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39. 39 Diagnosis and classification of Diabetes Mellitus Professor Eiad A. Alfaris

40. 40Contents Clinical cases Clinical cases Definition and presentations Definition and presentations Pathophysiology Pathophysiology Classifications and diagnosis Classifications and diagnosis Prevalence Prevalence Lessons learned Lessons learned Summary Summary

41. 41 Objectives At the end of this session, we should be able to demonstrate understanding of: 1. T he definition and symptoms of diabetes 2. T he classification and diagnosis 3. W hen to screen for diabetes 4. T he pathophysiology of diabetes

42. 42 Introduction

43. 43

44. 44 The benefit of good control

45. 45 Clinical Cases

46. 46 Case 1: Ahmed Ahmed Ahmed is 47 years old gentleman presented with back pain and as part of the investigations, you found the following: FBS FBS 103 103 mg /dl today 113 113 mg /dl one week ago He He asked you: What is the result of my blood sugar?

47. 47 SOLUTIONS one minute alone

48. 48 Case 2 Norah Norah Is A 55-year-old Lady Not Known To Be Diabetic Before. FBS= 7.3 mmol/Lit. (average of two readings) 2 2h PP=15 mmol/Lit.

49. 49 Weight 95 KG Height 158 cm T. Cholestrol = 5.4 mmol/ L LDL-C = 3.4 mmol/ L HDL-C = 0.85 mmol/ L Trig. = 2.8 mmol/ L 24 hours albumin = 50 mg What Is Your interpretation of the findings?

50. 50 SOLUTIONS one minute alone and one minute with your neighbor

51. 51 CASE 3 ALI IS A 43-YEAR-OLD SAUDI THIN MAN TYPE II D.M. FOR THE LAST 5 YEARS. HE IS COMPLIANT WITH DIET AND EXERCISE. BP136/88 mmHg (ON THREE OCCASIONS)

52. 52 Cont’d. CASE 3 HE IS ON :METFORMIN 850 mg BDAM and PM Glibenclamide15 mg AM5 mg PM HIS FBS IS 24 mmoL/Litre ANY PROBLEM IN THE MANAGEMENT? WHAT IS YOUR PLAN OF ACTION?

53. 53

54. 54 DEFINITION A group of metabolic disorders characterized by hyperglycemia resulting from defects in insulin secretion, insulin action or both. A group of metabolic disorders characterized by hyperglycemia resulting from defects in insulin secretion, insulin action or both.

55. 55 What are the symptoms and presentattions of diabetes mellitus?

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57. 57 Symptoms and presentations Asymptomatic Polyuria and polydipsia Weight loss Polyphagia, Blurred vision Impairment of growth Susceptibility to certain infections.

58. 58 Acute life-threatening consequences Hyperglycemia with keto-acidosis The nonketotic hyperosmolar syndrome

59. 59 Long-term complications Retinopathy with potential loss of vision Nephropathy leading to renal failure Peripheral neuropathy with risk of foot ulcers, amputations, and Charcot joints and autonomic neuropathy causing gastrointestinal, genitourinary, and cardiovascular symptoms and sexual dysfunction.

60. 60 An increased incidence of atherosclerotic cardiovascular, peripheral arterial, and cerebrovascular disease. Hypertension and abnormalities of lipoprotein metabolism are often found in people with diabetes.

61. 61 Pathophysiology of Diabetes

62. 62 Tissue Response to Insulin Fat and Adipose tissue Lipolysis FFA Muscle Glucose uptake Liver Hepatic glucose production Tissue Response to Insulin Fat and Adipose tissue Lipolysis FFA Muscle Glucose uptake Liver Hepatic glucose production

63. 63 Insulin Resistance Decreased insulin Secretion Insulin Resistance Decreased insulin Secretion Pathophysiology of Diabetes Hyperglycemia Obesity

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70. 70 CLASSIFICATION Type 1 diabetes (absolute insulin deficiency) Type 1 diabetes (absolute insulin deficiency) Type 2 diabetes (insulin resistance with relative insulin def.) Type 2 diabetes (insulin resistance with relative insulin def.) Gestational diabetes mellitus Gestational diabetes mellitus Other types (genetic or secondary types) Other types (genetic or secondary types)

71. 71 How to differentiate between type 1 and type 2 Type 2 Type 1 Characteristics Age Symptoms Family history ketonurea Weight loss Endogenous insulin

72. 72 DIAGNOSIS A symptomatic patient plus casual plasma glucose ≥ 11.1 mmol/L or FPG ≥ 7.0 mmol/L. A symptomatic patient plus casual plasma glucose ≥ 11.1 mmol/L or FPG ≥ 7.0 mmol/L. During an OGTT 2-hr post 75 gm-glucose During an OGTT 2-hr post 75 gm-glucose ≥ 11.1 mmol/L. ≥ 11.1 mmol/L. ● In the absence of symptoms suggestive of DM, these criteria should be confirmed by repeat testing on a different day.

73. 73 DIAGNOSIS FPG ≤ 5.5 mmol/L = normal FPG ≤ 5.5 mmol/L = normal FPG ≥ 5.6 mmol/L to 6.9 mmol/L= IFG FPG ≥ 5.6 mmol/L to 6.9 mmol/L= IFG FPG ≥ 7.0 mmol/L = provisional diagnosis of DM and must be confirmed FPG ≥ 7.0 mmol/L = provisional diagnosis of DM and must be confirmed in asymptomatic person. in asymptomatic person.

74. 74 Prevalence of Retinopathy by Deciles NHANES III FPG90939698101104109120 2h PG8694102112120133154195 HbA1c5.15.25.45.55.65.75.96.2 Diabetes Care 1997;20, 1183-1197 Retinopathy %

75. 75 Impact of HbA 1c on Retinopathy in Type 1 Diabetes 11%10% 9% 8% 7% Time ( years ) Rate per 100 person years Diabetes 1995; 44:968 Progression of retinopathy from DCCT study in relation to mean HbA 1c.

76. 76 Prevalence of DM in Saudi Arabia A community based study of 17232 subjects A community based study of 17232 subjects conducted between 1995 and 2000 in KSA. conducted between 1995 and 2000 in KSA. The examining age group, 30-70 years of selected The examining age group, 30-70 years of selected households during 5-year period households during 5-year period Mansour M. Al-Nozha et al,The prevalence of CAD among Saudis of both sexes, in rural as well as urban communities, as well as modifiable risk factors for CAD. Saudi Medical Journal 2004; Vol. 25 (9): 1165-1171 Saudi Medical Journal 2004; Vol. 25 (9): 1165-1171

77. 77 Prevalence of DM in Saudi Arabia The overall prevalence of DM obtained from this study is 23.7% in KSA. The overall prevalence of DM obtained from this study is 23.7% in KSA. The prevalence in males and females were 26.2% and 21.5% respectively (p<0.00001). The prevalence in males and females were 26.2% and 21.5% respectively (p<0.00001). A large number of diabetic patients 1116 (27.9%) were unaware of having DM. A large number of diabetic patients 1116 (27.9%) were unaware of having DM. Mansour M. Al-Nozha et al,The prevalence of CAD among Saudis of both sexes, in rural as well as urban communities, as well as modifiable risk factors for CAD. Mansour M. Al-Nozha et al,The prevalence of CAD among Saudis of both sexes, in rural as well as urban communities, as well as modifiable risk factors for CAD. Saudi Medical Journal 2004; Vol. 25 (9): 1165-1171 Saudi Medical Journal 2004; Vol. 25 (9): 1165-1171

78. 78 Diagnosis based on: Glucose Tolerance Test 2 hr post 75 gm glucose 2 hr post 75 gm glucose If < 7.8 mmol/L = normal GTT If < 7.8 mmol/L = normal GTT If ≥ 7.8 mmol/L and < 11.1 mmol/L = If ≥ 7.8 mmol/L and < 11.1 mmol/L = Impaired GTT Impaired GTT If ≥ 11.1 mmol/L = provisional diagnosis of If ≥ 11.1 mmol/L = provisional diagnosis of Diabetes Diabetes

79. 79 Annual Screening FOR DM IN ASYMPTOMATIC All individuals aged 40 years or above. All individuals aged 40 years or above. At younger age or more frequently in those who: At younger age or more frequently in those who: ■ Are Obese ■ Are Obese ■ Have a first degree relative with diabetes ■ Have a first degree relative with diabetes ■ Are Hypertensive ≥ 140/90 ■ Are Hypertensive ≥ 140/90 ■ Have been diagnosed with GDM ■ Have been diagnosed with GDM ■ Have Dyslipidaemia ■ Have Dyslipidaemia ■ Had IGT or IFG ■ Had IGT or IFG

80. 80 Impaired Glucose Tolerance At glucose levels above normal but below the diabetes threshold diagnostic now referred to as pre-diabetes. At glucose levels above normal but below the diabetes threshold diagnostic now referred to as pre-diabetes. There is growing evidence that there is a substantially increased risk of CVD and death. There is growing evidence that there is a substantially increased risk of CVD and death. 1- The DECODE Study Group: Glucose tolerance and cardiovascular mortality: comparison of fasting and 2-hour diagnostic criteria. Arch Intern Med 161:397–405, 2001 2- Saydah SH, Loria CM, Eberhardt MS, Brancati FL: Subclinical states of glucose intolerance and risk of death in the U.S. Diabetes Care 24:447–453, 2001

81. 81 Impaired Glucose Tolerance ■ In the Finnish study, 522 middle-aged obese (mean BMI 31 kg/m 2 ) subjects with IGT were randomized to receive either brief diet and exercise counseling (control group) or intensive individualized instruction on weight reduction, food intake, and guidance on increasing physical activity (intervention group). After an average follow-up of 3.2 years, there was a 58% relative reduction in the incidence of diabetes in the intervention group compared with the control subjects. After an average follow-up of 3.2 years, there was a 58% relative reduction in the incidence of diabetes in the intervention group compared with the control subjects. Tuomilehto J et al Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 344:1343 – 1350, 2001 Tuomilehto J et al Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 344:1343 – 1350, 2001

82. 82 Impaired Glucose Tolerance ■ Three diabetes prevention trials used pharmacological therapy, and all have reported a significant lowering of the incidence of diabetes. ■ Three diabetes prevention trials used pharmacological therapy, and all have reported a significant lowering of the incidence of diabetes. 1- The Biguanide Metformin reduced the risk of diabetes by 31% in the DPP (1) 1- The Biguanide Metformin reduced the risk of diabetes by 31% in the DPP (1) 2- The -Glucosidase Inhibitor Acarbose reduced the risk by 10% in the STOP-NIDDM trial (2) 2- The -Glucosidase Inhibitor Acarbose reduced the risk by 10% in the STOP-NIDDM trial (2) 3- The Thiazolidinedione Troglitazone reduced the risk by 6.7% in the TRIPOD study (3) 3- The Thiazolidinedione Troglitazone reduced the risk by 6.7% in the TRIPOD study (3) 1- Diabetes Prevention Research Group: Reduction in the evidence of type 2 diabetes with life-style intervention or metformin. N Engl J Med 346:393 – 403, 2002 1- Diabetes Prevention Research Group: Reduction in the evidence of type 2 diabetes with life-style intervention or metformin. N Engl J Med 346:393 – 403, 2002 2- Chiasson JL et al for the STOP-NIDDM Trial Research Group: Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Lancet 359:2072 – 2077, 2002 2- Chiasson JL et al for the STOP-NIDDM Trial Research Group: Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Lancet 359:2072 – 2077, 2002 3- Diabetes 51:2796 – 2803, 2002 3- Diabetes 51:2796 – 2803, 2002

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84. 84 Copyright ©2006 BMJ Publishing Group Ltd. Heine, R J et al. BMJ 2006;333:1200-1204 Fig 1 Traditional treatment strategy for type 2 diabetes and its consequences. In type 2 diabetes beta cell function declines over the years, irrespective of treatment with metformin, sulfonylurea (as monotherapy or dual therapy), or insulin. Treatment therefore has to be adjusted at regular intervals according to the level of glycaemia. Because doctor and patient need to agree about adding another drug at each step, glycated haemoglobin values will recurrently fail to reach target

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86. 86 Risk factors The risk factors of IHD in diabetic patients: The risk factors of IHD in diabetic patients:SmokingHypertensionNephropathy Death rate / 1000 / year Diabetes care 1993, 16, 434-444. Risk factors for IHD in Diabetics

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88. 88 Etiologic classification of diabetes mellitus Diagnostic criteria for diabetes mellitus The new criteria 123123 Fasting plasma glucose ( FPG ) ( at least 8hours fast) = or > 126 mg/dL ( 7.0 mmol/L ) Two hours plasma glucose (2PG ) after 75 anhydrous glucose in water = or > 200 mg/dL ( 11.1 mmol/L ) Symptoms of diabetes ( polyuria, polydepsia, and weight loss ) + Random Blood Sugar ( RBS ) (casual plasma glucose) = or > 200 mg/dL ( 11.1 mmol/L )

89. 89 Risk Stratification and Treatment Risk Stratification and Treatment BP Stage Normal Risk Group Risk Group A: No risk factor; No TOD/ACC B: At least one risk factor, Not including diabetes: No TOD/ACC C: TOD/ACC and/or Diabetes, with or without other risk factors High Normal Life style modification Drug therapy Stage I Life style modification (up to 12 months) Life style modification ( up to 6 months) Drug therapy Stage II Drug therapy

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94. 94 Case 1: Ahmed Ahmed Ahmed is 47 years old gentleman presented with back pain and as part of the investigations, you found the following: FBS FBS 103 103 mg /dl today 113 113 mg /dl one week ago He He asked you: What is the result of my blood sugar?

95. 95 Case 2 Norah Norah Is A 55-year-old Lady Not Known To Be Diabetic Before. FBS= 7.3 mmol/Lit. (average of two readings) 2 2h PP=15 mmol/Lit.

96. 96 Weight 95 KG Height 158 cm T. Cholestrol = 5.4 mmol/ L LDL-C = 3.4 mmol/ L HDL-C = 0.85 mmol/ L Trig. = 2.8 mmol/ L 24 hours albumin = 50 mg What Is Your interpretation of the findings?

97. 97 CASE 3 ALI IS A 43-YEAR-OLD SAUDI THIN MAN TYPE II D.M. FOR THE LAST 5 YEARS. HE IS COMPLIANT WITH DIET AND EXERCISE. BP136/88 mmHg (ON THREE OCCASIONS)

98. 98 Cont’d. CASE 3 HE IS ON :METFORMIN 850 mg BDAM and PM Glibenclamide15 mg AM5 mg PM HIS FBS IS 24 mmoL/Litre ANY PROBLEM IN THE MANAGEMENT? WHAT IS YOUR PLAN OF ACTION?

99. 99 What was learnt?

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102. 102 MANAGEMENT OF TYPE 2 DM Diet and Exercise should be offered for all patients for 2 months. Diet and Exercise should be offered for all patients for 2 months. Obese patients: Obese patients: ■ METFORMIN is the drug of choice ■ METFORMIN is the drug of choice Start with 500 mg PO three times a day up Start with 500 mg PO three times a day up up to 850 mg or 1 gm PO TDS. up to 850 mg or 1 gm PO TDS. ■ If not controlled add Sulphonylurea or ■ If not controlled add Sulphonylurea or Glitazones Glitazones

103. 103 MANAGEMENT OF TYPE 2 DM Non-Obese patients Non-Obese patients Diet and Exercise Diet and Exercise Add Sulphonylurea (e.g. Glibenclamide or Gliclazide) Add Sulphonylurea (e.g. Glibenclamide or Gliclazide) If not controlled add Metformin If not controlled add Metformin In secondary failure, consider shifting to Insulin In secondary failure, consider shifting to Insulin

104. 104 PHYSICAL EXAMINATION Height and Weight Height and Weight Blood Pressure Blood Pressure Fundus Examination Fundus Examination Cardiac examination Cardiac examination Lower Limbs: Lower Limbs: ■ Skin Examination ■ Skin Examination ■ Evaluation of pulses ■ Evaluation of pulses ■ Foot Examination ■ Foot Examination ■ Neurologic Examination ■ Neurologic Examination

105. 105 LABORATORY EVALUATION FPG and 2 hr PP FPG and 2 hr PP Midstream Urine Midstream Urine Urea and Creatinine Urea and Creatinine Lipid Profile (total cholesterol, LDLc, HDLc and triglycerides) Lipid Profile (total cholesterol, LDLc, HDLc and triglycerides) HbA1c HbA1c 24 hr urine collection for protein 24 hr urine collection for protein ECG ECG Chest X-Ray Chest X-Ray

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107. 107 CASE 1 CASE 1 A 50-year-old man presents to your office to check the results of some routine investigations. A 50-year-old man presents to your office to check the results of some routine investigations. FBS : 6.6 mmol/L FBS : 6.6 mmol/L what is your diagnosis ? what is your diagnosis ? what further investigations are you going to do ? what further investigations are you going to do ?

108. 108 CASE 2 CASE 2 A 48-year-old man presents to your office for routine checkup for hypertension. Asymptomatic. A 48-year-old man presents to your office for routine checkup for hypertension. Asymptomatic. On Atenolol 50 mg a day. On Atenolol 50 mg a day. FH : his father is diabetic FH : his father is diabetic BMI 38 Bp: 150/94 BMI 38 Bp: 150/94 FBS: 14.6 mmol/L U and E: normal FBS: 14.6 mmol/L U and E: normal Cholesterol: 5.7 mmol/L Cholesterol: 5.7 mmol/L Trig. 2.86 mmol/L Trig. 2.86 mmol/L How are you going to deal with him? How are you going to deal with him?

109. 109 CASE 3 CASE 3 A 44-year-old woman presents to your office with 2 month H/O loss of weight and polyurea. A 44-year-old woman presents to your office with 2 month H/O loss of weight and polyurea. BMI 20 BMI 20 RBS : 24.4 mmol/L RBS : 24.4 mmol/L Urine dipstick : glucose: 4+ Urine dipstick : glucose: 4+ ketones : nil ketones : nil Protein : ++ Protein : ++ what is your diagnosis ? what is your diagnosis ? what is your management ? what is your management ?

110. 110 Case 4 Case 4 A 22-year-old university student, presents to your office with one week H/O fatigue and nocturia. A 22-year-old university student, presents to your office with one week H/O fatigue and nocturia. He lost 6 kg per last month. He lost 6 kg per last month. RBS : 24.6 mmol/L RBS : 24.6 mmol/L What is the most important next step to do ? What is the most important next step to do ?

111. 111 CASE 5 CASE 5 A 52-year-old man is known case of DM presents to your office for follow up. A 52-year-old man is known case of DM presents to your office for follow up. He is on : glibenclamide 10 mg po bid He is on : glibenclamide 10 mg po bid Metformin 1 gm po tid Metformin 1 gm po tid FBS : 16.2 mmol/L Cholesterol : 7.3 mmo/L FBS : 16.2 mmol/L Cholesterol : 7.3 mmo/L 2hPP: 21.4 mmol/L LDL-C : 4.8 mmol/L 2hPP: 21.4 mmol/L LDL-C : 4.8 mmol/L HDL-C : 0.88 mmol/L HDL-C : 0.88 mmol/L Trig. 4.6 mmol/L Trig. 4.6 mmol/L U& E : norm. U& E : norm. BMI 33 BMI 33 ? : ? : How are you going to manage this patient ? How are you going to manage this patient ?

112. 112 Oral medication for type 2 DM 1- Sulphonylurea group: 1- Sulphonylurea group: Glibenclamide Glibenclamide Gliclazide Gliclazide Glipizide Glipizide Action: stimulate the pancreace to secrete Action: stimulate the pancreace to secrete insulin. insulin. Note: Gliclazide is suitable for patients Note: Gliclazide is suitable for patients with impaired hepatic and renal with impaired hepatic and renal functions. functions.

113. 113 Oral Medication for type 2 DM 2- Biguanide Group (METFORMIN) 2- Biguanide Group (METFORMIN) Action: ▪ Inhibit the process of Gluconeogenesis. Action: ▪ Inhibit the process of Gluconeogenesis. ▪ Increasing the peripheral utilization of ▪ Increasing the peripheral utilization of Glucose. Glucose. ▪ It acts only in the presence of insulin. ▪ It acts only in the presence of insulin. Precaution : Not given in patients with impaired Precaution : Not given in patients with impaired liver or renal functions, severe infections, liver or renal functions, severe infections, heart failure,…. heart failure,….

114. 114 Oral Medication for type 2 DM 3- Alpha Glucosidase Inhibitors (ACARBOSE) 3- Alpha Glucosidase Inhibitors (ACARBOSE) ■ Used for Post Prandial Hyperglycaemia ■ Used for Post Prandial Hyperglycaemia Action : inhibit the absorption of carbohydrate. Action : inhibit the absorption of carbohydrate. Side effects : flatulance, distension, soft Side effects : flatulance, distension, soft stool,.. stool,..

115. INCRETINS

116. Glucagon-like Peptide-1 GLP-1 is secreted throughout the day by intestinal mucosa in response to oral glucose in the gut. GLP-1 is secreted throughout the day by intestinal mucosa in response to oral glucose in the gut. GLP-1 causes anabolic actions on the synthesis of insulin in beta cells by stimulating all steps of insulin biosynthesis. GLP-1 causes anabolic actions on the synthesis of insulin in beta cells by stimulating all steps of insulin biosynthesis. GLP-1 provides continued and augmented release of insulin for secretion in response to glucose without overproduction that could lead to hypoglycemia. GLP-1 provides continued and augmented release of insulin for secretion in response to glucose without overproduction that could lead to hypoglycemia. GLP-1 also acts on islet alpha cells, causing strong inhibition of postprandial glucagon secretion. GLP-1 also acts on islet alpha cells, causing strong inhibition of postprandial glucagon secretion. GLP-1 slows gastric emptying and promotes early satiety with reduced food intake GLP-1 slows gastric emptying and promotes early satiety with reduced food intake

117. Dipeptidyl Peptidase-4 Within minutes of secretion or exogenous Within minutes of secretion or exogenous administration, GLP-1 is rapidly degraded by administration, GLP-1 is rapidly degraded by dipeptidyl peptidase-4 (DPP-4). dipeptidyl peptidase-4 (DPP-4). DPP-4 is found in many body tissues, DPP-4 is found in many body tissues, including liver, renal, and intestinal brush- including liver, renal, and intestinal brush- border membranes; lymphocytes; and border membranes; lymphocytes; and endothelial cells. endothelial cells.

118. INCRETINS The incretin system is impaired in patients with T2DM, which, as a consequence of its insulinotropic actions, contributes to fasting and postprandial hyperglycemia. The impairment of GLP-1 secretion varies directly with the degree of insulin resistance; those who are more insulin resistant have a lower rise in GLP-1 in response to a meal.

119. The American Association of Clinical Endocrinologists (AACE) guidelines make it clear that Incretins can be used early and are not limited to third- or fourth-line therapy for T2DM

120. Medication: Two agents are currently available in the US that act upon the Incretin hormone system – ● Exenatide (Byetta), a twice-daily glucagon-like peptide-1 (GLP-1) receptor agonist. ● Sitagliptin (Januvia), a dipeptidyl peptidase-4 (DPP-4) inhibitor. ● Agents are currently under review by (FDA). These include the once-daily human GLP-1 analog liraglutide and the DPP-4 inhibitors Alogliptin, Saxagliptin, and Vildagliptin.

121. 121 Oral Medication for type 2 DM 4- Meglitinides ( REPAGLINIDE ) 4- Meglitinides ( REPAGLINIDE ) ■ Used for Post Prandial Hyperglycaemia ■ Used for Post Prandial Hyperglycaemia Action : Similar in action to Sulphonylurea Action : Similar in action to Sulphonylurea Rapid onset of action Rapid onset of action Taken immediately before meals Taken immediately before meals ■ Used as Monotherapy or in combination with ■ Used as Monotherapy or in combination with Metformin Metformin

122. 122 Oral Medication for type 2 DM 4- Thiozolidinediones: 4- Thiozolidinediones: ● ROSIGLITAZONE ● ROSIGLITAZONE ● PIOGLITAZONE ● PIOGLITAZONE Reduce insulin resistance Reduce insulin resistance Promotes glucose uptake by skeletal muscles and adipose tissue Promotes glucose uptake by skeletal muscles and adipose tissue Inhibits hepatic gluconeogenesis Inhibits hepatic gluconeogenesis Used in combination with metformin and sulphonylurea Used in combination with metformin and sulphonylurea Periodic monitoring of liver enzymes Periodic monitoring of liver enzymes Not given in patients with heart failure Not given in patients with heart failure