1. 1. Diabetes Mellitus Diabetes Mellitus is a group of multifactorial, polygenic syndromes characterized by an elevation of blood glucose caused by a relative or absolute deficiency in insulin.
2. 2. Insulin Insulin is the most important hormone coordinating the use of fuels by tissues. Its metabolic effects are anabolic, favoring, for example, synthesis of glycogen, triacylglycerols, and protein.
3. 3. Insulin Structure Insulin is composed of 51 amino acids arranged in two polypeptide chains, designated A and B. Linked together by two disulfide bridges and an intramolecular disulfide bridge between amino acid residues of the A chain.
4. 4. Insulin Synthesis Insulin is produced by the cells of the islets of Langerhans, in pancreas. The islets of Langerhans make up only about 1 2% of the total cells of the pancreas
5. 5. Steps of Insulin Synthesis Preproinsulin synthesized in RER cleavage of presignal proinsulin stored in secretory granules cleavage of proinsulin Exocytosis of insulin and C-peptide in equimolar amounts by beta cells upon stimulation
6. 6. Regulation of Insulin Secretion Stimulation of insulin secretion: 1. Glucose 2. Amino acids 3. Beta adrenergic stimulation 4. GI hormones: e.g. GIP (Gastric Inhibitory Peptide) CCK (cholecystokinin)
7. 7. Regulation of Insulin Secretion Inhibition of insulin secretion: By far, the most important inhibitor of insulin secretion is Epinephrine. In conditions of stress, such as exercise, infection surgery, this action of epinephrine is necessary to maintain adequate blood glucose levels.
8. 8. Metabolic Effects of Insulin Increased glucose transport in liver, skeletal muscle and adipose tissue Most cells of the body take up glucose by an Insulin- independent mechanism. Increased glycogen synthesis and storage Decreased glycogenolysis and gluconeogenesis
9. 9. Metabolic Effects of Insulin Increased triglyceride synthesis Decreased triglyceride degradation Increased Na+ retention (kidneys) Increased protein synthesis (muscles, proteins) Increased cellular uptake of K+ and amino acids Decreased glucagon release
10. 10. In the absence of Insulin there is Decreased GLUCOSE UPTAKE, Decreased GLYOGENESIS and Increased GLYCOGENOLYSIS and Increased GLUCONEOGENSIS This results in HYPERGLYCEMIA.
11. 11. In the absence of Insulin there is Decreased LIPOGENESIS, Decreased PROTEOGENESIS and Increased LIPOLYSIS, Increased PROTEOLYSIS This results in decreased muscle mass and increased levels of fatty acids in the body.
12. 12. Diabetes Mellitus Diabetes Mellitus is a group of multifactorial, polygenic syndromes characterized by an elevation of blood glucose caused by a relative or absolute deficiency in insulin.
13. 13. OVERVIEW OF DIABETES MELLITUS Most cases of diabetes mellitus can be separated into two Groups, type 1 (formerly called insulin-dependent diabetes mellitus) type 2 (formerly called noninsulin-dependent diabetes).
14. 14. Type 1 Diabetes Type 2 Diabetes Age of Onset Usually during childhood or puberty; symptoms develop rapidly Frequently after age 35; symptoms develop gradually NUTRITIONAL STATUS AT TIME OF DISEASE ONSET Frequently undernourished Obesity usually present PREVALENCE 10 % of diagnosed diabetics 90 % of diagnosed diabetics Genetic Predisposition Moderate Very strong DEFECT OR DEFICIENCY Cells are destroyed, eliminating production of insulin Insulin resistance combined with inability of cells to produce appropriate quantities
15. 15. Type 1 Diabetes Type 2 Diabetes FREQUENCY OF KETOSIS Common Rare PLASMA INSULIN Low to absent High early in disease; low in disease of long duration ACUTE COMPLICATIONS Ketoacidosis Hyperosmolar Coma RESPONSE TO ORAL HYPOGLYCEMIC DRUGS Unresponsive Usually responsive TREATMENT Insulin is always necessary Diet, exercise, oral hypoglycemic drugs; insulin may or may not be necessary.
16. 16. Type 1 DM Formerly called Insulin- Dependent DM Characterized by an absolute deficiency of insulin Caused by destruction of cells of the pancreas (most commonly an auto-immune attack) Over a period of years, this autoimmune attack on the cells leads to gradual depletion of the -cell population.
17. 17. However, symptoms appear abruptly when 80 90% of the cells have been destroyed At this point, the pancreas fails to respond adequately to ingestion of glucose, and insulin therapy is required to restore metabolic control and prevent life-threatening ketoacidosis.
18. 18. Clinical Symptoms: The onset of type 1 diabetes is typically during childhood or puberty, and symptoms develop suddenly: polyuria (frequent urination), polydipsia (excessive thirst), and polyphagia (excessive hunger), often triggered by stress or an illness. These symptoms are usually accompanied by fatigue, weight loss, and weakness
19. 19. Metabolic changes in type 1 diabetes The metabolic abnormalities of type 1 diabetes mellitus result from a deficiency of insulin which profoundly affects metabolism in three tissues: liver, muscle, adipose tissue.
20. 20. Hyperglycemia Elevated levels of blood glucose and ketones are the hallmarks of untreated type 1 diabetes mellitus. Hyperglycemia is caused by increased hepatic production of glucose, combined with diminished peripheral utilization muscle and adipose have the insulin-sensitive Glucose transporters.
21. 21. Ketoacidosis Ketosis results from increased mobilization of fatty acids from adipose tissue, combined with accelerated hepatic fatty acid -oxidation and synthesis of 3-hydroxybutyrate and aceto - acetate. Diabetic ketoacidosis (DKA, a type of metabolic acidosis) occurs in 2540% of those newly diagnosed with type 1 diabetes, and may recur if the patient becomes ill (most commonly with an infection) or does not comply with therapy.
22. 22. Ketoacidosis DKA is treated by replacing fluid and electrolytes, and administering short-acting insulin to gradually correct hyperglycemia without precipitating hypoglycemia.
23. 23. Signs & Symptoms of DKA Acidotic breathing (rapid/deep breathing), Headache nausea/vomiting, abdominal pain, dehydration. Fruity breath odor (due to exhaled acetone).
24. 24. LAB Findings in DKA Hyperglycemia, Increased [H+], Decreased [HCO3] ( metabolic acidosis), Increased blood ketone levels, Hyperkalemia, but depleted intracellular K+. Glucosuria and Ketonuria
25. 25. Type 2 DM Type 2 diabetes is the most common form of the disease. Typically, type 2 diabetes develops gradually without obvious symptoms Often detected during routine screening tests. The classical signs and symptoms of polyuria, polydipsia and polyphagia may also be present.
26. 26. Type 2 DM Patients with type 2 diabetes have a combination of insulin resistance and dysfunctional cells The metabolic alterations observed in type 2 diabetes are milder than those described for type 1, This is because insulin secretion in type 2 diabetesalthough not adequatedoes restrain ketogenesis and blunts the development of DKA.
27. 27. Insulin Resistance Insulin resistance is the decreased ability of target tissues, such as liver, adipose, and muscle, to respond properly to normal (or elevated) circulating concentrations of insulin. For example, insulin resistance is characterized by uncontrolled hepatic glucose production, and decreased glucose uptake by muscle and adipose tissue.
28. 28. Dysfunctional cells In type 2 diabetes, the pancreas initially retains - cell capacity, resulting in insulin levels that vary from above normal to below normal. However, with time, the cell becomes increasingly dysfunctional and fails to secrete enough insulin to correct the prevailing hyperglycemia
29. 29. Metabolic changes in type 2 diabetes The metabolic abnormalities of type 2 diabetes mellitus are the result of insulin resistance expressed primarily in liver, muscle, and adipose tissue
30. 30. Hyperglycemia Hyperglycemia is caused by increased hepatic production of glucose, combined with diminished peripheral use. Ketosis is usually minimal or absent in type 2 patients because the presence of insulineven in the presence of insulin resistancediminishes hepatic ketogenesis
31. 31. Dyslipidemia VLDL and Chylomicrons are responsible for transporting hepatic and dietary lipids to the peripheral tissues by the help of Lipoprotein Lipase in adipose and muscle tissues. Lipoprotein lipase is low in diabetics, the plasma chylomicron and VLDL levels are elevated, resulting in hypertriacylglycerolemia Low HDL levels are also associated with type 2 diabetes.
32. 32. Hyperglycemic Hyperosmolar non- ketotic coma (HONK) HONK usually presents in older patients with type 2 DM and carries a higher mortality than DKA In a preexisting lack of or resistance to insulin, a physiologic stress such as an acute illness can cause further net reduction in circulating insulin and increase in glucagon, epinephrine and other stress hormones. This can lead to severe hyperglycemia.
33. 33. HONK HONK is characterized by hyperglycemia and hyperosmolarity, and osmotic diuresis without significant ketoacidosis. Most patients present with severe dehydration most notably cerebral dehydration and can lead to focal or global neurologic deficits, such as Drowsiness and lethargy Delirium Coma Focal or generalized seizures Visual changes or disturbances
34. 34. Laboratory Findings in HONK These include: Plasma glucose level of 600 mg/dL or greater Effective serum osmolality of 320 mOsm/kg or greater Profound dehydration, up to an average of 9 L Serum pH greater than 7.30 Normal Range =285 - 295 mOsm/kg
35. 35. DKA and HONK at a glance
36. 36. CHRONIC EFFECTS OF DIABETES Available therapies moderate the hyperglycemia of diabetes, but fail to completely normalize metabolism. The long-standing elevation of blood glucose is associated with the chronic complications of diabetes.
37. 37. HbA1C HbA1C is a measure of Haemoglobin Glycosylation. It occurs non-enzymatically Proportional to blood glucose concentration As average lifespan of RBCs is 3 months, HbA1C can be used as a measure of blood glucose conc. control over three months.
38. 38. HbA1C The better the control, lesser is the HbA1C It is expressed as a percentage, not mmol/l Normal HbA1C is < 5.7%
39. 39. Hyperglycemia Can Cause Serious Long-Term Problems
40. 40. How hyperglycemia causes the chronic complications of diabetes? Two main mechanisms: 1. In cells where entry of glucose is not dependent on insulin, elevated blood glucose leads to increased intracellular glucose and its metabolites. For example, increased intracellular sorbitol contributes to the formation of cataracts. 2. Hyperglycemia promotes the non-enzymic condensation of glucose with cellular proteins and proteins of the basement membrane in a manner analogus to that of formation of HbA1C
41. 41. Vascular Complications of Type 2 Diabetes Vascular complications are the major cause of morbidity and mortality in Type 2 diabetes Microvascular nephropathy retinopathy neuropathy Macrovascular cardiovascular disease peripheral vascular disease cerebrovascular disease
42. 42. Microvascular Complications-- Retinopathy Diabetic retinopathy-leading cause of blindness in those 20-75 and above. Blood vessel changesworst case scenario, proliferative retinopathy. Also an increased incidence of cataracts and glaucoma in diabetics. Need regular eye exams Control BP, control BS and cessation of smoking can help
43. 43. Microvascular complications- Nephropathy Accounts for 50% of patients with ESRD Earliest clinical sign of nephropathy is microalbuminuria. Warrants frequent periodic monitoring for microalbuminuriaif exceeds 30mg/24h on two consecutive random urines, need 24h urine sample
44. 44. Nephropathy Diabetes causes hypertension in renal vessels which cause leaking glomeruli, deposits in narrow vessels, scarring and vascular damage
45. 45. Microvascular disease-Nephropathy Medical management: control BP (ACE or ARB) Tx of UTIs Avoid nephrotoxic agents, contrast dyes Low sodium diet Low protein diet Tight glycemic control
46. 46. Nephropathy May require dialysis May have co-existent retinopathy Kidney transplantationsuccess now 75-80% for 5 years Pancreas transplantation may also be performed at time of kidney transplantation
47. 47. Neuropathies Group of diseases that affect all types of nerves. Includes peripheral, autonomic and spinal nerves. Prevalence increases with duration of the disease and degree of glycemic control
48. 48. Capillary basement membrane thickening and capillary closure may be present. May be demyelination of the nerves, nerve conduction is disrupted. Two most common types of neuropathies are: sensorimotor polyneuropathy and autonomic neuropathy. Neuropathies
49. 49. Macrovascular Complications Coronary artery disease Cerebrovascular disease Peripheral arterial disease
50. 50. Macrovascular Complications Macrovascular complications are due to atherosclerosis, if it is in Coronary blood vessels: angina and MI Cerebral blood vessels: Stroke Peripheral blood vessels: gangrene.
51. 51. Criteria for the Diagnosis of Diabetes A1C 6.5% OR Fasting plasma glucose (FPG) 126 mg/dL (7.0 mmol/L) OR 2-h plasma glucose 200 mg/dL (11.1 mmol/L) during an OGTT OR A random plasma glucose 200 mg/dL (11.1 mmol/L) ADA. I. Classification and Diagnosis. Diabetes Care 2014;37(suppl 1):S15; Table 2
52. 52. EXTRA SLIDES
53. 53. Websites http://www.cdc.gov/diabetes/consumer/index.ht m http://www.emedicinehealth.com/diabetes/articl e_em.htm#Diabetes%20Overview http://www.diabetes.org/
54. 54. Criteria for the Diagnosis of Diabetes A1C 6.5% The test should be performed in a laboratory using a method that is NGSP certified and standardized to the DCCT assay* Diabetes Control and Complications Trial (DCCT) National Glycohemoglobin Standardization Program(NGSP) *In the absence of unequivocal hyperglycemia, result should be confirmed by repeat testing. ADA. I. Classification and Diagnosis. Diabetes Care 2014;37(suppl 1):S15; Table 2
55. 55. Criteria for the Diagnosis of Diabetes Fasting plasma glucose (FPG) 126 mg/dL (7.0 mmol/L) Fasting is defined as no caloric intake for at least 8 h* *In the absence of unequivocal hyperglycemia, result should be confirmed by repeat testing. ADA. I. Classification and Diagnosis. Diabetes Care 2014;37(suppl 1):S15; Table 2
56. 56. Criteria for the Diagnosis of Diabetes 2-h plasma glucose 200 mg/dL (11.1 mmol/L) during an OGTT The test should be performed as described by the WHO, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water* *In the absence of unequivocal hyperglycemia, result should be confirmed by repeat testing. ADA. I. Classification and Diagnosis. Diabetes Care 2014;37(suppl 1):S15; Table 2
57. 57. Criteria for the Diagnosis of Diabetes In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose 200 mg/dL (11.1 mmol/L) ADA. I. Classification and Diagnosis. Diabetes Care 2014;37(suppl 1):S15; Table 2
58. 58. 70 Diagnostic Criteria Any one test should be confirmed with a second test, most often fasting plasma glucose (FPG). This criteria for diagnosis should be confirmed by repeating the test on a different day.
59. 59. 71