceride excursion and less suppression of plasma FFA after a mixed meal compared with matched control subjects without a family history of diabetes (12). The precise mechanisms causing this postprandial elevation of plasma FFA are not known.
|
), and insulin-mediated glucose uptake is diminished in insulin resistance (2). Less is known about direct insulin-stimulatory effects on esterification enzymes, and it is not entirely clear whether insulin directly stimulates the enzyme that catalyzes the final step in triglyceride synthesis, acyl coenzyme A:diacylglycerol acyltransferase [DGAT (44, 45)]. Although insulin directly stimulates enzymes responsible for de novo fatty acid synthesis, de novo fatty acid synthesis in the adipocyte is quantitatively insignificant in normal physiological conditions. The activity of lipoprotein lipase (LPL) is an important first step in plasma triglyceride clearance and FFA delivery to the adipocyte, particularly in the postprandial state (46). Insulin and glucose have been shown to stimulate adipose tissue LPL activity and to reduce LPL activity in muscle, implying a preferential postprandial partitioning of lipoprotein- derived fatty acids toward adipose tissue and away from muscle (47). In obesity and type 2 diabetes, insulin activation of LPL in adipose tissue is delayed, and LPL activity in skeletal muscle is increased instead of decreased by hyperinsulinemia (48, 49). The importance of LPL in tissue FFA uptake has recently been demonstrated by experiments in which either muscle-specific or liver-specific overexpression in mice induces marked tissue lipid accumulation (50). Although LPL may be viewed as a first step leading to the uptake of FFA by adipose tissue, it is clear that the deposition of FFA is also regulated downstream of LPL (46).
We are only beginning to elucidate the mechanisms of fatty acid transporter regulation in IRS and type 2 diabetes, and there is still considerable controversy as to whether the cellular uptake of fatty acids occurs predominantly by facilitated transmembrane transport or by passive diffusion (for reviews, see Refs. 51, 52, 53). The "scavenger" receptor CD36 has recently been identified as a fatty acid receptor/transporter (54), with particular abundance in adipose tissue, heart, and skeletal muscle but with low expression in kidney and liver (53). A deficiency in CD36, a protein analogous to CD36/fatty acid transporter (FAT) in humans, has been reported to underlie the metabolic abnormalities of the insulin-resistant spontaneously hypertensive rat (55, 56) and has been associated with functionally significant impairment of intracellular FFA transport (57, 58). Furthermore, transgenic expression of CD36 in the spontaneously hypertensive rat ameliorates insulin resistance and lowers serum fatty acids (59), perhaps by improving FFA uptake in adipose tissue. Mice with CD36 overexpression targeted to muscle tissue (MCK/CD36) have less body fat and lower serum FFAs and very low density lipoprotein (VLDL) triglycerides but elevated plasma glucose and insulin, suggesting that they are insulin resistant (60). One may speculate that the increased FFA uptake and oxidation in muscle tissues of these animals impairs muscle glucose utilization, thereby inducing insulin resistance in a fashion analogous to that seen in mice with muscle-specific LPL overexpression (50). In contrast, the uptake of fatty acids by heart, skeletal muscle, and adipose tissues from CD36-null mice is markedly reduced (by 50–80%), whereas that of glucose is increased severalfold (61). CD36 deficiency is present in 2–3% of the Japanese population, and recent evidence suggests that it may be associated with insulin resistance, dyslipidemia (62), and absence of myocardial uptake of FFA tracers in vivo (63). An association between IRS or diabetes and mutations in CD36 has not yet, however, been reported in other human populations. At the present time, the link between CD36 deficiency and the development of insulin resistance in humans cannot be incorporated into a consistent model due to our lack of knowledge regarding the functional consequence of CD36 deficiency on FFA metabolism in the various tissues in vivo. Animal models of obesity, insulin resistance, and type 2 diabetes are generally characterized by an increase, not a decrease, in adipose tissue fatty acid binding and transport proteins (64). Furthermore, marked compensation of other functionally redundant proteins can occur, which could limit the physiological impact of any deletion or defect of fatty acid binding proteins in adipose tissue (65). To date, there has been no demonstrated defect in adipose tissue fatty acid uptake caused by a defect in any of the FFA transport or binding proteins in humans (66).
The production of acylation stimulating protein (ASP), a proteolytic cleavage product of the third component of complement, is stimulated by hydrolyzed chylomicrons and is an important regulator of adipocyte fatty acid esterification by increasing the activity of diacylglycerol acyltransferase through a PKC-dependent pathway (35). There is controversy in the literature regarding the physiological importance of ASP, because some (67) but not others (68) have described abnormalities of postprandial lipoprotein metabolism in ASP-null mice. Although a blunted response to ASP in IRS and type 2 diabetes cannot as yet be ruled out, evidence in support of such a defect is currently lacking. ASP levels are increased in obesity (69), and adipocytes from obese humans remain responsive to ASP (70).
C. Total fat mass and regional fat depots
Aside from putative intrinsic abnormalities in adipocytes, these two other factors have important bearing on adipose tissue fat storage and release in IRS and type 2 diabetes. Firstly, because the pool of FFAs in adipocytes is released into the circulation in relation to its size, the greater overall fat mass of adipose tissue in obese individuals will result in an elevation of fatty acid flux to nonadipose tissues, even in the absence of a qualitative abnormality in adipose tissue metabolism (31). Secondly, there is an undisputed relationship between "central" fat distribution (i.e., fat in the visceral and sc abdominal region) and features of the IRS (71), although the causal nature of this relationship (72, 73) and the relative importance of visceral vs. sc abdominal fat remains a matter of debate (72, 74, 75). Visceral fat cells are more sensitive than sc fat cells to the lipolytic effect of catecholamines and less sensitive to the antilipolytic and fatty acid re-esterification effect of insulin (reviewed in Ref. 2), a phenomenon which could further enhance FFA flux in those who are predisposed to store fat in the visceral area. Furthermore, the venous effluent of visceral fat depots leads directly into the portal vein, resulting in greater FFA flux to the liver in viscerally obese individuals than in those with predominantly sc obesity. Although visceral fat depots have been estimated to represent only approximately 20% of total body fat mass in men and 6% in women (76, 77), approximately 80% of hepatic blood supply is derived from the portal vein (78). Furthermore, total splanchnic blood supply increases postprandially (79) as might the proportion of lipolysis from splanchnic vs. sc fat (because of increased insulin and sympathetic activation after meals). Thus, the contribution of visceral fat to hepatic FFA uptake and systemic FFA appearance could be more substantial in the postprandial than in the fasting state.
D. Fat diversion from adipose to nonadipose tissue
The net result of increased FFA lipolysis and diminished FFA fractional esterification in IRS and type 2 diabetes is diversion of FFAs toward nonadipose tissues such as liver (Fig. 2), muscle, heart, and pancreatic ß-cells. Extreme examples, at opposite ends of the spectrum, of adipose tissue capacity to take up and store incoming fatty acids are illustrated by the clinical conditions of congenital lipoatrophy and massive obesity. In humans (80) and animal models of lipoatrophy (81, 82, 83), in which there is absence of adipose tissue, nonadipose tissues accumulate cytosolic triglycerides to a massive extent and manifest many of the consequences of extreme insulin resistance. Furthermore, all aspects of the fatless mouse phenotype are alleviated in a dose-response fashion with surgical implantation of adipose tissue (81). Based on his studies with animal models of lipodystrophy, Shulman (84) has recently proposed that insulin resistance develops because of an imbalance of fat distribution between tissues. Consistent with this hypothesis is the observation that some massively obese individuals have surprisingly few manifestations of the IRS (85, 86). Normoglycemic and normolipidemic obese individuals display improved postprandial fat storage compared with lean subjects (87). Individuals with morbid obesity (body mass index > 40 kg/m2) have been recently shown to display a greater meal-derived storage capacity than weight- and age-matched subjects after successful gastric bypass surgery, despite a slightly lower postprandial plasma insulin response (88). Presumably, the more efficient adipose tissue fat-storing capacity in these individuals could confer relative protection against lipotoxicity in nonadipose tissues.
|
).
|
The mechanism accounting for the relationship between muscle triglyceride accumulation and insulin resistance is not known. It remains an open question as to whether muscle triglyceride accumulation is merely a marker or plays a causative role in the insulin resistance. A key issue is whether triglycerides accumulate in muscle tissue of insulin-resistant individuals as a result of a primary defect in fatty acid oxidation, increased total FFA flux to muscle, or due to an imbalance between FFA uptake, esterification, triglyceride lipolysis, and fatty acid oxidation. Muscle from obese, insulin-resistant individuals and type 2 diabetic patients has been shown to have reduced capacity for uptake and oxidation of fatty acids derived from the plasma FFA pool during fasting and exercise (101, 102, 103, 104, 105). These changes could perhaps be attributed to defects of fatty acid oxidation at the carnitine palmitoyl-transferase-1 (CPT-1) and post-CPT-1 levels (106). Furthermore, weight reduction using low-calorie diets in patients with type 2 diabetes has been shown to reduce plasma FFA flux during fasting but not exercise, without significant change in plasma-derived FFA oxidation or muscle mitochondrial oxidative enzymes (102, 107). Prolonged pharmacological inhibition of muscle CPT-1 in rats has also been associated with IMTG accumulation and development of insulin resistance (108). These findings have been interpreted to suggest that impaired muscle fatty acid oxidation is the primary defect causing the IMTG accumulation and muscle insulin resistance in patients with obesity, IRS, and type 2 diabetes (100). Impaired muscle FFA oxidation in these conditions could also be the result of excessive chronic exposure to FFA, because the elevation of malonyl-coenzyme A (CoA) due to energy excess has been associated with reduced muscle fat oxidation through inhibition of CPT-1 (109, 110). It should be pointed out that the reduction of plasma-derived FFA oxidation seen in patients with obesity and diabetes has been shown by some to occur in association with unaltered or even elevated total fat oxidation and with elevated muscle triglyceride lipolysis (104, 105). Thus, while the capacity for fat oxidation appears to be reduced, total fat oxidation may be increased because of the mass action effect of increased FFA delivery from plasma and from increased intracellular triglyceride stores. Furthermore, net fat oxidation is not reduced in obese individuals in response to elevation of plasma FFAs using iv infusion of heparin and lipid emulsion (111). In addition, weight loss secondary to fat malabsorption after bariatric surgery in morbidly obese individuals corrects both the low respiratory quotient and insulin resistance seen in these individuals, suggesting that improvement in insulin resistance with correction of obesity is associated with reduction of lipid oxidation relative to carbohydrate oxidation (112). Because plasma FFA delivery itself, as well as glucose delivery and plasma insulin levels, may determine the rate of muscle FFA oxidation (113, 114, 115, 116), these factors should also be carefully controlled for in in vivo experiments before drawing any conclusion regarding the presence of a primordial defect in muscle FFA oxidation in patients at risk for or with established type 2 diabetes.
Skeletal muscle has a high fractional extraction of FFAs in the postabsorptive state, and lipid oxidation accounts for the majority of its energy production (100). Some studies in humans have suggested that muscle fatty acid binding and transport proteins may be altered in obesity and type 2 diabetes. Skeletal muscle cytoplasmic fatty acid binding protein (FABP) content has been shown to be reduced together with reduced in vivo muscle plasma FFA uptake and oxidation in obese type 2 diabetic patients (105), but not in glucose-tolerant obese subjects (102). As mentioned above in the discussion of CD36, muscle-specific overexpression of the CD36/FAT is associated with insulin resistance (60). The skeletal muscle expression of another FAT protein, FATP-1, was found to be reduced in obese women with or without type 2 diabetes, but not in men (51, 66, 117), and their potential role in intramyocellular triglyceride accumulation and insulin resistance remains unclear. Despite the fact that the efficiency of skeletal muscle FFA uptake and utilization in the postabsorptive state has been shown to be impaired in obese patients with type 2 diabetes (118, 119) and in nondiabetic individuals with visceral obesity (120), we need to be cautious in interpreting this observation to mean that total 24-h fatty acid flux to muscle is reduced in insulin resistance and type 2 diabetes. Experimental evidence suggests that excessive FFA delivery to muscle from the circulation can be a source of muscle triglyceride accumulation (121, 122, 123, 124). An extramuscular defect of fatty acid metabolism could contribute to the intramyocellular triglyceride accumulation and the skeletal muscle lipotoxic effects seen in obesity and type 2 diabetes.
F. Potential abnormalities in intestinal fatty acid uptake
It has been proposed that gain-of-function mutations of FABP-2, a FABP highly expressed in the small intestine, could result in postprandial lipid abnormalities, insulin resistance, and diabetes (125). A common polymorphism of the intestinal FABP2 gene (A54T) that results in higher affinity of FABP2 for long-chain fatty acids in vitro has been associated with an increased prevalence of insulin resistance or diabetes in some populations (126, 127, 128, 129) but not in others (130, 131, 132, 133, 134). In vivo, this polymorphism has been inconsistently associated with increased total body fat oxidation and a small elevation of plasma FFA levels in different populations (126, 135, 136). The association with higher postprandial triglyceride and lipoprotein excursion has also been found in some (136, 137) but not all studies (134, 135). Although increased intestinal absorption of FFA has been postulated to be the cause of these abnormalities, this has not yet been convincingly demonstrated in humans (138). It is therefore likely that A54T polymorphism of the FABP2 gene could play some role in abnormal FFA metabolism and be linked with the development of insulin resistance and type 2 diabetes by an unknown mechanism in some populations, such as the Pima Indians, but not in others.
G. Protective role of leptin and adiponectin against lipotoxicity
Unger and colleagues (139, 140, 141, 142) have proposed that the physiological role of the hyperleptinemia that accompanies caloric excess is to protect nonadipocytes from steatosis and lipotoxicity by preventing up-regulation of lipogenesis and by increasing fatty acid oxidation. These researchers argue convincingly against the conventional view that the physiological role of leptin is to prevent obesity during overnutrition. Leptin has been shown to be antilipogenic in some tissues (143) and up-regulates fatty acid oxidation (144). Leptin-deficiency states, including lipodystrophic syndromes, are associated with massive nonadipose tissue fat accumulation due to increased lipogenesis and reduced fatty acid oxidation (145), with adverse consequences of nonadipose tissue lipid overaccumulation. Adenoviral-mediated leptin overexpression in normal rats is antilipogenic and up- regulates ß-oxidation (144). Transgenic overexpression of leptin rescues the insulin resistance and diabetes in a mouse model of lipoatrophic diabetes (146).
In humans, hyperleptinemia characterizes obesity, insulin-resistant states, and type 2 diabetes, suggesting that leptin resistance, not leptin deficiency, may be involved in the pathophysiology (147). The reduction of plasma leptin concentration after bariatric surgery in morbidly obese individuals occurs independently of the reduction of fat mass but correlates with the reduction of plasma insulin levels, suggesting that resistance to leptin and insulin are closely linked in humans (148). Although leptin resistance could play a role in extra-adipose tissue fat deposition and lipotoxicity, it could also be a consequence of elevated fatty acid availability to tissues (149, 150). Elevated plasma FFA could lead to relative suppression of leptin release by the adipose tissue, contributing to impaired leptin signaling in insulin-resistant states (151). Therefore, hyperleptinemia/leptin resistance may also be a consequence of abnormal FFA partitioning. Nevertheless, the important role of leptin in regulating rates of lipogenesis and fatty acid oxidation illustrates that factors in addition to fat spillover from adipose to nonadipose tissues may regulate the magnitude of triglyceride accumulation in nonadipose tissues in states of caloric overload.
Recently the adipocyte-derived hormone adiponectin has been shown to reverse insulin resistance associated with both lipoatrophy and obesity (152). Decreased expression of adiponectin was shown to correlate with insulin resistance in mouse models of insulin resistance. Insulin resistance in lipoatrophic mice was completely reversed by the combination of physiological doses of adiponectin and leptin, but only partially by either adiponectin or leptin alone. Adiponectin reduced the triglyceride content of muscle and liver in obese mice by increasing the expression of fatty acid oxidation and energy dissipation in muscle.
H. Summary of the abnormalities of FFA metabolism in obesity, IRS, and type 2 diabetes
Adipose tissue storage, release of fatty acids, and its control by insulin are grossly abnormal in IRS well before the development of type 2 diabetes. In the postabsorptive period, basal lipolysis is elevated and suppression by insulin diminished. In the postprandial period, there is likely to be a net diversion of fat away from adipose tissue depots and toward nonadipose tissues. FFA efflux from an enlarged and lipolytically active visceral fat depot plays a major role in the elevation of fatty acids, which are then free to exert their biological effects in nonadipose tissues.
A high capacity for efficient triglyceride accumulation in adipose as well as nonadipose tissue may have presented a survival advantage in the past, during times of starvation, thus accounting for selection of a "thrifty genotype" as originally proposed by Neel (153) in 1962. This phenotype is hypothesized to be characterized by low oxidative or fat oxidative capacity and a tendency toward a positive energy balance (154). With current high-calorie, high-fat diets and sedentary lifestyle, such a thrifty genotype would accumulate excess tissue triglyceride stores, despite resistance to glucose disposal (155). As indicated in Fig. 3, in the presence of a positive net energy balance there is ongoing accumulation of triglyceride in both adipose and nonadipose tissues. In addition, adipose cells could adaptively limit further fat accumulation by becoming insulin resistant, thereby diverting fat to nonadipose tissues. Perhaps a corollary of the thrifty genotype theory is that those whose adipocytes are able to most effectively protect themselves against ongoing caloric overload, i.e., by developing resistance to insulin’s anabolic effects, are also those most likely to develop extra-adipocyte fat overload, with consequent metabolic manifestations of insulin resistance. Perhaps the accumulation of adipose tissue represented an evolutionary disadvantage to those engaged in hunter-gatherer lifestyles. Cytosolic triglyceride accumulation in nonadipose tissues such as muscle and liver is linked to the development of insulin resistance as these tissues also attempt to protect themselves from energy overload. Insulin resistance imposes a chronic stress on pancreatic ß-cells, which may fail to hypersecrete insulin, as the same mechanisms that lead to insulin resistance may ultimately result in ß-cell dysfunction and damage (see Fig. 3 and Section VII).
|
III. Dyslipidemia and Fatty Liver Infiltration in IRS and Type 2 Diabetes |
|---|
The production rate of apolipoprotein B (apo B) is an important regulatory step in VLDL production, but the apo B transcription and translation rate does not regulate the pathway under most physiological conditions (168, 169, 170). Regulation of apo B occurs primarily at the posttranslational level, either during its translocation into the endoplasmic reticulum lumen or its rate of degradation. Protection against proteolysis is critically dependent on neutral lipid availability and is facilitated by a number of chaperone proteins and microsomal transfer protein [MTP (168)]. MTP catalyzes the transfer of lipids to the apo B molecule and is an important factor involved in the assembly of apo B-containing lipoproteins (171, 172). Primary rat hepatocytes, incubated in vitro with high concentrations of insulin for 3 d, no longer respond to insulin suppression of VLDL apo B secretion and secrete higher basal levels of VLDL apo B (173).
FFAs have been shown to directly stimulate hepatocyte VLDL triglyceride synthesis and secretion in HepG2 cells (174, 175, 176, 177, 178, 179, 180) and cultured hepatocytes (181, 182). Although it is generally believed that the rate of apo B secretion is determined by the extent of its intracellular degradation, several studies have shown that protection from degradation is insufficient to drive apo B secretion in the absence of available core lipoprotein lipids. Addition of oleate can rescue the protected apo B polypeptides and induce their lipidation and extracellular secretion in some but not all model systems. It has also been previously suggested that oleate treatment of HepG2 cells facilitates translocation of newly synthesized apo B across the endoplasmic reticulum membrane, which in turn reduces early degradation (183). However, whether or not this protection of early degradation stimulates apo B extracellular secretion appears to differ among cell types. In HepG2 cells (176, 179, 184), a rat hepatoma cell line (180), and freshly isolated rabbit hepatocytes (185), exogenous oleate significantly stimulates apo B secretion. In contrast, this is not the case in McArdle H7777 cells (186) and primary rat (187, 188), hamster (189), or human (190) hepatocytes, although oleate may increase the stability of apo B. Overall, the effect of oleate on the stability and secretion of apo B appears to be dependent on the cell type (primary vs. transformed cell line), turnover of the triglyceride/fatty acid in the cells, size of the cellular triglyceride pool, and duration of incubation with oleate.
Because FFAs entering the hepatocyte are predominantly re-esterified and enter a cytoplasmic pool before secretion in VLDL, the size of the cytoplasmic triglyceride pool, rather than the availability of extracellular oleic acid, correlates with VLDL secretion (181). Although it is well recognized that plasma FFAs stimulate VLDL production (191) and are an important source of VLDL triglyceride fatty acids (192, 193, 194, 195), an important contribution to the hepatocyte fatty acid pool also comes from three sources other than plasma FFAs: 1) de novo lipogenesis (DNL), 2) cytoplasmic triglyceride stores, and 3) intracellular lipolysis of lipoproteins taken up directly by the liver (Fig. 2). Hepatic re-esterification of plasma FFAs contributes the majority of fatty acids to VLDL triglycerides (195), with sources such as DNL, hepatic triglyceride stores, and lipoprotein remnants contributing somewhat less (194, 195). The contribution to VLDL triglycerides from plasma FFAs is lower in hypertriglyceridemic than in normotriglyceridemic individuals (195).
A. The contribution of de novo lipogenesis to elevated VLDL production
Chronic hyperinsulinemia and carbohydrate ingestion stimulate the production of newly synthesized fatty acids [DNL (196, 197, 198, 199)], by stimulating the activity of lipogenic enzymes in the liver (200) and by increasing the transcription of the genes for fatty acid synthase and acetyl-coenzyme A carboxylase [ACC (170, 201)]. Recent studies suggest that the mechanism by which insulin and perhaps glucose stimulate transcription of these lipogenic enzymes is by increasing transcription of sterol-regulatory element-binding protein-1c (SREBP-1c), a member of a family of regulated transcription factors (202). Despite down-regulation of the IRS-2-mediated insulin signaling pathway in insulin-resistant states, there appears to be up-regulation of SREBP-1c and chronic stimulation of DNL (and reduced fatty acid oxidation) in the liver (203, 204), which can in turn enhance intracellular availability of triglyceride, promoting fatty liver and driving VLDL assembly and secretion.
Under nonstimulated conditions, the contribution of DNL to VLDL triglyceride fatty acid is exceedingly small, estimated to be less than 5% in the postabsorptive state (194, 195, 205). Even with carbohydrate feeding, which usually stimulates DNL, newly synthesized fatty acids account for the minority of VLDL-triglyceride fatty acids (195, 206, 207, 208, 209). Nevertheless, even though DNL may not be a quantitatively significant contributor to VLDL triglyceride production, it appears to be an important marker of the relative rate of fatty acid re-esterification vs. oxidation (206), and there is a well-established correlation between the rates of DNL and the secretion of VLDL (210). Elevation of malonyl-CoA, which is the product of acetyl-CoA carboxylase, the rate-limiting enzyme in hepatic DNL, inhibits CPT-1 activity, thus resulting in diversion of fatty acids from an oxidative to a re-esterification pathway (211, 212). Conditions associated with high rates of DNL, such as high carbohydrate ingestion, hyperglycemia, and hyperinsulinemia, are invariably associated with a shift in cellular metabolism from lipid oxidation to triglyceride esterification, increasing the availability of liver triglyceride for VLDL synthesis and secretion. In accordance with the notion that the total capacity to secrete VLDL correlates with the rate of DNL (213, 214), hyperglycemia in the presence of constant FFA availability increases VLDL production in humans (215).
B. Contribution of hepatic cytosolic triglyceride stores to VLDL overproduction and fatty liver infiltration (nonalcoholic steatohepatitis)
There is debate about the quantitative contribution of cytosolic triglyceride stores to VLDL triglyceride production, but it does appear that the majority of FFAs esterified upon entering the hepatocyte enter this storage pool, at least temporarily, before their incorporation into VLDL (216, 217, 218, 219, 220). This intracellular triglyceride storage depot likely serves as a buffer, providing temporary disposal of potentially toxic FFA when their delivery to the liver exceeds its oxidative and VLDL secretory capacity. It also provides a means of regulating VLDL production in the face of widely fluctuating plasma FFA concentrations. Stored triglyceride turns over fairly rapidly, but only a minor proportion of the released fatty acids are used for VLDL assembly, the remainder being recycled back into the storage pool (216). Fatty acids released from lipolysis of stored triglycerides appear to be preferentially channeled into re-esterification rather than oxidative pathways (216). The cytosolic triglyceride droplets are not incorporated into VLDL en bloc across the endoplasmic reticulum membrane, but first have to be hydrolyzed (216). Hydrolysis of cytosolic triglycerides appears to be partial, to the level of diacylglycerol, followed by remodeling of some of its acyl chains, before re-esterification to form secretory triglyceride (221). Hydrolysis may also proceed to monoglyceride and FFA. The lipase involved in this process and the details of its regulation are not yet known (216). The partitioning of re-esterified triglycerides between secretory and storage (cytosolic) pathways can be acutely regulated and is a potentially important site for the regulation of VLDL secretion (221, 222). Secretion of the esterified fatty acids as VLDL triglycerides is limited by the availability of a number of factors other than the hepatocyte triglyceride pool size per se, including cholesteryl esters, apo B synthesis and translocation across the endoplasmic reticulum membrane, phospholipids, rate-limiting enzymes such as MTP, etc.
Fatty liver frequently coexists with obesity, type 2 diabetes, and metabolic features of IRS and responds to their amelioration (223, 224, 225, 226, 227, 228, 229, 230). The capacity of the liver to esterify and store incoming fatty acids as cytosolic triglycerides appears to be quite considerable under metabolic conditions when triglyceride synthesis exceeds the combination of hepatic fatty acid oxidation and VLDL-triglyceride secretion (216).
C. Hepatic lipoprotein remnant uptake also contributes to VLDL production
Postlipolysis remnants of triglyceride-rich lipoproteins, taken up by receptor-mediated mechanisms, are hydrolyzed in hepatic lysosomes, thereby contributing to the intracellular fatty acid and cholesteryl ester pool and stimulating VLDL secretion in a fashion similar to that of FFAs (231, 232). The quantitative contribution of fatty acids derived from remnant uptake is not known but could be quite substantial, particularly in the postprandial state. A self-perpetuating cycle is thus set up, in which elevated FFAs drive VLDL secretion, and FFAs derived from the elevated circulating pool of triglyceride-rich lipoproteins positively feed back on VLDL production by further increasing the FFA pool in the hepatocyte (Fig. 2).
D. The role of resistance to insulin action in the hepatocyte and chronic hyperinsulinemia per se in facilitating VLDL synthesis and secretion
The preceding discussion has emphasized the importance of fatty acid availability in the hepatocyte in driving VLDL production. Nevertheless, increased FFA availability per se is not sufficient to explain the high VLDL production rates seen in IRS and type 2 diabetes. The role of resistance to insulin action in the hepatocyte and chronic hyperinsulinemia per se in facilitating VLDL synthesis and secretion has been the focus of intense investigation for many years (159, 233, 234). There is still not widespread agreement regarding the acute effects of insulin on VLDL production, but the majority of studies have demonstrated that insulin acutely inhibits VLDL production, shown in both in vitro (170, 235, 236) and in vivo experiments in fasting humans (191, 237, 238, 239, 240, 241). The nutritional state of the organism, fed or fasted, has recently been shown to modify the acute effect of insulin on VLDL production (242), perhaps due to a switch in fatty acid partitioning in the hepatocyte (222, 243, 244). The acute inhibitory effect of insulin on VLDL production in fasting individuals appears to be independent of the profound FFA suppression induced by hyperinsulinemia in vivo (191), although this has been disputed by others (245). Chronically insulin-resistant hyperinsulinemic, obese humans and those with type 2 diabetes are resistant to the acute inhibitory effect of insulin on VLDL production (237, 241), in keeping with similar findings in hepatocytes derived from fructose-fed and insulin-resistant rats (197, 198, 246). The relationship between peripheral tissue insulin resistance with regard to insulin’s antilipolytic effect and VLDL secretion rate may not be direct and could depend on other concomitant factors found in insulin-resistant individuals. For example, we recently found that VLDL secretion rate in healthy individuals is not predicted by the sensitivity of insulin-mediated suppression of plasma FFA concentration in the postabsorptive state but appears to be much more dependent on body mass index (247). Furthermore, VLDL oversecretion is not present in recipients of combined kidney-pancreas transplantation with systemic venous anastomosis of their pancreatic graft who display marked peripheral tissue insulin resistance without gross hepatic insulin resistance/hepatic overinsulinization, compared with graft recipients with portal venous anastomosis or healthy subjects (248). VLDL oversecretion associated with the insulin resistance syndrome in humans may therefore depend of the combination of peripheral tissue insulin resistance, hepatic insulin resistance/overinsulinization, and/or the presence of visceral obesity.
We have recently shown in the fructose-fed hamster, an animal model of insulin resistance whose lipoprotein physiology has a number of similarities to that of humans, and in vitro in cultured hamster hepatocytes, that hepatic VLDL-apo B overproduction is associated with whole-body insulin resistance and attenuated hepatic insulin signaling (249, 250, 251). Fructose feeding was associated with hyperinsulinemia, enhanced MTP expression in the liver, increased intracellular apo B stability, and facilitated assembly of apo B-containing lipoproteins leading to VLDL oversecretion (249). Induction of insulin resistance was accompanied by a considerable rise in hepatic VLDL-apo B and VLDL-triglyceride production. Although there was an increase in total apo B secretion, the apo B fraction secreted as VLDL was more prominently enhanced in fructose-fed hamsters, suggesting an increase in both the number of VLDL particles and the proportion secreted as VLDL. Enhanced apo B secretion appeared to be caused by increased intracellular stability of apo B, elevated levels of MTP, and enhanced assembly of VLDL particles, with no apparent changes in apo B translocational status in the endoplasmic reticulum. Control studies showed that insulin resistance induced these changes rather than being direct effects of fructose itself. More recently, we obtained molecular evidence (251) for impairment of hepatic insulin signaling and insulin resistance, including reduced tyrosine phosphorylation of the insulin receptor, IRS-1 and IRS-2, and suppressed activity of PI3K associated with IRS proteins. Importantly, changes in the insulin signaling pathway coincided with drastic suppression of ER-60, a cysteine protease previously shown to be associated with apo B in HepG2 cells that has been postulated to play an important role in the degradation of apo B in the endoplasmic reticulum lumen (252). These changes were also accompanied by an increase in the secretion of apo B.
The rate of assembly and secretion of apo B-containing lipoproteins is critically linked with the expression level of MTP as demonstrated in an elegant series of studies in knockout mouse models (253) as well as a model of adenoviral-mediated overexpression (254). Chronic modulation of hepatic apo B secretion in insulin-resistant states may be mediated through changes in expression of MTP. The promoter region of the MTP gene has an insulin response element, which is negatively regulated by the hormone (255). Thus, it is reasonable to suggest that in insulin-resistant states, there may be a chronic up-regulation of MTP expression and protein levels due to resistance to suppressive effects of insulin on MTP gene expression, leading to hepatic VLDL overproduction.
Based on these recent data, we hypothesize that attenuated insulin signal transduction in hepatocytes causes suppression of ER-60 protease expression, which may contribute to the observed increase in apo B stability. Furthermore, impairment of hepatic insulin signal transduction may negate a negative regulatory effect of insulin on MTP expression, leading to the overexpression of this key protein, which may further facilitate VLDL assembly and secretion. Enhanced hepatic FFA flux to the liver, as observed in insulin-resistant states, can provide ample lipid substrate for the high rate of VLDL assembly and secretion. An important additional factor may be up-regulation of SREBP-1c and chronic stimulation of DNL (and reduced fatty acid oxidation) in the liver (204), which can in turn enhance intracellular availability of triglyceride and drive VLDL assembly and secretion. The important factor responsible for up-regulation of SREBP-1c seems to be hyperinsulinemia per se rather than insulin resistance (204). Thus, an interaction between hepatic insulin resistance, hyperinsulemia, increased flux of FFA, and enhanced DNL may be essential to induce the VLDL overproduction state in IRS.
E. Summary of the mechanisms of VLDL overproduction in relation to fat maldistribution between adipose and nonadipose tissue
In summary, VLDL overproduction occurs as a result of a composite set of factors, which includes increased flux of fatty acids from extrahepatic tissues to the liver and directly from lipoprotein remnant uptake, increased hepatic de novo fatty acid synthesis, preferential esterification vs. oxidation of fatty acids, reduced posttranslational degradation of apo B, and overexpression of MTP. These conditions, together with resistance to the normal acute suppressive effect of insulin on VLDL secretion, act in concert to channel fatty acids into secretory and storage rather than degradative pathways. The increased flux of FFAs to the liver arise from adipose tissue resistance to insulin action, as described above, but we do not know whether the hepatic effects of IRS and type 2 diabetes arise as a result of insulin resistance or hyperinsulinemia per se. It is possible that the changes in liver metabolism outlined above may be due to both increased and reduced insulin action, with some biochemical pathways in the liver remaining responsive to insulin (i.e., DNL and triglyceride esterification), whereas others are down-regulated (i.e., insulin-suppressive pathways of apo B biogenesis) in IRS and type 2 diabetes.
|
IV. Effects of FFA on Muscle Glucose Metabolism |
|---|
), but they may be initiated by a single event, i.e., increased energy availability, and may serve one predominant function, i.e., that of preventing further accumulation of intracellular energy substrates. There is general agreement, as discussed below, that an elevation of FFAs impairs cellular glucose uptake. Recently, however, controversy has arisen regarding the inhibitory effect of FFAs on glucose oxidation that has been postulated to account for the FFA-mediated inhibition of glucose uptake (i.e., the "Randle hypothesis"). Although this issue remains unresolved, we will attempt to provide a balanced analysis of existing data.
|
In skeletal muscle, which accounts for the bulk of whole-body insulin-mediated glucose uptake, in vitro studies only partially confirmed Randle’s hypothesis, as FFAs reduced glucose oxidation but did not consistently reduce glucose uptake (257, 258, 259). In vivo, FFA elevation obtained by Intralipid plus heparin infusion (Intralipid is a triglyceride emulsion and heparin activates LPL, thereby hydrolyzing the Intralipid triglycerides to FFAs and glycerol) consistently reduced glucose oxidation and decreased glucose uptake in the majority of hyperinsulinemic clamp studies in rats (260, 261, 262, 263, 264), dogs (265, 266, 267), and humans (118, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277). Under the latter conditions, most of the glucose uptake occurs in skeletal muscle. In addition, leg (118) and forearm balance studies (271, 272) and studies using positron emission tomography (277) have localized the reduction in whole-body glucose uptake to muscle. In these in vivo studies, the effect of FFA on glucose uptake was studied for a longer time than in in vitro preparations. The results showed that the expected reduction in glucose uptake is delayed (261, 268, 269, 274) and is more often associated with decreased (264, 269, 274), rather than increased (262), muscle content of glucose-6-phosphate. An early increase in muscle glucose-6-phosphate concentration followed by a decrease when glucose transport is inhibited, as found in rats (264), could still be consistent with Randle’s hypothesis. Nevertheless, studies in humans based on nuclear magnetic resonance measurements of glucose-6-phosphate (274, 275) could not detect such an early increase. In addition, FFAs may induce a delayed impairment in glycogen synthesis, which exceeds that expected from the reduction in glucose uptake (261, 269). It is therefore evident that in muscle, FFAs have effects on glucose metabolism other than or beyond those postulated by the classical Randle cycle (i.e., inhibition of PFK-1 by citrate).
B. Effects of long-chain fatty acyl-CoA (LCFA-CoA) and PKC activation on muscle glucose metabolism
Some studies have linked the impairing effects of FFAs on muscle glucose metabolism with increased LCFA-CoA (see for Ref. 278 review). LCFA-CoAs accumulate in the cytosol when increased FFA inflow is associated with malonyl-CoA inhibition of CPT-1 (the enzyme that transports fatty acid into the mitochondria for oxidation). In states of energy, excess glucose, insulin, and citrate (note the link with the Randle’s cycle) activate ACC, the enzyme that synthesizes malonyl-CoA, and the rise in malonyl-CoA is paralleled by a rise in cytosolic LCFA-CoA. LCFA-CoAs have allosteric effects on purified enzyme preparations such as glycogen synthase (279); however, the physiological importance of these effects in vivo in muscle is uncertain. The impairment in glucose metabolism induced by the Randle cycle and/or allosteric effects of LCFA-CoA could become more evident when glucose metabolism is stimulated by insulin, as suggested by the findings that: 1) Intralipid infusion had little or no effect on peripheral glucose uptake in obese insulin resistant subjects (280) and in patients with type 2 diabetes (281), and 2) FFA impaired insulin-mediated glucose utilization to a greater extent than non-insulin-mediated glucose utilization in vitro (258) and in vivo (270, 271, 282). Recent studies by Shulman and colleagues (262, 275), however, have also demonstrated that insulin signaling is directly and specifically impaired by FFAs. This specific impairment may occur through LCFA-CoA and/or FFA esterification pathways, as muscle triglyceride content, which is a source of cytosolic LCFA-CoA [via the action of HSL (283) and is a marker of overactive esterification pathways], consistently correlates with insulin resistance (14, 97).
By their esterification to diacylglycerol (DAG), and perhaps directly, LCFA-CoAs stimulate PKC activity (284). PKC has inhibitory effects on insulin action, due to serine-threonine phosphorylation of the insulin receptor and other intermediates in the insulin signaling cascade (285). PKC can also directly inhibit glycogen synthase (286). In rat skeletal muscle, Intralipid plus heparin infusion increased membrane-bound (active) PKC
(263). In addition, transgenic mice with inactivation of PKC have recently been shown to be protected from lipid-induced defects in insulin action and signaling in skeletal muscle (287), suggesting a direct role of PKC in the development of fat-induced insulin resistance in skeletal muscle. Other studies have found that high-fat feeding increased DAG and the percentage of membrane-associated PKC
and (288). Overexpression of PKC, in particular, in skeletal muscle is believed to be causally related to the development of nutritionally induced insulin resistance and diabetes in the sand rat [Psammomys obesus (289)], perhaps in part by increasing degradation of the insulin receptor. Recent studies in muscle cell lines have suggested that ceramides, which can be derived from palmitoyl-CoAs via de novo synthesis, can also inhibit insulin signaling (Ref. 290 , and for review see Ref. 139).
LCFA-CoA may also affect GLUT4 translocation by acylating proteins involved in membrane fusion processes (291), although further studies are required to investigate this mechanism in muscle.
C. Effects of FFAs on the hexosamine pathway and oxidative stress in muscle
A pathway that has been linked with the FFA-induced impairment of muscle glucose metabolism by some authors (264) but not by others (292) is the hexosamine pathway. This is also an energy-sensing pathway, which is stimulated by increased glucose uptake under conditions of hyperglycemia and hyperinsulinemia. FFAs could stimulate this pathway via increased fructose-6-phosphate due to FFA-induced inhibition of PFK-1. PFK-1 could be inhibited by citrate or by depletion of xylulose-5-phosphate (see Ref. 293 for the latter mechanism). The mechanism of hexosamine-induced insulin resistance is unknown, although O-glycosylation of insulin signaling molecules or transcription factors may be implicated (294).
Another pathway that may be involved in the FFA- induced impairment in glucose metabolism is oxidative stress. FFAs can directly increase reactive oxygen species (ROS) via peroxidation reactions (295) and via mitochondrial production (296). FFAs can also indirectly increase ROS via hexosamine biosynthetic products (297). Again, the oxidative stress pathway is shared by hyperglycemia/hyperinsulinemia (295). Recent data obtained in collaboration with Dr. I. G. Fantus (University of Toronto) and co-workers suggests that iv infusion of N-acetyl-L-cysteine (NAC), an antioxidant, abolishes hyperglycemia and glucosamine-induced insulin resistance (298) and prevents, in part, FFA-induced insulin resistance in rats (299). Infusion of reduced glutathione, an antioxidant, partially prevented FFA-induced insulin resistance in humans (273). The biochemical mechanisms of oxidative stress-induced insulin resistance are unknown; however, it is well known that ROS can affect both signal transduction and gene expression, perhaps via redox modification of critical molecules. It is known that both oxidative stress (300) and the glucosamine pathway (301) can induce PKC activation. Perhaps linked to FFA-induced oxidative stress and PKC activation is the activation of I
B kinase ß (IKK-ß), a serine-threonine kinase that phosphorylates the insulin receptor and IRSs, thus inhibiting their tyrosine kinase phosphorylation. The latter pathway has recently been implicated in FFA-induced inhibition of insulin signaling and action, because high-dose salicylate, an inhibitor of IKK-ß (302), prevented FFA-induced insulin resistance in skeletal muscle in vivo, and IKK-ß-knockout mice did not exhibit altered skeletal muscle insulin signaling and action after lipid infusion (303, 304). Also perhaps linked to oxidative stress and to synthesis of ceramides is the induction of inducible nitric oxide (iNOS) in muscle, which has recently been implicated in insulin resistance in the high-fat-fed rat (305).
D. Effects of FFAs on the gene expression of enzymes involved in muscle glucose metabolism
By activating all the signaling pathways described above, FFA can indirectly influence gene expression (306). FFAs and their eicosanoid derivatives can also directly affect gene expression by binding to PPARs (307). These nuclear receptors induce genes of peroxisomal and mitochondrial fatty acid oxidation (307), thus potentially up-regulating the Randle cycle. Paradoxically, however, PPAR activation increases muscle insulin sensitivity, presumably because of induction of uncoupling proteins, which dissipate intracellular energy and reduce intracellular triglycerides. This may be viewed as a protective mechanism whereby fat accumulation tends to be self-limited. Fat accumulation also depends on the type of fatty acid. n-3 fatty acids, which preferentially activate PPARs, are associated with less muscle fat accumulation and increased insulin sensitivity compared with saturated fatty acids (306). Fatty acid activation of PPAR
in the adipocyte, perhaps by increasing adipocyte insulin sensitivity and by stimulating adipogenesis, may also indirectly improve muscle insulin sensitivity in vivo by modulating a fat-derived signaling molecule or FFA flux from adipose to muscle tissue (308).
|
V. Effects of FFA on Hepatic Glucose Metabolism |
|---|
Hepatic autoregulation may break down, as evidenced by the increase in basal glucose production induced by Intralipid plus heparin in other studies (270, 282). The breakdown of autoregulation is facilitated under hyperinsulinemic clamp conditions (265, 269, 276, 280, 317), presumably because, at hyperinsulinemia, glycogenolysis is already maximally suppressed. It is also possible that, as is the case in muscle, FFAs eventually impair insulin signaling, leading to an increase of both glycogenolysis and gluconeogenesis and perhaps also to a decrease of hepatic glucose uptake (318). The latter is currently controversial (319, 320).
The effect of FFA on hepatic glucose production during hyperinsulinemic clamps, however, is more controversial than the effect of FFA on peripheral glucose uptake, as in some studies (260, 262, 270, 281). Intralipid plus heparin failed to increase glucose production. The negative results could be explained, in part, by the high rate of insulin infused, which completely suppressed glucose production, independent of FFA (262, 270, 281). In addition, in most studies, plasma glucose-specific activity was not maintained constantly during the clamp, which leads to an underestimation of glucose production, particularly in the early non-steady-state periods of the clamp (321). Due to this methodological problem, the time course of the effect of FFA on glucose production could not be accurately estimated in most studies (280, 317), although there is some suggestion that it might be more rapid than the time course of the effect of FFA on peripheral glucose uptake (269, 280, 317).
B. Effects of FFA oxidation on hepatic glucose metabolism
Some of the mechanisms that have been implicated in the FFA-induced impairment of hepatic glucose metabolism are shown in Table 1. The classical Randle hypothesis has been expanded to include FFA-induced stimulation of gluconeogenesis. As is the case with FFA-induced inhibition of glycolysis, this pathway is also related to FFA oxidation. Acetyl-CoA derived from FFA oxidation stimulates pyruvate carboxylase, and the increased NADH is necessary to produce glyceraldehyde-3-phosphate from 1,3 bisphosphoglycerate. Citrate-induced inhibition of PFK-1 (which reduces glycolysis) has been demonstrated in the perfused rat liver (322) and in isolated hepatocytes exposed to FFA (323). In the liver, in contrast to muscle, the increased content of glucose-6-phosphate (324) from reduction of glycolysis and stimulation of gluconeogenesis should not affect glucose uptake because liver glucokinase, unlike muscle hexokinase, is not inhibited by glucose-6-phosphate. However, translocation of glucokinase [i.e., dissociation of glucokinase from its binding protein, which correlates with glucokinase activity (325)] is inhibited by fructose-6-phosphate, NADH (which increases after FFA oxidation), and directly by LCFA-CoA (325, 326). As is the case with muscle, FFA oxidation might be inadequate to fully account for the FFA-induced changes in glucose metabolism in liver. In fact, Randle’s expanded hypothesis might not entirely explain why FFAs mainly affect the insulin-mediated suppression of glucose production rather than basal glucose production, consistent with an impairment in hepatic insulin signaling. In addition, in the high-fat-fed rat, the resistance of glucose production to insulin was not ameliorated by inhibitors of FFA oxidation (327).
C. Other effects of FFA on hepatic glucose metabolism
LCFA-CoAs accumulate in liver, when increased FFA exposure is combined with inhibition of fatty acid oxidation due to elevated malonyl-CoA (328). Numerous allosteric effects of LCFA-CoA on purified hepatic enzyme preparations, including an inhibition of glucokinase (329), inhibition or stimulation of glucose-6-phosphatase (330), inhibition of glycogen synthase (279), and stimulation of glycogen phosphorylase (331), have been described; however, the physiological importance of these effects in vivo is uncertain. LCFA-CoAs stimulate PKC in hepatocytes (332). Phosphorylation by PKC can directly influence enzyme activity [for example, PKC reduces hepatic glycogen synthase activity (286)] and impair hepatic insulin signaling. Accordingly, hepatic triglyceride content, which is proportional to cytosolic LCFA-CoA, seems to correlate with hepatic insulin resistance (333). Our recent data show that in liver, FFAs increase glucose production in the basal state and induce hepatic insulin resistance. The increase in basal glucose production is not progressive over time and is associated with increased hepatic citrate content (334). Hepatic insulin resistance is progressive over time and is associated with a progressive increase in PKC
membrane translocation (335).
Little is known about the role of the hexosamine pathway and of oxidative stress in the FFA-induced insulin resistance in the liver. However, transgenic mice with selective overexpression of glutamine-fructose amidotransferase in the liver (the rate-limiting enzyme for increasing flow through the hexosamine pathway) show hepatic insulin resistance (336). Furthermore, studies in collaboration with Dr. I. G. Fantus (299) suggest that the antioxidant NAC partially prevents FFA-induced hepatic insulin resistance in rats.
In the liver as well as in muscle, FFAs induce enzymes of FFA oxidation, including CPT-1 (337), an effect mediated by PPARs (338). In addition, in the liver, polyunsaturated fatty acids repress ACC gene expression by inhibiting SREBP-1 (338). This could also contribute to the establishment of a chronic Randle cycle by decreasing malonyl-CoA, which inhibits CPT-1. PPAR response elements have been shown on genes of enzymes that are not involved in the Randle cycle, such as phosphoenolpyruvate carboxykinase (339) and glucokinase (327). In addition, glucose-6-phosphatase mRNA and protein are induced by Intralipid infusion in vivo, an effect that may be PPAR dependent (340). Paradoxically, however, the predominant effect of PPAR activation is to increase rather than decrease hepatic insulin sensitivity, presumably by limiting fat accumulation. In the liver, PPAR-independent effects account for the repression of glycolytic and lipogenic enzymes by n-3 and n-6 fatty acids (the mechanism is through inhibition of SREBP-1) and by fatty acyl-CoA [the mechanism is through inhibition of hepatocyte nuclear factors (338)]. These effects may also improve hepatic glucose metabolism by limiting fat overload.
D. Effects of FFA on insulin resistance: concluding remarks
In summary, increased provision of FFAs in a setting of increased energy availability leads to insulin resistance, thus preventing further intracellular accumulation of energy substrates. It is unclear whether this response is entirely maladaptive or also provides some advantage in terms of avoidance of massive obesity and perhaps avoidance of cell toxicity from tissue fat overload, at least in cardiac muscle (341) and liver (230). The trade-off is a tendency to increased circulating energy substrates (fat and glucose) and compensatory hyperinsulinemia. Hepatic insulin resistance and hyperinsulinemia in a setting of elevated FFA influx to the liver lead to increased production of VLDL particles (reviewed in Ref. 159), which are also a source of FFA for peripheral cells and contribute to the fat overload (Fig. 2).
|
VI. Effect of FFA on Hepatic Insulin Extraction |
|---|
One of the factors that may account for the impaired hepatic insulin extraction in obesity is elevated circulating FFA levels. In the in situ-perfused rat liver, physiological FFA concentrations caused a decline in hepatic insulin extraction (343). We have found that an elevation of circulating FFA from an Intralipid plus heparin infusion decreases hepatic insulin extraction in vivo in dogs (265). In further studies, the impairment in hepatic insulin extraction appeared to be greater when equimolar oleate infusion was given portally vs. peripherally to selectively elevate the hepatic FFA levels and thus mimic visceral obesity (310). In agreement with our findings, Hennes et al. (344) showed in humans that Intralipid plus heparin decreased whole-body insulin clearance (which includes both hepatic and peripheral insulin extraction) during hyperglycemic clamps. We have obtained similar findings in humans (345) but only after prolonged Intralipid plus heparin infusion. On the contrary, others failed to show changes in hepatic insulin extraction after 48 h of Intralipid plus heparin infusion performed during a 48-h hyperglycemic clamp (346). The reason for the discrepancy between these studies is unclear but may be related to the experimental protocol, as 48 h of hyperinsulinemia/hyperglycemia in the latter study might have been sufficient to decrease hepatic insulin extraction independent of FFA.
The majority of studies in humans did not show differences in peripheral insulin levels when hyperinsulinemic euglycemic clamps were carried out with or without Intralipid plus heparin infusion (see, for example, Refs. 269, 280 , and 317). Because insulin was infused peripherally in these studies, however, the impact of the liver on the resultant peripheral insulin levels was less than with physiological portal insulin delivery. Furthermore, in most of these studies the duration of the Intralipid plus heparin infusion was not long. In rats, the reduction in insulin clearance that we observed during a hyperinsulinemic clamp was greater after 7 h than 2 h of the Intralipid plus heparin infusion (334).
Hepatic insulin extraction depends on insulin binding to its receptor. In isolated rat hepatocytes, low physiological concentrations of FFA reduced insulin binding and degradation in proportion to a decreased receptor number (347, 348). Fatty acid oxidation may partly mediate the effect of FFA on insulin binding (349) by increasing the rate of insulin receptor internalization and/or decreasing the rate of receptor recycling (Table 1). In addition, FFAs may activate PKC (Ref. 332 ; in this study 
- and ß-isoenzymes were analyzed by hydroxyapetite chromatography and the ß-isoenzyme was found to be preferentially translocated), which can increase insulin receptor internalization (350). In our preliminary studies on isolated rat hepatocytes, PKC inhibition abolished the FFA-induced reduction in insulin binding (351). We are currently determining the isoform of PKC involved. In vivo in rats, the progressive reduction of insulin clearance induced by Intralipid and heparin was associated with a progressive increase in PKC translocation (334, 335). Interestingly, PKC activation has also been implicated in FFA-induced insulin resistance, which would explain the association between impaired insulin extraction and sensitivity (265). The FFA-mediated reduction in hepatic insulin extraction may be viewed as an adaptive mechanism to generate peripheral hyperinsulinemia, and thus, to partially overcome the peripheral insulin resistance induced by FFAs. This adaptive mechanism could relieve, in part, the stress on pancreatic ß-cells imposed by insulin resistance (352).
|
VII. Effects of FFA and Islet Triglyceride Stores on Pancreatic ß-Cells |
|---|
The precise mechanisms responsible for the acute effects of FFAs on insulin secretion are still debated. Intracellular FFAs are rapidly converted to fatty acyl-CoA, which can be oxidized to produce ATP. However, contrary to glucose, ATP generation followed by closure of the K-ATP channels is not the main mechanism of the acute stimulatory effect of FFAs on insulin secretion. Instead, the key factor appears to be accumulation of cytosolic LCFA-CoA when FFA oxidation is inhibited by glucose-derived malonyl-CoA (353, 354, 361). This cytosolic accumulation of LCFA-CoA could then stimulate the K-ATP-independent insulin secretory pathway through activation of PKC (362, 363) and/or more directly by increasing the secretory granule fusion process (364). Of note, the acute effect of FFAs on insulin secretion does not appear to be specific for a glucose stimulus, which suggests that final common events in stimulus secretion coupling may be involved (365). Some of these mechanisms (PKC activation) may be operational in both ß-cells and peripheral tissues and thus link insulin resistance and hyperinsulinemia at the cellular level. Another of these mechanisms may be increased hexosamine flux. Recent findings in transgenic mice with selective overexpression of glutamine-fructose amidotransferase in the ß-cell suggest that increased hexosamine flux may lead to insulin hypersecretion with secondary insulin resistance (366).
B. Chronic effects of FFAs on insulin secretion
In contrast to the stimulatory effect of acute exposure to FFAs, Sako and Grill (367) have shown that prolonged Intralipid infusion (>24 h) results in reduced GSIS in the perfused rat pancreas at high glucose concentration, suggesting that chronic FFA elevation inhibits GSIS. Several in vitro studies in ß-cell lines and in rodent and human islets have subsequently confirmed that insulin secretion at high glucose concentrations is impaired in a time-dependent fashion by exposure to FFAs (368, 369, 370, 371, 372, 373, 374, 375). Islets from prediabetic Zucker diabetic fatty (ZDF) rats and from fructose-fed insulin-resistant rats appear to be more susceptible to this FFA-mediated desensitization of GSIS (370, 374). Under the same conditions, however, basal insulin secretion at low glucose concentrations was elevated in normal rodent islets and islet cell lines in most studies (367, 368, 370, 371, 372, 373, 374, 376), but not in human islets (377). Furthermore, insulin secretion at low glucose concentration is either unchanged or decreased by FFAs in islets from ZDF prediabetic rats or prediabetic Otsuka Long-Evans Tokushima fatty rats (370, 373).
The precise mechanism responsible for this "ß-cell lipotoxicity", a term coined by Unger (378) in 1995, has been debated. This term has been applied to describe FFA-induced functional impairments in GSIS as well as reduction in ß-cell mass. The functional effect of chronically elevated FFAs on insulin secretion, in contrast to the acute enhancing effect, appears to be specific for glucose in vitro (368) and in vivo (379), and at least part of the effect requires FFA oxidation (367, 368, 377). An early hypothesis was that chronic exposure of ß-cells to FFAs may result in diminished glucose oxidation [via a "Randle-like" effect (367, 368, 377)]. Prolonged exposure to FFAs may also lead to decreased GLUT2 and glucokinase expression, thereby decreasing the glucose-sensing capacity of the ß-cell (373, 380). Other studies, however, have shown that prolonged exposure to FFAs does not decrease and may even increase glucose utilization and ATP generation, and reduces glucose oxidation only slightly in ß-cells (370, 372, 381), casting doubts on FFA-mediated impairment of glucose metabolism as an important mechanism for the ß-cell lipotoxic effect.
Several other potential mechanisms have been proposed to explain the functional ß-cell defect induced by FFAs, such as direct activation of the ATP-sensitive K+ channels (382), down-regulation of PKC (372), or inhibition of specific PKC isoforms (363), induction of uncoupling protein 2 [UCP2 (383)], induction of oxidative stress (296, 375) and perhaps iNOS (384), and increased synthesis of ceramides (385). In addition, FFAs decrease insulin biosynthesis (368, 376, 377, 380, 386), alter proinsulin processing (387), and decrease insulin gene transcription (324, 327) by unclear mechanisms. Furthermore, reduced ß-cell mass may be caused by FFA-induced stimulation of apoptosis, which has been repeatedly demonstrated in in vitro studies and has been linked to FFA-mediated induction of iNOS, increase in ceramide synthesis, and perhaps oxidative stress (296, 388, 389, 390, 391). Some of the biochemical mechanisms of ß-cell lipotoxicity have also been implicated in the FFA-induced impairment in insulin action (Table 1) and may be common to glucotoxicity as well. Most of these lipotoxic mechanisms appear to be linked to fatty acid esterification rather than oxidation. For example, palmitate-induced reduction of rat islet insulin mRNA levels was shown to depend on induction of fatty acid esterification pathway at high glucose levels (392, 393). Interestingly, prolonged in vitro exposure of ß-cells to FFAs, triglycerides, or glucose leads to induction of lipogenic genes and/or to increased fatty acid esterification and intracellular fat deposition (373, 381, 393, 394, 395), which have been associated with the development of ß-cell dysfunction in animal models of type 2 diabetes (370). These intracellular triglycerides can be hydrolyzed by HSL, which is expressed and active in ß-cells (396) and, therefore, may constitute an in situ reservoir of long-chain fatty acids.
Furthermore, depletion of intracellular triglycerides in ZDF rat islets by activating intracellular FFA oxidation using leptin receptor overexpression with leptin treatment or troglitazone treatment restores the FFA-induced defects in cellular ultrastructure, mitochondrial integrity, glucose sensing, insulin biosynthesis, and GSIS (397, 398). UCP-2 has been implicated in the functional secretory defect chronically induced by FFAs and can decrease insulin secretion by decreasing ATP production from glucose (399). Paradoxically, however, adenovirus-mediated transfer of UCP-2 in pancreatic ß-cells from Zucker diabetic rats has been shown to increase fatty acid oxidation and improve insulin secretion (400).
C. Effect of chronically elevated FFAs on insulin secretion in vivo
The question of whether chronically elevated plasma FFAs actually impair GSIS in vivo, particularly in humans, remains controversial, with some groups showing an impairing effect of FFAs, whereas others claim that chronically elevated FFAs actually facilitate insulin secretion. As we will discuss, it is possible to explain the apparently discrepant findings from the various studies that have been reported in humans.
In vivo insulin secretion needs to be interpreted in relation to concurrent changes in insulin sensitivity and perhaps also insulin clearance. There is a well-described hyperbolic relationship between insulin secretion and insulin sensitivity (SI), implying that the product of insulin secretion and SI is a constant [called the disposition index (DI); Ref. 401 ]. In individuals with normal ß-cell function, a decline in SI should be followed by a compensatory increase in insulin secretion, thus maintaining the body’s ability to dispose of glucose (401). This relationship suggests that insulin sensitivity and insulin secretion are linked through a negative feedback loop and/or that common biochemical mechanisms link insulin resistance and ß-cell hypersecretion. In situations, such as in type 2 diabetes, in which ß-cell function is defective and cannot fully compensate for the decline in SI, there is a decline in DI but not necessarily in absolute insulin secretion. Because elevation of plasma FFAs results in a reduction in SI (269, 274, 345), it is critical to take this effect into account in interpreting any FFA-mediated change in insulin secretion. The FFA effect on insulin clearance (345) should also be taken into account, as this is expected to decrease, in part, the need for insulin secretion. Finally, when examining the in vivo data on the action of prolonged elevation of plasma FFAs, one has to keep in mind that iv infusion of triglyceride emulsion could also modulate autonomic nervous system activity, which can in turn affect both insulin sensitivity and insulin secretion (402).
The paper of Boden et al. (346) was the first to study the effect of prolonged elevation of plasma FFAs on insulin secretion in humans. These investigators found higher absolute insulin secretion during a 48-h hyperglycemic clamp with concurrent iv infusion of Intralipid plus heparin. They did not, however, examine insulin secretion in relationship to the FFA-mediated change in SI, which was reduced with infusion of Intralipid plus heparin in this study. In contrast to the above findings, Paolisso et al. (357) reported that a 6-h elevation of plasma FFAs results in an absolute increase in GSIS, as assessed by the first phase insulin response to an iv glucose tolerance test, but that prolonged FFA elevation for 24 h results in an absolute reduction in the acute insulin response to glucose. The impairment in GSIS was reversible, implicating a functional defect. The same group also showed, in first-degree relatives of patients with type 2 diabetes in whom FFAs were lowered for 1 wk using the nicotinic acid analog acipimox, that there was a 50% increase in first phase insulin secretion during an iv glucose tolerance test (403).
Our group (345) assessed insulin secretion in lean, healthy men after an iv infusion of Intralipid and heparin resulting in a 2-fold elevation of fasting plasma FFAs. We found that acute elevation of FFAs for 1.5 h before a two-step hyperglycemic clamp of 4-h duration resulted in elevated GSIS and reduced SI without a change in DI, showing that, acutely, the ß-cell precisely compensates for the FFA-induced reduction in insulin sensitivity. In contrast, the FFA-mediated potentiating effect on GSIS was completely lost after 48 h of elevation of plasma FFA, and there was a concomitant significant decrease in insulin sensitivity, and consequently, a significantly lower DI. In other words, prolonged elevation of FFAs disables the ß-cell’s ability to appropriately increase its secretion in response to a reduction in SI. We also found that obese nondiabetic subjects had an absolute reduction of insulin secretion after prolonged elevation of plasma FFA, whereas diabetic subjects displayed a slight but significant absolute increase in insulin secretion (404). These findings suggest that individuals at risk for developing type 2 diabetes may be more susceptible to FFA-mediated ß-cell desensitization than healthy insulin-sensitive individuals, but that those who already have type 2 diabetes may have no further FFA-induced deterioration in ß-cell function. Our findings in humans are supported by similar findings in rats (405). In addition, our studies in rats suggest that the type of fatty acid is an important determinant of the effect of prolonged plasma FFA on GSIS. Both oleate and Intralipid/heparin (405), but not lard oil/heparin (406), decreased the absolute rate of GSIS at high glucose concentrations, with a much greater impairing effect of oleate than Intralipid and heparin. At low glucose concentrations, Intralipid/heparin actually increased insulin secretion, which is consistent with other studies in rats (402). In our studies, all types of fat appeared to disable the ß-cell-compensatory response to FFA-induced insulin resistance (the latter is less in rats than in humans, probably accounting for the findings of a small absolute reduction of GSIS by Intralipid in rats but not in humans), perhaps to a different extent (406). Furthermore, our studies suggest that prediabetic rat models of type 2 diabetes (407), and perhaps also type 1 diabetes (408), may be particularly susceptible to the fat-induced impairment of GSIS. As to the mechanism of this effect, our preliminary experiments (in collaboration with Dr. I. G. Fantus) in normal rats suggest that oxidative stress may be involved, as iv infusion of NAC, an antioxidant, prevented the decrease in GSIS induced by prolonged oleate or Intralipid/heparin infusion (409).
In contrast to the impairing effect of a prolonged elevation of FFAs on GSIS, we recently failed to demonstrate a similar effect on arginine-stimulated insulin secretion (379). These findings are in keeping with in vitro studies that have suggested that the impairment of ß-cell insulin secretion mediated by prolonged exposure to FFAs may be specific for GSIS (368, 383, 410, 411). Because arginine is believed to stimulate insulin secretion distal in the insulin secretion cascade of events, primarily by inducing depolarization of the ß-cell membrane (412, 413), the absence of a significant effect, combined with our previous observation of a FFA-induced reduction of GSIS, would suggest that prolonged FFA exposure may alter GSIS primarily by interfering with the metabolism of glucose, leaving relatively intact the exocytotic machinery.
D. Summary of the effects of FFAs on insulin secretion
From the above discussion, the following conclusions can be drawn: 1) The effects of fatty acids on ß-cells are complex and probably involve multiple direct metabolic interactions as well as delayed modulation of gene expression, resulting in time-dependent differential effects on insulin secretion in vitro. 2) In states of caloric deprivation, fatty acids have an important role in maintaining basal insulin secretion, but whether this regulation is independent of FFA-mediated change in insulin sensitivity has yet to be answered. 3) Acute elevation or lowering of plasma FFAs clearly results in potentiation and blunting, respectively, of GSIS in vivo. 4) The bulk of evidence both from in vitro and in vivo studies suggests that chronic exposure of ß-cells to elevated fatty acids results in blunting of GSIS, particularly when insulin secretion is appropriately assessed in relation to concomitant changes in insulin sensitivity. Furthermore, based on our results in humans, it is possible that individuals at risk for developing type 2 diabetes may be more susceptible to the ß-cell lipotoxic effect of fatty acids. FFAs, therefore, appear to be an important link between obesity, insulin resistance, fat intolerance, and the development of ß-cell dysfunction and type 2 diabetes. The challenge for investigators is to better define the molecular basis for the ß-cell lipotoxic or glucolipotoxic effect, and to further delineate the metabolic phenotypes and genetic factors that interact with fatty acids in vivo, placing individuals at risk of developing ß-cell dysfunction.
|
VIII. Inhibition of Fatty Acid Flux from Adipose Tissue: Is it Effective in Ameliorating the Manifestations of IRS and Type 2 Diabetes? |
|---|
The agent that has been used most frequently to investigate the metabolic and clinical effects of reducing fatty acids is the antilipolytic, long-acting nicotinic acid analog, acipimox (414, 415). Acute administration of acipimox has been shown by numerous investigators to reduce plasma FFAs, fatty acid oxidation, and gluconeogenesis and to increase glucose oxidation rates, with some but not all studies showing suppression of endogenous glucose production, increased insulin-mediated suppression of glucose production, and insulin-mediated glucose uptake (416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428). In addition, large VLDL particle (VLDL1) production has been shown to be reduced (240), as LDL particle size shifted from the smaller, dense particles to larger particles, a change that may be associated with less atherogenicity (429), and insulin secretion was potentiated with 1-wk acipimox treatment (403). There is a rebound elevation of FFAs that occurs with longer-term acipimox treatment, which may limit its potential therapeutic benefit (419, 423, 430, 431). Diabetic patients treated with acipimox have shown variable but generally disappointing clinical improvement in glycemic control (419, 432, 433, 434, 435, 436), whereas the triglyceride-lowering and high density lipoprotein-raising effects of acipimox in hyperlipidemic patients have been more impressive (433, 434, 435, 436, 437, 438, 439, 440, 441). Acipimox has also been used with some success to reduce LDL in patients with hypercholesterolemia (442) and combined hyperlipidemia (443, 444, 445).
We speculate that drugs whose principal mechanism of action is to inhibit adipose tissue lipolysis are unlikely to prove totally effective in ameliorating the metabolic disturbances associated with IRS and type 2 diabetes. Firstly, they are destined to produce a rebound increase in adipocyte triglyceride lipolysis due to the mass effect of greater adipocyte triglyceride stores that occurs secondary to the drug-induced inhibition of lipolysis. Secondly, they fail to correct the fundamental defect of insulin-mediated fatty acid re-esterification in adipose tissue and are therefore unlikely to effectively reduce the postprandial diversion of FFAs from adipose tissue to other tissues of the body. On the other hand, agents such as PPAR activators that overcome insulin resistance of adipose tissue by improving adipocyte FFA esterification are postulated to more effectively reduce the deleterious metabolic effects of fat dysregulation. Unfortunately, the trade-off of therapies designed to improve FFA uptake and deposition in adipose tissue and to limit FFA efflux may be weight gain, unless accompanied by a reduction in total daily calorie intake and/or an increase in energy expenditure. Possibly the only truly effective therapies will be those designed to reduce positive net energy balance. At present, however, the most important of these therapies are lifestyle changes.
|
IX. Summary |
|---|
There is little question that abnormal fatty acid metabolism is an important component of IRS and type 2 diabetes. A major question that remains to be answered is precisely how important a role fatty acids play in the cross-talk between adipose tissue and extraadipocyte insulin-sensitive and insulin-secretory tissues. Are fatty acids the dominant signal between these tissues, or will other factors such as peptides and cytokines prove to play a more important role?
|
Acknowledgments |
|---|
|
Footnotes |
|---|
Abbreviations: ACC, Acetyl-CoA carboxylase, apo B, apolipoprotein B; ASP, acylation-stimulating protein; CoA, coenzyme A; CPT-1 carnitine palmitoyl-transferase-1; DAG diacylglycerol; DGAT, acyl coenzyme A:diacylglycerol acyltransferase; DI, disposition index; DNL, de novo lipogenesis; FABP, fatty acid binding protein; FAT, fatty acid translocase (transporter); FATP, fatty acid transport protein; GLUT, glucose transporter; GSIS, glucose-stimulated insulin secretion; HSL hormone- sensitive lipase; IKK-ß, IB kinase ß; IMTG, intramyocellular triglyceride; iNOS, inducible nitric oxide; IRS, insulin-resistance syndrome; LCFA-CoA, long-chain fatty acyl CoA; LPL lipoprotein lipase; MTP, microsomal transfer protein; NAC, N-acetyl-L-cysteine; NADH dihydronicotinamide adenine dinucleotide; PFK-1 phosphofructokinase-1; ROS, reactive oxygen species; Si insulin sensitivity index; SREBP-1, sterol-regulatory element-binding protein-1; UCP2, uncoupling protein 2; VLDL, very low density lipoprotein; ZDF, Zucker diabetic fatty.
|
References |
|---|
and alterations in the insulin signaling cascade. Diabetes 48:1270–1274[Abstract]
inhibits signaling by members of the insulin receptor family. J Biol Chem 270:21600–21605 are protected from lipid-induced defects in insulin action and signaling in skeletal muscle. Diabetes 50(Suppl 2):A58 (Abstract)
and are associated with insulin resistance in skeletal muscle of the high-fat-fed rat. Diabetes 46:169–178[Abstract]
in skeletal muscle precedes the onset of hyperinsulinemia and hyperglycemia. Diabetes 50: 584–592
translocation. Diabetes 50(Suppl 2):A304 (Abstract)
gene in the pancreatic ß-cell. J Biol Chem 275:35799–35806This article has been cited by other articles:
 |
|
 |
|
  J. K. Dowman, J.W. Tomlinson, and P.N. Newsome Pathogenesis of non-alcoholic fatty liver disease QJM, November 13, 2009; (2009) hcp158v1. [Full Text] [PDF]
|
|
|
|
 |
|
 P. C. Kienesberger, D. Lee, T. Pulinilkunnil, D. S. Brenner, L. Cai, C. Magnes, H. C. Koefeler, I. E. Streith, G. N. Rechberger, G. Haemmerle, et al. Adipose Triglyceride Lipase Deficiency Causes Tissue-specific Changes in Insulin Signaling J. Biol. Chem., October 30, 2009; 284(44): 30218 - 30229. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. E. Mulvihill, E. M. Allister, B. G. Sutherland, D. E. Telford, C. G. Sawyez, J. Y. Edwards, J. M. Markle, R. A. Hegele, and M. W. Huff Naringenin Prevents Dyslipidemia, Apolipoprotein B Overproduction, and Hyperinsulinemia in LDL Receptor-Null Mice With Diet-Induced Insulin Resistance Diabetes, October 1, 2009; 58(10): 2198 - 2210. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Basciano, A. E. Miller, M. Naples, C. Baker, R. Kohen, E. Xu, Q. Su, E. M. Allister, M. B. Wheeler, and K. Adeli Metabolic effects of dietary cholesterol in an animal model of insulin resistance and hepatic steatosis Am J Physiol Endocrinol Metab, August 1, 2009; 297(2): E462 - E473. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Ruge, L. Hodson, J. Cheeseman, A. L. Dennis, B. A. Fielding, S. M. Humphreys, K. N. Frayn, and F. Karpe Fasted to Fed Trafficking of Fatty Acids in Human Adipose Tissue Reveals a Novel Regulatory Step for Enhanced Fat Storage J. Clin. Endocrinol. Metab., May 1, 2009; 94(5): 1781 - 1788. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Steinberger, S. R. Daniels, R. H. Eckel, L. Hayman, R. H. Lustig, B. McCrindle, and M. L. Mietus-Snyder Progress and Challenges in Metabolic Syndrome in Children and Adolescents: A Scientific Statement From the American Heart Association Atherosclerosis, Hypertension, and Obesity in the Young Committee of the Council on Cardiovascular Disease in the Young; Council on Cardiovascular Nursing; and Council on Nutrition, Physical Activity, and Metabolism Circulation, February 3, 2009; 119(4): 628 - 647. [Full Text] [PDF]
|
|
|
|
 |
|
 S. Tejerina, A. De Pauw, S. Vankoningsloo, A. Houbion, P. Renard, F. De Longueville, M. Raes, and T. Arnould Mild mitochondrial uncoupling induces 3T3-L1 adipocyte de-differentiation by a PPAR{gamma}-independent mechanism, whereas TNF{alpha}-induced de-differentiation is PPAR{gamma} dependent J. Cell Sci., January 1, 2009; 122(1): 145 - 155. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Caron and B. Staels Apolipoprotein CIII: A Link Between Hypertriglyceridemia and Vascular Dysfunction? Circ. Res., December 5, 2008; 103(12): 1348 - 1350. [Full Text] [PDF]
|
|
|
|
|
|
C. F. Zizola, G. J. Schwartz, and S. Vogel Cellular retinol-binding protein type III is a PPAR{gamma} target gene and plays a role in lipid metabolism Am J Physiol Endocrinol Metab, December 1, 2008; 295(6): E1358 - E1368. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. N. Suh, H. T. Huong, C. H. Song, J. H. Lee, and H. J. Han Linoleic acid stimulates gluconeogenesis via Ca2+/PLC, cPLA2, and PPAR pathways through GPR40 in primary cultured chicken hepatocytes Am J Physiol Cell Physiol, December 1, 2008; 295(6): C1518 - C1527. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. W. Eriksson, P.-A. Jansson, B. Carlberg, A. Hagg, L. Kurland, M. K. Svensson, H. Ahlstrom, C. Strom, L. Lonn, K. Ojbrandt, et al. Hydrochlorothiazide, but not Candesartan, Aggravates Insulin Resistance and Causes Visceral and Hepatic Fat Accumulation: The Mechanisms for the Diabetes Preventing Effect of Candesartan (MEDICA) Study Hypertension, December 1, 2008; 52(6): 1030 - 1037. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Iankova, C. Chavey, C. Clape, C. Colomer, N. C. Guerineau, N. Grillet, J.-F. Brunet, J.-S. Annicotte, and L. Fajas Regulator of G Protein Signaling-4 Controls Fatty Acid and Glucose Homeostasis Endocrinology, November 1, 2008; 149(11): 5706 - 5712. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G Ferns, V Keti, and B Griffin Investigation and management of hypertriglyceridaemia J. Clin. Pathol., November 1, 2008; 61(11): 1174 - 1183. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Espiritu and T. Mazzone Oxidative Stress Regulates Adipocyte Apolipoprotein E and Suppresses Its Expression in Obesity Diabetes, November 1, 2008; 57(11): 2992 - 2998. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Anderson and J. Borlak Molecular Mechanisms and Therapeutic Targets in Steatosis and Steatohepatitis Pharmacol. Rev., September 1, 2008; 60(3): 311 - 357. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Pavlic, R. Valero, H. Duez, C. Xiao, L. Szeto, B. W. Patterson, and G. F. Lewis Triglyceride-Rich Lipoprotein-Associated Apolipoprotein C-III Production Is Stimulated by Plasma Free Fatty Acids in Humans Arterioscler Thromb Vasc Biol, September 1, 2008; 28(9): 1660 - 1665. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Ness-Abramof and C. M. Apovian Waist Circumference Measurement in Clinical Practice Nutr Clin Pract, August 1, 2008; 23(4): 397 - 404. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Yue, J. W. Christman, and T. Mazzone Tumor Necrosis Factor-{alpha}-Mediated Suppression of Adipocyte Apolipoprotein E Gene Transcription: Primary Role for the Nuclear Factor (NF)-{kappa}B Pathway and NF{kappa}B p50 Endocrinology, August 1, 2008; 149(8): 4051 - 4058. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Rigazio, H.-R. Lehto, H. Tuunanen, K. Nagren, M. Kankaanpaa, C. Simi, R. Borra, A. G. Naum, R. Parkkola, J. Knuuti, et al. The lowering of hepatic fatty acid uptake improves liver function and insulin sensitivity without affecting hepatic fat content in humans Am J Physiol Endocrinol Metab, August 1, 2008; 295(2): E413 - E419. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Johnston, C. L. Rose, A. C. Webster, and J. S. Gill Sirolimus Is Associated with New-Onset Diabetes in Kidney Transplant Recipients J. Am. Soc. Nephrol., July 1, 2008; 19(7): 1411 - 1418. [Full Text] [PDF]
|
|
|
|
|
|
C. Wolfrum, J. J. Howell, E. Ndungo, and M. Stoffel Foxa2 Activity Increases Plasma High Density Lipoprotein Levels by Regulating Apolipoprotein M J. Biol. Chem., June 13, 2008; 283(24): 16940 - 16949. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Puri, S. Ranjit, S. Konda, S. M. C. Nicoloro, J. Straubhaar, A. Chawla, M. Chouinard, C. Lin, A. Burkart, S. Corvera, et al. Cidea is associated with lipid droplets and insulin sensitivity in humans PNAS, June 3, 2008; 105(22): 7833 - 7838. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Duez, B. Lamarche, R. Valero, M. Pavlic, S. Proctor, C. Xiao, L. Szeto, B. W. Patterson, and G. F. Lewis Both Intestinal and Hepatic Lipoprotein Production Are Stimulated by an Acute Elevation of Plasma Free Fatty Acids in Humans Circulation, May 6, 2008; 117(18): 2369 - 2376. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. W. Yeckel, J. Dziura, and L. DiPietro Abdominal Obesity in Older Women: Potential Role for Disrupted Fatty Acid Reesterification in Insulin Resistance J. Clin. Endocrinol. Metab., April 1, 2008; 93(4): 1285 - 1291. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. A. A. Pires, J. B. Pescara, A. E. Brickner, N. Silva del Rio, A. P. Cunha, and R. R. Grummer Effects of Abomasal Infusion of Linseed Oil on Responses to Glucose and Insulin in Holstein Cows J Dairy Sci, April 1, 2008; 91(4): 1378 - 1390. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. R. Sheets, P. Fulop, Z. Derdak, A. Kassai, E. Sabo, N. M. Mark, G. Paragh, J. R. Wands, and G. Baffy Uncoupling protein-2 modulates the lipid metabolic response to fasting in mice Am J Physiol Gastrointest Liver Physiol, April 1, 2008; 294(4): G1017 - G1024. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Brassard, F. Frisch, F. Lavoie, D. Cyr, A. Bourbonnais, S. C. Cunnane, B. W. Patterson, R. Drouin, J.-P. Baillargeon, and A. C. Carpentier Impaired Plasma Nonesterified Fatty Acid Tolerance Is an Early Defect in the Natural History of Type 2 Diabetes J. Clin. Endocrinol. Metab., March 1, 2008; 93(3): 837 - 844. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. Kostiuk, M. M. Corvi, B. O. Keller, G. Plummer, J. A. Prescher, M. J. Hangauer, C. R. Bertozzi, G. Rajaiah, J. R. Falck, and L. G. Berthiaume Identification of palmitoylated mitochondrial proteins using a bio-orthogonal azido-palmitate analogue FASEB J, March 1, 2008; 22(3): 721 - 732. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. I. Oprescu, G. Bikopoulos, A. Naassan, E. M. Allister, C. Tang, E. Park, H. Uchino, G. F. Lewis, I. G. Fantus, M. Rozakis-Adcock, et al. Free Fatty Acid Induced Reduction in Glucose-Stimulated Insulin Secretion: Evidence for a Role of Oxidative Stress In Vitro and In Vivo Diabetes, December 1, 2007; 56(12): 2927 - 2937. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Kotronen, S. Vehkavaara, A. Seppala-Lindroos, R. Bergholm, and H. Yki-Jarvinen Effect of liver fat on insulin clearance Am J Physiol Endocrinol Metab, December 1, 2007; 293(6): E1709 - E1715. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-H. Hwang, D. T. Stein, N. Barzilai, M.-H. Cui, J. Tonelli, P. Kishore, and M. Hawkins Increased intrahepatic triglyceride is associated with peripheral insulin resistance: in vivo MR imaging and spectroscopy studies Am J Physiol Endocrinol Metab, December 1, 2007; 293(6): E1663 - E1669. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Roberge, A. C. Carpentier, M.-F. Langlois, J.-P. Baillargeon, J.-L. Ardilouze, P. Maheux, and N. Gallo-Payet Adrenocortical dysregulation as a major player in insulin resistance and onset of obesity Am J Physiol Endocrinol Metab, December 1, 2007; 293(6): E1465 - E1478. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Hessel, A. Eichinger, A. Isken, J. Amengual, S. Hunzelmann, U. Hoeller, V. Elste, W. Hunziker, R. Goralczyk, V. Oberhauser, et al. CMO1 Deficiency Abolishes Vitamin A Production from beta-Carotene and Alters Lipid Metabolism in Mice J. Biol. Chem., November 16, 2007; 282(46): 33553 - 33561. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Hodson, A. S.T. Bickerton, S. E. McQuaid, R. Roberts, F. Karpe, K. N. Frayn, and B. A. Fielding The Contribution of Splanchnic Fat to VLDL Triglyceride Is Greater in Insulin-Resistant Than Insulin-Sensitive Men and Women: Studies in the Postprandial State Diabetes, October 1, 2007; 56(10): 2433 - 2441. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Kumazawa, M. Kobayashi, F. Io, T. Kawai, M. Nishimura, T. Ohno, and F. Horio Searching for genetic factors of fatty liver in SMXA-5 mice by quantitative trait loci analysis under a high-fat diet J. Lipid Res., September 1, 2007; 48(9): 2039 - 2046. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. L Kuk, P. M Janiszewski, and R. Ross Body mass index and hip and thigh circumferences are negatively associated with visceral adipose tissue after control for waist circumference Am. J. Clinical Nutrition, June 1, 2007; 85(6): 1540 - 1544. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-C. Hogue, B. Lamarche, A. J. Tremblay, J. Bergeron, C. Gagne, and P. Couture Evidence of increased secretion of apolipoprotein B-48-containing lipoproteins in subjects with type 2 diabetes J. Lipid Res., June 1, 2007; 48(6): 1336 - 1342. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. A. Pires, A. H. Souza, and R. R. Grummer Induction of Hyperlipidemia by Intravenous Infusion of Tallow Emulsion Causes Insulin Resistance in Holstein Cows J Dairy Sci, June 1, 2007; 90(6): 2735 - 2744. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H.-Y. Liu, Q. F. Collins, Y. Xiong, F. Moukdar, E. G. Lupo Jr., Z. Liu, and W. Cao Prolonged Treatment of Primary Hepatocytes with Oleate Induces Insulin Resistance through p38 Mitogen-activated Protein Kinase J. Biol. Chem., May 11, 2007; 282(19): 14205 - 14212. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Wei, W. Gao, and R. Lehner Attenuation of Adipocyte Triacylglycerol Hydrolase Activity Decreases Basal Fatty Acid Efflux J. Biol. Chem., March 16, 2007; 282(11): 8027 - 8035. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Perseghin, G. Lattuada, F. De Cobelli, F. Ragogna, G. Ntali, A. Esposito, E. Belloni, T. Canu, I. Terruzzi, P. Scifo, et al. Habitual Physical Activity Is Associated With Intrahepatic Fat Content in Humans Diabetes Care, March 1, 2007; 30(3): 683 - 688. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. F. Crutchlow and R. D. Bloom Transplant-Associated Hyperglycemia: A New Look at an Old Problem Clin. J. Am. Soc. Nephrol., March 1, 2007; 2(2): 343 - 355. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. C. Carpentier, F. Frisch, P. Brassard, F. Lavoie, A. Bourbonnais, D. Cyr, R. Giguere, and J.-P. Baillargeon Mechanism of insulin-stimulated clearance of plasma nonesterified fatty acids in humans Am J Physiol Endocrinol Metab, March 1, 2007; 292(3): E693 - E701. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Juurinen, M. Tiikkainen, A.-M. Hakkinen, A. Hakkarainen, and H. Yki-Jarvinen Effects of insulin therapy on liver fat content and hepatic insulin sensitivity in patients with type 2 diabetes Am J Physiol Endocrinol Metab, March 1, 2007; 292(3): E829 - E835. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Sharma and B. Staels Peroxisome Proliferator-Activated Receptor {gamma} and Adipose Tissue--Understanding Obesity-Related Changes in Regulation of Lipid and Glucose Metabolism J. Clin. Endocrinol. Metab., February 1, 2007; 92(2): 386 - 395. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Qu, D. Su, J. Altomonte, A. Kamagate, J. He, G. Perdomo, T. Tse, Y. Jiang, and H. H. Dong PPAR{alpha} mediates the hypolipidemic action of fibrates by antagonizing FoxO1 Am J Physiol Endocrinol Metab, February 1, 2007; 292(2): E421 - E434. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. S.T. Bickerton, R. Roberts, B. A. Fielding, L. Hodson, E. E. Blaak, A. J.M. Wagenmakers, M. Gilbert, F. Karpe, and K. N. Frayn Preferential Uptake of Dietary Fatty Acids in Adipose Tissue and Muscle in the Postprandial Period Diabetes, January 1, 2007; 56(1): 168 - 176. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Blouin, C. Richard, G. Brochu, F.-S. Hould, S. Lebel, S. Marceau, S. Biron, V. Luu-The, and A. Tchernof Androgen inactivation and steroid-converting enzyme expression in abdominal adipose tissue in men J. Endocrinol., December 1, 2006; 191(3): 637 - 649. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. F. Collins, Y. Xiong, E. G. Lupo Jr., H.-Y. Liu, and W. Cao p38 Mitogen-activated Protein Kinase Mediates Free Fatty Acid-induced Gluconeogenesis in Hepatocytes J. Biol. Chem., August 25, 2006; 281(34): 24336 - 24344. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Pagano, C. Pilon, M. Olivieri, P. Mason, R. Fabris, R. Serra, G. Milan, M. Rossato, G. Federspil, and R. Vettor Reduced Plasma Visfatin/Pre-B Cell Colony-Enhancing Factor in Obesity Is Not Related to Insulin Resistance in Humans J. Clin. Endocrinol. Metab., August 1, 2006; 91(8): 3165 - 3170. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. T. Bloomgarden Third Annual World Congress on the Insulin Resistance Syndrome: Mediators, antecedents, and measurement Diabetes Care, July 1, 2006; 29(7): 1700 - 1706. [Full Text] [PDF]
|
|
|
|
|
|
V. van Weel, M. de Vries, P. J. Voshol, R. E. Verloop, P. H.C. Eilers, V. W.M. van Hinsbergh, J. H. van Bockel, and P. H.A. Quax Hypercholesterolemia Reduces Collateral Artery Growth More Dominantly Than Hyperglycemia or Insulin Resistance in Mice Arterioscler Thromb Vasc Biol, June 1, 2006; 26(6): 1383 - 1390. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Duez, B. Lamarche, K. D. Uffelman, R. Valero, J. S. Cohn, and G. F. Lewis Hyperinsulinemia Is Associated With Increased Production Rate of Intestinal Apolipoprotein B-48-Containing Lipoproteins in Humans Arterioscler Thromb Vasc Biol, June 1, 2006; 26(6): 1357 - 1363. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Yoshii, T. K. T. Lam, N. Gupta, T. Goh, C. A. Haber, H. Uchino, T. T. Y. Kim, V. Z. Chong, K. Shah, I. G. Fantus, et al. Effects of portal free fatty acid elevation on insulin clearance and hepatic glucose flux Am J Physiol Endocrinol Metab, June 1, 2006; 290(6): E1089 - E1097. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Beha, H.-P. Juretschke, J. Kuhlmann, C. Neumann-Haefelin, U. Belz, M. Gerl, W. Kramer, M. Roden, and A. W. Herling Muscle type-specific fatty acid metabolism in insulin resistance: an integrated in vivo study in Zucker diabetic fatty rats Am J Physiol Endocrinol Metab, May 1, 2006; 290(5): E989 - E997. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Desvergne, L. Michalik, and W. Wahli Transcriptional Regulation of Metabolism Physiol Rev, April 1, 2006; 86(2): 465 - 514. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Dimitriadis, P. Mitrou, V. Lambadiari, E. Boutati, E. Maratou, E. Koukkou, M. Tzanela, N. Thalassinos, and S. A. Raptis Glucose and Lipid Fluxes in the Adipose Tissue after Meal Ingestion in Hyperthyroidism J. Clin. Endocrinol. Metab., March 1, 2006; 91(3): 1112 - 1118. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Wang, L. A. Reaves, and N. K. Edens Ginseng Extract Inhibits Lipolysis in Rat Adipocytes In Vitro by Activating Phosphodiesterase 4 J. Nutr., February 1, 2006; 136(2): 337 - 342. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Pulinilkunnil and B. Rodrigues Cardiac lipoprotein lipase: Metabolic basis for diabetic heart disease Cardiovasc Res, February 1, 2006; 69(2): 329 - 340. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. S. Kahn The Lipid Accumulation Product Is Better Than BMI for Identifying Diabetes: A population-based comparison Diabetes Care, January 1, 2006; 29(1): 151 - 153. [Full Text] [PDF]
|
|
|
|
|
|
L. D. Monti, E. Setola, G. Fragasso, R. P. Camisasca, P. Lucotti, E. Galluccio, A. Origgi, A. Margonato, and P. Piatti Metabolic and endothelial effects of trimetazidine on forearm skeletal muscle in patients with type 2 diabetes and ischemic cardiomyopathy Am J Physiol Endocrinol Metab, January 1, 2006; 290(1): E54 - E59. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Hamaguchi, T. Kojima, N. Takeda, T. Nakagawa, H. Taniguchi, K. Fujii, T. Omatsu, T. Nakajima, H. Sarui, M. Shimazaki, et al. The Metabolic Syndrome as a Predictor of Nonalcoholic Fatty Liver Disease Ann Intern Med, November 15, 2005; 143(10): 722 - 728. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Larbi, A. Grenier, F. Frisch, N. Douziech, C. Fortin, A. C Carpentier, and T. Fulop Acute in vivo elevation of intravascular triacylglycerol lipolysis impairs peripheral T cell activation in humans Am. J. Clinical Nutrition, November 1, 2005; 82(5): 949 - 956. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Ghafoorunissa, A. Ibrahim, L. Rajkumar, and V. Acharya Dietary (n-3) Long Chain Polyunsaturated Fatty Acids Prevent Sucrose-Induced Insulin Resistance in Rats J. Nutr., November 1, 2005; 135(11): 2634 - 2638. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. C. Carpentier, F. Frisch, D. Cyr, P. Genereux, B. W. Patterson, R. Giguere, and J.-P. Baillargeon On the suppression of plasma nonesterified fatty acids by insulin during enhanced intravascular lipolysis in humans Am J Physiol Endocrinol Metab, November 1, 2005; 289(5): E849 - E856. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Teutonico, P. F. Schena, and S. Di Paolo Glucose Metabolism in Renal Transplant Recipients: Effect of Calcineurin Inhibitor Withdrawal and Conversion to Sirolimus J. Am. Soc. Nephrol., October 1, 2005; 16(10): 3128 - 3135. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. R. Van Gilst, H. Hadjivassiliou, and K. R. Yamamoto From The Cover: A Caenorhabditis elegans nutrient response system partially dependent on nuclear receptor NHR-49 PNAS, September 20, 2005; 102(38): 13496 - 13501. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Adiels, J. Boren, M. J. Caslake, P. Stewart, A. Soro, J. Westerbacka, B. Wennberg, S.-O. Olofsson, C. Packard, and M.-R. Taskinen Overproduction of VLDL1 Driven by Hyperglycemia Is a Dominant Feature of Diabetic Dyslipidemia Arterioscler Thromb Vasc Biol, August 1, 2005; 25(8): 1697 - 1703. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. B Ruige, D. P Ballaux, T. Funahashi, I. L Mertens, Y. Matsuzawa, and L. F Van Gaal Resting metabolic rate is an important predictor of serum adiponectin concentrations: potential implications for obesity-related disorders Am. J. Clinical Nutrition, July 1, 2005; 82(1): 21 - 25. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Saravanan, A. Haseeb, N. Z Ehtesham, and Ghafoorunissa Differential effects of dietary saturated and trans-fatty acids on expression of genes associated with insulin sensitivity in rat adipose tissue Eur. J. Endocrinol., July 1, 2005; 153(1): 159 - 165. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. H. Harris Elevated Liver Function Tests in Type 2 Diabetes Clin. Diabetes, July 1, 2005; 23(3): 115 - 119. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Charbonneau, A. Melancon, C. Lavoie, and J.-M. Lavoie Alterations in hepatic glucagon receptor density and in Gs{alpha} and Gi{alpha}2 protein content with diet-induced hepatic steatosis: effects of acute exercise Am J Physiol Endocrinol Metab, July 1, 2005; 289(1): E8 - E14. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B.-S. Cha, T. P. Ciaraldi, K.-S. Park, L. Carter, S. R. Mudaliar, and R. R. Henry Impaired fatty acid metabolism in type 2 diabetic skeletal muscle cells is reversed by PPAR{gamma} agonists Am J Physiol Endocrinol Metab, July 1, 2005; 289(1): E151 - E159. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. F. Lewis and D. J. Rader New Insights Into the Regulation of HDL Metabolism and Reverse Cholesterol Transport Circ. Res., June 24, 2005; 96(12): 1221 - 1232. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Lemieux, Y. Gelinas, J. Lalonde, F. Labrie, K. Cianflone, and Y. Deshaies Hypolipidemic action of the SERM acolbifene is associated with decreased liver MTP and increased SR-BI and LDL receptors J. Lipid Res., June 1, 2005; 46(6): 1285 - 1294. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Tamura, Y. Tanaka, F. Sato, J. B. Choi, H. Watada, M. Niwa, J. Kinoshita, A. Ooka, N. Kumashiro, Y. Igarashi, et al. Effects of Diet and Exercise on Muscle and Liver Intracellular Lipid Contents and Insulin Sensitivity in Type 2 Diabetic Patients J. Clin. Endocrinol. Metab., June 1, 2005; 90(6): 3191 - 3196. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Katoh, M. Lehtovirta, J. Kaprio, V. Harjutsalo, M. Koskenvuo, J. Eriksson, N. Tajima, and J. Tuomilehto Genetic and Environmental Effects on Fasting and Postchallenge Plasma Glucose and Serum Insulin Values in Finnish Twins J. Clin. Endocrinol. Metab., May 1, 2005; 90(5): 2642 - 2647. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Carroll, A. N. Carley, J. R. B. Dyck, and D. L. Severson Metabolic effects of insulin on cardiomyocytes from control and diabetic db/db mouse hearts Am J Physiol Endocrinol Metab, May 1, 2005; 288(5): E900 - E906. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. C. W. Lau, B. Dhillon, H. Yan, P. E. Szmitko, and S. Verma Adipokines: molecular links between obesity and atheroslcerosis Am J Physiol Heart Circ Physiol, May 1, 2005; 288(5): H2031 - H2041. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. H. Suh, Y. Kim, J. H. Bang, K. S. Choi, J. W. Lee, W.-H. Kim, T. J. Oh, S. An, and M. H. Jung Analysis of gene expression profiles in insulin-sensitive tissues from pre-diabetic and diabetic Zucker diabetic fatty rats J. Mol. Endocrinol., April 1, 2005; 34(2): 299 - 315. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. A. Adams, P. Angulo, and K. D. Lindor Nonalcoholic fatty liver disease Can. Med. Assoc. J., March 29, 2005; 172(7): 899 - 905. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. C. Heijboer, E. Donga, P. J. Voshol, Z.-C. Dang, L. M. Havekes, J. A. Romijn, and E. P. M. Corssmit Sixteen hours of fasting differentially affects hepatic and muscle insulin sensitivity in mice J. Lipid Res., March 1, 2005; 46(3): 582 - 588. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Giannopoulou, L. L. Ploutz-Snyder, R. Carhart, R. S. Weinstock, B. Fernhall, S. Goulopoulou, and J. A. Kanaley Exercise Is Required for Visceral Fat Loss in Postmenopausal Women with Type 2 Diabetes J. Clin. Endocrinol. Metab., March 1, 2005; 90(3): 1511 - 1518. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
|
Top
Abstract
I. Introduction
