1. Diabetes Mellitus Dr. CAI Mengyin Department of Endocrinology 3 rd Affiliated Hospital Sun Yat-sen University

3. Economy taking-off like a rocket with dramatic lifestyle change State “on Bicycle” Traffic jam in Beijing Coupon for food in Guangzhou One week’s food for a family in Beijing Exercise less Eat More

4. Prevalence rate of Diabetes Throughout the world: 150 millions ? 2% USA: 15 millions China: 9.7 % -- N Engl J Med 2010;362:1090-101. China: 1980 0.609% in 304537 Canton: 1980 0.411% in 42788

5. What is Diabetes Mellitus? Definition: Syndrome Metabolic disorder of multiple etiology (causes) characterized by hyperglycemia with carbohydrates, fat, and protein metabolic alterations, which result in defects in the secretion or action of insulin, or both.

6. Hyperglycemia X or Metabolic Syndrome Metabolic abnormalities and by long-term complications involving eyes, kidneys, nerves, and blood vessels Acute complications: diabetic ketoacidosis, hyperosmolar nonketotic diabetic coma. homogenous Heterogeneous

7. Genetic factors Environmental factors Chinese population  9% Monogenic Polygenic Aging Lifestyle Infections Diabetes Type I <10% Type II >90% Etiology and Development

8. Defect of β Cell in Insulin Secretion & Action

9. Non - diabetes Pre - diabetes Diabetes IGT/IFG Fasting plasma glucose Insulin requirement Insulin production <6.1mmol/L >7.0 mmol/L

10. Derangements are due to relative or absolute insulin deficiency and glucagon excessiveness. Normally, it is a rise in the molar ratio of glucagon to insulin which leads to diabetic decompensation . Why does metabolic derangement happen?

12. Spectrum of Diabetes Mellitus Insulin receptor gene mutations (<1%) Insulin gene mutations (<1%) Mitochondrial gene mutations (2%) Type 2 (70%) Type 1 (10%) LADA (10-12% ?) MODY (2-4% ?)

13. 1 yr 10 yr 21 yr 32 yr 45 yr 60 yr Age at diagnosis TYPE1 TYPE2 MODY LADA MIDD DIDMOAD ? Variable Faces of Diabetes Mellitus

14. Type 1 diabetes mellitus Usually onset before age of 40. In USA, peak incidence is around 14 years old. Onset of symptoms may be abrupt, with thirst, excessive urination, increased appetite and weight loss developing over a several-day period. In some cases, the disease is heralded by the appearance of DKA during and intercurrent illness or following surgery.

15. Type 2 Diabetes Mellitus Usually starts in middle age or older. Symptoms begin more gradually than in type 1 diabetes, and diagnosis is frequently made when an asymptomatic person is found to have an elevated plasma glucose on routine lab. Exam..

16. Type 1 vs. Type 2 Type 1 Type 2 Age of onset Childhood, young adult Adulthood, elder people Body cells Responsive to insulin Resistant to insulin Autoantibodies Positive Negative Body fatness Low to average High Endogenous insulin Little or none Normal or too much Pancreatic function Beta cells not functional Beta cell normal Severity of symptoms Severe; liable to DKA Mild; few or none, not liable to DKA Insulin shots? Yes, indispensable Not during early and middle stage Drugs? Not solely Yes

18. Maturity-onset diabetes of the young (MODY) 45 33 22 12 16 17 10 INS OHA OHA DIET DIET DIET INS Classical MODY-criteria: 1. Two patients diagnosed with diabetes before the age 25 years. 2. Autosomal dominant inheritance of diabetes (  3 generations) Note: Yellow figures indicating ages at on-set.

19. History of MODY genes MODY2 GCK MODY1 Linkage to chr20 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 MODY2 Linkage to chr7 MODY3 Linkage to chr12 MODY3 HNF-1  MODY1 HNF-4  MODY5 HNF-1  MODY4 IPF1

21. Severe insulin resistance syndrome Insulin signaling associated mutation Lypodystrophy syndrome linked mutation Other gene IR gene AKT2 gene BSCL FPLD MAD CaR gene AGPAT2 gene Seipin gene LMNA PPARγ gene LMNA ZMPSTE24 gene

23. Sequencing of IR exon20 Black Arrow ： P1174W Green Arrow ： P1178P Weng J. Clin Endocrinol (Oxf). 2009 Nov; 71(5):659-65. Epub 2009 Jan 19.

24. Weng J. Clin Endocrinol (Oxf). 2009 Nov; 71(5):659-65. Epub 2009 Jan 19.

25. HGPS, RD the “most” complicated and lethal type of laminopathies HGPS RD Hum Mol Genet, 2004, 13: 2493-2503. N Engl Med, 2008,358: 552-555.

27. Gestational Diabetes Mellitus ◆ Definition: Carbohydrates intolerance of variable severity with onset or first recognition during pregnancy ◆ Screening: American Diabetic Association(ADA) Recommend screening all pregnant women at 24-26 wks using 50g oral glucose test with 1 hour blood glucose value of 140mg or more as an indication for standard oral glucose tolerance test. No stipulations as to the time of last meal.

28. Clinical manifestation The manifestations of symptomatic diabetes mellitus vary from patient to patient. Most often medical help is sought because of symptoms related to hyperglycemia: polyuria, polydipsia, polyphagia.

29. But, the first event may be an acute metabolic decompensation resulting in diabetic coma. More occasionally, the initial expression can be a degenerative complication such as neuropathy in the absence of symptomatic hyperglycemia.

31. Increased coagulability Platelet hypersensitivity Increased blood viscosity Impaired microvascular flow Increased microvascular pressure and flow Microvascular sclerosis Limitation of maximum perfusion Failure of autoregulation Raised capillary pressure Tissue damage Hypothesis for Diabetic Microangiopathy

33. Background Proliferative Diabetic Retinopathy

37. Foot ulceration Charcot arthropathy Diabetic Foot

44. LDL-c mmol/L <2.5 2.5-4.4 >4.5 ★ According to UKPDS data . Targets for Diabetic Control Good Moderate Poor FPG mmol/L 4.4-6.1 ≤ 7.0 >7.0 PBS mmol/L 4.4-8.0 ≤ 10.0 >10.0 HbA1c ★ % <6.2 6.2-8.0 >8.0 BMI Kg/m 2 M<25 F<24 M<27 F<26 M ≥ 27 F ≥ 26 T ch mmol/L <4.5 ≥ 4.5 6.0 HDL-c mmol/L >1.1 1.1-0.9 <0.9 TG mmol/L <1.5 <2.2 ≥ 2.2

50. Exercise Guidelines ※ Monitor BG before and after exercise. ※ Avoid exercise if BG >250 mg/dl, ketones present. ※ Use caution with exercise if BG>300 mg/dl, without ketones. ※ Eat CHO if BG < 100 mg/dl ※ If exercise is planned for just after a meal, consider reducing the short acting insulin that covers that meal. ※ If exercise is planned for 3-4 hours after a meal, consider reducing the long-acting insulin. ※ For unplanned exercise, consider adding carbohydrate. ※ Consume CHO before, during, or after exercise to prevent hypoglycemia. ※ Always keep CHO foods readily available during exercise.

51. Oral Hypoglycemic Agents

53. Sulfonylurea Activates Insulin Secretion Small figure shows the site of action.

56. Biguanides (Metformin) Mode of action: ◇ reduces hepatic glucose production ◇ decreased intestinal absorption of glucose ◇ increases peripheral utalisation of glucose in muscle & fat tissue ◇ decreased insulin requirements for glucose disposal

57. Precautions: ● chronic renal or cardiac failure ● hepatic impairment ● elderly ● excessive alcohol intake Side effects: ◆ gastrointestinal disturbances ◆ metallic taste ◆ malabsorption of B12 Administer: with or after meals

61. Insulin preparations and time of reaching peak and duration

62. Lipoatrophy due to long term injection of ‘impure’ insulin preparations.

63. Novopen Inhaled insulin Insulin pump

65. Diabetic Ketoacidosis Presentation Physical examination Laboratory results Polyuria, polydipsia Nausea, vomiting Diarrhea, abd. Pain Evolution for a few days Stupor or coma in Loss of skin turgor Kussmaul breathing Acetone odor Cerebral edema PH <7.3, HCO 3 <15 Eq/L Glucose > 250 mg/dl Elevated anion gap High serum ketones High uric acid Normal osmolality

67. Treatment of DKA – IV fluid Normal saline 1 liter/hr until not orthostatic hypotensive, then NS at 500 ml/hr Electrolytes every 2 hrs initially, then every 4 hours Glucose <250 mg/dl, change to Dextrose with 1:4 regular insulin at 250-500 ml/hr When anion gap normal, bicarbonate >15 mEq/L, taking PO fluid, give meal and SC insulin

68. Treatment of DKA – Insulin IV insulin at 5-10 u/hr in adult, 0.1 u/kg/hr in child Check glucose hourly, if no change in 2 hrs double the insulin infusion Glucose <250 mg/dl, slow insulin to 2-4 u/hr Discontinue IV insulin 2-3 hrs after SC insulin dose

69. Treatment of DKA – Potassium Potassium repletion if initial K is normal or low at 10-40 mEq/hr Check potassium every 2- 4 hrs Replete total body potassium stores over 2- 3 days

70. Treatment of DKA – Bicarbonate, Phosphorus Bicarbonate replacement if pH less than 6.90 Check phosphorus 12 hrs into treatment. Replace if < 1 mEq/L