DIABETES MELLITUS TYPE 1 & MANAGEMENT OF DIABETIC KETOACIDOSIS PRESENTED BYDR ASHISH SHARMA GUIDED BYDR MEENA PATEL

DEFINITION Metabolic disorder of multiple etiologies characterized by chronic hyperglycemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects of insulin secretion, insulin action or both.

OLD CLASSIFICATION (1985)Type 1, Insulin-dependent (IDDM)Type 2, Non Insulin-dependent (NIDDM)obesenon-obeseMODY IGTGestational Diabetes

WHO CLASSIFICATION 2000Is based on etiology not on type of treatment or age of the patient.Type 1 Diabetes (idiopathic or autoimmune b-cell destruction)Type 2 Diabetes (defects in insulin secretion or action)Other specific types

Both type 1 & type 2 can be further subdivided into:Not insulin requiringInsulin requiring for controlInsulin requiring for survival

Type 1 Diabetes Mellitus Formerly called insulin-dependent diabetes mellitus (IDDM) or juvenile diabetes

T1DM is characterized by low or absent levels of endogenously produced insulin

EPIDEMIOLOGY The onset occurs predominantly in childhood, with median age of 7-15 yr, but it may present at any age.

Indian data suggest an incidence of 10.5/100,000/yr .

India would have 79 million diabetes by 2030, the highest for any country in the world.

Pathogenesis & Natural history The natural history includes distinct stages Initiation of autoimmunity Preclinical autoimmunity with progressive loss of -cell functionOnset of clinical diseaseTransient remission( Honeymoon period)Established diseaseDevelopment of complications

Both genetic ,environmental and autoimmune factors contribute to the pathogenesis.

Genetic factors- Genetic susceptibility to T1DM is determined by several genes .HLA complex accounts for almost 50 % of genetic risk for type 1 diabetes.Some of the known associations include the HLA DR3/4-DQ2/8 genotype

Association with DR3 has been reported in Indians.Risk of diabetes is also increased when a parent has diabetes and this risk differs between the 2 parents; the risk is 2% if the mother has diabetes, but 7% when the father has diabetes.In monozygotic twins, the concordance rate ranges from 30-65%, whereas dizygotic twins have a concordance rate of 6-10%.

Envoirmental factors

Many envoirmental agents are thought to trigger the development of type 1 diabetes including,Viral infections- Enterovirus , mumps , rubella Diet- Breast-feeding may lower the risk of T1DM. Early introduction of cow's milk protein and early exposure to gluten have both been implicated in the development of autoimmunity

Autoimmune factors

Whatever the triggering factor, it seems that in most cases of T1DM that are diagnosed in childhood.The 1st signs of autoimmunity appear before age 2yr.Insulin associated antibodies (IAA) Glutamic acid decarboxylase 65kd (GAD65) &tyrosine phosphatase insulinoma-associated

. The earliest antibodies are predominantly of the IgG1 subclass

The appearance of autoimmunity is followed by progressive destruction of cells.

Antibodies are a marker for the presence of autoimmunity, but the actual damage to the cells is primarily T-cell mediated

PathophysiologyInsulin performs a critical role in the storage and retrieval of cellular fuel.

In normal metabolism, there are regular swings between the postprandial, high-insulin anabolic state and the fasted, low-insulin catabolic state that affect liver, muscle, and adipose tissue

Pathophysiology.T1DM is a progressive low-insulin catabolic state in which feeding does not reverse but rather exaggerates these catabolic processes.

At even lower insulin levels, the liver produces excessive glucose via glycogenolysis and gluconeogenesis, and fasting hyperglycemia begins.

Pathophysiology.Hyperglycemia produces an osmotic diuresis (glycosuria) when the renal threshold is exceeded (180mg/dL; 10mmol/L). The resulting loss of calories and electrolytes, as well as the persistent dehydration, produce a physiologic stress with hypersecretion of stress hormones (epinephrine, cortisol, growth hormone, and glucagon)

Pathophysiology.These hormones, in turn, contribute to the metabolic decompensation by promoting glycogenolysis, gluconeogenesis, lipolysis, and ketogenesis (glucagon, epinephrine, growth hormone, and cortisol) while decreasing glucose utilization and glucose clearance.

CLINICAL PRESENTATIONSClassical symptom triad: polyuria, polydipsia and weight lossDKAAccidental diagnosisAnorexia nervosa like illness

DIAGNOSTIC CRITERIAFasting blood glucose levelDiabeticPlasma >7.0 mmol/ 126mg/dlCapillary >6.0 mmolIGTPlasma 6.0-6.9 mmolCapillary 5.6-6.0 mmol2 hours after glucose load(Plasma or capillary BS)IGT7.8-11.0Diabetic level> 11.1 (200 mg)

DIAGNOSISIn symptomatic children a random plasma glucose >11.1 mmol (200 mg) is diagnostic.A modified OGTT (fasting & 2h) may be needed in asymptomatic children with hyperglycemia if the cause is not obvious.Remember: acute infections in young non-diabetic children can cause hyperglycemia without ketoacidosis.

COMPLICATIONS OF DIABETESAcute:DKAHypoglycemiaLate-onset:Retinopathy NeuropathyNephropathyIschemic heart disease & stroke

TREATMENT GOALSPrevent death & alleviate symptomsAchieve biochemical controlMaintain growth & developmentPrevent acute complicationsPrevent or delay late-onset complications

TREATMENT ELEMENTSEducationInsulin therapyDiet and meal planningMonitoringHbA1c every 2-monthsHome regular BG monitoring Home urine ketones tests when indicated

EDUCATIONEducate child & care givers about: Diabetes Insulin Life-saving skills Recognition of Hypo & DKA Meal plan Sick-day management

INSULINA polypeptide made of 2 b-chains.Discovered by Bants & Best in 1921.Animal types (porcine & bovine) were used before the introduction of human-like insulin (DNA-recombinant types).Recently more potent insulin analogs are produced by changing aminoacid sequence.

FUNCTION OF INSULINInsulin being an anabolic hormone stimulates protein & fatty acids synthesis.Insulin decreases blood sugar By inhibiting hepatic glycogenolysis and gluconeogenesis.By stimulating glucose uptake, utilization & storage by the liver, muscles & adipose tissue.

Characteristics of InsulinThere are three characteristics of insulin:

Onset- Is the length of time before insulin reaches the bloodstream and begins lowering blood glucose.Peaktime- Is the time during which insulin is at maximum strength in terms of lowering blood glucose.Duration- Is how insulin continues to lower blood glucose.

The Basics of Insulin: 4 TypesRapid-acting insulin

Regular or short-acting insulin

Intermediate-acting insulin

Long-acting insulin

Rapid-acting InsulinExamples: insulin lispro or insulin aspart

Onset: Begins to work at about 5 minutes

Peaktime: Peak is about 1 hour

Duration: Continues to work for about 2-4 hours

Regular or Short-acting InsulinExamples: insulin lispro, Aspart

Onset: Reaches the bloodstream within 30 minutes after injection.

Peaktime: Peaks anywhere from 2-3 hours after injection.

Duration: Effective for approximately 3-6 hours.

Intermediate-acting InsulinExamples:NPH, Lente

Onset: Reaches the blood stream about 2 to 4 hours after injection.

Peaktime: Peaks 4-12 hours later.

Duration: Effective for about 12 to 18 hours

Long-acting Insulin

Examples: insulin glargine

Onset: Reaches the bloodstream 6-10 hours after injection Duration: Usually effective for 20-24 hours

INSULIN CONCENTRATIONSInsulin is available in different concentrations 40, 80 & 100 Unit/ml.WHO now recommends U 100 to be the only used insulin to prevent confusion.Special preparation for infusion pumps is soluble insulin 500 U/ml.

Insulin Pump TherapyContinuous subcutaneous insulin infusion (CSII) via battery-powered pumps provides a closer approximation of normal plasma insulin profiles.It accurately deliver a small baseline continuous infusion of insulin, coupled with parameters for bolus therapy. The bolus insulin determined by amount of carbohydrate intake and blood sugar level

INSULIN REGIMENSTwice daily: either NPH alone or NPH+SI.Thrice daily: SI before each meal and NPH only before dinner.Intensive 4 times/day: SI before meals + NPH or Glargine at bed time.Continuous s/c infusion using pumps loaded with SI.

NEW INSULIN PREPARATIONSInhaled insulin proved to be effective & will be available within 2 years.Nasal insulin was not successful because of variable nasal absorption.Oral insulin preparations are under trials.

ADVERSE EFFECTS OF INSULINHypoglycemiaLipoatrophyLipohypertrophyObesityInsulin allergyInsulin antibodiesInsulin induced edema

PRACTICAL PROBLEMSNon-availability of insulin in poor countriesinjection sites & techniqueInsulin storage & transferMixing insulin preparationsInsulin & school hoursAdjusting insulin dose at homeSick-day managementRecognition & Rx of hypo at home

DIET REGULATIONRegular meal plans with calorie exchange options are encouraged.50-60% of required energy to be obtained from complex carbohydrates.Distribute carbohydrate load evenly during the day preferably 3 meals & 2 snacks with avoidance of simple sugars.Encouraged low salt, low saturated fats and high fiber diet.

EXERCISEDecreases insulin requirement in diabetic subjects by increasing both sensitivity of muscle cells to insulin & glucose utilization.It can precipitate hypoglycemia in the unprepared diabetic patient.It may worsen pre-existing diabetic retinopathy.

MONITORINGCompliance (check records)HBG testsHbA1 every 2 monthsInsulin & meal planGrowth & developmentWell being & life styleSchool & hobbies

ADVANCES IN MONITORINGSmaller & accurate meters for intermittent BG monitoringGlucowatch continuous monitoring using reverse iontophoresis to measure interstitial fluid glucose every 20 minutesGlucosensor that measures s/c capillary BG every 5 minutesImplantable sensor with high & low BG alarm

ADVANCES IN MANAGEMENTBetter understanding of diabetes allows more rational approach to therapy.Primary prevention could be possible if the triggering factors are identified.The DCCT studies proves beyond doubt that chronic diabetic complication can be controlled or prevented by strict glycemic control.

TREATMENT MADE EASYInsulin pens & new delivery productsHandy insulin pumpsFine micro needles Simple accurate glucometersFree educational materialComputer programs for comprehensive management & monitoring

TELECARE SYSTEMSIT has improved diabetes careInternet sites for education & supportWeb-based systems for telecare are now available. The patient feeds his HBGM data and get the physician, nurse & dietician advice on the required modification to diet & insulin treatment.

PITFALLS OF MANAGEMENTDelayed diagnosis of IDDMThe honey-moon periodDetection & treatment of NIDDYProblems with diagnosis & treatment of DKA & hypoglycemiaSomogyis effect & dawn phenomenon may go unrecognized.

FUTURE PROMISESThe cure for IDDM is successful islet cell transplantation, which will be available in the near future.Primary prevention by a vaccine or drug will be offered to at risk subjects identified by genetic studies. Gene modulation therapy for susceptible subjects is a promising preventive measure.

Pancreas & Islet Cell TransplantationPancreas transplants are usually given to diabetics with end stage renal disease.Islet cell transplants, the ultimate treatment of type 1 diabetes is under trial in many centers in the US & Europe with encouraging results but graft rejection & recurrence of autoimmunity are serious limitations.

IMMUNE MODULATIONImmunosuppressive therapy forNewly diagnosedProlonged the honey moonFor high risk childrenImmune modulating drugsNicotinamidemycophenolate

GENE THERAPYBlocks the immunologic attack against islet-cells by DNA-plasmids encoding self antigen.Gene encode cytokine inhibitors.Modifying gene expressed islet-cell antigens like GAD.

PREDICTION OF DIABETESSensitive & specific immunologic markersGAD AntibodiesGLIMA antibodiesIA-2 antibodiesSensitive genetic markersHLA haplotypesDQ molecular markers

PREVENTION OF DIABETESPrimary preventionIdentification of diabetes geneTampering with the immune systemElimination of environmental factorSecondary preventionImmunosuppressive therapyTertiary preventionTight metabolic control & good monitoring

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MANAGEMENT OF DIABETIC KETOACIDOSIS

.INTRODUCTIONDKA,a life threatning complication of diabetes mellitus,occurs more commonly in children with type 1 DM than type 2 DM.Hyperglycemia,metabolic acidosis, ketonemia,dehydration and vaious electolyte abnormalities result from a relative and absolute deficiency of insulin with or without excess of counter regulatory hormones

.DefinitionDKA in children is defined as hypgerglycemia(serum glucose conc. >200-300mg/dl) in the presence of metabolic acidosis (blood pH

.CLINICAL HISTORYPolyuriaPolydipsiaWeight lossNausea,vomiting,abdominal painHeadacheRestlessness,irritabilityLethargy,altered sensorium,loss of conciousnessFever

.EXAMINATIONFruity odour in breathTachycardiaLow volume pulsesHypotensionImpaired skin turgorDelayed capillary refill timeDehydrationRapid,Deep sighing respiration Kussumaul respiration(met. Acidosis)Bradycardia,hypertension,pappiloedemaAbnormal pupillary reflex,cranial n. palsyposturing

.Biochemical signsKetones in urineElevated blood glucose(>200 mg%)Acidemia(pH

. Confirm diagnosis of Diabetic Ketoacidosis

.Mild:pH

.ShockReduced peripheral Pulse volumeReduced concious

Dehdration>5%Not in shockClinically acidoticVomitiing

Dehydration

.Resuscitation

Airway+NG tubeCirculation(10-20ml/kg of 0.9% NS over 30-60 mins)Repeat if necessary- initial expansion should not exceed total 30 ml/kg

Intravenous therapyCalculate fluid requirments (maintainence + deficit)Correct over 24 hrs with 0.9NS for first 8-12 hrs followed by 0.45%NS(Add KCl 40 mEq/L)Start insulin infusion 0.1 u/kg/hrECG for hypo/hyperkalemic changes

Start with subcutaneous insulin 0.25U/kg 3-4hrlyNo improvement

.Monitoring

Hourly blood glucoseNeurological status atleast hourlyHourly fluid input outputElectrolytes and then 4hrlyBlood gas at admission and then as indicatedMonitor ECG for hypo and hyperkalemic changesNo improvementReevaluate

Uncorrected hypovolemiaReview dose and rate of insulin infusionNeurological deterioration warning signs

HeadacheIrritabilitySlowing heart rateReduced conciousness levelHypertensionBradycardiaPupillary inequality

Consider Cerebral Edema(Exclude Hypoglycemia)

.Intravenous therapyConsider fluid to 0.45 NS +dextrose 5%Continue monitoring as aboveConsider reducing Insulin 0.05 U/kg/hr when >pH.7.3,blood glucose 16mEq/LpH>7.3

InsulinStart subcutaneius insulin and then stop iv insulin infusion 1 hr later

DIABETIC KETOACIDOSIS TREATMENT PROTOCOL.TIME THERAPY COMMENTS

1ST hr10-20 ml/kg IV bolus 0.9% NaCl or LRInsulin drip at 0.05 to 0.10 u/kg/hrQuick volume expansion;may be repeated.NPO.Monitor I/O,neurological status.Usefloe sheet. Have Mannitol at bedside;1 g/kg IV push for cerebral edema2nd hr until DKA resolution0.45%NaCl:plus continue Insulin drip20 mEq/l Kphos and 20 mEq/l Kac.5% glucose if blood sugar

.Note that initial IV bolus is considered as part of the total fluid allowed in the 1st 24 hr and is sutracted before calculating the IV rate.Sample calculation for a 30 kg child:1st hr=300ml IV bolus 0.9%NaCl or LR2nd and subsequent hrs=(85x30)+1750-300/23=175 ml/hr(0.45%NaCl with 20 mEq/L Kphos and 20 mEq/L Kac)

.The Milwaukee protocol can be used for children of all ages and with all degree of DKA.Children with milder DKA recover in 10-20 hr(and need less total IV fluid before switching to oral intake.)Those with more severe DKA require 30-36 hrs with this protocol.Blood testing should occur every 1-2 hr for children with severe DKA and 3-4 hr for those with mild to moderate DKA.

INSULIN THERAPYTiming-1-2 hr after starting fluid replacement.Type-Only IV Regular insulin used for m/m of DKA.Dose-low dose iv insulin 0.1 u/kg/hr is standard.high dose has risk of hypoglycemia,hypokalemia and rapid decline in osmolality.Prepration-50 units diluted in 50 ml NS to arrive conc. Of 1 u/mlDuration-administered at same rate(0.1u/kg/hr) until resolution of DKADose adjustment-If hypoglycemia occurs despite increase in strength of dextrose sol. the dose of insulin reduced in decrement of 0.02u/kg/hr upto 0.05 u/kg /hr

Transition to subcutaneous insulin therapyAs oral feeds advanced iv fluids reduced and change to subcutaneous insulin planned.Timing-ideal time to begin is just before a meal.Rapid acting insulin(lispro,aspart) are administered sc 15-30 mins prior and regular insulin 1-2 hr prior to stopping infusion to avois rebound hyperglycemia.Dose-For pt with DKA at ds onset,recommended TDD is 0.75-1 u/kg(pre pubertal) and 1-1.2 u/kg(pubertal).Before Breakfast-2/3 tdd(1/3 r.a. and 2/3 i.a. insulin)Before dinner-1/3 tdd(1/3 r.a. and 2/3 i.a. insulin)

Cerebral Edema.ManagementHead end elevationGive Mannitol 0.5-1 gm/kg and repeat if there is no response in 30 mins-2hrs3% Hypertonic saline (5 ml/kg over 30 mins) can be givenRestrict iv fluids to 2/3Replace deficit in 72 hr rather than 48 hrIntubation and ventilation if required

Sgch xcoddodok dovkdovkdo dpkd*Due to b-cell reserve optimal function & initiation of insulin therapy.Leads to normal blood glucose level without exogenous insulin.Observed in 50-60% of newly diagnosed patients & it can last up to one year but it always ends.Can confuse patients & parents if not educated about it early**Insulin associated antibodies (IAA) are usually the 1st to appear in young children, followed by glutamic acid decarboxylase 65kd (GAD65) and tyrosine phosphatase insulinoma-associated 2 (IA-2) antibodies. The earliest antibodies are predominantly of the IgG1 subclass*****Others:Arthropathy & limited joint mobilityMuco-cutaneous lesionsImpotenceAssociated autoimmune diseases

Between 3 and 8 a.m., your body starts to increase the amounts of counter-regulatory hormones (growth hormone, cortisol, and catecholamines). These hormones work against insulin's action to drop blood sugarsIt is also called "rebound hyperglycemia*Asadsxhj lkk;l **Adjuvant treatment that suppress autoimmunity include:InsulinC-peptideIGF1