Li B.,McGill University |
Lu Y.,McGill University |
Srikant C.B.,McGill University |
Gao Z.-H.,McGill University |
And 2 more authors.
American Journal of Physiology - Gastrointestinal and Liver Physiology | Year: 2013
The antidiabetic mechanism of bariatric surgery includes specific changes in the secretion of incretins. To identify additional players originating from the gut, we evaluated the effects of duodenal-jejunal bypass (DJB) in morbidly obese Zucker fatty rats. A fast relief of hyperglycemia and hyperinsulinemia was achieved even before a significant weight loss occurred. Fourteen days after DJB, we characterized the changes in intestinal histochemistry in the bypassed duodenum and shortcut jejunum that was reanastomosed directly to the starting point of the duodenum and compared with the corresponding regions of sham-operated rats. The bypassed duodenum exhibited mucosal atrophy and apoptosis and decreased proliferative renewal. In shortcut jejunum, DJB resulted in 40% significantly enlarged intestinal circumference and increased epithelial proliferation, especially in putative transit-amplifying (TA) cells and the crypt. Because Reg family proteins promote cell growth and survival, we explored their expression in the intestine. With the use of immunohistochemistry, Reg1, -3α, and -3β were normally expressed in intestinal mucosa. After DJB, the level of Reg1 protein was reduced, whereas Reg3α and -3β were not changed in bypassed duodenum. Downstream in shortcut jejunum, the levels of Reg1 and -3β were greatly induced and especially concentrated in the putative TA cells. Our results revealed significant changes in the integrity and proliferation of the intestinal mucosa as a consequence of DJB, and in cell- and isoform-specific expression of Reg proteins within the replicating mucosal epithelium, and provide evidence indicating that the activation of Reg proteins may contribute to intestinal compensation against increased load and/or to improving insulin sensitivity. © 2013 the American Physiological Society.
News Article | March 24, 2016
New research by Sylvie Lesage, a Ph.D. scientist at Maisonneuve-Rosemont Hospital (CIUSSS- East Montreal) and associate research Professor at University of Montreal, just published in the prestigious international scientific journal Nature Genetics, has discovered that a common genetic defect in beta cells may underlie both known forms of diabetes. Worldwide, 400 million people suffer from diabetes, with rapid increases projected. Patients with diabetes mostly fall into one of two categories, type 1 diabetics, triggered by auto-immunity at a young age, and type 2 diabetics, caused by metabolic dysfunction of the liver. Despite being labeled a “lifestyle disease”, diabetes has a strong genetic basis. “Our research finds that genetics is critical for the survival of beta cells – the cells that make insulin'' says Sylvie Lesage, who is also a member of the Montreal Diabetes Research Center. ‘'Thanks to our genetic make-up, some of us have beta cells that are tough and robust, while others have beta cells that are fragile and can't handle stress. It is these people who develop diabetes, either type 1 or type 2, while others with tougher beta cells will remain healthy even in if they suffer from autoimmunity or metabolic dysfunction of the liver.” Diabetes is a hidden killer. One out of every 11 adults is suffering from the disease, yet half of them have not even been diagnosed. Diabetes is caused by the inability of the body to lower blood glucose, a process normally driven by insulin. In patients with type 1 diabetes (T1D), this is caused by the immune system killing off the beta cells that produce insulin. In patients with type 2 diabetes (T2D), a metabolic dysfunction prevents insulin from working on the liver. In both cases, left untreated the extra glucose in the blood can cause blindness, cardiovascular disease, diabetic nephropathy, diabetic neuropathy and death. In this study led by Adrian Liston, Ph.D., an international team of researchers investigated how genetic variation controls the development of diabetes. While most previous work has focused on the effect of genetics in altering the immune system (in T1D) and metabolic dysfunction of the liver (in T2D), this research found that genetics also affected the beta cells that produce insulin. Mice with fragile beta cells that were poor at repairing DNA damage would rapidly develop diabetes when those beta cells were challenged by cellular stress. Other mice, with robust beta cells that were good at repairing DNA damage, were able to stay non-diabetic for life, even when those islets were placed under severe cellular stress. The same pathways for beta cell survival and DNA damage repair were also found to be altered in diabetic patient samples, indicating that a genetic predisposition for fragile beta cells may underlie who develops diabetes. Current treatments for T2D rely on improving the metabolic response of the liver to insulin. These antidiabetic drugs, in conjunction with lifestyle interventions, can control the early stages of T2D by allowing insulin to function on the liver again. However during the late stages of T2D, the death of beta cells means that there is no longer any insulin being produced. At this stage, antidiabetic drugs and lifestyle interventions have poor efficacy, and medical complications arise. Lydia Makaroff, Ph.D., of the International Diabetes Federation, commented this ground breaking work: ‘'The health cost for diabetes currently exceeds US$600 billion worldwide, 12 % of the global health budget, and will only increase as diabetes becomes more common. Much of this health care burden is caused by late-stage type 2 diabetes, where we do not have effective treatments, so we desperately need new research into novel therapeutic approaches. This discovery dramatically improves our understanding of type 2 diabetes, which will enable the design of better strategies and medications for diabetes in the future”. Liston, leader of the Belgian arm of the research, sees new promise in these results, especially through the new animal models used which will enable scientists, for the first time, to test new antidiabetic drugs that focus on preserving beta cells.
Peyot M.-L.,Montreal Diabetes Research Center |
Pepin E.,Montreal Diabetes Research Center |
Lamontagne J.,Montreal Diabetes Research Center |
Latour M.G.,Montreal Diabetes Research Center |
And 8 more authors.
Diabetes | Year: 2010
OBJECTIVE - C57Bl/6 mice develop obesity and mild hyperglycemia when fed a high-fat diet (HFD). Although diet-induced obesity (DIO) is a widely studied model of type 2 diabetes, little is known about β-cell failure in these mice. RESEARCH DESIGN AND METHODS - DIO mice were separated in two groups according to body weight gain: low- and high-HFD responders (LDR and HDR). We examined whether mild hyperglycemia in HDR mice is due to reduced β-cell mass or function and studied islet metabolism and signaling. RESULTS - HDR mice were more obese, hyperinsulinemic, insulin resistant, and hyperglycemic and showed a more altered plasma lipid profile than LDR. LDR mice largely compensated insulin resistance, whereas HDR showed perturbed glucose homeostasis. Neither LDR nor HDR mice showed reduced β-cell mass, altered islet glucose metabolism, and triglyceride deposition. Insulin secretion in response to glucose, KCl, and arginine was impaired in LDR and almost abolished in HDR islets. Palmitate partially restored glucose- and KCl-stimulated secretion. The glucose-induced rise in ATP was reduced in both DIO groups, and the glucose-induced rise in Ca2+ was reduced in HDR islets relatively to LDR. Glucose-stimulated lipolysis was decreased in LDR and HDR islets, whereas fat oxidation was increased in HDR islets only. Fatty acid esterification processes were markedly diminished, and free cholesterol accumulated in HDR islets. CONCLUSIONS - β-Cell failure in HDR mice is not due to reduced β-cell mass and glucose metabolism or steatosis but to a secretory dysfunction that is possibly due to altered ATP/Ca2+ and lipid signaling, as well as free cholesterol deposition. © 2010 by the American Diabetes Association.
News Article | October 27, 2016
Montreal, October 27, 2016. - You've tried all the diets. No matter: you've still regained the weight you lost, even though you ate well and you exercised regularly! This may be due to a particular enzyme in the brain: the alpha/beta hydrolase domain-6 enzyme, better known as ABHD6. A study published this week in Cell Reports demonstrates that when this enzyme is blocked in certain neurons of the mouse hypothalamus, it becomes impossible for them to lose weight, even if they adhere to an ideal regimen... ideal for mice that is! A research team at the University of Montreal Hospital Research Centre (CRCHUM) has generated genetically engineered mice, deprived of the ABHD6 enzyme in a localized area of the brain, namely in a specific population of hypothalamic neurons. Alexandre Fisette, postdoctoral researcher at CRCHUM and first author of the study, explains that, "under normal conditions of housing and food, these mice are identical to normal mice. However, when challenged, they are unable to adapt. They no longer consume food after a fast, they cannot maintain their body temperature during exposure to cold, and they are more susceptible to become obese when fed a high-fat diet. What's more, once they are obese and we try to make them lose weight by feeding them a normal diet, they do not lose weight." The researchers have discovered that this enzyme acts as a sort of switch for the body's adjustment to extremes. "It is a mechanism we had not suspected. Strikingly, the absence of one single enzyme within a precise region of the brain completely disrupts the normal metabolism and prevents the mice from losing weight," comments Thierry Alquier, CRCHUM researcher and professor at the University de Montréal. Is there an identical process taking place in humans? Thierry Alquier thinks that clinical studies will be required to find out. However, according to Alquier, "ABHD6 has a key role in the rebound effect that is often observed after a dietary regimen. People who experience difficulty losing weight might have a deficiency of this enzyme." Weight is controlled by several signals. Scientists have known for a long time that endocannabinoids - molecules secreted by the brain - are involved in the ingestion of nutrients and the expenditure of energy. The endocannabinoids stimulate appetite. Thus, this is an interesting area of exploration in the search for an appetite-suppressant drug. But all the products developed until now have been associated with serious side effects. The pursuit of the ABHD6 enzyme appears to be promising. In 2014, the team of Marc Prentki, another CRCHUM researcher, discovered that this enzyme breaks down endocannabinoids. Blocking ABHD6 in peripheral organs and adipose tissues protects against obesity and against type 2 diabetes. "We know today that ABHD6 plays a completely different role in certain neurons of the hypothalamus. Blocking the enzyme in this location promotes obesity, whereas blocking it elsewhere in the body has beneficial effects," emphasizes Stephanie Fulton, CRCHUM researcher and study co-author. Multiple signals and neuronal networks are involved in regulating the balance of energy so as to maintain a stable body weight. "We have shown the critical part played by the ABHD6 enzyme in preserving homeostasis in specific neurons of the hypothalamus. But we don't know what happens when we block the enzyme in the entire brain. This is what we are currently investigating in an ongoing study," the researcher explains. Many more years of research will be needed to develop an effective treatment for obesity. As science advances, we learn that weight management does indeed take place inside the head, but that it is not necessarily a question of lack of will. The study "a/b-Hydrolase Domain 6 in the Ventromedial Hypothalamus Controls Energy Metabolism Flexibility" was published on October 25, 2016, in Cell Report. Primary sponsoring institution: Instituts de recherche en santé du Canada (IRSC), (MOP115042), (MOP123280), and (MOP114974). The authors are grateful to the platform of rodent metabolomics and phenotyping of the CRCHUM and to the Montreal Diabetes Research Center for their support. To learn more, we invite you to read the study: http://dx.
Prentki M.,University of Montréal |
Madiraju S.R.M.,Montreal Diabetes Research Center
Molecular and Cellular Endocrinology | Year: 2012
Pancreatic β-cells secrete insulin in response to fluctuations in blood fuel concentrations, in particular glucose and fatty acids. However, chronic fuel surfeit can overwhelm the metabolic, signaling and secretory capacity of the β-cell leading to its dysfunction and death - often referred to as glucolipotoxicity. In β-cells and many other cells, glucose and lipid metabolic pathways converge into a glycerolipid/free fatty acid (GL/FFA) cycle, which is driven by the substrates, glycerol-3-phosphate and fatty acyl-CoA, derived from glucose and fatty acids, respectively. Although the overall operation of GL/FFA cycle, consisting of lipolysis and lipogenesis, is " futile" in terms of energy expenditure, this metabolic cycle likely plays an indispensable role for various β-cell functions, in particular insulin secretion and excess fuel detoxification.In this review, we discuss the significance of GL/FFA cycle in the β-cell, its regulation and role in generating essential metabolic signals that participate in the lipid amplification arm of glucose stimulated insulin secretion and in β-cell growth. We propose the novel concept that the lipolytic segment of GL/FFA cycle is instrumental in producing signals for insulin secretion, whereas, the lipogenic segment generates signals relevant for β-cell survival/death and growth/proliferation. © 2011.
Poitout V.,Montreal Diabetes Research Center |
Poitout V.,University of Montréal
Diabetologia | Year: 2013
The incretin hormones glucagon-like peptide-1 and glucose-dependent insulinotropic peptide are secreted by enteroendocrine cells and augment glucose-induced insulin secretion in response to food ingestion in a glucose-dependent manner. This mechanism forms the basis for incretin-based therapies in type 2 diabetes. However, the insulinotropic effect of incretins is diminished in type 2 diabetic patients, due in part to reduced expression of incretin receptors as a consequence of glucotoxicity. In this issue of Diabetologia, Kang et al (DOI: 10.1007/s00125-012-2776-x) provide evidence that in addition to glucotoxicity, lipotoxicity also affects incretin receptor expression and signalling in insulin-secreting cells and isolated islets. In animal models of diabetes, the authors show that co-administration of a lipid-lowering drug with a dipeptidyl peptidase-4 inhibitor or a glucagon-like peptide-1 agonist improved glucose tolerance and beta cell mass. These novel findings provide convincing support for the notion that restoring normal circulating lipid levels in type 2 diabetes might help improve the efficacy of incretin-based therapies. © 2012 Springer-Verlag Berlin Heidelberg.
Rancoule C.,University Paul Sabatier |
Dusaulcy R.,University Paul Sabatier |
Treguer K.,University Paul Sabatier |
Gres S.,University Paul Sabatier |
And 2 more authors.
Biochimie | Year: 2014
Autotaxin (ATX) is a secreted lysophospholipase D involved in synthesis of lysophosphatidic acid (LPA), a phospholipid growth factor acting via specific receptors (LPA1R to LPA6R) and involved in several pathologies including obesity. ATX is secreted by adipocytes and contributes to circulating LPA. ATX expression is up-regulated in obese patients and mice in relationship with insulin resistance and impaired glucose tolerance. LPA1R is the most abundant subtype in adipose tissue. Its expression is higher in non-adipocyte cells than in adipocytes and is not altered in obesity. ATX increases and LPA1R decreases while preadipocytes differentiate into adipocytes (adipogenesis). LPA inhibits adipogenesis through down-regulation of the pro-adipogenic transcription factor PPARγ2. Adipocyte-specific knockout (FATX-KO) mice or mice treated with the LPAR antagonist Ki16425 gain more weight and accumulate more adipose tissue than wild type or control mice fed a high fat diet (HFD). These observations suggest that LPA (via LPA1R) exerts a tonic inhibitory effect on adipose tissue expansion that could, at least in part, result from the anti-adipogenic activity of LPA. A possible negative impact of LPA on insulin-sensitivity might also be considered. Despite being more sensitive to nutritional obesity, FATX-KO and Ki16425-treated mice fed a HFD show improved glucose tolerance when compared to wild type mice. Moreover, exogenously injected LPA acutely impairs glucose tolerance and insulin secretion. These observations show that LPA exerts a tonic deleterious impact on glucose homeostasis. In conclusion, ATX and LPA1R represent potential interesting pharmacological targets for the treatment of obesity-associated metabolic diseases. © 2013 Elsevier Masson SAS. All rights reserved.
Fulton S.,Montreal Diabetes Research Center
Frontiers in Neuroendocrinology | Year: 2010
The tendency to engage in or maintain feeding behaviour is potently influenced by the rewarding properties of food. Affective and goal-directed behavioural responses for food have been assessed in response to various physiological, pharmacological and genetic manipulations to provide much insight into the neural mechanisms regulating motivation for food. In addition, several lines of evidence tie the actions of metabolic signals, neuropeptides and neurotransmitters to the modulation of the reward-relevant circuitry including midbrain dopamine neurons and corticolimbic nuclei that encode emotional and cognitive aspects of feeding. Along these lines, this review pulls together research describing the peripheral and central signalling molecules that modulate the rewarding effects of food and the underlying neural pathways. © 2009 Elsevier Inc. All rights reserved.
Eid H.M.,Montreal Diabetes Research Center |
Vallerand D.,Montreal Diabetes Research Center |
Muhammad A.,University of Ottawa |
Durst T.,University of Ottawa |
And 2 more authors.
Biochemical Pharmacology | Year: 2010
Caffeic acid phenethyl ester (CAPE) has recently been shown to potently stimulate glucose uptake in cultured skeletal muscle cells through the AMPK pathway and therefore to have anti-diabetic potential. We report here that CAPE increases glucose uptake in C2C12 muscle cells by 225 ± 21% at 50 μM, and that activation of AMPK is a consequence of the metabolic stress resulting from an uncoupling-type disruption of mitochondrial function (complete uncoupling at 50 μM). We also observe that the therapeutic potential of CAPE is offset by its high potential for toxicity. The purpose of this study was therefore to identify other active caffeic acid derivatives, evaluate their ratio of activity to toxicity, and elucidate their structure-activity relationship. Twenty naturally occurring derivatives were tested for glucose-uptake stimulating activity in C2C12 cells following 18 h of treatment and for uncoupling activity in isolated rat liver mitochondria. Cytotoxicity was assessed in C2C12 cells by the release of lactate dehydrogenase over 18 h. In addition to CAPE, four compounds were identified to be active, both stimulating glucose uptake and uncoupling isolated mitochondria. Activity required that the caffeic acid moiety be intact and that the compound not contain a strongly ionized group. Both activity and toxicity were found to be well-correlated to predicted lipophilicity. However, two compounds exhibited little to no toxicity while still stimulating glucose uptake by 65-72%. These results support a therapeutic potential for this family of compounds and provide the framework for the design of alternatives to Metformin with an optimized balance of safety and activity. © 2009 Elsevier Inc. All rights reserved.
Fergusson G.,Montreal Diabetes Research Center
Journal of visualized experiments : JoVE | Year: 2013
Chronic exposure to excessive levels of nutrients is postulated to affect the function of several organs and tissues and to contribute to the development of the many complications associated with obesity and the metabolic syndrome, including type 2 diabetes. To study the mechanisms by which excessive levels of glucose and fatty acids affect the pancreatic beta-cell and the secretion of insulin, we have established a chronic nutrient infusion model in the rat. The procedure consists of catheterizing the right jugular vein and left carotid artery under general anesthesia; allowing a 7-day recuperation period; connecting the catheters to the pumps using a swivel and counterweight system that enables the animal to move freely in the cage; and infusing glucose and/or Intralipid (a soybean oil emulsion which generates a mixture of approximately 80% unsaturated/20% saturated fatty acids when infused with heparin) for 72 hr. This model offers several advantages, including the possibility to finely modulate the target levels of circulating glucose and fatty acids; the option to co-infuse pharmacological compounds; and the relatively short time frame as opposed to dietary models. It can be used to examine the mechanisms of nutrient-induced dysfunction in a variety of organs and to test the effectiveness of drugs in this context.