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1、Diabetes Mellitus Renming Hu M.D,PhD Department of Endocrinology Huashan Hospital Institute 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 fr
2、om predominantly 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 exocrin
3、e pancreas 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 pancreas Type 2 DM：amyloidosis of pancreas Large vessel ：atherosclerosis Kidney ：dif
4、fuse or nodular glomerular sclerosis Retina：arteriolar sclerosis、microaneurysm、exudates、new vessel formation Nerve：axon degeneration 、myelinolysis,Pathophysiology,Abnormalities in metabolism,Carbohydrate ：anabolism ，catabolism、 utilization Lipid ： anabolism ，catabolism ，ketoplasia protein： anabolism
5、 ，catabolism ，glyconeogenesis,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
6、has already declined by 50% When 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
7、glucose guideline,IGT,75gOGTT 2hPG (mmol/L),FPG (mmol/L) 7.0 6.1,FPG,7.8 11.1,IGT,Comparison of type 1 and type 2 DM,type1 DM type2 DM Usual age of onset 40years Mode of onset acute chronic weight normal overweight or obesity or weight loss symptoms polyuria,polydipsia, similar but usually weight lo
8、ss less severe presentation Acute complications often few Chronic complications Large vessel disease less then type 2 DM leading cause of death Renal disease leading cause of death 5%10% Insulin and c-peptide low or lack peak value delayed ,high or deficiency Immune marker usually + usually - Therap
9、y insulin dependence oral antidiabetic agents are available,Chronic complications,Macrovascular disease Microangiopathy Diabetic retinopathy Diabetic renal disease Diabetic neuropathy Diabetic dermatopathy Infection,Mechanism of complications,Activation of polyol （or sorbitol）pathway Formation of no
10、n-enzyme saccharification products Change of hemodynamics Activation of PKC Microangiopathy 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 thera
11、py vs routine therapy） Intensive therapy group: diabetis associated 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
12、 slow the onset and/or progression of diabetic complications in overweight 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 M
13、acrovascular disease,Diabetics are easy to get atherosclerosis Monckebergs sclerosis 41.5 Intimal arteriosteogenesis 29.3 Coronary heart disease、cerebrovascular disease：24 times Risk of miocardial infarction： 10 times Risk of stroke : 3.8 times，especially in women Risk of lower limb amputation：15tim
14、es ，fatalness,Hypertension in DM,Morbidity rate diabetes: 20%40% Diabetes in EU(35-54years): 30%50% Diabetes in China: 29.2% pathogenesis aortosclerosis Arteriola resistance Hypertension associated with DN Renal hypertension caused by stenosis of renal artery,Diabetic retinopathyleading course of ne
15、w cases of blindness Pathogeny：state of illness 、course of disease、age of onset 5 years ：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 whi
16、te hard exudates , haemorrhages white soft exudates , haemorrhages spots Proliferative retinopathy 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
17、 DM died of uremia Incidence of DN in type 2 DM is about 20 In EU，DN accounts for 1/3 of dialysis and kidney transplantation cases In 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 diagn
18、osised GFR enlarged kidneys(B- ultrasonic) GFR130ml/min Stage II clinically silent phase DM 25year GFR 2040 renal enlargement， with continued glomerular hypertrophy, hyperfiltration and hypertrophy expansion of the mesangial matrix thickening of the glomerular basement membrane resulting in glomerul
19、osclerosis Stage III concealed DN microalbuminuria DM510year microalbuminuria 1/5 patients with hypertension (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 prote
20、inuria0.5g/d ， with hypertentio GFR(when UAER=100 and edema mg/24h , GER begin to decrease， about 1ml/min/month) retinopathy 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 multi
21、ple peripheral neuropathy sensibility multiple neuropathy numbness type pain type numbness-pain type sensomotor multiple neuropathy acute or sub-acute motor multiple neuropathy asymmetricsingle or multiple periphearal neuropathy member or torso mononeural cranial nerves disease radiculopathy proxima
22、l motor neuropathy autonomic neuropathy,Autonomic neuropathy diabetic myelopathy diabetic spinal ataxia spinal muscular atrophy Cerebropathy Hypoglycemia cerebropathy diabetic coma cerebrovascular disease,Diabetic sensability multiple neuropathy,more common in female Average age of onset is 58.7year
23、 Course of DM 15years Symptoms of sense Numbness type：large medullated fibers Pain type：little medullated fibers and nonmedullated fibers Numbness-pain type,Nervous symptom examination parasthesia Lower limbs pallesthetic disturbance or dissapear Tendon reflex low or dissappear Sensory staxia Paratr
24、ophy symptoms Charcot arthropathy、ischemic gangrenosis and foot ulcer,Diabetic autonomic neuropathy,Pupil disease Cardiovascular parafunction Fixed heart rate Postural hypertension Sudden cardiac death Gestrophageal ,diarrhea Neuropathic bladder,erectile failure Abnormal sweating,Glucosuria：associat
25、ed with renal threshold of sugar (only for clue) Ketonuria Blood sugar：plasma glucose，POD HBA1c：23 months blood sugar level Fructosamine：23 weeks blood sugar level OGTT：2 hour specimen Insulin and C-peptide release test,Laboratory tests,Diagnosis,Criteria for diagnosing diabetes,FPG Random OGTT plas
26、ma glucose 2hPG mmol/L mmol/L mmol/L DM 7.0 11.1 11.1 IGR IFG 6.1FPG7.0 IGT 7.8FPG11.1 Normal 6.1 7.8,Characteristics of new diabetic diagnostic criteria,FPG6.1mmol/L is normal fasting glucose，OGTT 2hPG7.8mmol/L is normal glucose tolerance； Impaired fasting glucose corresponding with impaired glucos
27、e 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 glucose level are still 11.1mmol/L； FPG is the initial screening test of diabetes ，OGTT is not recommended for routine diagnostic use. The diagnoses
28、 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 Asymtomatic persons tests should be repeated the once,latent autoimmune diabetes mellitus in adults （LADA）,Adult onset Symptoms are evident Secreti
29、on function of cell is low GADA positive HLA-DQ B chain is non aspartate homozygote,Management,Goals,Good metabolism control（blood sugar、blood lipid、HBA1C etc） Relieve symptoms Keeping good physiologic state and a social life Good quality of live Prevent the development of acute complications of dia
30、betes（hypoglycemia、DKA、hyperosmolar nonketotic syndrome、lactic acidosis） Preventing the development or delaying the progression of the chronic complications of diabetes,Principle of treatment,Early Life-long synthesis individual,Goals of control,good average bad PBG(mmol/L) fasting 4.4 - 6.1 7.0 7.0
31、 non-fasting 4.4 - 8.0 10.0 10.0 HBA1c() 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 patients 28patients measure HbA1c：8.12.6%，527.5 FPG：9.2 3.7mmol/L，55%7.8 mmol/L Determing rate of microalbumin in urine ：20,Diabetes Management Plan,Pat
32、ient education Health nutrition therapy Exercise therapy Drug therapy Monitoring of blood glucose,Phases therapy of DM,Early reaction Patient therapy Medical nutrition therapy Exercise therapy Single drug therapy decline of curative effect Combined drug therapy Secondary failure、distinct insufficien
33、cy of insulin Insulin therapy,Principles of medical nutrition theraphy,rational control of total calorific value Goal ： Keep ideal body weight Loss weight for obese patient Add weight for lean patient Standard body weight height（cm）105 male： （height100 ）0.9 female： （height100 ）0.85 Body mass index（B
34、MI） ：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 labor lean 20 25 35 40 40 normal 15 20 30 35 40 obesity 15 20 25 30 35,Nutrition principles of diabe
35、tics,Moderate weight control The distribution of total calorfic value ： carbohydrate 55 %60% fat 20%25% 1/5、 2/5、 2/5 protein 15 %20% Drink limitation Avoiding diabetic foods (which contain sorbitol or frucotose) Aspartame is an acceptable calorie-free sweetener salt10g/d，(3g/day if hypertensive),Ca
36、lculation,protein：0.8 1.2/kg standard weight fat：0.6 1.0/kg standard weight carbohydrate：total calorific value calories of protein and fat,Exercise therapy,Benefits Glycaemic control Increase cell sensitivity to glucose Blood lipid Weight reduction Estimation of quantity of exercise：heart rate170age
37、 (year),Drug therapy,Sulfonylureas Biguanides -glucosidase inhibitors Tniazolidinediones Meglitinides Insulin Dry-combination therapy,Sulfonylureas: mode of action,The principal action of these drugs is to stimulate endogenous insulin secretion from the pancreatic -cells Not to increase synthesis of
38、 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 excretion Tolbutamide (D860) short weak cheap renal Glyburide (micronas
39、e) long strong affirmed hypoglycemia effects in lowering blood glucose levels cheap renal Gliclazide (diamicvon) medium strong prevent and renal glipizide (minidiab) shot strong affirmed effects renal Gliquidone (glurenorm ) shot week not renal(only5%) Glipizide (tonbac) long strong good compliance
40、low incidence of hypoglycemia,Therapeutic effects of SU,Primary failure to respond to SU occurs in 20% to 25% of patients FPG and 2hPG HbA1c 1% 2 As the period of treatment progresses, effects decline： Secondary failure occurs at the rate of 10% to 15% per year After 5 years ，only half of the patien
41、ts 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,Indications Poor control of T2DM by weight control and physical activity Poor control of T2DM by
42、biguanides and - Combined with insulin Contraindications T1DM Acute or chronic diabetic complications Emergency Dysfunction of liver or kidney Pregnant or bleeding women,Side effects of SU,Hypoglycemia， most common in Old patients Long-term pharmaceutics Symptoms of digestive tract Liver dysfunction
43、 Tetter Change 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）,Mechanisms
44、 of action of biguanides,Increasing cell sensitivity to glucose Enhancing glucose uptake and utilization by muscle Reducing HGP by inhibiting gluconeogenesis. Decreasing intestinal glucose absorption Do Not stimulating endogenous insulin secretion from cell Do Not causing hypoglycemia when used sing
45、ly,indications and contraindications of Biguanides,Indications Obesity T2DM Poor control by SU Poor control by insulin，including T1DM Simple obesity Polycystic ovary syndrome Contraindications Allergic reactions Renal dysfunction，serum creatinine1.4mg/dl Acute or chronic acidosis Heart、lung disease：hypoxia、acidosis inclination Hypohepatia Severe gastroenteropathy Pregnancy,Side effects of Biguanides,Diarrhea Anaphylaxis Overt macies ：common in elderly patients Lactic acidosis,Inhibiting -glucosidase Delaying the digestion