Barbara E Corkey

Boston University | BU · Boston Nutrition Obesity Research Center

Changes correlating with increasing obesity include insulin resistance, hyperlipidaemia, hyperinsulinaemia, highly processed food and environmental toxins including plastics and air pollution. The relationship between the appearance of each of these potential causes and the onset of obesity is unknown. The cause(s) must precede obesity, the consequ...

Several unrelated findings led us to hypothesize that induction of autoimmunity is a consequence of a prior major inflammatory event in individuals with susceptible HLA phenotypes and elevated sensitivity to cytokines and free fatty acids (FFA). We observed provocative enhanced responsiveness of cultured human fibroblasts from individuals with type...

In this review, we focus on recent developments in our understanding of nutrient-induced insulin secretion that challenge a key aspect of the “canonical” model, in which an oxidative phosphorylation-driven rise in ATP production closes KATP channels. We discuss the importance of intrinsic β cell metabolic oscillations; the phasic alignment of relev...

Current thresholds for diagnosing diabetes are outdated and do not represent advancements in disease understanding or ability to impact course. Today, evidence supports intervening earlier along the disease continuum to mitigate transition to frank disease and delay/reduce adverse clinical outcomes. We believe it is time for lower diabetes diagnost...

We hypothesize that basal hyperinsulinemia is synergistically mediated by an interplay between increased oxidative stress and excess lipid in the form of reactive oxygen species (ROS) and long-chain acyl-CoA esters (LC-CoA). In addition, ROS production may increase in response to inflammatory cytokines and certain exogenous environmental toxins tha...

A role for fat overfeeding in metabolic dysfunction in humans is commonly implied in the literature. Comparatively less is known about acute carbohydrate overfeeding (COF). We tested the hypothesis that COF predisposes to oxidative stress by channeling electrons away from antioxidants to support energy storage. In a study of 24 healthy human subjec...

Combined fatty acid esterification and lipolysis, termed lipid cycling, is an ATP-consuming process that contributes to energy expenditure. Therefore, interventions that stimulate energy expenditure through lipid cycling are of great interest. Here we find that pharmacological and genetic inhibition of the mitochondrial pyruvate carrier (MPC) in br...

Key tissues are dysfunctional in obesity, diabetes, cardiovascular disease, fatty liver and other metabolic diseases. Focus has centered on individual organs as though each was isolated. Attention has been paid to insulin resistance as the key relevant pathosis, particularly insulin receptor signaling. However, many tissues play important roles in...

Significant advances have been made in deciphering the mechanisms underlying fuel-stimulated insulin secretion by pancreatic beta cells. The contribution of the triggering/ATP-sensitive potassium (KATP)-dependent Ca²⁺ signalling and KATP-independent amplification pathways, that include anaplerosis and lipid signalling of glucose-stimulated insulin...

Objective Medium chain triglycerides (MCT) have unique metabolic properties which may improve insulin sensitivity (Si) and beta cell function but data in humans are limited. We conducted a 6-week clinical trial of MCT oil supplementation. Methods 22 subjects without diabetes (8 males, 14 females, mean ± standard error age 39±2.9 years, baseline BM...

Futile lipid cycling is an ATP-wasting process proposed to participate in energy expenditure of mature fat-storing white adipocytes, given their inability to oxidize fat. The hallmark of activated brown adipocytes is to increase fat oxidation by uncoupling respiration from ATP synthesis. Whether ATP-consuming lipid cycling can contribute to BAT ene...

Mechanisms that regulate metabolites and downstream energy generation are key determinants of T cell cytokine production, but the processes underlying the Th17 profile that predicts the metabolic status of people with obesity are untested. Th17 function requires fatty acid uptake, and our new data show that blockade of CPT1A inhibits Th17-associate...

Hyperinsulinemia is strongly associated with type 2 diabetes. Racial and ethnic minority populations are disproportionately affected by diabetes and obesity-related complications. This mini-review provides an overview of the genetic and environmental factors associated with hyperinsulinemia with a focus on racial and ethnic differences and its meta...

Obesity-associated Type 2 diabetes (T2D) is driven by chronic inflammation. A combinatorial Th17 cytokine profile characterizes and mathematically predicts T2D in people, but the mechanisms that generate the Th17 profile are not clear. We tested the possibility that anaerobic glycolysis, which fuels inflammatory cytokine production from multiple im...

This review is motivated by the need to question dogma that has not yielded significant improvements in outcomes of Type 2 Diabetes treatment: that insulin resistance is the driver of ß-Cell failure and resulting hyperglycemia. We highlight the fact that hyperlipidemia, insulin resistance, and hyperinsulinemia all precede overt diabetes diagnosis a...

Purpose Globally, the age-standardised prevalence of type 2 diabetes mellitus (T2DM) has nearly doubled from 1980 to 2014, rising from 4.7% to 8.5% with an estimated 422 million adults living with the chronic disease. The MULTI sTUdy Diabetes rEsearch (MULTITUDE) consortium was recently established to harmonise data from 17 independent cohort studi...

Mitochondria associate with lipid droplets (LDs) in fat-oxidizing tissues, but the functional role of these peridroplet mitochondria (PDM) is unknown. Microscopic observation of interscapular brown adipose tissue reveals that PDM have unique protein composition and cristae structure and remain adherent to the LD in the tissue homogenate. We develop...

Triggers of the autoimmune response that leads to type 1 diabetes (T1D) remain poorly understood. A possibility is that parallel changes in both T cells and target cells provoke autoimmune attack. We previously documented greater Ca²⁺ transients in fibroblasts from T1D subjects than non-T1D after exposure to fatty acids (FA) and tumor necrosis fact...

T1D donor treatment information. Information regarding the age, sex and treatment at time of donation of all T1D donors (fibroblasts and PBMCs). (TIF)

Metabolic deceleration in pancreatic β-cells is associated with inhibition of glucose-induced insulin secretion (GIIS), but only in the presence of intermediate/sub-maximal glucose concentrations. Here, we used acute metformin treatment as a tool to induce metabolic deceleration in INS1 (832/13) β-cells, with the goal of identifying key pathways an...

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Purpose of review: This perspective is motivated by the need to question dogma that does not work: that the problem is insulin resistance (IR). We highlight the need to investigate potential environmental obesogens and toxins. Recent findings: The prequel to severe metabolic disease includes three interacting components that are abnormal: (a) IR...

Advances in understanding diabetes mellitus (DM) through basic and clinical research have helped clarify and reunify a disease state fragmented into numerous etiologies and subtypes. It is now understood that a common pathophysiology drives the diabetic state throughout its natural history and across its varied clinical presentations, a pathophysio...

Metabolism controls T cell function, but the role of cellular metabolism in regulating our published T2D-associated Th17 cytokine signature is untested. Published work showed Th17 function requires fatty acid (FA) uptake, and suggested Th17s burn fat to support inflammation. We thus hypothesized that chronic exposure of immune cells to FAs, which o...

Brown adipose tissue (BAT) thermogenic activity is thought to mediate its capacity to negate the development of insulin resistance. This hypothesis predicts that mediators of thermogenesis may counteract diet induced insulin resistance. Here, we report that the mitochondrial fusion protein Mitofusin-2 (Mfn2) in BAT is essential for cold-stimulated...

Glucose metabolism promotes insulin secretion in β-cells via metabolic coupling factors that are incompletely defined. Moreover, chronically elevated glucose causes β-cell dysfunction, but little is known about how cells handle excess fuels to avoid toxicity. Here we sought to determine which among the candidate pathways and coupling factors best c...

Objective: To review the metabolomic studies carried out so far to identify metabolic markers associated with surgical and dietary treatments for weight loss in subjects with obesity. Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. Results: Thirty-two studies successfully met t...

We have previously demonstrated that islet depolarization with 70 mM KCl opens Cx36 hemichannels and allows diffusion of small metabolites and cofactors through the β-cell plasma membrane. We have investigated in this islet “permeabilized” model whether glycolytic and citric acid cycle intermediates stimulate insulin secretion and how it correlates...

Background: Many tissues play an important role in metabolic homeostasis and the development of diabetes and obesity. We hypothesized that the circulating redox metabolome is a master metabolic regulatory system that impacts all organs and modulates reactive oxygen species (ROS) production, lipid peroxidation, energy production and changes in lipi...

Comparison of lipolysis after 1 and 4 hour incubation time. Lipolysis was measured as glycerol release [18]. Adipocytes day 14 after differentiation were incubated in KRB with 0.5 mM oleate complexed to 150 μM BSA with or without the positive control Forskolin (5 μM) for either 1 or 4 hours. Aliquots were removed and the glycerol content was measur...

We thank Drs. Kalra and and Baruah for their comments (1) on our article (2) in an effort improve the utility of our proposed β-cell–centric classification. We agree that “treatment” is more important than “classification.” We find it frustrating that governments and insurers often think otherwise, limiting therapies of choice on the basis of labe...

Displacement of Bromodomain and Extra-Terminal (BET) proteins from chromatin has promise for cancer and inflammatory disease treatments, but roles of BET proteins in metabolic disease remain unexplored. Small molecule BET inhibitors, such as JQ1, block BET protein binding to acetylated lysines, but lack selectivity within the BET family (Brd2, Brd3...

Numerical data from Affymetrix microarray experiments, in Excel format. (XLSX)

Supporting Materials and Methods: Supporting Text, Supporting References, Supporting Figs A–J, Supporting Tables A-D. (DOCX)

Lipid signals derived from lipolysis and membrane phospholipids play an important role in glucose-stimulated insulin secretion (GSIS), though the exact secondary signals remain unclear. Previous reports have documented a stimulatory role of exogenously added mono-acyl-glycerol (MAG) on insulin secretion from cultured β-cells and islets. In this rep...

The current classification system presents challenges to the diagnosis and treatment of patients with diabetes mellitus (DM), in part due to its conflicting and confounding definitions of type 1 DM, type 2 DM, and latent autoimmune diabetes of adults (LADA). The current schema also lacks a foundation that readily incorporates advances in our unders...

Our previous work has demonstrated that islet depolarization with KCl opens connexin36 hemichannels in β-cells of mouse pancreatic islets allowing the exchange of small metabolites with the extracellular medium. In this study, the opening of these hemichannels has been further characterized in rat islets and INS–1 cells. Taking advantage of hemican...

Introduction: To describe recruitment difficulties in a pediatric clinical trial targeting underserved pediatric obese populations. Methods: We planned a 6-month randomized, double-blind, placebo-controlled clinical trial of glutamine vs. placebo, to reduce HOMA-IR and weight gain in obese adolescents. Participation required 5 visits at a research...

A low glycemic response (LGR) vs. high glycemic response (HGR) diet helps curtail the development of obesity and diabetes, though the mechanisms are unknown. We hypothesized that consumption of a HGR vs. a LGR diet would lead to a more oxidized circulating redox state and predicted that a HGR diet would increase fat accumulation, reduce insulin sen...

Hyperinsulinemia (HI) is elevated plasma insulin at basal glucose. Impaired glucose tolerance is associated with HI, though the exact cause and effect relationship remains poorly defined. We tested the hypothesis that HI can result from an intrinsic response of the β-cell to chronic exposure to excess nutrients, involving a shift in the concentrati...

Circulating redox state changes, determined by the ratio of reduced/oxidized pairs of different metabolites, have been associated with metabolic diseases. However, the pathogenic contribution of these changes and whether they modulate normal tissue function is unclear. As alterations in hepatic gluconeogenesis and glycogen metabolism are hallmarks...

The “chemical obesogen” hypothesis conjectures that synthetic, environmental contaminants are contributing to the global epidemic of obesity. In fact, intentional food additives (e.g., artificial sweeteners and colors, emulsifiers) and unintentional compounds (e.g., bisphenol A, pesticides) are largely unstudied in regard to their effects on overal...

Adrenergic stimulation of brown adipocytes (BA) induces mitochondrial uncoupling, thereby increasing energy expenditure by shifting nutrient oxidation towards thermogenesis. Here we describe that mitochondrial dynamics is a physiological regulator of adrenergically-induced changes in energy expenditure. The sympathetic neurotransmitter Norepinephri...

The effects of cytokine and fatty acid treatment on signal transduction in dermal fibroblasts from type 1 diabetics and matched controls were compared. Chronic exposure to TNF, accentuated Ca(2+) mobilization in response to bradykinin (BK) in cells from both controls and diabetics; responses were three-fold greater in cells from diabetics than in c...

Traditionally, biomedical research has been carried out mainly within departmental boundaries. However, successful biomedical research increasingly relies on development of methods and concepts crossing these boundaries, requiring expertise in different disciplines. Recently, major research institutes have begun experimenting with ways to foster an...

Diabetes is prevalent and chronic (1). A meta-analysis of studies published between 1990 and 2006 showed that in adults, obesity prevalence increased from 13 to 32% between the 1960s and 2004. Currently, 66% of U.S. adults are overweight or obese. The incidence of diabetes is increasing and afflicting new populations including children and develop...

Obesity and diabetes are caused by defects in metabolically sensitive tissues. Attention has been paid to insulin resistance as the key relevant pathosis, with a detailed focus on signal transduction pathways in metabolic tissues. Evidence exists to support an important role for each tissue in metabolic homeostasis and a potential causative role in...

High fat diet and its induced changes in glucose homeostasis, inflammation and obesity continue to be an epidemic in developed countries. The A2b adenosine receptor (A2bAR) is known to regulate inflammation. We used a diet-induced obesity murine knockout model to investigate the role of this receptor in mediating metabolic homeostasis, and correlat...