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AIMS. Post-bariatric hypoglycemia (PBH) is an increasingly-recognized complication of bariatric surgery, but current therapies are limited. We hypothesized pramlintide would reduce hypoglycemia by slowing gastric emptying and reducing postprandial glucagon secretion, thus limiting postprandial glycemic excursions and insulin secretion. We thus determined the efficacy of pramlintide on frequency and severity of hypoglycemia in PBH. MATERIALS AND METHODS. Participants with PBH following gastric bypass were recruited from outpatient clinics at Joslin Diabetes Center, Boston, MA for an open-label study of pramlintide efficacy over 8 weeks. 23 participants were assessed for eligibility, 20 participants had at least 1 pramlintide dose, and 14 completed the study. Mixed meal tolerance test (MMTT) was performed at baseline and following 8 weeks of subcutaneous pramlintide with sequential dose increase to maximum of 120 micrograms (mean 69±32 mcg) 3 times daily. The primary endpoint was change in glucose excursions during MMTT. Secondary measures included MMTT insulin response, satiety and dumping score, percentage time with sensor glucose

There is limited Level-1 evidence from well-powered randomized controlled trials (RCTs) examining improved glycemic control after metabolic surgery in patients with type 2 diabetes (T2D) and obesity. ARMMS-T2D is a multi-center consortium conducting a follow-up study of 4 merged RCTs in 256 patients with baseline Class 1-3 obesity and T2D, randomly assigned to metabolic surgery (MS;Roux-en-Y gastric bypass, sleeve gastrectomy, or gastric banding) or intensive Medical/Lifestyle Intervention (MLI). Three years after randomization, T2D remission rates were higher after MS than MLI (37.5%, 60/160 vs. 2.6%, 2/76, respectively, P

Emerging literature suggests that obesity may be “protective” against mortality and cardiovascular outcomes, while dysglycemia may worsen outcomes regardless of obesity. The authors measured the association of weight, smoking, and glycemia with mortality in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Among 5423 ALLHAT participants without established diabetes or cardiovascular disease, 3980 (73%) had normal fasting glucose and 1443 (27%) had impaired fasting glucose (IFG) levels at study entry. After a median of 4.9 years follow-up, 554 (10%) had died (37% cardiovascular). IFG was associated with higher all-cause mortality (adjusted hazard ratio [HR], 1.23; 95% confidence interval [CI], 1.02–1.50), while obesity was associated with lower all-cause mortality (adjusted HR, 0.76; 95% CI, 0.60–0.96). However, after excluding underweight individuals (body mass index [BMI]

Introduction: The role of HDL in CVD risk is not fully understood. Hypothesis: We tested the hypothesis that HDL functions are significantly associated with HDL subpopulation profile. Methods: Lipoproteins, including apoA-I-containing HDL particles, cell-cholesterol efflux (Global, ABCA1- and SRB1-mediated) and HDL Inflammatory Index were measured in a total of 289 subjects. These included 60 CHD patients, 109 subjects with either abnormal lipids (high triglycerides/low HDL or elevated β-sitosterol) or increased levels of the inflammatory markers C-reactive protein (CRP), serum amyloid A (SAA), fibrinogen, or myeloperoxidase (MPO), as well as 120 controls. Results: Global efflux was highly correlated with ABCA1-mediated efflux (r=0.921). Cholesterol efflux via the ABCA1 pathway was significantly correlated with small prebeta-1 HDL particles (r=0.762). CHD patients had significantly higher preβ-1 level than controls; however, per-particle prebeta-1 HDL effluxed 41% less cholesterol in CHD patients as compared to controls, resulting in no significant difference in overall efflux capacity between cases and controls. Cholesterol efflux via the SRB1 pathway was significantly correlated with large α-1 (r=0.784) and α-2 (r=0.460) HDL particles. These two large HDL particles effluxed about 82% of cell cholesterol via the SRB1 pathway. There was no significant difference in SRB1-mediated cholesterol efflux between CHD cases and controls. The HDL Inflammatory Index (HII) was significantly higher (unfavorable) in CHD cases than in controls and was significantly (inversely) associated with α-2 HDL particles (r=454). Increased levels of β-sitosterol significantly altered the HDL subpopulation profile and increased HII. Moreover, HII was not correlated with the concentrations of CRP, SAA, fibrinogen and MPO. Conclusion: HDL subpopulation profile is a major determinant of HDL’s overall cholesterol-efflux capacity. Efflux capacity of preβ-1 particles are compromised in CHD patients by yet unknown factor(s). HDL Inflammatory Index correlates with HDL subpopulation profile, but not with markers of inflammation in plasma.

Micro- and macrovascular diseases are major causes of morbidity and mortality in the diabetic population, but the cellular and molecular mechanisms that link hyperglycemia to these complications remain incompletely understood. We proposed that in human diabetes, inhibition by glycation of the complement regulatory protein CD59 increases deposition of the membrane attack complex (MAC) of complement, contributing to the higher vascular risk. We report here 1) the generation and characterization of an anti-glycated human CD59 (hCD59) specific antibody, 2) the detection with this antibody of glycated hCD59 colocalized with MAC in kidneys and nerves from diabetic but not from nondiabetic subjects, and 3) a significantly reduced activity of hCD59 in erythrocytes from diabetic subjects, a finding consistent with glycation inactivation of hCD59 in vivo. Because hCD59 acts as a specific inhibitor of MAC formation, these findings provide a molecular explanation for the increased MAC deposition reportedly found in the target organs of diabetic complications. We conclude that glycation inactivation of hCD59 that leads to increased MAC deposition may contribute to the extensive vascular pathology that complicates human diabetes.