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1、Diabetes MellitusRenming Hu M.D,PhD Department of EndocrinologyHuashan HospitalInstitute of Endocrinology and Diabetes at Fudan University,Classification of diabetes(ADA-1997),Type 1(beta-cell destruction,usually leading to absolute insulin deficiency)Autoimmune Idiopathic Type 2(may range from pred
2、ominantly insulin resistance with relative insulin deficiency to a predominantly secretory defect with or without insulin resistance)Other specific types Gestational diabetes*,Other specific types,Genetic defects of beta-cell function Genetic defects in insulin action Diseases of the exocrine pancre
3、as Endocrinopathies Drug-or chemical-induced Infections Uncommon forms of immune-mediated diabetes Other genetic syndromes sometimes associated with diabetes,Pathogenesis,Pathology,Type 1 DM：inflammation of pancreasType 2 DM：amyloidosis of pancreasLarge vessel：atherosclerosisKidney：diffuse or nodula
4、r glomerular sclerosis Retina：arteriolar sclerosis、microaneurysm、exudates、new vessel formationNerve：axon degeneration、myelinolysis,Pathophysiology,Abnormalities in metabolism,Carbohydrate：anabolism，catabolism、utilization Lipid：anabolism，catabolism，ketoplasiaprotein：anabolism，catabolism，glyconeogenes
5、is,Insulin secretion curve:normal and diabetics,Clinical Presentation,Natural history of type 2 DM,After the diagnosis of type 2 diabetes:IR constantly exists Insulin secretion ability gradually declines:When FPG reachs the diagnostic criteria，insulin secretion ability has already declined by 50%Whe
6、n FPG7.0mmol/L，-cell insulin secretion ability When FPG1011.0mmol/L，-C insulin secretion ability has already neared absolute deficiency,Models of the onset of two phrases of type 2 DM,NGT IGR(IFG、IGT)DM,cell exhaustion,Insulin resistance,Insulin resistance,WHO plasma glucose guideline,IGT,75gOGTT2hP
7、G(mmol/L),FPG(mmol/L)7.06.1,FPG,7.8 11.1,IGT,Comparison of type 1 and type 2 DM,type1 DM type2 DMUsual age of onset 40yearsMode of onset acute chronicweight normal overweight or obesity or weight loss symptoms polyuria,polydipsia,similar but usually weight loss less severe presentation Acute complic
8、ations often fewChronic complicationsLarge vessel disease less then type 2 DM leading cause of deathRenal disease leading cause of death 5%10%Insulin and c-peptide low or lack peak value delayed,high or deficiencyImmune marker usually+usually-Therapy insulin dependence oral antidiabetic agents are a
9、vailable,Chronic complications,Macrovascular diseaseMicroangiopathyDiabetic retinopathyDiabetic renal diseaseDiabetic neuropathyDiabetic dermatopathyInfection,Mechanism of complications,Activation of polyol（or sorbitol）pathway Formation of non-enzyme saccharification products Change of hemodynamics
10、Activation of PKCMicroangiopathy theory,Hyperglycemia is the essential reason for diabetic complications,DCCT Diabetes Control and Complications Trial UKPDS United Kingdom Prospective Diabetes Study,UKPTS：results,HbA1c 0.9%，（intensive therapy vs routine therapy）Intensive therapy group:diabetis assoc
11、iated complications 12%，and the fatalness of microvascular complications 25%。It cannot evidently reduce the incidence of great vessel disease,such as miocardial infarction and strock.Most stimulating findings：Biguanides can prevent or slow the onset and/or progression of diabetic complications in ov
12、erweight patients Tight control of hypertension can prevent or slow the onset and/or progression of diabetic complications by 24%（144/82mmHg vs 154/87mmHg），stroke by 44%，microvascular complications by 37%。,Epidemiology of diabetes Macrovascular disease,Diabetics are easy to get atherosclerosis Monck
13、ebergs sclerosis 41.5Intimal arteriosteogenesis 29.3Coronary heart disease、cerebrovascular disease：24 timesRisk of miocardial infarction：10 timesRisk of stroke:3.8 times，especially in womenRisk of lower limb amputation：15times，fatalness,Hypertension in DM,Morbidity ratediabetes:20%40%Diabetes in EU(
14、35-54years):30%50%Diabetes in China:29.2%pathogenesisaortosclerosisArteriola resistance Hypertension associated with DNRenal hypertension caused by stenosis of renal artery,Diabetic retinopathyleading course of new cases of blindness Pathogeny：state of illness、course of disease、age of onset 5 years：
15、eyeground disease is not common 10 years：50eyeground disease 20 years：8090eyeground disease,Diabetic Retinopathy,Classifications(China),Background retinopathy microaneurysms、dots of hemorrhages yellow and white hard exudates,haemorrhages white soft exudates,haemorrhages spots Proliferative retinopat
16、hy new vessel formation、haemorrhage into the vitreous new vessel formation and fibrosis retinal detachment,Diabetic nephropathy,DN is the leading cause of ESRD(end-stage renal disease)Almost 40of Type 1 DM died of uremiaIncidence of DN in type 2 DM is about 20In EU，DN accounts for 1/3 of dialysis an
17、d kidney transplantation casesIn China,DN also accounts for quite a lot of dialyses and kidney transplantations,Stages of diabetic nephropathy(1),stage I increased kidney DM already filtration diagnosised GFR enlarged kidneys(B-ultrasonic)GFR130ml/minStage II clinically silent phase DM 25year GFR 20
18、40 renal enlargement，with continued glomerular hypertrophy,hyperfiltration and hypertrophy expansion of the mesangial matrix thickening of the glomerular basement membrane resulting in glomerulosclerosis Stage III concealed DN microalbuminuria DM510year microalbuminuria 1/5 patients with hypertensio
19、n(20-200g/min retinopothy,or30300mg/24h)proteinuria 0.150.5g/24h GFR or=normal,Stages of diabetic nephropathy(2),Stage IV Overt Nephropathy DM1025year albuminuria300mg/d 6070 patients proteinuria0.5g/d，with hypertentio GFR(when UAER=100 and edema mg/24h,GER begin to decrease，about 1ml/min/month)reti
20、nopathy Stage V end-stage renal disease,ESRD DM1530 year albuminuria azotemic uremia GFR 1/3 of normal,Classification of diabetes neuropathy（1）,Peripheral neuropathy symmetric multiple peripheral neuropathy sensibility multiple neuropathy numbness type pain type numbness-pain type sensomotor multipl
21、e neuropathy acute or sub-acute motor multiple neuropathy asymmetricsingle or multiple periphearal neuropathy member or torso mononeural cranial nerves disease radiculopathy proximal motor neuropathy autonomic neuropathy,Autonomic neuropathydiabetic myelopathy diabetic spinal ataxia spinal muscular
22、atrophyCerebropathy Hypoglycemia cerebropathy diabetic coma cerebrovascular disease,Diabetic sensability multiple neuropathy,more common in femaleAverage age of onset is 58.7yearCourse of DM 15yearsSymptoms of senseNumbness type：large medullated fibersPain type：little medullated fibers and nonmedull
23、ated fibersNumbness-pain type,Nervous symptom examinationparasthesiaLower limbs pallesthetic disturbance or dissapearTendon reflex low or dissappear Sensory staxiaParatrophy symptomsCharcot arthropathy、ischemic gangrenosis and foot ulcer,Diabetic autonomic neuropathy,Pupil diseaseCardiovascular para
24、functionFixed heart ratePostural hypertensionSudden cardiac deathGestrophageal,diarrheaNeuropathic bladder,erectile failureAbnormal sweating,Glucosuria：associated with renal threshold of sugar(only for clue)KetonuriaBlood sugar：plasma glucose，PODHBA1c：23 months blood sugar levelFructosamine：23 weeks
25、 blood sugar levelOGTT：2 hour specimenInsulin and C-peptide release test,Laboratory tests,Diagnosis,Criteria for diagnosing diabetes,FPG Random OGTT plasma glucose 2hPG mmol/L mmol/L mmol/LDM 7.0 11.1 11.1 IGR IFG 6.1FPG7.0 IGT 7.8FPG11.1Normal 6.1 7.8,Characteristics of new diabetic diagnostic crit
26、eria,FPG6.1mmol/L is normal fasting glucose，OGTT 2hPG7.8mmol/L is normal glucose tolerance；Impaired fasting glucose corresponding with impaired glucose tolerance(IFG)：6.1mmol/L FPG7.0 mmol/L；The cutoff value of FPG decline from 7.8mmol/L to 7.0mol/L.the cutoff values of OGTT2hrPG and random plasma g
27、lucose level are still 11.1mmol/L；FPG is the initial screening test of diabetes，OGTT is not recommended for routine diagnostic use.The diagnoses of Gestational diabetes is not changed,Practical problems in diagnosis,Symptoms random plasma glucose 11.1 mmol/L FPG：7.0 mmol/L OGTT：2hPG 11.1 mmol/L Asym
28、tomatic persons tests should be repeated the once,latent autoimmune diabetes mellitus in adults（LADA）,Adult onsetSymptoms are evidentSecretion function of cell is lowGADA positiveHLA-DQ B chain is non aspartate homozygote,Management,Goals,Good metabolism control（blood sugar、blood lipid、HBA1C etc）Rel
29、ieve symptomsKeeping good physiologic state and a social lifeGood quality of livePrevent the development of acute complications of diabetes（hypoglycemia、DKA、hyperosmolar nonketotic syndrome、lactic acidosis）Preventing the development or delaying the progression of the chronic complications of diabete
30、s,Principle of treatment,Early Life-longsynthesisindividual,Goals of control,good average badPBG(mmol/L)fasting 4.4-6.1 7.0 7.0 non-fasting 4.4-8.0 10.0 10.0HBA1c()7.5 BP(mmHg)130/80-140/90 BMI(Kg/m2)M 1.1 1.1-0.9 4.0,Control actuality of DM in China,26 centers、3965 patients28patients measure HbA1c：
31、8.12.6%，527.5FPG：9.2 3.7mmol/L，55%7.8 mmol/LDeterming rate of microalbumin in urine：20,Diabetes Management Plan,Patient educationHealth nutrition therapyExercise therapyDrug therapyMonitoring of blood glucose,Phases therapy of DM,Early reaction Patient therapyMedical nutrition therapyExercise therap
32、ySingle drug therapydecline of curative effect Combined drug therapySecondary failure、distinct insufficiency of insulinInsulin therapy,Principles of medical nutrition theraphy,rational control of total calorific value Goal：Keep ideal body weightLoss weight for obese patientAdd weight for lean patien
33、tStandard body weightheight（cm）105male：（height100）0.9female：（height100）0.85Body mass index（BMI）：weight（kg）/height2（m2）,Adult-onset diabetes thermal energy supply per day（therm/kg standard weight）,work intension Bodily form in bed light physical middle heavy labor physical physical labor laborlean 20
34、 25 35 40 40normal 15 20 30 35 40obesity 15 20 25 30 35,Nutrition principles of diabetics,Moderate weight control The distribution of total calorfic value：carbohydrate 55%60%fat 20%25%1/5、2/5、2/5protein 15%20%Drink limitation Avoiding diabetic foods(which contain sorbitol or frucotose)Aspartame is a
35、n acceptable calorie-free sweetenersalt10g/d，(3g/day if hypertensive),Calculation,protein：0.8 1.2/kg standard weight fat：0.6 1.0/kg standard weightcarbohydrate：total calorific value calories of protein and fat,Exercise therapy,BenefitsGlycaemic controlIncrease cell sensitivity to glucose Blood lipid
36、 Weight reductionEstimation of quantity of exercise：heart rate170age(year),Drug therapy,SulfonylureasBiguanides-glucosidase inhibitorsTniazolidinedionesMeglitinidesInsulinDry-combination therapy,Sulfonylureas:mode of action,The principal action of these drugs is to stimulate endogenous insulin secre
37、tion from the pancreatic-cells Not to increase synthesis of insulin Also to increase-cells sensitivity to glucose and exert some influence in diminishing insulin resistance.,Sulfonylureas（SU）：first choice of non-obesity T2DM,General name duration of action potency merits main site of excretionTolbut
38、amide(D860)short weak cheap renalGlyburide(micronase)long strong affirmed hypoglycemia effects in lowering blood glucose levels cheap renal Gliclazide(diamicvon)medium strong prevent and renalglipizide(minidiab)shot strong affirmed effects renalGliquidone(glurenorm)shot week not renal(only5%)Glipizi
39、de(tonbac)long strong good compliance low incidence of hypoglycemia,Therapeutic effects of SU,Primary failure to respond to SU occurs in 20%to 25%of patientsFPG and 2hPG HbA1c 1%2As the period of treatment progresses,effects decline：Secondary failure occurs at the rate of 10%to 15%per year After 5 y
40、ears，only half of the patients can keep ideal blood glucose control.UKPDS：first year:blood glucose，insulin then:blood glucose insulin the 6th year:returned to the state before therapy,Indications and contraindications of SU,IndicationsPoor control of T2DM by weight control and physical activityPoor
41、control of T2DM by biguanides and-Combined with insulinContraindications T1DMAcute or chronic diabetic complicationsEmergency Dysfunction of liver or kidneyPregnant or bleeding women,Side effects of SU,Hypoglycemia，most common inOld patientsLong-term pharmaceuticsSymptoms of digestive tractLiver dys
42、functionTetterChange of hematology,Biguanides：first choice of obesity type 2 DM,Generic name dosage merits NB phenformin 75mg/d cheap lactic acidosis（降糖灵）restrain oxygenic metabolism lower energy of oxygenic metabolism dimethylbiguanide 1.5g/d low gastrointestinal side-effects reaction（降糖片）,Mechanis
43、ms of action of biguanides,Increasing cell sensitivity to glucose Enhancing glucose uptake and utilization by muscleReducing HGP by inhibiting gluconeogenesis.Decreasing intestinal glucose absorptionDo Not stimulating endogenous insulin secretion from cellDo Not causing hypoglycemia when used singly
44、,indications and contraindications of Biguanides,Indications Obesity T2DMPoor control by SUPoor control by insulin，including T1DMSimple obesityPolycystic ovary syndromeContraindications Allergic reactionsRenal dysfunction，serum creatinine1.4mg/dlAcute or chronic acidosisHeart、lung disease：hypoxia、ac
45、idosis inclinationHypohepatiaSevere gastroenteropathyPregnancy,Side effects of Biguanides,DiarrheaAnaphylaxisOvert macies：common in elderly patientsLactic acidosis,Inhibiting-glucosidase Delaying the digestion of glucose2hPG Not stimulating the secretion of Insulin,-glucosidase inhibitors:mode of ac
46、tion,Therapeutic effects of Acarbose,2hPGFPGHbA1c about 1.When used in combination with SU,HbA1c:about2Serum insulin slightly declined Weight not a few patients When used as monotherapy,it do not cause hypoglycemia When used in combination with other oral antidiabetic agents,it may cause hypoglyceia
47、If hypoglycemia happens,patient should be treated by glucose.Other kinds of sugar are ineffective,Indications and contraindications of-glucosidase inhibitors,Indications Light casesusing drug separately or combinedIGT intervention，securityContraindications Allergic reactions Severe gastroenteropathy
48、Dysfunction of renal and liver Acute complications Emergency Pregnant and breast feeding women,thiazolidinedion（TZD）：insulin sensitizers,Insulin sensitizers;agonist at the peroxisome proliferator-activated receptor（PPAR）;increase glucose utilization in peripheral tissues.Reducing insulin resistance，
49、hyperglycemia and hyperlipaemia and hypertension can be improved at varies degrees For T2DM:used as monotherapy or in combination with SU,insulin.When used in combination with SU or insulin,hyperglycemia Without insulin，it cannot reduce hyperglycemiaLiver function should be monitored frequently.Stop
50、 using it in case liver dysfunction is found.Incidence of edema:45%It may cause Hb slightly,Meglitinides：repaglinide,Stimulate Pancreatic insulin secretion（similar with SU）：specific combinition with 36KDa protein K pathway closeStimulating the first phrase secretion of insulin Action:rapid onset，sho
