The steady-state basal plasma glucose and insulin concentrations are determined by their interaction in a feedback loop. A computer-solved model has been used to predict the homeostatic concentrations which arise from varying degrees beta-cell deficiency and insulin resistance. Comparison of a patient's fasting values with the model's predictions allows a quantitative assessment of the contributions of insulin resistance and deficient beta-cell function to the fasting hyperglycaemia (homeostasis model assessment, HOMA). The accuracy and precision of the estimate have been determined by comparison with independent measures of insulin resistance and beta-cell function using hyperglycaemic and euglycaemic clamps and an intravenous glucose tolerance test. The estimate of insulin resistance obtained by homeostasis model assessment correlated with estimates obtained by use of the euglycaemic clamp (Rs = 0.88, p less than 0.0001), the fasting insulin concentration (Rs = 0.81, p less than 0.0001), and the hyperglycaemic clamp, (Rs = 0.69, p less than 0.01). There was no correlation with any aspect of insulin-receptor binding. The estimate of deficient beta-cell function obtained by homeostasis model assessment correlated with that derived using the hyperglycaemic clamp (Rs = 0.61, p less than 0.01) and with the estimate from the intravenous glucose tolerance test (Rs = 0.64, p less than 0.05). The low precision of the estimates from the model (coefficients of variation: 31% for insulin resistance and 32% for beta-cell deficit) limits its use, but the correlation of the model's estimates with patient data accords with the hypothesis that basal glucose and insulin interactions are largely determined by a simple feed back loop.

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Homeostasis model assessment : insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man

Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33)

Resistance to insulin-stimulated glucose uptake is present in the majority of patients with impaired glucose tolerance (IGT) or non-insulin-dependent diabetes mellitus (NIDDM) and in ∼25% of nonobese individuals with normal oral glucose tolerance. In these conditions, deterioration of glucose tolerance can only be prevented if the β-cell is able to increase its insulin secretory response and maintain a state of chronic hyperinsulinemia. When this goal cannot be achieved, gross decompensation of glucose homeostasis occurs. The relationship between insulin resistance, plasma insulin level, and glucose intolerance is mediated to a significant degree by changes in ambient plasma free-fatty acid (FFA) concentration. Patients with NIDDM are also resistant to insulin suppression of plasma FFA concentration, but plasma FFA concentrations can be reduced by relatively small increments in insulin concentration.Consequently, elevations of circulating plasma FFA concentration can be prevented if large amounts of insulin can be secreted. If hyperinsulinemia cannot be maintained, plasma FFA concentration will not be suppressed normally, and the resulting increase in plasma FFA concentration will lead to increased hepatic glucose production. Because these events take place in individuals who are quite resistant to insulinstimulated glucose uptake, it is apparent that even small increases in hepatic glucose production are likely to lead to significant fasting hyperglycemia under these conditions. Although hyperinsulinemia may prevent frank decompensation of glucose homeostasis in insulin-resistant individuals, this compensatory response of the endocrine pancreas is not without its price. Patients with hypertension, treated or untreated, are insulin resistant, hyperglycemic, and hyperinsulinemic. In addition, a direct relationship between plasma insulin concentration and blood pressure has been noted. Hypertension can also be produced in normal rats when they are fed a fructose-enriched diet, an intervention that also leads to the development of insulin resistance and hyperinsulinemia. The development of hypertension in normal rats by an experimental manipulation known to induce insulin resistance and hyperinsulinemia provides further support for the view that the relationship between the three variables may be a causal one. However, even if insulin resistance and hyperinsulinemia are not involved in the etiology of hypertension, it is likely that the increased risk of coronary artery disease (CAD) in patients with hypertension and the fact that this risk if not reduced with antihypertensive treatment are due to the clustering of risk factors for CAD, in addition to high blood pressure, associated with insulin resistance. These include hyperinsulinemia, IGT, increased plasma triglyceride concentration, and decreased high-density lipoprotein cholesterol concentration, all of which are associated with increased risk for CAD. It is likely that the same risk factors play a significant role in the genesis of CAD in the population as a whole. Based on these considerations the possibility is raised that resistance to insulin-stimulated glucose uptake and hyperinsulinemia are involved in the etiology and clinical course of three major related diseases— NIDDM, hypertension, and CAD.

Role of Insulin Resistance in Human Disease

the growth of knowledge regarding the etiology and pathogenesis of diabetes has led many individuals and groups in the diabetes community to express the need for a revision of the nomenclature, diagnostic criteria, and classification of diabetes. As a consequence, it was deemed essential to develop an appropriate, uniform terminology and a functional, working classification of diabetes that reflects the current knowledge about the disease. (1)

Report of the expert committee on the diagnosis and classification of diabetes mellitus

http://www.klinikaikozpont.u-szeged.hu/pedia/images/pdf/CME_TEL/Full-Text/25.pdf

The Hallmarks of Aging

Sirt1 is an NAD-dependent, class III deacetylase that functions as a cellular energy sensor. In addition to its well-characterized effects in peripheral tissues, emerging evidence suggests that neuronal Sirt1 activity plays a role in the central regulation of energy balance and glucose metabolism. In this study, we generated mice expressing an enzymatically inactive form (N-MUT) or wild-type (WT) SIRT1 (N-OX) in mature neurons. N-OX male and female mice had impaired glucose tolerance, and N-MUT female, but not male, mice had improved glucose tolerance compared with that of WT littermates. Furthermore, glucose tolerance was improved in all mice with caloric restriction (CR) but was greater in the N-OX mice, who had better glucose tolerance than their littermates. At the reproductive level, N-OX females had impaired estrous cycles, with increased cycle length and more time in estrus. LH and progesterone surges were absent on the evening of proestrus in the N-OX mice, suggesting a defect in spontaneous ovulation, which was confirmed by the ovarian histology revealing fewer corpora lutea. Despite this defect, the mice were still fertile when mated to WT mice on the day of proestrus, indicating that the mice could respond to normal pheromonal or environmental cues. When subjected to CR, the N-OX mice went into diestrus arrest earlier than their littermates. Together, these results suggested that the overexpression of SIRT1 rendered the mice more sensitive to the metabolic improvements and suppression of reproductive cycles by CR, which was independent of circadian rhythms.

Neuronal SIRT1 Regulates Metabolic and Reproductive Function and the Response to Caloric Restriction.

The ability of temperature to influence insulin binding, hormone stimulation of glucose transport, and the coupling of these two events was studied in isolated rat adipocytes. Insulin binding was reduced as the temperature rose from 16°C to 37°C. Both total and cell surface binding varied in an inverse linear manner with temperature, and Scatchard analysis suggested that this was caused by an altered affinity with no change in receptor number. The insulin responsiveness of 3-O-methyl-glucose transport increased with temperature from a four-fold stimulation at 16°C to 12-fold at 37°C. Insulin sensitivity was also higher at elevated temperatures with the EC50 at 37°C (0.3 ng/mL) one-third that at 16°C (0.9 ng/mL). The stimulation by a single insulin concentration (0.75 ng/mL) varied linearly with temperature. Since the amount of cell-associated insulin that was internalized (non-acid extractable) also increased in a linear fashion with temperature, it was possible to compare the amount of insulin binding to the cell surface needed to attain a certain effect. At 37°C half-maximal stimulation was seen when each cell bound 1255 insulin molecules. The same level of effect required 2510 molecules per cell at 24°C and 6024 molecules per cell at 16°C. These results reveal several things about the insulin-response sequence in fat cells: (1) both total cell and cell surface binding vary inversely with temperature; (2) both insulin responsiveness and sensitivity increase with temperature; (3) the opposing behaviors of binding and sensitivity result in an increase in the effect of a set amount of insulin bound (the coupling efficiency); and (4) the coupling process between insulin receptors and glucose transport is regulated by temperature and could be subject to control by other physiologic factors.

Effect of temperature on coupling of insulin receptors to stimulation of glucose transport in isolated rat adipocytes

Chapter 40 – Type 2 Diabetes Mellitus: Etiology, Pathogenesis, and Natural History

Fellow AAP members, friends, and guests, it’s been a true pleasure serving the Association for the past 11 years, first as a Council member, then as an Officer, and this year as President. The entire 11 years has been a real honor and privilege, and also a thoroughly enjoyable experience. I’m glad to report that the organization is strong, financially stable, and moving forward, and I think this year’s meeting has been an excellent one, at least to this point. And this of course, brings me to the annual ritual of the Presidential Address.

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2006 Association of American Physicians Presidential Address:The US's changing competitiveness in the biomedical sciences

The present invention provides methods of treating a β-arrestin2 mediated and/or GPR120 mediated response in a subject. The β-arrestin2 mediated and/or GPR120 mediated response can be inflammation, including diabetes, inflammation associated with obesity and obesity. The methods can comprise administering to a subject a therapeutically effective amount of a compound predicted to bind a β-arrestin2 molecule and/or GPR120, wherein the compound selectively activates a β-arrestin2-dependent signaling pathway of GPR120.

Jerrold M. Olefsky

Papers

Neuronal SIRT1 Regulates Metabolic and Reproductive Function and the Response to Caloric Restriction.

Effect of temperature on coupling of insulin receptors to stimulation of glucose transport in isolated rat adipocytes

Chapter 40 – Type 2 Diabetes Mellitus: Etiology, Pathogenesis, and Natural History

2006 Association of American Physicians Presidential Address:The US's changing competitiveness in the biomedical sciences

Methods of treating inflammatory conditions