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1、2023/10/17,Beijing Xuanwu Hospital,1,Diabetes Mellitus,2023/10/17,Beijing Xuanwu Hospital,2,Diabetes Mellitus,definitiontypessymptoms diagnosisLaboratory findingstreatmentcomplications,2023/10/17,Beijing Xuanwu Hospital,3,Definition-WHO(4/2000),The term diabetes mellitus describes a metabolic disord
2、er of multiple aetiology characterized by chronic hyperglycaemia with disturbances of carbohydrate,fat and protein metabolism resulting from defects in insulin secretion,insulin action,or both,2023/10/17,Beijing Xuanwu Hospital,4,Definition,A metabolic condition characterised by high plasma glucose
3、levels and chronic vascular complicationsA vascular disease affecting small and large arteries with coexistent metabolic disturbance particularly high plasma glucose levels,2023/10/17,Beijing Xuanwu Hospital,5,Diabetes Mellitus,definitiontypessymptoms diagnosisLaboratory findingstreatmentcomplicatio
4、ns,2023/10/17,Beijing Xuanwu Hospital,6,Aetiological Classification of Disorders of Glycaemia,Type 1(betacell destruction,usually leading to absolute insulin deficiency):Autoimmune:IdiopathicType 2(may range from predominantly insulin resistance with relative insulin deficiency to a predominantly se
5、cretory defect with or without insulin resistance),Other specific types Genetic defects of betacell function Genetic defects in insulin actionDiseases of the exocrine pancreas Endocrinopathies Drug or chemicalinduced Infections Uncommon forms of immunemediated diabetesOther genetic syndromes sometim
6、es associated with diabetesGestational diabetes,2023/10/17,Beijing Xuanwu Hospital,7,Type 1 diabetes,Previously known as IDDM(Insulin dependent diabetes)Ketosis prone:Usually diagnosed in younger age group(30 years)(Peak incidence 11-13 yr)Prevalence highly variable but approximately 0.20%with an in
7、cidence of 15-20 per 100000 population aged less than 21Seasonal variation-with lowest rate in spring and summer,2023/10/17,Beijing Xuanwu Hospital,8,Type 1 diabetes mellitus,Immune-mediated type 1 diabetes acute LADA latent autoimmune diabetes in adults Idiopathic type 1 diabetes mellitus,2023/10/1
8、7,Beijing Xuanwu Hospital,9,Type 1 diabetes mellitus,GeneticsEnvironmental factor Viruses Chemical agentsAutoimmune Auto-antibodies:islet cell cytoplasm antibody(ICCA)islet cell surface antibody(ICSA)glutamic acid decarboxylase antibody GADA(64KD)Insulin antibody(IAA),2023/10/17,Beijing Xuanwu Hospi
9、tal,10,Type 1 diabetes,This presentation is the end point of recent and continuing beta cell function resulting in near total loss of Insulin productionHyperglycaemia itself begets further beta cell destruction as treatment with insulin often results in a“honeymoon”period when the patient can often
10、manage without insulin,2023/10/17,Beijing Xuanwu Hospital,11,Type 1 diabetes mellitususually autoimmune destruction of insulin-producing pancreatic islet cellsover monthsabsolute insulin deficiencyrapid presentation withthirst,polyuria,weight loss,blurred visionthrush,lethargy,dizziness.nausea,vomit
11、ing,abdominal cramps,and superficial infectionusually thin and ketotic at presentation Auto-antibodies identified:anti islet cell(ICCA.ICSA),anti GAD(64KD),anti Insulin(IAA),2023/10/17,Beijing Xuanwu Hospital,12,A progressive metabolic disordercharacterised by:,Insulin resistance,Type 2diabetes,-cel
12、l dysfunction,2023/10/17,Beijing Xuanwu Hospital,13,Type 2 diabetes,Previously known as NIDDMNon ketosis prone:,diagnosis 30 years1 in 1000 population as new cases each year Insidious presentation with symptoms of polyuria,polydipsia,lethargy,weight loss,nausea,vomiting,abdominal cramps,blurred visi
13、on and superficial infection.Often discovered at routine medicalThis presentation is the end point of the gradual loss of beta cell function in the setting of Insulin resistanceStrong(90-100%)concordance in TwinsReavans syndrome or Syndrome X Insulin resistance,2023/10/17,Beijing Xuanwu Hospital,14,
14、Type 2 diabetesUnderlying insulin resistancegenetic and ethnicityObesity BMI WHR inactivity/low physical fitnessintrauterine&childhood factorssmoking&drugsImpaired insulin secretionInsulin secretion worsens with time,2023/10/17,Beijing Xuanwu Hospital,15,Type 2 diabetes,2023/10/17,Beijing Xuanwu Hos
15、pital,16,Pancreatic-cell,Insulin resistance,Liver,HYPERGLYCAEMIA,Islet-cell degranulationReduced insulin content,Adipose tissue,Decreased glucose transport&activity(expression)of GLUT-4,Increased lipolysis,Elevated plasma NEFA,+,-,Low plasmainsulin,Increased glucose output,ElevatedTNF,Insulin resist
16、ance and-cell dysfunctionproduce hyperglycaemia in type 2 diabetes,2023/10/17,Beijing Xuanwu Hospital,17,Tissue Responses to InsulinResistance or Failure,LIVER a.increased glycogen hydrolysis to glucose b.increased gluconeogenesis.c.increased triacylglycerol hydrolysis and conversion of glycerol to
17、glucose d.increased conversion of FA and protein to ketones(AcAc and BHB)e.increased protein and amino acid catabolism f.increased production of urea,2023/10/17,Beijing Xuanwu Hospital,18,MUSCLE,a.serum glucose is poorly taken up by muscle(decrease GLUT activity)b.saturation of hexokinase activity,i
18、nability to retain cellular glu as glu-6-PO4c.increased LPL activity and increased FA productiond.increased b-oxidation,but TCA is overwhelmed because ATP is high alreadyee.increased breakdown of muscle and serum protein into amino acidsf.increased transfer of N onto ALA/GLN and sent back to liver,2
19、023/10/17,Beijing Xuanwu Hospital,19,ADIPOSE,a.increased LPL and HSL send more free FA into bloodstreamb.glucose can not be taken into cell via GLUT4 for glycogen synthesisc.active HSL means TAGs are not being made and stored,2023/10/17,Beijing Xuanwu Hospital,20,Insulin resistance and insulinhypers
20、ecretion precede type 2 diabetes,Insulin Insulin Macrovascularsensitivity secretion disease 30%50%50%50%70100%40%70%150%10%100%100%,Type 2 diabetes,IGT,Impaired glucose metabolism,Normal glucose metabolism,2023/10/17,Beijing Xuanwu Hospital,21,Clinical Reavans Syndrome,Insulin resistanceHypertension
21、Dyslipidaemia(increase LDL,decreased HDL)ObesityOther factors:hyperfibrinogenemia,hyperuricaemia,propensity to microvascular diseases“Metabolic syndrome”in most cases of type 2 diabetes,2023/10/17,Beijing Xuanwu Hospital,22,abdominal obesity,high blood pressure,HDL cholesterol VLDL triglyceride smal
22、l dense LDL,hyperinsulinaemiaglucose intolerancediabetes,hyperuricaemia,PAI-1 fibrinogen factor VII,microalbuminuria,insulin resistance,Syndrome of insulin resistance,AKA Reavens syndrome,syndrome Xmetabolic syndrome,2023/10/17,Beijing Xuanwu Hospital,23,Type 1 diabetestypical onset 30 yearscan star
23、t at any agesudden onsetsevere symptomsrecent weight lossusually thinspontaneous ketosisabsent C-peptidemarkers of autoimmunity,Type 2 diabetestypical onset 20 yearscan start at any agegradual onsetmay be no symptomsoften no weight lossusually obesenot ketoticdetectable C-peptideno autoimmune marker
24、s,2023/10/17,Beijing Xuanwu Hospital,24,Diabetes in pregnancyco-existent or newly diagnosed lifelong diabetestype 1 type 2(especially in South Asian women)other specific types of diabetesgestational diabetes,2023/10/17,Beijing Xuanwu Hospital,25,Other types of Diabetes,Genetic defects of betacell fu
25、nctionChrme 20,HNF4_(MODY1)Chrme 7,glucokinase(MODY2)Chrme 12,HNF1_(MODY3)Chrme 13,IPF1(MODY4)Mitochondrial DNA 3243 mutationGenetic defects in insulin actionType A insulin resistanceLeprechaunismRabsonMendenhall syndromeLipoatrophic diabetes&Others,Diseases of the exocrine-pancreasFibrocalculous pa
26、ncreatopathyPancreatitisTrauma/pancreatectomyNeoplasiaCystic fibrosisHaemochromatosis&OthersEndocrinopathiesCushings syndromeAcromegalyPhaeochromocytomaGlucagonomaHyperthyroidismSomatostatinoma&Others,2023/10/17,Beijing Xuanwu Hospital,26,Types-continued,InfectionsCongenital rubellaCytomegalovirusOt
27、hersUncommon forms of immunemediated diabetes Insulin autoimmune syndrome(antibodies to insulin)Antiinsulin receptor antibodies“Stiff Man”syndromeOthers,Drug or Chemicalinduced Diabetes Nicotinic acidGlucocorticoidsThyroid hormoneAlphaadrenergic agonistsBetaadrenergic agonistsThiazidesDilantinPentam
28、idineVacorInterferonalpha therapyOthers,2023/10/17,Beijing Xuanwu Hospital,27,Pathophysiology,Because glucose is not getting into cells,metabolism changesCatabolism of fats and proteins instead of carbohydratesLeads to increased fatty acids and ketoacidsKetoacidosis results in lowering of pHDiabetic
29、 comaDecompensated metabolic acidosis and death,2023/10/17,Beijing Xuanwu Hospital,28,Diabetes Mellitus,definitiontypessymptoms diagnosisLaboratory findingstreatmentcomplications,2023/10/17,Beijing Xuanwu Hospital,29,Symptoms of diabetes due to hyperglycaemia,HyperglycemiaDehydrationExcessive thirst
30、 and urinationExcessive hungerGlycosuria(glu spills into urine:180mg/dl),2023/10/17,Beijing Xuanwu Hospital,30,Symptoms of diabetes due to hyperglycaemia,plasma glucose renal thresholdabout 12 mmol/L,glucose in urineosmotic diuresis,hyperglycaemia,tiredness,2023/10/17,Beijing Xuanwu Hospital,31,Symp
31、toms of diabetes due to hyperglycaemia,hyperglycaemia,swelling of lensblurred visioncerebral effectslightheadednessmalaisemental changes,2023/10/17,Beijing Xuanwu Hospital,32,Diabetes Mellitus,definitiontypessymptoms diagnosisLaboratory findingstreatmentcomplications,2023/10/17,Beijing Xuanwu Hospit
32、al,33,ADA diagnostic criteria(1997),Symptoms of diabetes Casual is defined as any time of day without regards to time since last meal.The classic symptoms of diabetes include polyuria,polydipsia and unexplained weight lossorFPG more than or equal to 126 mg/dl(7.0 mmol/l).Fasting is defined as no cal
33、oric intake for at least 8 hoursor2 hour PG more than or equal to 200mg/dl(11.1 mmol/l)during an OGTT.The test should be performed as described by WHO,using a glucose load containing the equivalent of 75 g glucose dissolved in water,2023/10/17,Beijing Xuanwu Hospital,34,WHO diagnostic criteria,whole
34、 bloodplasmaDiabetes mellitus(fasting)6.1mmol/l 7.0mmol/l2 hour post glucose load 10.0 mmol/l 11.1mmol/lIGT(fasting)6.7 mmol/l 7.8 mmol/l IFG(fasting)5.6 mmol/l 6.1mmol/l&6.7 mmol/l 7.8 mmol/lIGH impaired glucose homeostasis,2023/10/17,Beijing Xuanwu Hospital,35,Changes from Old criteria,The class“I
35、mpaired Glucose Tolerance”is now classified as a stage of impaired glucose regulation,since it can be observed in any hyperglycaemic disorder,and is itself not diabetes.Clinical stage of Impaired Fasting Glycaemia has been introduced to classify individuals who have fasting glucose values above the
36、normal range,but below those diagnostic of diabetes.Gestational Diabetes is retained but now encompasses the groups formerly classified as Gestational Impaired Glucose Tolerance(GIGT)and Gestational Diabetes Mellitus(GDM).,2023/10/17,Beijing Xuanwu Hospital,36,Diagnosis of diabetessymptoms+elevated
37、blood glucose levelORelevated blood glucose levels on two occasions,2023/10/17,Beijing Xuanwu Hospital,37,Differential Diagnosis,Hyperglycemia secondary to other causesNondiabetic glycosuria,2023/10/17,Beijing Xuanwu Hospital,38,Diabetes Mellitus,definitiontypessymptoms diagnosisLaboratory findingst
38、reatmentcomplications,2023/10/17,Beijing Xuanwu Hospital,39,FPG:Fasting Plasma GlucoseCPG:Casual Plasma Glucose(non-fasting)OGTT:Oral Glucose Tolerance Test(75g)Hemoglobin A1c(glycated hemoglobin,glycosylated hemoglobin)Indicates average BG levels over approx.3 months.%of total Hgb attached to gluco
39、seNormal:4-6%(DM:8%),2023/10/17,Beijing Xuanwu Hospital,40,Laboratory findings,Glucose:FBG,2 hr OGTT,FBG is simple,accurate,convenient for patientGlycohemoglobinCreatinineUrinalysis glucose ketone bodiesMicroalbuminDyslipidemiaInsulin c-peptide,2023/10/17,Beijing Xuanwu Hospital,41,Diabetes Mellitus
40、,definitiontypessymptoms diagnosisLaboratory findingstreatmentcomplications,2023/10/17,Beijing Xuanwu Hospital,42,Treatment of Diabetes,Non Pharmacological Exercise and EducationDiet,Low in fat,low refined sugars,high carbohydrate,high fibre,low calories if obese,spacing of meals(Healthy eating)Low
41、cholesterol and triglyceride diet if hyperlipidemiaAll Type 1 patients will require Insulin and type 2 can be on diet only,tablets or insulin treated,2023/10/17,Beijing Xuanwu Hospital,43,Treatment of diabetes,type 1type 2GDM,diet,exercise&insulindiet,exercisemetformin or sulphonylurea alonemetformi
42、n and sulphonylureametformin,sulphonylurea&thiazolidinedioneinsulindietinsulin,2023/10/17,Beijing Xuanwu Hospital,44,Drugs to treat hyperglycaemiaInsulin and insulin analoguesInsulin secretagoguessulphonylureanon-sulphonylureaInsulin sensitizersbiguanidethiazolidinedioneIntestinal absorption inhibit
43、orsacarboseorlistat,gliclazide,glibenclamide,repaglinide,nateglinide,metformin,rosiglitazone,pioglitazone,2023/10/17,Beijing Xuanwu Hospital,45,sulphonylurea agentsgliclazide,glibenclamide,glimepiridebind to receptors on islet cellsincrease insulin secretion from islet cellslong duration of action 1
44、2-48 hours Advers effectincrease weightcan cause hypoglycaemiacan cause rashes Contraindications sulfa allergy type 1 DM,DKA,2023/10/17,Beijing Xuanwu Hospital,46,Meglitinides,Mechanism:Binds to site on beta-cell membrane leading to insulin releaseRapid oral absorption and elimination for use in con
45、trolling post-prandial hyperglycemia.Examples:repaglinide,nateglinideContraindicationsType 1 DM,DKAAdverse effects:Hypoglycemia,weight gain,2023/10/17,Beijing Xuanwu Hospital,47,metforminlowers liver glucose outputincreases tissue glucose uptakeacts like an insulin sensitizermild induction of nausea
46、possible interference with food absorptionno effect on weightused alone does not cause hypoglycaemiareduces risk of myocardial infarction1/3 patients get diarrhoea,wind or abdominal painnot used in renal failure,heart failure or severe intercurrent illness,2023/10/17,Beijing Xuanwu Hospital,48,Metfo
47、rmin Toxicity,Renally excreted,not metabolizedPotentially fatal lactic acidosisContraindications:renal insufficiency(decreases drug clearance)hepatic dysfunction(decreases lactate metabolism)tissue anoxia(increase lactate production),2023/10/17,Beijing Xuanwu Hospital,49,acarbose-glucosidase inhibit
48、orblocks digestion and absorption of sugars from bowellowers blood glucose and insulin levels after mealsweak antidiabetic drugno effect on weightused alone does not cause hypoglycaemianot absorbed into body1/2 patients get diarrhoea,wind or abdominal pain,2023/10/17,Beijing Xuanwu Hospital,50,a-glu
49、cosidase inhibitor toxicity,Unabsorbed CHOs:Bacterial fermentation in colon results in abdominal pain,flatulence from gasOsmotic diarrheaElevated serum transaminasesMetabolized and excreted in the GI tractSome metabolite is absorbed in GI and renally excreted Contraindicated for patients with chroni
50、c or inflammatory bowel diseaseRelatively weak antidiabetic effect,usually used adjunctively.,2023/10/17,Beijing Xuanwu Hospital,51,thiazolidinedione agents rosiglitazone,pioglitazone,MechanismBind to PPAR-gamma receptor in peripheral tissues mainly skeletal muscle Result in expression of cell-surfa
