Diabète de type 2 | EPFL Graph Search

Le « diabète de type 2 » (DT2) ou « diabète non insulinodépendant » (DNID) (aussi appelé « diabète insulinorésistant », « diabète de l'âge mûr », « diabète gras », parfois « diabète acquis »), est une maladie métabolique touchant la glycorégulation. Il fait partie des maladies associées à la forte augmentation contemporaine de l'obésité, au point qu'on parle aujourd'hui d'épidémie de diabète de type 2. Il est principalement lié à l'évolution des modes de vie, et notamment au changement des habitudes alimentaires et la sédentarité, mais il est parfois accentué par une composante génétique. Certains spécialistes suggèrent également, comme facteur aggravant, l'exposition à certains perturbateurs endocriniens. Il se caractérise par une résistance à l'insuline de l'organisme et par une hyper-insulinémie réactionnelle. Le pancréas fabrique de plus en plus d'insuline jusqu'à l'épuisement. Quand la quantité d'insuline ne suffit plus à

The role of nicotinamide riboside metabolism in pancreatic beta cells

Angélique Satoko Cercillieux

Pancreatic beta cells play a major role in the regulation of glucose homeostasis by secreting insulin in response to elevated blood glucose levels. A gradual deterioration of functional beta cell mass and the chronic elevation of blood glucose levels are central to development of type 2 diabetes. While the etiologies of Type 2 diabetes and age-related metabolic complications are complex, they are often associated with a decline of intracellular nicotinamide adenine dinucleotide (NAD+). NAD+ levels are maintained through the balance between its synthesis from NAD+ precursors and its degradation by several families of enzymes, including the sirtuin family of protein deacetylases, the ADP-ribosyl transferase enzymes (ARTDs or PARPs) and cADP ribose hydrolases (CD38). NAD+ declines are mostly associated with increased NAD+ consumption, which can be counteracted by dietary supplementation of NAD+ precursors. However, our knowledge on how different tissues utilize and respond to different NAD+ precursors for NAD+ synthesis is still incomplete. This, in turn, limits our ability to provide therapeutic benefits in clinical settings. In this project, we aim to understand the relevance of a particular NAD+ precursor, nicotinamide riboside (NR), in beta cell physiology and its potential use to treat beta cell dysfunction. To do so, we have used mice that are deficient for nicotinamide riboside kinase 1 (NRK1), the first and rate-limiting enzyme for the transformation of NR into NAD+. We demonstrate that NRK1 whole body knockout mice exhibit impaired insulin secretion after a meal or upon glucose challenge when fed a high fat diet. However, NRK1 deficiency in beta cell was not the causality for beta cell failure as differences observed in the NRK1 whole body KO mice were not phenocopied in NRK1 beta cell specific KO mice. Aged NRK1 whole body KO mice also exhibited dysfunctional beta cells and significant loss of insulin content and beta cell mass. Furthermore, NRK1 deficiency exacerbates the decline of NAD+ bioavailability and mitochondria function with age, even promoting fibrosis in multiple tissues. Together, our data suggests that endogenous NR metabolism is critical in maintaining whole body NAD+ homeostasis and to protect against mitochondria dysfunction and stress-related cell responses in pancreatic beta cells.

EPFL2022

Investigation of physiological roles of AMPK-activated protein kinase y3

Philipp Jurijvic Rhein

Clinical trials have shown that direct activators of an evolutionary-conserved metabolic sensor, AMP-activated protein kinase (AMPK), are beneficial in preventing/treating a range of metabolic disorders, including type 2 diabetes. These activators, including 991/MK-8722, bind at regulatory site, termed the allosteric drug and metabolite (ADaM-site) at the interface between the catalytic alpha subunit and regulatory beta subunit. In addition, another approach for direct activation of AMPK is through mimicking its natural ligands, AMP/ADP, by binding to the nucleotide site in the y3 subunit, e.g. 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR). Interestingly, their ability to influence glucose homeostasis is reported to be through activation of AMPK complexes found within the skeletal muscle. The AMPKy3 is unique as an AMPK subunit isoform since it is selectively expressed in glycolytic skeletal muscle fibres. To gain more insight into the y3 isoform-specific regulation of glucose metabolism, we used a y3 knock-out (y3-/-) mouse model to investigate the effects of the AICAR and 991/MK-8722. We confirm that y3 isoform expression and activity is high glycolytic muscles, including extensor digitorum longus (EDL), whereas there is very little detected in oxidative soleus (SOL) muscle. We show that AICAR and 991/MK-8722 stimulated glucose uptake in both EDL and SOL muscles. Interestingly, only the ability of AICAR to induce glucose uptake was blunted in EDL muscle taken from y3-/- mice. Consistent with this, whole-body glucose clearance was also impaired in y3-/- mice in response to an AICAR, whilst MK-8722 lowered blood glucose similarly between WT and y3-/- mice. Despite the presence of y1-containing complexes, which are the most predominant complexes in both EDL and SOL muscles, this suggests that different AMPKy isoforms play different roles in glucose homeostasis in response to AICAR. We further looked at de novo glycogen synthesis and glucose utilisation in skeletal muscle. Despite similar basal glucose uptake between muscles from WT and y3-/-, y3-deficiency results in lower basal glycogen content only in glycolytic muscles. We show that this is not due to an inability to synthesise glycogen de novo, since MK-8722 was able to increase glycogen levels in EDL. Instead, we show that the decrease in basal glycogen in y3-/- EDL, may be linked lower expression of UDP-glucose pyrophosphorylase 2 (UGP2). This suggests that AMPKy3 may play a role in steering the molecular fate of glucose inside the cell. Taken together, whilst we show that AMPKy3 is dispensable for ex vivo glucose transport and in vivo glucose homeostasis in response to ADaM-site AMPK activators, nucleotide-mediated activation of y3 by AICAR is impaired. Further research is required to understand the nucleotide regulation of different y-containing AMPK complexes. This differential activation mechanism could be exploited to specifically target AMPKy3 complexes in the muscle, and potentially avoid deleterious effects of activation of AMPK complexes in other tissues.

EPFL2021

Weight Loss Directly Influences Intermediate-Term Remission of Diabetes Mellitus After Bariatric Surgery: A Retrospective Case-Control Study

Purpose Roux en Y gastric bypass surgery (RYGB) is an effective therapy for patients with severe obesity. It induces both significant weight loss and rapid improvements of metabolic complications. This study was undertaken to better define the direct role of weight loss in the metabolic improvements. Methods A retrospective, case-control study of a cohort of 649 patients with obesity who underwent RYGB, comparing higher and lower responders at 2 years after surgery (n = 100 pairs). Pairs of patients were matched for age, gender, and initial BMI. The rates of remission of diabetes, hypertension, dyslipidemia, and hyperuricemia were compared using a mixed effects logistic regression analysis. Results Diabetes before surgery was present in 12/100 lower responders and 17/100 higher responders. Remission at 2 years was observed in 4/12 (33%) of lower responders, compared to 15/17 (88%) of higher responders. Thus, the odds of diabetes remission was significantly smaller in lower responders (OR = 0.067, 95% CI 0.01-0.447). A mixed model regression analysis of all the parameters for each patient showed that the odds of achieving remission of any comorbidity was significantly lower in lower responders (OR = 0.62, 95% CI = 0.39-0.97). Conclusion We could demonstrate that weight loss is a significant determinant of the remission of diabetes 2 years after RYGB. These data underline the importance of weight loss in the benefits of this procedure.