Glucose homeostasis

From the gut to the brain via the vagus nerve

The world is getting fatter and more diabetic. Close to 80 percent of those with type 2 diabetes are overweight or obese — leading to an increase in complications such as kidney and eye disease, peripheral artery disease and nerve damage. A recent minireview in The Journal of Biological Chemistry highlights the crucial role of the gastrointestinal tract in whole-body glucose homeostasis and suggests that it be given more attention.
The reemergence of the gastrointestinal tract as a primary regulator of insulin secretion and glucose homeostasis after a meal has led to a recent increase in the repertoire of available drugs for treating type 2 diabetes. However, only two drugs, exenatide and liraglutide, have received approval from the Food and Drug Administration for the treatment of type 2 diabetes, and both are based on the same gastrointestinal-tract-derived incretin.
GI-tract-derived incretins are hormones secreted from the stomach or small intestine after a meal. They decrease blood glucose by increasing glucose’s effect on pancreatic β-cells to increase insulin release and by suppressing liver glucose production. They also act in the brain to adjust food intake and energy expenditure to maintain whole-body energy homeostasis. There are at least eight gut-derived hormones, and a better understanding of how they work should lead to more effective diabetes therapies.
In their recent minireview, Tony Lam and colleagues at the University of Toronto Faculty of Medicine, Toronto General Research Institute, have proposed a working hypothesis that nutrient-induced, GI-tract-derived hormones act locally on their surrounding intestinal cells and signal via nerves to the brain to regulate glucose homeostasis.
Cholecystokinin, or CCK, is a gut-derived incretin secreted from the upper intestine primarily in response to fatty acids that induces satiety and suppresses glucose production in the liver. Studies have indicated that CCK mediates its effects via local vagal signaling rather than classical endocrine signaling. The ability of CCK to suppress liver glucose production is dependent on intracellular conversion of fatty acids to triglycerides within intestinal cells and on protein kinase C-δ signaling, which happens primarily in the upper intestine.

Gut nutrient-sensing mechanisms and subsequent peptide hormone release in normal and duodenal-jejunal bypass surgery settings
Gut nutrient-sensing mechanisms and subsequent peptide hormone release in normal and duodenal-jejunal bypass surgery settings. Nutrient influx in both the duodenum and jejunum triggers hormonal release and downstream signaling to lower glucose production through a neuronal network. In the duodenum, these mechanisms are disrupted upon high fat feeding. Duodenaljejunal bypass surgery results in the influx of nutrients and hormones, such as leptin, directly into the jejunum to suppress glucose production through downstream mechanisms.

Glucagon-like peptide-1, or GLP-1, is another gut-derived incretin, and it is secreted from the middle intestine in response to both fatty acids and glucose and acts on pancreatic β- and α-cells to increase insulin release and inhibit glucagon release, respectively. These effects initially were thought to be accomplished solely by GLP-1 binding its receptor on the outer membrane of β- and α-cells. However, GLP-1 is degraded in the blood within minutes, resulting in less than 10 percent reaching the circulation around β- and α-cells — suggesting that GLP-1 also may act in the intestine to mediate its effects via vagal signaling to the brain. Findings in rodents, in which inhibiting nerve signals from the brain to the intestine blocks GLP-1-induced insulin release, lend support to this new notion of GLP-1 signaling via a gut-brain-pancreas axis.
Bariatric surgery, a now-common treatment for the morbidly obese, bypasses the upper small intestine and has serendipitously led to the discovery of novel and exciting mechanisms of glucose regulation by the gut, known as gut-nutrient sensing. Type 2 diabetics who undergo bariatric surgery very often are cured of hyperglycemia prior to significant weight loss, suggesting that gut-nutrient sensing is a crucial aspect of glucose homeostasis.
Research from Lam and colleagues shows, in rodents, that administration of glucose and lipids directly into the middle small intestine, similar to the way nutrients are sensed in the gut after bariatric surgery, suppresses liver glucose production by a gut-brain-liver axis that is independent of insulin and dependent on leptin. Leptin administered directly into the middle small intestine suppresses liver glucose production in wild-type mice but not in mice without the leptin receptor or in wild-type mice to which leptin is co-administered with a phosphatidylinositol-4,5-bisphosphate 3-kinase, or PI3K, inhibitor.
Furthermore, blockade of vagal signaling from the middle small intestine to the brain eliminates the ability of leptin to suppress liver glucose production. These results demonstrate that middle intestine nutrient sensing is dependent on gastric leptin acting through an intestinal PI3K-brain-liver axis.

Joseph TianoJoseph P. Tiano (tiano233@ is a postdoctoral fellow at the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Md.

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