Pathophysiology of diabetes final 2

1. Pathophysiology of T2 Diabetes and its Clinical implications. INTESSAR SULTAN MD, MRCP PROF. OF MEDICINE @ TAIBA UNIVERSITY. CONSULTANT ENDOCRINOLOGIST@ DC, KFH, MADINAH .

2. DEFINITION Diabetes mellitus is metabolic disorder of multiple aetiology characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both. .

3. NORMAL FUEL METABOLISM

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 μ mol /(kg−min) Renal contribution: 2.0–2.5 μ mol /(kg−min) (20–25%) Hepatic contribution: 7.5–8.0 μ mol /(kg−min) (75–80%) Renal gluconeogenesis: 2.0–2.5 μ mol /(kg−min) (20–25%) Hepatic glycogenolysis : 4.5–5.5 μ mol /(kg−min) (45–50%) Hepatic gluconeogenesis: 2.5–3.0 μ mol /(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

16. Major Metabolic Effects of Insulin and Consequences of Insulin Deficiency

17. Insulin secretion

18. 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.

19. 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

20. 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.

21. Insulin Secretion Fig. 47-1

22. Adapted from Ward WK et al . Diabetes Care 1984; 7: 491–502 . Normal Type 2 diabetes 120 100 80 60 40 20 –30 0 30 60 90 120 Time (minutes) –30 0 30 60 90 120 Time (minutes) Plasma insulin (µU/ml) 120 100 80 60 40 20 20g glucose 20g glucose Plasma insulin (µU / ml) Pattern of insulin release is altered early in Type 2 diabetes Loss of Early-phase Insulin Release in Type 2 Diabetes

23. Overview of Insulin and Action

24. Insulin Preparations Fig. 47-3

25. 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.

26. 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

27. Pathophysiology in Type 2 DM Decreased insulin and increased glucagon secretion result in... elevated hepatic glucose output... reduced insulin-mediated glucose uptake Hyperglycaemia Renal glucose filtration and reabsorption is increased up to the renal threshold for glucose reabsorption (180 mg/ dL ): glucosuria Glucotoxicity of all organs, exposing the individual to the risk of complications and further impairing insulin secretion and action

28. 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

29. 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

30. 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

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 3     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 4

33. 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

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. 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 )

36. DeFronzo RA. Diabetes. 2009;58:773-795.

37. 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.

38. Increased Hepatic Glucose Production Impaired Insulin Secretion Hyperglycemia Decreased Glucose Uptake TZDs GLP-1 analogues DPP-4 inhibitors Sulfonylureas Thiazolidinediones Metformi n  Metformin Thiazolidinediones _  Pathophysiologic Approach to Treatment of T2DM DeFronzo RA. Diabetes. 2009;58:773-795.

39. Mechanism of action-SU nateglinide repaglinide (36 kD) SUR depolarization ATP glimipiride （ 65 kD ） glyburide （ 140 kD ） Kir 6.2 SUR

40. Mechanism of action - acarbose Acarbose Oligosaccharide Acarbose Small intestine mucosa Reversible inhibition of oligosaccharide breakdown by  -glucosidases

41. SGLT-2 INHIBITORS

42. 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 K m = 0.4 mM Low K m = 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.

43. Counter regulatory hormones

44. 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.

45. 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.

46. Cortisol . increases at times of stress. stimulate gluconeogenesis . slower than glucagon not effective in protecting against acute hypoglycemia .

47. 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 .

48. T1D and advanced T2D: counterregulatory deficiencies and impaired symptomatic awareness

49. VISCIOUS CIRCLE Hyperglycemia : Glucotoxicity : more hyper Hypogycemia -associated autonomic failure (HAAF): more hypo

50. 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.

51. 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.

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