Pathophysiology of diabetes by Dr Shahjada Selim
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Pathophysiology of Type 2 Diabetes
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Pathophysiology of diabetes by Dr Shahjada Selim
- 1. Pathophysiology of Type 2 Diabetes Dr Shahjada Selim Assistant Professor Department of Endocrinology Bangabandhu Sheikh Mujib Medical University, Dhaka Email: selimshahjada@gmail.com
- 2. DEFINITION Diabetes mellitus (DM) is a state of chronic hyperglycemia due to defect in insulin secretion and or its action.
- 4. NORMAL FUEL METABOLISM Fuel metabolism is regulated by complex system to: • Distribute nutrients to organs and tissues for mechanical or chemical work, growth or renewal • Provide storage of excess nutrients: glycogen or fat • Allow release of energy from storage depots as needed during fasting or high energy use
- 5. Carbohydrate Metabolism • Glucose is a major energy source for muscles and the brain. • The brain is nearly totally dependent on glucose • Muscles use Glucose And Fat for fuel. • Main sources of circulating glucose are hepatic glucose production, kidney and ingested carbohydrate.
- 6. Basal Hepatic glucose production: HGP • After absorption of the last meal is complete, liver produce glucose to supply glucose needed for tissues that do not store glucose as brain. • ~2 mg/kg body wt/min in adults.
- 7. BRIAN • Do not store glucose • Dependent on glucose
- 8. Mechanisms and sources of glucose release in the post-absorptive state Overall rate of glucose release: ~10 μmol/(kg−min) Renal contribution: 2.0–2.5 μmol/(kg−min) (20–25%) Hepatic contribution: 7.5–8.0 μmol/(kg−min) (75–80%) Renal gluconeogenesis: 2.0–2.5 μmol/(kg−min) (20–25%) Hepatic glycogenolysis: 4.5–5.5 μmol/(kg−min) (45–50%) Hepatic gluconeogenesis: 2.5–3.0 μmol/(kg−min) (25–30%)
- 9. High HGP In T2DM • Insulin suppresses hepatic glucose production (HGP) • In T2D: impaired hepatic insulin action (Liver resistance): increase BGP: high FBG: diagnosis • High HGP during fasting : hyperglycemia, hyperlipidemia, and ketosis (RAMADAN FASTING). • Metformin: act on liver resistance. Taken at PM , lowers liver production of glucose at night, lowers FBG .
- 10. Ingested carbohydrate • 60–70% is stored (glycogen) • 30-40% oxidized for immediate energy needs. • Produce postprandial blood glucose 90–120 min after meal. • The magnitude and rate of rise in BG: – size of the meal – physical state (solid, liquid, cooked, raw) – other nutrients: fat and fiber: slow digestion – amount and effect of insulin. – Type simple or complex: least effect – The rate of gastric emptying: delays PP surge with hypoglycemia and rebound hyperglycemia
- 11. Protein Metabolism Ingested protein is absorbed as amino acids: • synthesis of new protein • oxidation to provide energy • conversion to glucose (gluconeogenesis) during fasting: Alanine • In DM: gluconeogenesis: loss of weight and Fatigue
- 12. Fat Metabolism • Fat is the major form of stored energy as triglyceride in adipose tissue or muscle fat deposits. • TG is converted to free fatty acids plus glycerol by lipolysis: transported to muscle for oxidation: ketone bodies acetoacetate and –hydroxybutyrate . • Chronic nutritional excess: accumulation of stored fat, because ingested fat is not used and other excess nutrients (glucose) are used to synthesize fat: fatty liver.
- 13. CLINICAL IMPLICATIONS • Elevated circulating free fatty acids from ingested fat or lipolysis may: • induce hepatic insulin resistance at different sites: LIPOTOXICITY • Increase basal HGP • Slow the postabsorptive decline in blood glucose.
- 14. HORMONAL REGULATION OF FUEL METABOLISM
- 15. Insulin and Glucose Metabolism • Stimulates glucose uptake into muscle and adipose cells: lipogenesis • Inhibits hepatic glucose production Major Metabolic Effects of Insulin • Hyperglycemia osmotic diuresis and dehydration Consequences of Insulin Deficiency
- 16. Major Metabolic Effects of Insulin and Consequences of Insulin Deficiency Insulin effects: Stimulates glucose uptake into muscle and adipose cells: lipogenesis + inhibits lipolysis Consequences of insulin deficiency: elevated FFA levels Insulin effects: Inhibits ketogenesis • Consequences of insulin deficiency: ketoacidosis, production of ketone bodies Stimulates glucose uptake into muscle stimulates amino acid uptake and protein synthesis, inhibits protein degradation, regulates gene transcription • Consequences of insulin deficiency: muscle wasting
- 19. Basal Insulin • Constant low insulin levels • Prevent lipolysis and glucose production. • Low level of basal Insulin during exercise making stored energy available. • Low basal insulin during fasting: increase glucagon : glycogenolysis , lipolysis, and ketogenesis: hyperglycemia, hyperlipidemia, and ketosis.
- 20. Prandial insulin • Blood glucose is the dominant stimulus for insulin secretion. • Postprandial secretion increases rapidly> basal – Suppress glucose production – Supress lipolysis – stimulate uptake of ingested glucose by tissues
- 21. The Biphasic prandial Insulin Response Adapted from Howell SL. Chapter 9. In: Pickup JC, Williams G (Eds). Textbook of Diabetes. Oxford. Blackwell Scientific Publications 1991: 72–83.
- 23. Adapted from Ward WK et al. Diabetes Care 1984; 7: 491–502. Normal Type 2 diabetes 120 100 80 60 40 20 0 –30 0 30 60 90 120 Time (minutes) –30 0 30 60 90 120 Time (minutes) Plasmainsulin(µU/ml) 120 100 80 60 40 20 0 20g glucose 20g glucose Plasmainsulin(µU/ml) Pattern of insulin release is altered early in Type 2 diabetes Loss of Early-phase Insulin Release in Type 2 Diabetes
- 24. Overview of Insulin and Action
- 26. Glucotoxicity • Hyperglycemia inhibits insulin secretion and impairs insulin action. • Oral agents that increase insulin secretion or improve action could be ineffective at higher levels of hyperglycemia. • Treatment with insulin for a few days to reduce the marked hyperglycemia may make the patient more responsive to subsequent treatment with oral agents.
- 27. FPG, fasting plasma glucose. Adapted from: DeFronzo RA. Ann Intern Med 1999;131:281–303; Wright EM. Am J Physiol Renal Physiol 2001;280:F10–F18. Insulin Glucose Glucagon Insulin-mediated glucose uptake by skeletal muscle and adipose tissue Glucose filtration/ reabsorption FPG 90 mg/dL Normal glucose homeostasis
- 28. Pathophysiology in Type 2 DM 1.Decreased insulin and increased glucagon secretion result in... 2.elevated hepatic glucose output... 3. reduced insulin-mediated glucose uptake 4.Hyperglycaemia 5.Renal glucose filtration and reabsorption is increased up to the renal threshold for glucose reabsorption (180 mg/dL): glucosuria 6.Glucotoxicity of all organs, exposing the individual to the risk of complications and further impairing insulin secretion and action
- 29. Pathophysiology of Type 2 diabetes FPG, fasting plasma glucose. Adapted from: DeFronzo RA. Ann Intern Med 1999;131:281–303; Wright EM. Am J Physiol Renal Physiol 2001;280:F10–F18. Insulin Glucose Glucagon Insulin-mediated glucose uptake by skeletal muscle and adipose tissue Glucose filtration/ reabsorption 1 FPG 90 mg/dL
- 30. Insulin resistance is the decreased response of the liver and peripheral tissues (muscle, fat) to insulin Insulin resistance is a primary defect in the majority of patients with Type 2 diabetes Pathophysiology of Type 2 diabetes
- 31. Pathophysiology of Type 2 diabetes FPG, fasting plasma glucose. Adapted from: DeFronzo RA. Ann Intern Med 1999;131:281–303; Wright EM. Am J Physiol Renal Physiol 2001;280:F10–F18. Insulin Glucose Glucagon Insulin-mediated glucose uptake by skeletal muscle and adipose tissue Glucose filtration/ reabsorption 1 2 FPG 90 mg/dL
- 32. Pathophysiology of Type 2 diabetes FPG, fasting plasma glucose. Adapted from: DeFronzo RA. Ann Intern Med 1999;131:281–303; Wright EM. Am J Physiol Renal Physiol 2001;280:F10–F18. Insulin Glucose Glucagon Insulin-mediated glucose uptake by skeletal muscle and adipose tissue Glucose filtration/ reabsorption 1 2 3 FPG 90 mg/dL
- 33. Pathophysiology of Type 2 diabetes FPG, fasting plasma glucose. Adapted from: DeFronzo RA. Ann Intern Med 1999;131:281–303; Wright EM. Am J Physiol Renal Physiol 2001;280:F10–F18. Insulin Glucose Glucagon Insulin-mediated glucose uptake by skeletal muscle and adipose tissue Glucose filtration/ reabsorption 1 2 3 FPG 90 mg/dL 4
- 34. FPG, fasting plasma glucose. Adapted from: DeFronzo RA. Ann Intern Med 1999;131:281–303; Wright EM. Am J Physiol Renal Physiol 2001;280:F10–F18. Insulin Glucose Glucagon Insulin-mediated glucose uptake by skeletal muscle and adipose tissue Glucose filtration/ reabsorption 1 2 3 4 GLUCOSURIA GLUCOTOXICITY FPG 180 mg/dL Pathophysiology of Type 2 diabetes
- 35. FPG, fasting plasma glucose. Adapted from: DeFronzo RA. Ann Intern Med 1999;131:281–303; Wright EM. Am J Physiol Renal Physiol 2001;280:F10–F18. Insulin Glucose Glucagon Insulin-mediated glucose uptake by skeletal muscle and adipose tissue Glucose filtration/ reabsorption 1 2 3 4 GLUCOSURIA GLUCOTOXICITY FPG 180 mg/dL Pathophysiology of Type 2 diabetes
- 36. Glucogen synthesis Glucose oxidation Glucogen catabolism Hepatic glucose production Adipocytes uptake TG Lipid synthesis (lipoproteinesterase activity ) Lipid mobilization (Hormone sensitive lipase ) ketone (acetone, acetoacetic acid, beta-hydroxybutyric acid)
- 37. DeFronzo RA. Diabetes. 2009;58:773-795.
- 38. KIDNEY An adaptive response to conserve glucose.... ...becomes maladaptive in Type 2 diabetes Glucose Normal urine GLUCOSURIA GLUCOSE SGLT2 plays a crucial role in renal glucose reabsorption This highlights renal glucose reabsorption as a potential target for treatment of Type 2 diabetes In Type 2 diabetes, the kidney’s maximum glucose reabsorption threshold is exceeded, resulting in glycosuria SGLT2, sodium-glucose co-transporter-2.
- 39. Increased Hepatic Glucose Production Impaired Insulin Secretion Hyperglycemia Decreased Glucose Uptake TZDs GLP-1 analogues DPP-4 inhibitors Sulfonylureas Thiazolidinediones Metformin Metformin Thiazolidinediones _ Pathophysiologic Approach to Treatment of T2DM DeFronzo RA. Diabetes. 2009;58:773-795.
- 40. Mechanism of action-SU nateglinide repaglinide (36 kD) SUR depolarization ATP glimipiride（65 kD） glyburide（140 kD） Kir 6.2 SUR
- 41. Mechanism of action- acarbose Acarbose Oligosaccharide Acarbose Small intestine mucosa Reversible inhibition of oligosaccharide breakdown by -glucosidases
- 43. SGLTs SGLT1 SGLT2 Site Mostly intestine with some in the kidney Nearly exclusively in the kidney Sugar specificity Glucose or galactose Glucose Affinity for glucose High Km = 0.4 mM Low Km = 2 mM Capacity for glucose transport Low High Role Dietary glucose absorption Renal glucose reabsorption Renal glucose reabsorption SGLT1/2, sodium-glucose co-transporter-1/2. Abdul-Ghani MA, et al. Endocr Pract 2008;14:782–90.
- 45. Glucagon. • The first line of defense against hypoglycemia in normals • Glucagon rises rapidly when blood glucose levels fall and stimulates HGP. • In type 1 diabetes, glucagon secretion in response to hypoglycemia may be lost.
- 46. Catecholamines. • Produced at times of stress (“fight or flight”) • Stimulate release of stored energy. • Major defense against hypoglycemia in T1M (POOR glucagon). • IF DEFECTIVE: Hypoglycemia unawareness: severe and prolonged hypoglycemia: • Intensified glucose control only after a period of hypoglycemia avoidance and restoration of catecholamine response.
- 47. Cortisol. • increases at times of stress. • stimulate gluconeogenesis. • slower than glucagon • not effective in protecting against acute hypoglycemia.
- 48. Growth hormone • Slow effects on glucose metabolism. • major surge during sleep : rise in blood glucose levels in the early morning: dawn phenomenon. • In normal physiology, a slight increase in insulin secretion compensates • In diabetes: variable morning hyperglycemia related to variable nocturnal growth hormone secretion.
- 50. T1D and advanced T2D: counterregulatory deficiencies and impaired symptomatic awareness
- 51. VISCIOUS CIRCLE • Hyperglycemia : Glucotoxicity : more hyper • Hypogycemia-associated autonomic failure (HAAF): more hypo
- 52. Hypoglycemia Unawareness • No early warning symptoms of hypoglycemia • cognitive impairment may be first symptom • Clinical diagnosis • Reduced glucose thresholds for epinephrine-mediated warning symptoms • Autonomic dysfunction: inadequate catecholamic release to hypoglycemia.
- 53. Reversible!! • Avoidance of even mild hypoglycemia for 2–4 weeks. • Adjustments in glycemic goals • Education to estimate and detect blood glucose level fluctuations. • Increased monitoring of blood glucose • Modifying glycemic targets until hypoglycemia awareness is regained. • Symptom recognition • AFTER regaining hypoglycemia awareness: reassess the treatment plan to avoid episodes of hypoglycemia, especially • nocturnal hypoglycemia.
- 54. THANK YOU