UPDATE ON DIABETES AND UPDATE ON DIABETES AND INSULIN THERAPYINSULIN THERAPY

BYBYDr.M.SYED SULAIMAN.M.D;Dr.M.SYED SULAIMAN.M.D;

PHYSICIAN & PHYSICIAN & DIABETOLOGISTDIABETOLOGIST

DIABETES DIABETES ENVIRONMENT IN INDIAENVIRONMENT IN INDIA

Diabetes is no more an epidemic, it Diabetes is no more an epidemic, it

is a PANDEMIC. Diabetes related is a PANDEMIC. Diabetes related complications pose greatest risk of complications pose greatest risk of

morbidity and mortality.morbidity and mortality.

NoNo COUNTRYCOUNTRY 20002000 COUNTRYCOUNTRY 20302030

11 INDIAINDIA 31.731.7 INDIAINDIA 79.479.4

22 CHINACHINA 20.820.8 CHINACHINA 42.342.3

33 U.S.AU.S.A 17.717.7 U.S.AU.S.A 30.330.3

44 INDONESIAINDONESIA 8.48.4 INDONESIAINDONESIA 21.321.3

55 JAPANJAPAN 6.86.8 PAKISTANPAKISTAN 13.913.9

66 PAKISTANPAKISTAN 5.25.2 BRAZILBRAZIL 11.311.3

77 U.S.S.RU.S.S.R 4.64.6 BANGLADESHBANGLADESH 11.111.1

88 BRAZILBRAZIL 4.64.6 JAPANJAPAN 8.98.9

99 ITALYITALY 4.34.3 PHLIPPINESPHLIPPINES 7.87.8

1010 BANGLADEHBANGLADEH 3.23.2 EGYPTEGYPT 6.76.7

BURDEN OF DIABETES : MORBIDITY

DIABETIC RETINOPATHY#1 Cause of blindness in working age adults

DIABETIC NEPHROPATHY#1 Cause of ESRD

DIABETIC NEUROPATHY

AMPUTATIONS#1 Cause of non-traumatic amputations of lower

Extremity.

DIABETIC VASCULAR DISEASE

2 to 6 fold higher risk of CVD

DEFINITION

Diabetes Mellitus is a group of

metabolic diseases characterized

by Hyperglycemia resulting from

defects in Insulin secretion, Insulin

action, or both.

ETIOLOGIC CLASSIFICATION OFDIABETES MELLITUS

1.Type 1 DiabetesA.Immune mediated B.Idiopathic

2.Type 2 Diabetes

3.Other specific types:a. Genetic defects of b-cell functionb. Genetic defects in insulin actionc. Disease of exocrine pancreasd. Endocrinopathiese. Drug/chemical inducedf. Infectiong. Uncommon immune mediated

h. Other Genetic Syndromes

4. GESTATIONAL DIABETES MELLITUS(GDM)

IMPAIRED INSULIN SECRETION &INSULIN RESISTANCE

GENES AND ENVIRONMENT

IMPAIRED INSULINSECRETION

+ INSULIN RESISTANCE

IMPAIRED GLUCOSETOLERANCE

GENES & ENVIRONMENT

IMPAIRED INSULINSECRETION

INSULIN RESISTANCE

IMPAIRED GLUCOSETOLERANCE

TYPE 2 DM

ETIOLOGY OF TYPE 2 DM

IFG -Impaired Fasting GlucoseIFG -Impaired Fasting Glucose

IGT -Impaired Glucose ToleranceIGT -Impaired Glucose Tolerance

NORMALNORMAL IFG/IGTIFG/IGT DIABETESDIABETES

FPGFPG <100<100 ≥≥100<126100<126 ≥≥126126

2hrPost 2hrPost Glucose LoadGlucose Load

<140<140 ≥≥140<200140<200 ≥ ≥ 200200

DIAGNOSTIC CRITERIA OF DIABETES

What is pre diabetes?What is pre diabetes?

AbnormalAbnormal blood glucose Values blood glucose Values which is clearly Above the normal which is clearly Above the normal values but less than the Values values but less than the Values diagnostic of Diabetesdiagnostic of Diabetes

[IMPAIRED GLUCOSE METABOLISM][IMPAIRED GLUCOSE METABOLISM]

MAJOR RISK FACTORS FOR TYPE 2 DM

1. Age>452. Race / Ethnicity (Asian / Asian American / Hispanics / etc)3. Obesity (>30kg/m)4. Family h/o Diabetes5. Sedentary lifestyle6. h/o GDM or delivered a baby weighing>4.5kg7. PCOS

ACUTE METABOLIC COMPLICATIONS OF DIABETES MELLITUS

A.) DIABETIC KETOACIDOSIS

B) HYPEROSMOLAR HYPERLYCEMIC STATE

C) HYPOGLEMIA

Diabetes Mellitus and chronic Diabetes Mellitus and chronic complicationscomplications

Diabetes is a vascular diseaseDiabetes is a vascular disease

Affects both small and medium sized Affects both small and medium sized arteries (micro vascular &macro arteries (micro vascular &macro vascular)vascular)

Chronic complicationsChronic complications

MICRO MICRO VASCULARVASCULAR

RetinopathyRetinopathy NephropathyNephropathy NeuropathyNeuropathy

MacrovascularCVDCADPVD

MANAGEMENTMANAGEMENT

DietDiet ExerciseExercise InsulinInsulin Oral Antidiabetic DrugsOral Antidiabetic Drugs DPP 4 InhibitorsDPP 4 Inhibitors Amylin AnaloguesAmylin Analogues

ORAL ANTI DIABETIC DRUGSORAL ANTI DIABETIC DRUGS

SecretogaugesSecretogauges a) Sulphonyluriasa) Sulphonylurias b) Non sulphonyluriasb) Non sulphonylurias BiguanidesBiguanides Alpha Glucosidase Inhibitors( A G I )Alpha Glucosidase Inhibitors( A G I ) ThiozolidinedionesThiozolidinediones DPP 4 InhibitorsDPP 4 Inhibitors Amylin AnaloguesAmylin Analogues ExenatideExenatide

SECRETOGOUGESSECRETOGOUGES

Sulphonyluria GroupsSulphonyluria Groups First Generation SUFirst Generation SU 1.Tolbutamide1.Tolbutamide 2.Chlorpropamide2.Chlorpropamide Second Generation SUSecond Generation SU 1.Glibenclamide(Daonil,Euglucon)1.Glibenclamide(Daonil,Euglucon) 2.Glipizide(Glynase,Dibizide)2.Glipizide(Glynase,Dibizide) 3.Gliclazide(Diamicron,Reclide)3.Gliclazide(Diamicron,Reclide) 4.Glimipride(Amaryl,Glipride,Glimer)4.Glimipride(Amaryl,Glipride,Glimer)

SECRETOGOGUESSECRETOGOGUES

Currently available secretogogues Currently available secretogogues stimulate Insulin secretion by stimulate Insulin secretion by causing closure of ATP dependent causing closure of ATP dependent Potassium channel in Islet Potassium channel in Islet ββ cells. cells.

MeglitinidesMeglitinides

Repaglinide(Novonorm)Repaglinide(Novonorm)

NON SU SECRETOGOGUESNON SU SECRETOGOGUES

INSULIN SENSITIZERSINSULIN SENSITIZERS

Agents from this group enhances the Agents from this group enhances the effect of endogenous Insulin.effect of endogenous Insulin.

A reduction in Insulin resistance at A reduction in Insulin resistance at each and every stage of diabetes will each and every stage of diabetes will improve Glucose metabolism.improve Glucose metabolism.

Biguanide(Metformin),ThiozolidinedioBiguanide(Metformin),Thiozolidinediones(PIO,ROSI)nes(PIO,ROSI)

BIGUANIDESBIGUANIDES

METFORMIN(Glyciphage,Glycomet).METFORMIN(Glyciphage,Glycomet).

Primary site of action:Liver.Primary site of action:Liver.

Reduces hepatic glucose output.Reduces hepatic glucose output.

Reduce fasting hyperglycemia.Reduce fasting hyperglycemia.

THIOZOLIDINEDIONESTHIOZOLIDINEDIONESTroglitazoneTroglitazoneRosiglitazone(Rezult,Enselin)Rosiglitazone(Rezult,Enselin)Pioglitazone(Pioz,Pioglit)Pioglitazone(Pioz,Pioglit)Primary site of action : AdiposePrimary site of action : Adipose

Cells, Skeletal muscles.Cells, Skeletal muscles.

AGIAGI

Acarbose(Glucobay,Acarb)Acarbose(Glucobay,Acarb) Miglitol(Misobit,Mignor)Miglitol(Misobit,Mignor) Voglibose(Volibo,Volix)Voglibose(Volibo,Volix) Blocks alpha glucosidase enzymeBlocks alpha glucosidase enzyme Targets postprandial hyperglycemiaTargets postprandial hyperglycemia

DPP 4 InhibitorsDPP 4 Inhibitors(Dipeptidyl Pepsidase 4)(Dipeptidyl Pepsidase 4)

NateglinideNateglinide CitagliptinCitagliptin VidagliptinVidagliptin DPP 4 Inhibits GLP 1.Thus extends DPP 4 Inhibits GLP 1.Thus extends

Insulin action.Insulin action. Improves satiety,Increases Improves satiety,Increases ββ cell cell

production,Inhibits production,Inhibits ββ cell apoptosis cell apoptosis delays gastric emptying,stimulate delays gastric emptying,stimulate Insulin releaseInsulin release

AMYLIN ANALOGUESAMYLIN ANALOGUES

PramlintidePramlintide

INSULININSULIN

First hormone to be First hormone to be DiscoveredDiscovered Introduced in clinical practiceIntroduced in clinical practice Structurally characterizedStructurally characterized Synthesized – chemicallySynthesized – chemically Biosynthesized – by rDNA technologyBiosynthesized – by rDNA technology

Insulin – Definitive Therapy for Insulin – Definitive Therapy for DiabetesDiabetes

In diabetes there is impaired insulin In diabetes there is impaired insulin secretion and impaired insulin actionsecretion and impaired insulin action

Exogenously administered Insulin Exogenously administered Insulin can overcome both defectscan overcome both defects

Thus insulin is the definitive therapy Thus insulin is the definitive therapy for all types of diabetesfor all types of diabetes

INSULININSULINABSOLUTE INDICATIONSABSOLUTE INDICATIONS

Regular UseRegular UseType 1 Diabetes PatientsType 1 Diabetes PatientsType 2 Diabetes Patients with OHA failureType 2 Diabetes Patients with OHA failure - Primary- Primary - Secondary- SecondaryIntermittent UseIntermittent UseType 2 diabetes patients duringType 2 diabetes patients during - major surgery- major surgery - pregnancy, labour and delivery- pregnancy, labour and delivery - myocardial infarction- myocardial infarction - acute infections- acute infections - acute metabolic crisis like hyperosmolar non - acute metabolic crisis like hyperosmolar non ketotic coma and lactic acidosisketotic coma and lactic acidosisGestational diabetesmellitusGestational diabetesmellitus

Type 1 DM Insulin TherapyType 1 DM Insulin Therapy

Initiating insulin therapy in Initiating insulin therapy in uncomplicated ambulatory Type 1 uncomplicated ambulatory Type 1 patientspatients

Initiating insulin therapy in ill Initiating insulin therapy in ill patients with altered sensoriumpatients with altered sensorium

Type 1 DM Insulin Therapy : Type 1 DM Insulin Therapy : Initiation Initiation

In uncomplicated ambulatory Type 1 In uncomplicated ambulatory Type 1 patientspatients

Patients should preferably be Patients should preferably be admitted to hospitaladmitted to hospital

Initiate with short-acting insulin [0.5 Initiate with short-acting insulin [0.5 IU/Kg body weight per day] divided IU/Kg body weight per day] divided over 3 doses/day given pre-meal; over 3 doses/day given pre-meal; subcutaneouslysubcutaneously

Type 1 DM Insulin Therapy : Type 1 DM Insulin Therapy : InitiationInitiation

If hospital admission is not possible, If hospital admission is not possible, close continuous monitoring of the close continuous monitoring of the patient is necessarypatient is necessary

After adequate control is obtained After adequate control is obtained with the above treatment a minimum with the above treatment a minimum of twice daily regimen with a short of twice daily regimen with a short and intermediate-acting insulin may and intermediate-acting insulin may be given as per individual patient be given as per individual patient requirementrequirement

ACTION PROFILE OF INSULINACTION PROFILE OF INSULIN

TypeType OnsetOnset PeakPeak DurationDuration

Rapid-Acting Rapid-Acting Analogues Analogues

(Aspart, Lyspro)(Aspart, Lyspro)

10-15 10-15 minmin

1-1.5 h1-1.5 h 4-5 h4-5 h

ACTION PROFILE OF INSULINACTION PROFILE OF INSULIN

TypeType OnsetOnset PeakPeak DurationDuration

Short-Acting Short-Acting (Regular)(Regular)

30-60 30-60 minmin

2-4 h2-4 h 6-8 h6-8 h

ACTION PROFILE OF INSULINACTION PROFILE OF INSULIN

TypeType OnsetOnset PeakPeak DurationDuration

Intermediate-Intermediate-Acting(Basal)Acting(Basal)

NPHNPH

2-5 h2-5 h 6-8 h6-8 h 14-18 h14-18 h

ACTION PROFILE OF INSULINACTION PROFILE OF INSULIN

TypeType OnsetOnset PeakPeak DurationDuration

Pre-Mixed Pre-Mixed (30/70,50/50(30/70,50/50

Regular/NPH) Regular/NPH)

30 min30 min 2-8 h2-8 h 14-18 h14-18 h

ACTION PROFILE OF INSULINACTION PROFILE OF INSULIN

TypeType OnsetOnset PeakPeak DurationDuration

Long-Acting Long-Acting AnalogueAnalogue

(Detemir,Glargine)(Detemir,Glargine)

2-3 h2-3 h No peakNo peak 24-30 h24-30 h

TYPES OF INSULINSTYPES OF INSULINS

TypeType FormulationFormulation preparationpreparation Onset Onset (hr)(hr)

Max.Max.effect effect (hr)(hr)

Duration Duration (hr)(hr)

ShortShort RegularRegular H.Actrapid H.Actrapid ActrapidActrapid

0.50.5 1-31-3 88

IntermediateIntermediate - NPH (Neutral - NPH (Neutral protamine Hagedom)/ protamine Hagedom)/ IsophaneIsophane

H.Insulatard H.Insulatard InsulatardInsulatard

1.51.5 4-124-12 2424

IntermediateIntermediate - Insulin Zinc - Insulin Zinc Suspension/ LenteSuspension/ Lente

H.Monotard H.Monotard LentardLentard

2.52.5 7-157-15 2424

BiphasicBiphasic Regular (30%) + NPH Regular (30%) + NPH (70%)(70%)

H.Mixtard H.Mixtard MixtardMixtard

0.50.5 2-82-8 2424

REGIMENSREGIMENS

Should maintain normal blood Should maintain normal blood glucose levels (Normoglycemia)glucose levels (Normoglycemia)

Mimic normal physiological profileMimic normal physiological profile Regimens vary in Type 1 and type 2 Regimens vary in Type 1 and type 2

diabetes because of different diabetes because of different pathophysiologypathophysiology

INSULIN REGIMENS – Type 1 Diabetes Insulin secretion totally absentInsulin secretion totally absent Insulin administration tailored to match demandInsulin administration tailored to match demand (food intake)(food intake) Need for multiple injectionsNeed for multiple injections Popular RegimensPopular Regimens * Basal Bolus: Ideal but difficult to implement* Basal Bolus: Ideal but difficult to implement * Split mix therapy: Popular regimen; Patients find * Split mix therapy: Popular regimen; Patients find

mixing insulins difficultmixing insulins difficult Premixed Insulins: Most popular regimen world- Premixed Insulins: Most popular regimen world-

wide and in Indiawide and in India Right mix of compliance and controlRight mix of compliance and control Insulin requiredInsulin required - 0.4 - 0.6 i.u/kg body weight/day- 0.4 - 0.6 i.u/kg body weight/day - Regimen depends on blood glucose profiles- Regimen depends on blood glucose profiles

BASAL BOLUS THERAPYBASAL BOLUS THERAPY

At least four injections/dayAt least four injections/day Intermediate injection at bedtimeIntermediate injection at bedtime soluble insulin before breakfast, soluble insulin before breakfast,

lunch and dinnerlunch and dinner Regular blood monitoring mustRegular blood monitoring must Requires highly motivated patientRequires highly motivated patient

SPLIT MIX REGIMENSSPLIT MIX REGIMENS

Two injections (intermediate + Two injections (intermediate + soluble) per daysoluble) per day

before breakfast and before bedtimebefore breakfast and before bedtime Proportion/dosage of insulin titrated Proportion/dosage of insulin titrated

based on blood glucose profilebased on blood glucose profile Mixing insulin is tedious and Mixing insulin is tedious and

problematicproblematic

A. COMPLIANCEA. COMPLIANCE Defective insulin regimenDefective insulin regimen Incorrect technique of mixing and Incorrect technique of mixing and

measuringmeasuring Inconsistent eating and exercise habitsInconsistent eating and exercise habits Omission of insulin during inter current Omission of insulin during inter current

illnessillness Lack of awareness about diabetes at the Lack of awareness about diabetes at the

beginning and during the course of illness beginning and during the course of illness Emotional and psychological disturbance Emotional and psychological disturbance

B. CHANGE IN INSULIN REQUIREMENTS B. CHANGE IN INSULIN REQUIREMENTS

Inactivity Inactivity Weight gain / LossWeight gain / Loss Pregnancy and Post delivery phasePregnancy and Post delivery phase Change in the exercise patternChange in the exercise pattern Change in the food habitsChange in the food habits Stress period Stress period

PREMIXED REGIMENSPREMIXED REGIMENS – Human – Human MixtardMixtard

Very Popular regimenVery Popular regimen Most popular World-wide & in IndiaMost popular World-wide & in India Right balance of convenience and controlRight balance of convenience and control Improves complianceImproves compliance Popular schedule isPopular schedule is 2/3rd daily dose half an hour before 2/3rd daily dose half an hour before

breakfastbreakfast 1/3rd daily dose half an hour before dinner1/3rd daily dose half an hour before dinner

Insulin Therapy for Type 2 DMInsulin Therapy for Type 2 DM

Basal Insulin Supplementation: Basal Insulin Supplementation: Bedtime NPH Bedtime NPH

Suppresses basal hepatic productionSuppresses basal hepatic production Reduces fasting plasma glucoseReduces fasting plasma glucose Generally used in combination with Generally used in combination with

OHAOHA Helps initiate the patient on insulin Helps initiate the patient on insulin

therapy with Insulatard NovoLet therapy with Insulatard NovoLet

Guidelines for Initiating InsulinGuidelines for Initiating Insulin

Alone or in combination with an OHAAlone or in combination with an OHA 0.2 units/kg body wt./day of intermediate 0.2 units/kg body wt./day of intermediate

acting insulin e.g. Insulatard NovoLetacting insulin e.g. Insulatard NovoLet Increase dose by 2-4 u every 3-4 days if Increase dose by 2-4 u every 3-4 days if

necessary. If requirement exceeds 30-40 u, necessary. If requirement exceeds 30-40 u, split the dose into two daily : 2/3 before split the dose into two daily : 2/3 before breakfast, 1/3 before dinnerbreakfast, 1/3 before dinner

If postprandial glucose levels are high If postprandial glucose levels are high introduce short acting insulin in 30:70 or introduce short acting insulin in 30:70 or 50:50 ratio50:50 ratio

Early Insulin InitiationEarly Insulin Initiation Is therefore beneficial in:Is therefore beneficial in: Providing better control of hyperglycemiaProviding better control of hyperglycemia Reversing other metabolic defectsReversing other metabolic defects Controlling inflammation which may initiate and Controlling inflammation which may initiate and

aggravate development and progression of aggravate development and progression of diabetes and diabetes-induced tissue damagediabetes and diabetes-induced tissue damage

Preserving beta cell function and thus helping Preserving beta cell function and thus helping maintain better glycemic control in the long-termmaintain better glycemic control in the long-term

Should be done when it can be useful to the Should be done when it can be useful to the patientpatient

FACTORS AFFECTING INSULIN FACTORS AFFECTING INSULIN PHARMAKOKINETICSPHARMAKOKINETICS

Injection siteInjection site ExerciseExercise Depth of injectionDepth of injection Insulin sourceInsulin source Potency Potency Insulin antibodiesInsulin antibodies

Injection SiteInjection Site

The absorption varies with change of The absorption varies with change of areaarea

Rotation of site within the same area Rotation of site within the same area Short Acting - ABDOMEN - If rapid Short Acting - ABDOMEN - If rapid

action desiredaction desired Suspensions - THIGH - for longer Suspensions - THIGH - for longer

action action Random rotation of the site should Random rotation of the site should

be avoidedbe avoided

Rotation of Site in a given areaRotation of Site in a given area

Blood flow Blood flow Temperature Temperature Heavy massage in the injected areaHeavy massage in the injected area

ExerciseExercise

Exercise following insulin injection Exercise following insulin injection increases the increases the amount of insulin amount of insulin absorbedabsorbed as well as the as well as the rate at which rate at which it is absorbed it is absorbed

Exercise Exercise increases the peripheral increases the peripheral glucoseglucose utilisation utilisation by increasing the by increasing the insulin sensitivityinsulin sensitivity

Depth of injection Depth of injection IM Vs SC injIM Vs SC inj

Absorbed faster with IM injectionsAbsorbed faster with IM injections IM injections are not recommended for IM injections are not recommended for

routine useroutine use Useful only in patients with subcutaneous Useful only in patients with subcutaneous

insulin degradation or resistanceinsulin degradation or resistance IM injections are more painfulIM injections are more painful SC is therefore idealSC is therefore ideal Soluble [ Human Actrapid ] can be given IV Soluble [ Human Actrapid ] can be given IV

during surgery and diabetic emergenciesduring surgery and diabetic emergencies

Source of insulinSource of insulin

Human Insulin is absorbed quickerHuman Insulin is absorbed quicker Bovine Insulin is the slowestBovine Insulin is the slowest Porcine is absorbed little slower than Porcine is absorbed little slower than

HumanHuman Auxiliary SubstancesAuxiliary Substances Preservative - phenol, metacresolPreservative - phenol, metacresol Retarding Agent – protamine, zincRetarding Agent – protamine, zinc Water as solventWater as solvent

Insulin AntibodiesInsulin Antibodies

Circulating antibodies and exogenous Circulating antibodies and exogenous insulin bind to form insulin antibody insulin bind to form insulin antibody complexcomplex

The antibody bound insulin may The antibody bound insulin may produce a delayed effect at an produce a delayed effect at an unexpected timeunexpected time

Resulting from Reduced absorption , Resulting from Reduced absorption , Delayed clearance Delayed clearance