Impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) are intermediate states in glucose metabolism that exist between normal glucose tolerance and overt diabetes. Epidemiological studies demonstrate that the two categories describe distinct populations with only partial overlap, suggesting that different metabolic abnormalities characterize IGT and IFG. Insulin resistance and impaired ␤-cell function, the primary defects observed in type 2 diabetes, both can be detected in subjects with IGT and IFG. However, clinical studies suggest that the site of insulin resistance varies between the two disorders. While subjects with IGT have marked muscle insulin resistance with only mild hepatic insulin resistance, subjects with IFG have severe hepatic insulin resistance with normal or near-normal muscle insulin sensitivity. Both IFG and IGT are characterized by a reduction in early-phase insulin secretion, while subjects with IGT also have impaired late-phase insulin secretion. The distinct metabolic features present in subjects with IFG and IGT may require different therapeutic interventions to prevent their progression to type 2 diabetes. Diabetes Care 29:1130 -1139, 2006G lucose is the principal fuel used by humans and is the sole source of energy for the brain. Not surprisingly, glucose homeostasis is tightly controlled, and the fasting plasma glucose concentration is maintained within a very narrow range (70 -90 mg/dl) (1). In type 2 diabetes, both insulin secretion and action are impaired (2-4), and chronic hyperglycemia is a characteristic feature of this common metabolic disorder. Unlike type 1 diabetes, where the disease onset is relatively acute, the course of type 2 diabetes is slow and the metabolic abnormalities that lead to hyperglycemia are established long before overt diabetes (as defined by World Health Organization/ American Diabetes Association criteria [5,6]) develops (7-9). This state, where abnormalities in glucose metabolism are present but elevation in glucose is below the cutoff point for establishing the diagnosis of type 2 diabetes, is referred to as pre-diabetes (10). Defining cut points for pre-diabetes and diabetes has generated much debate among the medical community (11,12), and these cut off points have been subject to revision over time (5,6,13,14). Pre-diabetes includes subjects with high fasting plasma glucose (FPG) concentration and normal response to a glucose load (IFG), subjects with abnormal postprandial glucose excursion but normal FPG concentration (IGT), and combination of IGT plus IFG (14).In 1979, an international workgroup defined type 2 diabetes as an FPG Ն140 mg/dl (7.8 mmol/l) or 2-h plasma glucose Ն200 mg/dl (11.1 mmol/l) following 75-g oral glucose load (14). It also created a new category, IGT, defined as a 2-h plasma glucose of 140 -199 mg/dl (7.8 -11.0 mmol/l) with normal FPG. IGT was meant to replace the terms "borderline" and "chemical" diabetes. In 1997, the American Diabetes Association revised its diagnostic criteria for diabetes (6), lowering the...

Chronic hyperglycemia impairs insulin action, resulting in glucotoxicity, which can be ameliorated in animal models by inducing glucosuria with renal glucose transport inhibitors. Here, we examined whether reduction of plasma glucose with a sodium-glucose cotransporter 2 (SGLT2) inhibitor could improve insulin-mediated tissue glucose disposal in patients with type 2 diabetes. Eighteen diabetic men were randomized to receive either dapagliflozin (n = 12) or placebo (n = 6) for 2 weeks. We measured insulin-mediated whole body glucose uptake and endogenous glucose production (EGP) at baseline and 2 weeks after treatment using the euglycemic hyperinsulinemic clamp technique. Dapagliflozin treatment induced glucosuria and markedly lowered fasting plasma glucose. Insulin-mediated tissue glucose disposal increased by approximately 18% after 2 weeks of dapagliflozin treatment, while placebo-treated subjects had no change in insulin sensitivity. Surprisingly, following dapagliflozin treatment, EGP increased substantially and was accompanied by an increase in fasting plasma glucagon concentration. Together, our data indicate that reduction of plasma glucose with an agent that works specifically on the kidney to induce glucosuria improves muscle insulin sensitivity. However, glucosuria induction following SGLT2 inhibition is associated with a paradoxical increase in EGP. These results provide support for the glucotoxicity hypothesis, which suggests that chronic hyperglycemia impairs insulin action in individuals with type 2 diabetes.

This study was conducted to observe changes in insulin secretion and insulin action in subjects with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT). A total of 319 subjects were studied with an oral glucose tolerance test (OGTT). Fasting plasma glucose and insulin concentrations were measured at baseline and every 30 min during the OGTT. Fifty-eight subjects also received a euglycemic-hyperinsulinemic clamp. Insulin sensitivity was calculated as the total glucose disposal (TGD) during the last 30 min of the clamp. Homeostasis model assessment of insulin resistance (HOMA-IR) was calculated from fasting plasma glucose and insulin concentrations. Subjects with IFG had TGD similar to normal glucose-tolerant subjects, while subjects with IGT and combined IFG/IGT had significantly reduced TGD. HOMA-IR in subjects with IFG was similar to that in subjects with combined IFG/IGT and significantly higher than HOMA-IR in subjects with IGT or NGT. Insulin secretion, measured by the insulinogenic index (⌬I 0 -30 /⌬G 0 -30 ) and by the ratio of the incremental area under the curve (AUC) of insulin to the incremental AUC of glucose (0 -120 min), was reduced to the same extent in all three glucoseintolerant groups. When both measurements of ␤-cell function were adjusted for severity of insulin resistance, subjects with IGT and combined IFG/IGT had a significantly greater reduction in insulin secretion than subjects with IFG. Subjects with IGT and IFG have different metabolic characteristics. Differences in insulin sensitivity and insulin secretion may predict different rates of progression to type 2 diabetes and varying susceptibility to cardiovascular disease.

OBJECTIVE -To derive indexes for muscle and hepatic insulin sensitivity from the measurement of plasma glucose and insulin concentrations during an oral glucose tolerance test (OGTT). RESEARCH DESIGN AND METHODS-A total of 155 subjects of Mexican-American origin (58 male and 97 female, aged 18 -70 years, BMI 20 -65 kg/m 2 ) with normal glucose tolerance (n ϭ 100) or impaired glucose tolerance (n ϭ 55) were studied. Each subject received a 75-g OGTT and a euglycemic insulin clamp in combination with tritiated glucose. The OGTTderived indexes of muscle and hepatic insulin sensitivity were compared with hepatic and muscle insulin sensitivity, which was directly measured with the insulin clamp, by correlation analysis.RESULTS -The product of total area under curve (AUC) for glucose and insulin during the first 30 min of the OGTT (glucose 0 -30 [AUC] ϫ insulin 0 -30 [AUC]) strongly correlated with the hepatic insulin resistance index (fasting plasma insulin ϫ basal endogenous glucose production) (r ϭ 0.64, P Ͻ 0.0001). The rate of decay of plasma glucose concentration from its peak value to its nadir during the OGTT divided by the mean plasma insulin concentration (dG/dt Ϭ I) strongly correlated with muscle insulin sensitivity measured with the insulin clamp (P ϭ 0.78, P Ͻ 0.0001).CONCLUSIONS -Novel estimates for hepatic and muscle insulin resistance from OGTT data are presented for quantitation of insulin sensitivity in nondiabetic subjects. Diabetes Care 30:89 -94, 2007S keletal muscle and hepatic insulin resistance are characteristic features in type 2 diabetes (1). Insulin resistance is also commonly observed in nondiabetic subjects who are overweight and is associated with a cluster of metabolic and cardiovascular risk factors (dyslipidemia, hypertension, visceral obesity, and elevated inflammatory markers) known as the insulin resistance syndrome or dysmetabolic syndrome (2). Individuals with the insulin resistance syndrome have an approximate threefold increased risk for coronary heart disease and type 2 diabetes (3). Their risk for cardiovascular and allcause mortality is also increased compared with insulin-sensitive individuals (3). It is estimated that in the year 2000, more than one-third of the adult population (Ͼ20 years of age) in the U.S. had the insulin resistance syndrome and therefore are at high risk for the development of type 2 diabetes and cardiovascular disease (4).Improved insulin sensitivity with lifestyle intervention, e.g., weight reduction and increased physical activity, lowers the risk of future type 2 diabetes in insulinresistant individuals by more than onehalf (5,6), reduces the prevalence of cardiovascular risk factors (7), and decreases cardiovascular morbidity and mortality (8). Pharmacological intervention with agents that improve insulin sensitivity, including thiazolidinediones and metformin, also reduces the risk of conversion from impaired glucose tolerance (IGT) to type 2 diabetes (5,9) and decreases the risk of cardiovascular disease in individuals with established type 2 ...

Insulin resistance in skeletal muscle is manifested by decreased insulin-stimulated glucose uptake and results from impaired insulin signaling and multiple post-receptor intracellular defects including impaired glucose transport, glucose phosphorylation, and reduced glucose oxidation and glycogen synthesis. Insulin resistance is a core defect in type 2 diabetes, it is also associated with obesity and the metabolic syndrome. Dysregulation of fatty acid metabolism plays a pivotal role in the pathogenesis of insulin resistance in skeletal muscle. Recent studies have reported a mitochondrial defect in oxidative phosphorylation in skeletal muscle in variety of insulin resistant states. In this review, we summarize the cellular and molecular defects that contribute to the development of insulin resistance in skeletal muscle.

Hyperglycemia plays an important role in the pathogenesis of type 2 diabetes mellitus, i.e., glucotoxicity, and it also is the major risk factor for microvascular complications. Thus, effective glycemic control will not only reduce the incidence of microvascular complications but also correct some of the metabolic abnormalities that contribute to the progression of the disease. Achieving durable tight glycemic control is challenging because of progressive β-cell failure and is hampered by increased frequency of side effects, e.g., hypoglycemia and weight gain. Most recently, inhibitors of the renal sodium-glucose cotransporter have been developed to produce glucosuria and reduce the plasma glucose concentration. These oral antidiabetic agents have the potential to improve glycemic control while avoiding hypoglycemia, to correct the glucotoxicity, and to promote weight loss. In this review, we will summarize the available data concerning the mechanism of action, efficacy, and safety of this novel antidiabetic therapeutic approach.

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OBJECTIVE -We sought to assess insulin secretion/insulin resistance index in predicting the risk for future type 2 diabetes RESEARCH DESIGN AND METHODS -A total of 1,551 nondiabetic subjects from the San Antonio Heart Study received an oral glucose tolerance test (OGTT) with measurement of plasma glucose and insulin concentrations at 0, 30, 60, and 120 min at baseline and after 7-8 years of follow-up. Insulin secretion/insulin resistance index was calculated as the product of Matsuda index and ⌬I 0 -30 /⌬G 0 -30 or ⌬I 0 -120 /⌬G 0 -120 . The discriminatory power of various prediction models for development of type 2 diabetes was tested with the area under the receiver-operating characteristic (ROC) curve.RESULTS -Insulin secretion/insulin resistance index (0-to 30-and 0-to 120-min time periods) had the greatest areas under the ROC curve (0.85 and 0.86, respectively), which were significantly greater than the 2-h plasma glucose concentration during the OGTT or the San Antonio Diabetes Prediction Model (SADPM) (P Ͻ 0.001 and P Ͻ 0.0001, respectively). A model based on the combination of the SADPM and a modified version of the insulin secretion/insulin resistance index or 1-h plasma glucose concentration had equal power to predict the risk for future type 2 diabetes compared with the insulin secretion/insulin resistance index.CONCLUSIONS -The insulin secretion/insulin resistance index is useful as a predictor of future development of type 2 diabetes. A model based on the combination of the SADPM and either a modified version of the insulin secretion/insulin resistance index or 1-h plasma glucose concentration can equally predict future type 2 diabetes. Diabetes Care 30:1544-1548, 2007T he worldwide prevalence of type 2 diabetes is increasing at epidemic proportions. In the year 2000, there were 150 million individuals with type 2 diabetes worldwide, and this number is expected to double in the next 25 years (1). This increase in type 2 diabetes prevalence is also associated with increases in both morbidity and mortality (2), despite the decrease in cardiovascular morbidity and mortality in nondiabetic individuals over the same time period (3). For example, in the year 2000 (when compared with 1990), the rate of cardiac events in nondiabetic subjects in New York City declined by 14%, while it increased by 54% in individuals with type 2 diabetes over the same period (2).Recent clinical trials have demonstrated that, in subjects at high risk for type 2 diabetes, both lifestyle changes and pharmacological intervention can reduce the incidence of type 2 diabetes. A moderate increase in physical activity, accompanied with modest (5-7%) reduction in body weight, reduced the conversion rate of impaired glucose tolerance (IGT) to type 2 diabetes by 58% (4,5). Pharmacological intervention with metformin, troglitazone, and acarbose also have been shown to reduce conversion rate from IGT to diabetes by 31% (3), 75% (6), and 25% (7), respectively. The results of these long-term, prospective studies emphasize the importance of i...