The beta-cell response to metabolic stress

We are currently conducting a study to examine the mechanisms of beta-cell compensation to insulin resistance during puberty. 


The pancreatic beta cell has a strong capacity to adjust to a changing metabolic environment. For example, the vast majority of people who gain weight and become resistant to the action of insulin do not develop diabetes because their beta cells are able to compensate for insulin resistance by two mechanisms: 1- a large increase in insulin secretion; 2- cell proliferation which leads to enhanced functional beta-cell mass. In about 20% of individuals, however, these compensatory mechanisms are deficient or absent and T2D develops. Our laboratory seeks to understand the cellular and molecular basis of these compensatory mechanisms and of their failure under conditions of metabolic stress.

Since its inception, our lab has focused on elucidating the mechanisms of glucolipotoxicity, the combination of excessive levels of glucose and fatty-acids which is proposed to mediate, at least in part, the deterioration of beta-cell function in T2D (1). In vitro, we have shown that prolonged exposure of isolated islets of Langerhans to elevated levels of fatty acids and glucose impairs insulin gene expression (2; 3) via transcriptional mechanisms that involve de novo synthesis of ceramide (4; 5). Inhibition of insulin gene transcription involves reduction of MafA expression as well as exclusion of PDX-1 from the nuclear compartment (6). We showed that this transcriptional effect is mediated by the enzyme PAS kinase (7; 8) (in collaboration with Chris Rhodes, then at U Chicago and Jared Rutter, U Utah). We have established an in vivo model to study glucolipotoxicity in rats (9) and showed that prolonged infusion of glucose and Intralipid in this model also leads to a decrease in insulin gene expression and nuclear exclusion of PDX-1 (10) which, in older animals, in turn impairs insulin biosynthesis and secretion (11) (in collaboration with Tom Jetton, U Vermont; Raghu Mirmira, U Indiana; and Marc Prentki, U Montréal). 

During the course of these project we have generated novel research tools, including a transgenic rat expressing a Renilla luciferase (RLuc)-enhanced yellow fluorescent protein (YFP) fusion under the control of a 9-kb genomic fragment from the rat ins2 gene (RIP7-RLuc-YFP) (12). This rat line is available from the Rat Resource and Research Center (RRRC) at

The observation that infusion of excess nutrients in rats leads to a marked increase in beta-cell mass (11) led us to investigate the underlying mechanisms. We found that the increase in beta-cell mass in infused rats is a compensatory mechanism involving the growth factor HB-EGF, the EGF receptor, the kinase mTOR and the transcription factor FoxM1 which promote beta-cell proliferation (13). Further examination of this phenomenon revealed that excess glucose and lipids synergistically and reversibly promote beta-cell proliferation via direct action on the beta-cell (14) but also indirectly through the brain via the autonomic nervous system (15) (in collaboration with Thierry Alquier, U Montréal). We have recently expanded these findings by showing that the HB-EGF/EGFR signaling pathway is implicated in glucose-induced beta-cell proliferation in rodent and human islets (16) (in collaboration with Don Scott, Mount Sinai School of Medicine). 

We have also examined the beta-cell response to other situations or disease states. We showed that mice carrying the most frequent human mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) causing cystic fibrosis do not have an intrinsic beta-cell secretory defect but develop insulin resistance and a beta-cell mass deficit with age (17) (in collaboration with Yves Berthiaume, U Montréal). We have demonstrated that the uremic toxin urea impairs insulin secretion via excessive O-glycosylation of the glycolytic enzyme phosphofructokinase-1, a phenomenon that may explain, at least in part, the prevalence of dysregulations of glucose homeostasis in chronic kidney disease (18). 

To further identify the mechanisms by which fatty acids induce beta-cell proliferation using an unbiased approach, we recently performed single-cell RNA sequencing of rodent islets exposed to palmitate or oleate and are currently analyzing these data in collaboration with Rob Sladek at the McGill Genome Center. In addition, we are exploring the role of the de novo ceramide synthesis pathway in oleate-induced beta-cell proliferation by sphingolipidomic analysis in collaboration with Scott Summers and Will Holland at U Utah. A strong emphasis is placed on the translational value of our findings by systematically testing their applicability to human islets, which we receive on a regular basis from the NIH-funded Integrated Islet Distribution Program and the Islet Core of U Alberta. 

We are currently conducting a study to examine the mechanisms of beta-cell compensation to insulin resistance during puberty. 


These projects are funded by the US National Institutes of Health (NIH), the Canadian Institutes of Health Research (CIHR) and the Quebec Cardiometabolic Health, Diabetes and Obesity Research Network. 

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