Diabetes Remission in the Alliance of Randomized Trials of Medicine Versus Metabolic Surgery in Type 2 Diabetes (ARMMS-T2D).

OBJECTIVE: The overall aim of the Alliance of Randomized Trials of Medicine versus Metabolic Surgery in Type 2 Diabetes (ARMMS-T2D) consortium is to assess the durability and longer-term effectiveness of metabolic surgery compared with medical/lifestyle management in patients with type 2 diabetes (NCT02328599). RESEARCH DESIGN AND METHODS: A total of 316 patients with type 2 diabetes previously randomly assigned to surgery (N = 195) or medical/lifestyle therapy (N = 121) in the STAMPEDE, TRIABETES, SLIMM-T2D, and CROSSROADS trials were enrolled into this prospective observational cohort. The primary outcome was the rate of diabetes remission (hemoglobin A1c [HbA1c] ≤6.5% for 3 months without usual glucose-lowering therapy) at 3 years. Secondary outcomes included glycemic control, body weight, biomarkers, and comorbidity reduction. RESULTS: Three-year data were available for 256 patients with mean 50 ± 8.3 years of age, BMI 36.5 ± 3.6 kg/m2, and duration of diabetes 8.8 ± 5.7 years. Diabetes remission was achieved in more participants following surgery than medical/lifestyle intervention (60 of 160 [37.5%] vs. 2 of 76 [2.6%], respectively; P < 0.001). Reductions in HbA1c (Δ = -1.9 ± 2.0 vs. -0.1 ± 2.0%; P < 0.001), fasting plasma glucose (Δ = -52 [-105, -5] vs. -12 [-48, 26] mg/dL; P < 0.001), and BMI (Δ = -8.0 ± 3.6 vs. -1.8 ± 2.9 kg/m2; P < 0.001) were also greater after surgery. The percentages of patients using medications to control diabetes, hypertension, and dyslipidemia were all lower after surgery (P < 0.001). CONCLUSIONS: Three-year follow-up of the largest cohort of randomized patients followed to date demonstrates that metabolic/bariatric surgery is more effective and durable than medical/lifestyle intervention in remission of type 2 diabetes, including among individuals with class I obesity, for whom surgery is not widely used.

Serum Urate Lowering with Allopurinol and Kidney Function in Type 1 Diabetes.

BACKGROUND: Higher serum urate levels are associated with an increased risk of diabetic kidney disease. Lowering of the serum urate level with allopurinol may slow the decrease in the glomerular filtration rate (GFR) in persons with type 1 diabetes and early-to-moderate diabetic kidney disease. METHODS: In a double-blind trial, we randomly assigned participants with type 1 diabetes, a serum urate level of at least 4.5 mg per deciliter, an estimated GFR of 40.0 to 99.9 ml per minute per 1.73 m2 of body-surface area, and evidence of diabetic kidney disease to receive allopurinol or placebo. The primary outcome was the baseline-adjusted GFR, as measured with iohexol, after 3 years plus a 2-month washout period. Secondary outcomes included the decrease in the iohexol-based GFR per year and the urinary albumin excretion rate after washout. Safety was also assessed. RESULTS: A total of 267 patients were assigned to receive allopurinol and 263 to receive placebo. The mean age was 51.1 years, the mean duration of diabetes 34.6 years, and the mean glycated hemoglobin level 8.2%. The mean baseline iohexol-based GFR was 68.7 ml per minute per 1.73 m2 in the allopurinol group and 67.3 ml per minute per 1.73 m2 in the placebo group. During the intervention period, the mean serum urate level decreased from 6.1 to 3.9 mg per deciliter with allopurinol and remained at 6.1 mg per deciliter with placebo. After washout, the between-group difference in the mean iohexol-based GFR was 0.001 ml per minute per 1.73 m2 (95% confidence interval [CI], -1.9 to 1.9; P = 0.99). The mean decrease in the iohexol-based GFR was -3.0 ml per minute per 1.73 m2 per year with allopurinol and -2.5 ml per minute per 1.73 m2 per year with placebo (between-group difference, -0.6 ml per minute per 1.73 m2 per year; 95% CI, -1.5 to 0.4). The mean urinary albumin excretion rate after washout was 40% (95% CI, 0 to 80) higher with allopurinol than with placebo. The frequency of serious adverse events was similar in the two groups. CONCLUSIONS: We found no evidence of clinically meaningful benefits of serum urate reduction with allopurinol on kidney outcomes among patients with type 1 diabetes and early-to-moderate diabetic kidney disease. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; PERL ClinicalTrials.gov number, NCT02017171.).

Preventing Early Renal Loss in Diabetes (PERL) Study: A Randomized Double-Blinded Trial of Allopurinol-Rationale, Design, and Baseline Data.

OBJECTIVE: Higher serum uric acid (SUA) is associated with diabetic kidney disease (DKD). Preventing Early Renal Loss in Diabetes (PERL) evaluates whether lowering SUA with allopurinol slows glomerular filtration rate (GFR) loss in people with type 1 diabetes (T1D) and mild to moderate DKD. We present the PERL rationale, design, and baseline characteristics. RESEARCH DESIGN AND METHODS: This double-blind, placebo-controlled, multicenter trial randomized 530 participants with T1D, estimated GFR (eGFR) of 40-99.9 mL/min/1.73 m2, SUA ≥4.5 m/dL, and micro- to macroalbuminuric DKD or normoalbuminuria with declining kidney function (NDKF) (defined as historical eGFR decline ≥3 mL/min/1.73 m2/year) to allopurinol or placebo. The primary outcome is baseline-adjusted iohexol GFR (iGFR) after 3 years of treatment plus a 2-month washout period. RESULTS: Participants are 66% male and 84% white. At baseline, median age was 52 years and diabetes duration was 35 years, 93% of participants had hypertension, and 90% were treated with renin-angiotensin system inhibitors (median blood pressure 127/71 mmHg). Median HbA1c was 8%, SUA 5.9 mg/dL, iGFR 68 mL/min/1.73 m2, and historical eGFR slope -3.5 mL/min/1.73 m2/year. Compared with participants with albuminuria (n = 419), those with NDKF (n = 94) were significantly older (56 vs. 52 years), had lower HbA1c (7.7 vs. 8.1%) and SUA (5.4 vs. 6.0 mg/dL), and had higher eGFR (82 vs. 74 mL/min/1.73 m2) and historical eGFR loss (-4.7 vs. -2.5 mL/min/1.73 m2/year). These differences persisted when comparing groups with similar rates of historical eGFR loss. CONCLUSIONS: PERL will determine the effect of allopurinol on mild to moderate DKD in T1D, with or without albuminuria. Participants with normoalbuminuria and rapid GFR loss manifested many DKD risk factors of those with albuminuria, but with less severity.

Plasma FGF-19 Levels are Increased in Patients with Post-Bariatric Hypoglycemia.

BACKGROUND: Hypoglycemia is an increasingly recognized complication of bariatric surgery. Mechanisms contributing to glucose lowering remain incompletely understood. We aimed to identify differentially abundant plasma proteins in patients with post-bariatric hypoglycemia (PBH) after Roux-en-Y gastric bypass (RYGB), compared to asymptomatic post-RYGB. METHODS: Proteomic analysis of blood samples collected after overnight fast and mixed meal challenge in individuals with PBH, asymptomatic RYGB, severe obesity, or overweight recruited from outpatient hypoglycemia or bariatric clinics. RESULTS: The top-ranking differentially abundant protein at 120 min after mixed meal was fibroblast growth factor 19 (FGF-19), an intestinally derived hormone regulated by bile acid-FXR signaling; levels were 2.4-fold higher in PBH vs. asymptomatic post-RYGB (mean + SEM, 1094 ± 141 vs. 428 ± 45, P < 0.001, FDR < 0.01). FGF-19 ELISA confirmed 3.5-fold higher concentrations in PBH versus asymptomatic (360 ± 70 vs. 103 ± 18, P = 0.025). To explore potential links between increased FGF-19 and GLP-1, residual samples from other human studies in which GLP-1 was modulated were assayed. FGF-19 levels did not change in response to infusion of GLP-1 and PYY in overweight/obese individuals. Infusion of the GLP-1 receptor antagonist exendin 9-39 in recently operated asymptomatic post-RYGB did not alter FGF-19 levels after mixed meal. By contrast, GLP-1 receptor antagonist infusion yielded a significant increase in FGF-19 levels after oral glucose in individuals with PBH. While plasma bile acids did not differ between PBH and asymptomatic post-RYGB, these data suggest unique interrelationships between GLP-1 and FGF-19 in PBH. CONCLUSIONS: Taken together, these data support FGF-19 as a potential contributor to insulin-independent pathways driving postprandial hypoglycemia in PBH.

PET-CT reveals increased intestinal glucose uptake after gastric surgery.

BACKGROUND: Mechanisms of metabolic improvement after bariatric surgery remain incompletely understood. Intestinal glucose uptake is increased after gastric bypass in rodents, potentially contributing to reduced blood glucose and type 2 diabetes remission. OBJECTIVE: We assessed whether intestinal glucose uptake is increased in humans after gastric surgery. SETTING: University Hospital, United States. METHODS: In a retrospective, case-control cohort study, positron emission tomography-computerized tomography scans performed for clinical indications were analyzed to quantify intestinal glucose uptake in patients with or without history of gastric surgery. We identified 19 cases, defined as patients over age 18 with prior gastric surgery (Roux-en-Y gastric bypass [n = 10], sleeve gastrectomy [n = 1], or Billroth I [n = 2] or II gastrectomy [n = 6]), and 43 controls without gastric surgery, matched for age, sex, and indication for positron emission tomography-computerized tomography. Individuals with gastrointestinal malignancy or metformin treatment were excluded. Images were obtained 60 minutes after 18F-fluorodeoxyglucose injection (4.2 MBq/kg), and corrected by attenuation; noncontrast low-dose computerized tomography was obtained in parallel. Fused and nonfused images were analyzed; standardized uptake values were calculated for each region by volumes of interest at the region of highest activity. RESULTS: Both standardized uptake values maximum and mean were significantly increased by 41% to 98% in jejunum, ascending, and transverse colon in patients with prior gastric surgery (P < .05 versus controls). CONCLUSION: Intestinal glucose uptake is increased in patients with prior gastric surgery. Prospective studies are important to dissect the contributions of weight loss, dietary factors, and systemic metabolism, and to determine the relationship with increased insulin-independent glucose uptake and reductions in glycemia.

Adjustable gastric band surgery or medical management in patients with type 2 diabetes and obesity: three-year results of a randomized trial.

BACKGROUND: Few randomized trials have compared surgical versus lifestyle and pharmacologic approaches for type 2 diabetes (T2D) patients with mild to moderate obesity. OBJECTIVES: This study examined resolution of hyperglycemia (A1C <6.5% and fasting glucose <126 mg/dL) 3 years after randomization to either a laparoscopic adjustable gastric band (LAGB) or 1-year diabetes and weight management (DWM) program. SETTING: University medical center, United States. METHODS: Forty T2D patients (mean ± SD: age, 51.3 ±10.0 yr; weight 109.5 ± 15.0 kg; body mass index [BMI] 36.5 ± 3.7 kg/m2; HBA1C 8.2% ± 1.2%) were randomized to LAGB (n = 18) or DWM (n = 22). RESULTS: At 3 years, 13% of 16 patients in LAGB and 5% of 17 patients in DWM achieved resolution of hyperglycemia (P = .601), with a modestly greater reduction in antidiabetic medications in the surgical group (P = .054). Reductions from baseline in A1C were sustained at 3 years in LAGB (-.82% [95% CI: -1.62 to -.01], P = .046) compared with DWM (+.23% [95% CI: -.57 to 1.03], P = .567). The surgical group had greater weight loss (-12.0 kg [95% CI: -15.9 to -8.1] versus -4.8 [95% CI: -8.6 to -.9], P = .010). HDL-cholesterol increased more after surgery (P = .003), but changes in triglycerides, LDL-cholesterol, and blood pressure did not differ between treatments. Diabetes- and obesity-specific quality of life improved comparably with both therapies. CONCLUSIONS: Achievement of American Diabetes Association targets for glucose, lipids, and blood pressure was similar with both treatment strategies. LAGB leads to greater sustained weight loss and higher HDL cholesterol compared with a DWM program. These findings may help guide patients with T2D and obesity when exploring options for diabetes and weight management.

Metabolic Effects of Betaine: A Randomized Clinical Trial of Betaine Supplementation in Prediabetes.

Context: Plasma betaine correlates with insulin sensitivity in humans. Betaine supplementation improves metabolic effects in mice fed a high-fat diet. Objective: To assess metabolic effects of oral betaine in obese participants with prediabetes. Design: A 12-week, parallel arm, randomized, double-masked, placebo-controlled trial. Setting: University-affiliated hospital. Participants and Interventions: Persons with obesity and prediabetes (N = 27) were randomly assigned to receive betaine 3300 mg orally twice daily for 10 days, then 4950 mg twice daily for 12 weeks, or placebo. Main Outcome Measures: Changes from baseline in insulin sensitivity, glycemia, hepatic fat, and endothelial function. Results: There was a 16.5-fold increase in plasma dimethylglycine [dimethylglycine (DMG); P < 0.0001] levels, but modest 1.3- and 1.5-fold increases in downstream serine and methionine levels, respectively, in the betaine vs placebo arm. Betaine tended to reduce fasting glucose levels (P = 0.08 vs placebo) but had no other effect on glycemia. Insulin area under curve after oral glucose was reduced for betaine treatment compared with placebo (P = 0.038). Insulin sensitivity, assessed by euglycemic hyperinsulinemic clamp, was not improved. Serum total cholesterol levels increased after betaine treatment compared with placebo (P = 0.032). There were no differences in change in intrahepatic triglyceride or endothelial function between groups. Conclusion: DMG accumulation supports DMG dehydrogenase as rate limiting for betaine metabolism in persons with prediabetes. Betaine had little metabolic effect. Additional studies may elucidate mechanisms contributing to differences between preclinical and human responses to betaine, and whether supplementation of metabolites downstream of DMG improves metabolism.

Clinical and Patient-Centered Outcomes in Obese Patients With Type 2 Diabetes 3 Years After Randomization to Roux-en-Y Gastric Bypass Surgery Versus Intensive Lifestyle Management: The SLIMM-T2D Study.

OBJECTIVE: To compare the effect of Roux-en-Y gastric bypass (RYGB) surgery versus intensive medical diabetes and weight management (IMWM) on clinical and patient-reported outcomes in obese patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: We prospectively randomized 38 obese patients with type 2 diabetes (15 male and 23 female, with mean ± SD weight 104 ± 16 kg, BMI 36.3 ± 3.4 kg/m2, age 52 ± 6 years, and HbA1c 8.5 ± 1.3% [69 ± 14 mmol/mol]) to laparoscopic RYGB (n = 19) or IMWM (n = 19). Changes in weight, HbA1c, cardiovascular risk factors (UKPDS risk engine), and self-reported health status (the 36-Item Short-Form [SF-36] survey, Impact of Weight on Quality of Life [IWQOL] instrument, and Problem Areas in Diabetes Survey [PAID]) were assessed. RESULTS: After 3 years, the RYGB group had greater weight loss (mean -24.9 kg [95% CI -29.5, -20.4] vs. -5.2 [-10.3, -0.2]; P < 0.001) and lowering of HbA1c (-1.79% [-2.38, -1.20] vs. -0.39% [-1.06, 0.28] [-19.6 mmol/mol {95% CI -26.0, -13.1} vs. -4.3 {-11.6, 3.1}]; P < 0.001) compared with the IMWM group. Changes in cardiometabolic risk for coronary heart disease and stroke were all more favorable in RYGB versus IMWM (P < 0.05 to P < 0.01). IWQOL improved more after RYGB (P < 0.001), primarily due to subscales of physical function, self-esteem, and work performance. SF-36 and PAID scores improved in both groups, with no difference between treatments. A structural equation model demonstrated that improvement in overall quality of life was more strongly associated with weight loss than with improved HbA1c and was manifest by greater improvements in IWQOL than with either SF-36 or PAID. CONCLUSIONS: Three years after randomization to RYGB versus IMWM, surgery produced greater weight loss, lower HbA1c, reduced cardiovascular risk, and improvements in obesity-related quality of life in obese patients with type 2 diabetes.

The Foxo1-Inducible Transcriptional Repressor Zfp125 Causes Hepatic Steatosis and Hypercholesterolemia.

Liver-specific disruption of the type 2 deiodinase gene (Alb-D2KO) results in resistance to both diet-induced obesity and liver steatosis in mice. Here, we report that this is explained by an ∼60% reduction in liver zinc-finger protein-125 (Zfp125) expression. Zfp125 is a Foxo1-inducible transcriptional repressor that causes lipid accumulation in the AML12 mouse hepatic cell line and liver steatosis in mice by reducing liver secretion of triglycerides and hepatocyte efflux of cholesterol. Zfp125 acts by repressing 18 genes involved in lipoprotein structure, lipid binding, and transport. The ApoE promoter contains a functional Zfp125-binding element that is also present in 17 other lipid-related genes repressed by Zfp125. While liver-specific knockdown of Zfp125 causes an "Alb-D2KO-like" metabolic phenotype, liver-specific normalization of Zfp125 expression in Alb-D2KO mice rescues the phenotype, restoring normal susceptibility to diet-induced obesity, liver steatosis, and hypercholesterolemia.

Design and Clinical Evaluation of a Novel Low-Glucose Prediction Algorithm with Mini-Dose Stable Glucagon Delivery in Post-Bariatric Hypoglycemia.

BACKGROUND: Postbariatric hypoglycemia (PBH) is a complication of bariatric surgery with limited therapeutic options. We developed an event-based system to predict and detect hypoglycemia based on continuous glucose monitor (CGM) data and recommend delivery of minidose liquid glucagon. METHODS: We performed an iterative development clinical study employing a novel glucagon delivery system: a Dexcom CGM connected to a Windows tablet running a hypoglycemia prediction algorithm and an Omnipod pump filled with an investigational stable liquid glucagon formulation. Meal tolerance testing was performed in seven participants with PBH and history of neuroglycopenia. Glucagon was administered when hypoglycemia was predicted. Primary outcome measures included the safety and feasibility of this system to predict and prevent severe hypoglycemia. Secondary outcomes included hypoglycemia prediction by the prediction algorithm, minimization of time below hypoglycemia threshold using glucagon, and prevention of rebound hyperglycemia. RESULTS: The hypoglycemia prediction algorithm alerted for impending hypoglycemia in the postmeal state, prompting delivery of glucagon (150 µg). After observations of initial incomplete efficacy to prevent hypoglycemia in the first two participants, system modifications were implemented: addition of PBH-specific detection algorithm, increased glucagon dose (300 µg), and a second glucagon dose if needed. These modifications, together with rescue carbohydrates provided to some participants, contributed to progressive improvements in glucose time above the hypoglycemia threshold (75 mg/dL). CONCLUSIONS: Preliminary results indicate that our event-based automatic monitoring algorithm successfully predicted likely hypoglycemia. Minidose glucagon therapy was well tolerated, without prolonged or severe hypoglycemia, and without rebound hyperglycemia.

Heterogeneity of proliferative markers in pancreatic ß-cells of patients with severe hypoglycemia following Roux-en-Y gastric bypass.

AIMS: Severe postprandial hypoglycemia with neuroglycopenia is an increasingly recognized, debilitating complication of Roux-en-Y gastric bypass (RYGB) surgery. Increased secretion of insulin and incretin hormones is implicated in its pathogenesis. Histopathologic examination of pancreas has demonstrated increased islet size and/or nuclear diameter in post-RYGB patients who underwent pancreatectomy for severe refractory hypoglycemia with neuroglycopenia (RYGB + NG). We aimed to determine whether ß-cell proliferation or apoptosis is altered in RYGB + NG. METHODS: We performed an observational study to analyze markers of proliferation, apoptosis, cell cycle, and transcription factor expression in pancreatic tissue from affected RYGB + NG patients (n = 12), normoglycemic patients undergoing pancreatic surgery for benign lesions (controls, n = 6), and individuals with hypoglycemia due to insulinoma (n = 52). RESULTS: Proliferative cell nuclear antigen (PCNA) expression was increased in insulin-positive cells in RYGB + NG patients (4.5-fold increase, p < 0.001 vs. controls) and correlated with ß-cell mass. Ki-67 immunoreactivity was low in both RYGB + NG and controls, but did not differ between groups. Phospho-histone H3 levels did not differ between RYGB + NG and controls. PCNA and Ki-67 were both significantly lower in both controls and RYGB + NG than insulinomas. Markers of apoptosis and cell cycle (M30, p27, and p21) did not differ between groups. PDX1 and menin exhibited similar expression patterns, while FOXO1 appeared to be more cytosolic in RYGB + NG. CONCLUSIONS: Markers of proliferation are heterogeneous in patients with severe post-RYGB hypoglycemia. Increased ß-cell proliferation in some individuals may contribute to increased ß-cell mass observed in severely affected patients.

Physical Activity in Obese Type 2 Diabetes After Gastric Bypass or Medical Management.

BACKGROUND: The purpose of this study was to compare effects of Roux-en-Y gastric bypass versus a multidisciplinary, group-based medical diabetes and weight management program on physical fitness and behaviors. METHODS: Physical behavior and fitness were assessed in participants of the study Surgery or Lifestyle With Intensive Medical Management in the Treatment of Type 2 Diabetes (SLIMM-T2D) (NCT01073020), a randomized, parallel-group trial conducted at a US academic hospital and diabetes clinic with 18- to 24-month follow-up. Thirty-eight type 2 diabetes patients with hemoglobin A1c ≥6.5% and body mass index 30-42 kg/m2 were randomized to Roux-en-Y gastric bypass or the medical program. A 6-minute walk test to evaluate fitness, self-reported physical activity, standardized physical surveys, and cardiometabolic risk assessment were performed at baseline and after intervention. RESULTS: Both groups similarly improved 6-minute walk test distance, with greater improvements in oxygen saturation and reduced heart rate after surgery. Self-reported physical activity improved similarly at 18-24 months after interventions, although exercise increased gradually after surgery, whereas early substantial increases in the medical group were not fully sustained. Self-reported total and physical health were similar by Short Form-36 but improved more in the Impact of Weight on Quality of Life survey after surgery. Improvement in cardiovascular risk scores, HbA1c, and body mass index were greater after surgery. CONCLUSION: In this small, randomized study, both interventions led to therapeutic lifestyle changes and improved objective and self-reported physical fitness. Greater improvements in heart rate, oxygen saturation, and perceived impact of weight on health were seen after surgery, which could be attributable to greater weight loss. The clinical importance of these improvements with greater weight loss warrants further investigation.

Ebselen does not improve oxidative stress and vascular function in patients with diabetes: a randomized, crossover trial.

Oxidative stress is a key driver of vascular dysfunction in diabetes mellitus. Ebselen is a glutathione peroxidase mimetic. A single-site, randomized, double-masked, placebo-controlled, crossover trial was carried out in 26 patients with type 1 or type 2 diabetes to evaluate effects of high-dose ebselen (150 mg po twice daily) administration on oxidative stress and endothelium-dependent vasodilation. Treatment periods were in random order of 4 wk duration, with a 4-wk washout between treatments. Measures of oxidative stress included nitrotyrosine, plasma 8-isoprostanes, and the ratio of reduced to oxidized glutathione. Vascular ultrasound of the brachial artery and plethysmographic measurement of blood flow were used to assess flow-mediated and methacholine-induced endothelium-dependent vasodilation of conduit and resistance vessels, respectively. Ebselen administration did not affect parameters of oxidative stress or conduit artery or forearm arteriolar vascular function compared with placebo treatment. There was no difference in outcome by diabetes type. Ebselen, at the dose and duration evaluated, does not improve the oxidative stress profile, nor does it affect endothelium-dependent vasodilation in patients with diabetes mellitus.

Dietary Betaine Supplementation Increases Fgf21 Levels to Improve Glucose Homeostasis and Reduce Hepatic Lipid Accumulation in Mice.

Identifying markers of human insulin resistance may permit development of new approaches for treatment and prevention of type 2 diabetes. To this end, we analyzed the fasting plasma metabolome in metabolically characterized human volunteers across a spectrum of insulin resistance. We demonstrate that plasma betaine levels are reduced in insulin-resistant humans and correlate closely with insulin sensitivity. Moreover, betaine administration to mice with diet-induced obesity prevents the development of impaired glucose homeostasis, reduces hepatic lipid accumulation, increases white adipose oxidative capacity, and enhances whole-body energy expenditure. In parallel with these beneficial metabolic effects, betaine supplementation robustly increased hepatic and circulating fibroblast growth factor (Fgf)21 levels. Betaine administration failed to improve glucose homeostasis and liver fat content in Fgf21(-/-) mice, demonstrating that Fgf21 is necessary for betaine's beneficial effects. Together, these data indicate that dietary betaine increases Fgf21 levels to improve metabolic health in mice and suggest that betaine supplementation merits further investigation as a supplement for treatment or prevention of type 2 diabetes in humans.

Effects of Gastric Bypass and Gastric Banding on Bone Remodeling in Obese Patients With Type 2 Diabetes.

CONTEXT: Roux-en-Y gastric bypass (RYGB) leads to high-turnover bone loss, but little is known about skeletal effects of laparoscopic adjustable gastric banding (LAGB) or mechanisms underlying bone loss after bariatric surgery. OBJECTIVE: To evaluate effects of RYGB and LAGB on fasting and postprandial indices of bone remodeling. DESIGN AND SETTING: Ancillary investigation of a prospective study at 2 academic institutions. PARTICIPANTS: Obese adults aged 21-65 years with type 2 diabetes who underwent RYGB (n = 11) or LAGB (n = 8). OUTCOMES: Serum C-terminal telopeptide (CTX), procollagen type 1 N-terminal propeptide (P1NP), and PTH were measured during a mixed meal tolerance test at baseline, 10 days and 1 year after surgery. Changes in 25-hydroxyvitamin D, polypeptide YY (PYY), glucagon-like peptide-1, glucose-dependent insulinotropic peptide, and insulin were also assessed. RESULTS: Fasting CTX increased 10 days after RYGB but not LAGB (+69 ± 23% vs +12±12%, P < .001), despite comparable weight loss at that time. By 1 year, fasting CTX and P1NP increased more after RYGB than LAGB (CTX +221 ± 60% vs +15 ± 6%, P<0.001; P1NP +93 ± 25% vs -9 ± 10%, P < .001) and weight loss was greater with RYGB. Changes in CTX were independent of PTH and 25-hydroxyvitamin D but were associated with increases in fasting PYY. Postprandial suppression of CTX was more pronounced after RYGB than LAGB at 10 days and 1 year postoperatively. CONCLUSIONS: RYGB is accompanied by early increases in fasting indices of bone remodeling, independent of weight loss or changes in PTH or 25-hydroxyvitamin D. LAGB did not affect bone markers. PYY and other enterohormonal signals may play a role in RYGB-specific skeletal changes.

Adjustable Gastric Band Surgery or Medical Management in Patients With Type 2 Diabetes: A Randomized Clinical Trial.

CONTEXT: Recommendations for surgical, compared with lifestyle and pharmacologically based, approaches for type 2 diabetes (T2D) management remain controversial. OBJECTIVE: The objective was to compare laparoscopic adjustable gastric band (LAGB) to an intensive medical diabetes and weight management (IMWM) program for T2D. DESIGN: This was designed as a prospective, randomized clinical trial. SETTING: The setting was two Harvard Medical School-affiliated academic institutions. INTERVENTIONS AND PARTICIPANTS: A 12-month randomized trial comparing LAGB (n = 23) vs IMWM (n = 22) in persons aged 21-65 years with body mass index of 30-45 kg/m(2), T2D diagnosed more than 1 year earlier, and glycated hemoglobin (HbA(1c)) ≥ 6.5% on antihyperglycemic medication(s). MAIN OUTCOME MEASURE: The proportion meeting the prespecified primary glycemic endpoint, defined as HbA(1c) < 6.5% and fasting glucose < 7.0 mmol/L at 12 months, on or off medication. RESULTS: After randomization, five participants did not undergo the surgical intervention. Of the 40 initiating intervention (22 males/18 females; age, 51 ± 10 y; body mass index, 36.5 ± 3.7 kg/m(2); diabetes duration, 9 ± 5 y; HbA(1c), 8.2 ± 1.2%; 40% on insulin), the proportion meeting the primary glycemic endpoint was achieved in 33% of the LAGB patients and 23% of the IMWM patients (P = .457). HbA(1c) reduction was similar between groups at both 3 and 12 months (-1.2 ± 0.3 vs -1.0 ± 0.3%; P = .496). Weight loss was similar at 3 months but greater 12 months after LAGB (-13.5 ± 1.7 vs -8.5 ± 1.6 kg; P = .027). Systolic blood pressure reduction was greater after IMWM than LAGB, whereas changes in diastolic blood pressure, lipids, fitness, and cardiovascular risk scores were similar between groups. Patient-reported health status, assessed using the Short Form-36, Impact of Weight on Quality of Life, and Problem Areas in Diabetes, all improved similarly between groups. CONCLUSIONS: LAGB and a multidisciplinary IMWM program have similar 1-year benefits on diabetes control, cardiometabolic risk, and patient satisfaction, which should be considered in the context of other factors, such as personal preference, when selecting treatment options with obese T2D patients. Longer duration studies are important to understand emergent differences.

Insulin response to oral stimuli and glucose effectiveness increased in neuroglycopenia following gastric bypass.

OBJECTIVE: Hyperinsulinemic hypoglycemia with neuroglycopenia is a rare complication following Roux-en-Y gastric bypass (RYGB) surgery for weight management. Insulin secretion and action in response to oral and intravenous stimuli in persons with and without neuroglycopenia following RYGB are evaluated in this study. METHODS: Cross-sectional cohort studies were performed at a single academic institution to assess insulin secretion and action during oral mixed meal tolerance test and intravenous glucose tolerance test (IVGTT). RESULTS: Insulin secretion was increased more following oral mixed meal than intravenous glucose in individuals with neuroglycopenia compared to the asymptomatic group. Reduced insulin clearance did not contribute to higher insulinemia. Glucose effectiveness at zero insulin, estimated during the IVGTT, was also higher in those with neuroglycopenia. Insulin sensitivity did not differ between groups. CONCLUSIONS: Increased beta-cell response to oral stimuli and insulin-independent glucose disposal may both contribute to severe hypoglycemia after RYGB.

Effect of paricalcitol on endothelial function and inflammation in type 2 diabetes and chronic kidney disease.

AIMS: Patients with type 2 diabetes (T2DM) and chronic kidney disease (CKD) have impaired endothelial function. Vitamin D and its analogs may play a role in regulation of endothelial function and inflammation. We studied effects of paricalcitol compared to placebo on endothelial function and markers of inflammation and oxidative stress in patients with T2DM and CKD. METHODS: A double blind, randomized, placebo-controlled trial was conducted in 60 patients with T2DM and stage 3 or 4 CKD. Paricalcitol 1 mcg or placebo was administered orally once daily for three months. Brachial artery flow mediated dilatation (FMD), nitroglycerine mediated dilation (NMD), and plasma concentrations of inflammatory cytokines, tumor necrosis factor -α and interleukin-6, highly-sensitive C-reactive protein; endothelial surface proteins, intercellular adhesion molecule -1 and monocyte chemo attractant protein-1, and plasma glucose, insulin, free fatty acids, and urinary isoprostane were measured at baseline and end of three months. RESULTS: 27 patients in the paricalcitol group and 28 patients in the control group completed the study, though analysis of FMD at both time points was possible in 23 patients in each group. There was no significant difference in the change in FMD, NMD or the biomarkers examined after paricalcitol or placebo treatment. CONCLUSIONS: Treatment with paricalcitol at this dose and duration did not affect brachial artery FMD or biomarkers of inflammation and oxidative stress. The lack of significance may be due to the fact that the study patients had advanced CKD and that effects of paricalcitol are not additive to the effects of glycemic, lipid and anti-hypertensive therapies.

Roux-en-Y gastric bypass surgery or lifestyle with intensive medical management in patients with type 2 diabetes: feasibility and 1-year results of a randomized clinical trial.

IMPORTANCE: Emerging data support bariatric surgery as a therapeutic strategy for management of type 2 diabetes mellitus. OBJECTIVE: To test the feasibility of methods to conduct a larger multisite trial to determine the long-term effect of Roux-en-Y gastric bypass (RYGB) surgery compared with an intensive diabetes medical and weight management (Weight Achievement and Intensive Treatment [Why WAIT]) program for type 2 diabetes. DESIGN, SETTING, AND PARTICIPANTS: A 1-year pragmatic randomized clinical trial was conducted in an academic medical institution. Participants included persons aged 21 to 65 years with type 2 diabetes diagnosed more than 1 year before the study; their body mass index was 30 to 42 (calculated as weight in kilograms divided by height in meters squared) and hemoglobin A1c (HbA1c) was greater than or equal to 6.5%. All participants were receiving antihyperglycemic medications. INTERVENTIONS: RYGB (n = 19) or Why WAIT (n = 19) including 12 weekly multidisciplinary group lifestyle, medical, and educational sessions with monthly follow-up thereafter. MAIN OUTCOMES AND MEASURES: Proportion of patients with fasting plasma glucose levels less than 126 mg/dL and HbA1c less than 6.5%, measures of cardiometabolic health, and patient-reported outcomes. RESULTS: At 1 year, the proportion of patients achieving HbA1c below 6.5% and fasting glucose below 126 mg/dL was higher following RYGB than Why WAIT (58% vs 16%, respectively; P = .03). Other outcomes, including HbA1c, weight, waist circumference, fat mass, lean mass, blood pressure, and triglyceride levels, decreased and high-density lipoprotein cholesterol increased more after RYGB compared with Why WAIT. Improvement in cardiovascular risk scores was greater in the surgical group. At baseline the participants exhibited moderately low self-reported quality-of-life scores reflected by Short Form-36 total, physical health, and mental health, as well as high Impact of Weight on Quality of Life-Lite and Problem Areas in Diabetes health status scores. At 1 year, improvements in Short Form-36 physical and mental health scores and Problem Areas in Diabetes scores did not differ significantly between groups. The Impact of Weight on Quality of Life-Lite score improved more with RYGB and correlated with greater weight loss compared with Why WAIT. CONCLUSIONS AND RELEVANCE: In obese patients with type 2 diabetes, RYGB produces greater weight loss and sustained improvements in HbA1c and cardiometabolic risk factors compared with medical management, with emergent differences over 1 year. Both treatments improve general quality-of-life measures, but RYGB provides greater improvement in the effect of weight on quality of life. These differences may help inform therapeutic decisions for diabetes and weight loss strategies in obese patients with type 2 diabetes until larger randomized trials are performed. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01073020.