Florencia Halperin

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.

The role of total and high-molecular-weight complex of adiponectin in vascular function in offspring whose parents both had type 2 diabetes

Aims/hypothesisAdiponectin is an adipokine with insulin-sensitising and anti-atherogenic properties. We studied the role played by total adiponectin and by the bioactive high-molecular-weight (HMW) oligomeric complexes of adiponectin in vascular function in offspring whose parents both had type 2 diabetes, a population at high risk of diabetes and atherosclerosis.MethodsTotal and %HMW adiponectin, the cytokines C-reactive protein, interleukin-6 and plasminogen activator inhibitor-1 (PAI-1), as well as lipid profiles were assayed in 19 offspring, each with two type 2 diabetic parents. Subjects underwent OGTTs and IVGTTs. Endothelium-dependent vasodilation (EDV) was assessed by brachial artery ultrasonography.ResultsThere was a significant relationship between %HMW and total adiponectin levels (r=0.72, p=0.001). Despite an expected strong positive correlation between HDL-cholesterol and adiponectin levels (r=0.52, p=0.04), as well as HDL-cholesterol and EDV (r=0.56, p<0.02), there was no significant relationship between either total adiponectin or % HMW adiponectin and EDV. Adiponectin was inversely associated with PAI-1 (r=0.50, p=0.05), but did not correlate with the inflammatory markers C-reactive protein or interleukin-6.Conclusions/interpretationIn offspring of diabetic parents, a population at high risk of diabetes and atherosclerotic disease, there is no relationship between total or %HMW adiponectin and endothelium-dependent vasodilation. However, low adiponectin was associated with impaired fibrinolysis as manifested by increased levels of plasminogen activator inhibitor-1.

Continuous Glucose Monitoring for Evaluation of Glycemic Excursions after Gastric Bypass

Background. Hyperinsulinemic hypoglycemia with neuroglycopenia is a rare complication of Roux-en-Y gastric bypass (RYGB). We hypothesized that continuous glucose monitoring (CGM) would be useful to characterize glycemic variability after RYGB. Methods. CGM and mixed meal tolerance testing (MMTT) were performed on sixteen post-RYGB subjects, ten with a history of neuroglycopenia on medical treatment and six asymptomatic controls. Results. 9 of 10 subjects with neuroglycopenia developed hypoglycemia defined by glucose <70 mg/dL on CGM, and 3 of 9 on MMTT. In asymptomatic subjects, 3 of 6 had asymptomatic hypoglycemia during CGM, and 3 of 5 on MMTT. Therefore, the sensitivity and specificity to detect clinically significant hypoglycemia was 90% and 50% for CGM and 33% and 40% for MMTT. Conclusions. Asymptomatic hypoglycemia after RYGB is more frequent than commonly recognized. For clinicians evaluating patients for postbypass neuroglycopenia, CGM may be a valuable diagnostic tool.

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 Augmentation of Glucose-Stimulated Insulin Secretion Is Impaired in Insulin-Resistant Humans

Type 2 diabetes (T2D) is characterized by insulin resistance and pancreatic β-cell dysfunction, the latter possibly caused by a defect in insulin signaling in β-cells. We hypothesized that insulin’s effect to potentiate glucose-stimulated insulin secretion (GSIS) would be diminished in insulin-resistant persons. To evaluate the effect of insulin to modulate GSIS in insulin-resistant compared with insulin-sensitive subjects, 10 participants with impaired glucose tolerance (IGT), 11 with T2D, and 8 healthy control subjects were studied on two occasions. The insulin secretory response was assessed by the administration of dextrose for 80 min following a 4-h clamp with either saline infusion (sham) or an isoglycemic-hyperinsulinemic clamp using B28-Asp-insulin (which can be distinguished immunologically from endogenous insulin) that raised insulin concentrations to high physiologic concentrations. Pre-exposure to insulin augmented GSIS in healthy persons. This effect was attenuated in insulin-resistant cohorts, both those with IGT and those with T2D. Insulin potentiates glucose-stimulated insulin secretion in insulin-resistant subjects to a lesser degree than in normal subjects. This is consistent with an effect of insulin to regulate β-cell function in humans in vivo with therapeutic implications.

Glucocorticoid-remediable aldosteronism.

Glucocorticoid-remediable aldosteronism (GRA) is a hereditary form of primary hyperaldosteronism and the most common monogenic cause of hypertension. A chimeric gene duplication leads to ectopic aldosterone synthase activity in the cortisol-producing zona fasciculata of the adrenal cortex, under the regulation of adrenocorticotropin (ACTH). Hypertension typically develops in childhood, and may be refractory to standard therapies. Hypokalemia is uncommon in the absence of treatment with diuretics. The discovery of the genetic basis of the disorder has permitted the development of accurate diagnostic testing. Glucocorticoid suppression of ACTH is the mainstay of treatment; alternative treatments include mineralocorticoid receptor antagonists.

The Great Debate: Medicine or Surgery: What is best for the patient with type 2 diabetes?

In 1991, a National Institutes of Heath expert consensus panel recommended bariatric surgery to treat obesity for informed and motivated patients with BMI >40 kg/m2, or between 35 and 40 kg/m2 with high-risk comorbid conditions including diabetes, in whom operative risks are acceptable (1). In December 2010, these guidelines were reviewed by the Gastroenterology and Urology Devices Panel of the Medical Devices Advisory Committee of the Food and Drug Administration, with recommendation to lower the criteria for use of the laparoscopic adjustable gastric band to BMI >30 kg/m2 for patients with comorbidity. Surgical treatments of obesity induce impressive absolute weight loss of 30–40 kg (∼60% excess weight, or a 10–15 kg/m2 reduction in BMI) (2), which may be sustained over 10–15 years (3). Increasing medical and public awareness of sustained weight loss, increased ease of recovery, and lowered complications with newer laparoscopic surgical procedures and the ongoing increased incidence of obesity have contributed to a 15-fold increase in bariatric surgical procedures in the past decade, with estimates of >200,000 procedures having been performed in the United States in 2007 (4). Recent observational studies demonstrate that bariatric surgical procedures reduce the incidence of type 2 diabetes and lead to substantial improvement or “resolution” for many patients with preexisting disease. Type 2 diabetes has “resolved” (defined in the surgical literature as maintenance of normal blood glucose after discontinuation of all diabetes-related medications, in most studies with HbA1c <7%) in ∼77% of patients who undergo obesity surgery, and resolved or improved in ∼85%, with sustained improvements in multiple metabolic measures, such as fasting plasma glucose and insulin, percent glycosylated hemoglobin, and use of antidiabetic medications (2,5–9). Patients with shorter duration of disease seem to have more complete or sustained disease resolution (10 …

Glucagon Treatment for Post-Gastric Bypass Hypoglycemia

Hyperinsulinemic hypoglycemia is a recently described complication of Roux‐en‐Y gastric bypass (RYGB). We hypothesized that glucagon administration would help maintain normal postprandial plasma glucose concentrations by stimulating hepatic glucose output, and if so, represent a new therapeutic option for postbypass hypoglycemia. In this study, we compared the insulin and glycemic response to a mixed meal with and without concomitant glucagon infusion in a patient with severe recurrent hypoglycemia after RYGB. Although effective in transiently raising postprandial plasma glucose values, glucagon infusion was also associated with higher insulin concentrations, and failed to prevent symptomatic hypoglycemia. This case demonstrates that glucagon may have limited clinical utility in the treatment of post‐RYGB hyperinsulinemic hypoglycemia.

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.

Impact of Bariatric Surgery on Patients With Rheumatoid Arthritis

To investigate the effect of weight loss after bariatric surgery among patients with rheumatoid arthritis (RA).