Diabetes melitus in. lec. VI 12pptx.pptx

about insulin

1. Diabetes melitus . “If you skew the endocrine system, you lose the pathways to self.” —Hilary Mantel

2. Endocrine pancreas cell types Islets of Langerhans are collections of α, β, and δ cells. Islets arise from pancreatic buds. α = glucagon (peripheral) β = insulin (central) δ = somatostatin (interspersed)

3. α cell β cell δ cell Capillaries

4. Preproinsulin cleavage of “ presignal ” proinsulin (stored in secretory granules) cleavage of proinsulin exocytosis of insulin and C-peptide equally. Insulin and C-peptide are in insulinoma and sulfonylurea use, whereas exogenous insulin lacks C-peptide.

5. Anabolic effects of insulin: glucose transport in skeletal muscle and adipose tissue glycogen synthesis and storage triglyceride synthesis Na+ retention (kidneys) protein synthesis (muscles) cellular uptake of K+ and amino acids glucagon release lipolysis in adipose tissue Unlike glucose, insulin does not cross placenta.

6. Glucose is the major regulator of insulin release. insulin response with oral vs IV glucose because of incretins such as glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which are released after meals and β cell sensitivity to glucose. Release by α 2, by β2 (2 = regulates insulin)

7. Insulin Binds in sulin receptors (tyrosine kinase activity ), in ducing glucose uptake ( carriermediated transport) in to insulin-dependent tissue and gene transcription

8. Insulin-dependent glucose transporters : GLUT4: adipose tissue, striated muscle (exercise can also increase GLUT4 expression) Insulin-independent transporters: GLUT1: RBCs, brain, cornea, placenta GLUT2 (bidirectional): β islet cells, liver, kidney, small intestine GLUT3: brain, placenta GLUT5 (fructose): spermatocytes , GI tract

9. Insulin BRICK L (insulin-independent glucose uptake): B rain, R BCs, I ntestine, C ornea, K idney, L iver.

10. Insulin Brain utilizes glucose for metabolism normallyand ketone bodies during starvation. RBCs utilize glucose because they lack mitochondria for aerobic metabolism.

11. Epidemiology of DM Diabetes mellitus (DM) is the second most common chronic disease of childhood, affecting 1 of 500 children. Two times more common in boys than in girls

12. Types of Diabetes Type 1—insulin deficiency (insulin-dependent) Type 2—insulin resistant (non–insulin-dependent)

13. Type 1 Diabetes Mellitus ( Etiology) Genetic factors Environmental factors A utoimmune factors

14. Genetic factors Strong genetic influences, but inheritance has not been found to fit into classic Mendelian patterns (autosomal or X-linked). 95 % of patients with type 1 DM have HLA haplotype DR3 or DR4. Monozygotic twins -50 % concordance rate, dizygotic twins - 30 % concordance rate.

15. Environmental triggers Viral infections have been implicated, including enteroviruses (coxsackie) and rubella. Whether the early introduction of cow's milk might trigger DM is controversial (!???!)

16. Autoimmune factors. The autoimmune process begins with lymphocytic infiltration of the pancreas. Islet cell antibodies (ICA) are present in 85% of patients. ICA may be detected in asymptomatic patients 10 years before the onset of clinical symptom s.

17. Autoimmune factors (cont) Immunologic markers may also be detected long before the onset of clinical signs, including antibodies against insulin and against glutamic acid decarboxylase (GAD).

18. Note Up to 10% of the general population may have ICA . To develop type 1 DM, children must have a combination of ICA, environmental factors , and a genetic predisposition.

19. Clinical Features of DM Several weeks of polyuria , polydipsia , nocturia , and occasionally enuresis . As symptoms progress, weight loss , vomiting , and dehydration occur. Diabetic ketoacidosis (DKA) may be the initial in 25% of patients. The younger the patient - the shorter the course of symptoms before DKA occurs

20. Clinical Features of DM (cont) Girls who have protracted cases of monilial vulvovaginitis may have early type 1 DM. Adolescents may present with type 1 DM during pubertal growth spurt with hormones that are antagonistic to insulin action (specifically growth hormone and the sex steroids ).

21. Diagnosis of DM hyperglycemia documented by a random blood sugar above 200 mg/ dL polyuria polydipsia weight loss , or nocturi a.

22. Management of DM - Insulin Types of insulin include short-acting , intermediate-acting, long-acting, very long-acting. Administration in newly diagnosed patients may involve combining the above types of insulin. Insulin pumps are now being used in children to achieve better glucose control and to improve lifestyle.

23. Monitoring Daily blood glucose measurements before all meals and at bedtime. Glycosylated hemoglobin level - diabetic control for the past 2–3 months, should be checked every 3 months . Control hypoglycemia : all patients - parenteral glucagon available in case of seizure or coma secondary to low blood sugar.

24. “Honeymoon” period. Within a few weeks after initial diagnosis, 75% of patients exhibit a temporary progressive reduction in their daily insulin requirements due to transient recovery of residual islet cell function , resulting in endogenous release of insulin in response to carbohydrate exposure - may last anywhere from months to 1–2 years.

25. Somogyi phenomenon. This occurs when the evening dose of insulin is too high , causing hypoglycemia in the early morning hours , resulting in the release of counter-regulatory hormones (epinephrine and glucagon ) to counteract this insulin-induced hypoglycemia. The patient then has high blood glucose and ketones in the morning . The treatment is to actually lower the bedtime insulin dose and not to raise it.

26. Diet. Follow the Diabetic Association (ADA) diet. Education and close follow-up every 3 months.

27. Long-Term Complications Microvascular complications include diabetic retinopathy , nephropathy , neuropathy . Macrovascular complications are usually seen in adulthood and include atherosclerotic disease , hypertension, heart disease, stroke . DKA when ill or noncompliant

28. Type 2 Diabetes Mellitus Epidemiology Occurs in 2–3% of all child cases with diabetes. In the last decade - a 10-fold increase in the incidence of type 2 DM in children due to an increase in obesity .

29. Etiology Very strong hereditary component (stronger for type 2 than for type 1) The cause is likely a combination of peripheral tissue resistance to insulin and progressive decline in insulin secretion , both of which result in a hyperglycemic state

30. Clinical Features of DM II Asymptomatic (50%) to mild DKA. Serious DKA is uncommon because type 2 DM is more of an insulin resistance than insulin deficiency. Obesity Acanthosis nigricans (velvety and hyperpigmented skin of the neck and axillary folds) is common.

31. Management Oral hypoglycemic agents may be used if blood sugar levels are not very high . Insulin therapy may be required for those patients who have high blood sugar or who fail oral agents .

32. Diabetic Ketoacidosis (DKA) Hyperglycemia usually greater than 300 mg/ dL with ketonuria and a serum bicarbonate level <15 mmol /L or a serum pH < 7.30.

33. Pathophysiology of DKA Insulin deficiency creates a state of diminished glucose substrate at the cellular level, despite the high serum levels of glucose. The body's need for substrate to make energy therefore results in gluconeogenesis . Hyperglycemia resulting from this insulin deficiency leads to an osmotic diuresis with polyuria and eventual dehydration.

34. Pathophysiology of DKA (cont) Counter-regulatory stress hormones (i.e., glucagon, epinephrine, cortisol , and growth hormone) are released and contribute to fat breakdown ( lipolysis ). Glucagon stimulates conversion of free fatty acids into ketone bodies (acetone, acetoacetate , and β - hydroxybutyrate ). The counter-regulatory stress hormones, in the face of insulin deficiency, lead to fat lipolysis and ketone forma tion and eventually DKA .

35. Clinical Features of DKA Mild DKA - vomiting , polyuria, polydipsia, and mild to moderate dehydration. Severe DKA - severe dehydration, severe abdominal pain that may mimic appendicitis, rapid and deep ( Kussmaul ) respirations, and coma. Ketones gives “ fruity breath” Ketones also contribute to coma in severe DK A.

36. Laboratory Findings of DKA Anion gap metabolic acidosis Hyperglycemia and glucosuria Ketonemia and ketonuria Hyperkalemia caused by metabolic acidosis (potassium moves out of the cells in the face of acidosis) or normokalemia

37. Management of DKA Fluid and electrolyte therapy and replacement of the depleted intravascular volume using isotonic saline should begin immediately. A gradual decline in osmolality is critical to minimize the risks of cerebral edema

38. Management of DKA (cont) Potassium repletion (once urine output has been established) is very important because all patients are potassium depleted Potassium acetate is helpful in managing the patient's metabolic acidosis . Potassium phosphate increase serum levels of 2, 3-diphosphate glycerate (2, 3-DPG), which in turn shifts the oxygen dissociation curve to the right and makes oxygen more readily available to the tissues.

39. Management of DKA Regular insulin (usually of 0.1 U/kg per hour ) with monitoring of serum glucose IV fluids + insulin : reverse the ketogenesis stop the hepatic production of glucose shut down the release of counter-regulatory hormones enhance peripheral glucose uptak e.

40. Complications of DKA - Cerebral edema - Usually - 6–12 hours into therapy Rarely after 24 hours Risk factors : - <5 years of age - initial drops in serum glucose levels >100 mg/ dL per hour - fluid administration > 4 L/m 2 per 24 hours. Mortality rate - 70 %.

41. Complications of DKA (Cont) Severe hypokalemia Hypocalcemia , due to either excessive use of potassium phosphate or osmotic losses.