Glucose Metabolism Dr Lenon T Gwaunza MBChB, BSc (Hons), MSc (UCL) Dept of Physiology (UZ)

Objectives To describe the normal physiology of glucose metabolism and state how the above relates to the pathophysiology and management of Diabetes Mellitus

Plasma Glucose Plasma glucose concentration is a function of rate of glucose entering the circulation balanced by rate of glucose removal from circulation The normal plasma glucose level is 3.8 – 5.5mM

Glucose entering the circulation is derived from: Intestinal absorption during the fed state - Speed of entry is dependent on the rate of gastric emptying Glycogenolysis Usually for the first 8 -12 hours of fasting Glucagon is the main hormone responsible Later in the course of fasting gluconeogenesis is more prominent Gluconeogenesis from lactate and amino acids during fasting

Hormones regulating glucose metabolism: Beta cell hormones Insulin Amylin Alpha cell hormone (Glucagon) Incretins Glucagon Like Peptide 1 (GLP 1) Gastrointestinal insulinotropic Peptide (GIP) Epinephrine Cortisol Growth hormone

Role of regulatory hormones: These hormones are designed to maintain circulating glucose concentration in a relatively narrow range Fasting state: Glucose leaves circulation at a constant rate To keep pace with this, endogenous glucose production is necessary Role of Liver vs role of kidney Post meal: Glucose production is suppressed Insulin reduces glucose production in the liver and reduces glucagon secretion by pancreas

Hormones:

Insulin Is a 51 amino acid peptide secreted by B cells of pancreas It lowers blood glucose levels It is secreted in 2 phases Rapid secretion of preformed insulin Secretion of insulin that has been synthesised Secreted at a rate of ~1U/hr and increases 5 – 10 fold following a meal Its secretion is in response to glucose (>3.3mM) and amino acids following meal ingestion and various other stimuli

Effects of Insulin It controls post prandial glucose in 3 ways: Increase uptake of glucose in insulin sensitive tissues Increase liver glycogenesis Inhibit glucagon secretion (to stop gluconeogenesis and glycogenolysis) Other effects of insulin include increasing fat and protein synthesis, and increasing activity of the Na pump Also promotes glucose metabolism

Amylin Secreted from the B cell with insulin at a rate of 50:1 but after hepatic extraction of insulin 20:1 Amylin follows insulin secretory patterns It regulates the rate of appearance of glucose from endogenous and exogenous sources by Slowing gastric emptying Suppressing post prandial glucagon secretion Also regulates food intake and body weight

Glucagon Is a catabolic 29 amino acid peptide Maintains blood glucose concentrations within normal range during the fasting state In DM there is failure of suppression of glucagon secretion The influence of exogenous insulin on postprandial glucose levels and glucagon is minimal?

Glucose homeostasis: roles of insulin and glucagon. 1A. Glucose homeostasis: roles of insulin and glucagon. 1A. For nondiabetic individuals in the fasting state, plasma glucose is derived from glycogenolysis under the direction of glucagon (1). Basal levels of insulin control glucose disposal (2). Insulin's role in suppressing gluconeogenesis and glycogenolysis is minimal due to low insulin secretion in the fasting state (3). 1B. For nondiabetic individuals in the fed state, plasma glucose is derived from ingestion of nutrients (1). In the bi-hormonal model, glucagon secretion is suppressed through the action of endogenous insulin secretion (2). This action is facilitated through the paracrine route (communication within the islet cells) (3). Additionally, in the fed state, insulin suppresses gluconeogenesis and glycogenolysis in the liver (4) and promotes glucose disposal in the periphery (5). 1C. For individuals with diabetes in the fasting state, plasma glucose is derived from glycogenolysis and gluconeogenesis (1) under the direction of glucagon (2). Exogenous insulin (3) influences the rate of peripheral glucose disappearance (4) and, because of its deficiency in the portal circulation, does not properly regulate the degree to which hepatic gluconeogenesis and glycogenolysis occur (5). 1D. For individuals with diabetes in the fed state, exogenous insulin (1) is ineffective in suppressing glucagon secretion through the physiological paracrine route (2), resulting in elevated hepatic glucose production (3). As a result, the appearance of glucose in the circulation exceeds the rate of glucose disappearance (4). The net effect is postprandial hyperglycemia (5).

Incretin hormones Ingested glucose is a more potent stimulus for insulin release than iv glucose (incretin effect) Hormonal signal from the gut regulates insulin secretion These hormones may regulate gastric emptying and motility The dominant incretin hormones are GIP and GLP

GIP Regulates fat metabolism Insulin secretion No effect on glucagon and gastric emptying Levels are normal and slightly increased in DM type 2

GLP 1 More physiologically relevant in humans than GIP Increases insulin secretion in a glucose dependent manner Reduces glucagon secretion Reduces gastric emptying Satiety hormone Also enhances beta cell mass Has a half life of 2 mins (metabolised by dipeptidyl peptidase IV – a CD26 which is also involved in the immune system)

Postprandial glucose flux in nondiabetic controls. Postprandial glucose flux in nondiabetic controls. Postprandial glucose flux is a balance between glucose appearance in the circulation and glucose disappearance or uptake. Glucose appearance is a function of hepatic (endogenous) glucose production and meal-derived sources and is regulated by pancreatic and gut hormones. Glucose disappearance is insulin mediated. Calculated from data in the study by Pehling et al.26

Glucose homeostasis: roles of insulin, glucagon, amylin, and GLP-1.

Would like to acknowledge The Beit Trust My mentors: Prof Chinyanga, Dr Ngwende and Dr Zaranyika ZIMA for inviting me THANK YOU….