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1.  Metabolic Effects of Bariatric Surgery in Patients With Moderate Obesity and Type 2 Diabetes 
Diabetes Care  2013;36(8):2175-2182.
OBJECTIVE
To evaluate the effects of two bariatric procedures versus intensive medical therapy (IMT) on β-cell function and body composition.
RESEARCH DESIGN AND METHODS
This was a prospective, randomized, controlled trial of 60 subjects with uncontrolled type 2 diabetes (HbA1c 9.7 ± 1%) and moderate obesity (BMI 36 ± 2 kg/m2) randomized to IMT alone, IMT plus Roux-en-Y gastric bypass, or IMT plus sleeve gastrectomy. Assessment of β-cell function (mixed-meal tolerance testing) and body composition was performed at baseline and 12 and 24 months.
RESULTS
Glycemic control improved in all three groups at 24 months (N = 54), with a mean HbA1c of 6.7 ± 1.2% for gastric bypass, 7.1 ± 0.8% for sleeve gastrectomy, and 8.4 ± 2.3% for IMT (P < 0.05 for each surgical group versus IMT). Reduction in body fat was similar for both surgery groups, with greater absolute reduction in truncal fat in gastric bypass versus sleeve gastrectomy (−16 vs. −10%; P = 0.04). Insulin sensitivity increased significantly from baseline in gastric bypass (2.7-fold; P = 0.004) and did not change in sleeve gastrectomy or IMT. β-Cell function (oral disposition index) increased 5.8-fold in gastric bypass from baseline, was markedly greater than IMT (P = 0.001), and was not different between sleeve gastrectomy versus IMT (P = 0.30). At 24 months, β-cell function inversely correlated with truncal fat and prandial free fatty acid levels.
CONCLUSIONS
Bariatric surgery provides durable glycemic control compared with intensive medical therapy at 2 years. Despite similar weight loss as sleeve gastrectomy, gastric bypass uniquely restores pancreatic β-cell function and reduces truncal fat, thus reversing the core defects in diabetes.
doi:10.2337/dc12-1596
PMCID: PMC3714483  PMID: 23439632
2.  Equivalent Weight Loss with Marked Metabolic Benefit Observed in a Matched Cohort with and without Type 2 Diabetes Twelve Months Following Gastric Bypass Surgery 
Obesity surgery  2012;22(11):1723-1729.
Background
Bariatric surgery results in dramatic weight loss and improves metabolic syndrome and Type 2 diabetes (T2DM). However, previous studies have noted that morbidly obese patients with T2DM experience less weight loss benefits than non-diabetic patients following bariatric surgery. We sought to determine longitudinal effects of laparoscopic Roux-en-Y gastric bypass (LRYGB) on percent excess BMI loss (%EBMIL) and clinical metabolic syndrome parameters in patients with T2DM compared to appropriately matched cohort without T2DM.
Methods
Retrospective cohort analysis of T2DM patients (n=126) to non-T2DM patients (n=126) matched on age (M=48.1±9.5), sex (81% Female), race (81% Caucasian) and pre-surgical body mass index (BMI; M=49.3±9.5). Lipids, glucose, hemoglobin A1c, blood pressure (BP), co-morbidities of obesity, medications for co-morbidities and T2DM medications were collected at baseline, 6 months and 12 months post-surgery. %EBMIL was collected at 1, 3, 6, 9 and 12 months post-surgery. One-way ANOVAs with effect sizes estimates were conducted to compare the two groups.
Results
As expected, T2DM subjects had significantly greater pre-surgical HbA1c, blood glucose, blood pressure and lipid parameters at baseline vs. non-T2DM (all p's<0.05). At 1, 3, 6, 9, and 12 months after LRYRB, both groups had similar reduction in %EBMIL (p>0.10). At 6 months, there was a significant reduction in HbA1c, blood glucose and lipid in the T2DM cohort compared to pre-surgical levels (p<0.0001). At 12 months, these values were not different to that of the non-T2DM subjects (p>0.10).
Conclusion
When matched on appropriate factors associated with weight loss outcomes, severely obese patients with T2DM have similar post-LRYGB weight loss outcomes in the first twelve months following surgery compared to non-T2DM patients. Further, T2DM surgical patients achieved significant improvement in metabolic syndrome components.
doi:10.1007/s11695-012-0719-8
PMCID: PMC4023564  PMID: 22895804
Type 2 Diabetes Mellitus; Morbid obesity; Roux-en-Y anastomosis; Weight loss; Metabolic Syndrome; Gastric bypass; Bariatric surgery; Insulin
3.  Reduced Cardiovascular Risk Following Bariatric Surgeries is Related to a Partial Recovery from “Adiposopathy” 
Obesity surgery  2011;21(12):1928-1936.
Background
Altered cytokine secretion from dysfunctional adipose tissue or “adiposopathy” is implicated in obesity related inflammation and may mediate reduced CVD risk in response to weight loss after bariatric surgery. We hypothesized that bariatric surgery reduces CVD risk by favorably altering the pro-inflammatory profile of adipose tissue as a result of weight loss.
Methods
In this observational study with repeated measures, 142 patients underwent bariatric surgery of which 45 returned for follow up at ~6 months. At both time-points, lipid profiles and levels of plasma adiponectin, leptin, and TNF-α were obtained. Ratios of various adipokine parameters were related to pre- and post- surgical (gastric bypass vs. other restrictive bariatric procedures) lipid ratios.
Results
Prior to surgery, circulating adiponectin and the adiponectin/TNF-α ratio was strongly associated with CVD risk characterized by levels of triglycerides, HDL, and the TC/HDL, LDL/HDL and TG/HDL ratios (all P < 0.05). Following bariatric surgery, BMI was decreased by 22%, adiponectin was increased by 93%, and leptin decreased by 50% as compared to baseline (all P < 0.01). TNF-α levels increased by 120% (P < 0.01) following surgery. Post-surgical changes in adiponectin and the leptin/adiponectin ratio were strongly associated with incremental improvements in triglycerides, HDL, and TC/HDL, LDL/HDL and TG/HDL ratios (all P < 0.05). Roux-en-y gastric bypass surgery (RYGB) as compared to other bariatric procedures was associated with more robust improvements in BMI, HDL, and leptin/adiponectin ratio than other gastric restrictive procedures (P < 0.05).
Conclusions
Thus, bariatric surgery, especially RYGB, ameliorates CVD risk through a partial recovery from “adiposopathy”, distinctively characterized by improved adiponectin and the leptin/adiponectin ratio.
doi:10.1007/s11695-011-0447-5
PMCID: PMC3165064  PMID: 21625910
obesity; cholesterol; adipokines; adiponectin; tumor necrosis factor; leptin; bariatric surgery; gastric bypass
4.  Weight Loss as a Cure for Type 2 Diabetes? Fact or Fantasy 
Although individuals with obesity and type 2 diabetes are insulin resistant, pancreatic beta cell failure is the core defect that distinguishes individuals who eventually develop diabetes. This process is known to occur well before the onset of hyperglycemia. Although clinical trial data support the effectiveness of intensive lifestyle modification in delaying the onset of diabetes in obese subjects, less is known about the effects of and mechanisms underlying bariatric surgery, particularly gastric bypass surgery, on diabetes. The paper under evaluation clarifies the role of both lifestyle intervention and gastric bypass surgery on pancreatic beta cell function and raises questions regarding the role of weight loss versus incretin related mechanisms on recovery of beta cell failure.
PMCID: PMC3145356  PMID: 21804860
obesity; type 2 diabetes; gastric bypass surgery; weight loss; lifestyle modification; beta cell function; insulin resistance
5.  Cancer Risk in Type 2 Diabetes Mellitus: Metabolic Links and Therapeutic Considerations 
Type 2 diabetes mellitus (DM2) is increasing in incidence, creating worldwide public health concerns and impacting morbidity and mortality rates. An increasing number of studies have demonstrated shared associations between DM2 and malignancy, including key clinical, biochemical, and metabolic commonalities. This paper will attempt to explore the relationship between the various types of cancer and diabetes, the common metabolic pathways underlying cancer development, and the potential impact of various antidiabetes therapies on cancer risk.
doi:10.1155/2011/708183
PMCID: PMC3136221  PMID: 21773024
6.  Insulin Reduces Plasma Arginase Activity in Type 2 Diabetes Patients 
Diabetes care  2007;31(1):134-139.
Objective
We sought to determine whether dysregulation of arginine metabolism is related to insulin resistance and underlies impaired nitric oxide generation in type 2 diabetic (T2DM) patients.
Research Design and Methods
We measured plasma arginase activity, arginine metabolites and skeletal muscle NOS activity in 12 T2DM and 10 age/BMI matched non-diabetic subjects before and following 4 hour euglycemic hyperinsulinemic clamp with muscle biopsies. Arginine metabolites were determined by tandem mass spectroscopy. Arginase activity was determined by conversion of [14C] guanidoinoarginine to [14 C] urea.
Results
Glucose disposal (Rd) was reduced by 50% in diabetic vs. control subjects. NOS activity was 4 fold reduced in the diabetic group (107 ± 45 vs. 459 ± 100 pmol/min•mg protein, P<0.05) and failed to increase with insulin. Plasma arginase activity was increased by 50% in diabetic vs. control group (0.48 ± 0.11 vs.0.32 ± 0.12 umol/ml•hr, P < 0.05) and markedly declined in diabetic subjects with 4-h insulin infusion (to 0.13 ± 0.04 vs. basal, P <0.05). In both groups collectively, plasma arginase activity correlated positively with fasting plasma glucose (R = 0.46, P < 0.05) and HbA1c levels (R = 0.51, P < 0.02), but not with Rd.
Conclusions
Plasma arginase activity is increased in T2DM subjects with impaired NOS activity, correlates with the degree of hyperglycemia, and is reduced by physiologic hyperinsulinemia. Elevated arginase activity may contribute to impaired nitric oxide generation in type 2 diabetes and insulin may ameliorate this defect via reducing arginase activity.
doi:10.2337/dc07-1198
PMCID: PMC3101496  PMID: 17928367
type 2 diabetes; insulin; arginase; nitric oxide; hyperglycemia; insulin resistance
7.  Weight Considerations in Pharmacotherapy for Type 2 Diabetes 
Journal of Obesity  2010;2011:984245.
Obesity has been increasing in prevalence worldwide and the majority of patients with type 2 diabetes are either overweight or obese. Diabetes management in this population has been difficult since a number of antidiabetes agents are associated with weight gain. The effects of various antidiabetes agents and antiobesity agents on glycemic control and body weight will be reviewed. Briefly, sulfonylureas, thiazolidinediones, and insulin are associated with weight gain, whereas metformin and amylin analogs are weight neutral or associated with modest weight loss. Dipeptidyl-peptidase-4 inhibitors are weight neutral, whereas glucagon-like peptide-1 analogs are associated with weight loss. The effect of orlistat and sibutramine in type 2 diabetes is also evaluated. The treatment of diabetes should not only focus on glycemic control as its sole intention, but it should factor in the effect of these various agents on weight, as well, since obesity aggravates insulin resistance, beta cell failure, and cardiovascular risk.
doi:10.1155/2011/984245
PMCID: PMC2946585  PMID: 20885921
8.  Lipid Induced Insulin Resistance is Associated with Increased Monocyte Expression of Scavenger Receptor CD36 and Internalization of Oxidized LDL 
Obesity (Silver Spring, Md.)  2009;17(12):2142-2148.
Elevated free fatty acids (FFAs) contribute to the development of insulin resistance, type 2 diabetes, and may be atherogenic. We tested the relationship between lipid induced insulin resistance, endothelial dysfunction and monocyte capacity to form foam cells through scavenger receptor A (SRA) and CD36. Ten healthy subjects underwent 24 hour infusion of Intralipid/heparin and saline (0.5ml/min) on two separate occasions followed by brachial artery reactivity testing and a euglycemic hyperinsulinemic (80 mU/(kg *min)) clamp study to determine insulin sensitivity. Isolation of blood monocytes was performed 24 hr following infusion. Surface expression and function of CD36 and SRA to take up oxidized LDL was determined by flow cytometry and quantitative confocal imaging. Lipid infusion resulted in a 2 fold increase in serum FFA levels, reduced whole body glucose disposal by ~20% (P< 0.05), and possibly impaired endothelial dependent vasodilation (P = 0.1). Blood monocytes obtained during lipid infusion demonstrated a ~25% increase in cell surface expression of CD36 (P < 0.05) but no change in SRA expression. Enhanced CD36 expression was associated with a 50% increase in internalization of oxidized LDL (P < 0.05). The increase in CD36 surface expression during lipid infusion correlated inversely with glucose disposal (P < 0.05) and not with FFA levels or brachial artery dilation. These data support a role for FFAs in induction of insulin resistance and provide a link to atherogenic mechanisms mediated by expression of scavenger receptor CD36.
doi:10.1038/oby.2009.179
PMCID: PMC2836489  PMID: 19521352
FFA; FAT/CD36; euglycemic hyperinsulinemic clamp; monocyte; insulin; oxidized LDL
9.  Triglyceride Levels and Not Adipokine Concentrations Are Closely Related to severity of Nonalcoholic Fatty Liver Disease in an Obesity surgery Cohort 
Obesity (Silver Spring, Md.)  2009;17(9):1696-1701.
Although nonalcoholic fatty liver disease (NAFLD) is frequent in obesity, the metabolic determinants of advanced liver disease remain unclear. Adipokines reflect inflammation and insulin resistance associated with obesity and may identify advanced NAFLD. At the time of obesity surgery, 142 consecutive patients underwent liver biopsy and had their preoperative demographic and clinical data obtained. Liver histology was scored by the NAFLD activity score, and patients subdivided into four groups. Concentrations of retinol-binding protein 4 (RBP4), adiponectin, tumor necrosis factor-α (TNF-α), and leptin were determined ~1 week prior to surgery and results were related to liver histology. The prevalence of no NAFLD was 30%, simple steatosis 23%, borderline nonalcoholic steatohepatitis (NASH) 28%, and definitive NASH 18%. Type 2 diabetes mellitus (T2DM) and metabolic syndrome (MS) prevalence were 39 and 75%, respectively, and did not differ across the four histological groups (P = NS). Triglyceride (TG) and alanine transaminase (ALT) levels, strongly associated with advanced stages of NAFLD and NASH (P = 0.04). TG levels >150 mg/dl, increased the likelihood of NASH 3.4-fold, whereas high-density lipoprotein (HDL) levels predicted no NAFLD (P < 0.01). Concentrations of TNF-α, leptin, and RBP4 did not differ among histological groups and thus did not identify NASH; however, there was a trend for adiponectin to be lower in NASH vs. no NAFLD (P = 0.061). In summary, both TG and ALT levels assist in identification of NASH in an obesity surgery cohort. These findings underscore the importance of fatty acid delivery mechanisms to NASH development in severely obese individuals.
doi:10.1038/oby.2009.89
PMCID: PMC2829436  PMID: 19360015
10.  Lower Dipeptidyl peptidase-4 following exercise training plus weight loss is related to increased insulin sensitivity in adults with metabolic syndrome 
Peptides  2013;47:10.1016/j.peptides.2013.07.008.
Dipeptidyl peptidase-4 (DPP-4) is a circulating glycoprotein that impairs insulin-stimulated glucose uptake and is linked to obesity and metabolic syndrome. However, the effect of exercise on plasma DPP-4 in adults with metabolic syndrome is unknown. Therefore, we determined the effect of exercise on DPP-4 and its role in explaining exercise-induced improvements in insulin sensitivity. Fourteen obese adults (67.9±1.2yr, BMI: 34.2±1.1kg/m2) with metabolic syndrome (ATP III criteria) underwent a 12-week supervised exercise intervention (60 min/d for 5 d/wk at ~85% HRmax). Plasma DPP-4 was analyzed using an enzyme-linked immunosorbent assay. Insulin sensitivity was measured using the euglycemic-hyperinsulinemic clamp (40mU/m2/min) and estimated by HOMA-IR. Visceral fat (computerized tomography), 2-hour glucose levels (75g oral glucose tolerance), and basal fat oxidation as well as aerobic fitness (indirect calorimetry) were also determined before and after exercise. The intervention reduced visceral fat, lowered blood pressure, glucose and lipids, and increased aerobic fitness (P<0.05). Exercise improved clamp-derived insulin sensitivity by 75% (P<0.001) and decreased HOMA-IR by 15% (P<0.05). Training decreased plasma DPP-4 by 10% (421.8±30.1 vs. 378.3±32.5ng/ml; P<0.04), and the decrease in DPP-4 was associated with clamp-derived insulin sensitivity (r=−0.59; P<0.04), HOMA-IR (r=0.59; P<0.04) and fat oxidation (r=−0.54; P<0.05). Increased fat oxidation also correlated with lower 2-hour glucose levels (r=−0.64; P<0.02). Exercise training reduces plasma DPP-4, which may be linked to elevated insulin sensitivity and fat oxidation. Maintaining low plasma DPP-4 concentrations is a potential mechanism whereby exercise plus weight loss prevents/delays the onset of type 2 diabetes in adults with metabolic syndrome.
doi:10.1016/j.peptides.2013.07.008
PMCID: PMC3825405  PMID: 23872069
impaired glucose tolerance; obesity; cytokine; diabetes
11.  Can Diabetes Be Surgically Cured? 
Annals of surgery  2013;258(4):628-637.
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.
doi:10.1097/SLA.0b013e3182a5034b
PMCID: PMC4110959  PMID: 24018646
bariatric; diabetes; gastric banding; gastric bypass; LAGB; long term; metabolic; nephropathy; RYGB; sleeve gastrectomy
12.  Reduced cardiovascular risk after bariatric surgery is linked to plasma ceramides, apolipoprotein-B100 and the ApoB100/A1 ratio 
Background
Obesity-associated hyperlipidemia and hyperlipoproteinemia are risk factors for cardiovascular disease (CVD). Recently, ceramide-derived sphingolipids were identified as a novel independent CVD risk factor. We hypothesized that the beneficial effect of RYGB on CVD risk is related to ceramide-mediated improvement in lipoprotein profile.
Methods
A prospective study of patients undergoing RYGB was conducted. Patients clinical data and biochemical markers related to cardiovascular risk were documented. Plasma ceramide subspecies (C14:0, C16:0, C18:0, C18:1, C20:0, C24:0, and C24:1), ApoB100 and ApoA-1 were quantified preoperatively, 3 and 6 months post-RYGB, as was Framingham risk score. Brachial artery reactivity testing (BART) was performed before and 6 months after RYGB.
Results
Ten patients (9 female; age 48 yrs; BMI, 48.5±5.8 kg/m2) were included in the study. At 6 months post-op, mean BMI decreased to 35.7±5.0 corresponding to 51.3±10.0 % excess weight loss. Fasting total cholesterol, triglycerides, LDL, free fatty acids, ApoB100, ApoB100/ApoA-1 ratio and insulin resistance estimated from HOMA-IR were significantly reduced compared to pre-surgery values. The ratio of ApoB100/ApoA-1 correlated with a reduction in ceramide subspecies (C18:0, C18:1, C20, C24:0 and C24:1) (p<0.05). ApoB100 and the ApoB100/ApoA-1 ratio also positively correlated with the reduction in TG, LDL and HOMA-IR (p<0.05). BART inversely correlated with ApoB100 and total ceramide (p=0.05). Furthermore, the change in BART correlated with the decrease in C16:0 (p<0.03).
Conclusion
Our data suggests that improvements in lipid profiles and CVD risk factors after gastric bypass surgery may be linked to changes in ceramide lipid. Mechanistic studies are needed to determine if this link is causative or purely correlative.
doi:10.1016/j.soard.2011.11.018
PMCID: PMC3337956  PMID: 22264909
RYGB; bariatric surgery; cardiovascular risk; ceramide; sphingolipids; apolipoproteins; ApoB100; Apo A-1; ApoB100/Apo A-1 ratio
13.  Exercise training with weight loss and either a high or low glycemic diet reduces metabolic syndrome severity in older adults 
Annals of nutrition & metabolism  2012;61(2):135-141.
Background
The efficacy of combining carbohydrate quality with exercise on metabolic syndrome risk is unclear. Thus, we determined the effects of exercise training with a low or high glycemic diet on metabolic syndrome severity (Z-score).
Methods
Twenty-one adults (66.2 ± 1.1 yr; BMI = 35.3 ± 0.9 kg/m2) with metabolic syndrome were randomized to 12 weeks of exercise (60 minutes/d for 5 d/week at ~85% HRmax) and provided a low-glycemic (n=11; LoGIx) or high glycemic (n=10; HiGIx) diet. Z-scores were determined from: blood pressure, triglycerides (TG), high-density lipoproteins (HDL), fasting plasma glucose (FPG), and waist circumference (WC) before and after the intervention. Body composition, aerobic fitness, insulin resistance, and non-esterfied fatty acid (NEFA) suppression were also assessed.
Results
LoGIx and HiGIx decreased body mass and insulin resistance and increased aerobic fitness comparably (p < 0.05). LoGIx and HiGIx decreased the Z-score similarly, as each intervention decreased blood pressure, TG, FPG, and WC (p < 0.05). HiGIx tended to suppress NEFA during insulin stimulation compared to LoGIx (p = 0.06).
Conclusions
Our findings highlight that exercise with weight loss reduces metabolic syndrome severity whether individuals were randomized to a high or low glycemic index diet.
doi:10.1159/000342084
PMCID: PMC3586384  PMID: 23036993
aging; obesity; lifestyle modification; diabetes; impaired glucose tolerance
14.  Effect of acute physiological hyperinsulinemia on gene expression in human skeletal muscle in vivo 
This study was undertaken to test the hypothesis that short-term exposure (4 h) to physiological hyperinsulinemia in normal, healthy subjects without a family history of diabetes would induce a low grade inflammatory response independently of glycemic status. Twelve normal glucose tolerant subjects received a 4-h euglycemic hyperinsulinemic clamp with biopsies of the vastus lateralis muscle. Microarray analysis identified 121 probe sets that were significantly altered in response to physiological hyperinsulinemia while maintaining euglycemia. In normal, healthy human subjects insulin increased the mRNAs of a number of inflammatory genes (CCL2, CXCL2 and THBD) and transcription factors (ATF3, BHLHB2, HES1, KLF10, JUNB, FOS, and FOSB). A number of other genes were upregulated in response to insulin, including RRAD, MT, and SGK. CITED2, a known coactivator of PPARα, was significantly downregulated. SGK and CITED2 are located at chromosome 6q23, where we previously detected strong linkage to fasting plasma insulin concentrations. We independently validated the mRNA expression changes in an additional five subjects and closely paralleled the results observed in the original 12 subjects. A saline infusion in healthy, normal glucose-tolerant subjects without family history of diabetes demonstrated that the genes altered during the euglycemic hyperinsulinemic clamp were due to hyperinsulinemia and were unrelated to the biopsy procedure per se. 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.
doi:10.1152/ajpendo.00607.2007
PMCID: PMC3581328  PMID: 18334611
gene expression; muscle; insulin action; euglycemic hyperinsulinemic clamp; inflammation
15.  Bariatric Surgery versus Intensive Medical Therapy in Obese Patients with Diabetes 
The New England Journal of Medicine  2012;366(17):1567-1576.
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.)
doi:10.1056/NEJMoa1200225
PMCID: PMC3372918  PMID: 22449319
16.  Hypoadiponectinemia Is Closely Associated with Impaired Nitric Oxide Synthase Activity in Skeletal Muscle of Type 2 Diabetic Subjects 
Abstract
Objective
In vitro studies suggest that adiponectin plays an important role in nitric oxide (NO) generation. We studied the relationship between plasma adiponectin and skeletal muscle nitric oxide synthase (NOS) activity in type 2 diabetic (T2DM) patients.
Methods
We determined NOS activity in skeletal muscle of 7 T2DM and 8 nondiabetic control subjects under basal conditions and after a 4-h euglycemic insulin (80 mU/m2 · min) clamp.
Results
Insulin-stimulated glucose disposal (Rd) (5.2 ± 0.4 vs. 9.0 ± 0.9 mg/kg-min, P < 0.01) and basal NOS activity (107 ± 45 vs. 459 ± 100 pmol/min-mg protein, P < 0.05) were reduced in T2DM versus controls. In response to hyperinsulinemia, NOS activity increased approximately two-fold in controls (757 ± 244, P < 0.05 vs basal) but failed to increase in T2DM (105 ± 38, P < 0.01 vs. T2DM). Basal NOS protein content was similar in controls and T2DM and did not change following insulin. Plasma adiponectin was decreased in T2DM (4.5 ± 0.8 vs. 7.0 ± 1.0 μg/mL, P < 0.02) and correlated with insulin-stimulated NOS activity (r = 0.49, P < 0.05) and with Rd (r = 0.50, P < 0.05). In controls and T2DM collectively, Rd correlated with insulin-stimulated NOS activity (r = 0.48, P < 0.05).
Conclusion
Decreased plasma adiponectin correlates with impaired insulin-stimulated NOS activity and severity of insulin resistance in T2DM. Because impaired NO generation plays a central role in endothelial dysfunction and development of atherosclerosis, our results may provide a link between reduced plasma adiponectin levels and accelerated atherosclerosis in T2DM.
doi:10.1089/met.2010.0018
PMCID: PMC3125557  PMID: 20854065
17.  Improved Pancreatic β-Cell Function in Type 2 Diabetic Patients After Lifestyle-Induced Weight Loss Is Related to Glucose-Dependent Insulinotropic Polypeptide 
Diabetes Care  2010;33(7):1561-1566.
OBJECTIVE
Restoration of insulin secretion is critical for the treatment of type 2 diabetes. Exercise and diet can alter glucose-induced insulin responses, but whether this is due to changes in β-cell function per se is not clear. The mechanisms by which lifestyle intervention may modify insulin secretion in type 2 diabetes have also not been examined but may involve the incretin axis.
RESEARCH DESIGN AND METHODS
Twenty-nine older, obese (aged 65 ± 1 years; BMI 33.6 ± 1.0 kg/m2) subjects, including individuals with newly diagnosed type 2 diabetes (obese-type 2 diabetic) and individuals with normal glucose tolerance (obese-NGT), underwent 3 months of nutritional counseling and exercise training. β-Cell function (oral glucose–induced insulin secretion corrected for insulin resistance assessed by hyperinsulinemic-euglycemic clamps) and the role of glucose-dependent insulinotropic polypeptide (GIP) were examined.
RESULTS
After exercise and diet-induced weight loss (−5.0 ± 0.7 kg), oral glucose–induced insulin secretion was increased in the obese-type 2 diabetic group and decreased in the obese-NGT group (both P < 0.05). When corrected for alterations in insulin resistance, the change in insulin secretion remained significant only in the obese-type 2 diabetic group (1.23 ± 0.26 vs. 2.04 ± 0.46 arbitrary units; P < 0.01). Changes in insulin secretion were directly related to the GIP responses to oral glucose (r = 0.64, P = 0.005), which were augmented in the obese-type 2 diabetic group and only moderately suppressed in the obese-NGT group.
CONCLUSIONS
After lifestyle-induced weight loss, improvements in oral glucose–induced insulin secretion in older, obese, nondiabetic subjects seem to be largely dependent on improved insulin sensitivity. However, in older obese diabetic patients, improved insulin secretion is a consequence of elevated β-cell function. We demonstrate for the first time that changes in insulin secretion after lifestyle intervention may be mediated via alterations in GIP secretion from intestinal K-cells.
doi:10.2337/dc09-2021
PMCID: PMC2890359  PMID: 20200305
18.  Bariatric surgery for type 2 diabetes: Weighing the impact for obese patients 
Obesity is a potent risk factor for the development and progression of type 2 diabetes, and weight loss is a key component of diabetes management. Bariatric surgery results in significant weight loss and remission of diabetes in most patients. After surgery, glycemic control is restored by a combination of enforced caloric restriction, enhanced insulin sensitivity, and increased insulin secretion.
doi:10.3949/ccjm.77a.09135
PMCID: PMC3102524  PMID: 20601620
19.  Urinary Albumin Excretion, HMW Adiponectin, and Insulin Sensitivity in Type 2 Diabetic Patients Undergoing Bariatric Surgery 
Obesity surgery  2010;20(3):308-315.
Background
Microalbuminuria portends an increased risk for renal and cardiovascular diseases in diabetes. In this pilot study, we determined the effect of weight loss induced by different types of bariatric surgery on albuminuria in severely obese type 2 diabetic (T2DM) subjects.
Methods
Fifteen consecutive T2DM patients (9M/6F, 51 ± 14 years, body mass index (BMI) 49±9 kg/m2, HbA1c 7.2±1.1%) undergoing either Roux-en-Y gastric bypass (RYGB; N=9) or other types of bariatric surgery (N=6) underwent determination of urine albumin/creatinine ratio (UACR) and adipokine and insulin sensitivity during a mixed meal tolerance test performed 2 weeks prior to and 6 months following surgery.
Results
Following RYGB, there was a significant decrease in BMI (−4.74±−5.05 kg/m2), fasting glucose, cholesterol, and leptin levels. Insulin sensitivity (Matsuda index [12.05± 3.81, p=0.003]) and high molecular weight (HMW) adiponectin increased significantly along with a significant reduction in UACR (median, 36 mg/g [7–94] vs. 27 mg/g [5.5–42.5], p=0.01). The reduction in UACR following RYGB was inversely correlated with the Matsuda index (r=−0.74, p=0.02) and HMW adiponectin (r=−0.67, p=0.04). In contrast, despite reduction in BMI (−4.11±−4.10 kg/m2) following other types of bariatric surgery (n=6), there was no significant improvement in insulin sensitivity (0.88±2.40, p=0.63), UACR, or HMW adiponectin levels.
Conclusions
RYGB in severely obese DM subjects is associated with a reduction in albuminuria that correlates to the improvement in insulin sensitivity and HMW adiponectin. The data point to a need for larger studies to confirm these findings and evaluate the micro–macro-vascular benefits including renal parenchymal benefits of different types of bariatric surgery in T2DM.
doi:10.1007/s11695-009-0026-1
PMCID: PMC2891346  PMID: 20217955
Albuminuria; Insulin sensitivity; Adiponectin; Adipokines; Obesity; Type 2 diabetes; Gastric bypass surgery; Bariatric surgery
20.  Changes in Whole Blood Gene Expression in Obese Subjects with Type 2 Diabetes Following Bariatric Surgery: a Pilot Study 
PLoS ONE  2011;6(3):e16729.
Background
A pilot study was performed in order to investigate the effects of bariatric surgery on whole blood gene expression profiles in obese subjects with type 2 diabetes.
Methodology/Principal Findings
Whole blood from eleven obese subjects with type 2 diabetes was collected in PAXgene tubes prior to and 6–12 months after bariatric surgery. Total RNA was isolated, amplified, labeled and hybridized to Illumina gene expression microarrays. Clinical and expression data were analyzed using a paired t-test, and correlations between changes in clinical trait and transcript levels were calculated. Pathways were identified using Ingenuity Pathway Analysis and DAVID gene ontology software. Overall, bariatric surgery resulted in significant reduction of body mass index, fasting plasma glucose, fasting plasma insulin, and normalization of glycosylated hemoglobin levels. The expression levels of 204 transcripts, representing 200 unique genes, were significantly altered after bariatric surgery. Among the significantly regulated genes were GGT1, CAMP, DEFA1, LCN2, TP53, PDSS1, OLR1, CNTNAP5, DHCR24, HHAT and SARDH, which have been previously implicated in lipid metabolism, obesity and/or type 2 diabetes. Selected findings were replicated by quantitative real-time-PCR. The changes in expression of seven transcripts, WDR35, FLF45244, DHCR24, TIGD7, TOPBP1, TSHZ1, and FAM8A1 were strongly correlated with the changes in body weight, fasting plasma glucose and glycosylated hemoglobin content. The top pathways associated with gene expression changes after bariatric surgery was lipid metabolism, small molecule biochemistry and gene expression. Two antimicrobial peptides were among the transcripts with the largest changes in gene expression after bariatric surgery.
Conclusions/Significance
Data from this pilot study suggest that whole blood expression levels of specific transcripts may be useful as biomarkers associated with susceptibility for type 2 diabetes and/or therapeutic response.
doi:10.1371/journal.pone.0016729
PMCID: PMC3053356  PMID: 21423737
21.  Retinol-binding Protein 4 (RBP4) Protein Expression Is Increased in Omental Adipose Tissue of Severely Obese Patients 
Obesity (Silver Spring, Md.)  2009;18(4):663-666.
Visceral fat has been linked to insulin resistance and type 2 diabetes mellitus (T2DM); and emerging data links RBP4 gene expression in adipose tissue with insulin resistance. In this study, we examined RBP4 protein expression in omental adipose tissue obtained from 24 severely obese patients undergoing bariatric surgery, and 10 lean controls (4 males/6 females, BMI = 23.2 ± 1.5 kg/m2) undergoing elective abdominal surgeries. Twelve of the obese patients had T2DM (2 males/10 females, BMI: 44.7 ± 1.5 kg/m2) and 12 had normal glucose tolerance (NGT: 4 males/8 females, BMI: 47.6 ± 1.9 kg/m2). Adipose RBP4, glucose transport protein-4 (GLUT4), and p85 protein expression were determined by western blot. Blood samples from the bariatric patients were analyzed for serum RBP4, total cholesterol, triglycerides, and glucose. Adipose RBP4 protein expression (NGT: 11.0 ± 0.6; T2DM: 11.8 ± 0.7; lean: 8.7 ± 0.8 arbitrary units) was significantly increased in both NGT (P = 0.03) and T2DM (P = 0.005), compared to lean controls. GLUT4 protein was decreased in both NGT (P = 0.02) and T2DM (P = 0.03), and p85 expression was increased in T2DM subjects, compared to NGT (P = 0.03) and lean controls (P = 0.003). Regression analysis showed a strong correlation between adipose RBP4 protein and BMI for all subjects, as well as between adipose RBP4 and fasting glucose levels in T2DM subjects (r = 0.76, P = 0.004). Further, in T2DM, serum RBP4 was correlated with p85 expression (r = 0.68, P = 0.01), and adipose RBP4 protein trended toward an association with p85 protein (r = 0.55, P = 0.06). These data suggest that RBP4 may regulate adiposity, and p85 expression in obese-T2DM, thus providing a link to impaired insulin signaling and diabetes in severely obese patients.
doi:10.1038/oby.2009.328
PMCID: PMC2919818  PMID: 19816414
22.  Plasma Ceramides Are Elevated in Obese Subjects With Type 2 Diabetes and Correlate With the Severity of Insulin Resistance 
Diabetes  2009;58(2):337-343.
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.
doi:10.2337/db08-1228
PMCID: PMC2628606  PMID: 19008343
23.  Cytokeratin 18 Fragment Levels as a Noninvasive Biomarker for Nonalcoholic Steatohepatitis in Bariatric Surgery Patients 
Background & Aims
Nonalcoholic fatty liver disease (NAFLD) is extremely common among morbidly obese patients. We assessed the usefulness of plasma caspase-generated cytokeratin 18 (CK-18) fragments as a novel marker for NAFLD in a bariatric cohort.
Methods
The cohort consisted of 99 consecutive patients who underwent liver biopsy at the time of bariatric surgery. CK-18 levels were measured using an enzyme-linked immunosorbant assay before and 6 months after surgery. Patients were subdivided into four histological groups: not NAFLD (normal liver biopsy), NAFL, borderline diagnosis, and definitive nonalcoholic steatohepatitis (NASH).
Results
CK-18 levels were significantly higher in subjects with NASH compared to those with not NAFLD, NAFL, or borderline diagnosis (median [Q25, Q75]: 389 U/L [275, 839] vs. 196 U/L [158, 245], vs. 217 U/L [154, 228], or vs. 200 U/L [176, 274], respectively; P<0.0001). CK-18 levels were significantly higher in subjects with moderate to severe fibrosis versus those with no or mild fibrosis (334.5 U/L [240.5, 896] vs. 207 U/L [175, 275], respectively; P=0.007). A significant decrease in CK-18 levels was observed in most patients 6 months postoperatively. The area under the ROC curve for NASH diagnosis was estimated to be 0.88 (95% CI: 0.77, 0.99). The values with the best combination of sensitivity and specificity were 252 U/L (sensitivity = 82%, specificity = 77%) and 275 U/L (sensitivity = 77%, specificity = 100%).
Conclusion
These results support the potential utility of this test for diagnosis and staging of NAFLD before bariatric surgery.
doi:10.1016/j.cgh.2008.07.016
PMCID: PMC2628560  PMID: 18995215
Nonalcoholic fatty liver disease; NASH; apoptosis; biomarker; cytokeratin 18; bariatric surgery; morbid obese
24.  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).
doi:10.1136/bmj.f5934
PMCID: PMC3806364  PMID: 24149519

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