Types, classification, clinical features and treatment

Types,classification, pathogenesis, causes, diagnosis and treatment

1. Approach to DM Professor/ Mohammed Ahmed Bamashmos Professor of internal medicine and endocrinology Faculty of medicine Sanaa University

2. Defination Diabetes is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. The chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction, and failure of differentorgans , especially the eyes, kidneys, nerves, heart, and blood vessels.The degree of hyperglycemia (if any) may change over time, depending on the extent of the underlying disease process .A disease process may be present but may not have progressed far enough to cause hyperglycemia. The same disease process can cause impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) without fulfilling the criteria for the diagnosis of diabetes. In some individuals with diabetes, adequate glycemic control can be achieved with weight reduction, exercise, and/or oral glucose-lowering agents. These individuals therefore do not require insulin. Other individuals who have some residual insulin secretion but require exogenous insulin for adequate glycemic control can survive without it. Individuals with extensive β-cell destruction and therefore no residual insulin secretion require insulin for survival. The severity of the metabolic abnormality can progress, regress, or stay the same. Thus, the degree of hyperglycemia reflects the severity of the underlying metabolic process and its treatment more than the nature of the process itself.

3. classification

4. Diabetes can be classified into the following general categories: 1. Type 1 diabetes (due to autoimmune b-cell destruction, usually leading to ab- solute insulin deficiency, including latent autoimmune diabetes of adulthood) 2. Type 2 diabetes (due to a non-autoimmune progressive loss of adequate b-cell insulin secretion frequently on the background of insulin resistance and metabolic syndrome) 3. Specific types of diabetes due to other causes, e.g., monogenic diabetes syn - dromes (such as neonatal diabetes and maturity-onset diabetes of the young), diseases of the exocrine pancreas (such as cystic fibrosis and pancreatitis), and drug- or chemical-induced diabetes (such as with glucocorticoid use, in the treat- ment of HIV/AIDS, or after organ transplantation) 4. Gestational diabetes mellitus (diabetes diagnosed in the second or third tri- mester of pregnancy that was not clearly overt diabetes prior to gestation)

5. SYMPTOMS 1- Classic symptoms of hyperglycemia include polyuria, polydipsia, nocturia , blurred vision and, infrequently, weight loss. These symptoms are often noted only in retrospect, after a blood glucose value has been shown to be elevated. Polyuria occurs when the serum glucose concentration rises significantly above 180 mg/ dL (10 mmol /L), exceeding the renal threshold for glucose, which leads to increased urinary glucose excretion. Glycosuria causes osmotic diuresis ( ie , polyuria) and hypovolemia, which in turn can lead to polydipsia. Patients who replete their volume losses with concentrated sugar drinks, such as non-diet sodas, exacerbate their hyperglycemia and osmotic diuresis. 2- Acute complication as - Diabetic ketoacidosis ( 20% of patients with type 1diabetes) - Rarely adults with type 2 diabetes can present with a hyperosmolar hyperglycemic state, characterized by marked hyperglycemia without ketoacidosis, severe dehydration, and obtundation . Diabetic ketoacidosis (DKA) as the presenting symptom of type 2 diabetes is also uncommon in adults but may occur under certain circumstances (usually severe infection or other illness) and in non-Caucasian ethnic groups. 3- Chronic complication Among patients with type 2 diabetes in the United Kingdom Prospective Diabetes Study, 25% had retinopathy; 9%, neuropathy; and 8%, nephropathy at the time of diagnosis. 4- Asymptomatic ;in older studies, the typical patient with type 2 diabetes had diabetes for at least 4-7 years at the time of diagnosis. 5- Atypical presentation ; Presentation of diabetes in elderly is less classical. Index of suspicion has to be high as patients usually do not develop glycosuria (increased renal threshold) and polydipsia (impaired thirst mechanism). They may present with non-specific features (failure to thrive, falls, dizziness, confusion, nocturia , etc ) and Non Ketotic Hyperosmolar State (NKHS) . They may also present with infectious complications like malignant otitis externa, septicaemia , diabetic foot and complicated renal infections

6. Diagnosis 1- Is the patients has diabetes ; - If there is any symptom or sign suggest DM Order for one or more the following tests to diagnose DM 1- HbA1C. FBS , RBS ,GTT 2- Other tests to be ordered as needed ( serum insulin , C-peptide , autoantibodies , HOMA-IR, genes ) Interpretation of the results ;

7. Criteria for diagnosis

8. advantage and disadvantage of test

9. Which types of diabetes that patients has 1- Type 1 diabetes Clinical supports ; a- Age ; usually young but may present in middle or old as (LADA) b- Family history ; less frequent c- Duration of illness , short d- Onset is progressive and may present with acute complication e- Body weight ; normal - Laboratory support ; a-Assessment of beta cell function ; Method used to assess beta cells function 1- Serum insulin level ; Disadvantage ; a- It has short half life b- 30% undergo hepatic clearance c- Its measurement is interfered with exogenous insulin by RIA 2- C-peptide - Plasma C-peptide - Urine creatinine to C-peptide ratio Advantages ; a- Long half life b- No hepatic clearance c- No interference with exogenous insulin 3- HOMA-B-cell

10. B- presence of autoantibodies - types

11. importance ; - diagnosis - subtype of type 1 ;

12. - for staging

13. 2-Type 2 diabetes 1- Clinical supports a- Age ; usually middle and old but may present in children and adult as (type 2 diabetes of youth ) b- Family history ; more frequent c- Duration of illness , long d- Onset is slow progressive and may present with chronic complication e- Body weight ; usually obese - 2- Laboratory support ; A- assessment of IR B- Assessment of beta cell function ; 1- Serum insulin 2- Serum C-peptide level

14. 3-Latent autoimmune diabetes of adult(LADA) ; 1- Clinical support a- Age ; usually 45-70 years b-Family history ; more frequent c - Duration of illness , long d- Onset is slow progressive and may present with chronic complication e- Body weight ; usually normal 2- Laboratory support ; a- Assessment of beta cell function ; 1- Serum insulin ; low 2- Serum C-peptide level ; low b-The presence of autoantibodies ; positive

15. 4-Type 2 diabetes of youth 1- Clinical support ; a- Age ; 12-18 y b- Family history ; positive c- Onset ; slow , about is asymptomatic d- Duration ; long e- Over weight f- Ethenic variation g- Feature of insulin resistance ; as acanthosis negrecans , hypertension , POS , dyslipidemia h- History of GDM 2- Laboratory support ; a- Assessment of beta cell function ; 1- Serum insulin ; normal 2- Serum C- peptide ; normal b- No auto antibodies

16. 5-Ketosis prone type 2 DM 1-Sudden in onset 2-No obesity 3-Positive FH 4-May present with DKA 5-Absence of markers of autoimmunity 6-No insulin resistance 7-There is decrease in first phase insulin secretion

17. 6- MONOGENIC DIABETES A- neonatal B- MODY

18. 7-Diagnosis of GDM

19. TYPE 1 DM Defination ; Prevalence ; Pathogenesis ;

20. Natural history

21. Staging

22. Subtype of type 1 1- Acute 2- slowely progressive

23. diagnosis A- clinical B- laboratory 1- Presence of autoantibodies importance 2- assessment of beta cell function

24. Prevention

25. treatment 1- treatment target Blood glucose - FBS - RBS - HbA1C -

26. treatment types A- diet

27. Treatment type 1- insulin According to source A - human insulin ; - SHORT ACTING ; - soluble - intermediate acting - NBH - long acting ultralente B- insulin analogue - rapid acting - aspart - lispro - glargine

28. long acting ; - glargine - detemer

29. according to onset and duration

30. who the pancreas secreate insulin basal insulin secretion ( 1iu|hr ) its aim is to suppress glycogenolysis , lipolysis and proteolysis Meal related insulin secretion as following ( 4 iu before breakfast , 3iu before lunch , 6 iu before dinner , 2 iu at bed time snack ) PHASES OF INSULIN SECRETION In nondiabetic individuals, approximately 50% of the total daily insulin is secreted during basal periods, suppressing lipolysis, proteolysis, and glycogenolysis . The remainder of insulin secretion is postprandial. In response to a meal, there is a rapid and sizable release of preformed insulin from storage granules within the beta cell. This "first phase" of insulin secretion promotes peripheral utilization of the prandial nutrient load, suppresses hepatic glucose production, and limits postprandial glucose elevation. First-phase insulin secretion begins within 2 minutes of nutrient ingestion and continues for 10 to 15 minutes. The second phase of prandial insulin secretion follows, and is sustained until normoglycemia is restored. First-phase insulin secretion is often represented in clinical studies by the acute insulin response to an intravenous glucose bolus. While an intravenous glucose bolus is not equivalent to an oral mixed meal, it serves as a standardized beta-cell stimulus by which first-phase insulin secretion can be carefully compared among different subjects. Further, it demonstrates the sensitivity to and insulin response of the beta cell specifically to the glucose stimulus. It is this loss of beta-cell glucose sensitivity and responsiveness that declines early in the development of type 2 diabetes, even while responses to amino acid and other stimuli are preserved. Evidence of impaired first-phase insulin release can be seen in the  glucose tolerance test , demonstrated by a substantially elevated blood glucose level at 30 minutes, a marked drop by 60 minutes, and a steady climb back to baseline levels over the following hourly time points

31. dose of insulin ; - dose of insulin 0.5-1 iu /kg / day Higher amount is required during - puberty - pregnancy - medical illness half of the total dose is given as basal insulin and half as prandial Method ; 1- multidose regimen ;

32. drugs used in type 1 DM ; - Amylin analogues ; Mechanism of action ; -

33. Pramlintide is based on the naturally occurring b-cell peptide amylin and is approved for use in adults with type 1 diabetes. Clinical trials have demonstrated a modest reduction in A1C (0.3–0.4%) and modest weight loss (1 kg) with pramlintide 2- metformin 3- GLP1RA ; Liraglutide dose ; 1.8mg /day advantage ; - decrease HbA1C - decrease body weight - reduction in insulin dose 4- SGLT2I

34. Type 2 DM Definition ; This form of diabetes, which accounts for ∼90–95% of those with diabetes, previously referred to as non-insulin-dependent diabetes, type II diabetes, or adultonset diabetes, encompasses individuals who have insulin resistance and usually have relative (rather than absolute) insulin deficiency At least initially, and often throughout their lifetime, these individuals do not need insulin treatment to survive Pathogenesis ; 1- Insulin resistance 2- Decreased insulin secretion by beta cells 3- Increased glucose production by liver 4- Incretin hormones deficiency and resistance 5- Increased renal tubular reabsorption of glucose 6- Hyperglucogenemia 7- Amylin deficiency 8- Rule of CNS

35. 1- insulin resistance ; Defination ; Definition ; Insulin resistance (IR) is a physiological condition in which cells fail to respond to the normal actions of the hormone insulin. The body produces insulin, but the cells in the body become resistant to insulin and are unable to use it as effectively, leading to hyperglycemia. Beta cells in the pancreas subsequently increase their production of insulin, further contributing to hyperinsulinemia Causes ; rule of obesity in IR

36. site of insulin resistance ‘Sites ; a- Liver ; normally insulin suppress the hepatic glucose production , in case of insulin resistance the glucose production by liver is increased leadind to fasting hyperglycemia b- skeletal muscle ; its important for oxidation and storage of glucose as glycogen in insulin resistance thereis defect in both uptake and storage of glucose ; which is due to ; -defect in the upregulation of GLUT 4 - Increased FFA flux to the skeletal muscle leads to inhibition of muscle glucose uptake ( Randle hypothesis ) , FFA inhibit muscle glucose utilization by inhibiting phosphofructokinase leading to increased muscle glucose with decreased uptake – c- adipose tissue ; insulin resistance at adipose tissue leads to increased activity of enzyme lipoprotein lipase this leads to increase FFA production which in turn leads to - Insulin resistance at liver -Insulin resistance at skeletal muscle - Deposition in beta cells of pancrease leads to decreased insulin secretion

37. Sequale of IR

38. 2-Beta cells dysfunction ; Causes ;

39. 3-Incretin deficiency and resistance Incretins are a group of gastrointestinal hormones that cause an increase in the amount of insulin released from the beta cells of the islets of Langerhans after eating, before blood glucose levels become elevate d. They also slow the rate of absorption of nutrients into the blood stream by reducing gastric emptying and may directly reduce food intake. As expected, they also inhibit glucagon release from the alpha cells of the Islets of Langerhans. The two main candidate molecules that fulfill criteria for an incretin are glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (also known as: glucose-dependent insulinotropic polypeptide or GIP). Both GLP-1 and GIP are rapidly inactivated by the enzyme dipeptidyl peptidase-4 (DPP-4). 

40. 4- Rules of the kidney Rules of kidneys:Sodium-dependent glucose cotransporters (or sodium-glucose linked transporter, SGLT) are a family of glucose transporter found in the intestinal mucosa(enterocytes of the small intestine (SGLT1) and the proximal tubule of the nephron (SGLT2 in PCT and SGLT1 in DCT). They contribute to renal glucose reabsorption. In the kidneys, 100% of the filtered glucose in the glomerulus has to be reabsorbed along the nephron (98% in PCT, via SGLT2). In type 2 diabetes there is increased glucose reabsorption by the kidneys .

41. 5- Amylin hormone affect the rate of postprandial glucose appearance through a variety of mechanisms: — - CNS-mediated (hypothalamic) mediated anorectic effects todecrease food intake; mediated by stimulation of central amylin receptors, which are different from the receptors mediating the anorectic effects of GLP-1 — - slows gastric emptying due to activation of amylin receptors located in the nucleus accumbens & dorsal vagal complex of the CNS. This increases parasympathetic (vagal) stimulation of the GI tract, resulting in depressed GI motility & slowing of gastric emptying (Ryan et al, 2005) — -suppresses glucagon secretion from pancreatic α cells by a neuroendocrine pathway that is not well understood; this results in suppression of endogenous glucose output from the liver (Ryan et al, 2005)

42. 6-Rule of central nerve system In type 2 DM early morning dopamine level is increased this leads to increased hhypothalamic CNS activity  increased hepatic glucose production  increased lipolysis and FFA  increased lipogenesis and TG all these changes leads to glucose intolerance insulin resistance dyslipidemia CVD

43. 7-Increased glucagon secretion by pancrease glucagon had been discovered earlier than insulin, T2DM would well be defined as a state of hyperglucagonemia resulting in hyperglycemia due to glucagon-induced hepatic gluconeogenesis. Hyperglucagonemia is a characteristic of both T1DM and T2DM. Unger RH (1971,27 1974,28 197729) has discussed the role of pancreatic islet a and b cell inter-relationship in health and disease and the role of glucogon in diabetes. The normal reciprocal response of insulin and glucagon regulates postprandial glucose levels. Impaired a cell regulation leads to excessive glucagon release in the fasting and post-prandial state, with increase hepatic glucose production (HGP) and hyperglycaemia

44. Natural history

45. Staging

46. Diagnosis 1- clinical 2- investigation - to diagnose DM - for screening in asymptomatic

47. for DD - PRESENCE OF AUTOANTIBODIES - Assessment of IR ; IMPORTANCE ; - staging of type 2DM - -

48. For subtype of type 2 DM For chocing proper treatment 3- Assessment of beta cell function importance

49. Treatment treatment goal

50. treatment types ; 1- exercise

51. Drugs Who to choice

52. Types

53. Mechanism of action

54. Safty profile ;