CARBOHYDRATE S METABOLISM DISORDERS

1. CARBOHYDRATES METABOLISM DISORDERS

2. GLUCOSE METABOLISM • the cornerstone of life • neurons are especially dependent on glucose • regulatory mechanisms: • hyperglycemic hormones = glycogenolysis, gluconeogenesis • hypoglycemic hormone = insulin

4. HYPERGLICEMIA(diabetes mellitus) • Diabetes - Greek word = to siphon or to pass thru. • Mellitus - Latin word = sweet or honey. • group of chronic disorders • insulin deficiencyABSOLUTE/RELATIVE !!! also affects protein and fat metabolism

5. CLASSIFICATION • type 1 DM - autoimmune pancreatic β-cell destruction = absolute insulin deficiency; • type 2 DM - insulin resistance = relative insulin deficiency; • “other” specific types of DM (associated with identifiable clinical conditions or syndromes); • gestational DM - appears or is first detected during pregnancy.

6. !!! pre-diabetes • impaired glucose tolerance (IGT) • impaired fasting glucose (IFG)

7. ADA diagnosis of DM 1.classic symptoms of diabetes (polyuria, polydipsia, and unexplained weight loss) plus random plasma glucose concentration ≥ 200 mg/dL (≥11.1 mmol/L);or 2.fasting (≥8-hour) plasma glucose concentration ≥ 126 mg/dL (≥7.0 mmol/L);or 3.   a 2-hour postload plasma glucose concentration ≥ 200 mg/dL (≥11.1 mmol/L) during a 75-g oral glucose tolerance test.

8. ETIOLOGY Type 1 diabetes • Genetic • Environmental • Autoimmune

10. Type 2 diabetes = relative insulin deficiency – insulin resistance / inadequate secretory response • complex genetic interactions unrelated to HLA genes • environmental factors such as body weight (obesity) and exercise (lack of physical activity).

11. MODY • autosomal dominant inheritance • onset in at least 1 family member younger than 25 years • absence of autoantibodies • correction of fasting hyperglycemia without insulin for at least 2 years • absence of ketosis.

12. Type 2 DM pathogenic mechanisms: • progressive loss of insulin secretory capacity. • impaired insulin action : • impaired mitochondrial function and the resulting accumulation of free fatty acids in insulin-responsive tissues. • defects of the insulin receptor. • defects in “postreceptor” pathways • Adipocyte-Derived Hormones and Cytokines • Leptin • Adiponectin • other adipocyte-derived factors (resistin, angiotensinogen, interleukin-6, transforming growth factor-β, plasminogen activator inhibitor 1) • TNF-α.

13. Glucotoxicity. • Lipotoxicity. • accelerate hepatic gluconeogenesis • inhibit muscle glucose metabolism • impair pancreatic β-cell function.

14. Type 1 DM produces profound β-cell failure and insulin deficiency with secondary insulin resistance, • Type 2 DM is associated with less severe insulin deficiency but greater insulin resistance.

16. diabetes mellitus pathogenesis

17. fasting hyperglycemia • mobilization of substrates from muscle and adipose tissue • accelerated hepatic gluconeogenesis, glycogenolysis, ketogenesis • impaired removal of endogenous and exogenous fuels by insulin-responsive tissues.

18. fasting free fatty acids • Insuline deficiency - increase lipolysis • Glucagon - accelerating hepatic ketogenesis • Catecholamines growth hormone, and cortisol - increase lipolysis. • type 1 diabetes- converted to ketone bodies • type 2 diabetes– insulin suppress the conversion of free fatty acids to ketones !!! The increase in substrate delivery - hepatic steatosis and severe hypertriglyceridemia (endogenous).

19. Postprandial Hyperglycemia • type 1 diabetes – insulin deficiency • type 2 diabetes - delayed insulin secretion + hepatic insulin resistance • the liver fails to arrest glucose production • fails to appropriately take up glucose for storage as glycogen • glucose uptake by peripheral tissues is impaired

20. Hyperglycaemia  renal threshold for glucose surpassed (>170mg/dl)  GLUCOSURIA  osmotic diuresis  POLYURIA  dehydration  thirst  POLYDIPSIA

21. Type 1 diabetic- defects in the disposal of ingested proteins and fats as well. • Hyperaminoacidemia • Hypertriglyceridemia (exogenous)

22. ACUTE METABOLIC COMPLICATIONS • diabetic ketoacidosis (DKA) • hyperosmolar hyperglycemic syndrome (HHS) • hypoglycemia

23. DKA • deficient circulating insulin activity • excessive secretion of counter-regulatory hormones. • hyperglycemia, ketosis, acidosis !!! osmotic diuresis - dehydration and electrolyte loss.

24. Hyperosmolar Hyperglycemic Syndrome (HHS) • patients cannot drink enough liquid to keep pace with a vigorous osmotic diuresis. • Severe hyperosmolarity (>320 mOsm/L) • Severe hyperglycemia (>600 mg/dL). • severe acidosis and ketosis are generally absent in the HHS!!!

25. Hypoglycemia • the earliest subjective warning signs = autonomic symptoms (sweating, tremor, palpitations) • Central nervous system symptoms and signs = neuroglycopenia: • nonspecific (e.g., fatigue or weakness) • more clearly neurologic (e.g., double vision, oral paresthesias, slurring of speech, apraxia, personality change, or behavioral disturbances). • irreversible brain damage. • Hypoglycemic unawareness syndrome • duration of diabetes • autonomic neuropathy • switched to intensive insulin regimens.

26. Somogyi phenomenon – • normal or increased blood glucose levels at bedtime • blood glucose drops in early morning hours (2 to 3 A.M.) usually because nighttime insulin dose is too high. • compensate by producing counterregulatory hormones resulting in hyperglycemia on awakening. • Dawn phenomenon=Decrease in the tissue sensitivity to insulin between 5 and 8 A.M. - prebreakfast hyperglycemia ??? release of nocturnal growth hormone

27. CHRONIC DIABETIC COMPLICATIONSMICROVASCULAR AND NEUROPATHIC COMPLICATIONS • Intracellular glucose • advanced glycationend products (AGEs) • accelerated polyol pathway • reactive oxygen species • Others: cytokines, angiotensin II, endothelin, growth factor stimulation, depletion of basement membrane glycosaminoglycans • Hemodynamic changes in the microcirculation

32. Diabetic retinopathy • vascular-neuroinflammatory disease. • breakdown of the blood-retinal barrier (BRB) function and loss of retinal neurons. • activated macroglia and neuronal death. • activated microglia exacerbate the damage.

35. Diabetic Nephropathy • rise in glomerular filtration rate. • glomerular lesions • increased glomerular permeability. • microalbuminuria (30 to 300 mg/day) • diffuse glomerulosclerosis • massive proteinuria - nephrotic syndrome • Systemic hypertension • progression to ESRD.

36. Diabetic Neuropathy • metabolic factors • vascular • Nerve growth factor diminished • Autoimmune mechanisms.

37. Distal symmetrical (sensorimotor) polyneuropathy • Acute sensory neuropathy • Focal diabetic neuropathies (mononeuropathies) – pain • Entrapment syndromes • Proximal motor neuropathy (diabetic amyotrophy)

38. Autonomic neuropathy • Cardiovascular abnormalities • preferential dysfunction of parasympathetic fibers • impaired sympathetic vasoconstrictor response and impaired cardiac reflexes. • Altered gastrointestinal function • hypermotility / hypomotility • Gastroparesis

39. Genitourinary alterations • bladder hypotonia • Erectile dysfunction • Abnormal sweat production • Xerosis. • Distal anhidrosis - truncal-facial sweating • Generalized anhidrosis

41. atherosclerosis • lipid abnormalities • procoagulant state = accentuated platelet aggregation and adhesion, endothelial cell dysfunction. • hyperinsulinemia

43. The diabetic foot • chronic sensorimotor neuropathy • vascular disease • abnormal immune function

44. HYPOGLICEMIA • Physiological hypoglycaemia • 3-5 hours after ingestion of glucose or during prolonged fast • Pathological HYPOGLICEMIA Whipple’s triad: • LOW BLOOD GLUCOSE below 50 mg/dl • symptoms of hypoglycaemia • symptoms relieved by glucose

46. Classification: • Fasting hypoglycaemia • With hyperinsulinemia • Without hyperinsulinemia • Non-fasting, postprandial or reactive hypoglycaemia

47. Fasting hypoglycemia with hyperinsulinemia • diabetes • islet cell tumours • factitious hypoglycemia • autoimmune hypoglycaemia • drugs

48. Fasting hypoglycemia without hyperinsulinemia • Chronic renal impairment • Decreased renal gluconeogenesis • impaired hepatic glycogenolysis and gluconeogenesis !!! • increased insulin half-life due to decreased renal degradation • exaggerated glucose-induces insulin secretion

49. severe liver disease = hepatogenous hypoglycaemia • deficient caloric intake and exercise-induced hypoglycaemia

50. septicaemia early phase - hyperglycemia • decrease in insulin-stimulated phosphorylation of insulin receptor • increased clearance of insulin • increased production of corticosteroids. late phase – hypoglycemia • cytokines from macrophages stimulates insulin secretion • direct hypoglycemic effect of endotoxins (inhibit gluconeogenesis) • association of renal failure.