Resolution of type 2 diabetes following gastric bypass surgery: involvement of gut-derived glucagon and glucagonotropic signalling?

Abstract

Certain types of bariatric surgical procedures have proved not only to be effective with regard to treating obesity, but they also seem to be associated with endocrine changes which independently of weight loss give rise to remission of type 2 diabetes. Currently, it is speculated that surgical re-routing of nutrients triggers changes in the release of gastrointestine-derived hormones, which in turn cause amelioration of the diabetic state. The 'hindgut hypothesis' states that surgical re-routing of nutrients to the distal part of the small intestine results in increased secretion and concomitant glucose-lowering effects of glucagon-like peptide-1, whereas the 'foregut hypothesis' emphasises that surgical bypass of the foregut prevents the release of a hitherto unidentified nutrient-induced diabetogenic signal in susceptible individuals. Recent studies have shown that in patients with type 2 diabetes, glucagon is differentially secreted in response to oral and i.v. glucose, respectively, with lack of suppression (and initial net secretion) during oral glucose administration and a perfectly normal suppression during isoglycaemic i.v. glucose administration. These findings could point towards a role for glucagon or gut-derived glucagonotropic signalling as putative diabetogenic signals of the foregut hypothesis. In the present paper the hypotheses describing the glucoselowering mechanisms of bariatric surgical procedures sharing the common feature of a bypass of the duodenum and the proximal jejunum are outlined and a possible role for glucagon in these is proposed.

Phenotype of entero‐endocrine L cells becomes restricted during development

“…In addition, we also determined that a subset of ileal L cells of embryos coexpress glucagon, a cell type that is not present in normal adult rodents. However, enteric glucagon cells may reappear in adults during alterations in metabolic homeostasis (Knop, 2009). Therefore, the understanding of the signals that regulate the differentiation and number of cells expressing GIP and/or the glucagon family of peptides will provide fundamental insight into the maintenance of glucose homeostasis.…”

Le tractus digestif comme organe endocrine : une nouvelle vision de la chirurgie bariatrique

“…Il est apparu de diverses expérimentations animales et des observations faites chez l'homme que l'exclusion de la partie proximale de l'intestin (duodénum et partie initiale du jéjunum) permettait d'obtenir une amélioration métabolique significative, en particulier en ce qui concerne le contrôle glycémique [36,37]. Il a été postulé que des facteurs avec effet anti-incrétine étaient sécrétés par la partie proximale de l'intestin et que l'exclusion de celle-ci entraînait une diminution de leur libération, conduisant à une potentialisation de l'insulinosécrétion et à une réduction de l'insulinorésistance [38]. L'étape suivante, capitale, est Actuellement, cette technique a surtout été testée pour obtenir une perte de poids avant la réalisation d'une chirurgie bariatrique plus classique [41,42].…”

Bariatric surgery in patients with Type 2 diabetes: benefits, risks, indications and perspectives

“…Several mechanisms probably mediate the direct antidiabetic impact of RYGB, including: enhanced nutrient stimulation of L-cell peptides [for example, glucagon-like peptide-1 (GLP-1)] from the lower intestine ('hindgut hypothesis'); the intriguing, but as yet uncharacterized, phenomena related to exclusion of the upper intestine from contact with ingested nutrients ('foregut hypothesis'); compromised ghrelin secretion; and most likely other effects that have yet to be identified [30,35,36]. Indeed, a role for glucagon or gut-derived glucagonotropic signalling as putative diabetogenic signals from the foregut has been recently proposed [37]. Research designed to prioritize these mechanisms and identify potential additional mechanisms promises to help in the optimalization of surgical design (see Perspectives below) and may also reveal novel pharmaceutical targets for antidiabetes drug treatments [36].…”

“…Certain types of bariatric surgical procedures have proved not only to be effective for treating obesity, but also appear to be associated with endocrine changes that, independent of weight loss, give rise to remission of T2DM [37,51]. Observations in animals and in humans suggest that changes in the gut hormonal milieu after bypass of the distal stomach, duodenum and proximal jejunum can influence T2DM, despite the absence of significant weight loss [17,51].…”

“…The hindgut hypothesis states that surgical rerouting of nutrients to the distal part of the small intestine results in increased secretion, and concomitant glucose-lowering effects, of GLP-1, whereas the foregut hypothesis emphasizes that surgical bypass of the foregut prevents the release of hitherto unidentified nutrient-induced diabetogenic signals (? glucagon/glucagonotropic signalling) in susceptible individuals [37]. Recent animal investigations using duodenojejunal bypass, a stomach-preserving experimental model of RYGB, have shown that diabetes control is not a mere collateral effect of the treatment of obesity, but directly results from exclusion of the duodenum and proximal jejunum from the flow of nutrients.…”