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Madame Curie Bioscience Database [Internet]. Austin (TX): Landes Bioscience; 2000-.

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Insulin Resistance

and *.

* Corresponding Author: University of California San Diego, San Diego, California, U.S.A. Email: olefsky@popmail.ucsd.edu

Insulin resistance can be said to exist “whenever normal concentrations of hormone produce a less than normal biological response”.1 In the 1930s, Himsworth first differentiated patients with diabetes mellitus into “insulin sensitive” and “insulin insensitive” based on the ability of subcutaneous insulin administration to dispose of an oral glucose load.2 He further suggested that this differentiation corresponded to the clinical presentation of diabetes: that of either young ketosis-prone insulin sensitive or middle aged, nonketotic, insulin insensitive patients. The former is now classified as type 1 diabetes mellitus with the latter “insulin insensitive” classified as type 2 diabetes mellitus. Upon the development of the radioimmunoassay technique in 1960, Yalow and Berson demonstrated that patients with the adult-onset form of diabetes had, on average, higher circulating insulin levels than nondiabetic subjects.3 It was thus concluded that “the tissues of the maturity onset diabetic do not respond to insulin as well as the tissues of the nondiabetic subjects respond to insulin.”

The term “Syndrome X” or “Metabolic syndrome” has been coined to refer to subjects exhibiting features of insulin resistance4 and this has been further defined by the National Cholesterol Education Program (Table 1) and modified by the WHO to add the requirement of hyperinsulinemia (upper quartile of the nondiabetic population) or elevated fasting plasma glucose (110 mg/dl, but <126 mg/dl).5 Besides insulin resistance, associated manifestations of the syndrome include hypertension, dyslipidemia and obesity. Given its increasing prevalence and association with subsequent cardiovascular disease, insulin resistance represents a condition of considerable importance.

Table 1. NCEP definition of metabolic syndrome.

Table 1

NCEP definition of metabolic syndrome.

Methods of Assessing Insulin Sensitivity

In view of the significance of insulin resistance it is important that insulin action be accurately assessed. Several in vivo techniques have emerged over recent years, some of which are discussed below.

Glucose Clamp Technique

The hyperinsulinemic euglycemic clamp is regarded as the “gold standard” method of determining insulin sensitivity.6 In this technique, while a fixed amount of insulin is infused, the blood glucose is “clamped” at a predetermined level by the titration of a variable rate glucose infusion. The underlying principle is that upon reaching steady state, by definition, glucose disposal is equivalent to glucose appearance. During hyperinsulinemia, glucose disposal (Rd) is primarily accounted for by glucose uptake into skeletal muscle, and glucose appearance is equal to the sum of the exogenous glucose infusion rate plus the rate of hepatic glucose output (HGO).

The addition of isotope dilution permits measurement of HGO (Ra), thus allowing determination of insulin action in the liver by the degree of suppression of HGO. Peripheral glucose disposal is also measured (Rd) and this largely represents insulin action in skeletal muscle, since 80-90% of overall in vivo glucose disposal is into skeletal muscle. Typically, labeled glucose is given as a constant infusion in addition to the insulin and variable rate glucose infusions. Regular samples are obtained for the determination of specific activity from which overall rates of glucose appearance (Ra) can be calculated. As the rate of glucose appearance is the sum of HGO and the exogenous glucose infusion rate, HGO can be calculated as the total Ra - exogenous glucose infusion rate.7 Additionally, by performing several studies at different insulin levels in the same subject, the dose-response curve for insulin-stimulated glucose disposal and suppression of hepatic glucose output can be constructed.8

Assessment of insulin action in adipose tissue can be inferred from the rate and extent of the reduction of circulating free fatty acids (FFA) upon commencement of hyperinsulinemia. The circulating FFA concentration represents the balance between FFA release and uptake, both of which are influenced by insulin. Adipocyte FFA release is suppressed by the action of insulin on hormone sensitive lipase and stimulation of lipoprotein lipase by insulin promotes cellular FFA uptake which could increase FFA removal. Reduction of the circulating FFA concentration by insulin is thus an integrated measure of the action of insulin on both processes.

The use of indirect calorimetry, in combination with the glucose clamp technique, allows estimation of carbohydrate and fat oxidation by measuring oxygen consumption and carbon dioxide production.9 It is possible therefore to assess the proportions of glucose undergoing oxidative versus nonoxidative disposal, permitting conclusions to be drawn regarding the route of intracellular glucose metabolism.

Minimal Model - Frequently Sampled Intravenous Glucose Tolerance Test (FSIVGTT)

The glucose clamp technique described above is experimentally complex requiring intravenous lines, the use of radioisotopes and supervision of the subject over several hours. Alternative means have been sought therefore to simplify assessment of insulin sensitivity. The minimal model method provides a measure of insulin sensitivity (SI) using computer modeling to analyze glucose and insulin levels following injection of intravenous glucose.10 Injection of glucose stimulates insulin release causing glucose uptake, with a consequent decline in plasma glucose levels. By modeling the dynamics of the relationship between insulin concentration and the change in glucose concentration, an insulin sensitivity index (SI) can be calculated. In patients with type 2 diabetes who have impaired insulin secretion, the test has been adapted by the addition of an injection of exogenous insulin 20 minutes after the glucose bolus.

The insulin sensitivity index (SI) determined from the minimal model method is equivalent to measures of insulin sensitivity derived from the glucose clamp technique11 and thus it provides an experimental method of assessing insulin action that is relatively easy to perform. Furthermore, SI can be used in outpatient, epidemiological studies and also at multiple time points in the same patient.

Although the minimal model method provides an integrated assessment of overall insulin action in an individual, it is however only an estimate. In comparison, the glucose clamp technique is able to differentiate insulin action in muscle (glucose Rd), liver (suppression of HGO) and fat (suppression of FFA) and furthermore allows insulin dose responses to be characterized.

Nuclear Magnetic Resonance (NMR) Studies

NMR spectroscopy provides a noninvasive means of repeatedly measuring intracellular metabolite concentrations in the same tissues, allowing substrate fluxes through insulin-mediated pathways to be monitored. Recent studies have utilized the technique to assess pathways such as glycogen synthesis and breakdown in both liver and skeletal muscle.12,13 The utility of this technique to contribute to understanding the pathophysiology of insulin resistance will be outlined later.

As will be discussed in detail subsequently, altered fat metabolism is important in the pathophysiology of insulin resistance. Accumulation of triglyceride in insulin responsive tissues, such as skeletal muscle, has been found to strongly correlate with measures of insulin resistance.14 NMR spectroscopy permits the noninvasive measurement of intramyocellular triglyceride content, with the added advantage that intramyocellular triglyceride and triglyceride in adipocytes between the muscle fibers can be distinguished.15,16 This technique therefore allows convenient further investigation into the role of altered muscle triglyceride metabolism in insulin resistance.

Insulin Resistance in Type 2 Diabetes Mellitus and Obesity

Type 2 diabetes mellitus is characterized in almost all cases by insulin resistance. This has been clearly demonstrated by the glucose clamp technique, as shown by the data presented in Figure 1, in which glucose clamps were performed in normal subjects, subjects with impaired glucose tolerance (IGT) and subjects with type 2 diabetes. Despite similar steady-state insulin levels, the glucose disposal rate was decreased by 24% in the subjects with IGT and by 58% in those with type 2 diabetes compared with normals.17

Figure 1. Mean steady-state glucose disposal rates (Panel B) and plasma insulin levels (Panel A) for control subjects, nonobese subjects with impaired glucose tolerance, and type 2 diabetic subjects (T2DM) during euglycemic glucose clamp studies performed at an insulin infusion rate of 40 mU/m2/min.

Figure 1

Mean steady-state glucose disposal rates (Panel B) and plasma insulin levels (Panel A) for control subjects, nonobese subjects with impaired glucose tolerance, and type 2 diabetic subjects (T2DM) during euglycemic glucose clamp studies performed at an (more...)

By plotting mean glucose disposal rates at multiple steady-state plasma insulin levels, insulin dose-response curves can be generated (Fig. 2). The rightward shift of the dose-response curve from normal controls, through subjects with IGT, to those with diabetes is clearly demonstrated indicating increasing insulin resistance. Furthermore, the presence of obesity confers an additional degree of insulin resistance as exemplified by the further rightward shift of the dose-response curve in the obese versus lean diabetic subjects.

Figure 2. Mean insulin dose-response curves for glucose disposal in control subjects (●), subjects with impaired glucose tolerance (◯), and nonobese (▲) and obese (■) type 2 diabetic subjects.

Figure 2

Mean insulin dose-response curves for glucose disposal in control subjects (●), subjects with impaired glucose tolerance ([large circle]), and nonobese (▲) and obese (■) type 2 diabetic subjects. Reprinted with permission from Kolterman (more...)

Obese subjects with normal glucose tolerance are also insulin resistant, as indicated by a rightward shift in the dose-response curve for insulin-stimulated glucose disposal during a glucose clamp.8 Potential mechanisms to explain the deleterious effect of adipose tissue on insulin action will be discussed later.

In insulin resistant states, insulin action is impaired in the liver, skeletal muscle and adipose tissue. Each of these organ abnormalities will be dealt with separately.

Hepatic Glucose Metabolism

In the fasting state, glucose is produced from the liver by both glycogenolysis and gluconeogenesis such that HGO accounts for approximately 90% of the glucose released into the circulation. Conversely, in the postprandial state, HGO is suppressed to help limit the rise in plasma glucose levels and furthermore the liver stores fuel by conversion of glucose carbons to glycogen. These effects are mediated in the fasting state by an increase in gluconeogenic substrate supply, a reduction in insulin concentration and an increase in other hormones such as glucagon with the converse changes occurring postprandially.

The ability of insulin to suppress HGO occurs by both direct and indirect means. Insulin directly reduces HGO by inhibition of gluconeogenic enzymes, such as phosphoenolpyruvate carboxykinase.18 Indirectly, insulin may reduce HGO via its antilipolytic action, as a strong correlation exists between plasma FFA levels and HGO.19 FFAs stimulate gluconeogenesis by increasing ATP and NADH production, generated from their oxidation in the liver.20 The effect of insulin to inhibit HGO has been shown to closely relate to the ability of systemic insulin to suppress plasma FFA levels.21

Increased basal HGO is a characteristic feature of both obese and nonobese patients with type 2 diabetes, who by definition have fasting hyperglycemia. Conversely, subjects with IGT, who by definition have normal fasting glucose levels, have normal basal HGO values.17,22,23 In the basal state, insulin-mediated glucose disposal accounts for only ˜30% of overall glucose disposal, whereas noninsulin-mediated glucose disposal (primarily in the CNS) compromises ˜70%. Therefore impairment in insulin-mediated glucose disposal due to insulin resistance will have little effect on overall basal glucose disposal or fasting glucose levels. As the fasting glucose level reflects the balance between HGO and glucose disposal, it follows that if reduced glucose disposal does not contribute to significant fasting hyperglycemia, then increased glucose entry into the circulation (increased HGO) is the factor most directly responsible for fasting hyperglycemia.

The elevation of HGO in type 2 diabetes is largely due to increased gluconeogenesis.24,25 This is secondary to several factors, including a decrease in the ability of insulin to reduce gluconeogenic precursor flux26 and suppress FFA levels.19 Additional factors such as increased glucagon concentration also play a role.27

In addition to increased basal HGO, patients with type 2 diabetes also have a defect in postprandial hepatic glucose metabolism. In normal individuals, HGO is suppressed postprandially by insulin release and while high physiologic or supraphysiologic insulin levels will completely suppress HGO in type 2 diabetics, there is resistance to suppression of HGO at lower insulin concentrations, resulting in a higher total quantity of glucose entering the circulation.28 This contributes to the postprandial hyperglycemia. Postprandial hyperglycemia is further compounded by impaired hepatic uptake of glucose, which, in itself, is a manifestation of hepatic insulin resistance.29 Despite normal basal HGO, obese subjects demonstrate hepatic insulin resistance as evidenced by reduced suppression of HGO by insulin.8

Skeletal Muscle Glucose Metabolism

As indicated previously, in the basal state, 30% of glucose uptake is insulin mediated, whereas in the post-prandial state, insulin-mediated glucose disposal increases to ˜85%. Limb catheterization studies have shown that 80-90% of this increased insulin-mediated glucose disposal is into skeletal muscle.30 Consequently, in insulin resistant states, an inability to respond to insulin stimulation with an adequate increase in glucose disposal largely contributes to post-prandial hyperglycemia.

While most quantitative assessments of in vivo insulin resistance report impaired insulin action based on steady-state measurements, kinetic defects in insulin action in obesity have also been demonstrated thus the rate of activation of insulin's effect to stimulate glucose disposal is decreased and the rate of deactivation of insulin's effect is increased.31 Given that under physiologic post-prandial conditions insulin is secreted in a phasic rather than steady state manner in response to meal ingestion, it is likely that the kinetic defects in insulin action are of functional importance and that steady-state measurements of insulin action underestimate the functional defect in insulin sensitivity. This has been demonstrated by phasic administration of insulin during a glucose clamp, mimicking the time course and height of the mean insulin levels, as determined during a prior oral glucose tolerance test. Total insulin-stimulated glucose disposal during the “phasic” clamp was reduced by 64% in obese subjects compared to lean controls.32 This is greater than the 20-50% decrease in steady-state insulin-mediated glucose disposal observed in glucose clamp studies in these same subjects8,31 confirming the functional importance of kinetic abnormalities in insulin action.

Defects in muscle glycogen synthesis have been demonstrated in insulin resistant states, with a 50% defect in insulin-stimulated muscle glycogen synthesis in subjects with type 2 diabetes compared to normal subjects.33 As glycogen synthesis is known to account for the majority of nonoxidative glucose metabolism, a defect in glucose incorporation into glycogen is an important manifestation of insulin resistance. The impairment in skeletal muscle glycogen synthesis has been attributed to defects in glucose transport,34 hexokinase II35 and glycogen synthase36 (Fig. 3). To determine the rate-controlling step in the pathway, in vivo skeletal muscle NMR has been utilized to measure intracellular free glucose and glucose-6-phosphate levels during insulin stimulated glucose clamp conditions. If a defect in glycogen synthase activity were the rate-controlling step this would lead to an increase in intracellular glucose-6-phosphate concentration. No increase in glucose-6-phosphate upon insulin stimulation was observed in diabetic subjects compared to normal controls, implying either a defect in glucose transport or hexokinase II activity.34 Furthermore, in offspring of type 2 diabetic subjects, who while insulin resistant, are lean and normoglycemic, a similar defect in insulin-stimulated intramuscular glucose-6-phosphate was shown.37 This implies that reduced glucose transport or hexokinase II activity is an early defect in development of type 2 diabetes and not secondary to factors such as glucotoxicity.

Figure 3. Pathway of glucose uptake, transport and glycogen synthesis.

Figure 3

Pathway of glucose uptake, transport and glycogen synthesis.

Glucose transport is recognized as a vital step in the action of insulin to cause skeletal muscle glucose uptake and is indeed rate-limiting for whole body glucose metabolism.38 To distinguish between a defect in glucose transport and hexokinase II in muscle glycogen synthesis in insulin resistant states, NMR has been utilized to measure intracellular free glucose levels. A defect in hexokinase II would be anticipated, under hyperinsulinemic conditions, to result in increased intracellular free glucose relative to glucose-6-phosphate, whereas a defect in glucose transport would be expected, under similar conditions, to result in proportional changes in free glucose and glucose-6-phosphate. In diabetic subjects, the insulin-stimulated increase in free glucose was attenuated, indicating the primacy of a defect in glucose transport in the reduced glycogen synthesis and impaired insulin-stimulated glucose disposal of type 2 diabetes.39

In insulin resistant states in humans, many cellular defects in insulin action have been described, although as it is unclear whether these are primary or secondary, the principal defects in insulin resistance remain undetermined. This area has been reviewed recently in detail.40

Adipose Tissue and Lipid Metabolism

Adipose tissue exists principally to store energy in the form of triglyceride, which in the post-absorptive state can then provide fuel for the body as FFA and glycerol following lipolysis. Lipolysis is markedly sensitive to suppression by insulin, with half-maximal suppression of FFA levels occurring in normal subjects at an insulin concentration of approximately 20 μU/ml.41 The increase in FFA release, associated with an expanded fat mass results in increased circulating FFA levels, particularly in the post-prandial period, in subjects with obesity and type 2 diabetes.41,42

Randle and coworkers demonstrated many years ago that FFAs compete with glucose for oxidative metabolism in skeletal and cardiac muscle43 and hypothesized that elevated FFA levels could therefore impair peripheral glucose use. It was originally proposed that enhanced cellular FFA uptake and oxidation would result in inhibition of pyruvate dehydrogenase by lipid-derived acetyl-CoA. This in turn would increase glucose-6-phosphate levels, resulting in impairment of phosphorylation of incoming glucose and hence glucose uptake. FFA oversupply can indeed cause impaired insulin-mediated glucose disposal, as shown in glucose clamp studies in which FFA levels were elevated by lipid/heparin infusion.44,45 The decrease in carbohydrate oxidation however occurs rapidly (1-2 h), whereas, the reduction in glucose disposal takes longer to develop (4-5 h), suggesting that the latter effect is not acutely related to changes in FFA oxidation. In addition, the increased intracellular glucose-6-phosphate predicted by Randle has not been observed; indeed skeletal muscle glucose-6-phosphate levels decrease during glucose clamp studies when circulating FFA levels are elevated by lipid/heparin infusion.44 Furthermore, intracellular free glucose levels were also lower in these studies, implying additional effects of the lipid infusion to impair insulin signaling to glucose transport. Thus, some aspect of intracellular lipid metabolism leads to insulin resistance.

Elevated FFAs do not appear to influence skeletal muscle insulin receptor autophosphorylation46,47 but other defects in insulin signaling distal to the receptor have been demonstrated. In rats and man, lipid infusion led to a decrease in both insulin-stimulated tyrosine phosphorylation of IRS-1 and activation of PI3K in skeletal muscle.48

To speculate as to the mechanism by which FFA elevation may impair insulin signaling, it is necessary to review FFA metabolism within the cell. Upon intake into the cell, FFAs are converted to long-chain fatty acyl-CoAs (LCFA-CoA), which are transported into the mitochondria by carnitine palmitoyltransferases (CPT-1) prior to oxidation. Alternatively, if not transported into the mitochondria, LCFA-CoAs may be reesterified via diacylglyercol (DAG) to form triglycerides and phospholipids. Palmitoyl-CoA may also be converted into ceramide. Elevated circulating FFA levels lead to increased uptake of FFA into the cell, whereupon intracellular levels of LCFA-CoAs, intermediates such as DAG and ceramide, and triglyceride are increased (Fig. 4).49,50

Figure 4. Pathways of fatty acid disposal in skeletal muscle cells.

Figure 4

Pathways of fatty acid disposal in skeletal muscle cells. ACC acetyl CoA carboxylase, AMPK adenosine monophosphate activated protein kinase, CPT-1 carnitine palmitoyltransferase-1, DAG diacylglycerol, GPAT glycerol-3-phosphate transferase, MCD malonyl (more...)

Intramyocellular triglyceride content, measured either by muscle biopsy or NMR spectroscopy, is increased in obesity and type 2 diabetes51 and is a strong predictor of insulin resistance in both animals and humans.52,53 It is likely that increased intramyocellular triglyceride content may not in itself impair insulin signaling, but act as a marker of increased intracellular LCFA-CoAs and lipid intermediates. A strongly negative correlation has been demonstrated between whole body insulin sensitivity, as determined by the glucose clamp, and the content of LCFA-CoAs measured in muscle biopsy samples.54

There are several mechanisms by which fatty-acid intermediates can induce insulin resistance. Both LCFA-CoAs and DAG can activate protein kinase C (PKC), especially novel PKC isozymes such as PKC θ.48 IRS-1 can be serine phosphorylated by PKC θ, impairing its ability to associate with the insulin receptor,55 and interfering with PI3K activation and insulin signaling. Further evidence implicating PKC θ in the development of fat-induced skeletal muscle insulin resistance comes from studies of PKC θ knockout mice which are protected from fat infusion induced insulin resistance.56 Additionally, other intracellular fatty acid intermediates such as ceramide may impair insulin signaling. Thus direct inhibition of Akt with decreased insulin-stimulated glucose transport has been reported in 3T3-L1 adipocytes exposed to ceramide analogues.57

Lipid oversupply also activates the inflammatory cascade (Fig. 5). PKC θ is an upstream activator of IKKβ, a serine threonine kinase that activates the NFκB system. IKKβ phosphorylates the natural NFκB inhibitor IκB, which upon phosphorylation dissociates from NFκB, allowing NFκB to translocate to the nucleus where it functions as a transcription factor modulating target gene expression, including genes involved in the inflammatory response, such as inducible nitric oxide synthase (iNOS).58-60 Evidence supportive of the involvement of this pathway comes from data showing that lipid-induced insulin resistance can be reversed by inhibition of IKKβ, either by salicylate administration or by IKKβ gene deletion.61,62 Furthermore, mice with targeted disruption of iNOS are protected from high-fat feeding induced insulin resistance further implicating this pathway in the pathogenesis of lipid-induced insulin resistance.63 The mechanism by which iNOS may affect insulin action remains unclear, although iNOS induction in obese wild-type mice resulted in impaired insulin stimulated PI3-kinase and Akt activation in muscle, defects which were prevented in obese iNOS knockout mice.63

Figure 5. Activation of inflammatory cascade and JNK pathway by lipid oversupply.

Figure 5

Activation of inflammatory cascade and JNK pathway by lipid oversupply.

Recent data has also implicated c-Jun amino-terminal kinase (JNK) as a mediator of FFA and inflammatory cytokine induced insulin resistance.64 JNK is activated by both FFA and inflammatory cytokines65 and influences gene transcription by transcription factors such as c-jun and ATF 2 (activating transcription factor 2). JNK activity is increased in various animal models of obesity (Fig. 5).64 In addition, genetic knockout of JNK1 resulted in reduced adiposity, enhanced insulin action and improved insulin receptor signaling in obese mouse models.64 It is postulated that JNK might impair insulin signaling via serine phosphorylation of IRS-1.66

Impact of Regional Fat Distribution and Adipocyte Size

Intraperitoneal (visceral) adipose tissue may be particularly deleterious. Due to its anatomical location, visceral fat drains directly to the liver via the portal vein, therefore exposing the liver to high concentrations of FFA from this depot. Furthermore, visceral adipocytes appear to be more responsive to catecholamine-stimulated lipolysis and less responsive to suppression of lipolysis by insulin.67,68 It has long been recognized that excess fat in the upper part of the body (central or abdominal) termed “android” obesity is associated with increased risk for type 2 diabetes, dyslipidemia and increased mortality compared to lower body (gluteo-femoral) or “gynoid” obesity.69-71 While the relationship between visceral fat and cardiovascular risk is established, the association of insulin sensitivity with visceral versus subcutaneous truncal adipose tissue remains controversial. Visceral fat area, as determined by CT scan is correlated with decreased insulin action as measured by the glucose clamp.72 On the other hand, using similar techniques, the total volume of subcutaneous truncal adipose tissue is a better predictor of insulin resistance than visceral fat.14 It is possible that subcutaneous truncal adipose tissue contributes more FFA to the systemic circulation than visceral fat and, therefore, may have a more important influence on peripheral insulin action.

Subjects with deficiency of adipose tissue, as in lipodystrophy or lipoatrophy, are also insulin resistant, with excess triglyceride deposition in skeletal muscle and the liver.73 In transgenic animal models with absence of white adipose tissue, insulin resistance is also associated with lipid infiltration of skeletal muscle and the liver,74,75 a phenotype which can be reversed by surgical implantation of adipose tissue.76 These findings suggest that adipose tissue plays a pivotal role in the buffering of fatty acid flux, with insufficient fat tissue leading to “ectopic triglyceride” storage in muscle and the liver resulting in deleterious metabolic effects.77,78 The more common scenario however is of excess adipose tissue in obesity, and in this situation the antilipolytic effects of insulin are impaired. This could result in increased FFA flux into muscle and liver contributing to the increased intramyocellular and hepatic triglyceride content and insulin resistance observed in this condition.79

Another aspect of lipid metabolism that influences insulin action is that of adipocyte size. Larger adipocytes are more resistant to insulin stimulated glucose uptake and to insulin suppression of lipolysis80,81 and larger subcutaneous abdominal adipocytes may predict the development of type 2 diabetes, independent of insulin resistance.82 Smaller fat cells may be more efficient at fatty acid uptake and better able to buffer lipid flux. Indeed, it has been hypothesized that failure of adipogenic precursor cells to differentiate into adipocytes results in glucose intolerance,83 which may be due to inefficient buffering of lipid flux by the remaining large adipocytes.

Cross-Talk between Adipocytes and Other Tissues

Another way in which adipose cells “talk” to other tissues is through an endocrine mechanism. Adipocytokines are peptides secreted by adipose tissue which have diverse effects on food intake, energy expenditure, insulin sensitivity and systemic metabolism. These adipocyte-derived factors include leptin, tumor necrosis factor (TNF)- α, adiponectin and resistin. In this manner adipocytes carry out an endocrine function, and indeed the adipose tissue is the largest endocrine organ in the body.


Leptin, the product of the ob gene, exerts wide-ranging effects, involving not only food intake and energy expenditure, but also aspects of neuro-endocrinology such as menstruation and fertility.84-86 The effect of leptin on energy homeostasis, mediated predominantly via the ventrobasal hypothalamus, is to inhibit food intake and increase thermogenesis. Leptin deficient ob/ob mice are hyperphagic, massively obese, severely insulin resistant and diabetic, with reversal of this phenotype upon replacement of leptin.87 The diabetic phenotype was corrected even in mice receiving low dose leptin, in whom significant weight loss did not occur, suggesting that the effects of leptin on glucose metabolism are not solely due to changes in body mass. Humans with rare mutations resulting in leptin deficiency are similarly hyperphagic and obese, and these symptoms are ameliorated by leptin administration.88 It has also been suggested that leptin has an antilipogenic role, increasing FA oxidation and reducing nonoxidative FA metabolism.89 In the leptin-resistant Zucker diabetic fatty rat (fa/fa), triglyceride accumulation has been demonstrated in pancreatic islets, with consequential lipotoxicity and development of glucose intolerance.89

Furthermore, an insulin-sensitizing effect of leptin administration has been reported both in studies in normal rodents90,91 and in animals rendered insulin resistant by a high-fat diet92,93 although it remains unclear whether this effect is mediated centrally or via a direct effect on insulin target tissues.85,94

In most cases of obesity-related insulin resistance in humans, leptin levels are elevated rather than reduced, suggesting the presence of leptin resistance.95 This may be at a central level, as reduced leptin transport into the CNS has been reported in obesity,96 although evidence of peripheral leptin resistance has also emerged. In isolated human skeletal muscle preparations from lean subjects, the addition of leptin promoted partitioning of FA from storage towards oxidation, a phenomenon not observed in muscle from obese subjects.97 This reduced ability of leptin to stimulate fat oxidation in skeletal muscle in obese subjects may contribute to the development of increased intramyocellular triglyceride content found in this condition. It is unclear whether the mechanism by which leptin influences FA partitioning is solely by a direct effect on some aspect of intracellular FA flux or oxidative capacity or whether indirect effects may also be contributory. Furthermore, the mechanisms by which peripheral resistance to leptin might arise are also unclear, although SOCS-3 (suppressors of the cytokine signaling family) may play a role. SOCS-3 is a member of the SOCS family of cytokine-inducible intracellular proteins that feedback to inhibit cytokine receptors and cytoplasmic signaling adaptor molecules. Forced expression of SOCS-3 has been shown to block leptin receptor mediated signal transduction in mammalian cell lines.98

The presence of leptin resistance has been postulated to limit the utility of leptin as a therapeutic anti-obesity agent. Studies examining administration of leptin to obese humans have largely reported no effect on body weight or metabolic parameters although appetite was reduced.99,100 One study did observe modest but significant weight loss and reduction of body fat, but without any changes in glycemic control or insulin action.101 Concern has however been raised that an effect may have been missed in some studies due to inadequate dosing, an inappropriate dosage schedule or insufficient study power.102

Leptin administration to animal models and humans with lipodystrophy has also been examined. In lipodystrophy there is loss of adipose tissue with subsequent severe defects in insulin action in both liver and skeletal muscle and in addition, leptin levels are low. On leptin administration, insulin action, both in the liver and muscle is improved, in association with reduced hepatic and intramyocellular triglyceride content.103,104

In summary, leptin may influence insulin action directly or indirectly via its effects to modulate appetite and weight. The importance of its role both in the pathophysiology of insulin resistance and as a therapeutic agent remain less clearly defined.

TNF Alpha

In animal models of obesity and insulin resistance and in human subjects with obesity and impaired glucose tolerance, both TNF-α mRNA and protein in adipose tissue and circulating TNF-α levels are increased.105,106 Animals with an aP2 null mutation, who fail to synthesize TNF-α on high fat feeding, develop a similar degree of obesity as fat-fed controls, although without the accompanying hyperinsulinemia and hyperglycemia, suggesting a role for TNF-α in carbohydrate metabolism.107 Furthermore, TNF-α infusion in rats has been reported to reduce peripheral insulin-mediated glucose disposal and insulin suppression of HGO,108 a situation completely prevented by pretreatment with the PPAR γ agonist, troglitazone.109 Furthermore, in vivo neutralization of TNF-α improves insulin action in Zucker fa/fa rats,110 implicating TNF-α as a contributor to insulin resistance.

Several possible mechanisms could explain a negative effect of TNF-α on insulin action. An effect of TNF-α on insulin signaling has been postulated as TNF-α treatment of 3T3-L1 adipocytes increases serine phosphorylation of IRS-1 thus impairing its ability to associate with the insulin receptor and interfering with PI3K activation and insulin signaling.55 This effect however follows chronic (6h to 5 days) TNF-α treatment, whereas rapid (< 1h) effects of TNF-α on adipocyte gene expression have been reported.111,112 This involves suppression of genes known to be involved in insulin action such as adiponectin, PPAR γ and GLUT4 with an increase in inflammatory pathway genes such as NF-κB.

Evidence implicating TNF-α as a factor in the pathogenesis of insulin resistance from knockout mice deficient in TNF-α or one or both of its receptors however has been less consistent and has shown at best only partial protection from obesity-induced insulin resistance.113,114 Further doubt as to the extent of the role played by TNF-α in humans comes from the failure of TNF-α neutralizing antibody to alter insulin sensitivity in obese115 or type 2 diabetic subjects.116


Resistin is a recently discovered adipocytokine that is elevated in animal models of obesity.117,118 Administration of resistin to normal mice leads to modest impairment of glucose tolerance117 and severe hepatic but not peripheral insulin resistance in rats119 suggesting that resistin antagonizes the action of insulin. Furthermore, neutralization of resistin by an anti-resistin antibody enhances insulin-mediated glucose uptake in adipocytes and treatment of ob/ob mice with the insulin-sensitizing PPAR γ agonist, rosiglitazone causes reduction in resistin levels.117 However, other studies in mice have reported different results, arguing against a role for resistin as a modulator of insulin action.120 In humans the role of resistin in determining insulin action has been questioned, as no relationship has been found between adipocyte resistin expression and body weight, insulin sensitivity or other metabolic parameters.121,122 However, substantial sequence differences exist between mouse and human resistin.


Adiponectin, also known as AdipoQ or Acrp30 (in rodents) has received considerable interest in view of its influence on insulin action. It is a protein expressed exclusively in adipose tissue and circulates at relatively high concentrations. It is composed of an N-terminal end, a short hypervariable region, a collagen-like sequence and a C-terminal globular region.123 The globular head group may be proteolytically cleaved from the full-length molecule and as described below also may have biological effects. Furthermore, adiponectin combines to form higher order complexes such as trimers and hexamers, all of which circulate in human serum.124 The regulation and relative bioactivity of the various forms of adiponectin remain unclear.

Circulating levels of adiponectin are reduced in insulin resistant ob/ob mice and in humans with insulin resistant states such as obesity and type 2 diabetes mellitus. Concentrations of adiponectin positively correlate with measures of insulin sensitivity as determined by the glucose clamp, independent of the degree of adiposity.125 In a longitudinal study of obese Rhesus monkeys genetically predisposed to develop insulin resistance and type 2 diabetes, circulating adiponectin levels decreased in parallel with the progression of insulin resistance.126 In mice high fat feeding leads to the development of insulin resistance and is associated with a reduction in circulating adiponectin.127

These findings indicate decreased adiponectin levels in states of insulin resistance suggesting a possible role for adiponectin in maintaining insulin sensitivity. Further support for this concept comes from studies examining the effects of administration of adiponectin. Administration of the full-length molecule to db/db, KKAy (KK mice overexpressing agouti) and high-fat fed wild type mice, in whom pretreatment serum adiponectin levels were low, resulted in amelioration of the insulin resistant phenotype in each case.127 This was associated with a reduction in both triglyceride content in skeletal muscle and liver and in circulating FFA and triglycerides. Additionally, adiponectin resulted in increased expression and activity of Acyl-CoA oxidase in skeletal muscle with consequently enhanced FA oxidation. Adiponectin administration has also been shown to activate 5'-AMP-activated protein kinase (AMPK) in both skeletal muscle and hepatocytes128,129 with subsequent phosphorylation of acetyl CoA carboxylase (ACC) resulting in reduced malonyl CoA in skeletal muscle. Malonyl-CoA inhibits CPT 1, which as indicated previously is necessary for transfer of LCFA-CoA molecules into the mitochondria prior to oxidation. Reduced malonyl-CoA with resultant increased mitochondrial lipid oxidation may possibly thus explain the lowered intramyocellular triglyceride content produced by adiponectin.

Adiponectin has been shown to inhibit TNF-α induced IκB-α phosphorylation and subsequent NF-κB activation in human aortic endothelial cells.130 While this has not yet been examined in insulin responsive tissues, it is possible that a similar effect may ameliorate the deleterious effect of activation of the inflammatory cascade on insulin action.

In mice models with diabetes (ob/ob and NOD) a single intraperitoneal injection of full-length adiponectin, but not the globular head alone, caused an acute reduction of blood glucose level with no corresponding elevation in insulin levels.131 In a subsequent study, the same group using the glucose clamp technique attributed the glucose lowering effect to a reduction in HGO with no effect demonstrated on peripheral glucose disposal.132 Hepatic expression of the gluconeogenic enzymes phosphoenolpyruvate carboxykinase and glucose-6-phosphatase were significantly reduced by adiponectin administration.

The active moiety of adiponectin producing these effects is unclear. Both the globular head and full-length molecule induced muscle effects in one study129 whereas only the globular head was effective in another.128 The full-length molecule only, and not the globular head, produced hepatic effects.129 The reasons for these differences are unclear and furthermore it has become apparent that the circulating full-length protein is composed of both low molecular weight (LMW) trimer-dimer complexes and high molecular weight (HMW) complexes133 although the relative functional importance of these complexes are as yet unknown.

Further attempts to elucidate the role of adiponectin have utilized genetic manipulations of mice. Differing results have, however, been obtained. Mice homozygous for adiponectin KO have been reported as insulin resistant in some studies.134 Others have found a normal phenotype on regular chow, with insulin resistance only on a high fat/high sucrose diet135 while Ma et al reported normal insulin sensitivity even on high fat feeding.136 The reason for these differences is unclear. Support for a role for adiponectin in modulation of insulin action comes from transgenic mice overexpressing globular region adiponectin. On high fat feeding, transgenic mice have increased glucose tolerance and insulin sensitivity compared with wild type controls.137 Additionally, globular head adiponectin transgenic mice crossed with ob/ob mice demonstrate partial amelioration of diabetes, despite having similar body weight as ob/ob controls.

A significant increase in plasma adiponectin levels occurs upon treatment with the insulin-sensitizing thiazolidinediones (TZD) and indeed, in vitro, adiponectin has been shown to be a direct TZD-response gene.138,139 Analysis of the oligomeric forms of adiponectin has shown that the TZD-induced increase is largely accounted for by an increase in the HMW form, reflected by an increase in the SA index, which is defined as the ratio HMW:(HMW+LMW).140 The SA index is reduced in insulin resistant type 2 diabetic subjects compared to insulin sensitive controls and the TZD-induced increase in SA strongly correlates with improvements in hepatic insulin sensitivity.

Differential alteration in the oligomeric forms of adiponectin may explain the recognized phenomenon of a uniform TZD-induced increase in total adiponectin levels in all subjects, including normal controls, in whom no other metabolic effect of TZDs are observed. Total adiponectin levels are also observed to increase in response to TZDs in diabetic patients termed “TZD nonresponders” who have had no insulin-sensitizing or hypoglycemic response to the drug.139

It is unlikely that increased adiponectin is the sole mediator of TZD-induced insulin sensitization, although adiponectin would seem to be a convenient biomarker for TZD administration.

Adiponectin appears to be a significant modulator of insulin action and thus may be promising as a therapeutic tool in the future. Further clarification of its role is awaited.


A role for malonyl-CoA as a modulator of insulin action and hence possible contributor to insulin resistance has been described. Malonyl-CoA is found in insulin-responsive tissues such as liver and skeletal muscle and acts as an inhibitor of CPT-1, the enzyme regulating FA oxidation by controlling LCFA-CoA entry into the mitochondria.

Malonyl-CoA increases with excess carbohydrate supply or muscle inactivity, resulting in inhibition of CPT-1 and hence FA oxidation. Inhibition of oxidation of LCFA-CoAs causes their accumulation in the cytoplasm with the subsequent deleterious effects on insulin action that have been detailed earlier in this chapter. Conversely, starvation and exercise cause a reduction in skeletal muscle malonyl-CoA, with a corresponding increase in FA oxidation.141,142 It is possible therefore that malonyl-CoA acts as a fuel-sensor but also by virtue of its effects on FA oxidation, may modulate insulin action. In rodent models with insulin resistance, skeletal muscle malonyl-CoA is elevated with a corresponding increase in LCFA-CoA concentration.143 Amelioration of insulin resistance with the PPAR γ agonist, pioglitazone, is associated with a reduction in skeletal muscle malonyl-CoA but without any effect on muscle triglyceride levels.144 However, increased malonyl-CoA is not always observed in insulin resistant conditions, as high-fat feeding in rodents, while inducing insulin resistance, has not been associated with a corresponding increase in malonyl-CoA.145 Additionally, data in humans has not shown any difference in skeletal muscle malonyl-CoA levels in type 2 diabetic patients versus controls.146

Malonyl-CoA appears to be regulated, at least in part, by ACC which catalyzes its formation from acetyl-CoA and by malonyl CoA decarboxylase (MCD) which catalyzes its degradation (Fig. 4). Insulin and glucose increase the activity of ACC by decreasing its phosphorylation147 and LCFA-CoAs themselves may allosterically inhibit ACC activity.148 Furthermore, citrate also activates ACC and may directly increase malonyl-CoA concentration given that it is a precursor of acetyl-CoA and hence malonyl-CoA.149 The relative importance of each of these factors in vivo however remains controversial. ACC is also phosphorylated by AMPK, leading to decreased ACC activity and this will be discussed in more detail later in this chapter.

Supporting the effect of insulin and glucose to increase malonyl-CoA, infusion of insulin and glucose in rats stimulates skeletal muscle malonyl-CoA production with a corresponding decrease in FA oxidation.141 In humans during euglycemic-hyperinsulinemia, skeletal muscle FA oxidation is reduced secondary to inhibition of LCFA-CoA entry into the mitochondria.150 This is consistent with an inhibitory effect of malonyl-CoA on CPT-1 and indeed during a high-dose insulin clamp, an increase in malonyl-CoA concentration in skeletal muscle, associated with a reduction in FA oxidation has been reported.151 Low dose insulin infusion however also decreased FA oxidation without any corresponding increase in malonyl-CoA, suggesting that increased malonyl-CoA is at best only partially responsible for the insulin-induced inhibition of FA oxidation. In another study however in which a similar insulin level was achieved, but with hyperglycemia rather than euglycemia and maintenance of circulating FFA levels by an exogenous infusion, reduced functional CPT-1 activity and muscle FA oxidation was reported in association with increased skeletal muscle malonyl-CoA.152 ACC may therefore not only be directly activated by insulin/glucose, but also may be regulated by citrate. Stimulation of carbohydrate metabolism by glucose and insulin administration will increase citrate, which as indicated above activates ACC and also increases substrate supply for the generation of malonyl-CoA.

Citrate also participates in the glucose-fatty acid cycle as in situations of FA excess, phosphofructokinase and thus glycolysis are inhibited.43 Citrate therefore potentially links both the malonyl-CoA fuel-sensing mechanism and the glucose-fatty acid cycle, acting as a general signal to the muscle cell, indicating conditions of excess fuel.149 A surplus of glucose will increase intracellular citrate, which via increased ACC and malonyl-CoA will inhibit FA oxidation and via inhibition of phosphofructokinase further use of glucose in glycolysis. An excess of FFA supply will also increase citrate and hence inhibit glycolysis. Malonyl-CoA also increases to inhibit FA oxidation, but this is limited by the concomitant increase in LCFA-CoA which will inhibit ACC and also compete with malonyl-CoA for binding on CPT-1.153,154 The relevance of this system to the development of insulin resistance remains unclear. As indicated earlier, during human clamp studies in which insulin resistance was induced by fat infusion, a disparity exists in the time course between the reduction in carbohydrate oxidation and the decrease in insulin-mediated glucose disposal, suggesting additional factors are involved. Furthermore, increasing circulating FFA has not been associated with an increase in skeletal muscle citrate levels.155 No difference has been observed between post-absorptive skeletal muscle citrate levels in type 2 diabetic patients and normal controls,146 although during hyperinsulinemia the increase in citrate in the diabetic subjects was much less than in controls. Despite this, both groups had a similar increase in malonyl-CoA, suggesting the possibility of an abnormality in the regulation of malonyl-CoA in diabetes.

AMP-Activated Protein Kinase (AMPK)

AMPK is a regulatory protein kinase that phosphorylates all isozymes of ACC resulting in enzyme inactivation thus increasing FA oxidation.156 AMPK itself is activated by an increase in the intracellular AMP:ATP ratio, and has therefore been proposed as an important link between cellular energy charge and intracellular fuel metabolism.

Muscle contraction increases intramuscular AMP:ATP ratio and activates AMPK.157 This inactivates ACC, thus reducing malonyl-CoA and thereby increasing FA oxidation (Fig. 4). Activation of muscle AMPK with a concomitant decrease in ACC activity and malonyl-CoA content has been reported in rats exercised on a treadmill, with the level of AMPK activation proportional to the intensity of exercise.158 The effect of these changes on fat oxidation has been examined in perfused rat hindlimbs exposed to AICAR (5-aminoimidazole- 4-carboxamide-riboside), an activator of AMPK, which resulted in reduction of malonyl-CoA and increased palmitate oxidation.159 Additionally, glucose uptake was also enhanced by AICAR administration and by contraction rather than the reduction that would have been predicted by the glucose-fatty acid cycle given the increase in intracellular FA oxidation. Furthermore, the glucose uptake was not mediated by PI-3 kinase activation160 and therefore may be the consequence of phosphorylation of target proteins not yet identified. AMPK is important in the contraction-induced utilization of both carbohydrate and FA as fuel. Demonstration of these effects however has been less clear in humans. During exercise, phosphorylation and inactivation of ACC in skeletal muscle has been reported, but a corresponding decrease in malonyl-CoA has not always been found.161,162

In hepatocytes, AMPK has similar effects on ACC, also resulting in increased FA oxidation.163 Furthermore, AMPK also appears to inhibit glycerol-3-phosphate acyltransferase (GPAT), the enzyme which catalyzes the initial step in glycerolipid biosynthesis.164

The overall effect of AMPK activation is stimulation of FA oxidation and glucose uptake in skeletal muscle and stimulation of FA oxidation with inhibition of cholesterol and triglyceride synthesis in the liver. It has been hypothesized that a defect in AMPK signaling could account for many of the abnormalities observed in insulin resistant states.165 Activation of AMPK has been reported to be necessary for the glucose lowering effects of metformin166 and incubation of myoblasts with the TZD rosiglitazone increased AMP:ATP ratio with consequent activation of AMPK.167 Little data yet exists however on the function of AMPK in either insulin resistant animal models or humans.


TZDs are a class of drugs which act as agonists for the peroxisome proliferator-activated receptor γ (PPAR γ) nuclear receptor.168 Administration of TZDs to a wide variety of insulin resistant animal models results in insulin sensitization with lowered plasma glucose levels and concomitant reduction of hyperinsulinemia, indicating improvement in insulin action. This phenomenon occurs regardless of the mechanism of the underlying insulin resistance.109,169-172 Similarly, administration of TZDs to insulin resistant humans with type 2 diabetes causes insulin sensitization with reduction in both fasting and postprandial plasma glucose levels and circulating insulin levels.173 Amelioration of insulin resistance has also been demonstrated in nondiabetic insulin resistant conditions such as obesity, impaired glucose tolerance and women with polycystic ovarian syndrome.174-176 The improvement in insulin action is associated with increased insulin-stimulated glucose disposal, which is usually in the order of 20-40%, thus representing only a partial recovery of insulin resistance, unlike animal studies in which a complete reversal is often seen. An effect of TZDs to improve insulin-mediated suppression of hepatic glucose output has been reported in some173 but not all studies.177 The beneficial effects on glucose homeostasis are often associated with improvements in other aspects of Syndrome X, such as decreased blood pressure, modest increases in HDL cholesterol and reductions in PAI-1 levels.174,178,179

In view of these effects on insulin action, intense interest has arisen in understanding the targets and mechanism of TZD action. TZDs behave as agonists for the PPAR γ receptor, a member of the nuclear receptor superfamily of transcription factors. Ligand binding causes dissociation of a corepressor complex from the receptor and recruitment of a coactivator complex resulting in activation of target genes. The activation of PPAR γ by ligands correlates well with the insulin sensitizing actions of TZDs implicating activation of PPAR-response genes as the means of action of TZDs. The actual genes responsible for the insulin sensitizing effects however remain unclear. One difficulty is distinguishing between primary effects causing insulin sensitization, effects that are secondary to improvements in glucose homeostasis and changes unrelated to glucose lowering action.

Descriptions of the phenotypes resulting from genetic gain or loss of PPAR γ function have added complexity. Mice, homozygous for PPAR γ knockout are nonviable, but heterozygous PPAR γ knockout mice have been studied.180,181 Contrary to expectation, these mice, with 50% reduction in whole body PPAR γ receptors, had marked enhancement of insulin sensitivity during glucose clamp studies compared to wild type controls.181 Similarly, Kubota and colleagues reported protection from high fat feeding induced insulin resistance in mice with heterozygous for PPAR γ knockout.182

Human subjects with PPARγ mutations have been described. Subjects with PPAR γ mutations within the ligand-binding domain, which act in a dominant negative manner, develop lipodystrophy and severe insulin resistance that is apparent even in early childhood.183,184 While such mutations are rare, the Pro12Ala polymorphism is however more commonly found in the population. It also confers loss-of-function, although it has less potent effects on PPARγ receptor action. In the original report of this mutation, subjects carrying the Ala allele rather than being insulin resistant, displayed decreased insulin levels, improved insulin sensitivity and amelioration of other features of Syndrome X.185 However, these subjects also had a lower body mass index which may have confounded the results somewhat. Subsequent studies of the Pro12Ala polymorphism have reported conflicting results in terms of glucose metabolism,186,187 although a meta-analysis of published studies suggested a modest protection from diabetes in those carrying the Ala allele.188

Conversely, the Pro115Glu PPARγ mutation results in a modest increase in receptor activity. It appears to promote obesity and insulin resistance in human subjects, although only a small number of patients have to date been described.189

Gurnell and colleagues have attempted to reconcile the differing phenotypic expressions of PPARγ genotypes by suggesting a sinusoidal relationship between insulin sensitivity and PPARγ activity.190 In this model, marked impairment of PPAR activity, resulting from loss-of-function mutations in the PPARγ receptor ligand binding domain, is associated with severe insulin resistance. Conversely, a modest reduction in PPARγ activity increases insulin sensitivity, as seen in heterozygous PPARγ knockout mice and possibly human subjects with a Pro12Ala polymorphism. A modest increase in receptor activity, such as in the Pro115Glu variant may be associated with a decrease in insulin sensitivity, whereas enhanced activation of PPARγ receptors by TZDs improves insulin sensitivity.

The principle site of TZD action has also been difficult to elucidate. As indicated previously, the majority of insulin stimulated glucose disposal is into skeletal muscle and thus improvement of insulin action in skeletal muscle is necessary for the insulin sensitizing effects of TZDs. PPAR γ is expressed however at much higher levels in adipose tissue than in skeletal muscle,191-192 suggesting that the insulin-sensitizing effect of TZDs on muscle is either via a direct effect of activation of muscle PPAR γ receptors or via the indirect action of PPAR γ activation in adipose tissue, or indeed a combination of both. There are several means by which TZDs may act on adipose tissue and cross-talk to skeletal muscle resulting in improved insulin action. It has been proposed that reduced FFA flux may be an important mechanism in this regard. TZDs may reduce FFA flux by firstly altering body fat distribution causing an accumulation of subcutaneous fat with a concomitant reduction in visceral fat.193 As indicated previously, visceral fat is less responsive to suppression of lipolysis by insulin and more responsive to catecholamine-stimulated lipolysis. TZDs also induce adipocyte differentiation194 resulting in smaller adipocytes in rat models,195 which are likely to be more insulin sensitive, thus decreasing FFA flux.196 Additionally, TZDs alter expression of other adipocytokines including that of leptin,197 TNF- α,198 resistin117 and adiponectin138 all of which may have a secondary effect on skeletal muscle insulin action.

Evidence supportive of a direct role for muscle PPAR γ receptors in skeletal muscle insulin action has come from studies of mice with muscle specific PPAR γ gene deletion. These animals have postprandial hyperglycemia, hyperinsulinemia and are strikingly insulin resistant with no amelioration of this phenotype by TZD treatment.199 This indicates the primacy of muscle PPAR γ receptors in both skeletal muscle insulin action and in the insulin sensitizing effect of TZDs.

Additional effects of TZDs in skeletal muscle include a reduction in intramyocellular triglyceride and LCFA-CoA concentration reported in insulin resistant high fat fed rats,200 although an effect on intramyocellular triglycerides was not observed in humans with type 2 diabetes.201 As indicated above, the TZD pioglitazone reduces skeletal muscle malonyl-CoA and LCFA-CoA in insulin resistant rodent tissue144 and myoblasts cultured with rosiglitazone show increased AMPK activation.167

An effect of TZDs on aspects of the inflammatory cascade has also been described. Treatment of type 2 diabetic subjects with troglitazone increased IκB concentration and decreased NFκB binding activity in mononuclear cell nuclear extracts.202 Furthermore, in vitro liganded PPAR γ inhibits lipopolysaccharide-induced iNOS gene transcription.203

Although much remains to be learned about PPAR γ receptors and TZD action, TZDs have contributed significantly to elucidating the pathophysiology of insulin resistance. Further discoveries in the mechanism of TZD action will undoubtedly advance understanding of the causes and treatment of insulin resistance.


In conclusion, it is well established that insulin resistance is fundamental to the pathogenesis of type 2 diabetes mellitus and thus is an important cause of morbidity in the Western and developed world. Insulin resistance however is not simply a defect in glucose disposal but underlies a much more widespread dysregulation of metabolism that significantly contributes to the development of cardiovascular disease.

An understanding of the pathogenetic mechanisms behind insulin resistance is of great interest as it potentially allows design of appropriate therapeutic interventions. Substantial progress has been achieved in recent years in our understanding of the intracellular signaling pathways mediating insulin's varied biologic effects. A further area of progress is the understanding of “cross-talk” that exists between metabolically active tissues as exemplified by the adipocytokines, which can influence glucose homeostasis by acting on nonadipose tissues. Also of profound importance has been studies of the role played by PPAR γ receptors in insulin signaling and the effect of their agonists, the TZDs. These agents represent a major advance in this field, as they are the first direct pharmacologic means available to treat insulin resistance. While much remains to be learned about their exact mode of action, a more complete understanding of this could permit development of more efficacious treatments for insulin resistance.


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