2. Learning objectives 1.Discuss the pathophysiology and pathogenesis of diabetes mellitus 2.Describe the symptoms and clinical presentation of diabetes mellitus 3.Enumerate the investigations to diagnose diabetes mellitus and the complications of diabetes mellitus.

3. In simple words, Diabetes mellitus is a disease in which the body either doesn't produce enough insulin or doesn’t properly use insulin or both. This causes glucose levels to rise too high in the blood (hyperglycemia) and also leads to abnormalities in lipid and protein metabolism. INTRODUCTION

4. Defining diabetes ? Diabetes is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both.

5. Epidemiology of DM (International Diabetes federation 2012) Global Prevalence: 371 million people (8.3 % of world population) Middle East and North Africa: 34 million (10.9 % of the people in this region) Saudi Arabia: 3.4 million (Out of a total of about 26.5 million)

6. History of Diabetes Mellitus An Egyptian manuscript from 1500 BC described a disease mentioning “too great emptying of the urine. The term "diabetes" or "to pass through" was first used in 230 BCE by the Greek Appollonius Of Memphis The first complete description of diabetes was given by the Ancient Greek physician Aretaeus of Cappadocia (1st century AD), who gave the disease the name “diabetes” because he noted the excessive amount of urine which is passed through the kidneys

7. History of Diabetes Mellitus In Arabia, Ibn Sīnā (980–1037) provided a detailed account on diabetes mellitus

9. History of Diabetes Mellitus The term "mellitus" or "from honey" was added by the Britain John Rolle in the late 1700s to separate the condition from other causes of increased urination In 1776 the English physician Matthew Dobson confirmed that the sweet taste comes from an excess of a kind of sugar in the urine and blood

10. History of Diabetes Mellitus Joseph von Mering and Oskar Minkowski in 1889 found that dogs whose pancreas was removed developed all the signs and symptoms of diabetes Sir Edward Albert Sharpey-Schafer in 1910 suggested that people with diabetes were deficient in a single chemical produced by the pancreas. He named this insulin, ( Latin: insula meaning island), because of the islets of Langerhans which produce insulin In 1921, Frederick Grant Banting and Charles Herbert Best confirmed the existence of and discovered Insulin at Toronto, Canada BantingBest Marjorie

11. Insulin is the main hormone that regulates uptake of glucose from the blood into cells (mainly muscle and fat cells). PATHOGENESIS OF DIABETES

12. Insulin is secreted into the blood by beta cells (β-cells) of the Islets of Langerhans in the pancreas. This occurs in response to rising levels of blood glucose, such as after a meal. Insulin is used by the body's cells to take up glucose from the blood for use as fuel. PATHOGENESIS OF DIABETES

13. Insulin Secretion In Response To Elevations In Blood Glucose Levels After Meals

14. Insulin is also the main hormone that signals the conversion of glucose to glycogen (Glycogenesis) for storage in the liver and muscle cells. On the other hand, lowered glucose levels lead to reduced release of insulin from the beta cells and to the conversion of glycogen to glucose (glycogenolysis) when glucose levels fall. PATHOGENESIS OF DIABETES

15. 3 Muscle Fat 3 Muscle Fat 2 Liver Glycogenolysis 2 Liver Glycogenolysis 1 Pancreas 1 Pancreas 4 GIT 4 GIT Plasma glucose INSULIN DEFICIENCY ABSORPTION

16. What would happen if the amount of insulin available is insufficient ? Insulin will not have its usual effect and glucose will not be absorbed properly by body cells. What would happen if the body’s cells respond poorly to the effects of insulin ?(insulin resistance) Once again, Insulin will not have its usual effect and glucose will not be absorbed properly by body cells. The net effect is persistent high levels of blood glucose, poor protein synthesis, and other metabolic abnormalities. PATHOGENESIS OF DIABETES

17. INSULIN RESISTANCE Pancreas trying hard to increase insulin production to meet the demands

18. DIABETES MELLITUS PRE CLINICAL DM

19. HOMEOSTASISCLINICAL MOLECULARENVIRONMENT GENETISSUE PANCREATIC OVERLOAD INSULIN FAILURE

20. HOMEOSTASISCLINICAL MOLECULARENVIRONMENT GENETISSUE PANCREATIC OVERLOAD INSULIN FAILURE Usual Time of diagnosis of DM

21. The common types of Diabetes mellitus are: Type 1 DM: which results from the failure of beta cells to produce insulin. This form was previously called insulin-dependent diabetes mellitus (IDDM) but this term SHOULD NOT BE USED. Type 2 DM: results from insulin resistance, in which cells fail to use insulin properly, sometimes combined with a relative insulin deficiency. This form was previously called non insulin-dependent diabetes mellitus (NIDDM) but this term SHOULD NOT BE USED. Gestational diabetes: occurs in pregnant women, who have never had diabetes before, develop high blood glucose levels during pregnancy. This condition may precede development of type 2 DM. TYPES OF DIABETES

22. Other forms of diabetes mellitus include 1)DM due to genetic defects of beta cell function affecting insulin production ( also called monogenic diabetes or MODY (Maturity onset Diabetes of the Young)) 2)Diseases of the Pancreas (eg Cystic fibrosis-related diabetes, Pancreatitis, Viral infections) 3)Steroid induced diabetes induced by high doses of glucocorticoids (Secondary DM) TYPES OF DIABETES

23. THE CLASSIFICATION OF DM Diagnosis and Classification of Diabetes Mellitus. Diabetes Care, Volume 36, Supplement 1, January 2013 : S70

24. Copyright © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins Types of Diabetes Mellitus Type 1: pancreatic beta cell destruction predominantly by an autoimmune process Type 2: a combination of beta cell dysfunction and insulin resistance Other –Genetic defects in insulin production –Genetic defects in insulin action –Diabetes secondary to other diseases –Drug interactions Gestational diabetes mellitus

25. DM classification at diagnosis T1 DM Majority T2DM Others

26. Type 2 diabetes is the most common form. This condition usually appears in middle-aged adults; but nowadays adolescents and young adults are developing type 2 diabetes at an increasing rate. It develops when the body cells are unable to efficiently use the insulin (insulin resistance) usually due to problems with insulin receptors, post receptor mechanisms, elevated plasma levels of free fatty acids and proinflammatory cytokines. The pancreas initially tries to make more insulin (hyperinsulinemia) in order to overcome insulin resistance, but eventually there is beta cell exhaustion and failure and then the beta cells don’t make enough insulin leading to relative or absolute insulin deficiency (especially if Type 2 DM has been present for a long time) FEATURES OF TYPE 2 DM

27. Type 2 DM is characterized by a combination of insulin resistance and inadequate insulin secretion by pancreatic beta cells Insulin resistance, leads to decreased glucose transport into muscle cells, elevated hepatic glucose production, and increased breakdown of fat. Also there is evidence that the reciprocal relationship between the glucagon- secreting alpha cell and the insulin-secreting beta cell is lost, leading to hyperglucagonemia which may worsen hyperglycemia. Susceptibility to type 2 diabetes is also be affected by genetic variants and a number of genetic variants are associated with beta-cell dysfunction and insulin resistance As T2DM progresses postprandial blood glucose levels increase first. Eventually, fasting hyperglycemia develops as suppression of hepatic gluconeogenesis fails.

28. Type 2 DM

29. Copyright © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins Pathogenesis of Type 2 Diabetes

30. Beta cell level Peripheral tissue level

33. There is a well established preclinical asymptomatic period for diabetes The duration varies from 6 to 12 years but the exact course is unknown Cardiovascular damage in this period is equal to established diabetes Diagnosis in this period is crucial for macrovascular and microvascular risk reduction There is a well established preclinical asymptomatic period for diabetes The duration varies from 6 to 12 years but the exact course is unknown Cardiovascular damage in this period is equal to established diabetes Diagnosis in this period is crucial for macrovascular and microvascular risk reduction

34. A B C D E F Am Fam Physician. 2004 Aug 1;70(3):489-500.

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41. Type 2 DM ++ Insulin resistance Abnormal beta cell function Normal Beta cell function Normal Beta cell function Compensatory hyperinsulinemia Euglycemia Relative Insulin deficiency Relative Insulin deficiency Hyperglycemia T2DM Genes Lifestyle Gluco-toxicity Lipotoxicity Others Genes Lifestyle Gluco-toxicity Lipotoxicity Others Genes Lifestyle Genes Lifestyle Genesis of T2DM

42. Insulin resistance Beta cell failure C Macro-vascular disease 1.Heart 2.Brain 3.Limbs C Macro-vascular disease 1.Heart 2.Brain 3.Limbs B Micro-vascular disease 1.Eyes 2.Kidney 3.Nerves B Micro-vascular disease 1.Eyes 2.Kidney 3.Nerves A HYPERGLYCEMIA T2DM at a glance + Obesity Smoking Hypertension Dyslipidemia Other factors Obesity Smoking Hypertension Dyslipidemia Other factors

43. Pathogenesis of Type2 DM Genetic factors Acquired (environmental) factors. – Obesity – Inactivity Obesity: central obesity, decrease adiponectin release

44. Insulin Resistance and the Metabolic Syndrome. Hyperglycemia Intra-abdominal obesity, high levels of plasma triglycerides and low levels of high density lipoproteins (HDLs), hypertension, systemic inflammation (as detected by C-reactive protein[CRP] and other mediators), abnormal Fibrinolysis, abnormal function of the vascular endothelium, and Macro-vascular disease (coronary artery, cerebrovascular, andperipheral arterial disease).

46. TYPE 1 DM

47. Type 1 diabetes usually occurs in children and young adults. This condition results from autoimmune destruction of insulin- producing beta cells of the pancreas In Type 1 DM, the beta cells of the pancreas produce little or no insulin and this leads to absolute insulin deficiency Also, in Type 1 DM the C-peptide levels, which reflect endogenous insulin production, are low FEATURES OF TYPE 1 DM

48. Type 1 Diabetes Mellitus Type 1A immune mediated Diabetes – Against β cell (GAD) – Against insulin (IAAs) Honeymoon Period: short period of β cell regeneration Idiopathic type 1B

49. Autoimmunity is the major factor in the pathophysiology of type 1 DM. Approximately 85% of type 1 DM patients have circulating islet cell antibodies. The most commonly found islet cell antibodies are those directed against glutamic acid decarboxylase (GAD) which is an enzyme found within pancreatic beta cells Moreover, in a genetically susceptible individual, a viral infection may stimulate the production of antibodies against a viral protein that trigger an autoimmune response against antigenically similar beta cell molecules. There is lymphocytic infiltration and destruction of pancreatic beta cells. FEATURES OF TYPE 1 DM

50. As the number of beta-cells (beta cell mass) decreases, insulin secretion decreases until the available insulin no longer is adequate to maintain normal blood glucose levels. Once about 80-90% of the beta cells are destroyed, hyperglycemia develops and diabetes manifests. Therefore these patients need exogenous insulin to prevent the consequences of Insulin deficiency (such as ketosis) and to normalize lipid and protein metabolism. FEATURES OF TYPE 1 DM TYPE 1 DM PATIENTS MUST BE TREATED WITH EXOGENOUS INSULIN

51. FEATURES OF TYPE 1 DM

53. http://www.youtube.com/watch?list=UUXFFcY oTl244oguj2NAisiw&feature=player_detailpag e&v=jHRfDTqPzj4 VIDEO ANIMATION OF PATHOGENESIS AND TYPES OF DIABETES MELLITUS

54. THE DIAGNOSIS OF DIABETES MELLITUS

55. What is diabetes ? Diabetes is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both.

56. What is diabetes ? Diabetes is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both.

57. What is diabetes ? Diabetes is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both.

58. What is diabetes ? Diabetes is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both.

59. What is diabetes ? Diabetes is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both.

60. What is diabetes ? Diabetes is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both.

62. 62 WHEN IS DM SUSPECTED Non classic presentations Infection Skin (carbuncles) Urinary tract infection Ear infection (fungal) No Infection Pruritus Fatigue Visual symptoms Sensory symptoms Delayed healing Classic presentation Polyuria Polydipsia Polyphagia Weight loss Hyperglycemic crisis Clinical clues to DM

63. Diagnosis of DM Classification Proving hyperglycemia 1 1 2 2

64. NORMALABNORMAL PRE DIABETES DIABETES Copyright Aftab SA RANGE OF GLYCEMIA

65. DIAGNOSTIC CRITERIA FOR DM DIABETES CARE, VOLUME 36, SUPPLEMENT 1, JANUARY 2013

66. 66 Pre diabetes: diagnostic criteria Prediabetes FPG 100 - 125 mg/dL (5.5 - 6.9 mmol/L) 2hPP 140 - 199 mg/dL ( 7.8 - 11 mmol/L) HbA1c 5.7 - 6.4 % Prediabetes FPG 100 - 125 mg/dL (5.5 - 6.9 mmol/L) 2hPP 140 - 199 mg/dL ( 7.8 - 11 mmol/L) HbA1c 5.7 - 6.4 %

67. Diagnosis of Gestational Diabetes Mellitus (GDM)

68. Clinical Features, Complications and Investigations in a Diabetes patient

69. The main symptoms of undiagnosed diabetes may include: 1) Polyuria: Passing urine more often than usual, especially at night (Nocturia) 2) Polydipsia : Increased thirst 3) Polyphagia : Excess eating because of feeling hungry all the time 4) Extreme tiredness 5) Unexplained weight loss 6) Generalized or genital itching 7) Recurrent fungal infections 8) Slow healing of cuts and wounds 9) Blurred vision In Type 1 diabetes the signs and symptoms are usually very obvious and develop rapidly very quickly (over few weeks). The symptoms are quickly relieved once the diabetes is treated and under control. In Type 2 diabetes the signs and symptoms may not be so obvious. The condition develops over a period of years and may only be picked up on routine check up. Clinical Features in Diabetes mellitus

70. INITIAL PRESENTATION Of DM NON CLASSICINFECTION SKIN UTI FUNGAL (ear) NON INFECTION PRURITUS FATIGUE VISION SENSORY HEALING CLASSIC POLYURIA POLYDIPSIA POLYPHAGIA WEIGHT LOSS Hyperglycemic emergencies