郑佳辉 李英伟 任为正 张铁红 高会杰 陈 鹏 樊明德 冯小迪

CaseCase Wang Ming, male, 6 years old .He was sent to Wang Ming, male, 6 years old .He was sent to

hospital for cold ,headache ,felt unusual thirhospital for cold ,headache ,felt unusual thirsty,so he drinks very much and urinate frequsty,so he drinks very much and urinate frequently day and night .Eat much,but weight losently day and night .Eat much,but weight loss, abdomenal pain,No fever, sweating, visual s, abdomenal pain,No fever, sweating, visual blurring or edema on lower limb.blurring or edema on lower limb.

Blood routine and urine routine have been cBlood routine and urine routine have been carried out. which show that : blood glucose arried out. which show that : blood glucose (after fasting for 8 hrs) (after fasting for 8 hrs) ＞＞ 27.8mmol/l, WBC 27.8mmol/l, WBC ＞＞ 17.2 × 109 L, Urinary glucose ++++,ketone 17.2 × 109 L, Urinary glucose ++++,ketone body +++body +++

Immunological tests show that ICA is positivImmunological tests show that ICA is positivee

DIAGNOSISDIAGNOSIS

““drink much, polyuria, more food,drink much, polyuria, more food, weight loss” weight loss”

““blood glucose (after fasting for 8 blood glucose (after fasting for 8 hrs )hrs ) ＞＞ 27.8mmol/l, Urinary gluco27.8mmol/l, Urinary glucose :4 +,”se :4 +,”

Diabetes

Complications of diabetesComplications of diabetes Keto acidosisKeto acidosis pathological changes of heart: pathological changes of heart:

heart failure, angina, miocardiheart failure, angina, miocardial infarctional infarction

pathological changes of eyes: ipathological changes of eyes: iritis, glaucoma, cataractritis, glaucoma, cataract

pathological changes of foot : pathological changes of foot : GangreneGangrene

pathological changes of nerve, pathological changes of nerve, kidneykidney

Classification of diabetesClassification of diabetes

Diabetes others

type1 type2 GDM

Immune mediated Idiopathic

Autoimmune type1 diabetes Autoimmune type1 diabetes mellitusmellitus

•apparent keto acidosis• Immunological tests show that ICAs(self—Ab) is positive

Autoimmue type1 diabetes mAutoimmue type1 diabetes mellitusellitus

Clinical manifestationClinical manifestation Cause and MechanismCause and Mechanism Prevention and treatmentPrevention and treatment

Clinical manifestationClinical manifestation

Two typesTwo types ：：• Adolescent type1Adolescent type1 LADALADA• (latent-onset diabetes in adult)(latent-onset diabetes in adult)• Onset : Onset : Acute Acute chronic chronic • Classical syndrom:Classical syndrom:apparent apparent hiddenhidden• Keto acidosis : Keto acidosis : yes yes under infection/stressunder infection/stress• both lack of insulin absolutelyboth lack of insulin absolutely• treatment:insulintreatment:insulin• self—Ab(ICA, GAD-Ab ,IA-2,IAA)self—Ab(ICA, GAD-Ab ,IA-2,IAA)

CauseCause

Function of heredityFunction of heredity

Environmental factor

Function of heredityFunction of heredity

Consistent rate of type1 diabetes in Consistent rate of type1 diabetes in monozygotic twins is 30%----50%monozygotic twins is 30%----50%

The probability that relatives of patients The probability that relatives of patients suffer type 1 diabetes is 5%----10%,while suffer type 1 diabetes is 5%----10%,while the probability of common people is the probability of common people is 0.4%0.4%

Statistics indicate that type1 diabetes is highly related to heredity ,so far many susceptible genes of the disease have been discovered

Susceptible genes of type1 Susceptible genes of type1 diabetesdiabetes

Susceptible genesSusceptible genes chromosomechromosome Link markerLink marker

IDDM1IDDM1 6P216P21 HLA-DQBHLA-DQB

IDDM2IDDM2 11P1511P15 Insulin VNTRInsulin VNTR

IDDM3IDDM3 15q2615q26 Insulin VNTRInsulin VNTR

IDDM4IDDM4 11q1311q13 FGF3,D11S1337FGF3,D11S1337

IDDM5IDDM5 6q256q25 D6S476-ESR-D6S476-ESR-D6S448D6S448

IDDM6IDDM6 2q312q31 D2S152D2S152

IDDM7IDDM7 6q276q27 D6S281D6S281

IDDM8IDDM8 14q24,3-q3114q24,3-q31 D14S67D14S67

IDDM11IDDM11 2q332q33 CTLA-4CTLA-4

IDDM12IDDM12 7q347q34 IGFBP-2,-5IGFBP-2,-5

HLA-DR and HLA-DQ linked with IDDM1 are HLA-DR and HLA-DQ linked with IDDM1 are closely related to type1 diabetes closely related to type1 diabetes

The 57The 57thth aa residue on the product of DQβch aa residue on the product of DQβchain:ain:

Asp –resistanceAsp –resistance Ala ,vla: susceptibleAla ,vla: susceptible The mutation of the genes can change the sThe mutation of the genes can change the s

pecificity of MHC-Ⅱbinding with self/non-sepecificity of MHC-Ⅱbinding with self/non-self Aglf Ag

Environmental factorsEnvironmental factors

Virus: Virus: 科萨奇科萨奇 B4 B4 病毒病毒 , , 风疹病毒风疹病毒 , , 腮腺腮腺炎病毒炎病毒

Chemical substance: Vacor( 一种硝基酚脲类鼠药）Milk albumin

Cytotoxic substance: 如腐烂的木薯淀粉

Autoimmune trigger Autoimmune trigger mechanism mechanism

Molecular mimicry ( cross reaction )Molecular mimicry ( cross reaction )

Abnormal expression of HLA-Ⅱ

Molecular mimicry (cross Molecular mimicry (cross reaction)reaction)

Basis of cross reaction : Basis of cross reaction : common antigen determina common antigen determinantnt

科萨奇科萨奇 B4B4 病毒和病毒和 GAD(GAD( 谷氨酸谷氨酸脱羧酶）脱羧酶）

牛乳白蛋白与牛乳白蛋白与 P69P69 蛋白（胰岛素蛋白（胰岛素ββ 细胞表面蛋白）细胞表面蛋白）

Nonself antigen

Activated T cell

CTL

B ____ TH2 cell cell

TH1

Ab

MMФФIsletβ cells

Abnormal expression of Abnormal expression of HLA-Ⅱ HLA-Ⅱ

Islet βcell CD4+

T

TH1↑

TH2↓

CKs

macrophage

CD8+T

MHC-Ⅱ

Fas-fasLFas-fasL

Activated T cell

macrophage

βcell

FasCTL

FasL

Isletβcell apoptosis

IFN-r

IL-1

lymphocytes infiltration in lymphocytes infiltration in pancreas (rat)pancreas (rat)

characteristiccharacteristic Autoimmune type1 diabetes mellitus is Autoimmune type1 diabetes mellitus is

caused by destruction of islet β cell caused by destruction of islet β cell mediated by autoimmune response 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

Therapy and preventionTherapy and prevention

Now the Insulin Now the Insulin therapy is the most therapy is the most effective. Once the effective. Once the Type I diabetics is Type I diabetics is diagnosed, they will diagnosed, they will have to rely on have to rely on insulin all the life, or insulin all the life, or else their lives will else their lives will be endangered. 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。

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

Sugar or not?Sugar or not?

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

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

TRPV1+ sensory neurons control TRPV1+ sensory neurons control beta cell stress and islet beta cell stress and islet

inflammation in autoimmune inflammation in autoimmune

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

Thank you so much!Thank you so much!

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

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