Ralph A. DeFronzo

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.

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.

International Expert Committee Report on the Role of the A1C Assay in the Diagnosis of Diabetes

Members of the International Expert Committee have recommended that diabetes should be diagnosed if A1C is ≤6.5%, without need to measure the plasma glucose concentration (1). We are concerned that practical limitations will lead to false positives and negatives with this approach. A given A1C instrument may identify some but not other abnormal hemoglobins (http://www.ngsp.org/prog/index2.html). How, therefore, can we be sure whether a hemoglobinopathy is causing (or preventing) diagnosis? Before diagnosis, should we not also exclude iron deficiency anemia, which may increase A1C by 1–1.5%, as well as hemolytic anemia and renal failure or chronic infections, which also lower …

Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: Potential role of PGC1 and NRF1

Type 2 diabetes mellitus (DM) is characterized by insulin resistance and pancreatic β cell dysfunction. In high-risk subjects, the earliest detectable abnormality is insulin resistance in skeletal muscle. Impaired insulin-mediated signaling, gene expression, glycogen synthesis, and accumulation of intramyocellular triglycerides have all been linked with insulin resistance, but no specific defect responsible for insulin resistance and DM has been identified in humans. To identify genes potentially important in the pathogenesis of DM, we analyzed gene expression in skeletal muscle from healthy metabolically characterized nondiabetic (family history negative and positive for DM) and diabetic Mexican–American subjects. We demonstrate that insulin resistance and DM associate with reduced expression of multiple nuclear respiratory factor-1 (NRF-1)-dependent genes encoding key enzymes in oxidative metabolism and mitochondrial function. Although NRF-1 expression is decreased only in diabetic subjects, expression of both PPARγ coactivator 1-α and-β (PGC1-α/PPARGC1 and PGC1-β/PERC), coactivators of NRF-1 and PPARγ-dependent transcription, is decreased in both diabetic subjects and family history-positive nondiabetic subjects. Decreased PGC1 expression may be responsible for decreased expression of NRF-dependent genes, leading to the metabolic disturbances characteristic of insulin resistance and DM.

The Effect of Insulin on the Disposal of Intravenous Glucose: Results from Indirect Calorimetry and Hepatic and Femoral Venous Catheterization

The effect of insulin on the disposal of intravenous glucose was examined employing the euglycemic insulin clamp technique in 24 normal subjects. When the plasma insulin concentration was raised by approximately 100 μU/ml, total glucose metabolism rose to 6.63 ± 0.38 mg/kg · min. Basal splanchnic (hepatic venous catheter technique) glucose production, 2.00 increased only slightly. These results suggest that the ability of higher doses of insulin to further stimulate glucose metabolism is primarily the result of increased glucose storage by peripheral tissues, most likely muscle. 0.15 ± mg/kg · min, reverted to a small net glucose uptake which averaged 0.33 mg/kg · min over the ensuing 2 h. This represented only 5% of the total glucose metabolized. In contrast, leg (femoral venous catheterization) glucose uptake rose from 1.18 ± 0.14 to 8.40 ± 1.06 mg/kg of leg wt. per min. If all muscles in the body respond similarly to those in the leg, muscle would account for 85% of the total glucose metabolism. To determine the relative contributions of glucose oxidation versus glucose storage by peripheral tissues following hyperinsulinemia, we performed euglycemic insulin clamp studies in combination with indirect calorimetry. Basal glucose oxidation, 1.21 ± 0.10 mg/kg min, rose to 2.28 ± 0.16 (P < 0.01), and this increase above baseline accounted for only 20% of the total glucose metabolized, 5.44 ± 0.38 mg/kg · min. Following insulin, glucose storage increased to 3.18 ± 0.34 mg/kg min and was responsible for 59% of the total glucose metabolized. These results indicate that the primary effect of insulin on muscle tissue is to enhance glucose storage, presumably as glycogen. When a higher degree of hyperinsulinemia (163 ± 19 μl/ml) was created while maintaining euglycemia, total glucose metabolism (7.99 ± 0.58) and glucose storage (5.30 ± 0.80) both increased (P < 0.01) compared with the lower dose insulin clamp study, but glucose oxidation (2.70 ± 0.16 mgμkg min)increased only slightly. These results suggest that the ability of higher doses of insulin to further stimulate glucose metabolism is primarily the result of increased glucose storage by peripheral tissues, most likely muscle.

From the Triumvirate to the Ominous Octet: A New Paradigm for the Treatment of Type 2 Diabetes Mellitus

Insulin resistance in muscle and liver and β-cell failure represent the core pathophysiologic defects in type 2 diabetes. It now is recognized that the β-cell failure occurs much earlier and is more severe than previously thought. Subjects in the upper tertile of impaired glucose tolerance (IGT) are maximally/near-maximally insulin resistant and have lost over 80% of their β-cell function. In addition to the muscle, liver, and β-cell (triumvirate), the fat cell (accelerated lipolysis), gastrointestinal tract (incretin deficiency/resistance), α-cell (hyperglucagonemia), kidney (increased glucose reabsorption), and brain (insulin resistance) all play important roles in the development of glucose intolerance in type 2 diabetic individuals. Collectively, these eight players comprise the ominous octet and dictate that: 1 ) multiple drugs used in combination will be required to correct the multiple pathophysiological defects, 2 ) treatment should be based upon reversal of known pathogenic abnormalities and not simply on reducing the A1C, and 3 ) therapy must be started early to prevent/slow the progressive β-cell failure that already is well established in IGT subjects. A treatment paradigm shift is recommended in which combination therapy is initiated with diet/exercise, metformin (which improves insulin sensitivity and has antiatherogenic effects), a thiazolidinedione (TZD) (which improves insulin sensitivity, preserves β-cell function, and exerts antiatherogenic effects), and exenatide (which preserves β-cell function and promotes weight loss). Sulfonylureas are not recommended because, after an initial improvement in glycemic control, they are associated with a progressive rise in A1C and progressive loss of β-cell function. The natural history of type 2 diabetes has been well described in multiple populations (1–16) (rev. in (17,18). Individuals destined to develop type 2 diabetes inherit a set of genes from their parents that make their tissues resistant to insulin (1,16,19–24). In liver, the insulin resistance is manifested by …

Efficacy of Metformin in Patients with Non-Insulin-Dependent Diabetes Mellitus

BACKGROUND Sulfonylurea drugs have been the only oral therapy available for patients with non-insulin-dependent diabetes mellitus (NIDDM) in the United States. Recently, however, metformin has been approved for the treatment of NIDDM. METHODS We performed two large, randomized, parallel-group, double-blind, controlled studies in which metformin or another treatment was given for 29 weeks to moderately obese patients with NIDDM whose diabetes was inadequately controlled by diet (protocol 1: metformin vs. placebo; 289 patients), or diet plus glyburide (protocol 2: metformin and glyburide vs. metformin vs. glyburide; 632 patients). To determine efficacy we measured plasma glucose (while the patients were fasting and after the oral administration of glucose), lactate, lipids, insulin, and glycosylated hemoglobin before, during, and at the end of the study. RESULTS In protocol 1, at the end of the study the 143 patients in the metformin group, as compared with the 146 patients in the placebo group, had lower mean (+/- SE) fasting plasma glucose concentrations (189 +/- 5 vs. 244 +/- 6 mg per deciliter [10.6 +/- 0.3 vs. 13.7 +/- 0.3 mmol per liter], P < 0.001) and glycosylated hemoglobin values (7.1 +/- 0.1 percent vs. 8.6 +/- 0.2 percent, P < 0.001). In protocol 2, the 213 patients given metformin and glyburide, as compared with the 210 patients treated with glyburide alone, had lower mean fasting plasma glucose concentrations (187 +/- 4 vs. 261 +/- 4 mg per deciliter [10.5 +/- 0.2 vs. 14.6 +/- 0.2 mmol per liter], P < 0.001) and glycosylated hemoglobin values (7.1 +/- 0.1 percent vs. 8.7 +/- 0.1 percent, P < 0.001). The effect of metformin alone was similar to that of glyburide alone. Eighteen percent of the patients given metformin and glyburide had symptoms compatible with hypoglycemia, as compared with 3 percent in the glyburide group and 2 percent in the metformin group. In both protocols the patients given metformin had statistically significant decreases in plasma total and low-density lipoprotein cholesterol and triglyceride concentrations, whereas the values in the respective control groups did not change. There were no significant changes in fasting plasma lactate concentrations in any of the groups. CONCLUSIONS Metformin monotherapy and combination therapy with metformin and sulfonylurea are well tolerated and improve glycemic control and lipid concentrations in patients with NIDDM whose diabetes is poorly controlled with diet or sulfonylurea therapy alone.

Pharmacologic Therapy for Type 2 Diabetes Mellitus

In the United States, approximately 15.6 million persons have type 2 diabetes mellitus, and about 13.4 million have impaired glucose tolerance (1). Throughout the world, the prevalence of type 2 diabetes mellitus has increased dramatically in the past two decades (1). Decreased physical activity, increasing obesity, and changes in food consumption have been implicated in this epidemic (2). Patients with diabetes experience significant morbidity and mortality from microvascular (retinopathy, nephropathy, and neuropathy) and macrovascular (heart attacks, stroke, and peripheral vascular disease) complications. Proliferative retinopathy, macular edema, or both occur in 40% to 50% of patients with type 2 diabetes, and diabetes is the leading cause of blindness in the United States (3). The prevalence of renal disease varies considerably among ethnic populations, from 5% to 10% in white persons to 50% in Native Americans (4). Diabetes is the leading cause of end-stage renal failure, accounting for one of every three patients who enter dialysis or transplantation programs (4). Peripheral and autonomic neuropathy occur in 50% to 60% of patients with type 2 diabetes, whereas heart attacks and stroke occur two to four times more frequently in persons with diabetes than in those without the disease (5). The cost of treating diabetes and associated microvascular and macrovascular complications exceeds

Quantitation of muscle glycogen synthesis in normal subjects and subjects with non-insulin-dependent diabetes by 13C nuclear magnetic resonance spectroscopy.

100 billion per year (6). I briefly review the pathogenesis of type 2 diabetes mellitus; provide a rationale for the importance of good glycemic control in this disease; and provide a therapeutic strategy, with a focus on oral agents alone and in combination with each other and with insulin. Indications for insulin are discussed briefly, but the major emphasis is on therapy with oral agents. This review primarily relies on evidence-based medicine. Wherever possible, the results of large, prospective, double-blind, placebo-controlled studies published in peer-reviewed journals have been used. For several of the recently approved oral agents, I used information filed by the drug company with the U.S. Food and Drug Administration (FDA). Where controversy exists, I delineate both points of view and offer commentary that attempts to synthesize and reconcile published results. Statements that are not founded on evidence-based medicine are clearly indicated. Pathogenesis of Type 2 Diabetes Mellitus The appropriate treatment of any disease is based on an understanding of its pathophysiology (7). The mechanisms responsible for impaired glucose homeostasis in type 2 diabetes mellitus (Figure 1) are discussed briefly to provide the foundation for discussion of currently available oral agents, including their mechanism of action, efficacy, and side effects. Figure 1. Pathogenesis of type 2 diabetes mellitus. After ingestion of glucose, maintenance of normal glucose tolerance depends on three events that must occur in a tightly coordinated fashion: 1) stimulation of insulin secretion; 2) insulin-mediated suppression of endogenous [primarily hepatic] glucose production by the resultant hyperinsulinemia; and 3) insulin-mediated stimulation of glucose uptake by peripheral tissues, primarily muscle. Hyperglycemia also has its own independent effect of suppressing hepatic glucose production and enhancing muscle glucose uptake, but these effects are modest compared to those of insulin. In patients with type 2 diabetes and established fasting hyperglycemia, the rate of basal hepatic glucose production is excessive, despite plasma insulin concentrations that are increased twofold to fourfold (8) (Figure 1). These findings provide unequivocal evidence for hepatic resistance to insulin, and this evidence is substantiated by an impaired ability of insulin to suppress hepatic glucose production (9). Accelerated gluconeogenesis is the major abnormality responsible for the increased rate of basal hepatic glucose production (10). The increased rate of basal hepatic glucose production is closely correlated with the increase in fasting plasma glucose level (7-10). Because the fasting plasma glucose level is the major determinant of the mean day-long blood glucose level (which clinically is reflected by the hemoglobin A1c [HbA1c] value), it follows that agents that reduce the elevated basal rate of hepatic glucose production will be especially effective in improving glycemic control (Figure 1). Muscle tissue in patients with type 2 diabetes is resistant to insulin (7, 9, 11) (Figure 1). Defects in insulin receptor function, insulin receptor-signal transduction pathway, glucose transport and phosphorylation, glycogen synthesis, and glucose oxidation contribute to muscle insulin resistance (7). In response to a meal, the ability of endogenously secreted insulin to augment muscle glucose uptake is markedly impaired (12, 13), and muscle insulin resistance and impaired suppression of hepatic glucose production contribute approximately equally to the excessive postprandial increase in the plasma glucose level (13). It follows that drugs that improve muscle insulin sensitivity will be effective in decreasing the excessive increase in plasma glucose level after carbohydrate ingestion (Figure 1). From a quantitative standpoint, however, in diabetic patients with established fasting hyperglycemia (glucose level>7.8 mmol/L [>140 mg/dL]), the excessive increase in the plasma glucose level above baseline after a meal plays a much smaller role in determining the mean day-long plasma glucose concentration than does the elevated fasting plasma glucose level. This is clear from studies that have examined the mean day-long glycemic excursions in diabetic patients who consume typical mixed meals. For example, in a study by Jeppesen and colleagues (14), the fasting glucose level in diabetic patients was (10.6 mmol/L [190 mg/dL]), indicating an increase in basal glucose level of 5.6 mmol/L (100 mg/dL) above that in nondiabetic controls (5 mmol/L [90 mg/dL]). This increase above baseline was present 24 hours per day, giving a hyperglycemic index of 2400 (100 mg/dL 24 hours). After each of three daily meals, the increase in plasma glucose concentration was greater in diabetic patients than in controls by about 1.9 mmol/L (35 mg/dL) but returned to the baseline value by 4 to 6 hours. The hyperglycemic index accounted for by the excessive increase in plasma glucose level during each meal is 525 (35 mg/dL 3 meals 5 hours). Thus, the contribution of postprandial hyperglycemia to day-long hyperglycemia is only 22% (525/2400). Impaired insulin secretion also plays a major role in the pathogenesis of glucose intolerance in patients with type 2 diabetes (15). Although debate still continues about which defectinsulin resistance or impaired insulin secretioninitiates the cascade of events leading to overt diabetes mellitus , essentially all patients who have type 2 diabetes with elevated fasting plasma glucose levels have a defect in insulin secretion (15). In diabetic patients with mild fasting hyperglycemia (glucose level<7.8 mmol/L [<140 mg/dL]), plasma insulin levels during an oral glucose tolerance test or a mixed meal usually are elevated in absolute terms (16). However, relative to the severity of insulin resistance and prevailing hyperglycemia, even these elevated plasma insulin levels are deficient (16, 17). As the fasting plasma glucose level increases to more than 7.8 mmol/L (>140 mg/dL), insulin secretion decreases progressively, and essentially all diabetic patients with a fasting plasma glucose level that exceeds 10.0 to 11.1 mmol/L (180 to 200 mg/dL) have a plasma insulin response that is deficient in absolute terms (16, 17). It follows, therefore, that drugs that improve insulin secretion will be effective in treating type 2 diabetes (Figure 1). In summary, patients with type 2 diabetes mellitus are characterized by defects in both insulin secretion and insulin action. A recent extensive review (7) provides more detailed discussion about the pathogenesis of type 2 diabetes mellitus. Glycemic Control and Complications The Diabetes Control and Complications Trial (DCCT) (18) established that in type 1 diabetes mellitus, the risk for microvascular complications could be reduced by maintaining near-normal blood glucose levels with intensive insulin therapy. No glycemic threshold for the development of long-term microvascular complications was observed in the DCCT (19). As the HbA1c value was reduced to less than 8.0%, the risk for microvascular complications continued to decrease (19). Until recently, no large prospective long-term study had demonstrated that improved glycemic control in patients with type 2 diabetes can prevent microvascular complications. Nonetheless, convincing arguments suggested that the DCCT results could be extrapolated to type 2 diabetes. First, retinal, renal, and neurologic anatomical lesions seem to be identical in type 1 and type 2 diabetes mellitus (3, 20, 21). Second, epidemiologic studies have shown a close association between glycemic control and microvascular complications (3, 22-24). Third, a randomized clinical trial in Japanese patients with type 2 diabetes (15) showed that attainment of near-normal glycemia with intensive insulin therapy resulted in improvements in retinopathy, nephropathy, and neuropathy similar to those observed in the DCCT. Finally, short-term prospective studies (25, 26) have shown that reduction of the plasma glucose level reduces microalbuminuria and improves nerve conduction velocity in patients with type 2 diabetes. On the basis of these arguments, most diabetes experts have concluded that the DCCT results are applicable to type 2 diabetes mellitus (27). More definitive information on the relation between improved glycemic control and prevention of complications was recently provided by the United Kingdom Prospective Diabetes Study (UKPDS) (28, 29). In the main randomization group of the UKPDS (28), after a diet

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

To examine the extent to which the defect in insulin action in subjects with non-insulin-dependent diabetes mellitus (NIDDM) can be accounted for by impairment of muscle glycogen synthesis, we performed combined hyperglycemic-hyperinsulinemic clamp studies with [13C]glucose in five subjects with NIDDM and in six age- and weight-matched healthy subjects. The rate of incorporation of intravenously infused [1-13C]glucose into muscle glycogen was measured directly in the gastrocnemius muscle by means of a nuclear magnetic resonance (NMR) spectrometer with a 15.5-minute time resolution and a 13C surface coil. The steady-state plasma concentrations of insulin (approximately 400 pmol per liter) and glucose (approximately 10 mmol per liter) were similar in both study groups. The mean (+/- SE) rate of glycogen synthesis, as determined by 13C NMR, was 78 +/- 28 and 183 +/- 39 mumol-glucosyl units per kilogram of muscle tissue (wet weight) per minute in the diabetic and normal subjects, respectively (P less than 0.05). The mean glucose uptake was markedly reduced in the diabetic (30 +/- 4 mumol per kilogram per minute) as compared with the normal subjects (51 +/- 3 mumol per kilogram per minute; P less than 0.005). The mean rate of nonoxidative glucose metabolism was 22 +/- 4 mumol per kilogram per minute in the diabetic subjects and 42 +/- 4 mumol per kilogram per minute in the normal subjects (P less than 0.005). When these rates are extrapolated to apply to the whole body, the synthesis of muscle glycogen would account for most of the total-body glucose uptake and all of the nonoxidative glucose metabolism in both normal and diabetic subjects. We conclude that muscle glycogen synthesis is the principal pathway of glucose disposal in both normal and diabetic subjects and that defects in muscle glycogen synthesis have a dominant role in the insulin resistance that occurs in persons with NIDDM.