Intestinal Gluconeogenesis Is a Key Factor for Early Metabolic Changes after Gastric Bypass but Not after Gastric Lap-Band in Mice

Institut National de la Sante et de la Recherche Medicale, U695, Faculté de Médecine Xavier Bichat, Universite Paris 7, Paris, F-75870, France.
Cell metabolism (Impact Factor: 17.57). 10/2008; 8(3):201-11. DOI: 10.1016/j.cmet.2008.08.008
Source: PubMed


Unlike the adjustable gastric banding procedure (AGB), Roux-en-Y gastric bypass surgery (RYGBP) in humans has an intriguing effect: a rapid and substantial control of type 2 diabetes mellitus (T2DM). We performed gastric lap-band (GLB) and entero-gastro anastomosis (EGA) procedures in C57Bl6 mice that were fed a high-fat diet. The EGA procedure specifically reduced food intake and increased insulin sensitivity as measured by endogenous glucose production. Intestinal gluconeogenesis increased after the EGA procedure, but not after gastric banding. All EGA effects were abolished in GLUT-2 knockout mice and in mice with portal vein denervation. We thus provide mechanistic evidence that the beneficial effects of the EGA procedure on food intake and glucose homeostasis involve intestinal gluconeogenesis and its detection via a GLUT-2 and hepatoportal sensor pathway.

Download full-text


Available from: Christophe Magnan,
20 Reads
  • Source
    • ", D). 3.3. Rescuing IGN improves glucose tolerance and hepatic insulin sensitivity and restores GSIS in I-G6pc À/À mice To ascertain whether the alteration of glucose control in I-G6pc À/À mice was caused by the absence of intestinal glucose production, we rescued IGN by infusing glucose at a rate mimicking IGN [27] "
    [Show abstract] [Hide abstract]
    ABSTRACT: Certain nutrients positively regulate energy homeostasis via intestinal gluconeogenesis (IGN). The objective of this study was to evaluate the impact of a deficient IGN in glucose control independently of nutritional environment. We used mice deficient in the intestine glucose-6 phosphatase catalytic unit, the key enzyme of IGN (I-G6pc (-/-) mice). We evaluated a number of parameters involved in energy homeostasis, including insulin sensitivity (hyperinsulinemic euglycaemic clamp), the pancreatic function (insulin secretion in vivo and in isolated islets) and the hypothalamic homeostatic function (leptin sensitivity). Intestinal-G6pc (-/-) mice exhibit slight fasting hyperglycaemia and hyperinsulinemia, glucose intolerance, insulin resistance and a deteriorated pancreatic function, despite normal diet with no change in body weight. These defects evoking type 2 diabetes (T2D) derive from the basal activation of the sympathetic nervous system (SNS). They are corrected by treatment with an inhibitor of α-2 adrenergic receptors. Deregulation in a key target of IGN, the homeostatic hypothalamic function (highlighted here through leptin resistance) is a mechanistic link. Hence the leptin resistance and metabolic disorders in I-G6pc (-/-) mice are corrected by rescuing IGN by portal glucose infusion. Finally, I-G6pc (-/-) mice develop the hyperglycaemia characteristic of T2D more rapidly under high fat/high sucrose diet. Intestinal gluconeogenesis is a mandatory function for the healthy neural control of glucose homeostasis.
    Molecular Metabolism 12/2014; 4(2). DOI:10.1016/j.molmet.2014.12.009
  • Source
    • "Bariatric surgery offers a vivid example in which type 2 diabetes can be corrected in a few days after surgery showing a time-lapse that does not correlate with body weight loss. Although the mechanisms are still an active matter of research, it illustrates how obesity and its most common corollary disease can be separated [5] [6] [7] [8]. It is tempting to speculate that a rapid reshaping of the reciprocal nervous dialogue between the brain and the periphery could be instrumental in the restoration of proper nutrient partitioning. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The arcuate nucleus of the hypothalamus (ARC) is particularly regarded as a critical platform that integrates circulating signals of hunger and satiety reflecting energy stores and nutrient availability. Among ARC neurons, Pro-opiomelanocortin (POMC) and agouti-related protein and neuropeptide Y (NPY/AgRP neurons) are considered as two opposing branches of the melanocortin signaling pathway. Integration of circulating signals of hunger and satiety results in the release of the melanocortin receptor ligand α-melanocyte stimulating hormone (αMSH) by the POMC neurons system and decreases feeding and increases energy expenditure. The orexigenic/anabolic action of NPY/AgRP neurons is believed to rely essentially on their inhibitory input onto POMC neurons and second-orders targets. Recent updates in the field have casted a new light on the role of the ARC neurons in the coordinated regulation of peripheral organs involved in the control of nutrient storage, transformation and substrate utilization independent of food intake.
    Best Practice & Research: Clinical Endocrinology & Metabolism 10/2014; 28(5). DOI:10.1016/j.beem.2014.03.003 · 4.60 Impact Factor
  • Source
    • "On a conceptual viewpoint, in addition to the metabolic benefits linked to the increased glucose production from the intestine [19,38], the data reported here emphasize that HGP should no longer be equaled to EGP. Moreover, we point out that the control of HGP per se could be a crucial objective in the management of metabolic diseases taken as a whole. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Type 2 diabetes is characterized by a deterioration of glucose tolerance, which associates insulin resistance of glucose uptake by peripheral tissues and increased endogenous glucose production. Here we report that the specific suppression of hepatic glucose production positively modulates whole-body glucose and energy metabolism. We used mice deficient in liver glucose-6 phosphatase that is mandatory for endogenous glucose production. When they were fed a high fat/high sucrose diet, they resisted the development of diabetes and obesity due to the activation of peripheral glucose metabolism and thermogenesis. This was linked to the secretion of hepatic hormones like fibroblast growth factor 21 and angiopoietin-like factor 6. Interestingly, the deletion of hepatic glucose-6 phosphatase in previously obese and insulin-resistant mice resulted in the rapid restoration of glucose and body weight controls. Therefore, hepatic glucose production is an essential lever for the control of whole-body energy metabolism during the development of obesity and diabetes.
    Molecular Metabolism 08/2014; 3(5). DOI:10.1016/j.molmet.2014.05.005
Show more