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.

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.

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 (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. 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.

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 subjects^8,31 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.

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 autophosphorylation^46,47 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. 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.

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 lipolysis^80,81 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.

Conclusion

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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