At doses between 1 and 2 g/day, resveratrol improves insulin sensitivity and postmeal plasma glucose in subjects with IGT. These preliminary findings support the conduct of larger studies to further investigate the effects of resveratrol on metabolism and vascular function.

Whereas thiazolidinediones (TZDs) are known to rapidly improve insulin action in animals, short durations of TZD therapy have never been studied in humans. Among the many known actions of TZDs, increased circulating levels of the high molecular weight (HMW) multimer of adiponectin may be an important insulinsensitizing mechanism. We examined the effects of only 21 days of 45 mg of pioglitazone (P؉) versus placebo (P؊) in nine subjects with type 2 diabetes (HbA 1c , 10.9 ؎ 0.6%; BMI, 31.9 ؎ 1.5 kg/m 2 ). Total adiponectin levels increased by approximately twofold in P؉ in association with increased adipose tissue gene expression. However, plasma free fatty acid and glucose levels were unchanged, and there were only minimal changes in other "adipokines." Glucose fluxes ([3-3 H]glucose infusion) were measured during 6-h euglycemic (5 mmol/l) "pancreatic clamp" studies (somatostatin/glucagon/growth hormone) with stepped insulin levels. Pioglitazone induced marked decreases in endogenous glucose production (P؉ ‫؍‬ 0.9 ؎ 0.1 vs. P؊ ‫؍‬ 1.7 ؎ 0.3 mg ⅐ kg ؊1 ⅐ min ؊1 ; P < 0.05) at physiologic hyperinsulinemia (ϳ50 U/ml), which was highly correlated with an increased ratio of HMW adiponectin/total levels (r 2 ‫؍‬ 0.90). Maximal insulin stimulation (ϳ400 U/ml) revealed pioglitazone-associated increases in glucose uptake (P؉ ‫؍‬ 10.5 ؎ 0.9 vs. P؊ ‫؍‬ 8.9 ؎ 0.8 mg ⅐ kg ؊1 ⅐ min ؊1 ; P < 0.05), which did not correlate with HMW or total adiponectin levels. Thus, only 21 days of pioglitazone therapy improved insulin action in humans with type 2 diabetes. Increased abundance of the HMW adiponectin multimer may contribute to the hepatic insulin-sensitizing effects of these agents.

Recent studies have indicated that the mass/content of intramyocellular lipid (IMCL), intrahepatic triglyceride (IHTG), visceral fat (VF), and even deep abdominal subcutaneous fat (SF) may all be correlated with insulin resistance. Since simultaneous measurements of these parameters have not been reported, the relative strength of their associations with insulin action is not known. Therefore, the goals of this study were 1) to simultaneously measure IMCL, IHTG, VF, and abdominal SF in the same nondiabetic individuals using noninvasive (1)H-magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI) and 2) to examine how these fat stores are correlated with systemic insulin sensitivity as measured by whole body glucose disposal (R(d)) during euglycemic-hyperinsulinemic clamp studies. Positive correlations were observed among IMCL, IHTG, and VF. There were significant inverse correlations between whole body R(d) and both IMCL and VF. Notably, there was a particularly tight inverse correlation between IHTG and whole body R(d) (r = -0.86, P < 0.001), consistent with an association between liver fat and peripheral insulin sensitivity. This novel finding suggests that hepatic triglyceride accumulation has important systemic consequences that may adversely affect insulin sensitivity in other tissues.

Increased endogenous glucose production (EGP) is a hallmark of type 2 diabetes mellitus. While there is evidence for central regulation of EGP by activation of hypothalamic ATP-sensitive potassium (K ATP ) channels in rodents, whether these central pathways contribute to regulation of EGP in humans remains to be determined. Here we present evidence for central nervous system regulation of EGP in humans that is consistent with complementary rodent studies. Oral administration of the K ATP channel activator diazoxide under fixed hormonal conditions substantially decreased EGP in nondiabetic humans and Sprague Dawley rats. In rats, comparable doses of oral diazoxide attained appreciable concentrations in the cerebrospinal fluid, and the effects of oral diazoxide were abolished by i.c.v. administration of the K ATP channel blocker glibenclamide. These results suggest that activation of hypothalamic K ATP channels may be an important regulator of EGP in humans and that this pathway could be a target for treatment of hyperglycemia in type 2 diabetes mellitus.

Letter to the editor: Unexpected high mortality in COVID-19 and diabetic ketoacidosis To the EditorPatients with diabetes mellitus (DM) appear to be at a greater risk for severe symptoms and complications, including death from 2]. DM is a common comorbidity in patients affected with COVID-19 and may cause ketosis, ketoacidosis, and diabetic ketoacidosis (DKA) [3]. In patients with DM, acute hyperglycemic crises such as DKA and hyperosmolar hyperglycemic state can be precipitated by an acute illness such as COVID-19 and it can result in catastrophic outcomes. At Jacobi Medical Center, an epicenter of the COVID-19 pandemic crisis, we noted that a significant proportion of patients with COVID-19 also presented with DKA. We identified 50 such patients admitted with COVID-19 from March 10th to April 30th of 2020 who concomitantly had DKA upon admission or developed DKA during their hospital course. DKA was defined as blood glucose N250 mg/dL, an elevated anion gap, and positive ketones in blood or urine. COVID-19 was confirmed by real-time reverse-transcription polymerase chain reaction (PCR) assay (BioReference Laboratories, Elmwood Park, NJ).Among the evaluated patients, 32 (64%) were male, the median age was 59 years (IQR 42.3-70), 16 (31%) were Hispanic, 15 (30%) were African American, and the median body mass index (BMI) was 27.15 kg/m 2 (see Table 1). Six of the 50 patients (12%) had a previous diagnosis of Type 1 DM with a median hemoglobin A1C (HbA1C) before the admission of 11%. Forty-four (88%) patients had previously diagnosed type 2 DM and their median HbA1c before the admission was 8.05%. Eight patients (16%) had previously undiagnosed DM. Twenty (40%) patients were on oral hypoglycemic agents with only 2 on SGLT2 inhibitors (which are known to increase the risk of ketoacidosis), 24 (48%) were on a home insulin regimen, and 4 (8%) patients were receiving treatment with GLP-1 agonists.The median value of the initial glucose on presentation in our sample population was 506.5 mg/dL (252.0-1485.0 mg/dL). Forty-three (86%) patients were treated with intravenous insulin infusion protocol and 7 (14%) were treated with subcutaneous insulin protocol. The mean insulin and the intravenous fluids requirements in the first 24 h were 115. 5Author contributions NCP, SP, JA, and PK contributed to the design and implementation of the data collection, and to the analysis of the results. All author's discussed the results and contributed to the final manuscript.

Obesity is associated with increased adipose tissue macrophage (ATM) infiltration, and rodent studies suggest that inflammatory factors produced by ATMs contribute to insulin resistance and type 2 diabetes. However, a relationship between ATM content and insulin resistance has not been clearly established in humans. Since thiazolidinediones attenuate adipose tissue inflammation and improve insulin sensitivity, we examined the temporal relationship of the effects of pioglitazone on these two parameters. The effect of 10 and 21 days of pioglitazone treatment on insulin sensitivity in 26 diabetic subjects was assessed by hyperinsulinemic-euglycemic clamp studies. Because chemoattractant factors, cytokines, and immune cells have been implicated in regulating the recruitment of ATMs, we studied their temporal relationship to changes in ATM content. Improved hepatic and peripheral insulin sensitivity was seen after 21 days of pioglitazone. We found early reductions in macrophage chemoattractant factors after only 10 days of pioglitazone, followed by a 69% reduction in ATM content at 21 days and reduced ATM activation at both time points. Although markers for dendritic cells and neutrophils were reduced at both time points, there were no significant changes in regulatory T cells. These results are consistent with an association between adipose macrophage content and systemic insulin resistance in humans.

Increased circulating free fatty acids (FFAs) inhibit both hepatic and peripheral insulin action. Because the loss of effectiveness of glucose to suppress endogenous glucose production and stimulate glucose uptake contributes importantly to fasting hyperglycemia in type 2 diabetes, we examined whether the approximate twofold elevations in FFA characteristic of poorly controlled type 2 diabetes contribute to this defect. Glucose levels were raised from 5 to 10 mmol/l while maintaining fixed hormonal conditions by infusing somatostatin with basal insulin, glucagon, and growth hormone. Each individual was studied at two FFA levels: with (NA؉) and without (NA؊) infusion of nicotinic acid in nine individuals with poorly controlled type 2 diabetes (HbA 1c ‫؍‬ 10.1 ؎ 0.7%) and with (LIP؉) and without (LIP؊) infusion of lipid emulsion in nine nondiabetic individuals. Elevating FFA to ϳ500 mol/l blunted the ability of glucose to suppress endogenous glucose production (LIP؊ ‫؍‬ ؊48% vs. LIP؉ ‫؍‬ ؊28%; P < 0.01) and increased glucose uptake (LIP؊ ‫؍‬ 97% vs. LIP؉ ‫؍‬ 51%; P < 0.01) in nondiabetic individuals. Raising FFA also blunted the endogenous glucose production response in 10 individuals with type 2 diabetes in good control (HbA 1c ‫؍‬ 6.3 ؎ 0.3%). Conversely, normalizing FFA nearly restored the endogenous glucose production (NA؊ ‫؍‬ ؊7% vs. NA؉ ‫؍‬ ؊41%; P < 0.001) and glucose uptake (NA؊ ‫؍‬ 26% vs. NA؉ ‫؍‬ 64%; P < 0.001) responses to hyperglycemia in individuals with poorly controlled type 2 diabetes. Thus, increased FFA levels contribute substantially to the loss of glucose effectiveness in poorly controlled type 2 diabetes. Diabetes 52:2748 -2758, 2003 T ype 2 diabetes is a multifaceted disorder characterized by hyperglycemia with insulin resistance and impaired insulin secretion, resulting in decreased peripheral glucose uptake and increased endogenous glucose production (1,2). The progression toward worsening glycemic control in type 2 diabetes is accompanied by moderate elevations in plasma free fatty acid (FFA) levels (3,4). These chronically elevated FFA levels result from resistance to the effects of both insulin and glucose on adipose tissue lipolysis and triglyceride storage (5). Important consequences of increased circulating FFAs include hepatic and peripheral insulin resistance (6,7), hepatic steatosis (8), diminished hepatic insulin clearance (9,10), and impaired pancreatic ␤-cell function (11,12).Increased endogenous glucose production is believed to be the major cause of postabsorptive hyperglycemia in type 2 diabetes (1,2). Hepatic insulin resistance probably contributes to these inappropriate elevations in endogenous glucose production, given the known suppressive effects of insulin on endogenous glucose production (13,14). In addition, the effectiveness of glucose per se to inhibit endogenous glucose production seems to be markedly blunted in individuals with less optimally controlled type 2 diabetes (4,15,16). Indeed, there are prominent inhibitory effects of hyperglycemia, independent of othe...

Macrophages are more abundant in adipose tissue from obese individuals than from those of normal weight and may contribute to the metabolic consequences of obesity by producing various circulating factors. One of these factors is plasminogen activator inhibitor-1 (PAI-1), which contributes to both atherosclerosis and insulin resistance. Because nutritional factors appear to regulate PAI-1 expression, we hypothesized that exposure to fatty acids and adipocyte secretory products could stimulate production of PAI-1 by adipose macrophages. Increased free fatty acid (FFA) concentrations in blood for 5 hours in nondiabetic, overweight subjects markedly suppressed insulin-stimulated glucose uptake and raised circulating PAI-1 concentrations, with a concomitant increase in the expression of the PAI-1 gene in adipose tissue. FFAs also rapidly increased PAI-1 gene expression in adipose macrophages and PAI-1 protein immunofluorescence surrounding these cells. By contrast, PAI-1 expression in circulating monocytes was very low and was not affected by raising the concentration of FFAs. Medium from cultured adipocytes stimulated PAI-1 expression in cultured macrophages and potentiated the increase in PAI-1 messenger RNA expression in response to FFAs. Together, our data suggest that adipocyte-derived factors prime adipose macrophages so that they respond to nutritional signals (FFAs) by releasing a key inflammatory adipokine, PAI-1.