Peripheral and central regulation of insulin by the intestine and microbiome

Author:

Schertzer Jonathan D.1ORCID,Lam Tony K.T.234ORCID

Affiliation:

1. Department of Biochemistry and Biomedical Sciences, Farncombe Family Digestive Health Research Institute, Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada

2. Toronto General Hospital Research Institute, UHN, Toronto, Ontario, Canada

3. Departments of Physiology and Medicine, University of Toronto, Toronto, Ontario, Canada

4. Banting and Best Diabetes Centre, University of Toronto, Toronto, Ontario, Canada

Abstract

Blood glucose and insulin homeostasis is disrupted during the progression of type 2 diabetes. Insulin levels and action are regulated by both peripheral and central responses that involve the intestine and microbiome. The intestine and its microbiota process nutrients and generate molecules that influence blood glucose and insulin. Peripheral insulin regulation is regulated by gut-segment-dependent nutrient sensing and microbial factors such as short-chain fatty acids and bile acids that engage G-protein-coupled receptors. Innate immune sensing of gut-derived bacterial cell wall components and lipopolysaccharides also alter insulin homeostasis. These bacterial metabolites and postbiotics influence insulin secretion and insulin clearance in part by altering endocrine responses such as glucagon-like peptide-1. Gut-derived bacterial factors can promote inflammation and insulin resistance, but other postbiotics can be insulin sensitizers. In parallel, activation of small intestinal sirtuin 1 increases insulin sensitivity by reversing high fat-induced hypothalamic insulin resistance through a gut-brain neuronal axis, whereas high fat-feeding alters small intestinal microbiome and increases taurochenodeoxycholic acid in the plasma and the dorsal vagal complex to induce insulin resistance. In summary, emerging evidence indicates that intestinal molecular signaling involving nutrient sensing and the host-microbe symbiosis alters insulin homeostasis and action. Gut-derived host endocrine and paracrine factors as well as microbial metabolites act on the liver, pancreas, and the brain, and in parallel on the gut-brain neuronal axis. Understanding common nodes of peripheral and central insulin homeostasis and action may reveal new ways to target the intestinal host-microbe relationship in obesity, metabolic disease, and type 2 diabetes.

Funder

Gouvernement du Canada | Canadian Institutes of Health Research

University of Toronto

Publisher

American Physiological Society

Subject

Physiology (medical),Physiology,Endocrinology, Diabetes and Metabolism

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