Eleuterio Ferrannini

Insulin Resistance: A Multifaceted Syndrome Responsible for NIDDM, Obesity, Hypertension, Dyslipidemia, and Atherosclerotic Cardiovascular Disease

Diabetes mellitus is commonly associated with systolic/diastolic hypertension, and a wealth of epidemiological data suggest that this association is independent of age and obesity. Much evidence indicates that the link between diabetes and essential hypertension is hyperinsulinemia. Thus, when hypertensive patients, whether obese or of normal body weight, are compared with age- and weight-matched normotensive control subjects, a heightened plasma insulin response to a glucose challenge is consistently found. A state of cellular resistance to insulin action subtends the observed hyperinsulinism. With the insulin/glucose-clamp technique, in combination with tracer glucose infusion and indirect calorimetry, it has been demonstrated that the insulin resistance of essential hypertension is located in peripheral tissues (muscle), is limited to nonoxidative pathways of glucose disposal (glycogen synthesis), and correlates directly with the severity of hypertension. The reasons for the association of insulin resistance and essential hypertension can be sought in at least four general types of mechanisms: Na+ retention, sympathetic nervous system overactivity, disturbed membrane ion transport, and proliferation of vascular smooth muscle cells. Physiological maneuvers, such as calorie restriction (in the overweight patient) and regular physical exercise, can improve tissue sensitivity to insulin; evidence indicates that these maneuvers can also lower blood pressure in both normotensive and hypertensive individuals. Insulin resistance and hyperinsulinemia are also associated with an atherogenic plasma lipid profile. Elevated plasma insulin concentrations enhance very-low-density lipoprotein (VLDL) synthesis, leading to hypertriglyceridemia. Progressive elimination of lipid and apolipoproteins from the VLDL particle leads to an increased formation of intermediate-density and low-density lipoproteins, both of which are atherogenic. Last, insulin, independent of its effects on blood pressure and plasma lipids, is known to be atherogenic. The hormone enhances cholesterol transport into arteriolar smooth muscle cells and increases endogenous lipid synthesis by these cells. Insulin also stimulates the proliferation of arteriolar smooth muscle cells, augments collagen synthesis in the vascular wall, increases the formation of and decreases the regression of lipid plaques, and stimulates the production of various growth factors. In summary, insulin resistance appears to be a syndrome that is associated with a clustering of metabolic disorders, including non-insulin-dependent diabetes mellitus, obesity, hypertension, lipid abnormalities, and atherosclerotic cardiovascular disease.

Insulin Resistance in Essential Hypertension

High blood pressure is prevalent in obesity and in diabetes, both conditions with insulin resistance. To test whether hypertension is associated with insulin resistance independently of obesity and glucose intolerance, we measured insulin sensitivity (using the euglycemic insulin-clamp technique), glucose turnover (using [3H]glucose isotope dilution), and whole-body glucose oxidation (using indirect calorimetry) in 13 young subjects (38 +/- 2 years [+/- SEM]) with untreated essential hypertension (165 +/- 6/112 +/- 3 mm Hg), normal body weight, and normal glucose tolerance. In the postabsorptive state, all measures of glucose metabolism were normal. During steady-state euglycemic hyperinsulinemia (about 60 microU per milliliter), hepatic glucose production and lipolysis were effectively suppressed, and glucose oxidation and potassium disposal were normally stimulated. However, total insulin-induced glucose uptake was markedly impaired (3.80 +/- 0.32 vs. 6.31 +/- 0.42 mg per minute per kilogram of body weight in 11 age- and weight-matched controls, P less than 0.001). Thus, reduced nonoxidative glucose disposal (glycogen synthesis and glycolysis) accounted for virtually all the defect in overall glucose uptake (1.19 +/- 0.24 vs. 3.34 +/- 0.44 mg per minute per kilogram, P less than 0.001). Total glucose uptake was inversely related to systolic or mean blood pressure (r = 0.76 for both, P less than 0.001). These results provide preliminary evidence that essential hypertension is an insulin-resistant state. We conclude that this insulin resistance involves glucose but not lipid or potassium metabolism, is located in peripheral tissues but not the liver, is limited to nonoxidative pathways of intracellular glucose disposal, and is directly correlated with the severity of hypertension.

The metabolic syndrome: time for a critical appraisal. Joint statement from the American Diabetes Association and the European Association for the Study of Diabetes.

BackgroundThe term ‘metabolic syndrome’ refers to a clustering of specific cardiovascular disease (CVD) risk factors whose underlying pathophysiology is thought to be related to insulin resistance.MethodsSince the term is widely used in research and clinical practice, we undertook an extensive review of the literature in relation to the syndrome’s definition, underlying pathogenesis, association with cardiovascular disease and to the goals and impact of treatment.DiscussionWhile there is no question that certain CVD risk factors are prone to cluster, we found that the metabolic syndrome has been imprecisely defined, there is a lack of certainty regarding its pathogenesis, and there is considerable doubt regarding its value as a CVD risk marker. Our analysis indicates that too much critically important information is missing to warrant its designation as a ‘syndrome’.ConclusionUntil much-needed research is completed, clinicians should evaluate and treat all CVD risk factors without regard to whether a patient meets the criteria for diagnosis of the ‘metabolic syndrome’.

Pathogenesis of NIDDM: A Balanced Overview

Non-insulin-dependent diabetes mellitus (NIDDM) results from an imbalance between insulin sensitivity and insulin secretion. Both longitudinal and cross-sectional studies have demonstrated that the earliest detectable abnormality in NIDDM is an impairment in the bodys ability to respond to insulin. Because the pancreas is able to appropriately augment its secretion of insulin to offset the insulin resistance, glucose tolerance remains normal. With time, however, the β-cell fails to maintain its high rate of insulin secretion and the relative insulinopenia (i.e., relative to the degree of insulin resistance) leads to the development of impaired glucose tolerance and eventually overt diabetes mellitus. The cause of pancreatic “exhaustion” remains unknown but may be related to the effect of glucose toxicity in a genetically predisposed β-cell. Information concerning the loss of first-phase insulin secretion, altered pulsatility of insulin release, and enhanced proinsulin-insulin secretory ratio is discussed as it pertains to altered β-cell function in NIDDM. Insulin resistance in NIDDM involves both hepatic and peripheral, muscle, tissues. In the postabsorptive state hepatic glucose output is normal or increased, despite the presence of fasting hyperinsulinemia, whereas the efficiency of tissue glucose uptake is reduced. In response to both endogenously secreted or exogenously administered insulin, hepatic glucose production fails to suppress normally and muscle glucose uptake is diminished. The accelerated rate of hepatic glucose output is due entirely to augmented gluconeogenesis. In muscle many cellular defects in insulin action have been described including impaired insulin-receptor tyrosine kinase activity, diminished glucose transport, and reduced glycogen synthase and pyruvate dehydrogenase. The abnormalities account for disturbances in the two major intracellular pathways of glucose disposal, glycogen synthesis, and glucose oxidation. In the earliest stages of NIDDM, the major defect involves the inability of insulin to promote glucose uptake and storage as glycogen. Other potential mechanisms that have been put forward to explain the insulin resistance, include increased lipid oxidation, altered skeletal muscle capillary density/fiber type/blood flow, impaired insulin transport across the vascular endothelium, increased amylin, calcitonin gene-related peptide levels, and glucose toxicity.

The theoretical bases of indirect calorimetry: A review

Indirect calorimetry is the method by which the type and rate of substrate utilization, and energy metabolism are estimated in vivo starting from gas exchange measurements. This technique provides unique information, is noninvasive, and can be advantageously combined with other experimental methods to investigate numerous aspects of nutrient assimilation, thermogenesis, the energetics of physical exercise, and the pathogenesis of metabolic diseases. Since its use as a research tool in metabolism is growing, the theoretical bases of indirect calorimetry are here reviewed in a detailed and orderly fashion. Special cases, such as the occurrence of net lipid synthesis or gluconeogenesis, are formally considered with derivation of explicit stoichiometric equations. The limitations of indirect calorimetry, both theoretical and technical, are discussed in the context of circumstances of clinical interest in metabolism.

Effect of fatty acids on glucose production and utilization in man.

Since the initial proposal of the glucose fatty acid cycle, considerable controversy has arisen concerning its physiologic significance in vivo. In the present study, we examined the effect of acute, physiologic elevations of FFA concentrations on glucose production and uptake in normal subjects under three controlled experimental conditions. In group A, plasma insulin levels were raised and maintained at approximately 100 microU/ml above base line by an insulin infusion, while holding plasma glucose at the fasting level by a variable glucose infusion. In group B, plasma glucose concentration was raised by 125 mg/100 ml and plasma insulin was clamped at approximately 50 microU/ml by a combined infusion of somatostatin and insulin. In group C, plasma glucose was raised by 200 mg/100 ml above the fasting level, while insulin secretion was inhibited with somatostatin and peripheral glucagon levels were replaced with a glucagon infusion (1 ng/min X kg). Each protocol was repeated in the same subject in combination with a lipid-heparin infusion designed to raise plasma FFA levels by 1.5-2.0 mumol/ml. With euglycemic hyperinsulinemia (study A), lipid infusion caused a significant inhibition of total glucose uptake (6.3 +/- 1.3 vs. 7.4 +/- 0.6 mg/min X kg, P less than 0.02). Endogenous glucose production (estimated by the [3-3H]glucose technique) was completely suppressed both with and without lipid infusion. With hyperglycemic hyperinsulinemia (study B), lipid infusion also induced a marked impairment in glucose utilization (6.2 +/- 1.1 vs. 9.8 +/- 1.9 mg/min X kg, P less than 0.05); endogenous glucose production was again completely inhibited despite the increase in FFA concentrations. Under both conditions (A and B), the percentage inhibition of glucose uptake by FFA was positively correlated with the total rate of glucose uptake (r = 0.69, P less than 0.01). In contrast, when hyperglycemia was associated with relative insulinopenia and hyperglucagonemia (study C), thus simulating a diabetic state, lipid infusion had no effect on glucose uptake (2.9 +/- 0.2 vs. 2.6 +/- 0.2 mg/min X kg) but markedly stimulated endogenous glucose production (1.4 +/- 0.5 vs. 0.5 +/- 0.4 mg/min X kg, P less than 0.005). Under the same conditions as study C, a glycerol infusion producing plasma glycerol levels similar to those achieved with lipid-heparin, enhanced endogenous glucose production (1.5 +/- 0.5 vs. 0.7 +/- 0.6 mg/min X kg, P less than 0.05). We conclude that, in the well-insulinized state raised FFA levels effectively compete with glucose for uptake by peripheral tissues, regardless of the presence of hyperglycemia. When insulin is deficient, on the other hand, elevated rates of lipolysis may contribute to hyperglycemia not by competition for fuel utilization, but through an enhancement of endogenous glucose output.

HYPERINSULINAEMIA : THE KEY FEATURE OF A CARDIOVASCULAR AND METABOLIC SYNDROME

SummaryIn a population-based survey of 2,930 subjects, prevalence rates for obesity, Type 2 (non-insulin-dependent) diabetes mellitus, impaired glucose tolerance, hypertension, hypertriglyceridaemia, and hypercholesterolaemia were 54.3, 9.3, 11.1, 9.8, 10.3 and 9.2%, respectively. The prevalence, however, of each of these conditions in its isolated form (free of the other five) was 29.0% for obesity, 1.3% for Type 2 diabetes, 1.8% for impaired glucose tolerance, 1.5% for hypertension, 1.0% for hypertriglyceridaemia, and 1.7% for hypercholesterolaemia. Two-by-two associations were even rarer. The large differences in prevalence between isolated and mixed forms indicate a major overlap among the six disorders in multiple combinations. In the isolated form, each condition was characterized by hyperinsulinaemia (both fasting and 2 h after oral glucose), suggesting the presence of insulin resistance. In addition, in any isolated condition most of the variables categorising other members of the sextet were still significantly altered in comparison with 1,049 normal subjects. In the whole of the subjects who presented with one or another disorder (1,881 of 2,930 or 64%), marked fasting and post-glucose hyperinsulinaemia was associated with higher body mass index, waist:hip ratio, fasting and post-glucose glycaemia, systolic and diastolic blood pressure, serum triglycerides and total cholesterol levels, and with lower HDL-cholesterol concentrations (all p <0.001). We conclude that (1) insulin sensitivity, glucose tolerance, blood pressure, body fat mass and distribution, and serum lipids are a network of mutually interrelated functions; and (2) an insulin resistance syndrome underlies each and all of the six disorders carrying an increased risk of coronary artery disease.

Glucose and free fatty acid metabolism in non-insulin-dependent diabetes mellitus. Evidence for multiple sites of insulin resistance.

The effect of graded, physiologic hyperinsulinemia (+5, +15, +30, +70, +200 microU/ml) on oxidative and nonoxidative pathways of glucose and FFA metabolism was examined in nine lean non-insulin dependent diabetic patients (NIDDM) and in eight age- and weight-matched control subjects. Glucose and FFA metabolism were assessed using stepwise insulin clamp in combination with indirect calorimetry and infusion of [3H]3-glucose/[14C]palmitate. The basal rate of hepatic glucose production (HGP) was higher in NIDDM than in control subjects, and suppression of HGP by insulin was impaired at all but the highest insulin concentration. Glucose disposal was reduced in the NIDD patients at the three highest plasma insulin concentrations, and this was accounted for by defects in both glucose oxidation and nonoxidative glucose metabolism. In NIDDs, suppression of plasma FFA by insulin was impaired at all five insulin steps. This was associated with impaired suppression by insulin of plasma FFA turnover, FFA oxidation (measured by [14C]palmitate) and nonoxidative FFA disposal (an estimate of reesterification of FFA). FFA oxidation and net lipid oxidation (measured by indirect calorimetry) correlated positively with the rate of HGP in the basal state and during the insulin clamp. In conclusion, our findings demonstrate that insulin resistance is a general characteristic of glucose and FFA metabolism in NIDDM, and involves both oxidative and nonoxidative pathways. The data also demonstrate that FFA/lipid and glucose metabolism are interrelated in NIDDM, and suggest that an increased rate of FFA/lipid oxidation may contribute to the impaired suppression of HGP and diminished stimulation of glucose oxidation by insulin in these patients.

Management of hyperglycaemia in type 2 diabetes mellitus: a consensus algorithm for the initiation and adjustment of therapy

The consensus algorithm for the medical management of type 2 diabetes was published in August 2006 with the expectation that it would be updated, based on the availability of new interventions and new evidence to establish their clinical role. The authors continue to endorse the principles used to develop the algorithm and its major features. We are sensitive to the risks of changing the algorithm cavalierly or too frequently, without compelling new information. An update to the consensus algorithm published in January 2008 specifically addressed safety issues surrounding the thiazolidinediones. In this revision, we focus on the new classes of medications that now have more clinical data and experience.

Regulation of Splanchnic and Peripheral Glucose Uptake by Insulin and Hyperglycemia in Man

We investigated the effects of hyperinsulinemia and hyperglycemia on peripheral glucose uptake, hepatic glucose production, and splanchnic glucose uptake in man. Euglycemic and hyperglycemic clamp studies were carried out in 37 healthy subjects in combination with hepatic vein catheterization and [3H-3]glgcose infusion. In the basal state, hepatic glucose production ([3H-3]glucose) exceeded net splanchnic glucose output (catheter) in every subject (2.3 ± 0.04 versus 1.7 ± 0.07 mg/min · kg, P < 0.001), indicating uptake of glucose by the splanchnic region at a rate of 0.6 ± 0.05 mg/ min · kg. In agreement with this estimate, [3H-3]glucose concentration was consistently lower in hepatic venous than in arterial blood, by 3.0 ± 0.2% (P < 0.001). When plasma insulin levels were raised to 37 ± 2, 53 ± 2, 101 ± 2, 428 ± 37, and 1189 ± 14 μU/ml, with maintenance of euglycemia, total glucose uptake rose to 2.9 ± 0.4, 3.9 ± 1.0, 5.1 ± 0.4, 9.9 ±1.1, and 11.8 ± 1.3 mg/min · kg, respectively. The whole body glucose clearance rose significantly above baseline at each hyperinsulinemic plateau (P < 0.05 or less). Hepatic glucose production fell by 68% (P < 0.01) at the lowest hyperinsulinemic level, by 87% at insulin levels of 53 ± 2 μU/ml, and by over 95% with each higher insulin dose. Splanchnic glucose uptake was not significantly increased over basal values at any insulin concentration. When plasma glucose levels were raised to 137 ± 3 and 224 ± 2 mg/dl peripheral plasma insulin levels rose to 20 ± 4 and 55 ± 5 μU/ml, respectively. Total glucose uptake was enhanced (2.5 ± 0.4 and 5.3 ± 1.0 mg/min · kg, P < 0.05 and P < 0.01, respectively). Suppression of hepatic glucose production was <90% at the lower hyperglycemic level, and virtually complete at the higher one. Splanchnic glucose uptake was not changed by mild hyperglycemia (0.5 ± 0.05 mg/min · kg), but rose significantly (1.3 ± 0.3 mg/ min · kg, P < 0.01) with further hyperglycemia. The latter effect resulted primarily from increased glucose delivery to the splanchnic area, since the splanchnic glucose extraction ratio (4.0 ± 0.3%) was not different from baseline (3.0 ± 0.3%). When hyperglycemia (224 ± 1 mg/dl) was combined with a somatostatin infusion, thereby reducing plasma insulin from 15 ± 3 to 10 ± 1 μU/ml (P < 0.01), both total glucose uptake (2.8 ± 0.03 mg/min · kg) and clearance (1.3 ± 0.01 mg/min · kg) were significantly (P < 0.01) lower than in the hyperglycemic studies in which insulin secretion was not blocked. Hepatic glucose production, however, was effectively suppressed (by 74%, P < 0.001), whereas splanchnic glucose uptake was only slightly increased above baseline. Replacement of insulin (via an exogenous infusion at a rate of 0.3 mU/min · kg) restored total glucose uptake, splanchnic glucose uptake, and suppression of hepatic glucose production to the levels seen with hyperglycemia without somatostatin. When hyperglycemia (216 ± 2 mg/dl) was combined with somatostatin and glucagon replacement (no insulin), hepatic glucose production was still suppressed by 47 ± 1% to 1.18 ± 0.01 mg/kg · min (P < 0.001 versus hyperglycemia + SRIF without glucagon replacement). The results indicate that both hyperglycemia and hypoglucagonemia contribute to the decline in hepatic glucose production following somatostatin infusion. In conclusion, hyperinsulinemia alone stimulates glucose uptake by peripheral but not splanchnic tissues. The dose-response characteristics of stimulation of peripheral glucose uptake and inhibition of hepatic glucose production by insulin are very different, the half-maxima being ∼120 and ∼50 μU/ml, respectively. Hyperglycemia enhances glucose uptake by both peripheral and splanchnic tissues, but this action requires an intact endogenous insulin response. In contrast, hyperglycemia can suppress endogenous glucose production even in the presence of low insulin levels.