Diabetes mellitus and it's complications pathology for MBBS/BDS

Diabetes mellitus and it's complications for pathology for MBBS /BDS second year, I have tried my best to explain the disease and it's complications

1. DIABETES MELLITUS AND ITS COMPLICATIONS Submitted by: Vipin(BDS 2 nd yr) Submitted to: Dr Shalini Rana

2. DIABETES MELLITUS Diabetes Mellitus represents a heterogeneous group of disorders that have hyperglycemia as common feature with disturbance in carbohydrate, protein and fat metabolism results from Defect in insulin secretion Defect in insulin action Or both

3. Worldwide estimation of adults with diabetes

4. Normal insulin metabolism Tyrosine kinase Tyrosine kinase

5. Insulin is a major anabolic hormone and necessary for:- Transmembrane transport of glucose and amino acid Glycogen formation in liver and skeletal muscle Conversion of glucose into triglyceride Nucleic acid & protein synthesis

6. SYMPTOMS POLYPHAGIA GLUCOSUREA POLYUREA POLYDIPSIA

7. Classification Type 1 diabetes previously called insulin dependent DM or juvenile-onset diabetes Accounts for 5-10% of all cases There are two subgroups Type 1 A (autoimmune destruction of B cells) Type 1 B (severe insulin deficiency) Type 2 diabetes previously called non insulin dependent or adult-onset DM Accounts for 80% of all the cases

8. diabetes due to absolute deficiency of insulin diabetes due to insulin resistance and inadequate compensatory insulin secretory response

9. Classification Important: it should be stressed that although two major types have different pathogenetic mechanism and metabolic characteristics, the long term complications in blood vessel, kidney, eyes, and nerves occur in both type

10. Pathogenesis of type 1 DM This form of diabetes results from destruction of B-cells mass, leading to absolute insulin deficiency Type 1 A is immune-mediated Type 1 B remains idiopathic Three interlocking mechanism are responsible for the islet cell destruction Genetic susceptibility Autoimmunity Environmental insult

11. Genetic susceptibility Type 1A DM involves inheritance of multiple genes to confer susceptibility to the disorder About half the cases with genetic predispositions to type 1A DM have the susceptibility gene located in he HLA region of chromosome 6(MHC class II region ), particularly HLA DR3,HLA DR4 and HLA DQ locus It has been observed in identical twins that one twin has type 1A DM, there is about 50% chance of second twin developing it, but not all this means that some additional modifying factors are involved in development of DM in these cases.

12. Autoimmunity i) Presence of islet cell antibodies against GAD (glutamic acid decarboxylase), insulin etc. ii) Occurrence of lymphocytic infiltrate in and around the pancreatic islets termed insulitis . It chiefly consists of CD8+ T lymphocytes with variable number of CD4+ T lymphocytes and macrophages. iii) Selective destruction of B -cells while other islet cell remain unaffected since this is mediated by T-cell mediated cytotoxicity or by apoptosis. v) Association of type 1A DM with other autoimmune diseases in about 10-20% cases such as Graves’ disease, Addison’s disease, Hashimoto’s thyroiditis, pernicious anaemia . vi) Remission of type 1A DM in response to immunosuppressive therapy such as administration of cyclosporine A.

13. Environmental factors Certain viral and dietary proteins share antigenic properties with human cell surface proteins and trigger the immune attack on B-cells by a process of molecular mimicry . These factors include the following: i) Certain viral infections preceding the onset of disease e.g. mumps, measles, coxsackie B virus, cytomegalovirus and infectious mononucleosis. ii) Experimental induction of type 1A DM with certain chemicals has been possible e.g. alloxan, streptozotocin and pentamidine . Iii) Geographic and seasonal variations in its incidence suggest some common environmental factors

14. PATHOGENESIS OF TYPE 2 DM The basic metabolic defect in type 2 DM is either a delayed insulin secretion relative to glucose load (impaired insulin secretion), or the peripheral tissues are unable to respond to insulin (insulin resistance). It is a heterogeneous disorder with a more complex etiology and is far more common than type 1, but much less is known about its pathogenesis A number of factors have been implicated though, but HLA association and autoimmune phenomena are not implicated

15. Genetic factor Constitutional factors Insulin resistance Impaired insulin secretion

16. 1. Genetic factors . Genetic component has a stronger basis for type 2 DM than type 1A DM. i) There is approximately 80% chance of developing diabetes in the other identical twin if one twin has the disease. 2 . Constitutional factors . Certain environmental factors such as obesity, hypertension, and level of physical activity play contributory role and modulate the phenotyping of the disease.

17. 3. Insulin resistance. One of the most prominent metabolic features of type 2 DM is the lack of responsiveness of peripheral tissues to insulin, especially of the skeletal muscle and liver. i) Resistance to action of insulin impairs glucose utilization and hence hyperglycemia. ii) There is increased hepatic synthesis of glucose. iii) Hyperglycemia in obesity is related to high levels of free fatty acids and cytokines (e.g. TNF-a and adiponectin) affect peripheral tissue sensitivity to respond to insulin

18. 4. Impaired insulin secretion. In type 2 DM There is failure of B -cell function to secrete adequate insulin However, following possibilities are proposed: Islet amyloid polypeptide (amylin) which forms fibrillar protein deposits in pancreatic islets Metabolic environment of chronic hyperglycaemia surrounding the islets (glucose toxicity) may paradoxically impair islet cell function. Elevated free fatty acid levels (lipotoxicity)

19. Morphological features of diabetes mellitus Morphological features in islets have been demonstrated in both types of diabetes, through the changes are more distinctive in Type 1 DM Insulitis Islet cell mass Amyloidosis B –cell degranulation

20. Insulitis

21. 1. Insulitis: In type 1 DM , characteristically, in early stage there is lymphocytic infiltrate(mainly by T cells), which may be accompanied by a few macrophages and polymorphs. Diabetic infants born to diabetic mothers, however, have eosinophilic infiltrate in the islets. In type 2 DM , there is no significant leucocytic infiltrate in the islets but there is variable degree of fibrous tissue in the islets.

22. ISLET CELL MASS

23. 2. Islet cell mass: In type 1 DM , as the disease becomes chronic there is progressive depletion of B-cell mass, eventually resulting in total loss of pancreatic B-cells and its hyalinisation. In type 2 DM , B-cell mass is either normal or mildly reduced. Infants of diabetic mothers, however, have hyperplasia and hypertrophy of

24. 3. Amyloidosis

25. 3. Amyloidosis In type 1 DM , deposits of amyloid around islets are absent. In type 2 DM , characteristically chronic long-standing cases show deposition of amyloid material, amylin, around the capillaries of the islets causing compression and atrophy of islet tissue

26. 4. B-cell degranulation: In type 1 DM , EM shows degranulation of remaining B-cells of islets. In type 2 DM , no such change is observed

27. Clinical features Type 1 DM: i) Patients of type 1 DM usually manifest at early age, generally below the age of 35. ii) The onset of symptoms is often abrupt. iii) At presentation, these patients have polyuria, polydipsia and polyphagia. iv) The patients are not obese but have generally progressive loss of weight. v) These patients are prone to develop metabolic complications such as ketoacidosis and hypoglycaemic episodes.

28. Type 2 DM: i) This form of diabetes generally manifests in middle life or beyond, usually above the age of 40. ii) The onset of symptoms in type 2 DM is slow and insidious. iii) Generally, the patient is asymptomatic when the diagnosis is made on the basis of glucosuria or hyperglycemia during physical examination, or may present with polyuria and polydipsia. iv) The patients are frequently obese and have unexplained weakness and loss of weight. v) Metabolic complications such as ketoacidosis are infrequent.

29. Complications of diabetes 1.Acute metabolic complications: includes diabetic ketoacidosis, hyperosmolar nonketotic coma and hypoglycemia Late systemic complications: these are atherosclerosis, diabetic meaningiopathy, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy and infection

30. Pathogeneis 1. Non-enzymatic protein glycosylation: The free amino group of various body proteins binds by non-enzymatic mechanism to glucose; this process is called glycosylation 2. Polyol pathway mechanism: This mechanism is responsible for producing lesions in the aorta, lens of the eye, kidney and peripheral nerves. These tissues have an enzyme, aldose reductase, that reacts with glucose to form sorbitol and fructose in the cells of the hyperglycemic patient 3. Excessive oxygen free radicals: In hyperglycemia, there is increased production of reactive oxygen free radicals from mitochondrial oxidative phosphorylation which may damage various target cells in diabetes.

31. ACUTE METABOLIC COMPLICATIONS 1. DIABETIC KETOACIDOSIS (DKA ) Severe lack of insulin causes lipolysis in the adipose tissues, resulting in release of free fatty acids into the plasma. These free fatty acids are taken up by the liver and oxidised through acetyl coenzyme-A to ketone bodies Ketone bodies can be utilised by the muscles and other tissues, ketonaemia and ketonuria occur.

32. 2. HYPEROSMOLAR HYPERGLYCAEMIC NONKETOTIC COMA (HHS) It is caused by severe dehydration resulting from sustained hyperglycemic dieresis. The loss of glucose in urine is so intense that the patient is unable to drink sufficient water to maintain urinary fluid loss. Acidosis are absent but prominent central nervous signs are present. Blood sugar is extremely high and plasma osmolality is high. Thrombotic and bleeding complications are frequent due to high viscosity of blood. The mortality rate in hyperosmolar nonketotic coma is high.

33. 3. HYPOGLYCAEMIA It may result from excessive administration of insulin, missing a meal, or due to stress. Hypoglycaemic episodes are harmful as they produce permanent brain damage, or may result in worsening of diabetic control and rebound hyperglycaemia , so called Somogyi’s effect .

34. Late systemic complications A number of systemic complications may develop after a period of 15-20 years in either type of diabetes. Late complications are largely responsible for morbidity and premature mortality in diabetes mellitus.

35. Atherosclerosis Consequently, atherosclerotic lesions appear earlier than in the general population, are more extensive, and are more often associated with complicated plaques such as ulceration, calcification and thrombosis . Suggested factors are hyperlipidaemia, reduced HDL levels, nonenzymatic glycosylation, increased platelet adhesiveness, obesity and associated hypertension in diabetes . The possible ill-effects of accelerated atherosclerosis in diabetes are early onset of coronary artery disease, silent myocardial infarction, cerebral stroke and gangrene of the toes and feet.

36. Diabetic microangiopathy Microangiopathy of diabetes is characterized by basement membrane thickening of small blood vessels and capillaries of different organs and tissues Similar type of basement membrane-like material is also deposited in nonvascular tissues such as peripheral nerves, renal tubules and Bowman’s capsule. The pathogenesis of diabetic microangiopathy as well as of peripheral neuropathy in diabetics is believed to be due to recurrent hyperglycemia that causes increased glycosylation of haemoglobin and other proteins (e.g. collagen and basement membrane material) resulting in thickening of basement membrane.

37. Diabetic nephropathy End-stage kidney with renal failure accounts for deaths in more than 10% of all diabetics. A variety of clinical syndromes are associated with diabetic nephropathy that includes asymptomatic proteinuria, nephrotic syndrome, progressive renal failure and hypertension . Cardiovascular disease is 40 times more common in patients of end-stage renal disease in diabetes mellitus than in non-diabetics

38. Diffuse glomerulosclerosis Nodular glomerulosclerosis

39. Diabetic Neuropathy Diabetic neuropathy may affect all parts of the nervous system but symmetric peripheral neuropathy is most characteristic. The basic pathologic changes are segmental demyelization, Schwann cell injury and axonal damage. The pathogenesis of neuropathy is not clear but it may be related to diffuse microangiopathy or may be due to accumulation of sorbitol and fructose as a result of hyperglycemia , leading to deficiency of myoinositol .

40. Diabetic Retinopathy Diabetic retinopathy is an important cause of blindness. It is related to the degree and duration of glycaemic control. The condition develops in more than 60% of diabetics 1520 years after the onset of disease, and in about 2% of diabetics causes blindness. Other ocular complications of diabetes include glaucoma, cataract and corneal disease. Women are more prone to diabetes as well as diabetic retinopathy. Diabetic retinopathy is directly correlated with Kimmelstiel-Wilson nephropathy

41. Infections Diabetics have enhanced susceptibility to various infections such as tuberculosis, pneumonias, pyelonephritis, otitis, carbuncles and diabetic ulcers. This could be due to various factors such as impaired leucocyte functions, reduced cellular immunity, poor blood supply due to vascular involvement and hyperglycaemia

42. DIAGNOSIS Hyperglycemia remains the fundamental basis for the diagnosis of diabetes mellitus In symptomatic cases can be confirmed by finding glucosuria and a random plasma glucose concentration above 200 mg/dl. The problem arises in asymptomatic patients who have normal fasting glucose level in the plasma but are suspected to have diabetes on other grounds and are thus subjected to oral glucose tolerance test(GTT) These subjects are said to have chemical diabetes

43. Diagnosis can be done by following method Urine testing Single blood sugar estimation Screening test by fassting glucose Oral GTT Other tests

44. Urine testing Glucosuria Benedict’s qualitative test Renal glucosuria Alimentary (lag storage) glucosuria Ketonurea Rothera’s test (nitroprusside reaction)

45. Benedicts qualitative test It detects any reducing substance in the urine and is not specific for glucose. It is dipstick method based on enzyme-coated paper strip which turns purple when dipped in urine containing glucose. The main disadvantage of relying on urinary glucose test alone is the individual variation in renal threshold.

46. Renal glucosuria After diabetes, the next most common cause of glucosuria is the reduced renal threshold for glucose. In such cases although the blood glucose level is below 180 mg/dl but glucose still appears regularly and consistently in the urine due to lowered renal threshold Renal glucosuria is a benign condition unrelated to diabetes and runs in families and may occur temporarily in pregnancy without symptoms of diabetes.

47. Alimentary glucosuria A rapid and transitory rise in blood glucose level above the normal renal threshold may occur in some individuals after a meal. During this period, glucosuria is present. This type of response to meal is called ‘lag storage curve’ or more appropriately ‘alimentary glucosuria’. A characteristic feature is that unusually high blood glucose level returns to normal 2 hours after meal.

48. Ketonuria Tests for ketone bodies in the urine are required for assessing the severity of diabetes and not for diagnosis of diabetes. if both glucosuria and ketonuria are present, diagnosis of diabetes is almost certain. Rothera’s test (nitroprusside reaction) and strip test are conveniently performed for detection of ketonuria. Besides uncontrolled diabetes, ketonuria may appear in individuals with prolonged vomiting, fasting state or exercising for long periods.

49. Single blood sugar estimation For diagnosis of diabetes, blood sugar determinations are absolutely necessary. Folin-Wu method of measurement of all reducing substances in the blood including glucose is now obsolete. Currently used are O-toluidine, SomogyiNelson and glucose oxidase methods. A fasting plasma glucose value above 126 mg/dl (>7 mmol/L) is certainly indicative of diabetes. In other cases, oral GTT is performed.

50. Screening test by fasting glucose test It is recommended that all individuals above 45 years of age must undergo screening fasting glucose test every 3-years, and relatively earlier if the person is overweight or at risk because of the following reasons: i) Many of the cases meeting the current criteria of DM are asymptomatic and do not know that they have the disorder. ii) Studies have shown that type 2 DM may be present for about 10 years before symptomatic disease appears. iii) About half the cases of type 2 DM have some diabetes related complication at the time of diagnosis. iv) The course of disease is favorably altered with treatment.

51. Oral GTT Oral GTT is performed principally for patients with borderline fasting plasma glucose value (i.e. between 100-140 mg/dl The patient who is scheduled for oral GTT is instructed to eat a high carbohydrate diet for at least 3 days prior to the test and come after an overnight fast on the day of the test A fasting blood sugar sample is first drawn. Then 75 gm of glucose dissolved in 300 ml of water is given. Blood and urine specimen are collected at half hourly intervals for at least 2 hour

52. Normal cut off value for fasting blood glucose level is considered as 100 mg/dl. Cases with fasting blood glucose value in range of 100125 mg/dl are considered as impaired fasting glucose tolerance (IGT During pregnancy, a case of IGT is treated as a diabetic. Individuals with fasting value of plasma glucose higher than 126 mg/dl and 2-hour value after 75 gm oral glucose higher than 200 mg/dl are labeled as diabetics In symptomatic case, the random blood glucose value above 200 mg/dl is diagnosed as diabetes mellitus.

53. Thank you