Brain-Gut Interactions in Diabetes Shanthi Srinivasan, M.D. Associate Professor of Medicine

Outline Brain-gut anatomy Extrinsic innervation of the gut Enteric nervous system Gut hormones Central regulation of appetite Alterations in diabetes and obesity

Brain–Gut Axis Fig. 1. From Cegla et al. Curr Opinion Clin Nutr Metab Care 13: 588–593, Available at clinicalnutrition/Abstract/2010/09000/Gut_brain_cross_talk_in_appetite _regulation.14.aspxhttp://journals.lww.com/co- clinicalnutrition/Abstract/2010/09000/Gut_brain_cross_talk_in_appetite _regulation.14.aspx

Brain Hypothalamus-Regulates Metabolism &feeding behavior –Neurons Serotonin NPY AGRP-Agouti-related peptide –Thyroxine –Sensors Leptin Ghrelin PYY Hypothalamus

Regulation of the Hypothalamus Fig. 1. From Kalra PS and Kalra SP. Drugs Today 38(11): 745, Available at journals.prous.com/journals/servlet/xmlxsl/pk_journals.xml_summary_pr?p_Journa lId=4&p_RefId=740201&p_IsPs=N journals.prous.com/journals/servlet/xmlxsl/pk_journals.xml_summary_pr?p_Journa lId=4&p_RefId=740201&p_IsPs=N

VAGUS PELVIC NERVE Sympathetic Nerves Greater Splanchnic Lesser Splanchnic Extrinsic Innervation: GI tract

Enteric Nervous System

Enteroendocrine Cells Fig. 1. From Dockray GJ. J Physiol Pharmacol 54 (Suppl 4): 9-17, Freely available at 01_article.html 01_article.html

Table 1. From Woods et al. Diabetes 55 (Suppl 2): S114-S121, Freely available at diabetes.diabetesjournals.org/content/55/Supplement_2/S114.full?sid =6727b8bb-97eb-4f3e-a292-5f6ae17af396 diabetes.diabetesjournals.org/content/55/Supplement_2/S114.full?sid =6727b8bb-97eb-4f3e-a292-5f6ae17af396 Gastrointestinal Hormones That Affect Satiety

Role of Insulin Fig. 1. From Woods et al. Diabetes 55 (Suppl 2): S114-S121, Freely available at diabetes.diabetesjournals.org/content/55/Supplement_2/S114.full?sid =6727b8bb-97eb-4f3e-a292-5f6ae17af396 diabetes.diabetesjournals.org/content/55/Supplement_2/S114.full?sid =6727b8bb-97eb-4f3e-a292-5f6ae17af396

Adiposity Signals Tonically secreted Insulin: reflects visceral fat and ongoing metabolism Leptin: reflects total body fat Adiponectin

Brain-Gut Axis Fig. 1. From Cegla et al. Curr Opinion Clin Nutr Metab Care 13: 588–593, Available at clinicalnutrition/Abstract/2010/09000/Gut_brain_cross_talk_in_appetite _regulation.14.aspxhttp://journals.lww.com/co- clinicalnutrition/Abstract/2010/09000/Gut_brain_cross_talk_in_appetite _regulation.14.aspx

Hormonal Regulation Figure freely available from 5AppetiteRegulation.jpg 5AppetiteRegulation.jpg

Regulation of Appetite Figure from The Medical Biochemistry Page Freely available at themedicalbiochemistrypage.org/gut-brain.phpthemedicalbiochemistrypage.org/gut-brain.php

Regulation of Appetite Fig. 1. From Arora et al. Appetite 56(2): , Available at

Drug Influencing CNS Regulation of Appetite Drugs that reduce food intake by acting on the CNS –Phenterimine (Adipex) –Diethylproprion (Anorex)

Alteration in Brain in DM Diabetes can alter the HPA axis Astrogliosis in the dentate gyrus- hypothalamus Increased circulation glucocorticoids Beauquis et al. Neuroimmunomodulation 15(1): 61-67, 2008.

Alteration in Brain in DM Fig. 7, A-F. From McNay et al. J Clin Invest 122(1): , Freely available at

High-fat Diet Induced Hypothalamic Injury Fig. 3. From Thaler et al. J Clin Invest 122(1): , Freely available at

Alteration in Extrinsic Innervation in DM There is evidence of altered central processing to visceral stimulation, and both peripheral and central mechanisms seem involved. Central neuronal re-organization may contribute to our understanding of the gastrointestinal symptoms in patients with diabetic autonomic neuropathy

Alteration in Vagal Afferents and Gut Endocrine Cells in DM Fig. 1B. From Lee et al. Am J Physiol Regul Integr Comp Physiol 302(6): R657-R666, Available at ajpregu.physiology.org/content/302/6/R657ajpregu.physiology.org/content/302/6/R657

Alteration In Gut Hormones in DM GLP-1, the gut-brain, and brain- periphery axes GLP-1R that are distributed throughout the periphery (e.g. pancreatic β-cells, vagus nerve), as well as action on many GLP- 1R-expressing nuclei within the central nervous system (CNS).

The density of gut endocrine cells in GK rats. Fig. 6. From Speck et al. Am J Physiol Endocrinol Metab 300: E923-E932, Freely available at ajpendo.physiology.org/content/300/5/E923.fullajpendo.physiology.org/content/300/5/E923.full

Gastric Bypass and Insulin Sensitivity Hormonal changes related to the nutrient diversion from the duodenum, the entire jejunum, and the proximal portion of the ileum. In fact, the enteroendocrine cells are largely found in these tracts of the small intestine.

Oral meal consumption increases glucagon-like peptide 1 (GLP-1) release which maintains euglycemia by increasing insulin secretion. This effect is exaggerated during short-term follow-up of Roux-en-y gastric bypass (RYGB). Gastric Bypass and Insulin Sensitivity

Proposed Mechanism of Diabetes Resolution After RYGB Surgery Fig. 1. From Holst JJ. Diabetes 60: , Freely available at diabetes.diabetesjournals.org/content/60/9/2203.full diabetes.diabetesjournals.org/content/60/9/2203.full

Alteration in the ENS in DM Fig. 8, A and B. From Anitha et al. J Clin Invest 116(2): , Freely available at

Obesity and Gut Microbiota Fig. 1. From Flier JS and Mekalanos JJ. Sci Transl Med 1 (6): 6ps7, Available at

Obesity and Toll-Like Receptors Fig. 1, A – C. From Vijay-Kumar et al. Science 328(5975): , Available at

Interaction Between Microbes and ENS Adapted from Fig. 2.4 From Moffet D, Moffet S, Schauf C (ed.). Human Physiology. Foundations & Frontiers St Louis, MO: Mosby-Year Book. Freely available at html

Interaction between Microbes and ENS Adapted from Fig. 2.4 From Moffet D, Moffet S, Schauf C (ed.). Human Physiology. Foundations & Frontiers St Louis, MO: Mosby-Year Book. Freely available at a/biola/vk/peuhkuri/chap2.html (Overlay figure of correct size in box)

Summary Review of basic brain-gut anatomy Role of gut hormones Central regulation of appetite Brain-gut alterations in diabetes and obesity