1、2022-7-5.12022-7-5.2ldefinitionltypeslsymptoms ldiagnosislLaboratory findingsltreatmentlcomplications2022-7-5.3The term diabetes mellitus describes a metabolic disorder of multiple aetiology characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulti
2、ng from defects in insulin secretion, insulin action, or both2022-7-5.4l A metabolic condition characterised by high plasma glucose levels and chronic vascular complicationsl A vascular disease affecting small and large arteries with coexistent metabolic disturbance particularly high plasma glucose
3、levels2022-7-5.5ldefinitionltypeslsymptoms ldiagnosislLaboratory findingsltreatmentlcomplications2022-7-5.6lType 1 (betacell destruction, usually leading to absolute insulin deficiency) : Autoimmune: IdiopathiclType 2 (may range from predominantly insulin resistance with relative insulin deficiency
4、to a predominantly secretory defect with or without insulin resistance)lOther specific types Genetic defects of betacell function lGenetic defects in insulin actionlDiseases of the exocrine pancreas Endocrinopathies lDrug or chemicalinduced lInfections lUncommon forms of immunemediated diabeteslOthe
5、r genetic syndromes sometimes associated with diabeteslGestational diabetes2022-7-5.7lPreviously known as IDDM(Insulin dependent diabetes)lKetosis prone:Usually diagnosed in younger age group( 30 yearsl1 in 1000 population as new cases each year lInsidious presentation with symptoms of polyuria, pol
6、ydipsia, lethargy, weight loss, nausea, vomiting, abdominal cramps, blurred vision and superficial infection. Often discovered at routine medicallThis presentation is the end point of the gradual loss of beta cell function in the setting of Insulin resistancelStrong (90-100%) concordance in TwinslRe
7、avans syndrome or Syndrome X Insulin resistance2022-7-5.14Type 2 diabetesUnderlying insulin resistance genetic and ethnicity Obesity BMI WHR inactivity / low physical fitness intrauterine & childhood factors smoking & drugsImpaired insulin secretionInsulin secretion worsens with timepost-receptorcel
8、lular mechanismsmechanismunclear-cellexhaustion2022-7-5.15Prandial glucoseFasting glucoseInsulin resistanceInsulin secretionPlasma glucose-cell 126 mg/dLyears2022-7-5.16Pancreatic -cell Insulin resistanceLiverHYPERGLYCAEMIAIslet -cell degranulationReduced insulin contentMuscle(PKCAdipose tissueDecre
9、ased glucose transport& activity (expression) of GLUT-4Increased lipolysisElevated plasma NEFA+-Low plasmainsulinIncreased glucose outputElevatedTNF Insulin resistance and -cell dysfunctionproduce hyperglycaemia in type 2 diabetes2022-7-5.17 LIVER a. increased glycogen hydrolysis to glucose b. incre
10、ased gluconeogenesis. c. increased triacylglycerol hydrolysis and conversion of glycerol to glucose d. increased conversion of FA and protein to ketones (AcAc and BHB) e. increased protein and amino acid catabolism f. increased production of urea2022-7-5.18a. serum glucose is poorly taken up by musc
11、le (decrease GLUT activity)b. saturation of hexokinase activity, inability 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 amin
12、o acidsf. increased transfer of N onto ALA / GLN and sent back to liver2022-7-5.19a. 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 stored2022-7-5.20Insulin Insulin Macrovas
13、cularsensitivity secretion disease 30% 50% 50% 50% 70100% 40% 70% 150% 10% 100% 100%Type 2 diabetesIGTImpaired glucose metabolismNormal glucose metabolism2022-7-5.21lInsulin resistancelHypertensionlDyslipidaemia( increase LDL, decreased HDL)lObesitylOther factors: hyperfibrinogenemia, hyperuricaemia
14、, propensity to microvascular diseasesl“Metabolic syndrome” in most cases of type 2 diabetes2022-7-5.22abdominal obesityhigh blood pressureHDL cholesterol VLDL triglyceride small dense LDL hyperinsulinaemiaglucose intolerancediabeteshyperuricaemiaPAI-1 fibrinogen factor VII microalbuminuriainsulin r
15、esistanceSyndrome of insulin resistanceAKA Reavens syndrome, syndrome Xmetabolic syndrome2022-7-5.23Type 1 diabetestypical onset 20 yearscan start at any agegradual onsetmay be no symptomsoften no weight lossusually obesenot ketoticdetectable C-peptideno autoimmune markers2022-7-5.24Diabetes in preg
16、nancyco-existent or newly diagnosed lifelong diabetes type 1 type 2 (especially in South Asian women) other specific types of diabetesgestational diabetes2022-7-5.25lGenetic defects of betacell functionChrme 20, HNF4_ (MODY1)Chrme 7, glucokinase (MODY2)Chrme 12, HNF1_ (MODY3)Chrme 13, IPF1 (MODY4)Mi
17、tochondrial DNA 3243 mutationlGenetic defects in insulin actionType A insulin resistanceLeprechaunismRabsonMendenhall syndromeLipoatrophic diabetes & OtherslDiseases of the exocrine -pancreasFibrocalculous pancreatopathyPancreatitisTrauma / pancreatectomyNeoplasiaCystic fibrosisHaemochromatosis & Ot
18、herslEndocrinopathiesCushings syndromeAcromegalyPhaeochromocytomaGlucagonomaHyperthyroidismSomatostatinoma & Others 2022-7-5.26lInfectionsCongenital rubellaCytomegalovirusOthers lUncommon forms of immunemediated diabetes Insulin autoimmune syndrome (antibodies to insulin)Antiinsulin receptor antibod
19、ies“Stiff Man” syndromeOtherslDrug or Chemicalinduced Diabetes lNicotinic acidlGlucocorticoidslThyroid hormonelAlphaadrenergic agonistslBetaadrenergic agonistslThiazideslDilantinlPentamidinelVacorlInterferonalpha therapylOthers2022-7-5.27lBecause glucose is not getting into cells, metabolism changes
20、 Catabolism of fats and proteins instead of carbohydrates Leads to increased fatty acids and ketoacids Ketoacidosis results in lowering of pH Diabetic coma Decompensated metabolic acidosis and death2022-7-5.28ldefinitionltypeslsymptoms ldiagnosislLaboratory findingsltreatmentlcomplications2022-7-5.2
21、9lHyperglycemia Dehydration Excessive thirst and urination Excessive hungerlGlycosuria (glu spills into urine: 180mg/dl)2022-7-5.30Symptoms of diabetes due to hyperglycaemiaplasma glucose renal thresholdabout 12 mmol/Lglucose in urineosmotic diuresisurine volumethirstgenital thrushweight losshypergl
22、ycaemiatiredness2022-7-5.31Symptoms of diabetes due to hyperglycaemiahyperglycaemiaswelling of lensblurred visioncerebral effectslightheadednessmalaisemental changes2022-7-5.32ldefinitionltypeslsymptoms ldiagnosislLaboratory findingsltreatmentlcomplications2022-7-5.33lSymptoms of diabetes & a casual
23、 glucose concentration more than or equal to 200 mg/dl(11.1 mmol/l); 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 lossorlFPG more than or equal to 126 mg/dl (7.0 mmol/l). Fasting is
24、defined as no caloric intake for at least 8 hoursorl2 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 water2022-7-5.34whole bloodplasmaDiabetes mellitus (
25、fasting) 6.1mmol/l 7.0mmol/l2 hour post glucose load 10.0 mmol/l 11.1mmol/lIGT (fasting) 6.1mmol/l 6.7 mmol/l 7.8 mmol/l IFG (fasting) 5.6 mmol/l 6.1mmol/l&6.1 mmol/l &6.7 mmol/l 8%)2022-7-5.40lGlucose: FBG, 2 hr OGTT ,FBG is simple, accurate, convenient for patientlGlycohemoglobinlCreatininelUrinal
26、ysis glucose ketone bodieslMicroalbuminlDyslipidemialInsulin c-peptide2022-7-5.41ldefinitionltypeslsymptoms ldiagnosislLaboratory findingsltreatmentlcomplications2022-7-5.42lNon Pharmacological lExercise and EducationlDiet, Low in fat, low refined sugars, high carbohydrate, high fibre, low calories
27、if obese, spacing of meals (Healthy eating)lLow cholesterol and triglyceride diet if hyperlipidemialAll Type 1 patients will require Insulin and type 2 can be on diet only, tablets or insulin treated2022-7-5.43Treatment of diabetestype 1type 2GDMdiet, exercise & insulindiet, exercisemetformin or sul
28、phonylurea alonemetformin and sulphonylureametformin, sulphonylurea & thiazolidinedioneinsulindietinsulin2022-7-5.44Drugs to treat hyperglycaemiaInsulin and insulin analoguesInsulin secretagoguessulphonylureanon-sulphonylureaInsulin sensitizersbiguanidethiazolidinedioneIntestinal absorption inhibito
29、rsacarboseorlistatlispro insulinaspart insulininsulin glarginegliclazide, glibenclamiderepaglinide, nateglinidemetforminrosiglitazone, pioglitazone2022-7-5.45sulphonylurea agentsgliclazide, glibenclamide, glimepiride bind to receptors on islet cells increase insulin secretion from islet cells long d
30、uration of action 12-48 hours Advers effect increase weight can cause hypoglycaemia can cause rashes Contraindications sulfa allergy type 1 DM, DKA2022-7-5.46l Mechanism: Binds to site on beta-cell membrane leading to insulin release Rapid oral absorption and elimination for use in controlling post-
31、prandial hyperglycemia. Examples: repaglinide, nateglinide Contraindications Type 1 DM, DKA Adverse effects: Hypoglycemia, weight gain2022-7-5.47metformin lowers liver glucose output increases tissue glucose uptake acts like an insulin sensitizer mild induction of nausea possible interference with f
32、ood absorption no effect on weight used alone does not cause hypoglycaemia reduces risk of myocardial infarction 1/3 patients get diarrhoea, wind or abdominal pain not used in renal failure, heart failure or severe intercurrent illness2022-7-5.48lRenally excreted, not metabolizedlPotentially fatal l
33、actic acidosis Contraindications: renal insufficiency (decreases drug clearance) hepatic dysfunction (decreases lactate metabolism) tissue anoxia (increase lactate production)2022-7-5.49acarbose -glucosidase inhibitor blocks digestion and absorption of sugars from bowel lowers blood glucose and insu
34、lin levels after meals weak antidiabetic drug no effect on weight used alone does not cause hypoglycaemia not absorbed into body 1/2 patients get diarrhoea, wind or abdominal pain2022-7-5.50lUnabsorbed CHOs: Bacterial fermentation in colon results in abdominal pain, flatulence from gas Osmotic diarr
35、healElevated serum transaminaseslMetabolized and excreted in the GI tract Some metabolite is absorbed in GI and renally excreted lContraindicated for patients with chronic or inflammatory bowel diseaselRelatively weak antidiabetic effect, usually used adjunctively.2022-7-5.51 MechanismBind to PPAR-g
36、amma receptor in peripheral tissues mainly skeletal muscle Result in expression of cell-surface glucose transporters. Cautions Not recommended in NYHA Class III/IV CHF May cause fluid retention and precipitate CHF May cause mild anemia (? Dilutional effect)2022-7-5.52 Associated with weight gain Liv
37、er toxicity seen in older TZD (troglitazone) but not with newer agents; recommended to check LFTs q 2 mo for 1st year of use. Advantages No hypoglycemia Possible improvement in vascular function2022-7-5.53lMetabolism: hepatic conjugation by the CYP450 systemlExcretion: biliarylHepatotoxic, especiall
38、y troglitazone, and contraindicated in cases of hepatic dysfunctionlCan cause edema and hypoglycemia when used in combination with other hypoglycemics2022-7-5.54Treating hyperglycaemia in type 2 diabetesdietary changeexerciseobesemetforminnot obesesulphonylureametformin & sulphonylureaglitazone & me
39、tformin OR glitazone & sulphonylureainsulin metforminAim: HbA1c 6.5%Fasting glucose microaneurysms edema Proliferative (VEGF) New blood vessels that extend into vitreous, bleeding loss of visionlGlaucoma, intraocular pressure ocular tissue damage 2022-7-5.66 Non-proliferative diabetic retinopathy (N
40、PDR) Earliest stage Microaneurisms and intraretinal “dot and blot” hemorrhages Macular edema or hard exudates at/near macula can cause visual impairment Proliferative diabetic retinopathy (PDR) Nonperfusion of retina angiogenesis growth of abnormal new vessels extending onto inner surface of retina
41、or into vitreous cavity. Substantial risk for rupture hemorrhage or retinal detachment. Treated with panretinal photcoagulation.2022-7-5.67Diabetic nephropathy Affects 25% of type 1 and type 2 diabetes patients Risk factors similar to those for retinopathy Is a progressive condition leading to renal
42、 failure Characterised by proteinuria and high blood pressure2022-7-5.68lGlomerulosclerosis (Capillary basement membr. thickening)lMicroalbuminuria (30-300 mg/24hr)lHyperfiltration (GFR)lAlbuminuria (300 mg/24hr)lHypertensionlNephrotic syndrome (approx 1/3 of Type 1 progress to end stage renal dis r
43、equiring dialysis)lRenal failure ( GFR, Creat)2022-7-5.69lTypes of Neuropathy Sensory Pain/ paresthesias in feet particularly at night Numbness in “stocking and glove” distribution High risk for foot ulceration Autonomic Cardiovascular: resting tachycardia, painless MI, orthostasis GI: esphageal dys
44、function, gastroparesis, diabetic diarrhea, constipation, fecal incontinence Genitourinary ED, retrograde ejaculation, neurogenic bladder Other “gustatory” sweating, heat intolerance2022-7-5.70Diabetic neuropathy Affects type 1 and type 2 diabetes patients similarly Risk factors similar to those for
45、 retinopathy may lead to loss of sensation in feet foot ulceration erectile dysfunction gastroparesis and vomiting postural hypotension2022-7-5.71lMacrovascular ( 70% hosp/deaths) 60% of patients die of coronary disease 10% of patients die of stroke 10% suffer from fatal complications related to per
46、ipheral vascular disease2022-7-5.72lAnginalMIlSilent infarctlCCFlECGlCardiac enzymeslTroponin IlExercise stress testlEchocardiographylAngiographylAngioplasty/CABG2022-7-5.73lTIAslCVAslDementialCT scanlCarotid DopplerslTreat risk factorslCarotid bypass surgery2022-7-5.74lIntermittent ClaudicationlCol
47、d LegslPulseless LeglFoot UlcerslGangrenelDoppler StudieslDuplex ScanninglAngiographylAngioplastylTreat risk factors2022-7-5.75lNeuropathylPVDlCharcot ArthropathylUlcerationlMRIlAngiography2022-7-5.76lAcute (several days rather than hours)lCaused by Inadequate insulin Infection Stress Underdosing Fo
48、od or alcohol bingelResults in hyperglycemia & mobilization of lipids2022-7-5.77lType 1 Diabetics, Severe Insulin Def.lBreakdown of fat stores Fatty AcidslOxidation Ketone Bodies ( by glucagon)lAccumul of Acetoacetic acid/ hydroxybutyric acid Plasma Hl Metabolic Ketoacidosis (Hydration vs dehydratio
49、n) 2022-7-5.78lDKA results in altered lipid metabolism increased concentrations of total lipids, cholesterol, triglycerides, and free fatty acids free fatty acids are shunted into ketone body formation due to lack of insulin; the rate of formation exceeds the capacity for their peripheral utilizatio
50、n and renal excretion leading to accumulation of ketoacids, and therefore metabolic acidosislWith progressive dehydration, acidosis, hyperosmolality, and diminished cerebral oxygen utilization, consciousness becomes impaired, and the patient ultimately becomes comatose2022-7-5.79 early manifestation
