Allison Goldfine

Joslin Diabetes Center · Section on Clinical, Behavioral and Outcomes Research

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 o...

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 dete...

Background and aims The regulation of cell-cholesterol efflux is not completely understood. Our aim was to assess the role of HDL- and non-HDL-related parameters in ATP-binding cassette transporter-A1 (ABCA1) and scavenger receptor class B-type-I (SRBI) cell-cholesterol efflux capacity (CEC) in coronary heart disease (CHD) cases and controls. Meth...

Aims Insulin potentiates glucose-stimulated insulin secretion. These effects are attenuated in beta cell–specific insulin receptor knockout mice and insulin resistant humans. This investigation examines whether short duration insulin exposure regulates beta cell responsiveness to arginine, a non-glucose secretagogue. Materials and methods Arginine...

To improve the power of mediation in high-throughput studies, here we introduce High-throughput mediation analysis (Hitman), which accounts for direction of mediation and applies empirical Bayesian linear modeling. We apply Hitman in a retrospective, exploratory analysis of the SLIMM-T2D clinical trial in which participants with type 2 diabetes wer...

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...

Background: Several glucagon-like peptide agonists (GLP-1RA) and sodium-glucose co-transporter 2 inhibitors (SGLT2i) have demonstrated cardiovascular benefit in type 2 diabetes in large randomized controlled trials in patients with established cardiovascular disease or multiple risk factors. However, few trial participants were on both agents and i...

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...

SGLT2 inhibitors (SGLT2i) may provide cardiovascular (CV) benefit when added to GLP-1 receptor agonists (GLP-1RA) given the orthogonal mechanisms of action, although combined use is incompletely understood. Patients adding either SGLT2i or sulfonylureas to baseline GLP-1RA were identified within 3 U.S. datasets (2013-2018) and were 1:1 propensity s...

Aims: To examine whether the presence of two common missense variants in the CYP2C9 gene (rs1799853, encoding Arg144Cys and denoted as *2, and rs1057910, encoding Ile359Leu and denoted as *3) influences the acute physiological response to a single glipizide dose in individuals naïve to diabetes medications. Methods: In the Study to Understand th...

Molecular mechanisms by which Roux-en-Y gastric bypass (RYGB) improves glycemic control and metabolism in type 2 diabetes (T2D) remain incompletely understood. In the SLIMM-T2D trial, participants with T2D were randomized to RYGB or nonsurgical management and their fasting plasma proteome and metabolome were analyzed for up to 3 years. To identify...

Objective: Insulin resistance is associated with increased lipolysis and elevated concentrations of free fatty acids (FFA), which in turn contribute to impaired vascular function. It was hypothesized that lowering FFA with acipimox, a nicotinic acid derivative that impairs FFA efflux, would improve endothelial function, measured by flow-mediated d...

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...

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 chara...

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 gast...

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 ban...

Context Plasma betaine correlates with insulin sensitivity in humans. Betaine supplementation in high-fat fed mice improves glucose homeostasis, hepatic fat, insulin sensitivity, and increases energy expenditure and oxidative capacity of inguinal white adipose tissue. Objective To assess metabolic effects of oral betaine in obese participants with...

To identify molecular mechanisms contributing to postoperative metabolic improvements after Roux-en-Y gastric bypass (RYGB), we performed comprehensive proteomic analysis of fasting human plasma samples obtained from the SLIMM-T2D longitudinal clinical trial, which randomized obese individuals with T2D to RYGB surgery or a one-year intensive medica...

Bariatric surgery has emerged as a potent approach to improve obesity-related metabolic comorbidities including type 2 diabetes (T2D). However, molecular mechanisms responsible for metabolic improvement after bariatric surgery remain incompletely understood. We profiled and integrated the fasting plasma proteome (aptamer-based Somalogic platform) a...

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 (T2D). Research design and methods: We prospectively randomized 38 obese patients with T2D (15 male and 23 female, with mean ±...

Objective To evaluate the cardiovascular safety of canagliflozin, a sodium-glucose cotransporter 2 inhibitor for the treatment of type 2 diabetes mellitus, in direct comparisons with DPP-4 inhibitors (DPP-4i), GLP-1 receptor agonists (GLP-1RA), or sulfonylureas, as used in routine practice. Design Population based retrospective cohort study. Sett...

Appendix: Supplementary materials

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 stud...

Objective: The rs7903146 T allele in transcription-factor-7-like-2 (TCF7L2) is strongly associated with type 2 diabetes (T2D), but the mechanisms for increased risk remain unclear. We evaluated the physiologic and hormonal effects of TCF7L2 genotype before and after interventions that influence glucose physiology. Research design and methods: We...

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 in 26 subjects with either type 1 or type 2 diabetes to evaluate effects of high-dose ebselen (150 mg orally twice daily) administration on oxidative...

Purpose: To compare effects of Roux-en-Y gastric bypass versus a multi-disciplinary, group-based medical diabetes and weight management program on physical fitness and behaviors. Methods: Physical behavior and fitness was assessed in participants of the study Surgery or Lifestyle With Intensive Medical Management in the Treatment of Type 2 Diabe...

Objective: Plasma levels of branched-chain amino acids (BCAA) are consistently elevated in obesity and type 2 diabetes (T2D) and can also prospectively predict T2D. However, the role of BCAA in the pathogenesis of insulin resistance and T2D remains unclear. Methods: To identify pathways related to insulin resistance, we performed comprehensive gene...

Cardiovascular disease remains the principal cause of death and disability among patients with diabetes mellitus. Diabetes mellitus exacerbates mechanisms underlying atherosclerosis and heart failure. Unfortunately, these mechanisms are not adequately modulated by therapeutic strategies focusing solely on optimal glycemic control with currently ava...

Importance Inflammation may contribute to pathological associations among obesity, diabetes mellitus, and cardiovascular disease. Objective To determine whether targeting inflammation using salsalate compared with placebo reduces progression of noncalcified coronary artery plaque. Design, Setting, and Participants In the Targeting Inflammation Usin...

The U.S. Food and Drug Administration (FDA) issued a Guidance for Industry in 2008 defining preapproval and postapproval requirements for the demonstration of cardiovascular safety for all new medications developed for glycemic management in type 2 diabetes. Seventeen large, prospective, randomized, controlled clinical trials involving more than 14...

Aims: To evaluate the comparative cardiovascular (CVD) safety of GLP-1 receptor agonists (GLP-1 RA) in head-to-head comparisons with DPP-4 inhibitors (DPP-4i), sulfonylureas, or insulin, when added to metformin, as used in real-world patients with type 2 diabetes mellitus (T2DM). Methods: Within a large U.S. commercial health plan database linke...

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 res...

Objective: We aimed to compare metabolic control in adults with diabetes in the general population to those newly referred to a diabetes center and after one year of specialty care. Methods: Retrospective comparison of adults with diabetes aged ≥20 years data from the National Health and Nutrition Examination Survey (NHANES, n=1674) and a diabetes...

Although compensatory islet hyperplasia in response to insulin resistance is a recognized feature in diabetes, the factor(s) that promote β cell proliferation have been elusive. We previously reported that the liver is a source for such factors in the liver insulin receptor knockout (LIRKO) mouse, an insulin resistance model that manifests islet hy...

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 set...

Background: Dietary supplement use is widespread in the United States. Although it has been suggested that chromium has potential beneficial effects in type 2 diabetes (T2D) in in vitro and small in vivo human studies, chromium supplementation in diabetes has not been investigated at the population level. Objective: The objective of this study w...

Wound healing is impaired in diabetes, resulting in significant morbidity and mortality. Neutrophils are the main leukocytes involved in the early phase of healing. As part of their anti-microbial defense, neutrophils form extracellular traps (NETs) by releasing decondensed chromatin lined with cytotoxic proteins. NETs, however, can also induce tis...

Recommendations for surgical compared with lifestyle and pharmacologic based approaches for type 2 diabetes (T2D) management remain controversial. Comparing laparoscopic adjustable gastric band (LAGB) to an intensive diabetes medical and weight management (IMWM) program for T2D. Prospective, randomized clinical trial. Two Harvard Medical School aff...

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD) in the USA. The aim of this study was to determine whether there were skin fibroblast (SF) gene expression differences between subjects with type 1 diabetes (T1D) with or without DN. Cross-sectional Setting: This study was conducted in the University of Minnesota. Stud...

Objective: Genome-wide association studies have uncovered a large number of genetic variants associated with type 2 diabetes or related phenotypes. In many cases the causal gene or polymorphism has not been identified, and its impact on response to anti-hyperglycemic medications is unknown. The Study to Understand the Genetics of the Acute Respons...

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 st...

IntroductionAdults with type 2 diabetes (T2D) have an increased risk of fractures [1]. This increased risk, despite normal bone mineral density (BMD) [2, 3], has led to investigation of deficits in diabetic skeletal properties. Skeletal dynamics are reduced in T2D [4, 5], possibly as a result of inflammation [6]. Inflammation plays an important rol...

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...

Aims Vascular disease is the leading cause of morbidity and mortality in type 1 diabetes mellitus (T1DM). We previously demonstrated that patients with T1DM have impaired endothelial function, a forme fruste of atherosclerosis, as a result of increased oxidative stress. Bilirubin has emerged as a potent endogenous antioxidant with higher concentra...

This study sought to evaluate differential effects of visceral fat (VF) and subcutaneous fat and their effects on metabolic syndrome (MetS) risk across body mass index (BMI) categories. The regional distribution of adipose tissue is an emerging risk factor for cardiometabolic disease, although serial changes in fat distribution have not been extens...

Aims: Two recent randomized controlled trials of type 2 diabetes mellitus (T2DM) patients with history of, or at high risk of, cardiovascular disease (CVD) showed no risk of ischemic cardiovascular events associated with dipeptidyl peptidase-4 inhibitors (DPP4i), but an increased risk of heart failure (HF) with saxagliptin. We evaluated the risk o...

Objective: Higher hemoglobin A1c (HbA1c) is associated with lower cognitive function in type 2 diabetes. To determine whether associations persist at lower levels of dysglycemia in patients who have established cardiovascular disease, cognitive performance was assessed in the Targeting INflammation Using SALsalate in CardioVascular Disease (TINSAL...

Aims: Impact of weight loss on cardiac structure has not been extensively investigated in large, multi-ethnic, community-based populations. We investigated the longitudinal impact of weight loss on cardiac structure by cardiac magnetic resonance (CMR). Methods and results: 2351 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) who...

Objective: Dipeptidyl peptidase-4 (DPP4), also known as CD26, is a transmembrane glycoprotein that has a costimulatory function in the immune response. DPP4 inhibitors (DPP4i) are oral glucose-lowering drugs for type 2 diabetes mellitus (T2DM). This study evaluated the risk of incident rheumatoid arthritis (RA) and other autoimmune diseases (AD) s...

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 (Wei...

Significance Elevated circulating proinsulin and a poor biological response to insulin are observed early in individuals with type 2 diabetes. Genome-wide association studies have recently identified genes associated with proinsulin processing, and clinical observations suggest that elevated proinsulin and its intermediates are markers of dysfuncti...

In our study to target inflammation using salsalate in patients with type 2 diabetes, we demonstrate improvement in glycemia but no change in either flow-mediated, endothelium-dependent (FMD) or nitroglycerin-mediated, endothelium-independent dilation over 6 months in salsalate (3.5 g/day) compared with placebo-treated patients (1). It is important...

Roux-en-Y gastric bypass (RYGB) surgery leads to substantial and sustained weight loss and improved cardiometabolic parameters in obese people (1). Approximately 80% of patients with type 2 diabetes (T2D) experience complete remission, defined as normoglycemia without medication, and another 15% have improvement, albeit remaining on medication (2)....

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). Am...

Context: Human CD59, an inhibitor of the membrane attack complex of complement, is inactivated by glycation. Glycation inactivation of CD59 enhances complement-mediated injury in target organs of diabetes complications. Objective: We hypothesized that circulating soluble glycated CD59 (GCD59) represents a novel biomarker of blood glucose handlin...

Context: Bile acids (BAs) are newly recognized signaling molecules in glucose and energy homeostasis. Differences in BA profiles with type 2 diabetes mellitus (T2D) remain incompletely understood. Objective: The objective of the study was to assess serum BA composition in impaired glucose-tolerant, T2D, and normal glucose-tolerant persons and to...

Local insulin-induced lipoatrophy, an immune-mediated loss of subcutaneous adipose tissue at insulin administration sites, is now a rare complication of insulin therapy in patients with diabetes. Lipoatrophy incidence, previously noted in 10–55% of patients using animal-derived insulins (1), declined considerably with the advent of and improved pur...

Background Salsalate is a non-acetylated salicylate that lowers glucose levels in people with type 2 diabetes (T2DM). Here we examined whether salsalate also lowered serum protein-bound levels of early and advanced glycation end products (AGEs) that have been implicated in diabetic vascular complications.Methods Participants were from the Targeting...

In the Swedish Obese Subjects (SOS) study, the largest and longest-duration study comparing bariatric surgical procedures with conventional medical care for patients with obesity, the study group undergoing bariatric procedures including gastric banding, vertical banded gastroplasty, and gastric bypass achieved greater and more sustained weight los...

OBJECTIVE To test whether inhibiting inflammation with salsalate improves endothelial function in patients with type 2 diabetes (T2D).RESEARCH DESIGN AND METHODS We conducted an ancillary study to the National Institutes of Health-sponsored, multicenter, randomized, double-masked, placebo-controlled trial evaluating the safety and efficacy of salsa...

Vanadium, abbreviated V, is an early transition metal that readily forms coordination complexes with a variety of biological products such as proteins, metabolites, membranes and other structures. The formation of coordination complexes stabilizes metal ions, which in turn impacts the biodistribution of the metal. To understand the biodistribution...

Increasing evidence links the complement system with complications of human diabetes. The complement regulatory protein CD59, an inhibitor of formation of membrane attack complex (MAC), is inhibited by hyperglycemia-induced glycation fostering increased deposition of MAC, a major effector of complement-mediated tissue damage. CD59, an ubiquitous GP...

Salicylate is one of the oldest drugs in clinical practice, with documented use of relevant plant extracts for treating pain and inflammation dating back at least 3500 years (1). Nevertheless, its medicinal properties and mechanisms of action remain incompletely understood. Chemically pure forms were introduced during the 19th century (2, 3), but b...

Background: Short-duration studies show that salsalate improves glycemia in type 2 diabetes mellitus (T2DM). Objective: To assess 1-year efficacy and safety of salsalate in T2DM. Design: Placebo-controlled, parallel trial; computerized randomization and centralized allocation, with patients, providers, and researchers blinded to assignment. (Clinic...

We thank Dr Koh for his important comments on this emerging field.1 We fundamentally agree that it is essential to consider the cardiovascular and metabolic health of the patient for whom statin therapy may be prescribed. Indeed, our suggestion is for clinicians to administer statin therapy when indicated by guidelines outlined by major professiona...

This invention relates to methods for reducing chronic subacute inflammatory states associated with obesity and improve glycemia, thereby preventing or delaying the development of type 2 diabetes (T2D) in obese subjects, or subjects with the metabolic syndrome, using non-acetylated forms of salicylate, e.g., salsalate or trilisate.

Diabetic kidney disease causes significant morbidity and mortality among people with type 1 diabetes (T1D). Intensive glucose and blood pressure control have thus far failed to adequately curb this problem and therefore a major need for novel treatment approaches exists. Multiple observations link serum uric acid levels to kidney disease developmen...

Abstract Accumulation of ceramides within tissues induces insulin resistance. Moreover, adiponectin exerts its beneficial metabolic effects at least partially through ceramide catabolism. We hypothesized that specific plasma ceramide subspecies are elevated in obese children and adolescents with type 2 diabetes (T2D), and that they inversely correl...

Bariatric surgery has emerged as a highly effective treatment for obesity and is increasingly recognized to have benefits for glycemic management in patients with pre-existing type 2 diabetes mellitus (T2DM), and for diabetes prevention. This article will review the efficacy and mechanisms of metabolic surgery for the treatment of T2DM. Recent smal...

The implementation of electronic health records (EHRs) may support evaluations of health care delivery, such as the prescription of newly approved medications, to adults with diabetes. We aimed to evaluate prescribing patterns of thiazolidinediones and novel glucose-lowering drug classes using electronic prescribing data contained in an outpatient...

Aims/hypothesis: Chronic sub-acute inflammation contributes to the pathogenesis of type 2 diabetes mellitus and cardiovascular disease. High doses of salicylate reduce inflammation, glucose and triacylglycerols, and may improve insulin sensitivity, suggesting therapeutic potential in impaired fasting glucose and/or impaired glucose tolerance. This...

For any prescription drug, the potential benefits to health must be balanced against potential risks. Understanding these potential risks can help physicians and patients make informed decisions on whether to use a medication. Recently, statins, a class of medications prescribed to treat high cholesterol levels, have been found to modestly increase...

Both decreased insulin secretion and action contribute to the pathogenesis of type 2 diabetes (T2D) in humans. The insulin receptor and insulin signalling proteins are present in the rodent and human β-cell and modulate cell growth and function. Insulin receptors and insulin signalling proteins in β-cells are critical for compensatory islet growth...

The US Food and Drug Administration (FDA), Center for Drug Evaluation and Research, convened a meeting of the Division of Metabolism and Endocrinology Products on March 28-29, 2012, to consider cardiovascular safety requirements for approval of new drugs to treat obesity. The broader context at that time involved 4 recent individual drug product re...

No drug provides health benefits without some degree of risk, and risk-benefit assessments require ongoing review as new data become available. This is certainly the case for the use of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors - statins - and the risk of new-onset diabetes. Cardiovascular disease is the leading cause of...

We would like to respond to Brosch et al. regarding our manuscript "Expression of the Splicing Factor Gene SFRS10 Is Reduced in Human Obesity and Contributes to Enhanced Lipogenesis" (Pihlajamäki et al., 2011b). Brosch performed RT-PCR in liver samples from 13 lean and 34 obese individuals, finding no differences in SFRS10 or LPIN1 expression. We w...