Pathophysiology of diabetes by Dr Shahjada Selim
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1. Insulin resistance and impaired insulin secretion lead to elevated hepatic glucose production and hyperglycemia in type 2 diabetes. 2. The decreased uptake of glucose by tissues like muscle results in high blood glucose levels. 3. Over time, the persistent hyperglycemia can damage organs and tissues, worsening insulin resistance and beta-cell function in a vicious cycle.
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: [email protected]
- 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: ā¢ Distribute nutrients to organs and tissues for mechanical or chemical work, growth or renewal ā¢ Provide storage of excess nutrients: glycogen or fat ā¢ Allow release of energy from storage depots as needed during fasting or high energy use
- 5. Carbohydrate Metabolism ā¢ Glucose is a major energy source for muscles and the brain. ā¢ The brain is nearly totally dependent on glucose ā¢ Muscles use Glucose And Fat for fuel. ā¢ Main sources of circulating glucose are hepatic glucose production, kidney and ingested carbohydrate.
- 6. Basal Hepatic glucose production: HGP ā¢ After absorption of the last meal is complete, liver produce glucose to supply glucose needed for tissues that do not store glucose as brain. ā¢ ~2 mg/kg body wt/min in adults.
- 7. BRIAN ā¢ Do not store glucose ā¢ Dependent on glucose
- 8. Mechanisms and sources of glucose release in the post-absorptive state Overall rate of glucose release: ~10 Ī¼mol/(kgāmin) Renal contribution: 2.0ā2.5 Ī¼mol/(kgāmin) (20ā25%) Hepatic contribution: 7.5ā8.0 Ī¼mol/(kgāmin) (75ā80%) Renal gluconeogenesis: 2.0ā2.5 Ī¼mol/(kgāmin) (20ā25%) Hepatic glycogenolysis: 4.5ā5.5 Ī¼mol/(kgāmin) (45ā50%) Hepatic gluconeogenesis: 2.5ā3.0 Ī¼mol/(kgāmin) (25ā30%)
- 9. High HGP In T2DM ā¢ Insulin suppresses hepatic glucose production (HGP) ā¢ In T2D: impaired hepatic insulin action (Liver resistance): increase BGP: high FBG: diagnosis ā¢ High HGP during fasting : hyperglycemia, hyperlipidemia, and ketosis (RAMADAN FASTING). ā¢ Metformin: act on liver resistance. Taken at PM , lowers liver production of glucose at night, lowers FBG .
- 10. Ingested carbohydrate ā¢ 60ā70% is stored (glycogen) ā¢ 30-40% oxidized for immediate energy needs. ā¢ Produce postprandial blood glucose 90ā120 min after meal. ā¢ The magnitude and rate of rise in BG: ā size of the meal ā physical state (solid, liquid, cooked, raw) ā other nutrients: fat and fiber: slow digestion ā amount and effect of insulin. ā Type simple or complex: least effect ā The rate of gastric emptying: delays PP surge with hypoglycemia and rebound hyperglycemia
- 11. Protein Metabolism Ingested protein is absorbed as amino acids: ā¢ synthesis of new protein ā¢ oxidation to provide energy ā¢ conversion to glucose (gluconeogenesis) during fasting: Alanine ā¢ In DM: gluconeogenesis: loss of weight and Fatigue
- 12. Fat Metabolism ā¢ Fat is the major form of stored energy as triglyceride in adipose tissue or muscle fat deposits. ā¢ TG is converted to free fatty acids plus glycerol by lipolysis: transported to muscle for oxidation: ketone bodies acetoacetate and āhydroxybutyrate . ā¢ 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 ā¢ Elevated circulating free fatty acids from ingested fat or lipolysis may: ā¢ induce hepatic insulin resistance at different sites: LIPOTOXICITY ā¢ Increase basal HGP ā¢ Slow the postabsorptive decline in blood glucose.
- 14. HORMONAL REGULATION OF FUEL METABOLISM
- 15. Insulin and Glucose Metabolism ā¢ Stimulates glucose uptake into muscle and adipose cells: lipogenesis ā¢ Inhibits hepatic glucose production Major Metabolic Effects of Insulin ā¢ Hyperglycemia ļ 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 ā¢ 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 ā¢ Consequences of insulin deficiency: muscle wasting
- 19. Basal Insulin ā¢ Constant low insulin levels ā¢ Prevent lipolysis and glucose production. ā¢ Low level of basal Insulin during exercise making stored energy available. ā¢ Low basal insulin during fasting: increase glucagon : glycogenolysis , lipolysis, and ketogenesis: hyperglycemia, hyperlipidemia, and ketosis.
- 20. Prandial insulin ā¢ Blood glucose is the dominant stimulus for insulin secretion. ā¢ Postprandial secretion increases rapidly> basal ā Suppress glucose production ā Supress lipolysis ā 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: 72ā83.
- 23. Adapted from Ward WK et al. Diabetes Care 1984; 7: 491ā502. Normal Type 2 diabetes 120 100 80 60 40 20 0 ā30 0 30 60 90 120 Time (minutes) ā30 0 30 60 90 120 Time (minutes) Plasmainsulin(ĀµU/ml) 120 100 80 60 40 20 0 20g glucose 20g glucose Plasmainsulin(ĀµU/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 ā¢ Hyperglycemia inhibits insulin secretion and impairs insulin action. ā¢ Oral agents that increase insulin secretion or improve action could be ineffective at higher levels of hyperglycemia. ā¢ 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;131:281ā303; Wright EM. Am J Physiol Renal Physiol 2001;280:F10āF18. 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;131:281ā303; Wright EM. Am J Physiol Renal Physiol 2001;280:F10āF18. Insulin Glucose Glucagon Insulin-mediated glucose uptake by skeletal muscle and adipose tissue Glucose filtration/ reabsorption 1 ļ£ ļ¤ FPG 90 mg/dL
- 30. ļ® Insulin resistance is the decreased response of the liver and peripheral tissues (muscle, fat) to insulin ļ® 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;131:281ā303; Wright EM. Am J Physiol Renal Physiol 2001;280:F10āF18. Insulin Glucose Glucagon Insulin-mediated glucose uptake by skeletal muscle and adipose tissue Glucose filtration/ reabsorption 1 2 ļ£ ļ¤ ļ£ FPG 90 mg/dL
- 32. Pathophysiology of Type 2 diabetes FPG, fasting plasma glucose. Adapted from: DeFronzo RA. Ann Intern Med 1999;131:281ā303; Wright EM. Am J Physiol Renal Physiol 2001;280:F10āF18. Insulin Glucose Glucagon Insulin-mediated glucose uptake by skeletal muscle and adipose tissue Glucose filtration/ reabsorption 1 2 3 ļ£ ļ¤ ļ£ ļ¤ FPG 90 mg/dL
- 33. Pathophysiology of Type 2 diabetes FPG, fasting plasma glucose. Adapted from: DeFronzo RA. Ann Intern Med 1999;131:281ā303; Wright EM. Am J Physiol Renal Physiol 2001;280:F10āF18. Insulin Glucose Glucagon Insulin-mediated glucose uptake by skeletal muscle and adipose tissue Glucose filtration/ reabsorption 1 2 3 ļ£ ļ¤ ļ£ ļ¤ ļ£ FPG 90 mg/dL 4
- 34. FPG, fasting plasma glucose. Adapted from: DeFronzo RA. Ann Intern Med 1999;131:281ā303; Wright EM. Am J Physiol Renal Physiol 2001;280:F10āF18. Insulin Glucose Glucagon Insulin-mediated glucose uptake by skeletal muscle and adipose tissue Glucose filtration/ reabsorption 1 2 3 4 GLUCOSURIA ļ£ ļ¤ ļ£ ļ¤ ļ£ GLUCOTOXICITY FPG 180 mg/dL Pathophysiology of Type 2 diabetes
- 35. FPG, fasting plasma glucose. Adapted from: DeFronzo RA. Ann Intern Med 1999;131:281ā303; Wright EM. Am J Physiol Renal Physiol 2001;280:F10āF18. Insulin Glucose Glucagon Insulin-mediated glucose uptake by skeletal muscle and adipose tissue Glucose filtration/ reabsorption 1 2 3 4 GLUCOSURIA ļ£ ļ¤ ļ£ ļ¤ ļ£ GLUCOTOXICITY FPG 180 mg/dL Pathophysiology of Type 2 diabetes
- 36. Glucogen synthesis ļÆ Glucose oxidation ļÆ Glucogen catabolism ļ Hepatic glucose productionļ Adipocytes uptake TG ļÆ Lipid synthesis ļÆ (lipoproteinesterase activity ļÆ) Lipid mobilization ļ(Hormone sensitive lipase ļ) ketone ļ(acetone, acetoacetic acid, beta-hydroxybutyric acid)
- 37. DeFronzo RA. Diabetes. 2009;58:773-795.
- 38. KIDNEY An adaptive response to conserve glucose.... ļ§...becomes maladaptive ļ§in Type 2 diabetes ļ§Glucose Normal urine GLUCOSURIA ļ§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 kidneyās 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 ļ Metformin Thiazolidinediones _ ļ 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 glimipirideļ¼65 kDļ¼ glyburideļ¼140 kDļ¼ Kir 6.2 SUR
- 41. Mechanism of action- acarbose Acarbose Oligosaccharide Acarbose Small intestine mucosa Reversible inhibition of oligosaccharide breakdown by ļ”-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;14:782ā90.
- 45. Glucagon. ā¢ The first line of defense against hypoglycemia in normals ā¢ Glucagon rises rapidly when blood glucose levels fall and stimulates HGP. ā¢ In type 1 diabetes, glucagon secretion in response to hypoglycemia may be lost.
- 46. Catecholamines. ā¢ Produced at times of stress (āfight or flightā) ā¢ Stimulate release of stored energy. ā¢ Major defense against hypoglycemia in T1M (POOR glucagon). ā¢ IF DEFECTIVE: Hypoglycemia unawareness: severe and prolonged hypoglycemia: ā¢ Intensified glucose control only after a period of hypoglycemia avoidance and restoration of catecholamine response.
- 47. Cortisol. ā¢ increases at times of stress. ā¢ stimulate gluconeogenesis. ā¢ slower than glucagon ā¢ not effective in protecting against acute hypoglycemia.
- 48. Growth hormone ā¢ Slow effects on glucose metabolism. ā¢ major surge during sleep : rise in blood glucose levels in the early morning: dawn phenomenon. ā¢ In normal physiology, a slight increase in insulin secretion compensates ā¢ 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 ā¢ Hyperglycemia : Glucotoxicity : more hyper ā¢ Hypogycemia-associated autonomic failure (HAAF): more hypo
- 52. Hypoglycemia Unawareness ā¢ No early warning symptoms of hypoglycemia ā¢ cognitive impairment may be first symptom ā¢ Clinical diagnosis ā¢ Reduced glucose thresholds for epinephrine-mediated warning symptoms ā¢ Autonomic dysfunction: inadequate catecholamic release to hypoglycemia.
- 53. Reversible!! ā¢ Avoidance of even mild hypoglycemia for 2ā4 weeks. ā¢ Adjustments in glycemic goals ā¢ Education to estimate and detect blood glucose level fluctuations. ā¢ Increased monitoring of blood glucose ā¢ Modifying glycemic targets until hypoglycemia awareness is regained. ā¢ Symptom recognition ā¢ AFTER regaining hypoglycemia awareness: reassess the treatment plan to avoid episodes of hypoglycemia, especially ā¢ nocturnal hypoglycemia.
- 54. THANK YOU