Cut the Waist

Cut the Waist

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The philosophy of Cut the Waist is to prevent obesity related ill health through education resources

Duodenal Rest Hypothesis and GIP

Gastric Inhibitory Polypeptide (GIP) is secreted by K-cells of the duodenum. GIP should perhaps more correctly be called GAP (Gastric Adipocyte Polypeptide) as emerging evidence supports a role for this gut-derived hormone in the translation of dietary fat into adipose tissue stores.

Dietary fat ingestion in particular results in strong and protracted GIP secretion by the duodenal K-cells.

Adipoctyes have GIP receptors. Stimulation this receptor results in glucose uptake by adipocytes and activation of lipoprotein lipase (LPL) to cleave triglycerides. This facilitates fatty acid uptake by adipocytes and in turn allows synthesis of triglycerides and storage of dietary fat in adipose tissue.

In obesity-diabetes GIP levels are chronically elevated and an exaggerated GIP secretory response to dietary fat ingestion is seen. Obesity-diabetes is associated with duodenal K-cell hyperplasia in keeping with elevated GIP secretion.

Increasing evidence suggests that GIP produced by the proximal small bowel in response to fat ingestion provides a link between excess dietary fat consumption and the development of insulin resistance and type 2 diabetes.

Inhibition of GIP signalling

Experimental blockage if GIP signalling results in preferential oxidation and mobilisation of fat, clearing triglyceride from the liver and skeletal muscle. This restores insulin sensitivity of the liver restore the insulin-mediated ability to inhibit hepatic glucose output. A reduction intramyocellular lipid within skeletal muscle also restores insulin responsiveness of muscle, facilitating peripheral glucose uptake. Blockade of GIP therefore brings about a reduction insulin resistance.

Animal models of GIP-receptor uncoupling (GPR knockout mice) fed high fat diets demonstrate a significantly increased energy expenditure in situations of high fat feeding and reduced capacity to store dietary fat. The GPR knockout results in reduced adipocyte size, reduced adipose tissue mass and reduce storage of triglyceride in non-adipose tissues such as liver and skeletal muscle. Mice with and obesity-diabetes phenotype e.g. ob/ob mice demonstrate dramatic improvements in metabolic state with GPR knockout.

Inactivation of the GIP receptor is advantageous for these mice, reducing their tendency to develop metabolic obesity and diabetes as a direct result of a reduced capacity to store dietary fat as a result of uncoupling of the GIP signalling mechanism.

Gastric bypass, GIP uncoupling and remission of type 2 diabetes

Dramatic remission of type 2 diabetes and normalisation in glucose metabolism occurs within 1-2 weeks of gastric bypass (Roux en Y). These immediate metabolic benefits of gastric bypass surgery occur much before significant weight reduction, which takes place over several months following this procedure.

GIP levels fall rapidly immediately following gastric bypass. This reduction in GIP secretion by the duodenum appears to be a direct result of inducing "duodenal rest". Following gastric bypass the duodenum and K-cells are no longer in contact with dietary fat.

Complete re-routing of ingested nutrients away from the duodenum makes gastric bypass the most effective way of inducing duodenal rest.

Reduction of dietary fat intake either by lifestyle intervention or by inducing satiety via the use of GLP-1 agonists (exenatide/ Liraglutide) or gastric bypass (LAGB) may also facilitate a degree of improvement or remission of type 2 diabetes as a result of achieving a variable degree of duodenal rest [see graph below]. Very low calorie diets are an effective way of inducing duodenal rest but should be used for a maximum of 12 weeks, thus limiting their usefulness long term.

Graph: The 'Duodenal Rest' hypothesis

The duodenal rest hypothesis serves to explain the link between excess dietary fat intake, insulin resistance and development of obesity-diabetes.

The effect of a variety of approaches in inducing improvement or remission of type 2 diabetes appears to reflect their effectiveness in uncoupling GIP-signaling via inducing partial or complete duodenal rest.

GIP receptor blockers and endobarrier technology as future treatments for type 2 diabetes?

Emerging evidence regarding the role of GIP in the pathogenesis of metabolic obesity and type 2 diabetes, together with the duodenal rest hypothesis may yield important new treatments for these conditions.

Development of drugs which block the GIP receptor may result in dramatic reductions in insulin resistance and significant improvement in glucose regulation for patients with type 2 diabetes.

Endobarrier technology is currently being developed with the idea that a state of complete duodenal rest may be induced by inhibiting contact of ingested nutrients with the duodenal K cells.

Development of the endobarrier may obviate the need for Roux en Y surgery to bypass the duodenum. Instead duodenal rest may be induced via endoscopic placement of a physical barrier to line the lumen of the duodenum, which would act to prevent contact between duodenal K calls and ingested dietary fat.

The endobarrier or GIP receptor blocking drugs may have a future role in augmenting remission of type 2 diabetes in patients who have failed to achieve diabetes resolution post LAGB surgery.

These interventions may of course also have an important future role in the management of type 2 diabetes independent to a bariatric surgical approach to this disease.

References

P.R Flatt. Gastric inhibitory polypeptide revisited: a new therapeutic target for obesity-diabetes. Diabetic Medicine 2008; 25(7): 759-764