Pathophysiology of diabetes final 2
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Pathophysiology of diabetes final 2

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Lecture By Prof.Intessar Sultan ...

Lecture By Prof.Intessar Sultan
Taibah Universty,Consultant Endocrinology,KFH,Madina

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  • The kidneys and the liver both contribute to the overall quantity of glucose produced by the body (approximately 10 μmol/kg min in total). The human liver and kidneys provide roughly equal amounts of glucose via gluconeogenesis in the post-absorptive state, but the overall production by the liver exceeds that of the kidney due to additional hepatic glycogenolysis.The liver releases the majority of glucose in the post-absorptive state (75–80%) by gluconeogenesis (25–30%)from precursors such as lactate, glycerol, alanineGlycogenolysis makes up the rest of the liver’s glucose production (45–50%, from breakdown of stored glycogen)The kidney, by contrast, contributes 20–25% of the overall glucose productionThe kidney stores very little glycogen and most renal cells lack the necessary enzyme for glucose release from glucagon; hence its glucose production comes entirely from gluconeogenesisReference:Gerich JE. Diabet Med 2010;27:136–42.
  • <Note: Slide title is animated and cannot be viewed properly in slide notes view>Under normal conditions, glucose homeostasis is kept under tight control.The pancreas, skeletal muscle, liver, adipose tissue and kidney are all important in regulating plasma glucose concentrationsInsulin from the pancreas mediates glucose uptake by skeletal muscle and adipose tissue when blood glucose is high, whilst glucagon increases hepatic glucose secretion when blood levels are lowThe kidney mediates glucose filtration and reabsorptionIn Type 2 diabetes, a number of pathophysiological changes take place:Decreased insulin and increased glucagon secretion result in......elevated hepatic glucose output...... and reduced insulin-mediated glucose uptake in the peripheryAs a result, hyperglycaemia occursUnder these circumstances renal glucose filtration and reabsorption is increased up to the renal threshold for glucose reabsorption (about 180 mg/dL), above which glucosuria developsDevelopment of hyperglycaemia causes glucotoxicity, which affects all organs, exposing the individual to the risk of complications and further impairing insulin secretion and actionReferences:DeFronzo RA. Ann Intern Med 1999;113:281–303.Wright EM. Am J Physiol Renal Physiol 2001;280:F10–F18.
  • <Note: Slide title is animated and cannot be viewed properly in slide notes view>Under normal conditions, glucose homeostasis is kept under tight control.The pancreas, skeletal muscle, liver, adipose tissue and kidney are all important in regulating plasma glucose concentrationsInsulin from the pancreas mediates glucose uptake by skeletal muscle and adipose tissue when blood glucose is high, whilst glucagon increases hepatic glucose secretion when blood levels are lowThe kidney mediates glucose filtration and reabsorptionIn Type 2 diabetes, a number of pathophysiological changes take place:Decreased insulin and increased glucagon secretion result in......elevated hepatic glucose output...... and reduced insulin-mediated glucose uptake in the peripheryAs a result, hyperglycaemia occursUnder these circumstances renal glucose filtration and reabsorption is increased up to the renal threshold for glucose reabsorption (about 180 mg/dL), above which glucosuria developsDevelopment of hyperglycaemia causes glucotoxicity, which affects all organs, exposing the individual to the risk of complications and further impairing insulin secretion and actionReferences:DeFronzo RA. Ann Intern Med 1999;113:281–303.Wright EM. Am J Physiol Renal Physiol 2001;280:F10–F18.
  • <Note: Slide title is animated and cannot be viewed properly in slide notes view>Under normal conditions, glucose homeostasis is kept under tight control.The pancreas, skeletal muscle, liver, adipose tissue and kidney are all important in regulating plasma glucose concentrationsInsulin from the pancreas mediates glucose uptake by skeletal muscle and adipose tissue when blood glucose is high, whilst glucagon increases hepatic glucose secretion when blood levels are lowThe kidney mediates glucose filtration and reabsorptionIn Type 2 diabetes, a number of pathophysiological changes take place:Decreased insulin and increased glucagon secretion result in......elevated hepatic glucose output...... and reduced insulin-mediated glucose uptake in the peripheryAs a result, hyperglycaemia occursUnder these circumstances renal glucose filtration and reabsorption is increased up to the renal threshold for glucose reabsorption (about 180 mg/dL), above which glucosuria developsDevelopment of hyperglycaemia causes glucotoxicity, which affects all organs, exposing the individual to the risk of complications and further impairing insulin secretion and actionReferences:DeFronzo RA. Ann Intern Med 1999;113:281–303.Wright EM. Am J Physiol Renal Physiol 2001;280:F10–F18.
  • <Note: Slide title is animated and cannot be viewed properly in slide notes view>Under normal conditions, glucose homeostasis is kept under tight control.The pancreas, skeletal muscle, liver, adipose tissue and kidney are all important in regulating plasma glucose concentrationsInsulin from the pancreas mediates glucose uptake by skeletal muscle and adipose tissue when blood glucose is high, whilst glucagon increases hepatic glucose secretion when blood levels are lowThe kidney mediates glucose filtration and reabsorptionIn Type 2 diabetes, a number of pathophysiological changes take place:Decreased insulin and increased glucagon secretion result in......elevated hepatic glucose output...... and reduced insulin-mediated glucose uptake in the peripheryAs a result, hyperglycaemia occursUnder these circumstances renal glucose filtration and reabsorption is increased up to the renal threshold for glucose reabsorption (about 180 mg/dL), above which glucosuria developsDevelopment of hyperglycaemia causes glucotoxicity, which affects all organs, exposing the individual to the risk of complications and further impairing insulin secretion and actionReferences:DeFronzo RA. Ann Intern Med 1999;113:281–303.Wright EM. Am J Physiol Renal Physiol 2001;280:F10–F18.
  • <Note: Slide title is animated and cannot be viewed properly in slide notes view>Under normal conditions, glucose homeostasis is kept under tight control.The pancreas, skeletal muscle, liver, adipose tissue and kidney are all important in regulating plasma glucose concentrationsInsulin from the pancreas mediates glucose uptake by skeletal muscle and adipose tissue when blood glucose is high, whilst glucagon increases hepatic glucose secretion when blood levels are lowThe kidney mediates glucose filtration and reabsorptionIn Type 2 diabetes, a number of pathophysiological changes take place:Decreased insulin and increased glucagon secretion result in......elevated hepatic glucose output...... and reduced insulin-mediated glucose uptake in the peripheryAs a result, hyperglycaemia occursUnder these circumstances renal glucose filtration and reabsorption is increased up to the renal threshold for glucose reabsorption (about 180 mg/dL), above which glucosuria developsDevelopment of hyperglycaemia causes glucotoxicity, which affects all organs, exposing the individual to the risk of complications and further impairing insulin secretion and actionReferences:DeFronzo RA. Ann Intern Med 1999;113:281–303.Wright EM. Am J Physiol Renal Physiol 2001;280:F10–F18.
  • <Note: Slide title is animated and cannot be viewed properly in slide notes view>Under normal conditions, glucose homeostasis is kept under tight control.The pancreas, skeletal muscle, liver, adipose tissue and kidney are all important in regulating plasma glucose concentrationsInsulin from the pancreas mediates glucose uptake by skeletal muscle and adipose tissue when blood glucose is high, whilst glucagon increases hepatic glucose secretion when blood levels are lowThe kidney mediates glucose filtration and reabsorptionIn Type 2 diabetes, a number of pathophysiological changes take place:Decreased insulin and increased glucagon secretion result in......elevated hepatic glucose output...... and reduced insulin-mediated glucose uptake in the peripheryAs a result, hyperglycaemia occursUnder these circumstances renal glucose filtration and reabsorption is increased up to the renal threshold for glucose reabsorption (about 180 mg/dL), above which glucosuria developsDevelopment of hyperglycaemia causes glucotoxicity, which affects all organs, exposing the individual to the risk of complications and further impairing insulin secretion and actionReferences:DeFronzo RA. Ann Intern Med 1999;113:281–303.Wright EM. Am J Physiol Renal Physiol 2001;280:F10–F18.
  • <Note: Slide title is animated and cannot be viewed properly in slide notes view>Under normal conditions, glucose homeostasis is kept under tight control.The pancreas, skeletal muscle, liver, adipose tissue and kidney are all important in regulating plasma glucose concentrationsInsulin from the pancreas mediates glucose uptake by skeletal muscle and adipose tissue when blood glucose is high, whilst glucagon increases hepatic glucose secretion when blood levels are lowThe kidney mediates glucose filtration and reabsorptionIn Type 2 diabetes, a number of pathophysiological changes take place:Decreased insulin and increased glucagon secretion result in......elevated hepatic glucose output...... and reduced insulin-mediated glucose uptake in the peripheryAs a result, hyperglycaemia occursUnder these circumstances renal glucose filtration and reabsorption is increased up to the renal threshold for glucose reabsorption (about 180 mg/dL), above which glucosuria developsDevelopment of hyperglycaemia causes glucotoxicity, which affects all organs, exposing the individual to the risk of complications and further impairing insulin secretion and actionReferences:DeFronzo RA. Ann Intern Med 1999;113:281–303.Wright EM. Am J Physiol Renal Physiol 2001;280:F10–F18.
  • The adaptive response of the kidney – reabsorption of glucose to provide substrate for energy generation – is largely mediated by SGLT2. Under normal conditions, glucose is filtered and reabsorbed in the kidney, predominantly by SGLT2, and none appears in the urineThis response becomes dysregulated in Type 2 diabetes, when, due to greater expression of SGLT2 (in part a result of hyperglycaemia), glucose filtration and reabsorption is increased. However, excess glucose concentrations also exceed the maximum reabsorption threshold of SGLT2, resulting in glycosuriaIt is therefore possible that renal glucose reabsorption could be targeted to reduce plasma glucose concentrations in patients with Type 2 diabetes
  • At least five different genes encoding SGLTs have been identified in humans, but only two (SGLT1 and 2) have been well characterised.SGLT1 is a high-affinity, low-capacity transporter that is mostly expressed in the intestine, with lesser expression in the kidney. SGLT1 plays a role in absorption of glucose from both the diet and the glomerular filtrateSGLT2 is a low-affinity, high-capacity transporter that is exclusively expressed in the kidney. It is responsible for the majority (~90%) of glucose reabsorption from the glomerular filtrateReference:Abdul-Ghani MA, et al. EndocrPract2008;14:782–90.

Transcript

  • 1. Pathophysiology of T2 Diabetes and its Clinical implications. INTESSAR SULTAN 单击此处编辑母版副标题样式 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 Renal contribution: 2.0–2.5 μmol/(kg−min) (20–25%) Hepatic contribution: 7.5–8.0 μmol/(kg−min) (75–80%) Hepatic glycogenolysis: 4.5–5.5 μmol/(kg−min) (45–50%) Renal gluconeogenesis: 2.0–2.5 μmol/(kg−min) (20–25%) Hepatic gluconeogenesis: 2.5–3.0 μmol/(kg−min) (25–30%) Overall rate of glucose release: ~10 μmol/(kg−min)
  • 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 Major Metabolic Effects of Insulin • Stimulates glucose uptake into muscle and adipose cells: lipogenesis • Inhibits hepatic glucose production Consequences of Insulin Deficiency • Hyperglycemia  osmotic diuresis and dehydration
  • 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
  • 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. Loss of Early-phase Insulin Release in Type 2 Diabetes Pattern of insulin release is altered early in Type 2 diabetes 120 100 20g glucose 80 60 40 20 0 –30 0 30 60 90 120 Time (minutes) Type 2 diabetes Plasma insulin (µU / ml) Plasma insulin (µU/ml) Normal 120 20g glucose 100 80 60 40 20 0 –30 0 30 60 90 120 Time (minutes) Adapted from Ward WK et al. Diabetes Care 1984; 7: 491–502.
  • 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. Normal glucose homeostasis Insulin-mediated glucose uptake by skeletal muscle and adipose tissue Glucagon Insulin FPG 90 mg/dL Glucose Glucose filtration/ reabsorption 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.
  • 27. 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
  • 28. Pathophysiology of Type 2 diabetes Insulin-mediated glucose uptake by skeletal muscle and adipose tissue  Glucagon 1  Insulin FPG 90 mg/dL Glucose Glucose filtration/ reabsorption 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.
  • 29. Pathophysiology of Type 2 diabetes   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
  • 30. Pathophysiology of Type 2 diabetes Insulin-mediated glucose uptake by skeletal muscle and adipose tissue  Glucagon  Insulin 1 FPG 90 mg/dL 2  Glucose Glucose filtration/ reabsorption 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.
  • 31. Pathophysiology of Type 2 diabetes 3 Insulin-mediated glucose uptake by  skeletal muscle and adipose tissue  Glucagon  Insulin 1 FPG 90 mg/dL 2  Glucose Glucose filtration/ reabsorption 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.
  • 32. Pathophysiology of Type 2 diabetes 3 Insulin-mediated glucose uptake by  skeletal muscle and adipose tissue  Glucagon  Insulin 1 FPG 90 mg/dL 2  Glucose 4  Glucose filtration/ reabsorption 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.
  • 33. Pathophysiology of Type 2 diabetes 3 Insulin-mediated glucose uptake by  skeletal muscle and adipose tissue  Glucagon  Insulin 1 FPG 180 mg/dL 2 GLUCOTOXICITY  Glucose 4  Glucose filtration/ reabsorption GLUCOSURIA 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.
  • 34. Pathophysiology of Type 2 diabetes 3 Insulin-mediated glucose uptake by  skeletal muscle and adipose tissue  Glucagon  Insulin 1 FPG 180 mg/dL 2 GLUCOTOXICITY  Glucose 4  Glucose filtration/ reabsorption GLUCOSURIA 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.
  • 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.... Glucose ...becomes maladaptive in Type 2 diabetes GLUCOSE SGLT2 plays a crucial role in renal glucose reabsorption In Type 2 diabetes, the kidney’s maximum glucose reabsorption threshold is exceeded, resulting in glycosuria This highlights renal glucose reabsorption as a potential target for treatment of Type 2 diabetes Normal urine GLUCOSURIA SGLT2, sodium-glucose co-transporter-2.
  • 38. Pathophysiologic Approach to Treatment of T2DM Impaired Insulin Secretion  Metformin Thiazolidinediones _ TZDs GLP-1 analogues DPP-4 inhibitors Sulfonylureas Thiazolidinediones Metformin  Hyperglycemia Increased Hepatic Glucose Production Decreased Glucose Uptake DeFronzo RA. Diabetes. 2009;58:773-795.
  • 39. Mechanism of action-SU repaglinide (36 kD) Kir 6.2 nateglinide SUR depolarization SUR ATP glimipiride(65 kD) glyburide(140 kD)
  • 40. Mechanism of action- acarbose Reversible inhibition of oligosaccharide breakdown by -glucosidases Acarbose Acarbose Oligosaccharide Small intestine mucosa
  • 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 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.
  • 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.
  • 52. THANK YOU