Production of insulin resistance by hyperinsulinaemia in man

Summary It has been proposed that hyperinsulinaemia may cause or exacerbate insulin resistance. The present studies were undertaken to test this hypothesis in man. Glucose utilization, glucose production, and overall glucose metabolism at submaximally and maximally effective plasma insulin concentrations (80 and 1700 mU/l), and monocyte and adipocyte insulin binding were measured in normal volunteers on two occasions: once after 40 h of hyperinsulinaemia (25–35 mU/l) produced by infusion of insulin and once after infusion of saline (75 mmol/l; plasma insulin 10 mU/l). After 40 h of hyperinsulinaemia, glucose utilization and overall glucose metabolism at submaximally and maximally effective plasma insulin concentrations were both slightly, but significantly, reduced compared with values observed after the infusion of saline (p<0.05), whereas glucose production rates were unaffected. Monocyte and adipocyte binding were also unaffected. These results indicate that hyperinsulinaemia of the magnitude observed in insulin resistant states, such as obesity, can produce insulin resistance in man. Assuming that human insulin sensitive tissues possess spare insulin receptors and that monocyte and adipocyte insulin binding accurately reflect insulin binding in insulin-sensitive tissues, the decreased maximal responses to insulin and the lack of change in insulin binding suggest that this insulin resistance occurred at a post-binding site.     

The assessment of insulin resistance in man.

BACKGROUND: Insulin resistance exists when a normal concentration of insulin produces a less than normal biological response. The ability to measure insulin resistance is important in order to understand the aetiopathology of Type 2 diabetes, to examine the epidemiology and to assess the effects of intervention. METHODS: We assess and compare methods of measurement and have undertaken a literature review from 1966 to 2001. RESULTS: Quantitative estimates of insulin resistance can be obtained using model assessments, clamps or insulin infusion sensitivity tests. There is considerable variation in the complexity and labour intensity of the various methods. The most well-established methods are the euglycaemic clamp, minimal model assessment and homeostatic model assessment (HOMA). No single test is appropriate under all circumstances. CONCLUSIONS: There are a number of well-established tests used to measure insulin resistance: the choice of method depends on the size and type of study to be undertaken. Although the so-called 'gold-standard' test, the euglycaemic clamp, is useful for intensive physiological studies on small numbers of subjects, a simpler tool such as HOMA is more appropriate for large epidemiological studies. It is important to be aware that most techniques measure stimulated insulin resistance whereas HOMA gives an estimate of basal insulin resistance. Caution should be exercised when making comparisons between studies due to variations in infusion protocols, sampling procedures and hormone assays used in different studies.     

Reversal of insulin resistance in type 1 diabetes following initiation of insulin treatment

The biological action and pharmacokinetics of insulin were assessed in nine type 1 (insulin-dependent) diabetic patients before and after 3 months conventional insulin treatment, and in seven age and weight-matched non-diabetic controls, by means of the euglycaemic insulin clamp technique. The mean (+/- S.E.) metabolic clearance rate of insulin, when infused at 1 mU/kg/min, was similar in untreated and treated diabetic patients and in controls (22.7 +/- 2.0, 19.3 +/- 3.8, and 22.9 +/- 3.3 ml/kg/min) but, when infused at 6 mU/kg/min, was greater (p less than 0.01 and less than 0.01) in untreated patients (18.0 +/- 2.5 ml/kg/min) than in treated patients (11.5 +/- 1.4 ml/kg/min) and controls (12.7 +/- 1.3 ml/kg/min). Insulin-mediated glucose disposal was reduced (p less than 0.01 and less than 0.01) at insulin infusion rates 1 and 6 mU/kg/min in untreated patients (18.5 +/- 1.9 and 33.8 +/- 4.5 mumol/kg/min) when compared with controls (35.8 +/- 3.4 and 62.0 +/- 4.7 mumol/kg/min) and was improved (p less than 0.01 and less than 0.01) following insulin treatment (36.1 +/- 4.6 and 64.8 +/- 4.2 mumol/kg/min). Daily insulin requirement fell by 33% following 3 months insulin treatment with improvement in mean HbA1 from 16.3 +/- 0.7 to 8.2 +/- 0.4%, but without significant increase in endogenous insulin secretion. The 'honeymoon phenomenon', which has traditionally been attributed exclusively to resurrection of endogenous insulin release, may also be related to normalization of insulin action following institution of insulin treatment.     

Reversal of insulin resistance postpartum is linked to enhanced skeletal muscle insulin signaling

The restoration of maternal insulin sensitivity postpartum represents an important physiological and metabolic adaptation in a woman's reproductive lifespan. The present study was conducted to examine the potential cellular mechanisms underlying the changes in insulin sensitivity from late pregnancy to postpartum in human skeletal muscle. Nine nonobese women (age, 32 +/- 2 yr; body mass index, 21.2 +/- 0.8 kg/m(2)) with normal glucose tolerance were studied during late pregnancy (30-36 wk) and again approximately 1 yr postpartum using a euglycemic-hyperinsulinemic clamp (5 mm glucose, 40 mU/m(2).min insulin) to determine insulin sensitivity. Biopsies of the vastus lateralis muscle were obtained in the basal state before each clamp. Insulin sensitivity improved by 74% from late pregnancy to 1 yr postpartum (5.5 +/- 0.6 vs. 9.6 +/- 0.9 mg/kg fat-free mass.min; P < 0.005). Skeletal muscle insulin receptor (IR) protein expression increased by 42% postpartum, as measured by ELISA (4.0 +/- 0.6 vs. 5.7 +/- 0.6 ng/g protein; P < 0.05) and by Western blotting of the IR beta-subunit (28.7 +/- 4.7 vs. 42.0 +/- 4.8 arbitrary units; P < 0.003). However, in vitro studies showed that when adjusted for IR concentration, maximal insulin-stimulated (100 nm) IR tyrosine phosphorylation (0.75 +/- 0.06 vs. 0.92 +/- 0.08 U) and IR tyrosine kinase activity (183.8 +/- 27.0 vs. 204.3 +/- 23.7 fmol ATP/ng IR) were unchanged. There was a 69% increase in IR substrate-1 (IRS-1) protein expression (P = 0.05) in muscle postpartum. In addition, the p85alpha regulatory subunit of phosphatidylinositol 3-kinase was markedly reduced by 55% (P < 0.02) postpartum. The change in insulin sensitivity from late pregnancy to postpartum correlated highly with the corresponding change in IRS-1 protein (r = 0.84; P < 0.007). Downstream signaling proteins, including total Akt and p70s6 kinase, and the glucose transporter protein GLUT-4, were similar at both time points. These data suggest that reduced IR tyrosine kinase activity is not a major factor in the IR of pregnancy in lean women with normal glucose tolerance. Rather, the reversal of insulin resistance 1 yr postpartum is accompanied by increased skeletal muscle IRS-1 along with a down-regulation of the p85alpha subunit of phosphatidylinositol 3-kinase. These changes may allow for greater p85/p110 binding to IRS-1 and play a significant physiological role in the underlying metabolic adaptation to normal human pregnancy and restoration of insulin sensitivity postpartum.     

Potentiation of insulin release by glucose in man.

Glucose-induced potentiation of glucose-induced insulin release was quantitatively evaluated in 14 non-obese subjects with normal glucose tolerance but decreased insulin response, and in six non-obese patients with mild, adult-onset diabetes, by measuring the insulin responses to two consecutive glucose infusion tests, administered with 40 or 70 min interval. Enhancement of the second insulin response occurred in both groups. In low insulin responders, the dose-response relationship between blood glucose and plasma insulin was flatter and shifted to the right when compared to the control. Pretreatment with glucose increased strikingly the slope of this relationship, the responses now being within the normal range. The enhancement induced by glucose seems to be of multiplicative type. In mildly diabetic subjects, insulin response to glucose infusion was low and sluggish, only a minor initial response being observed. Pretreatment with glucose modified the profile of the insulin response, a clear-cut initial response of greater magnitude being obtained at least in some of the patients. The sensitivity of the islet to the potentiating action of glucose was higher in low insulin responders than in controls, the minimal glucose concentration needed to induce potentiations of the forthcoming response being much lower. The dose-response curve for the relationship between the blood glucose level of the preinfusion period and the percentual enhancement of the insulin response obtained at the second stimulation was, in low insulin response obtained at the second stimulation was, in low insulin responders, higher than and shifted to the left of the curve of the control subjects. In the group of diabetics, sensitivity for potentiation by glucose seemed not different from the controls.     

Reversal of insulin resistance in adipose tissue of non-insulin-dependent diabetics by treatment with diet and sulphonylurea

The effect of conventional treatment on insulin action in subcutaneous adipose tissue was studied in 6 patients with non-insulin-dependent diabetes mellitus (NIDDM). Insulin receptor binding and the effect of the hormone on glucose oxidation were determined before and after 6-14 months of treatment with diet plus sulphonylurea. Glycaemic control and in vivo insulin sensitivity were significantly improved by the treatment. Before treatment, the adipocyte insulin receptor binding and the sensitivity to insulin stimulation of adipose tissue glucose oxidation were normal and did not change after treatment. In contrast, the maximum insulin-induced glucose oxidation was markedly decreased before treatment, whereas it was totally normalized after treatment. The conclusion is that insulin resistance in adipose tissue of NIDDM subjects is solely due to post-receptor defects in insulin action. This resistance is completely off-set by conventional treatment with diet plus sulphonylurea.     

Mechanisms of insulin resistance in man. Assessment using the insulin dose-response curve in conjunction with insulin-receptor binding

During the past few years it has become increasingly apparent that insulin resistance may be a more frequent cause of carbohydrate intolerance or contributing factor in carbohydrate intolerance than was hitherto appreciated. Abnormal insulin action may result from prereceptor, receptor or postreceptor defects. These may be manifested by an increase in the concentration of insulin necessary for a half-maximal effect (decreased sensitivity) or a decrease in the maximal response to insulin (decreased responsiveness), or both. Alterations in sensitivity and responsiveness to insulin can be distinguished only by evaluating insulin dose-response curves. When used in conjunction with measurements of insulin binding to its receptor, the characteristics of these curves can provide insight into the mechanism or mechanisms responsible for insulin resistance.     

Artificial induction of intravascular lipolysis by lipid-heparin infusion leads to insulin resistance in man

Summary Although extensive evidence indicates that free fatty acids can decrease glucose utilization in vitro, it is still controversial how an increase in lipolysis affects glucose metabolism in man. To test the hypothesis that an increase in lipolysis is related to insulin resistance, we examined the effect of lipid-heparin infusion on glucose metabolism in ten normal subjects by the euglycaemic glucose clamp technique and isotopic determination of glucose turnover. In the control euglycaemic clamp studies with insulin infusion at 0.2 and 1.0 mU·kg^–1·min^–1, endogenous glucose production was suppressed from the basal rate of 2.0±0.3 mg· kg^–1min^–1 to 1.1±0.7 mg·kg^–1·min^–1 and -0.4±0.7mg· kg^–1min^–1 respectively. Glucose utilization increased from the basal rate of 2.0±0.3 mg·kg^–1min^–1 to 2.3±0.5mg· kg^–1min^–1 and 5.9±1.8 mg·kg^–1min^–1 respectively. When the euglycaemic clamp studies were coupled with lipid-heparin infusion at comparable low and high rates of insulin infusion, endogenous glucose production increased (1.8± 0.7 mg·kg^–1·min^–1, p<0.001, and 0.3±0.6 mg·kg^–1· min^–1, p<0.05, respectively), and glucose utilization decreased (2.1±0.3 mg·kg^–1·min^–1, not significant, and 3.2±0.7 mg·kg^–1·min^–1, p<0.001 respectively). These data suggest that the artificial induction of intravascular lipolysis by lipid-heparin infusion leads to a state of insulin resistance in man.     

Reversal of muscle insulin resistance with exercise reduces postprandial hepatic de novo lipogenesis in insulin resistant individuals

Skeletal muscle insulin resistance has been implicated in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and atherogenic dyslipidemia associated with the metabolic syndrome by altering the distribution pattern of postprandial energy storage. We conducted a study to examine this hypothesis by reversing muscle insulin resistance with a single bout of exercise and measuring hepatic de novo lipogenesis and hepatic triglyceride synthesis after a carbohydrate-rich meal. We studied 12 healthy, young, lean, insulin resistant individuals in an interventional, randomized cross-over trial. The response to the ingestion of a carbohydrate-rich meal was studied at rest and after one 45-min bout of exercise on an elliptical trainer. Hepatic de novo lipogenesis was assessed by using (2)H(2)O, and changes in glycogen and fat content in liver and muscle were measured by (13)C and (1)H magnetic resonance spectroscopy, respectively. Exercise resulted in a greater than threefold increase in postprandial net muscle glycogen synthesis (P < 0.001), reflecting improved muscle insulin responsiveness, and a ≈40% reduction (P < 0.05) in net hepatic triglyceride synthesis. These changes in whole body energy storage were accompanied by a ≈30% decrease in hepatic de novo lipogenesis (P < 0.01) and were independent of changes in fasting or postprandial plasma glucose and insulin concentrations. These data demonstrate that skeletal muscle insulin resistance is an early therapeutic target for the treatment and prevention of atherogenic dyslipidemia and NAFLD in young insulin resistant individuals who are prone to develop the metabolic syndrome and type 2 diabetes.     

Stimulation of insulin secretion in man by oral glycerol administration.

The effects of an orally administered glycerol load (1 g/Kg body weight) on blood glucose, plasma FFA, and plasma insulin levels have been determined in eight normal fasting or glucose loaded (1 g/Kg body weight) volunteers. Blood glucose levels were not affected by glycerol loading while glicemia followed the same pattern of a glucose tolerance test in the group treated with glucose plus glycerol. Plasma FFA were significantly lowered only 90 min after glycerol loading while they had markedly and persistently decreased by glycerol plus glucose per os. Finally, though glicemia did not change, insulinemia was markedly increased by glycereol, 90 min after loading; moreover, plasma IRI was significantly higher in the group treated with glycerol plus glucose than in the group treated with glucose alone. These data suggest that the release of insulin may be stimulated by a very small increment of blood glucose, which derives from glycerol.     

Importance of substrate competition in the mechanism of insulin resistance in man

Carbohydrate (CHO) oxidation induced by a glucose or fructose (0.5 g/kg X h) infusion over two hours was compared for 160 minutes by means of continuous indirect calorimetry in seven normal subjects without or with a concomitant infusion of Intralipid, a neutral fat emulsion. The glucose infusion was accompanied by a rise over basal values in both glucose (99 +/- 10 mg/dL) and insulin (36 +/- 7 microU/mL) plasma levels, with a further rise of both curves during the Intralipid infusion (140 +/- 7 mg/dL and 53 +/- 12 microU/mL). By contrast, plasma glucose and insulin rose only minimally during the fructose infusion (3.5 +/- 2.9 mg/dL and 5.3 +/- 1.4 microU/mL, respectively, without Intralipid, and 10.6 +/- 2.1 mg/dL and 9.6 +/- 2.0 microU/mL with Intralipid). During the two-hour sugar infusion, a mean quantity of 68.7 g glucose or fructose was infused. The total CHO oxidation was 15.6 +/- 1.2 g for glucose and 21.6 +/- 2.6 for fructose infusion for the 160 minutes of the test. During the Intralipid infusion, CHO oxidation was inhibited with values of 5.9 +/- 1.3 g for glucose (P less than .005) and 13.8 +/- 1.8 g (P less than .05) for fructose infusion. Lipid oxidation was increased in both cases during the Intralipid infusion. These results show that the lipid-induced inhibition of CHO oxidation observed with glucose infusion also occurs to some extent with fructose, suggesting that insulin might not be primarily involved. They suggest a metabolic origin for insulin resistance during elevated fat metabolism.     

Biochemical basis of fat cell insulin resistance in obese rodents and man

It now appears established that glucose utilization in isolated fat cells prepared from adult $\text{ob}\text{ob}$ mice, as well as spontaneosly obese rats, exhibits a markedly impaired responsiveness to insulin compared to controls. In neither case do decreased insulin receptors or a defective insulin effector system contribute significantly to this impaired response. The principal findings that support this conclusion are that (1) the impaired responsiveness of glucose metabolism in these cells is not overcome by addition of supermaximal concentrations of the hormone and (2) the hexose transport activity in these same fat cells is fully sensitive to activation by insulin under conditions where glucose utilization is not. Thus in both model systems the activity of one or more intracellular enzymes involved in glucose metabolism must be decreased and accounts for the defective response. Recent studies on fat cells from the spontaneously obese rat have identified the pentose shunt and fatty acid synthesis as the key inhibited pathways that lead to their inability to utilize glucose at rates comparable to the activity of insulin-stimulated hexose transport. Further studies will be required to identify the altered metabolic parameters that account for the impaired insulin responsiveness in fat cells from the adult $\text{ob}\text{ob}$ mouse. In addition, it is striking that fat cells from young, 4–7-wk-old $\text{ob}\text{ob}$ mice actually exhibit increased responsiveness to the action of insulin on glucose transport and metabolism when their capacity for fatty acid synthesis is exceedingly high. It seems possible that this amplified responsiveness to insulin in these very young $\text{ob}\text{ob}$ mice may be intimately involved in the etiology of this obese syndrome. Experiments on human fat cells in obesity have been contradictory and indicate that dietary intake and age play major roles in determining the responsiveness of glucose metabolism in these cells to insulin. Too little biochemical information is available on these cells to allow definite conclusions with regard to the cellular locus which contributes most to altered insulin responsiveness. However, the few key studies available suggest that, when observed, impaired insulin responsiveness of fat cells from obese humans also reflects altered metabolic activities rather than insulin receptors or the hormone effector system. That these latter cellular components play a major role in the insulin resistance of muscle or liver remains a possibility that future studies must clarify.     

Insulin mediators in man: effects of glucose ingestion and insulin resistance

Summary Insulin mediators (inositol phosphoglycans) have been shown to mimic insulin action in vitro and in intact mammals, but it is not known which mediator is involved in insulin action under physiological conditions, nor is it known whether insulin resistance alters the mediator profile under such conditions. We therefore investigated the effects of glucose ingestion on changes in the bioactivity of serum inositol phosphoglycan-like substances (IPG) in healthy men and insulin resistant (obese, non-insulin-dependent diabetic) men. Two classes of mediators were partially purified from serum before and after glucose ingestion. The first was eluted from an anion exchange resin with HCl pH 2.0, and bioactivity was determined by activation of pyruvate dehydrogenase in vitro. The second was eluted with HCl pH 1.3, and bioactivity was determined by inhibition of cyclic AMP-dependent protein kinase. In healthy men, the bioactivity of the pH 1.3 IPG was not altered by glucose ingestion, whereas bioactivity of the pH 2.0 IPG increased to approximately 120 % of the pre-glucose ingestion value at 60–240 min post-glucose ingestion (p < 0.05 vs pre-glucose). There was no change in either IPG after glucose ingestion in the insulin-resistant group. These data suggest that the pH 2.0 IPG plays an important role in mediating insulin's effect on peripheral glucose utilization in man under physiological conditions. The data further show, for the first time, a defective change in the bioactivity of an insulin mediator isolated from insulin-resistant humans after hyperinsulinaemia, suggesting that inadequate generation/release of IPGs is associated with insulin resistance. [Diabetologia (1997) 40: 557–563] Received: 4 October 1996 and in revised form: 2 January 1997     

Reversal of anticancer multidrug resistance by the ardeemins

Two “reverse prenyl” hexahydropyrroloindole alkaloids, 5-N-acetylardeemin and 5-N-acetyl-8-demethylardeemin, were evaluated as reversal agents in cells exhibiting a multidrug resistant (MDR) phenotype. These ardeemins (i) reversed drug resistance to vinblastine (VBL) or to taxol as much as 700-fold at relatively noncytotoxic concentrations in vitro; (ii) as a single agent at high concentrations killed MDR cells more efficaciously than the respective parent wild-type cells; and (iii) exhibited strong synergistic effects with doxorubicin (DX) and VBL against the growth of MDR neoplastic cells, and to a lesser extent, of the parent wild-type cells. Mechanistic studies showed that photoaffinity labeling of P-glycoprotein (Pgp) with [³H] azidopine was competitively inhibited by the ardeemins. Resistance to DX in MDR-[Pgp⁺ and MDR-associated protein (MRP)⁺], MDR-Pgp⁺, lung resistance protein (LRP)⁺-expressing, and wild-type lung cancer cells were reversed 110- to 200-fold, 50- to 66-fold, 7- to 15-fold, and 0.9- to 3-fold, respectively, by 20 μM of the ardeemins. Moreover, these compounds increased the intracellular accumulation of VBL and markedly decreased its efflux. Finally, in vivo combination studies demonstrated that nontoxic doses of the ardeemins with DX significantly improved the chemotherapeutic effects in B6D2F₁ mice bearing DX-resistant P388 leukemia, and nude mice bearing human MX-1 mammary carcinoma xenografts. The above features indicate that the ardeemins may have utility in the therapy of cancer.     

Isoimmunization of man by recrystallized human insulin

Summary Ten non-diabetic psychiatric patients, who had not previously been treated with insulin, underwent insulin coma therapy by recrystallized, non-monocomponent human insulin in neutral solution. The treatment was given for 1–3 months, in maximum doses of 96–196 units daily. Several patients formed insulin antibodies. The cause of the antibody formation is discussed. The presence of small quantities of the a-fraction in the insulin is assumed to be of importance in the insulin antibody formation.

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Isoimmunisation des Menschen mit rekristallisiertem menschlichen Insulin

Zusammenfassung Zehn nicht-diabetische psychiatrische Patienten, die vorher nicht mit Insulin behandelt worden waren, wurden einer Insulinkomatherapie mit einem nicht-monokomponentartigen Humaninsulin in neutraler Lösung unterzogen. Die Behandlung wurde 1–3 Monate lang mit Maximaldosen von 96–196 E täglich durchgeführt. Mehrere Patienten erzeugten Insulinantikörper. Die Ursache der Antikörperentstehung wird diskutiert. Die Anwesenheit kleiner Mengen der a-Fraktion des Insulins könnte für die Insulinantikörperbildung von Bedeutung sein.

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Isoimmunisation de l'homme par de l'insuline humaine recristallisée

Résumé Dix patients non-diabétiques, atteints de maladie psychiatrique, n'ayant pas été traités auparavant par l'insuline, ont subi une thérapeutique par coma insulinique avec de l'insuline humaine contenant plusieurs fractions, recristallisée et mise en solution neutre. Le traitement a été administré pendant 1–3 mois, à des doses maximales de 96–196 unités par jour. Plusieurs patients ont élaboré des anticorps anti-insuline. La cause de la formation d'anticorps est discutée. La présence de petites quantités de la fraction-a dans l'insuline semble avoir une importance dans la formation des anticorps anti-insuline.

     

Nutrient-induced insulin resistance.

Impaired function of the hormone insulin (insulin resistance) is a major feature of type 2 diabetes, a condition that is expected to afflict over 200 million people by early next century. Intensive investigation has failed to find a genetic basis for insulin resistance in the majority of cases. In this brief review the evidence that insulin resistance may be caused by excess nutrient supply will be presented. Both excess glucose and excess fat can cause insulin resistance in muscle and fat tissue, while excess fat can cause impaired suppression of endogenous glucose production. Each nutrient may impair insulin action by several mechanisms, at least one of which may be common to both.     

Mechanisms of insulin resistance caused by nutrient toxicity.

Insulin resistance, the impaired action of insulin, has been linked to many important consequences, including Type 2 diabetes, hypertension, dyslipidemia, acanthosis nigricans and polycystic ovarian syndrome. Although there are some genetic causes for insulin resistance, the most common cause is an excess of nutrition a condition called "Nutrient Toxicity". Both excess glucose and excess fat can cause insulin resistance in muscle and fat tissues and excess fat can cause insulin resistance in the liver. High fat feeding and fat infusion rapidly lead to the development of insulin resistance caused by impairment in glucose transport. Other studies have shown defects in insulin signaling possibly secondary to activation of Protein Kinase C resulting from the accumulation of active fatty acyl CoA's. Glucose toxicity has been studied both in vivo and in vitro. In vivo it has been shown that rats over-expressing the gluconeogenic enzyme Phosphoenol Pyruvate Carboxykinase (PEPCK) develop insulin resistance in fat and muscle tissues and some features of the metabolic syndrome including mild obesity and dyslipidemia. Excess glucose entry in fat cells results in increased flux through the hexosamine biosynthesis pathway leading to activation of protein kinase C and impairment of glucose transport. Obesity resulting from excess nutrient intake can also cause insulin resistance by an increase in the production of agents that impair insulin action such as TNFalpha and resistin and a decrease in the production of an insulin sensitizing compound adiponectin. Both glucose and free fatty acids acutely stimulate insulin secretion but chronic exposure to high levels of either nutrient leads to impairment of beta cell function. The combination of insulin resistance and beta cell failure leads to diabetes. Nutrient toxicity is thus the driving cause of the diabetes epidemic that is being recorded around the world.