Sex-specific impact of severe obesity in the outcomes of hospitalized patients with COVID-19: a large retrospective study from the Bronx, New York.

It has been demonstrated that obesity is an independent risk factor for worse outcomes in patients with COVID-19. Our objectives were to investigate which classes of obesity are associated with higher in-hospital mortality and to assess the association between obesity and systemic inflammation. This was a retrospective study which included consecutive hospitalized patients with COVID-19 in a tertiary center. Three thousand five hundred thirty patients were included in this analysis (female sex: 1579, median age: 65 years). The median body mass index (BMI) was 28.8 kg/m2. In the overall cohort, a J-shaped association between BMI and in-hospital mortality was depicted. In the subgroup of men, BMI 35-39.9 kg/m2 and BMI ≥40 kg/m2 were found to have significant association with higher in-hospital mortality, while only BMI ≥40 kg/m2 was found significant in the subgroup of women. No significant association between BMI and IL-6 was noted. Obesity classes II and III in men and obesity class III in women were independently associated with higher in-hospital mortality in patients with COVID-19. The male population with severe obesity was the one that mainly drove this association. No significant association between BMI and IL-6 was noted.

A Case of Type V Hyperlipoproteinemia Resistant to Insulin Treatment.

Type V hyperlipoproteinemia or multifactorial chylomicronemia syndrome is a rare lipid disorder triggered mainly by uncontrolled diabetes, obesity, poor diet, or particular medications. It is associated with an increased risk of acute pancreatitis and accelerated coronary artery disease which may manifest in younger age groups. We present a case of a 42-year-old male who presented to the emergency department (ED) complaining of a non-healing hand injury. Upon laboratory workup, the patient was found to have an elevated total cholesterol (TC) of 1129 mg/dL, very low levels of high-density lipoprotein (HDL) and triglycerides (TG) > 4000 mg/dL with an inability to calculate low-density lipoprotein (LDL). Lipoprotein electrophoresis revealed an actual TG level of > 7000 mg/dL, increased chylomicrons, normal B and pre-B-lipoproteins, and increased L-lipoproteins with an elevated Apolipoprotein B. Despite these derangements, the patient did not exhibit any abdominal complaints, demonstrating a normal lipase level. The physical exam was indicative of bilateral arcus senilis and obesity. Insulin drip was initiated along with intravenous (IV) hydration and it required 12 days to bring triglycerides down to less than 1000 mg/dL. The total cholesterol was also seen to be down trending to around 500 mg/dL and the HDL improved to 22 mg/dL. We present this case as a unique presentation of asymptomatic chylomicronemia resistant to insulin treatment with an elevated ApoB but with no evidence of pancreatitis or coronary artery disease.

Glycemic control and cardiovascular disease: what's a doctor to do?

Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality in individuals with diabetes mellitus. Moreover, rates of CVD mortality are two to four times higher in diabetes than in those without diabetes. It was conventional thinking that achieving near-normoglycemia would help reduce CVD risk and overall mortality in type 2 diabetes mellitus. Several recent large trials attempted to answer this question using a randomized control trial design with a conventional therapy and an intensive control arm. Surprisingly, these trials did not demonstrate neither mortality nor a CVD advantage with intensive glycemic control. Moreover, some studies (e.g., the ACCORD [Action to Control Cardiovascular Risk in Diabetes] study) showed increased mortality in the intensive control arm. In this review, our goal is to summarize the findings of the major trials in this field and to explore the potential reasons for why these trials had largely negative results. We conclude with some lessons that may be applied to the clinical management of patients with diabetes.

Obesity, Inflammation, and Mortality in COVID-19: An Observational Study from the Public Health Care System of New York City.

Severe obesity increases the risk for negative outcomes in patients with coronavirus disease 2019 (COVID-19). Our objectives were to investigate the effect of BMI on in-hospital outcomes in our New York City Health and Hospitals' ethnically diverse population, further explore this effect by age, sex, race/ethnicity, and timing of admission, and, given the relationship between COVID-19 and hyperinflammation, assess the concentrations of markers of systemic inflammation in different BMI groups. A retrospective study was conducted in hospitalized patients with COVID-19 in the public health care system of New York City from 1 March 2020 to 31 October 2020. A total of 8833 patients were included in this analysis (women: 3593, median age: 62 years). The median body mass index (BMI) was 27.9 kg/m2. Both overweight and obesity were independently associated with in-hospital death. The association of overweight and obesity with death appeared to be stronger in men, younger patients, and individuals of Hispanic ethnicity. We did not observe higher concentrations of inflammatory markers in patients with obesity as compared to those without obesity. In conclusion, overweight and obesity were independently associated with in-hospital death. Obesity was not associated with higher concentrations of inflammatory markers.

Retrospective Diagnosis of Malignant Struma Ovarii After Discovery of Pulmonary Metastasis.

OBJECTIVE: Malignant struma ovarii diagnosis is challenging due to its benign histologic appearance and rarity. We present a case of struma ovarii determined malignant after pulmonary metastases were incidentally discovered. METHODS: A 29-year-old female with a history of benign struma ovarii presented to the emergency room with right lower abdominal pain. Abdomen and pelvis computed tomography showed multiple bilateral pulmonary nodules, which demonstrated well-differentiated thyroid tissue on biopsy. Review of prior ovarian pathology identified features of highly differentiated thyroid carcinoma. Laboratory studies were negative for thyroglobulin (TG) antibodies, thyrotropin was 0.713 mIU/L, and TG was 169 ng/mL. The patient underwent total thyroidectomy, revealing a 0.3 cm follicular variant papillary thyroid microcarcinoma without lymphovascular invasion. An I-123 whole-body scan revealed bilateral metastases in the thigh muscles. RESULTS: I-123 whole-body scan after receiving I-131 therapy demonstrated uptake in the lungs, thyroid bed, and bilateral thighs. A computed tomography scan 5 months later revealed a decreased size of the pulmonary nodules. CONCLUSIONS: Careful histologic examination is key in making an early diagnosis of malignant struma ovarii. It requires a high index of suspicion and close histologic examination to identify malignant features, mainly the presence of cytologic overlapping ground-glass nuclei and mitotic activity or vascular invasion. Additionally, a thorough review of the imaging is needed to identify any abnormal findings suggestive of metastases. Our case demonstrates that this diagnosis may be made retrospectively after the discovery of metastases and patients can have excellent response to I-131 therapy despite a relatively low TG level.

Cross-sectional study evaluating the seroprevalence of SARS-CoV-2 antibodies among healthcare workers and factors associated with exposure during the first wave of the COVID-19 pandemic in New York.

OBJECTIVE: Estimate the seroprevalence of SARS-CoV-2 antibodies among New York City Health and Hospitals (NYC H+H) healthcare workers during the first wave of the COVID-19 pandemic, and describe demographic and occupational factors associated with SARS-CoV-2 antibodies among healthcare workers. DESIGN: Descriptive, observational, cross-sectional study using a convenience sample of data from SARS-CoV-2 serological tests accompanied by a demographic and occupational survey administered to healthcare workers. SETTING: A large, urban public healthcare system in NYC. PARTICIPANTS: Participants were employed by NYC H+H and either completed serological testing at NYC H+H between 30 April 2020 and 30 June 2020, or completed SARS-CoV-2 antibody testing outside of NYC H+H and were able to self-report results from the same time period. PRIMARY OUTCOME MEASURE: SARS-CoV-2 serostatus, stratified by key demographic and occupational characteristics reported through the demographic and occupational survey. RESULTS: Seven hundred and twenty-seven survey respondents were included in analysis. Participants had a mean age of 46 years (SD=12.19) and 543 (75%) were women. Two hundred and fourteen (29%) participants tested positive or reported testing positive for the presence of SARS-CoV-2 antibodies (IgG+). Characteristics associated with positive SARS-CoV-2 serostatus were Black race (25% IgG +vs 15% IgG-, p=0.001), having someone in the household with COVID-19 symptoms (49% IgG +vs 21% IgG-, p<0.001), or having a confirmed COVID-19 case in the household (25% IgG +vs 5% IgG-, p<0.001). Characteristics associated with negative SARS-CoV-2 serostatus included working on a COVID-19 patient floor (27% IgG +vs 36% IgG-, p=0.02), working in the intensive care unit (20% IgG +vs 28% IgG-, p=0.03), being employed in a clinical occupation (64% IgG +vs 78% IgG-, p<0.001) or having close contact with a patient with COVID-19 (51% IgG +vs 62% IgG-, p=0.03). CONCLUSIONS: Results underscore the significance that community factors and inequities might have on SARS-CoV-2 exposure for healthcare workers.

Insulin-sensitizing effects of vitamin D repletion mediated by adipocyte vitamin D receptor: Studies in humans and mice.

OBJECTIVE: Adipose tissue inflammation and fibrosis appear to contribute to insulin resistance in obesity. Vitamin D receptor (Vdr) genes are expressed by adipocytes, macrophages, and fibroblasts, all of which could potentially play a role in adipose tissue inflammation and fibrosis. As vitamin D has been shown to have direct anti-inflammatory effects on adipocytes, we determined whether specific vitamin D receptor-mediated effects on adipocytes could impact adipose tissue inflammation and fibrosis and ultimately insulin resistance. METHODS: We examined the effects of repleting vitamin D in 25(OH)D-deficient, insulin resistant, overweight-to-obese human subjects (n = 19). A comprehensive assessment of whole-body insulin action was undertaken with stepped euglycemic (∼90 mg/dL) hyperinsulinemic clamp studies both before and after the administration of vitamin D or placebo. Adipose tissue fibrosis and inflammation were quantified by real-time rt-PCR and immunofluorescence in subcutaneous abdominal adipose tissue. To determine whether vitamin D's effects are mediated through adipocytes, we conducted hyperinsulinemic clamp studies (4 mU/kg/min) and adipose tissue analysis using an adipocyte-specific vitamin D receptor knockout (VDR-KO) mouse model (adiponectin-Cre + VDR+/fl) following high-fat diet feeding for 12 weeks. RESULTS: 25(OH)D repletion was associated with reductions in adipose tissue expression of pro-inflammatory and pro-fibrotic genes, decreased collagen immunofluorescence, and improved hepatic insulin sensitivity in humans. Worsening trends after six months on placebo suggest progressive metabolic effects of 25(OH)D deficiency. Ad-VDR-KO mice mirrored the vitamin D-deficient humans, displaying increased adipose tissue fibrosis and inflammation and hepatic insulin resistance. CONCLUSIONS: These complementary human and rodent studies support a beneficial role of vitamin D repletion for improving hepatic insulin resistance and reducing adipose tissue inflammation and fibrosis in targeted individuals, likely via direct effects on adipocytes. These studies have far-reaching implications for understanding the role of adipocytes in mediating adipose tissue inflammation and fibrosis and ultimately impacting insulin sensitivity.

Inhibiting gluconeogenesis prevents fatty acid-induced increases in endogenous glucose production.

Glucose effectiveness, the ability of glucose per se to suppress endogenous glucose production (EGP), is lost in type 2 diabetes mellitus (T2DM). Free fatty acids (FFA) may contribute to this loss of glucose effectiveness in T2DM by increasing gluconeogenesis (GNG) and impairing the response to hyperglycemia. Thus, we first examined the effects of increasing plasma FFA levels for 3, 6, or 16 h on glucose effectiveness in nondiabetic subjects. Under fixed hormonal conditions, hyperglycemia suppressed EGP by 61% in nondiabetic subjects. Raising FFA levels with Liposyn infusion for > or =3 h reduced the normal suppressive effect of glucose by one-half. Second, we hypothesized that inhibiting GNG would prevent the negative impact of FFA on glucose effectiveness. Raising plasma FFA levels increased gluconeogenesis by approximately 52% during euglycemia and blunted the suppression of EGP by hyperglycemia. Infusion of ethanol rapidly inhibited GNG and doubled the suppression of EGP by hyperglycemia, thereby restoring glucose effectiveness. In conclusion, elevated FFA levels rapidly increased GNG and impaired hepatic glucose effectiveness in nondiabetic subjects. Inhibiting GNG could have therapeutic potential in restoring the regulation of glucose production in type 2 diabetes mellitus.

Role of hepatic glycogen breakdown in defective counterregulation of hypoglycemia in intensively treated type 1 diabetes.

Impairment of hypoglycemic counterregulation in intensively treated type 1 diabetes has been attributed to deficits in counterregulatory hormone secretion. However, because the liver plays a critical part in recovery of plasma glucose, abnormalities in hepatic glycogen metabolism per se could also play an important role. We quantified the contribution of net hepatic glycogenolysis during insulin-induced hypoglycemia in 10 nondiabetic subjects and 7 type 1 diabetic subjects (HbA1c 6.5 +/- 0.2%) using 13C nuclear magnetic resonance spectroscopy, during 2 h of either hyperinsulinemic euglycemia (plasma glucose 92 +/- 4 mg/dl) or hypoglycemia (plasma glucose 58 +/- 3 mg/dl). In nondiabetic subjects, hypoglycemia was associated with a brisk counterregulatory hormone response (plasma epinephrine 246 +/- 38 vs. 2,785 +/- 601 pmol/l during hypoglycemia, plasma norepinephrine 1.9 +/- 0.2 vs. 2.5 +/- 0.3 nmol/l, and glucagon 38 +/- 7 vs. 92 +/- 17 pg/ml, respectively, P < 0.001 in all), and a relative increase in endogenous glucose production (EGP 0.83 +/- 0.14 mg x kg(-1) x min(-1) during euglycemia yet approximately 50% higher with hypoglycemia [1.30 +/- 0.20 mg x kg(-1) x min(-1)], P < 0.001). Net hepatic glycogen content declined progressively during hypoglycemia to 22 +/- 3% below baseline (P < 0.024). By the final 30 min of hypoglycemia, hepatic glycogen fell from 301 +/- 14 to 234 +/- 10 mmol/l (P < 0.001) and accounted for approximately 100% of EGP. In marked contrast, after an overnight fast, hepatic glycogen concentration in type 1 diabetic subjects (215 +/- 23 mmol/l) was significantly lower than in nondiabetic subjects (316 +/- 19 mmol/l, P < 0.001). Furthermore, the counterregulatory response to hypoglycemia was significantly reduced with small increments in plasma epinephrine and norepinephrine (126 +/- 22 vs. 448 +/- 16 pmol/l in hypoglycemia and 0.9 +/- 0.3 vs. 1.6 +/- 0.3 nmol/l, respectively, P < 0.05 for both) and no increase in plasma glucagon. EGP decreased during hypoglycemia with no recovery (1.3 +/- 0.5 vs. 1.2 +/- 0.3 mg x kg(-1) x min(-1) compared with euglycemia, P = NS), and hepatic glycogen concentration did not change significantly with hypoglycemia. We conclude that glycogenolysis accounts for the majority of EGP during the first 90 min of hypoglycemia in nondiabetic subjects. In intensively treated type 1 diabetes, despite some activation of counterregulation, hypoglycemia failed to stimulate hepatic glycogen breakdown or activation of EGP, factors that may contribute to the defective counterregulation seen in such patients.

Time-dependent effects of free fatty acids on glucose effectiveness in type 2 diabetes.

Impaired effectiveness of glucose to suppress endogenous glucose production (EGP) is an important cause of worsening hyperglycemia in type 2 diabetes. Elevated free fatty acids (FFAs) may impair glucose effectiveness via several mechanisms, including rapid changes in metabolic fluxes and/or more gradual changes in gene expression of key enzymes or other proteins. Thus, we examined the magnitude and time course of effects of FFAs on glucose effectiveness in type 2 diabetes and whether glucose effectiveness can be restored by lowering FFAs. Glucose fluxes ([3-(3)H]-glucose) were measured during 6-h pancreatic clamp studies, at euglycemia (5 mmol/l glucose, t=0-240 min), and hyperglycemia (10 mmol/l, t=240-360 min). We studied 19 poorly controlled subjects with type 2 diabetes (HbA(1c) 10.9 +/- 0.4%, age 50 +/- 3 years, BMI 30 +/- 2 kg/m(2)) on at least two occasions with saline (NA- group) or nicotinic acid (NA group) infusions for 3, 6, or 16 h (NA3h, NA6h, and NA16h groups, respectively) to lower FFAs to nondiabetic levels. As a reference group, glucose effectiveness was also assessed in 15 nondiabetic subjects. There was rapid improvement in hepatic glucose effectiveness following only 3 h of NA infusion (NA3h = 31 +/- 6% suppression of EGP with hyperglycemia vs. NA- = 8 +/- 7%; P<0.01) and complete restoration of glucose effectiveness after 6 h of NA (NA6h = 41 +/- 8% suppression of EGP; P = NS vs. nondiabetic subjects). Importantly, the loss of hepatic glucose effectiveness in type 2 diabetes is completely reversible upon correcting the increased FFA concentrations. A longer duration of FFA lowering may be required to overcome the chronic effects of increased FFAs on hepatic glucose effectiveness.

Central Regulation of Glucose Production May Be Impaired in Type 2 Diabetes.

The challenges of achieving optimal glycemic control in type 2 diabetes highlight the need for new therapies. Inappropriately elevated endogenous glucose production (EGP) is the main source of hyperglycemia in type 2 diabetes. Because activation of central ATP-sensitive potassium (KATP) channels suppresses EGP in nondiabetic rodents and humans, this study examined whether type 2 diabetic humans and rodents retain central regulation of EGP. The KATP channel activator diazoxide was administered in a randomized, placebo-controlled crossover design to eight type 2 diabetic subjects and seven age- and BMI-matched healthy control subjects. Comprehensive measures of glucose turnover and insulin sensitivity were performed during euglycemic pancreatic clamp studies following diazoxide and placebo administration. Complementary rodent clamp studies were performed in Zucker Diabetic Fatty rats. In type 2 diabetic subjects, extrapancreatic KATP channel activation with diazoxide under fixed hormonal conditions failed to suppress EGP, whereas matched control subjects demonstrated a 27% reduction in EGP (P = 0.002) with diazoxide. Diazoxide also failed to suppress EGP in diabetic rats. These results suggest that suppression of EGP by central KATP channel activation may be lost in type 2 diabetes. Restoration of central regulation of glucose metabolism could be a promising therapeutic target to reduce hyperglycemia in type 2 diabetes.

Contribution of elevated free fatty acid levels to the lack of glucose effectiveness in type 2 diabetes.

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 approximately 500 micro 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.

Mechanisms of early insulin-sensitizing effects of thiazolidinediones in type 2 diabetes.

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 insulin-sensitizing 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. kg(-1). min(-1); P < 0.05) at physiologic hyperinsulinemia ( approximately 50 microU/ml), which was highly correlated with an increased ratio of HMW adiponectin/total levels (r(2) = 0.90). Maximal insulin stimulation ( approximately 400 microU/ml) revealed pioglitazone-associated increases in glucose uptake (P+ = 10.5 +/- 0.9 vs. P- = 8.9 +/- 0.8 mg. kg(-1). 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.

The effects of short-term vitamin D supplementation on glucose metabolism in dialysis patients: a systematic review and meta-analysis.

PURPOSE: We tested whether short-term vitamin D supplementation improves insulin resistance in patients with kidney disease, a condition with little intrinsic vitamin D activity. METHODS: PubMed, EMBASE and CENTRAL were searched for relevant observational studies and randomized clinical trials (RCTs). Random-effects models were employed for meta-analysis, and effect sizes were summarized as standardized mean difference (SMD) with 95% confidence intervals. Separate analyses were done for RCTs and non-randomized intervention studies (NRIS). RESULTS: Seventeen studies (5 RCTs and 12 NRIS) were included. The meta-analysis population (n = 131) was mostly middle aged (40-50 years), male and non-diabetic, and on hemodialysis. The duration (4-12 weeks) and type of supplementation varied between studies. Among RCTs, compared to placebo, vitamin D supplementation was associated with significant decrease in fasting glucose [SMD -1.13, (-2.11 to -0.11)] and PTH levels [SMD -1.50, (-2.95 to -0.04)] but no difference in fasting insulin levels [SMD 1.32, (-0.15 to 2.79)]. Among NRIS, there was only a significant decrease in PTH levels [SMD -1.68, (-2.55 to -0.82)] between pre- and post-vitamin D treatment levels. CONCLUSIONS: Short-term (4-12 weeks) supplementation with vitamin D is associated with lower fasting glucose levels in ESRD with no change in fasting insulin levels. However, the findings from this study are limited by the studies that were used in the meta-analysis, which were mostly small, used multiple different vitamin D compounds and dosing regimens, and had large heterogeneity, and funnel plots showed that there was a dearth of studies with null or negative finding. Therefore, larger RCTs need to be performed to answer this important clinical question.

Insulin sensitizing and anti-inflammatory effects of thiazolidinediones are heightened in obese patients.

OBJECTIVE: The American Diabetes Association has called for further research on how patients' demographics should determine drug choices for individuals with type 2 diabetes mellitus (T2DM). Here, using in-depth physiology studies, we investigate whether obese patients with T2DM are likely to benefit from thiazolidinediones, medications with a known adverse effect of weight gain. MATERIALS AND METHODS: Eleven obese and 7 nonobese individuals with T2DM participated in this randomized, placebo-controlled, double-blind, crossover study. Each subject underwent a pair of "stepped" pancreatic clamp studies with subcutaneous adipose tissue biopsies after 21 days of pioglitazone (45 mg) or placebo. RESULTS: Obese subjects demonstrated significant decreases in insulin resistance and many adipose inflammatory parameters with pioglitazone relative to placebo. Specifically, significant improvements in glucose infusion rates, suppression of hepatic glucose production, and whole fat expression of certain inflammatory markers (IL-6, IL-1B, and inducible nitric oxide synthase) were observed in the obese subjects but not in the nonobese subjects. Additionally, adipose tissue from the obese subjects demonstrated reduced infiltration of macrophages, dendritic cells, and neutrophils as well as increased expression of factors associated with fat "browning" (peroxisome proliferator-activated receptor gamma coactivator-1α and uncoupling protein-1). CONCLUSIONS: These findings support the efficacy of pioglitazone to improve insulin resistance and reduce adipose tissue inflammation in obese patients with T2DM.

Reduced adipose tissue macrophage content is associated with improved insulin sensitivity in thiazolidinedione-treated diabetic humans.

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.

Pilot study of resveratrol in older adults with impaired glucose tolerance.

BACKGROUND: Resveratrol, a plant-derived polyphenol, has shown promising effects on insulin sensitivity and glucose tolerance in animal models and is also reported to have cardioprotective properties, but human studies are limited. In a pilot study, we tested the hypothesis that resveratrol improves glucose metabolism and vascular function in older adults with impaired glucose tolerance (IGT). METHODS: Ten subjects aged 72 ± 3 years (M ± SD) with IGT were enrolled in a 4-week open-label study of resveratrol (daily dose 1, 1.5, or 2 g). Following a standard mixed meal (110 g carbohydrate, 20 g protein, 20 g fat), we measured 3-hour glucose and insulin area under the curve (AUC), insulin sensitivity (Matsuda index), and secretion (corrected insulin response at 30 minutes). Endothelial function was assessed by reactive hyperemia peripheral arterial tonometry (reactive hyperemia index) before and 90 minutes postmeal. Results did not differ by dose, so data were combined for analysis. RESULTS: At baseline, body mass index was 29 ± 5 kg/m(2), fasting plasma glucose 110 ± 13 mg/dL, and 2-hour glucose 183 ± 33 mg/dL. After 4 weeks of resveratrol, fasting plasma glucose was unchanged, but peak postmeal (185 ± 10 vs 166 ± 9 mg/dL, p = .003) and 3-hour glucose AUC (469 ± 23 vs 428 ± 19, p = .001) declined. Matsuda index improved (3.1 ± 0.5 vs 3.8 ± 0.5, p = .03), and corrected insulin response at 30 minutes was unchanged (0.6 ± 0.1 vs 0.5 ± 0.5, p = .49). There was a trend toward improved postmeal reactive hyperemia index (baseline vs resveratrol postmeal delta -0.4 ± 0.2 vs 0.2 ± 0.3, p = .06). Weight, blood pressure, and lipids were unchanged. CONCLUSIONS: 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.