郑佳辉 李英伟 任为正 张铁红 高会杰 陈 鹏 樊明德 冯小迪

1. 郑佳辉 李英伟 任为正 张铁红 高会杰 陈 鹏 樊明德 冯小迪

2. Case • Wang Ming, male, 6 years old .He was sent to hospital for cold ,headache ,felt unusual thirsty,so he drinks very much and urinate frequently day and night .Eat much,but weight loss, abdomenal pain,No fever, sweating, visual blurring or edema on lower limb. • Blood routine and urine routine have been carried out. which show that : blood glucose (after fasting for 8 hrs) ＞27.8mmol/l, WBC ＞17.2 × 109 L, Urinary glucose ++++,ketone body +++ • Immunological tests show that ICA is positive

3. DIAGNOSIS • “drink much, polyuria, more food, weight loss” • “blood glucose (after fasting for 8 hrs )＞27.8mmol/l, Urinary glucose :4 +,” Diabetes

4. Complications of diabetes • Keto acidosis • pathological changes of heart: heart failure, angina, miocardial infarction • pathological changes of eyes: iritis, glaucoma, cataract • pathological changes of foot : Gangrene • pathological changes of nerve, kidney

5. Classification of diabetes Diabetes others type2 GDM type1 Immune mediated Idiopathic

6. Autoimmune type1 diabetes mellitus • apparent keto acidosis • Immunological tests show that ICAs(self—Ab) is positive

7. Autoimmue type1 diabetes mellitus • Clinical manifestation • Cause and Mechanism • Prevention and treatment

8. Clinical manifestation • Two types： • Adolescent type1LADA • (latent-onset diabetes in adult) • Onset : Acute chronic • Classical syndrom:apparent hidden • Keto acidosis : yes under infection/stress • both lack of insulin absolutely • treatment:insulin • self—Ab(ICA, GAD-Ab ,IA-2,IAA)

9. Cause • Function of heredity Environmental factor

10. Function of heredity • Consistent rate of type1 diabetes in monozygotic twins is 30%----50% • The probability that relatives of patients suffer type 1 diabetes is 5%----10%,while the probability of common people is 0.4% Statistics indicate that type1 diabetes is highly related to heredity ,so far many susceptible genes of the disease have been discovered

11. Susceptible genes of type1 diabetes

12. HLA-DR and HLA-DQ linked with IDDM1 are closely related to type1 diabetes • The 57th aa residue on the product of DQβchain: • Asp –resistance • Ala ,vla: susceptible • The mutation of the genes can change the specificity of MHC-Ⅱbinding with self/non-self Ag

13. Environmental factors • Virus: 科萨奇B4 病毒, 风疹病毒, 腮腺炎病毒 Chemical substance: Vacor(一种硝基酚脲类鼠药） Milk albumin Cytotoxic substance: 如腐烂的木薯淀粉

14. Autoimmune trigger mechanism • Molecular mimicry ( cross reaction ) Abnormal expression of HLA-Ⅱ

15. Molecular mimicry (cross reaction) • Basis of cross reaction : common antigen determinant • 科萨奇B4病毒和GAD(谷氨酸脱羧酶） • 牛乳白蛋白与P69蛋白（胰岛素β细胞表面蛋白）

16. Activated T cell Nonself antigen CTL TH1 MФ Isletβ cells Ab B ____ TH2 cell cell

17. Abnormal expression of HLA-Ⅱ Islet βcell MHC-Ⅱ CD4+T CKs TH1↑ CD8+T macrophage TH2↓

18. Fas-fasL Activated T cell IFN-r Fas FasL CTL βcell IL-1 macrophage Isletβcell apoptosis

19. lymphocytes infiltration in pancreas (rat)

20. characteristic • Autoimmune type1 diabetes mellitus is caused by destruction of islet β cell mediated by autoimmune response The marker of Autoimmune destruction of cells include:ICA GAD-Ab IA-2 Patients often have family history of Autoimmune diseases Polygenic susceptibility tendency Closely related to the HLA genes

21. Therapy and prevention

22. Now the Insulin therapy is the most effective. Once the Type I diabetics is diagnosed, they will have to rely on insulin all the life, or else their lives will be endangered. 1978年，美国化学家W·吉尔伯特（他1980年因发明基因测序技术获得诺贝尔化学奖）领导的研究小组，利用重组DNA技术成功地使大肠杆菌生产出胰岛素。

23. But nowadays, the most effective way in confronting diabetes is still healthy and proper diet and doing proper amount of physical exercises.

24. Sugar or not? A diet with a strict limitation on sugar is not suggest for type 1 diabetes. Yes, that means the patient is allowed to take food with sugar but just in case that insulin is injected regularly, and still, the intake of refined sugar should still be limited. Food rich in protein is suggested.

25. Breast feed is very important to prevent autoimmune type1 diabetes.since milk albumin can probably induce the disease

26. TRPV1+ sensory neurons control beta cell stress and islet inflammation in autoimmune diabetes In type 1 diabetes, T cell-mediated death of pancreatic beta cells produces insulin deficiency. However, what attracts or restricts broadly autoreactive lymphocyte pools to the pancreas remains unclear. We report that TRPV1(+) pancreatic sensory neurons control islet inflammation and insulin resistance. Eliminating these neurons in diabetes-prone NOD mice prevents insulitis and diabetes, despite systemic persistence of pathogenic T cell pools. Insulin resistance and beta cell stress of prediabetic NOD mice are prevented when TRPV1(+) neurons are eliminated. TRPV1(NOD), localized to the Idd4.1 diabetes-risk locus, is a hypofunctional mutant, mediating depressed neurogenic inflammation. Delivering the neuropeptide substance P by intra-arterial injection into the NOD pancreas reverses abnormal insulin resistance, insulitis, and diabetes for weeks. Concordantly, insulin sensitivity is enhanced in trpv1(-/-) mice, whereas insulitis/diabetes-resistant NODxB6Idd4-congenic mice, carrying wild-type TRPV1, show restored TRPV1 function and insulin sensitivity. Our data uncover a fundamental role for insulin-responsive TRPV1(+) sensory neurons in beta cell function and diabetes pathoetiology.

27. Thank you so much!

28. The complication of diabetes also costs the sights of many patients, leaving them in the world of darkness for ever.

29. Recently, there is data demonstrating that 70% of the patients that suffer from amputation are due to the complication of diabetes.