Ralph Defronzo

..In this review, we summarize the available data concerning the mechanism of action, efficacy, and safety of this novel antidiabetic class of therapeutic agents...

..The decreases in HbA(1c) with A12.5+P and A25+P were similar. All treatments were well tolerated...

..This ratio defines the predominancy of visceral or subcutaneous abdominal adiposity, independent of the body type of each individual...

..e. percent body fat by DXA and HbA1c). However, a simple method to screen and identify obese insulin resistant baboons for inclusion in interventional studies is not available...

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..The distinct metabolic features present in subjects with IFG and IGT may require different therapeutic interventions to prevent their progression to type 2 diabetes...

..This 24-week trial assessed the efficacy and safety of saxagliptin as add-on therapy in patients with type 2 diabetes with inadequate glycemic control with metformin alone...

..TRIAL REGISTRATION: clinical trials.gov identifier: NCT00220961...

..The objective of this study is to quantify the relationship between baseline HbA(1c) and reduction of HbA(1c) in clinical trials...

..In this review, we will summarize the available data concerning the mechanism of action, efficacy, and safety of this novel antidiabetic therapeutic approach...

..Insulin resistance and lipotoxicity represent the missing links (beyond the classical cardiovascular risk factors) that help explain the accelerated rate of CVD in type 2 diabetic patients...

..Optimal management of type 2 diabetes should include early initiation of therapy using multiple drugs, with different mechanisms of action, in combination...

..The aim of the study was to examine the determinants of oral glucose tolerance in 602 persons with impaired glucose tolerance (IGT) who participated in the Actos Now for Prevention of Diabetes (ACT NOW) study...

..Type 2 diabetes is usually associated with obesity, and both conditions are frequently detected in the Arab population in Israel. Recent studies have demonstrated that diabetes can be prevented by a change in lifestyle...

..This study investigates whether inhaled insulin (INH; Exubera) can achieve target glycemic control in patients failing on diet and exercise...

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..Therefore, preservation of the remaining 20-30% of ?-cell function is critical to prevent future development of T2DM...

..Study the effects of exenatide (EXE) plus rosiglitazone (ROSI) on beta-cell function and insulin sensitivity using hyperglycemic and euglycemic insulin clamp techniques in participants with type 2 diabetes on metformin...

..Although the long-term efficacy and safety of SGLT2 inhibitors remain under study, the class represents a novel therapeutic approach with potential for the treatment of both type 2 and 1 diabetes...

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..Impaired glucose tolerance is associated with increased rates of cardiovascular disease and conversion to type 2 diabetes mellitus. Interventions that may prevent or delay such occurrences are of great clinical importance...

..This study evaluated the effects of exenatide, a GLP-1 receptor agonist, and sitagliptin, a DPP-4 inhibitor, on 2-h postprandial glucose (PPG), insulin and glucagon secretion, gastric emptying, and caloric intake in T2D patients...

..Our aim was to assess the effect of chronic hyperglycemia on glucose- and insulin-mediated suppression of glucagon secretion by the alpha-cell...

..To evaluate the dipeptidyl peptidase-4 (DPP-4) inhibitor alogliptin in drug-naïve patients with inadequately controlled type 2 diabetes...

..We sought to assess insulin secretion/insulin resistance index in predicting the risk for future type 2 diabetes..

..The treatment of these CV risk factors should follow the same guidelines established for patients with type 2 diabetes, and should be aggressively followed to reduce future CV events...

..We examined the relationship between glycemic control, vascular reactivity, and inflammation in type 2 diabetic subjects...

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..Further studies are necessary to evaluate whether the same scenario is applicable to normoandrogenic women and individuals with type 2 diabetes mellitus...

..Improved splanchnic/peripheral glucose uptake and enhanced suppression of EGP contribute to the improvement in glycemic control in patients with type 2 diabetes...

..Plasma RBP4 levels are elevated in T2DM and associated with impaired glucose tolerance, but not associated with obesity or insulin resistance or impaired insulin secretion in Mexican Americans...

..Larger controlled trials of longer duration are warranted to assess the long-term clinical benefit of pioglitazone. (ClinicalTrials.gov number, NCT00227110 [ClinicalTrials.gov] .)...

..In conclusion, in type 2 diabetic patients, rosiglitazone treatment enhances downstream insulin receptor signaling in muscle and decreases plasma FFA concentration while improving glycemic control...

..CON). Acetaminophen((AUC)) was reduced by approximately 80% in EXE vs. CON (P < 0.01). We conclude that exenatide infusion attenuates postprandial hyperglycemia by decreasing EGP (by approximately 50%) and by slowing gastric emptying...

..CONCLUSIONS: Exenatide was generally well tolerated and reduced HbA(1c) with no weight gain and no increased incidence of hypoglycemia in patients with type 2 diabetes failing to achieve glycemic control with metformin...

..FGF-21 may play a role in pathogenesis of hepatic and whole-body insulin resistance in type 2 diabetes...

..To assess the contribution of decreased glucose clearance to the rise in fasting plasma glucose (FPG) in the nondiabetic range...

..The alogliptin-pioglitazone combination represents a pathophysiologically sound treatment of T2DM...

..Exercise-induced MCP-1 and IL-6 gene expression precedes increases in NF-?B activity, suggesting that other factors promote gene expression of these cytokines during exercise...

..Glargine insulin reduced basal EGP by increasing plasma insulin levels, while rosiglitazone decreased basal hepatic glucose production by improving hepatic insulin sensitivity...

..In male but not female T2DM, deep subcutaneous adipose tissue also is associated with peripheral and hepatic insulin resistance...

..To quantitate insulin sensitivity in lean and obese nondiabetic baboons and examine the underlying cellular/molecular mechanisms responsible for impaired insulin action to characterize a baboon model of insulin resistance...

..These results demonstrate that a shift of fat distribution from visceral to sc adipose depots after pioglitazone treatment is associated with improvements in hepatic and peripheral tissue sensitivity to insulin...

..These data suggest that an experimental increase in FFAs decreases the expression of PGC-1 and nuclear encoded mitochondrial genes and also increases the expression of extracellular matrix genes in a manner reminiscent of inflammation...

..Objective: The aim was to study the effect of pioglitazone on intramyocellular fat metabolism...

..These results suggest that impaired NOS activity may play an important role in the insulin resistance in type 2 diabetic individuals...

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..Head-to-head comparative trials as well as longer-term cardiovascular outcome studies are needed to determine whether there are differences in efficacy between the 2 thiazolidinediones...

..CONCLUSIONS- Abnormal TLR4 expression and signaling, possibly caused by elevated plasma FFA levels, may contribute to the pathogenesis of insulin resistance in humans...

..We examined the relationship between visceral/hepatic fat accumulation and hepatic IR/accelerated gluconeogenesis (GNG)...

..Mitochondrial dysfunction has been proposed as an underlying mechanism in the pathogenesis of insulin resistance and type 2 diabetes mellitus...

..44), and whole-body ISI (r=0.36) were observed. CONCLUSIONS: Pioglitazone improves glycemic control through the dose-dependent enhancement of beta-cell function and improved whole-body and hepatic insulin sensitivity...

..Oral HIM2 may provide an effective and reproducible means of controlling postprandial plasma glucose excursions in diabetic patients...

..However, suppression of EGP by IGF-I is not impaired in diabetic individuals, indicating normal hepatic sensitivity to IGF-I...

..37 +/- 2%, P < 0.01). In conclusion, an elevation in plasma FFA concentration impairs both peripheral and SGU in patients with type 2 diabetes...

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..In T2DM patients, TZD treatment leads to improved beta-cell function, which correlates strongly with improved glycemic control...

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..Differences in insulin sensitivity and insulin secretion may predict different rates of progression to type 2 diabetes and varying susceptibility to cardiovascular disease...

..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)...

..Sal infusion study (30 +/- 2 vs. 20 +/- 2%, P < 0.005). In conclusion, an elevation in plasma FFA concentration impairs whole body glucose R(d) and insulin-mediated suppression of EGP in healthy subjects but augments SGU...

..Vascular dysfunction and insulin resistance precede atherosclerosis in type 2 diabetes (T2DM). Better knowledge of the interaction between these is of considerable clinical interest...

..The goal of our study was to perform a genome-wide linkage scan to identify genetic regions that influence variation in plasma triglyceride levels in families that are enriched with individuals with type 2 diabetes...

..54, P = 0.02), and PGC-1alpha protein content (r = 0.81, P < 0.001). In summary, obese insulin-resistant rodents have abnormalities in the LKB1-AMPK-PGC-1 pathway in muscle, and these abnormalities can be restored by training...

..In summary, subjects with type 2 diabetes have reduced IkappaB protein abundance in muscle, suggesting excessive activity of the IkappaB/NFkappaB pathway. Moreover, this abnormality is reversed by exercise training...

..519, P < 0.0001), and different FPG levels were sensitive and specific to predict IA severity. Finally, a predictive model for islet amyloid severity was generated with age and FPG as required variables...

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..The late (120 to 240 minutes) stimulation of hepatic glucose output (which primarily reflects gluconeogenesis) by glucagon tends to be increased, especially at supraphysiologic plasma glucagon concentrations...

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..Taken together, our results provide strong evidence that Grb10 is a negative regulator of insulin signaling and action in vivo...

..The results of the present study demonstrate that insulin acutely regulates the levels of mRNAs involved in inflammation and transcription and identifies several candidate genes, including HES1 and BHLHB2, for further investigation...

..1%), sensitivity (81.3%), and specificity (76.3%). Thus, insulin-resistant individuals can be identified using simple decision rules that can be tailored to specific needs...

..To assess the efficacy of 1-h plasma glucose concentration and the metabolic syndrome in predicting future risk of type 2 diabetes...

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..However, little is known about the mechanism(s) by which vildagliptin promotes reduction in plasma glucose concentration...

..3 to 2.7. Thus, we have found strong evidence for a major gene on chromosome 6q that influences variation in birth weight in both Mexican- and European-Americans...

..Reduced muscle content of key glucose transport-regulating proteins (GLUT1, GLUT4, AS160) could play a role in the pathogenesis of neonatal hyperglycemia and reduced insulin-stimulated glucose disposal...

..After controlling for 1-h plasma glucose concentration, the increase in FPG concentration is not associated with an increase in the incidence of type 2 diabetes...

..In this review, we summarize the cellular and molecular defects that contribute to the development of insulin resistance in skeletal muscle...

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..In this article, we summarize the metabolic abnormalities that characterize each state and the contribution of these metabolic abnormalities to the increased risk of diabetes and cardiovascular disease...

..The aim of the study is to assess the relationship between the shape of plasma glucose concentration during the OGTT and future risk for T2DM...

..98). These preliminary results provide evidence for association of SNPs in the NPY5R gene with dyslipidemia (elevated triglyceride concentrations and reduced high-density lipoprotein levels) in our Mexican American population...

..These acquired mitochondrial defects, caused by a physiological increase in the concentration of FFA metabolites, provide a mechanistic link between lipotoxicity, mitochondrial dysfunction, and muscle insulin resistance...

..However, these results indicate that ENPP1 is a genetic determinant of these traits in this population, and are consistent with multiple positive association findings in independent studies in diverse human populations...

..This review summarizes evidence that implicates a defect in mitochondrial oxidative phosphorylation and its relationship to insulin resistance in common metabolic diseases characterized by impaired insulin action...

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..Our objective was to examine the mechanisms via which exenatide attenuates postprandial hyperglycemia in type 2 diabetes mellitus (T2DM)...

..05). We conclude that in patients with established type 2 diabetes, VF accumulation has a significant negative impact on glycemic control through a decrease in peripheral insulin sensitivity and an enhancement of gluconeogenesis...

..We conclude that the primary physiological target of the propensity to diabetes of Mexican-Americans is insulin resistance of glucose uptake...

..Our findings suggest that obese type 2 diabetic subjects may need to exercise at higher intensity to stimulate the AMPK-AS160 axis to the same level as lean subjects...

..We sought to determine whether dysregulation of arginine metabolism is related to insulin resistance and underlies impaired nitric oxide (NO) generation in type 2 diabetic patients...

..Thiazolidinediones (TZDs) improve peripheral insulin sensitivity, but the effect on the liver is less clear. The goal of this study was to examine the effect of TZDs on GNG...

..We believe that these studies will yield new insights into the etiology of insulin resistance in T2DM and identify novel therapeutic approaches to reverse the defects in insulin action and restore normoglycemia. ..

..We also shall examine the effects of chronic hyperinsulinemia on the oxidative and non-oxidative pathways of glucose disposal...

..Regardless, Mexican Americans comprise 5% of the US population (12 million people) and definition of the cause of NIDDM in this ethnic group alone would have major scientific, therapeutic, and health care delivery significance. ..

..We believe that these studies will yield new insights into the etiology of insulin resistance in T2DM and identify novel therapeutic approaches to reverse the defects in insulin action and restore normoglycemia. ..