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Update on the Pathogenesis of Type 2 Diabetes Mellitus

Update on the Pathogenesis of Type 2 Diabetes Mellitus. Ki-Up Lee Department of Internal Medicine Asan Medical Center, University of Ulsan. Case Presentation. M/31 김 O 철. C/C: weight loss, polyuria P/ I : 평소 건강하게 지내던 중 3 개월간 약 6kg 의 체중 감소 발생하고 전신 쇠약감

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Update on the Pathogenesis of Type 2 Diabetes Mellitus

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  1. Update on the Pathogenesis of Type 2 Diabetes Mellitus Ki-Up Lee Department of Internal Medicine Asan Medical Center, University of Ulsan

  2. Case Presentation

  3. M/31 김 O 철 • C/C: weight loss, polyuria • P/ I : 평소 건강하게 지내던 중 3개월간 약 6kg의 체중 감소 발생하고 전신 쇠약감 • 동반되면서, 다음, 다뇨 증상 있어 내분비내과 외래 방문 • F/Hx: mother – current insulin treatment for DM • P/Hx: N.C. • ROS: weight loss (6kg/3mo) general weakness(+) • polyuria(+) polydiasia(+) hearing disturbance(+) • P/Ex: height; 172cm weight; 64kg BMI; 21.6kg/m2 • WC; 84cm WHR; 0.82 slightly dehydrated tongue • Lab : FBS; 258 mg/dL PP2hrs; 342 mg/dL HbA1c; 11.5% • urine/serum ketone; (-)/(-) C-peptide; 0.9 ng/mL • anti-GAD Ab; (-)

  4. M/31 김 O 철 • Diagnosis: NIDDM without complications • Medication: Amaryl 1T bid • 6 mon later: FBS/ PP2hrs; 98/179 mg/dL HbA1c; 7.1% • Amaryl 1T bid • 1.5 year later: FBS/PP2hrs; 192/256 mg/dL HbA1c; 8.1% • C-peptide; 0.7 ng/mL • Amaryl 2T bid/ Glucophage 500mg bid • 2 years later: weight loss, 3p’s symptoms • FBS/PP2hrs; 362/480 mg/dL HbA1c; 13.2% • c-peptide; 0.3 ng/mL urine ketone; (+) serum ketone(-) • started insulin therapy

  5. History & Classificationof Diabetes mellitus

  6. History of DM Diabetes Greek for “passing water like a siphon” Mellitus Latin for “sweetened with honey” “Ebers Papyrus” (Egyptian, 1500 B.C.) first depiction of diabetes mellitus - urination of excess amounts - manipulation of diet therapy

  7. 국내 당뇨병의 역사 • 당뇨병에 관한 기술 - 향약구급방 (13세기 중엽 고려 고종) “소갈” - 향약집성방 (조선시대 1433년 세종 15년) “소변이 달다” - 동의보감 (조선시대 1613년 광해군 5년): 소갈증에 대한 자세한 기록 실명 등의 합병증 기록 치료, 당의 섭취제한과 안정

  8. Discovery of Insulin “insulin”= Latin for “island” • 1889; • 1st removal of pancreas from a dog to • determine the effect of an absent • pancreas by Oskar Minkowski • 1921; • discovery of insulin • successful treatment of de-pancreatized • dog with insulin • 1922; • 1st tested in a 14-year-old boy of diabetes • in Toronto • 1923; • Nobel Prize in Physiology & Medicine Charles Best (1899-1978) Frederick Banting (1891-1941)

  9. Measurement of insulin by RIA Rosalyn S. Yalow (1921- ) • 1950s; • first discovery of insulin antibody • 1960s; • insulin immunoasay • 1977; • Nobel prize for insulin RIA

  10. Classification of diabetes mellitus • Insulin dependency • (NDDG,1979 - WHO,1980) • IDDM • vs C-peptide • NIDDM • Age of disease onset (early 1970s) juvenile onset vs adult onset absolute insulin deficiency relative

  11. Multiple hitsand/or -cell regeneration Slowly progressive IDDM (SPIDDM) =Latent autoimmune diabetes in adult (LADA) 100 -CELL MASS (%) Fulminant Regular NIDDM 30 20 IDDM 10 Adulthood (LADA) Childhood Adolescence (Age)

  12. Etiologic classification of diabetes (ADA, 1997) • Type 1 diabetes • - A: autoimmune mediated -cell destruction • ICAs, islet cell autoantibodies • (Ab to insulin, GAD, ICA-512/IA-2, islet ganglioside…) • - B: idiopathic loss of -cells • no evidence of immunologic destruction of -cells • Type 2 diabetes • Other specific types of diabetes • Gestational diabetes mellitus

  13. Type 1 diabetes in different ethnic groups • Caucasians • - mostly, about 90-95%: • auto-antibodies to islet cells • Koreans • - about half: • auto-antibodies to islet cells • - significant remainder without autoimmune evidence: • other possible causes

  14. IDDM in Korean subjects 1870 Diabetes mellitus 117 C-peptide < 0.6 ng/mL 56 Glucagon-stimulated C-peptide <1.0 ng/mL 26 30 Typical IDDM Atypical IDDM insulin Tx within 1 year or initial DKA no insulin requirement for more than 1 year WJ Lee,et al., Diabetologia, 2001

  15. IDDM in Korean subjects Prevalence of islet auto-antibodies and mitochondrial DNA mutation WJ Lee,et al., Diabetologia, 2001

  16. mtDNA mutation among Korean IDDM • Maternally transmitted • Often associated with • sensorineural hearing loss • Usually young at onset (<25 yr) • Variable clinical phenotypes: • type 1 DM, type 2 DM • Tendency toward progression: • like SPIDDM (LADA) OH tRNALeu(UUR) 10.4 kb del C3303T A3302G A3243G T3250C A3251G A3252G C3254T C3256T A3260G T3271C OL “One of the possible causes of atypical type 1 DM in Koreans” (WJ Lee, et al., Diabetologia, 2001) tRNALys A8344G

  17. Novel subtype of IDDM in Japan • Some (11/20) patients with • idiopathic type 1 DM • - non-autoimmune cause: • absence of insulitis and • autoantibodies • - abrupt onset, fulminant course: • prone to diabetic ketoacidosis • - pancreatic exocrine dysfunction: • high level of pancreatic enzyme Imagawa A, et al., N Engl J Med, 2000

  18. GAD antibody & progression to insulin deficiency

  19. Classification of diabetes mellitus in Koreans Clinical base “IDDM / NIDDM” more acceptable than Etiological base “Type 1 / Type 2 DM"

  20. Pathogenesis oftype 2 diabetes mellitus

  21. Pathogenesis of type 2 diabetes Genes Genes Impaired Insulin Insulin Resistance Secretion ± Environment ± Environment Type 2 DM

  22. Insulin resistance in obesity 160 Meals Glucose Insulin 140 60 Blood Gllucose, mg/dl 14 120 50 12 100 Glucose (Mm) 10 40 80 Insulin (Pm) 8 30 obese 6 20 4 Plasma Insulin 10 lean 2 lean obese lean obese 12 24 8 16 20 8 Time

  23. Measurement of Insulin resistance “Euglycemic hyperinsulinemic clamp” Control Glucose infusion rate (mg/kg/.min) 30 NIDDM 25 20 15 10 5 Steady state plasma glucose level 0 0 60 120 180 240 300 Time (min) Plasma insulin Glucose uptake (mg/m2.min) 300 Non-oxidative Oxidative 250 200 Insulin independent outflow Insulin dependent outflow 150 100 50 0 Control Obesity NIDDM

  24. Natural history of NIDDM(from Pima Indians) Genetic Susceptibility Insulin Resistance IGT Diabetes Mellitus

  25. Normal visceral fat Visceral fat obesity Visceral fat amount & insulin resistance

  26. The glucose fatty acid cycle (Randle, 1963) Glycogen G6P Glucose HK F-6-P FPK F-1,6-P2 Pyruvate PDH FFA overload Acetyl-CoA Citrate TCA cycle

  27. Problems of FFA theory • Weak correlation between insulin sensitivity and plasma FFA concentration - correlation coefficient: less than 0.6 • The rate of FA oxidation in skeletal muscle - determined not only by plasma FFA concentration released from adipose tissue, but also by FA supplied by local lipolysis of TG stored in skeletal muscle ( high TG content in skeletal muscle in insulin resistance)

  28. * 500 0.5 LFD HFD 400 0.4 * (mmol/mg wet weight) Muscle TG content mol/l) Interstitial glycerol 300 0.3 m ( * 200 0.2 100 0.1 0 0.0 Basal Clamp LFD HFD Lipolysis from skeletal musclein high fat-fed rats CH Kim, Metabolism, 2003

  29. TG accumulation in skeletal muscle is not the cause of insulin resistance. FFA TG insulin signaling Long chain fatty acyl CoA (LCAC) CPT-1 acetyl CoA TCA cycle “-oxidation” -oxidation  LCAC  Insulin resistance

  30. Prevention ofdiabetes mellitusby PPAR activation

  31. OLETF (Otsuka Long-Evans Tokushima Fatty) rats • Obesity (esp. visceral obesity) & • maturity-onset hyperglycemia • ( 30 wks) • Hypertension & vascular dysfunction • Dyslipidemia (hypertriglyceridemia)

  32. Rate of diabetes development Untreated OLETF 18 78 (%) 16 14 12 10 No. of rats with glycosuria 8 6 OLETF + Fenofibrate 4 2 0 (%) 0 OLETF + Rosiglitazone 12 14 32 34 36 38 40 Age (week)

  33. PPARs (Peroxisome proliferator activated receptors) • PPAR- • - insulin sensitizing effect • - essential factor for fat cell differentiation • - reduce fat accumulation in non-adipose tissue • - distribution: adipose tissue >> muscle, islet • PPAR- • - lowers plasma triglyceride levels • - up-regulates fat oxidation enzymes expression • - abundant in non-adipose tissue esp. in liver

  34. Body weight at 40 wks ** * ** 1000 750 Body weight (g) 500 250 0 Rosi Feno Untreated LETO OLETF * P < 0.05, ** P < 0.001 between two groups

  35. Visceral fat mass LETO OLETF * * OLETF + Rosi OLETF + Feno * *

  36. Pancreas islet morphology OLETF Feno LETO Untreated Rosi 18 wks 27 wks 40 wks

  37. TG & FA oxidation in skeletal muscle 7.5 10000 * * * * 7500 5.0 Fatty acid oxidation (dpm/g tissue) 5000 TG content (mmol/5g protein) 2.5 2500 0 0 Feno Rosi Feno Rosi LETO OLETF LETO OLETF OLETF OLETF * P < 0.05 between two groups

  38. Summary Fenofibrate Rosiglitazone DM prevention yes yes Body weight decrease increase Visceral fat mass decrease no change Islet hypertrophy prevent not prevent Islet destruction prevent prevent FA oxidation increase increase TG in muscle decrease decrease

  39. Prevention of fat overload in non-adipose tissues: PPAR- vs. PPAR- activation PPAR- Increase in fatty acid oxidation PPAR- Shift in lipogenic burden

  40. Insulin action & secretion in type 2 diabetes Type 2 Diabetes Mellitus “Not all obese subjects develop type 2 diabetes mellitus.” “-cell function is also impaired in type 2 diabetes mellitus.”

  41. Acute insulin response to IV glucose:normal and type 2 diabetic subjects G l u c o s e 1 0 0 G l u c o s e 1 0 0 8 0 8 0 6 0 6 0 Plasma Insulin (U/mL) 4 0 4 0 2 0 2 0 0 0 T i m e T i m e – 3 0 0 3 0 – 3 0 0 3 0 ( m i n ) ( m i n ) T y p e 2 D i a b e t e s l N o r m a Robertson & Porte. J Clin Invest. 1973

  42. Prevalence (%) BMI (kg/m2) 40 35 * 30 25 20 15 10 5 0 Koreans Japanese Americans Pima Indians Caucasians Prevalence of diabetes mellitus 1971 전북옥구, 김경식 등 전국, 김정순 등 1990 경기연천, 박용수 등 1993 1995 경기연천, 신찬수 등 전북정읍, 김영일 등 * 1997 전국, 보건복지부 1998 전북정읍, 박중열 등** 2003 (%) 0 2 4 6 8 10 12

  43. Insulin resistance & insulin secretary capacity Insulin secretion Insulin resistance Caucasians Koreans

  44. impaired insulin secretion Hyperglycemia  HGP  Glucose Uptake insulin resistance Pathogenesis of type 2 diabetes “Both insulin resistance and insulin deficiency contribute to the development of type 2 diabetes.” “Diminished fatty acid oxidation and increased lipid accumulation in non-adipose tissues”

  45. Thank you!

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