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

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

In 1997, an International Expert Committee was convened to reexamine the classification and diagnostic criteria of diabetes, which were based on the 1979 publication of the National Diabetes Data Group (1) and subsequent WHO study group (2). As a result of its deliberations, the Committee recommended several changes to the diagnostic criteria for diabetes and for lesser degrees of impaired glucose regulation (IFG/IGT) (3). The following were the major changes or issues addressed. 1) The use of a fasting plasma glucose (FPG) test for the diagnosis of diabetes was recommended, and the cut point separating diabetes from nondiabetes was lowered from FPG 140 mg/dl (7.8 mmol/l) to 126 mg/dl (7.0 mmol/l). (All glycemic values represent venous plasma.) This change was based on data that showed an increase in prevalence and incidence of diabetic retinopathy beginning at approximately a FPG of 126 mg/dl, as well as on the desire to reduce the discrepancy that existed in the number of cases detected by the FPG cut point of 140 mg/dl and the 2-h value in the OGTT (2-h plasma glucose [2-h PG]) of 200 mg/dl (11.1 mmol/l). 2) Normal FPG was defined as 110 mg/dl (6.1 mmol/l). 3) The use of HbA1c (A1C) as a diagnostic test for diabetes was not recommended. The primary reason for this decision was a lack of standardized methodology resulting in varying nondiabetic reference ranges among laboratories. 4) Although the OGTT (which consists of an FPG and 2-h PG value) was recognized as a valid way to diagnose diabetes, the use of the test for diagnostic purposes in clinical practice was discouraged for several reasons (e.g., inconvenience, less reproducibility, greater cost). The diagnostic category of impaired glucose tolerance (IGT) was retained to describe people whose FPG was 126 mg/dl but whose 2-h PG after a 75-g oral glucose challenge was 140–199 mg/dl. 5) The range of FPG levels between “normal” and that diagnostic for diabetes was named “impaired fasting glucose” (IFG). IFG identified people whose FPG ranged from 110 mg/dl (6.1 mmol/l) to 125 mg/dl (6.9 mmol/l). This construct was established so that there would be a fasting category analogous to IGT. The WHO consultation (4) also adopted most of the above conclusions. The two significant differences were that, whenever feasible, individuals with IFG should receive an OGTT to exclude the presence of diabetes, and the adoption of different criteria for the diagnosis of gestational diabetes. Since the 1997 Expert Committee report, many new data related to the diagnosis of diabetes have been published. First, many analyses of both old and new epidemiological data have examined the equivalence of the FPG and the 2-h PG to predict diabetes, and questions have been raised about the preference of the FPG test over the 2-h PG to diagnose diabetes (5– 7). Second, the IGT category has now been associated with cardiovascular disease (CVD) risk factors (8–10) and CVD events (10,11), whereas IFG is much less strongly associated with CVD events and CVD mortality (10,11). Third, the National Glycosylated Hemoglobin Standardization Program (NGSP) has now ensured that most laboratories in the U.S. perform the assays using standardized controls and report glycated hemoglobin results in a manner traceable to the assay used in the Diabetes Control and Complications Trial (DCCT) (12). These development s have improved as say performance and now allow caregivers and patients to compare reported results obtained among laboratories. Additional studies have suggested that the A1C may assist in diagnosing diabetes (13–17). Finally, data from major clinical trials that tested whether the progression from IGT to diabetes could be delayed or prevented by a treatment intervention have produced concordant results: intensive lifestyle modification (nutritional and exercise interventions) (18,19), metformin (19,20), and acarbose (20,21) were effective to variable degrees. In addition, a thiazolidinedione drug (troglitazone) reduced the incidence of diabetes in high-risk women with prior gestational diabetes (22). An inherent difficulty in the diagnosis of diabetes is the present lack of an identified unique qualitative biological marker that separates all people with diabetes from all nondiabetic individuals. The closest such characteristic for practical purposes is diabetic retinopathy, but this suffers from the obvious defect that in most diabetic patients, retinopathy usually becomes evident years after the recognized onset of diabetes. The lack of a suitable, unique marker of diabetes has led to reliance on the metabolic abnormality historically associated with the disease, i.e., hyperglycemia (as measured by the FPG or 2-h PG) as the most useful diagnostic test. The selection of diagnostic cut points for these tests rests on two ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

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Follow-up report on the diagnosis of diabetes mellitus.

This statement examines the cardiovascular complications of diabetes mellitus and considers opportunities for their prevention. These complications include coronary heart disease (CHD), stroke, peripheral arterial disease, nephropathy, retinopathy, and possibly neuropathy and cardiomyopathy. Because of the aging of the population and an increasing prevalence of obesity and sedentary life habits in the United States, the prevalence of diabetes is increasing. Thus, diabetes must take its place alongside the other major risk factors as important causes of cardiovascular disease (CVD). In fact, from the point of view of cardiovascular medicine, it may be appropriate to say, “diabetes is a cardiovascular disease.”

The most prevalent form of diabetes mellitus is type 2 diabetes. This disorder typically makes its appearance later in life. The underlying metabolic causes of type 2 diabetes are the combination of impairment in insulin-mediated glucose disposal (insulin resistance) and defective secretion of insulin by pancreatic β-cells. Insulin resistance develops from obesity and physical inactivity, acting on a substrate of genetic susceptibility.1 2 Insulin secretion declines with advancing age,3 4 and this decline may be accelerated by genetic factors.5 6 Insulin resistance typically precedes the onset of type 2 diabetes and is commonly accompanied by other cardiovascular risk factors: dyslipidemia, hypertension, and prothrombotic factors.7 8 The common clustering of these risk factors in a single individual has been called the metabolic syndrome. Many patients with the metabolic syndrome manifest impaired fasting glucose (IFG)9 even when they do not have overt diabetes mellitus.10 The metabolic syndrome commonly precedes the development of type 2 diabetes by many years11 ; of great importance, the risk factors that constitute this syndrome contribute independently to CVD risk.

Recently, new criteria have been accepted for the diagnosis of diabetes.9 The upper threshold of fasting plasma glucose for the …

https://cdr.lib.unc.edu/downloads/m900nw482

Diabetes and cardiovascular disease : A statement for healthcare professionals from the American heart association

It is now clear that PCOS is often associated with profound insulin resistance as well as with defects in insulin secretion. These abnormalities, together with obesity, explain the substantially increased prevalence of glucose intolerance in PCOS. Moreover, since PCOS is an extremely common disorder, PCOS-related insulin resistance is an important cause of NIDDM in women (Table 3). The insulin resistance in at least 50% of PCOS women appears to be related to excessive serine phosphorylation of the insulin receptor. A factor extrinsic to the insulin receptor, presumably a serine/threonine kinase, causes this abnormality and is an example of an important new mechanism for human insulin resistance related to factors controlling insulin receptor signaling. Serine phosphorylation appears to modulate the activity of the key regulatory enzyme of androgen biosynthesis, P450c17. It is thus possible that a single defect produces both the insulin resistance and the hyperandrogenism in some PCOS women (Fig. 19). Recent studies strongly suggest that insulin is acting through its own receptor (rather than the IGF-I receptor) in PCOS to augment not only ovarian and adrenal steroidogenesis but also pituitary LH release. Indeed, the defect in insulin action appears to be selective, affecting glucose metabolism but not cell growth. Since PCOS usually has a menarchal age of onset, this makes it a particularly appropriate disorder in which to examine the ontogeny of defects in carbohydrate metabolism and for ascertaining large three-generation kindreds for positional cloning studies to identify NIDDM genes. Although the presence of lipid abnormalities, dysfibrinolysis, and insulin resistance would be predicted to place PCOS women at high risk for cardiovascular disease, appropriate prospective studies are necessary to directly assess this.

Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis.

The relationships between insulin secretion, insulin action, and fasting plasma glucose concentration (FPG) were examined in 34 southwest American Indians (19 nondiabetics, 15 noninsulin-dependent diabetics) who had a broad range of FPG (88-310 mg/100 ml). Fasting, glucose-stimulated, and meal-stimulated plasma insulin concentrations were negatively correlated with FPG in diabetics but not in nondiabetics. In contrast, fasting and glucose-stimulated plasma C-peptide concentrations did not decrease with increasing FPG in either group and 24-h urinary C-peptide excretion during a diet of mixed composition was positively correlated with FPG for all subjects (r = 0.36, P less than 0.05). Fasting free fatty acid (FFA) was correlated with FPG in nondiabetics (r = 0.49, P less than 0.05) and diabetics (r = 0.77, P less than 0.001). Fasting FFA was also correlated with the isotopically determined endogenous glucose production rate in the diabetics (r = 0.54, P less than 0.05). Endogenous glucose production was strongly correlated with FPG in the diabetics (r = 0.90, P less than 0.0001), but not in the nondiabetics. Indirect calorimetry showed that FPG was also negatively correlated with basal glucose oxidation rates (r = -0.61, P less than 0.001), but positively with lipid oxidation (r = 0.74, P less than 0.001) in the diabetics. Insulin action was measured as total insulin-mediated glucose disposal, glucose oxidation, and storage rates, using the euglycemic clamp with simultaneous indirect calorimetry at plasma insulin concentrations of 135 +/- 5 and 1738 +/- 59 microU/ml. These parameters of insulin action were significantly, negatively correlated with FPG in the nondiabetics at both insulin concentrations, but not in the diabetics although all the diabetics had markedly decreased insulin action. We conclude that decreased insulin action is present in the noninsulin-dependent diabetics in this population and marked hyperglycemia occurs with the addition of decreased peripheral insulin availability. Decreased peripheral insulin availability leads to increased FFA concentrations and lipid oxidation rates (and probably also increased concentrations of gluconeogenic precursors) that together stimulate gluconeogenesis, hepatic glucose production, and progressive hyperglycemia.

/pdf/relationships-between-insulin-secretion-insulin-action-and-9w8l1y2lrc.pdf

Relationships between insulin secretion, insulin action, and fasting plasma glucose concentration in nondiabetic and noninsulin-dependent diabetic subjects.

Previous studies have left unanswered whether human obesity, independent of glucose intolerance, is associated with a "postreceptor" defect in insulin action. We have studied the relationship between the degree of obesity (as estimated by underwater weighing) and the maximal insulin-stimulated glucose disposal rate (M) in vivo in 52 glucose-tolerant Pima Indian males. The relationship was examined independently of differences in age and maximal oxygen uptake (an estimate of "physical fitness"). The maximal insulin-stimulated glucose transport rate (MTR) was also measured in isolated abdominal adipocytes from the same subjects to determine whether differences in M could be explained by differences in glucose transport. The results showed that there was a large variance in M and MTR among these glucose-tolerant subjects. M was better correlated with glucose storage rates than with oxidation rates, as estimated by indirect calorimetry. The most obese subjects had only a 20% lower mean M and 30% lower MTR than the most lean subjects. The lower M in the obese subjects was due to both lower glucose oxidation and storage rates. There was no significant, independent correlation between age or degree of obesity and M or MTR. The maximal oxygen uptake (VO2 max) appeared to independently account for 20% of the variance observed in M. MTR was only weakly correlated with M (r = 0.36, P less than 0.02). We concluded that differences in M in these glucose-tolerant subjects must be explained by factor(s) other than maximal oxygen uptake, age, maximal insulin-stimulated glucose transport in vitro, or degree of adiposity per se.

/pdf/relationship-between-obesity-and-maximal-insulin-stimulated-k0az375o7c.pdf

Relationship between obesity and maximal insulin-stimulated glucose uptake in vivo and in vitro in Pima Indians.

In an effort to determine whether differences in basal and maximum insulin-stimulated glucose transport by isolated adipocytes are a function of donor sex, we measured glucose transport rates in the absence and presence of 8 nM insulin in adipocytes isolated from the abdominal subcutaneous fat tissue of nine male and ten female subjects with varying degrees of obesity and in adipocytes isolated from the abdominal subcutaneous and retroperitoneal fat tissue of (180-220 g) male and female rats. Because maximal insulin-stimulated glucose transport rate per cell of adipocytes isolated from subcutaneous abdominal tissue of male and female subjects was constant in each sex, the data have been normalized on the basis of transport per cell. The results demonstrated that basal and maximal insulin-stimulated glucose transport per cell was 53-75% higher per cell in the females versus males in adipocytes from human subcutaneous abdominal adipose tissue (P less than 0.01). A similar difference in glucose transport rate between males and females (P less than 0.001) was also found in rat abdominal subcutaneous adipose tissue. Adipocytes isolated from rat retroperitoneal adipose tissue had higher transport rates (approximately three-fold) and smaller sex differences (35% higher in females) than found in adipocytes from rat and human subcutaneous tissue. These results indicate that basal and maximum insulin-stimulated glucose transport is higher by adipocytes isolated from females and that this difference is independent of adipose cell size and species.

Sex difference in insulin-stimulated glucose transport in rat and human adipocytes

Relationship between degree of obesity and invivo insulin action in man

Ithasbeenpreviously reported that maximum insulin-stimulated glucose transport anduti- lization werebothdecreased, while basal lipolysis was increased inadipocytes fromobese subjects withnon- insulin-dependent diabetes mellitus (NIDDM). Tode- termine whether these values canbereturned towards those obtained inequally obese subjects withnormal glucose tolerance, these measures ofadipocyte metab- olism werequantified in10NIDDM subjects before andafter control ofhyperglycemia withinsulin. The results demonstrate that maximuminsulin-stimulated glucose transport (P<0.02) andglucose incorporation into triglyceride (P<0.01) andCO2(P<0.05) (at 5.5 mM glucose) increased andbasal lipolysis decreased (P<0.05) after 4wkofinsulin treatment. Incontrast, glucose incorporation into lactate andother glycolytic metabolites (at 5.5mM glucose), andsensitivity ofglu- cosetransport toinsulin, didnotimprove withinsulin therapy. Thelatter occurred despite anincrease in insulin binding (P<0.01). Finally, theimprovement inmaximal insulin-stimulated glucose transport cor- related with thefall infasting hyperglycemia (r=0.77, P<0.01). These findings demonstrate that several of theabnormalities ofcarbohydrate andlipid metabolism recently noted tobepresent inadipocytes frompatients withNIDDMcanbeshowntosignificantly improve withinsulin treatment.

G R Reaven

Papers

Relationships between insulin secretion, insulin action, and fasting plasma glucose concentration in nondiabetic and noninsulin-dependent diabetic subjects.

Relationship between obesity and maximal insulin-stimulated glucose uptake in vivo and in vitro in Pima Indians.

Sex difference in insulin-stimulated glucose transport in rat and human adipocytes

Relationship between degree of obesity and invivo insulin action in man

Measurements of glucose transport and metabolism, insulin binding,and lipolysis in isolated adipocytes