Diabetes

A complete knowledge about Diabetes Mellitus and its types including Type 1 Diabetes, Type 2 diabetes, gestational diabetes, pancreatic diabetes & monogenic diabetes along with clinical features, investigations and management
It also includes diabetic emergencies like Diabetic Ketoacidosis, Hyperglycaemic hyperosmolar state & hypoglycaemia.
It contains long term complications like neuropathy, nephropathy and retinopathy.
Lastly Diabetic Insipidus is also discussed here.

1. Diabetes Simran Shaw Sakshi Jaiswal Sneha Biswas Subham Bhattacharya

2. DIABETES MELLITUS Definition:- Diabetes mellitus (DM) is a clinical syndrome characterised by increased blood glucose level (hyperglycaemia) due to absolute or relative deficiency of insulin, or both (i.e. defects in insulin secretion, insulin action, or both).

3. Epidemiology The incidence of diabetes is rising. Globally it is estimated that 415 million people had diabetes in 2015(10% of the world adult population) and this figure is expected to reach 642 million by 2040. This global pandemic principally involves type 2 diabetes. Globally, in 2015, diabetes caused 5 million deaths in those aged 20-79 years, and health-care expenditure attributed to diabetes was estimated to be at least 673 billion US dollars, or 12% of total health-care expenditure. Despite all the treatments now available, long –term complications of diabetes still cause significant morbidity and mortality.

4. Classification Based on aetiology. Type 1 diabetes mellitus (insulin deficiency, more than 90% of beta cells of pancreas are destroyed by an autoimmune response or idiopathic cause) Type 1A – immune-mediated Type 1B – idiopathic Type 2 diabetes mellitus (there is insulin resistance, impaired insulin secretion & increased glucose production) Gestational diabetes mellitus Other forms of diabetes Pancreatic Disease Monogenic Diabetes - MODY (Maturity onset diabetes of the young) - Neonatal Diabetes

5. How the blood glucose level is regulated? The blood glucose level is regulated by two hormones:- Insulin Glucagon

6. Role of Insulin

7. Role of Glucagon

8. Type 1 Pathology Genetic Susceptibility Environmental event Insulitis Activation of autoimmunity Immune attacks on beta-cells Diabetes Mellitus

9. Type 2 Pathology Insulin Resistance Hyperinsulinemia Genetics Acquired conditions (Obesity, Sedentary lifestyle, Aging) Compensated insulin resistance Normal glucose tolerance Impaired Glucose Tolerance Beta-cells unable to Sustain hypersecretion Beta-cell failure Type 2 Diabetes Increased hepatic g lucose output

10. Gestational Diabetes Mellitus Definition :- Gestational Diabetes is defined as diabetes with first onset or recognition during pregnancy. Pathology :- It develops due to an inability to increase insulin secretion adequately to compensate for pregnancy-induced insulin resistance, and most women can expect to return to normal glucose tolerance immediately after pregnancy.

11. Pancreatic Disease This is a relatively common disease but is often unrecognised cause of diabetes. It is related to alcoholism. FIBRO CALCULUS PANCREATIC DIABETES(FCPD) It is form of chronic calcific pancreatitis but not caused by excess alcohol. It is characterised by recurrent severe abdominal pain.

12. Monogenic Diabetes Monogenic disorders of the beta cell cause two diabetes subtypes:- MODY – It is defined as non-insulin requiring diabetes that develops under the age of 25 years in one family member. MODY is dominantly inherited. Patients with MODY have stable, mild hyperglycaemia with only a slightly elevated HbA1c. Neonatal diabetes – It presents in neonatal period. The presentation is usually of profound insulin deficiency with marked hyperglycaemia and DKA.

13. Clinical Features The main cardinal features are:- Polyphagia Glycosuria Polyuria Polydipsia Others are:- Dry mouth Nocturia Tiredness, fatigue, lethargy Weight loss Blurring of vision Nausea, Headache

14. Clinical Features Type 1 Type 2 Usually begins before the age of 40. Body type is normal to wasted i.e. Thin. The onset of symptoms may be abrupt developing over days or weeks. These patients usually develop diabetic ketoacidosis followed by symptom free interval. The plasma insulin levels are low or immeasurable. Usually begins after the age of 40. The typical patient is obese. The symptoms begins gradually, over a period of months to years. Do not develop ket0acidosis. They are susceptible to the syndrome of hyperosmolar hyperglycaemic state. The plasma insulin levels are normal to high.

15. Investigations Urine Glucose Test Testing the urine for glucose with dipsticks is a common screening procedure for detecting diabetes. Testing should be performed on urine passed 1-2 hours after a meal to maximise sensitivity. Glycosuria is detected but its not confirmatory of diabetes. Urine Ketone Test Ketone bodies can be identified by the nitroprusside reaction, which measures acetoacetate using either tablets or dipsticks. Ketonuria is therefore not pathognomic of diabetes but, if associated with glycosuria the diagnosis of diabetes is highly likely. Urine Protein Test Microalbuminuria is an important indicator of diabetic nephropathy . Contd..

16. Blood Testing Normal Prediabetes diabetes Fasting Plasma Glucose Post Prandial plasma glucose Random plasma glucose Glycated haemoglobin <100mg/dl >100 - <126mg/dl >=126mg/dl <140mg/dl >140 - <200mg/dl >=200mg/dl <140mg/dl >=200mg/dl Along with PPP <5.7% >5.7% - <6.5% >=6.5 %

17. Oral Glucose Tolerance Test At least 8 Hours fasting is required. The patient should rest for at least half an hour before starting the test, and refrain from smoking during the test. The patient can take plain water but avoid any other beverages. Take a fasting blood glucose sample before the test. A glucose load of 75g dissolved in 300ml of water is given orally. Blood samples are withdrawn at half hourly intervals for 2 hours and glucose levels are estimated. MODY:- Patients with MODY have high fasting glucose (usually >99 mg/dl ) but a normal post prandial response.

18. Management The aims are to improve symptoms of hyperglycaemia and minimise the risks of long-term microvascular and macrovascular complications. Treatment methods for diabetes include dietary/lifestyle modification, oral antidiabetic drugs and injected therapies. So the treatments are as follows:-

19. Management For TYPE 1 DIABETES MELLITUS It cannot be prevented by lifestyle modification. Life Long Insulin Therapy is the mainstay of treatment. Fluid replacement therapy. Electrolytes replacement.

20. Insulin Insulin Preparations :- Based on source:- Bovine, Porcine and human insulins. Based on time course of action:- Rapid, intermediate and long-acting insulins. Based on purity:- Conventional, Single peak and Monocomponent insulins. Insulin Analogues:- Insulin Lispro – Short-acting Insulin Aspart – Short-acting Insulin Glargine – Long-acting Insulin Detemir – Long-acting

21. Insulin regimes:- Conventional insulin therapy One or two injections a day of intermediate acting insulin( lente ) is administered, with/without the addition of small amounts of regular insulin. Multiple subcutaneous injections Administration of intermediate or long acting insulin in the evening as a single dose together with regular insulin prior to each meal. Continuous subcutaneous insulin infusion This involves the use of a small battery-driven pump as a means of mimicking the physiological basal plus prandial pattern of insulin secretion. The insulin pump is worn externally and connected to a butterfly needle, which is inserted into the anterior abdominal wall. Insulin

22. Complications of insulin Hypoglycaemia. Hypokalaemia. Local allergic reactions at the injection site. Local itching, lypodystrophy. Erythematous and indurated lesions Oedema. May develop systemic reactions. Fat atrophy/hypertrophy may develop at injection site. Formation of anti-insulin antibodies.

23. For TYPE 2 DIABETES MELLITUS It is preventable with some basic life modifying strategies. Patient Education. Self assessment of glycaemic control. Healthy eating. Weight Management. Exercise. Controlled alcohol consumption. Management

24. Drug treatment for the management of type 2 diabetes adapted from the American Diabetes Association, 2015 is:- Monotherapy Metformin If HbA1c target not achieved -3 months of monotherapy, proceed to two-drug combination. Dual therapy Metformin + Sulphonylurea(SU) Metformin + Thiazolidinedione(TZD) Metformin + DPP-4 inhibitor Metformin + Insulin If HbA1c target not achieved -3 months of dual therapy, proceed to three-drug combination.

25. Triple therapy Metformin + Sulphonylurea + TZD Metformin + TZD + DPP-4 inhibitor Metformin + SU + Insulin If HbA1c target not achieved after -3 months of triple therapy then patient on oral combination are move to injectables. Combination injectable therapy Metformin + Basal insulin + mealtime insulin/ GLP-1-RA.

26. Dietary Management Aims Achieve good glycaemic control Reduce hyperglycaemia & avoid hypoglycaemia Assist with weight Mx. Reduce complications Dietary constituents Carbohydrate : 50% Sucrose upto 10% Fat (total) : <35% Eat 1 portion (140g) oily fish once or twice weekly. Protein: 10-15% (do not exceed 1 g/kg body wt/day) Fruit vegetables : 5 portions daily

27. Management For GESTATIONAL DIABETES Screening: All women at high risk should have an OGTT at 24-28 weeks. Measurement of HbA1c and/or blood glucose at booking visit is usually recommended. Mx : Reduce intake of refined carbohydrate. Drugs:- Metformin, glibenclamide &/ insulin if necessary. Usually maternal glucose returns to normal after delivery.

28. Management For PANCREATIC DIABETES & FIBRO CALCULUS PANCREATIC DIABETES(FCPD) Insulin Replacement Therapy.

29. Management For MONOGENIC DIABETES MODY – These patients do not require treatment and do not develop diabetes complications. It is therefore important to identify these patients, to avoid unnecessary diabetes treatment and monitoring. Neonatal diabetes - 90% of patients are managed by ORAL SULPHONYLUREA treatment. Insulin can be given.

30. Diabetic Emergencies 1. Diabetic Ketoacidosis 2. Hyperglycaemic Hyperosmolar state 3 . Hypoglycaemia

31. Diabetic Ketoacidosis(DKA) Diabetic Ketoacidosis is a complication of type 1 DM. It is rare in type 2. Precipitating Factors :- Too little or no insulin intake. Infections. Severe Stress. Pathogenesis :- DKA results from insulin deficiency and glucagon excess.

32. Pathology Insulin Deficiency Glucagon Excess Hyperglycaemia Activation of lipolysis Increased plasma FFA concentration Increased hepatic FFA concentration Osmotic diuresis Volume depletion and dehydration Activation of carnitine acyltransferase Accelerated Ketogenesis +

33. Clinical Features of DKA Begins with anorexia, nausea and vomiting. Altered consciousness /frank coma in untreated cases. Signs of volume depletion and dehydration. Kussmaul’s breathing. Hyperkalemia. High anion gap Fruity odour of breath.

34. Investigations of DKA Urine examination shows glucose and ketones. Plasma glucose levels are raised. Plasma Ketone values are raised. Plasma potassium levels are normal or raised in the initial stages despite a total body deficit. The levels drop once the treatment is commenced. Diagnosis criteria for DKA. Blood glucose > 250 mg/dl, arterial pH<7.3, serum bicarbonate <15 mEq/L and moderate degree of ketonaemia and/or ketonuria.

35. Management of DKA Insulin Therapy DKA should be treated with regular insulin ,preferably IV to maintain the plasma glucose level around 200 mg/dl. Low-dose insulin schedule is given in which 8-10 units of regular insulin are infused IV each hour. Fluid Replacement Usual fluid deficit is 3-5 L and should be replaced IV. When plasma glucose level falls <250 mg/dl , 5% glucose saline solution is given. If drops below 150mg/dl despite 5% dextrose saline, 10% dextrose saline should be started instead of reducing the dose of insulin. Potassium Replacement After 3-4 hrs of tx when potassium level drops then supplements are given. Bicarbonate Therapy Only in patients with severe acidosis.

36. Hyperglycaemic hyperosmolar state This is a syndrome characterised by extreme dehydration resulting from a sustained hyperglycaemic diuresis under circumstances in which the patient is unable to drink sufficient water. The biochemical hallmark of the syndrome is extreme hyperglycaemia in the absence of ketoacidosis. Hyperosmolar non-ketotic diabetic coma is usually a complication of type 2 diabetes.

37. Clinical Features 1. Extreme dehydration 2. Alteration in the level of consciousness ranging from clouded sensorium to coma. 3. Convulsions 4. Transient hemiplegia 5. Bleeding and acute pancreatitis may accompany. Investigations Plasma glucose is markedly elevated, usually around 1000 mg/dl (range 600-2400 mg/dl). Serum osmolality is markedly raised. Diagnostic criteria for HHS include:- Plasma glucose more than 600 mg/dl, osmolality more than 330 mOsm /kg and absence of severe ketoacidosis.

38. Management Fluid replacement. The average fluid deficit is about 10L that should be corrected IV. Initially 2-3 L of isotonic saline should be given over 1-2 hours. Insulin Regular insulin should be given as a low-dose IV infusion, as for DKA. The goal is to keep the plasma glucose around 200 mg/dl. Potassium supplementation is required early. Lactic acidosis should be treated with IV sodium bicarbonate. Infections should be treated with antibiotics.

39. Hypoglycaemia It is a dangerous complication, and in the short run, more serious than hyperglycaemia. Prolonged hypoglycaemia may cause permanent brain damage. Hypoglycaemia commonly complicates therapy with insulin and oral hypoglycaemic drugs. Pathogenesis:- Protection against hypoglycaemia is normally provided by 2 mechanisms: Cessation of insulin release Secretion of counter-regulatory hormones So diabetic patients are vulnerable to hypoglycaemia due to 2 reasons: Insulin excess Counter-regulatory Failure.

40. Clinical Features Adrenergic symptoms Sweating Trembling Pounding heart Hunger Anxiety CNS manifestations Delirium Drowsiness Speech difficulty Inability to concentrate Incoordination Irritability, anger Non-specific Nausea Tiredness Headache

41. Management Oral carbohydrate- if recognised early may be corrected by ingestion of carbohydrate. IV dextrose Glucagon Prevention of recurrence – adjustments in dosage of oral hypoglycaemic drugs, changing the timing of insulin injections, adjustments in diet and physical activity.

42. Diabetic Complications Long-term complications of diabetes can be divided into Macrovascular Diseases and Microvascular Diseases . Macrovascular Diseases include:- Coronary Artery Disease Cerebrovascular Disease Peripheral Vascular Disease Microvascular Diseases include:- Diabetic Retinopathy Diabetic Nephropathy Diabetic Neuropathy Diabetic Foot

43. Cardiovascular Complications The main cardiovascular complications of diabetes are accelerated atherosclerosis and increased platelet adhesiveness. The atherosclerotic lesions can manifest in variety of ways:- Coronary artery diseases leading to ischemic heart disease, specially silent myocardial infarctions. Diabetes amplifies the effects of the other major cardiovascular risk factors: smoking, hypertension and dyslipidaemia.

44. Cerebrovascular Complications Cerebrovascular complications make diabetic patients 2–6 times more susceptible to a stroke event and this risk is magnified in younger individuals and in patients with hypertension and complications in other vascular beds. In addition, when patients with diabetes and hyperglycemia experience an acute ischemic stroke they are more likely to die or be severely disabled.

45. Peripheral Vascular Disease Peripheral arterial disease (PAD) is a complication of diabetes that happens when blood vessels in the legs become blocked or narrowed due to fat deposits. The result is reduced blood flow to the feet and legs ultimately resulting into Claudication and Ischaemia.

46. Diabetic Retinopathy Damage to retina caused by complication of type 1 DM. Risk Factors:- Long duration of dm. Poor glycaemic control Pregnancy Hypertension Smoking Obesity Hyperlipidaemia

47. Pathology Stage 1 – Diabetes without retinopathy Stage 2 – Non proliferative Diabetic Retinopathy Stage 3 – Proliferative Diabetic Retinopathy Stage 1 Hyperglycaemia Damage to the retinal pericytes(it surrounds the retinal vasculature and help in blood flow throughout the retina) Stage 2 (appears 16-25 yrs after diagnosis of diabetes) Pericytes are damaged Weakening of the capillary wall and increased blood flow Formation of micro aneurysms. Retinal pericytes damage Increased permeability leakage of protein Exudation yellow white flakes present on retina Phenomenon known as HARD EXUDATE Stage 2 lasts for many years before progress to stage 3. Since there is no new blood vessels formation in this stage hence the name.

48. Stage 3 Damage from stage 1 and 2 Tissue Ischaemia Retina produces vascular endothelial growth factor to compensate Ischaemia causes angiogenesis abnormal blood vessels formation. The clinical course of stage 3 is unpredictable and ultimately causing potential threatening and retinal detachment. Blurred vision Impairment of colour vision Floaters/ transparent and colourless spots and dark strings that float in the patient’s field of vision. Patches or streaks that block person’s vision Poor night vision Sudden and total loss of vision Cataract Clinical Features

49. Diagnosis Diabetic Retinopathy generally starts without any noticeable change in vision but ophthalmologist can detect signs. Common methods:- Dilated eye exam Fluorescein angiography Optical coherence tomography Vitreous haemorrhage. Retinal detachment Glaucoma Complications

50. Management Tight control of diabetes and hypertension. Diabetic retinopathy is treated by photo coagulation (stops the growth of new blood vessels and aims to prevent serious complication like retinal detachment and vitreal haemorrhage. Pars plana vitrectomy is utilised for the tx of non resolving vitreal haemorrhage and retinal detachment.

51. Diabetic Nephropathy It is a complication of Type 1 Diabetes Mellitus. It is rarely seen is type 2 diabetes mellitus. Risk Factors :- Poor glycaemic control Long duration of diabetes Presence of other microvascular complications Family history of diabetic nephropathy Pre-existing/family history of hypertension

52. Pathology:- The earliest functional abnormality in the diabetic kidney is renal hypertrophy associated with a raised glomerulus filtration rate. As the kidney becomes damaged by diabetes the afferent arteriole becomes vasodilated to a better extent than the efferent glomerular arteriole. This increases the intraglomerular filtration pressure, further damaging the glomerulus capillaries leading to hypertrophy of mesangium cells to secrete mesangial matrix material. This process eventually leads to glomerular sclerosis. Thickening of the basement membrane occurs with associated changes resulting in disruption of protein cross-linkages which normally make the membrane an effective filter. In consequence there is a progressive leak of large molecules into the urine.

53. Clinical Features:- Nephromegaly Increased GFR Microalbuminuria(30-300mg/dl) Macroalbuminuria(>300mg/dl) Renal oedema Glycosuria Diagnosis:- Screening of Albuminuria. Exclude all other causes of protienuria Past history of retinopathy

54. Management:- ACE inhibitors and angiotensin receptor blocker. Calcium channel blockers Beta blockers Alpha blockers Diuretics Low protein diet

55. Diabetic Neuropathy Diabetic Neuropathy is an uncommon condition in childhood and increases with age. This is more common in Type 1 diabetic patient. Pathology:- In this condition, the peripheral nerve damage is related to poor control of diabetes. Damage results from either metabolic disturbances with sorbitol and fructose accumulation in axons and schwann cells, or an occlusion of the nutrient vessels supplying nerves( vasa vasorum ).

56. Classification Polyneuropathy. Asymmetrical Neuropathy. Cranial Nerve Palsy. Autonomic Neuropathy. Present in 30% of all diabetics, but only 10% are symptomatic. Symptoms include such as a) Paraesthesia in the feet and rarely hands also known as Glove and Stocking Impairment . Polyneuropathy

57. b) Pain felt at anterior aspect of the lower limb(mostly worse at night). c) burning sensation in the soles of the feet. d) Structural changes occur in the feet due to the weakness and atrophy of interosseous muscles. Distal weakness and sensory loss is usual. This is much less common than polyneuropathy. Pain and weakness rapidly develops. Asymmetrical Neuropathy (Diabetic Amyotrophy)

58. The anterior thigh is sequentially affected with wasting of the quadriceps, loss of knee jerk and minimal sensory loss. This condition is due to anterior spinal root or plexus disease. An oculomotor palsy, usually without pain, may occur with pupillary sparing. 6 th and 7 th cranial nerve may also be involved in diabetes. Cranial nerve palsy

59. Some degree of autonomic neuropathy is present in patients with peripheral neuropathy. This predominates:- Pupil abnormalities Loss of sweating Orthostatic hypotension Resting tachycardia Gastroparesis and diarrhoea Hypotonic dilated bladder Impotence Autonomic Neuropathy

60. Management of Diabetic Neuropathy Improved control of diabetes is essential. Carbamazepine, gabapentin, tricyclic antidepressants or alpha-adrenergic blockers e.g. Phenoxybenzene, help control pain. Tx for Autonomic Neuropathy is to improve diabetic control and treat symptoms e.g. Pseudocortisone for BP control. Asymmetrical neuropathy usually spontaneously recovers. Prognosis for symmetric neuropathies is less certain.

61. Diabetic Foot The foot is a frequent site of complications in patient with diabetes. Any trauma in presence of neuropathy and/or peripheral vascular disease may lead to formation of :- Foot ulcers, and Charcot neuropathy Foot ulcers occur as a result of trauma which is unnoticeable to the patient, due to the loss of sensation in the foot, patient is unaware of the disruption of the epidermis, therefore these ulcers develop at the site of a plaque of callus skin, beneath which tissue necrosis occurs and eventually breaks through the surface. Ischemia accounts for a minority of foot ulcers in diabetic patients. Foot ulcers

62. Debridement of dead tissues. Prolong treatment with antibiotics is required, as infection can accelerate tissue necrosis and lead to gangrene, Pressure release using customised insoles, specialised orthotic footwear and sometimes total contact plaster cast or an immovable aircast boot. Surgery may be required to allow the ulcer to heal. An amputation may be required for severe secondary infection or gangrene. Management of foot ulcers

63. It is a progressive condition affecting the bones and joints of the foot, characterised by early inflammation, then joint dislocation, subluxation and pathological fractures of the foot of neuropathic patients. The mainstay of treatment is immobilisation by total contact plaster cast or aircast boot. Avoidance of weight bearing on the affected foot. In post-acute phase, there is consolidation and remodelling of fracture fragments, eventually resulting in a stable foot. Charcot Neuropathy Management

64. Diabetic Insipidus Definition:- This is an uncommon disorder characterised by Polyuria and Polydipsia caused by either deficiency of ADH or lack of response to ADH. Causes Cranial Nephrogenic Deficient production Of vasopressin by the hypothalamus Renal tubules are Unresponsive to vasopressin

65. Pathophysiology

66. Causes of Nephrogenic DI Drug-induced – lithium Gene mutation Any chronic kidney disease Electrolyte imbalance Causes of Cranial DI Idiopathic High stalk lesion Genetic defect Head injury Brain malformation Infections Surgery Radiotherapy

67. Clinical Features of Cranial DI Polyuria Polydipsia Dehydration Postural hypotension Investigations Blood test – hypernatraemia Urine osmolality test – low osmolality High serum osmolality WATER DEPRIVATION TEST

68. WATER DEPRIVATION TEST Step 1- Fluid deprivation (Avoid any fluid or food for 8 hours) Step 2- Measurement of urine osmolality Step 3- Desmopressin given Step 4- Again measure urine osmolality after 8 hours. Interpretation- After deprivation Nephrogenic di Cranial di After AdH LOW HIGH LOW LOW

69. Management of DI For Cranial DI Vasopressin analogue – des-amino-des- aspartate - arginine vasopressin. For Nephrogenic DI Polyuria is improved by thiazide diuretics and NSAIDs.

70. Book references Medicine Prep Manual for Undergraduates by K. George Mathew and Praveen Aggarwal. Davidson’s principles and practice of Medicine. Kumar and Clark’s Clinical Medicine. Neurology and Neurosurgery illustrated by Kenneth W Lindsay, Ian Bone and Geraint Fuller. Essentials of Medical Pharmacology by KD Tripathi.

71. Thank You