Pathophysiology of Diabetes PDF

Pathophysiology of Diabetes Dr Seley Gharanei Assistant Professor Cell and Tissue Biomedicine Block 1 Lead Warwick Medical School, Email: [email protected]  Learning outcomes  Explain the processes involved in insulin production and secretion;  Descri...

Pathophysiology of Diabetes Dr Seley Gharanei Assistant Professor Cell and Tissue Biomedicine Block 1 Lead Warwick Medical School, Email: [email protected]  Learning outcomes  Explain the processes involved in insulin production and secretion;  Describe the mechanisms of insulin action relating to glucose homeostasis, fat and protein metabolism;  Discuss the role of insulin, glucagon, and other hormones in the regulation of blood glucose levels;  Describe the pathophysiology, diagnosis and classification of diabetes mellitus;  Relate dysfunction of glucose homeostasis to the signs and symptoms seen in diabetes mellitus;  Evaluate the epidemiology, socioeconomic impact and psychological aspects of diabetes mellitus.  Give examples of and explain the development of acute and long term complications of diabetes mellitus;  Diabetes Mellitus A complex metabolic disorder, characterised by chronic hyperglycaemia Due to either insulin deficiency +/or insulin resistance. Broadly speaking, can be classified as: Type 1 diabetes. Type 2 diabetes. Secondary diabetes.  Diabetes Mellitus: Epidemiology It is estimated globally that 537 million people have diabetes mellitus.* Responsible for 10.7% of all deaths in 2017 (globally). UK prevalence (2021) = 3.9 million. Plus, almost a million undiagnosed cases.** *International Diabetes Federation, 2023. **Diabetes.org.uk Glucose  Glucose The main source of metabolic fuel for the brain (in normal conditions). Derived from: Dietary sources. Breakdown of glycogen stores (glycogenolysis). Formation of new glucose (gluconeogenesis). Glucose is hydrophilic. Therefore, it requires specific transport proteins to move into cells. In health, plasma glucose levels are tightly regulated, usually between 3.5-8mmol/L. Via uptake/ release of glucose or potential glucose from tissues (Under hormonal influence). Insulin is a hormone whose action is to lower blood glucose levels, and is released from the beta cells in the pancreas. P1 B1 CTB Carbohydrates and Lipids P1 B1 CTB Physiology of the Small Intestine  Glucose transport: GLUT Facilitate transport family of glucose into cells Transport Protein Tissue Location GLUT-1 Most cells GLUT-2 Liver, pancreatic B cells (beta cells) GLUT-3 Brain (neurons) GLUT-4 Muscle and adipose tissue GLUT-5 Fructose transporter in intestinal tissue, kidney and sperm. SGLUT Intestine Insulin-dependent Insulin-independent GLUT-4 GLUT-1 GLUT-2 GLUT-3 GLUT-5 SGLUT P1 B1 CTB Carbohydrates and Lipids P1 B1 CTB Physiology of the Small Intestine GLUT-4 Insulin, Glucagon, and Diabetes Mellitus Hall, John E., PhD, Guyton and Hall Textbook of Medical Physiology, Chapter 79, 973-989 Copyright © 2021 Copyright © 2021 by Elsevier, Inc. All rights reserved. P1 B1 CTB Introduction to Endocrinology Glucose homeostasis Why is tight control of glucose important in health? Some tissues e.g. brain are highly dependent on glucose. High glucose concentrations can damage cellular proteins. Hypoglycaemia can be life-threatening, as can the effects of hyperglycaemia.  To regulate glucose, the system has to cope with changes in: Glucose delivery: fed vs fasted. Demand e.g. exercise/ physiological stress. Glucose homeostasis is a complex system including regulating hormones, storage in excess, and release and production in the fasted state (glucose deficit). Glucose homeostasis (2) Gluconeogenesis Formation of glucose from molecules E.g. Lactate, glycerol (from fats), glutamine and alanine (from protein) Takes place in liver and kidneys Glycogen & glycogenolysis Glycogen is formed from glucose and acts as stored energy in the liver and skeletal muscle. Glycogenolysis is the process of breaking down glycogen to release glucose. P1 B1 CTB Energy Metabolism Hormones & blood glucose regulation Glucagon Increases plasma Catecholamines glucose Cortisol Free fatty acids Growth hormone Decreases plasma glucose Insulin Insulin Insulin: history Reminder: Diabetes mellitus = the metabolic effects of absence of and/or resistance to insulin. Insulin: Identified as pancreatic in origin early 1900’s. Frederick Banting & Charles Best injected pancreatic extract into dogs who had their pancreas removed (and as a result became diabetic). The pancreatic extract was found to improve their condition. In 1922, the first patient, 14 year old boy was successfully treated with refined pancreatic extract. Insulin Insulin, Glucagon, and Diabetes Mellitus Insulin, Glucagon, and Diabetes Mellitus Hall, John E., PhD, Guyton and Hall Textbook of Medical Physiology, Chapter 79, 973-989 Hall, John E., PhD, Guyton and Hall Textbook of Medical Physiology, Chapter 79, 973-989 Copyright © 2021 Copyright © 2021 by Elsevier, Inc. All rights reserved. Copyright © 2021 Copyright © 2021 by Elsevier, Inc. All rights reserved. Insulin secretion from Beta-cells Insulin release is stimulated by an increase in plasma glucose: 1. Glucose transporters permit the influx of glucose. 2. Inside the cells glucose is phosphorylated by glucokinase to G6P. 3. G6P is then oxidised to from ATP, which inhibits ATP-sensitive K+ channels. 4. Closure of K+ channels causes depolarisation of the cell 5. The depolarisation stimulates the opening of voltage gated calcium channels. 6. The influx of calcium stimulates fusion of the Insulin, Glucagon, and Diabetes Mellitus insulin-containing vesicles with the membrane and Hall, John E., PhD, Guyton and Hall Textbook of Medical Physiology, Chapter 79, 973-989 exocytosis of insulin. Copyright © 2021 Copyright © 2021 by Elsevier, Inc. All rights reserved. Insulin secretion Insulin secretion is biphasic An initial surge. Followed by a plateau phase: Persists as long as blood glucose levels are high. Other molecules that can stimulate insulin secretion: Amino acids GI hormones Glucagon, GH, cortisol Diabetes mellitus Pearson, ER, Davidson's Principles and Practice of Medicine, 20, 719-762 Copyright © 2018 © 2018 Elsevier Ltd. All rights reserved. Actions of insulin Actions are brought about by activation of the insulin receptor on the target cell membrane. Outcome will depend upon which secondary pathway is activated. Its release is associated with energy abundance. Release of insulin increases in response to excess energy, particularly carbohydrates. Predominantly anabolic in nature. Action of insulin on glucose Facilitates glucose transport into cells. In muscle/adipose tissue, insulin binds to receptor – causing release of GLUT-4 transporters from vesicles to the cell membrane, where they facilitate the passage of glucose into cells. Inactivates liver phosphorylase and increases the activity of glucokinase, increasing storage of glucose in the liver. Promotes glycogen synthesis by increasing the action of glycogen synthase. Inhibits gluconeogenesis by exerting effects upon the activities of various liver enzymes, and also by decreasing the available precursors e.g. amino acids. Action of insulin on fats Promotes fatty acid synthesis: Converts excess glucose to fatty acids. Promotes storage of fat in the adipose cells: Activates enzymes that facilitate fatty acid absorption and subsequent storage as triglycerides. Inhibits the release of free-fatty acids from the adipose tissue. Promotes glucose transport into fat cells. This leads to creation of glycerol which combines with free fatty acids to form triglycerides in adipose cells. P1 B1 CTB Energy Metabolism Action of insulin on proteins Promotes protein synthesis and inhibits the breakdown of proteins. Stimulates transport of amino acids into cells. Inhibits gluconeogenesis (a process which uses amino acids as substrates). Inhibits the rate of amino acid release from cells. Leads to the formation of increased quantities of RNA. Increases translation of mRNA by ‘switching on,’ the ribosomes. Blood glucose regulation Glucagon A polypeptide hormone secreted from the alpha cells of the islets of Langerhans. Released in response to a fall in blood glucose concentration. Its main action is to increase blood glucose concentration: It stimulates glycogenolysis. It increases hepatic gluconeogenesis. Other selected effects (in high concentrations): Activates adipose cell lipase, increasing the production of free fatty acids. Inhibits storage of triglycerides, allowing additional free fatty acids to be available for energy. Stimuli for glucagon release/inhibition Stimulates release Inhibits release Hypoglycaemia Hyperglycaemia Exercise Insulin Physiological stress Somatostatin** High blood amino acid concentration* *High amino acid concentration also stimulates insulin **Both glucagon and insulin secretion are inhibited by somatostatin (a polypeptide hormone released from delta cells of the pancreas). The role of somatostatin is not well understood. It is thought that it lengthens the period of time over which food nutrients are assimilated in the blood. Insulin vs glucagon Blood glucose Glucagon Insulin ↑gluconeogenesis ↓gluconeogenesis ↑glycogenolysis ↑Glycogen synthesis Proteolysis Protein synthesis Lipolysis Lipogenesis Ketogenesis Suppresses Blood glucose ketogenesis Fed state (post-prandial) Blood glucose concentration rises, leading to a rise in insulin. Insulin Increased free fatty acids also increases basal and glucose-stimulated insulin production. Insulin vs glucagon Favours insulin Anabolic state Glucagon Fasted state (post- absorptive) Blood glucose concentration lowers, leading to increased glucagon release. Glucagon Loss of suppression of proteolysis and lipolysis by insulin. Insulin vs glucagon Favours glucagon Catabolic state Insulin Other influencers in glucose homeostasis ‘Incretins:’ Glucagon-Like Peptides (GLP); Gastric Inhibitory Peptide (GIP) Produced in the small intestine (L-cells). Augment the secretion of insulin in response to oral glucose. Cortisol & Growth hormone Promote gluconeogenesis. Inhibit glucose transport. Cortisol can directly inhibit the secretion of insulin. Catecholamines Released due to activation of the autonomic nervous system. E.g. ‘fight, flight, or fright,’ (sympathetic). Adrenaline promotes glucagon and inhibits insulin. Also, sympathetic neurons that innervate the pancreatic islets release noradrenaline. This stimulates glucagon and inhibits insulin. Diabetes Mellitus What is Diabetes Mellitus? A complex metabolic disorder, characterised by chronic hyperglycaemia Due to either insulin deficiency +/or insulin resistance. Broadly, can be divided into: Type 1 diabetes, which has an auto-immune pathogenesis (in the vast majority) and leads to severe insulin deficiency. Type 2 diabetes, which results from insulin resistance +/- less severe insulin deficiency. Secondary diabetes, a term that encompasses a multitude of acquired causes of diabetes e.g. secondary to drugs or genetic defects. There are also ‘pre-diabetic’ conditions; namely impaired fasting glycaemia and impaired glucose tolerance. Type 1 Diabetes Mellitus Autoimmune destruction of β-cells eventually resulting in complete insulin deficiency. The presence of antibodies to islet cells may pre-date the onset of the disease by years. Initially an asymptomatic phase. Then, symptoms appear when the remaining β-cells are unable to meet the body’s insulin needs. 5-10% of all cases of diabetes. Typically presents in children/ young adults. Genetic susceptibility. Possible environmental risk factors include: maternal gestational infection, enterovirus infection, environmental toxins, childhood obesity, early introduction to dairy/ low vit D in childhood. Associated with other autoimmune conditions e.g. Addison’s, autoimmune thyroid disease, coeliac disease. Case 1 Amit, a 19 year old sociology student with no medical problems, presents to his GP with a 6 week history of lethargy. On further questioning, he reports passing urine more than normal. He has been passing urine several times in the night. He also describes being unquenchably thirsty. He has lost 7kg in weight over the past 6 weeks. Amit’s GP checks a fasting plasma glucose level, which is 17mmol/L (normal