Sangeeta R. Kashyap

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.

Bariatric Surgery versus Intensive Medical Therapy in Obese Patients with Diabetes

BACKGROUND Observational studies have shown improvement in patients with type 2 diabetes mellitus after bariatric surgery. METHODS In this randomized, nonblinded, single-center trial, we evaluated the efficacy of intensive medical therapy alone versus medical therapy plus Roux-en-Y gastric bypass or sleeve gastrectomy in 150 obese patients with uncontrolled type 2 diabetes. The mean (±SD) age of the patients was 49±8 years, and 66% were women. The average glycated hemoglobin level was 9.2±1.5%. The primary end point was the proportion of patients with a glycated hemoglobin level of 6.0% or less 12 months after treatment. RESULTS Of the 150 patients, 93% completed 12 months of follow-up. The proportion of patients with the primary end point was 12% (5 of 41 patients) in the medical-therapy group versus 42% (21 of 50 patients) in the gastric-bypass group (P=0.002) and 37% (18 of 49 patients) in the sleeve-gastrectomy group (P=0.008). Glycemic control improved in all three groups, with a mean glycated hemoglobin level of 7.5±1.8% in the medical-therapy group, 6.4±0.9% in the gastric-bypass group (P<0.001), and 6.6±1.0% in the sleeve-gastrectomy group (P=0.003). Weight loss was greater in the gastric-bypass group and sleeve-gastrectomy group (-29.4±9.0 kg and -25.1±8.5 kg, respectively) than in the medical-therapy group (-5.4±8.0 kg) (P<0.001 for both comparisons). The use of drugs to lower glucose, lipid, and blood-pressure levels decreased significantly after both surgical procedures but increased in patients receiving medical therapy only. The index for homeostasis model assessment of insulin resistance (HOMA-IR) improved significantly after bariatric surgery. Four patients underwent reoperation. There were no deaths or life-threatening complications. CONCLUSIONS In obese patients with uncontrolled type 2 diabetes, 12 months of medical therapy plus bariatric surgery achieved glycemic control in significantly more patients than medical therapy alone. Further study will be necessary to assess the durability of these results. (Funded by Ethicon Endo-Surgery and others; ClinicalTrials.gov number, NCT00432809.).

Bariatric Surgery versus Intensive Medical Therapy for Diabetes — 3-Year Outcomes

BACKGROUND Long‐term results from randomized, controlled trials that compare medical therapy with surgical therapy in patients with type 2 diabetes are limited. METHODS We assessed outcomes 5 years after 150 patients who had type 2 diabetes and a body‐mass index (BMI; the weight in kilograms divided by the square of the height in meters) of 27 to 43 were randomly assigned to receive intensive medical therapy alone or intensive medical therapy plus Roux‐en‐Y gastric bypass or sleeve gastrectomy. The primary outcome was a glycated hemoglobin level of 6.0% or less with or without the use of diabetes medications. RESULTS Of the 150 patients who underwent randomization, 1 patient died during the 5‐year follow‐up period; 134 of the remaining 149 patients (90%) completed 5 years of follow‐up. At baseline, the mean (±SD) age of the 134 patients was 49±8 years, 66% were women, the mean glycated hemoglobin level was 9.2±1.5%, and the mean BMI was 37±3.5. At 5 years, the criterion for the primary end point was met by 2 of 38 patients (5%) who received medical therapy alone, as compared with 14 of 49 patients (29%) who underwent gastric bypass (unadjusted P=0.01, adjusted P=0.03, P=0.08 in the intention‐to‐treat analysis) and 11 of 47 patients (23%) who underwent sleeve gastrectomy (unadjusted P=0.03, adjusted P=0.07, P=0.17 in the intention‐to‐treat analysis). Patients who underwent surgical procedures had a greater mean percentage reduction from baseline in glycated hemoglobin level than did patients who received medical therapy alone (2.1% vs. 0.3%, P=0.003). At 5 years, changes from baseline observed in the gastric‐bypass and sleeve‐gastrectomy groups were superior to the changes seen in the medical‐therapy group with respect to body weight (‐23%, ‐19%, and ‐5% in the gastric‐bypass, sleeve‐gastrectomy, and medical‐therapy groups, respectively), triglyceride level (‐40%, ‐29%, and ‐8%), high‐density lipoprotein cholesterol level (32%, 30%, and 7%), use of insulin (‐35%, ‐34%, and ‐13%), and quality‐of‐life measures (general health score increases of 17, 16, and 0.3; scores on the RAND 36‐Item Health Survey ranged from 0 to 100, with higher scores indicating better health) (P<0.05 for all comparisons). No major late surgical complications were reported except for one reoperation. CONCLUSIONS Five‐year outcome data showed that, among patients with type 2 diabetes and a BMI of 27 to 43, bariatric surgery plus intensive medical therapy was more effective than intensive medical therapy alone in decreasing, or in some cases resolving, hyperglycemia. (Funded by Ethicon Endo‐Surgery and others; STAMPEDE ClinicalTrials.gov number, NCT00432809.)

Bariatric surgery versus non-surgical treatment for obesity: a systematic review and meta-analysis of randomised controlled trials

Objective To quantify the overall effects of bariatric surgery compared with non-surgical treatment for obesity. Design Systematic review and meta-analysis based on a random effects model. Data sources Searches of Medline, Embase, and the Cochrane Library from their inception to December 2012 regardless of language or publication status. Eligibility criteria Eligible studies were randomised controlled trials with ≥6 months of follow-up that included individuals with a body mass index ≥30, compared current bariatric surgery techniques with non-surgical treatment, and reported on body weight, cardiovascular risk factors, quality of life, or adverse events. Results The meta-analysis included 11 studies with 796 individuals (range of mean body mass index at baseline 30-52). Individuals allocated to bariatric surgery lost more body weight (mean difference −26 kg (95% confidence interval −31 to −21)) compared with non-surgical treatment, had a higher remission rate of type 2 diabetes (relative risk 22.1 (3.2 to 154.3) in a complete case analysis; 5.3 (1.8 to 15.8) in a conservative analysis assuming diabetes remission in all non-surgically treated individuals with missing data) and metabolic syndrome (relative risk 2.4 (1.6 to 3.6) in complete case analysis; 1.5 (0.9 to 2.3) in conservative analysis), greater improvements in quality of life and reductions in medicine use (no pooled data). Plasma triglyceride concentrations decreased more (mean difference −0.7 mmol/L (−1.0 to −0.4) and high density lipoprotein cholesterol concentrations increased more (mean difference 0.21 mmol/L (0.1 to 0.3)). Changes in blood pressure and total or low density lipoprotein cholesterol concentrations were not significantly different. There were no cardiovascular events or deaths reported after bariatric surgery. The most common adverse events after bariatric surgery were iron deficiency anaemia (15% of individuals undergoing malabsorptive bariatric surgery) and reoperations (8%). Conclusions Compared with non-surgical treatment of obesity, bariatric surgery leads to greater body weight loss and higher remission rates of type 2 diabetes and metabolic syndrome. However, results are limited to two years of follow-up and based on a small number of studies and individuals. Systematic review registration PROSPERO CRD42012003317 (www.crd.york.ac.uk/PROSPERO).

Can Diabetes Be Surgically Cured?: Long-Term Metabolic Effects of Bariatric Surgery in Obese Patients with Type 2 Diabetes Mellitus

Objective: Evaluate the long-term effects of bariatric surgery on type 2 diabetes (T2DM) remission and metabolic risk factors. Background: Although the impressive antidiabetic effects of bariatric surgery have been shown in short- and medium-term studies, the durability of these effects is uncertain. Specifically, long-term remission rates following bariatric surgery are largely unknown. Methods: Clinical outcomes of 217 patients with T2DM who underwent bariatric surgery between 2004 and 2007 and had at least 5-year follow-up were assessed. Complete remission was defined as glycated hemoglobin (A1C) less than 6% and fasting blood glucose (FBG) less than 100 mg/dL off diabetic medications. Changes in other metabolic comorbidities, including hypertension, dyslipidemia, and diabetic nephropathy, were assessed. Results: At a median follow-up of 6 years (range: 5–9) after surgery (Roux-en-Y gastric bypass, n = 162; gastric banding, n = 32; sleeve gastrectomy, n = 23), a mean excess weight loss (EWL) of 55% was associated with mean reductions in A1C from 7.5% ± 1.5% to 6.5% ± 1.2% (P < 0.001) and FBG from 155.9 ± 59.5 mg/dL to 114.8 ± 40.2 mg/dL (P < 0.001). Long-term complete and partial remission rates were 24% and 26%, respectively, whereas 34% improved (>1% decrease in A1C without remission) from baseline and 16% remained unchanged. Shorter duration of T2DM (P < 0.001) and higher long-term EWL (P = 0.006) predicted long-term remission. Recurrence of T2DM after initial remission occurred in 19% and was associated with longer duration of T2DM (P = 0.03), less EWL (P = 0.02), and weight regain (P = 0.015). Long-term control rates of low high-density lipoprotein, high low-density lipoprotein, high triglyceridemia, and hypertension were 73%, 72%, 80%, and 62%, respectively. Diabetic nephropathy regressed (53%) or stabilized (47%). Conclusions: Bariatric surgery can induce a significant and sustainable remission and improvement of T2DM and other metabolic risk factors in severely obese patients. Surgical intervention within 5 years of diagnosis is associated with a high rate of long-term remission.

Plasma Ceramides Are Elevated in Obese Subjects With Type 2 Diabetes and Correlate With the Severity of Insulin Resistance

OBJECTIVE—To quantitate plasma ceramide subspecies concentrations in obese subjects with type 2 diabetes and relate these plasma levels to the severity of insulin resistance. Ceramides are a putative mediator of insulin resistance and lipotoxicity, and accumulation of ceramides within tissues in obese and diabetic subjects has been well described. RESEARCH DESIGN AND METHODS—We analyzed fasting plasma ceramide subspecies by quantitative tandem mass spectrometry in 13 obese type 2 diabetic patients and 14 lean healthy control subjects. Results were related to insulin sensitivity measured with the hyperinsulinemic-euglycemic clamp technique and with plasma tumor necrosis factor-α (TNF-α) levels, a marker of inflammation. Ceramide species (C18:1, 18:0, 20:0, 24:1, and 24:0) were quantified using electrospray ionization tandem mass spectrometry after separation with high-performance liquid chromatography. RESULTS—Insulin sensitivity (mg · kg−1 · min−1) was lower in type 2 diabetic patients (4.90 ± 0.3) versus control subjects (9.6 ± 0.4) (P < 0.0001). Type 2 diabetic subjects had higher (P < 0.05) concentrations of C18:0, C20:0, C24:1, and total ceramide. Insulin sensitivity was inversely correlated with C18:0, C20:0, C24:1, C24:0, and total ceramide (all P < 0.01). Plasma TNF-α concentration was increased (P < 0.05) in type 2 diabetic subjects and correlated with increased C18:1 and C18:0 ceramide subspecies. CONCLUSIONS—Plasma ceramide levels are elevated in type 2 diabetic subjects and may contribute to insulin resistance through activation of inflammatory mediators, such as TNF-α.

Adiponectin receptors gene expression and insulin sensitivity in non-diabetic Mexican Americans with or without a family history of Type 2 diabetes.

Aims/hypothesisThe recent discovery of two adiponectin receptors (AdipoR1 and AdipoR2) will improve our understanding of the molecular mechanisms underlying the insulin-sensitising effect of adiponectin. The aim of this study was to determine for the first time whether skeletal muscle AdipoR1 and/or AdipoR2 gene expression levels are associated with insulin resistance.MethodsUsing RT-PCR and northern analysis we measured AdipoR1 and AdipoR2 gene expression in skeletal muscle from healthy Mexican Americans with normal glucose tolerance who had (n=8) or did not have (n=10) a family history of Type 2 diabetes.ResultsGene expression profiling indicated that the AdipoR1 and AdipoR2 isoforms are highly expressed in human skeletal muscle, unlike in mice where AdipoR2 expression was highest in the liver, and AdipoR1 was highest in skeletal muscle. In the study subjects, the expression levels of AdipoR1 (p=0.004) and AdipoR2 (p=0.04), as well as plasma adiponectin concentration (p=0.03) were lower in people with a family history of Type 2 diabetes than in those with no family history of the disease. Importantly, the expression levels of both receptors correlated positively with insulin sensitivity (r=0.64, p=0.004 and r=0.47, p=0.048 respectively).Conclusions/interpretationCollectively, these data indicate that both isoforms of the adiponectin receptor play a role in the insulin-sensitising effect of adiponectin.

Metabolic syndrome and kidney disease: a systematic review and meta-analysis.

BACKGROUND AND OBJECTIVES Observational studies have reported an association between metabolic syndrome (MetS) and microalbuminuria or proteinuria and chronic kidney disease (CKD) with varying risk estimates. We aimed to systematically review the association between MetS, its components, and development of microalbuminuria or proteinuria and CKD. DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS AND POPULATION: We searched MEDLINE (1966 to October 2010), SCOPUS, and the Web of Science for prospective cohort confidence interval (CI) studies that reported the development of microalbuminuria or proteinuria and/or CKD in participants with MetS. Risk estimates for eGFR <60 ml/min per 1.73 m(2) were extracted from individual studies and pooled using a random effects model. The results for proteinuria outcomes were not pooled because of the small number of studies. RESULTS Eleven studies (n = 30,146) were included. MetS was significantly associated with the development of eGFR <60 ml/min per 1.73 m(2) (odds ratio, 1.55; 95% CI, 1.34, 1.80). The strength of this association seemed to increase as the number of components of MetS increased (trend P value = 0.02). In patients with MetS, the odds ratios (95% CI) for development of eGFR <60 ml/min per 1.73 m(2) for individual components of MetS were: elevated blood pressure 1.61 (1.29, 2.01), elevated triglycerides 1.27 (1.11, 1.46), low HDL cholesterol 1.23 (1.12, 1.36), abdominal obesity 1.19 (1.05, 1.34), and impaired fasting glucose 1.14 (1.03, 1.26). Three studies reported an increased risk for development of microalbuminuria or overt proteinuria with MetS. CONCLUSIONS MetS and its components are associated with the development of eGFR <60 ml/min per 1.73 m(2) and microalbuminuria or overt proteinuria.

Acute effects of gastric bypass versus gastric restrictive surgery on β-cell function and insulinotropic hormones in severely obese patients with type 2 diabetes

Context:Hyperglycemia resolves quickly after bariatric surgery, but the underlying mechanism and the most effective type of surgery remains unclear.Objective:To examine glucose metabolism and β-cell function in patients with type 2 diabetes mellitus (T2DM) after two types of bariatric intervention; Roux-en-Y gastric bypass (RYGB) and gastric restrictive (GR) surgery.Design:Prospective, nonrandomized, repeated-measures, 4-week, longitudinal clinical trial.Patients:In all, 16 T2DM patients (9 males and 7 females, 52±14 years, 47±9 kg m−2, HbA1c 7.2±1.1%) undergoing either RYGB (N=9) or GR (N=7) surgery.Outcome measures:Glucose, insulin secretion, insulin sensitivity at baseline, and 1 and 4 weeks post-surgery, using hyperglycemic clamps and C-peptide modeling kinetics; glucose, insulin secretion and gut-peptide responses to mixed meal tolerance test (MMTT) at baseline and 4 weeks post-surgery.Results:At 1 week post-surgery, both groups experienced a similar weight loss and reduction in fasting glucose (P<0.01). However, insulin sensitivity increased only after RYGB, (P<0.05). At 4 weeks post-surgery, weight loss remained similar for both groups, but fasting glucose was normalized only after RYGB (95±3 mg 100 ml−1). Insulin sensitivity improved after RYGB (P<0.01) and did not change with GR, whereas the disposition index remained unchanged after RYGB and increased 30% after GR (P=0.10). The MMTT elicited a robust increase in insulin secretion, glucagon-like peptide-1 (GLP-1) levels and β-cell sensitivity to glucose only after RYGB (P<0.05).Conclusion:RYGB provides a more rapid improvement in glucose regulation compared with GR. This improvement is accompanied by enhanced insulin sensitivity and β-cell responsiveness to glucose, in part because of an incretin effect.

Lipid Infusion Decreases the Expression of Nuclear Encoded Mitochondrial Genes and Increases the Expression of Extracellular Matrix Genes in Human Skeletal Muscle

The association between elevated plasma free fatty acid (FFA) concentrations and insulin resistance is well known. Although the cause and effect relationship between FFAs and insulin resistance is complex, plasma FFA is negatively correlated with the expression of peroxisome proliferator activated receptor-γ cofactor-1 (PGC-1) and nuclear encoded mitochondrial genes. To test whether this association is causal, we infused a triglyceride emulsion (or saline as control) into healthy subjects to increase plasma FFA for 48 h followed by muscle biopsies, microarray analysis, quantitative real time PCR, and immunoblots. Lipid infusion increased plasma FFA concentration from 0.48 ± 0.02 to 1.73 ± 0.43 mm and decreased insulin-stimulated glucose disposal from 8.82 ± 0.69 to 6.67 ± 0.66 mg/kg·min, both with p < 0.05. PGC-1 mRNA, along with mRNAs for a number of nuclear encoded mitochondrial genes, were reduced by lipid infusion (p < 0.05). Microarray analysis also revealed that lipid infusion caused a significant overexpression of extracellular matrix genes and connective tissue growth factor. Quantitative reverse transcription PCR showed that the mRNA expression of collagens and multiple extracellular matrix genes was higher after the lipid infusion (p < 0.05). Immunoblot analysis revealed that lipid infusion also increased the expression of collagens and the connective tissue growth factor protein. 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.