PHARMACOLOGY OF TYPE 1 PHARMACOLOGY OF TYPE 1

DIABETES MELLITUS - DIABETES MELLITUS -

INSULININSULIN

Dr. CHANDANE R. D.Dr. CHANDANE R. D.Asst. ProfessorAsst. Professor

Dept. Of PharmacologyDept. Of Pharmacology

Govt Medical College, AkolaGovt Medical College, Akola

DIABETES MELLITUSDIABETES MELLITUS

Group of syndromes characterized by Group of syndromes characterized by hyperglycemia; altered metabolism of lipid, hyperglycemia; altered metabolism of lipid, CHO & Proteins and increase risk of CHO & Proteins and increase risk of complications from vascular diseasescomplications from vascular diseases

Sushruta – ayurvedaSushruta – ayurveda

Aeretaeus – Diabetes - first centuryAeretaeus – Diabetes - first century

Dobson – sugar in urine 1755Dobson – sugar in urine 1755

Classification of Diabetes MellitusClassification of Diabetes Mellitus

I) Type 1 DM ( IDDM )I) Type 1 DM ( IDDM ) a) Autoimmune (Type 1 A)a) Autoimmune (Type 1 A) b) Non autoimmune/ idiopathic (Type 1 B)b) Non autoimmune/ idiopathic (Type 1 B)

II) Type 2 DM (NIDDM)II) Type 2 DM (NIDDM)

III) Type 3 DM (Other specific types of DM)III) Type 3 DM (Other specific types of DM)A) Specific defined gene mutationA) Specific defined gene mutation a) Maturity onset diabetes of youth (MODY)a) Maturity onset diabetes of youth (MODY) i) MODY-1: Hepatic nuclear factor 4i) MODY-1: Hepatic nuclear factor 4αα (HNF4A) gene mutation (HNF4A) gene mutation ii) ii) MODY-2: GlucokinaseMODY-2: Glucokinase gene mutation gene mutation iii) iii) MODY-3: Hepatic nuclear factor 1MODY-3: Hepatic nuclear factor 1αα gene mutation gene mutation iv) iv) MODY-4: Insulin promotor factor 1MODY-4: Insulin promotor factor 1 (IPF1) gene mutation (IPF1) gene mutation v) v) MODY-5: Hepatic nuclear factor 1MODY-5: Hepatic nuclear factor 1ββ (HNF1B) gene mutation (HNF1B) gene mutation vi) vi) MODY-6: Neurogenic Differentiation 1MODY-6: Neurogenic Differentiation 1(NEUROD1) gene mutation(NEUROD1) gene mutation vii) vii) MODY-X: Unidentified gene mutationMODY-X: Unidentified gene mutation b) Insulin b) Insulin gene mutationgene mutation c) Insulin receptor gene mutationc) Insulin receptor gene mutation

Classification…….Classification……. B) Diabetes Secondary to Pancreatic diseasesB) Diabetes Secondary to Pancreatic diseases i) Chronic Pancreatitisi) Chronic Pancreatitis ii) Surgeryii) Surgery iii) Tropical Diabetes (Chronic Pancreatitis with nutritional/ toxic factors)iii) Tropical Diabetes (Chronic Pancreatitis with nutritional/ toxic factors)

C) Diabetes secondary to EndocrinopathiesC) Diabetes secondary to Endocrinopathies i) Cushings Disease i) Cushings Disease ii) Glucocorticoid administrationii) Glucocorticoid administration iii) Acromegalyiii) Acromegaly

D) Diabetes secondary to immune suppressionD) Diabetes secondary to immune suppression E) Diabetes associated with genetic syndromesE) Diabetes associated with genetic syndromes

Prader willi syndromePrader willi syndrome

F) Diabetes associated with Drug therapyF) Diabetes associated with Drug therapy

IV) Type 4 DM Gestational diabetes mellitus (GDM)IV) Type 4 DM Gestational diabetes mellitus (GDM)

Symptoms Of DMSymptoms Of DM

Classical Triad Classical Triad

Polyuria - ↑urinationPolyuria - ↑urination

Polydipsia - ↑thirst & fluid intakePolydipsia - ↑thirst & fluid intake

Polyphagia - ↑appetite Polyphagia - ↑appetite

↑↑BSL→incomplete reabsorption in prox. Renal tubuli→ GlycosuriaBSL→incomplete reabsorption in prox. Renal tubuli→ Glycosuria

→↑ →↑ osmotic pressure of urine →↓reabsorption of water →polyuria osmotic pressure of urine →↓reabsorption of water →polyuria

→→↑↑Fluid loss → Dehydration →Fluid loss → Dehydration →↑↑thirstthirst

Blurred vision – Glucose absorption →changes in shape of lensesBlurred vision – Glucose absorption →changes in shape of lenses

Diabetic ketoacidosis- Kaussmaul breathing, polyuria, nausea, Diabetic ketoacidosis- Kaussmaul breathing, polyuria, nausea,

vomitting & Abdominal pain, altered state of vomitting & Abdominal pain, altered state of

consciousness, coma, death consciousness, coma, death

DIAGNOSISDIAGNOSISNormal GTNormal GT Impaired GTImpaired GT DMDM

Fasting plasma Fasting plasma glucose (mg/dl)glucose (mg/dl)

< 100< 100 100 -125100 -125 >> 126 126

2hrs after glucose 2hrs after glucose load (mg/dl)load (mg/dl)

< 140< 140 >> 140-199 140-199 >> 200 200

HbA1c – Glycosylated Hb/glycated Hb/glycoHbHbA1c – Glycosylated Hb/glycated Hb/glycoHb

6% or more abnormal 6% or more abnormal

In DM Good glycemic control 6.5-7% HbA1c In DM Good glycemic control 6.5-7% HbA1c

Reflects avg. BSL over preceding 90 days Reflects avg. BSL over preceding 90 days

Used to monitor T/t in DMUsed to monitor T/t in DM

Sr. fructosamine- Glycemic control preceding 1-2 wksSr. fructosamine- Glycemic control preceding 1-2 wks

Type 1 DMType 1 DM Type 2 DMType 2 DM

Age at onsetAge at onset Childhood/puberty Childhood/puberty Over age 35 yrsOver age 35 yrs

Nutritional status at Nutritional status at time of onsettime of onset

Undernourished Undernourished Obesity presentObesity present

Prevalence Prevalence 10-20%10-20% 80-90% 80-90%

Genetic Genetic predispositionpredisposition

Moderate Moderate Very strongVery strong

DefectDefect Beta cells destroyed Beta cells destroyed eliminating insulin eliminating insulin productionproduction

Inadequate insulin Inadequate insulin production, production, Insulin resistance Insulin resistance

KetoacidosisKetoacidosis Frequent Frequent Absent Absent

Anti islet cell Anti islet cell antibodyantibody

>80%>80% <5%<5%

PATHOPHYSIOLOGY OF TYPE 1 DMPATHOPHYSIOLOGY OF TYPE 1 DM

A)A) AUTOIMMUNITYAUTOIMMUNITY- - Condition where ones own immune system attack Condition where ones own immune system attack

structure in one’s own bodystructure in one’s own bodyCirculating antibodies against b-cells and insulin Circulating antibodies against b-cells and insulin Cytoplasmic & membrane bound Ag IAAS GAD HSP etcCytoplasmic & membrane bound Ag IAAS GAD HSP etcInsulitisInsulitisBoth humoral & cell-mediated immunity are stimulatedBoth humoral & cell-mediated immunity are stimulatedtriggered by reaction to infectiontriggered by reaction to infection

B) B) GENETIC FACTORSGENETIC FACTORS Ethnic differences, Familial clustering, High concordance Ethnic differences, Familial clustering, High concordance rate in twins 25-50%rate in twins 25-50%HLA on Chromosome 6- HLA on Chromosome 6-

HLADR3/HLADR4HLADR3/HLADR4

C) ENVIRONMENTAL INFLUENCEC) ENVIRONMENTAL INFLUENCE

Viruses-Coxaschie B, Mumps, Rubella, ReovirusesViruses-Coxaschie B, Mumps, Rubella, Reoviruses

Nutrition & dietary factors-Nutrition & dietary factors-

Cow’s milk proteinCow’s milk protein

Contaminated sea foodContaminated sea food

Chemicals destroying beta cells – 1)Vacor 2) streptozotocinChemicals destroying beta cells – 1)Vacor 2) streptozotocin

Pancreatitis, trauma, tumoursPancreatitis, trauma, tumours

Vit D in I yr of lifeVit D in I yr of life

Faulty nerves in pancreas- Faulty nerves in pancreas-

HONEYMOON PERIODHONEYMOON PERIOD

Due to b-cell reserve optimal function & initiation of insulin Due to b-cell reserve optimal function & initiation of insulin therapy.therapy.

Leads to normal blood glucose level without exogenous insulin.Leads to normal blood glucose level without exogenous insulin.

Observed in 50-60% of newly diagnosed patients & it can last up to Observed in 50-60% of newly diagnosed patients & it can last up to one year but it always ends.one year but it always ends.

MANAGEMENT OF TYPE 1 DMMANAGEMENT OF TYPE 1 DM

EducationEducation

Diet and meal planningDiet and meal planning

Insulin therapyInsulin therapy

MonitoringMonitoring

Educate child & care givers about:Educate child & care givers about: DiabetesDiabetes InsulinInsulin Life-saving skillsLife-saving skills Recognition of Hypo & DKARecognition of Hypo & DKA Meal plan Meal plan Sick-day managementSick-day management

Diet and Meal planningDiet and Meal planning

Susrate and Charaka- 2,500 years agoSusrate and Charaka- 2,500 years ago John Rollo -eighteenth century John Rollo -eighteenth century

Frederick Allen -modern history of the diabetic diet Frederick Allen -modern history of the diabetic diet

Regular meal plans with calorie exchange options are Regular meal plans with calorie exchange options are encouraged.encouraged.

50-60% of required energy to be obtained from complex 50-60% of required energy to be obtained from complex carbohydrates.carbohydrates.

Distribute carbohydrate load evenly during the day preferably Distribute carbohydrate load evenly during the day preferably 3 meals & 2 snacks with avoidance of simple sugars.3 meals & 2 snacks with avoidance of simple sugars.

Encouraged low salt, low saturated fats and high fiber diet.Encouraged low salt, low saturated fats and high fiber diet.

INSULIN

HISTORY1500 BC Sushruta – ayurveda Diabetes First Described In Writing that flies and ants were attracted to urine of people with a mysterious disease that caused intense thirst, enormous urine output, and wasting away of the body-

250 BC Apollonius of Memphis coined the name "diabetes” meaning "to go through" or siphon. Latin word for honey is mellitus

150 BC Aretaeus the Cappadocian - melting down of the flesh and limbs into urine

Early Diabetes Treatments

1000- Greek physicians recommended horseback riding to reduce excess urination

1800s- bleeding, blistering, and doping were common

1915- Sir William Osler recommended opium

Overfeeding - compensate for loss of fluids and weight

Early 1900s Dr. Frederick Allen, recommended a starvation diet

Early Research

1798- John Rollo - excess sugar in the blood and urine

1813-Claude Bernard linked diabetes to glycogen metabolism

1869- Paul Langerhans- a German medical student, discovered islet cells in the pancreas

1889-Joseph von Mehring and Oskar Minkowski created diabetes in dogs by removing the pancreas

1910-Sharpey-Shafer of Edinburgh suggested a single chemical was missing from the pancreas. He proposed calling this chemical "insulin."

Pancreas Extractors

1908- a young internist in Berlin, Georg Ludwig Zuelzer created a pancreas extract named acomatrol. Try in dying diabetic patient

1911 - E. L. Scott was partially successful in extracting insulin with alcohol

1916-1920 - R. C. Paulesco, made an extract from the pancreas that lowered the blood glucose of dogs.

Before insulin was discovered in 1921, everyone with type 1 diabetes died within weeks to years of its onset

1922 BANTING & BEST1922 BANTING & BESTFrederick Banting & Charles Best – ligate pancreatic Frederick Banting & Charles Best – ligate pancreatic duct extract islets with alcohol and acid-↓BSL in dogduct extract islets with alcohol and acid-↓BSL in dogLeonard Thompson- age14-year wt 64 lb injected Leonard Thompson- age14-year wt 64 lb injected their extract - blood glucose to fall from 520 to 120 their extract - blood glucose to fall from 520 to 120 mg/dL in 24 hoursmg/dL in 24 hoursLeonard lived a relatively healthy Leonard lived a relatively healthy

life for 13 years before dying life for 13 years before dying of pneumonia (no Rx then) at 27of pneumonia (no Rx then) at 27

Macleod & J B Collip – stable extractMacleod & J B Collip – stable extract

Nobel PrizeNobel Prize 1923 – 1923 – Banting & MacleodBanting & Macleod nobel prize for nobel prize for

physiology /medicinephysiology /medicine 1930- Hagedorm – protamine1930- Hagedorm – protamine 1950- T.Scott & Fisher – added zinc1950- T.Scott & Fisher – added zinc 1955- 1955- SangerSanger- primary struct Nobel prize in - primary struct Nobel prize in

ChemistryChemistry 1969- 1969- HodgkinHodgkin- Tirtiary struct - Tirtiary struct 1977-1977-YalowYalow- Radioimmunoassay for insulin- Nobel - Radioimmunoassay for insulin- Nobel

prize in Medicineprize in Medicine 1978- Insulin gene cloned-Recombinant DNA Insulin1978- Insulin gene cloned-Recombinant DNA Insulin 1983 Intranasal1983 Intranasal 1988- Long acting insulin analogues1988- Long acting insulin analogues

Structure & ChemistryStructure & Chemistry

PancreasPancreas – – Islets 2% of PancreasIslets 2% of Pancreas

CellsCells %islets%islets HormoneHormone FunctionFunction

11 A(A(αα)) 20%20% GlucagonGlucagon HyperglycemicHyperglycemic

22 B(B(ββ)) 75%75% Insulin C-peptide Insulin C-peptide AmylinAmylin

Amylin- modulate appetite Amylin- modulate appetite Gastric emptyingGastric emptying

33 D (D (δδ)) 3-5%3-5% SomatostatinSomatostatin Inhibitor of secretory cellsInhibitor of secretory cells

44 F-PPF-PP <2%<2% Pancr polypeptPancr polypept Facilitate digestionFacilitate digestion

Insulin- polypeptide mol wt-6000, Insulin- polypeptide mol wt-6000,

2 aa chains A(21aa) & B(30aa)2 aa chains A(21aa) & B(30aa)

Linked by disulphide bridgeLinked by disulphide bridge

Structure & Chemistry…..Structure & Chemistry…..

Species Species AntigenicitAntigenicityy

A -ChainA -Chain B-ChainB-Chain

88thth aa aa 1010thth aa aa 3030thth aa aa

HumanHuman Least Least ThreonineThreonine IsoleucineIsoleucine ThreonineThreonine

PorkPork Negligible Negligible ThreonineThreonine IsoleucineIsoleucine AlanineAlanine

BeefBeef HighHigh AlanineAlanine ValineValine AlanineAlanineHuman Insulin – Human sequence insulin as primary structure Human Insulin – Human sequence insulin as primary structure identical to human insulin, chemical conversion of porcine insulin, identical to human insulin, chemical conversion of porcine insulin, - Synthesis by E.coli & Yeast cultures - Synthesis by E.coli & Yeast cultures

Insulin - Water solubleInsulin - Water soluble

Zn bring crystallizationZn bring crystallization

Prolong action-Zn & ProtamineProlong action-Zn & Protamine

Biosynthesis & Storage of InsulinBiosynthesis & Storage of Insulin Human pancrea contain ~8mg insulin (200U) (1mg=28U)Human pancrea contain ~8mg insulin (200U) (1mg=28U) Biosynthesis involves- Transcription from insulin gene, Biosynthesis involves- Transcription from insulin gene,

mRNA stabilization, mRNA Translation, Post translational mRNA stabilization, mRNA Translation, Post translational modificationsmodifications

Preproinsulin(110aa)Preproinsulin(110aa) peptidasepeptidase

Proinsulin + peptide(24aa)Proinsulin + peptide(24aa) Ca dependant enzyme PC2 PC3Ca dependant enzyme PC2 PC3

Carboxypeptidase ECarboxypeptidase E

Insulin + C-peptide(35aa)Insulin + C-peptide(35aa)

Granules store in crystal formGranules store in crystal form2 Zn + 6 Insulin mol2 Zn + 6 Insulin mol

INSULIN RELEASE

DEGRADATION OF INSULINDEGRADATION OF INSULIN

Insulin→Insulin→ Endogenous Endogenous Exogenous (s.c.)Exogenous (s.c.)

Liver clearsLiver clears 60%60% 30-40%30-40%

Kidney clearsKidney clears 35-40%35-40% 60%60%

Half life: 3-5 minHalf life: 3-5 min

Basal insulin value: 5-15Basal insulin value: 5-15μμU/mlU/ml

Meals peak value: 60-90 Meals peak value: 60-90 μμU/mlU/ml

INSULIN RECEPTORSINSULIN RECEPTORS

Beta subunit has tyrosin kinaseBeta subunit has tyrosin kinase

Insulin bind to Insulin bind to αα subunit subunit

High specificity & affinityHigh specificity & affinity

Glucose Transporters (GLUT)Glucose Transporters (GLUT)

TransporTransporterter

Tissue Tissue Glucose Glucose (mmol/L)(mmol/L)

FunctionsFunctions

GLUT 1GLUT 1 All tissue specilly All tissue specilly

red cells & brainred cells & brain

1-21-2 Basal uptake of glucose Basal uptake of glucose transport across BBBtransport across BBB

GLUT 2GLUT 2 ΒΒ-cells of pancrea -cells of pancrea Liver Kidney gutLiver Kidney gut

15-2015-20 Regulation of insulin rele- Regulation of insulin rele- -ase, glucose homeostasis-ase, glucose homeostasis

GLUT 3GLUT 3 Brain, Kidney, Brain, Kidney, Placenta & otherPlacenta & other

<1<1 Uptake into Neurons & Uptake into Neurons & other tissueother tissue

GLUT 4GLUT 4 Muscle AddiposeMuscle Addipose 55 Insulin mediated uptakeInsulin mediated uptake

GLUT 5GLUT 5 Gut & KidneyGut & Kidney 1-21-2 Absorption of FructoseAbsorption of Fructose

MECHANISM OF ACTIONMECHANISM OF ACTIONInsulin + Receptor Insulin + Receptor ((αα subunit) subunit)

↓ ↓

Tyrosine kinase (Tyrosine kinase (ββ subunit)subunit)

↓ ↓

Activate IRSActivate IRS

↓ ↓Activation of Phosphatidyl inositol 3 kinase pathway & MAP Activation of Phosphatidyl inositol 3 kinase pathway & MAP (mitogen activated protein) pathway(mitogen activated protein) pathway

↓ ↓

Translocation of GLUT to cell membraneTranslocation of GLUT to cell membrane

Translocation of GLUT-glucose uptakeTranslocation of GLUT-glucose uptake

Insulin activate transcription facton – enhance DNA Insulin activate transcription facton – enhance DNA synthesis, cell growth and divisionsynthesis, cell growth and division

Stimulate NaStimulate Na++ -K -K++ ATPase increase pump activity - ATPase increase pump activity - KK++ accumalation accumalation

REGULATION OF INSULIN SECRETIONREGULATION OF INSULIN SECRETION

B) HORMONAL :- B) HORMONAL :-

Hormones like Growth Hormone, Hormones like Growth Hormone, Corticosteroids, Thyroxin Corticosteroids, Thyroxin modify insulin releasemodify insulin release

PG E inhibit itPG E inhibit it

Intraislet paracrine interactionIntraislet paracrine interaction

B cell

insulin

A cell

glucagon

D cellD cell

SomatostatinSomatostatin

+

+

-

-

-

A)A)CHEMICAL :- Glucose sensing mechanism- glucose entry inCHEMICAL :- Glucose sensing mechanism- glucose entry in beta cell & phosphorylation (glukokinase) – insulin release beta cell & phosphorylation (glukokinase) – insulin release Other – Amino acids, Fatty acid & Ketone bodiesOther – Amino acids, Fatty acid & Ketone bodies Glucose induce 1st phase within 2 min f/b 2nd phase Glucose induce 1st phase within 2 min f/b 2nd phase sustainedsustained

C) NEURAL :- C) NEURAL :-

Islet- Sympathetic & Vagal n.Islet- Sympathetic & Vagal n.

1) 1) αα-2 stimulation-↓ insulin release (inhibition adenylyl cyclase)-2 stimulation-↓ insulin release (inhibition adenylyl cyclase)

2) 2) ββ-2 stimulation-↑ insulin release (stimulate adenylyl cyclase)-2 stimulation-↑ insulin release (stimulate adenylyl cyclase)

3) Cholinergic muscarinic activation - Ach/vagal stimulation → 3) Cholinergic muscarinic activation - Ach/vagal stimulation →

insulin release (IP3/DAG)→↑Ca intracellular insulin release (IP3/DAG)→↑Ca intracellular

Primary central site – Hypothalamus Primary central site – Hypothalamus

Stimulation of Ventrolat nu →↑ insulin release Stimulation of Ventrolat nu →↑ insulin release

Stimulation of Ventromed nu →↓ insulin releaseStimulation of Ventromed nu →↓ insulin release

PHARMACOLOGICAL ACTIONS OF INSULINPHARMACOLOGICAL ACTIONS OF INSULIN

LIVERLIVER ADDIPOSE ADDIPOSE SKEL MUSCLESKEL MUSCLE

CHOCHO CHOCHO CHOCHO

1.↑Glycogen synthesis1.↑Glycogen synthesis 1.↑Glucose uptake1.↑Glucose uptake 1.↑Glucose uptake1.↑Glucose uptake

2.↓Glycogenolysis2.↓Glycogenolysis 2. 2. Inhibt flow of Inhibt flow of gluconeogenic gluconeogenic precursor to liver precursor to liver

(Glycerol)(Glycerol)

2.↑Glycogen synth2.↑Glycogen synth

3.↓Gluconeogenesis3.↓Gluconeogenesis 3.3.Inhibt flow gluconeo -Inhibt flow gluconeo -genic precursor to liver genic precursor to liver (Lactate pyruvate)(Lactate pyruvate)4.↑hepatic Glu uptake4.↑hepatic Glu uptake

FatFat FatFat FatFat

1.↑Lipogenesis1.↑Lipogenesis 1.↓Lipolysis1.↓Lipolysis 1. ↓Lipolysis1. ↓Lipolysis

2.↓Ketogenesis2.↓Ketogenesis 2.↑Trigly formation2.↑Trigly formation

ProteinProtein ProteinProtein ProteinProtein

1.↓Protein breakdown1.↓Protein breakdown ------------------ 1.↑Protein synthesis1.↑Protein synthesis

2.↑Protein synthesis2.↑Protein synthesis ------------------ 2.↓Protein breakdown2.↓Protein breakdown

CLASSIFICATION OF INSULINCLASSIFICATION OF INSULINOn Basis of duration of actionOn Basis of duration of action

TypeType Appea-Appea-

-rance-rance

Added Added

proteinsproteins

Action in hrsAction in hrs

Onset Onset Peak Peak Duration Duration

RAPID ACTINGRAPID ACTING

1.Regular soluble Insulin1.Regular soluble Insulin Clear Clear NoneNone 0.5-0.70.5-0.7 2-42-4 5-85-8

2.Insulin Lispro2.Insulin Lispro ClearClear NoneNone 0.250.25 0.5-1.50.5-1.5 2-52-5

3.Insulin Aspart3.Insulin Aspart ClearClear NoneNone 0.250.25 0.5-0.80.5-0.8 3-53-5

4.Insulin Glulisine4.Insulin Glulisine ClearClear NoneNone ---- 0.5-1.50.5-1.5 1-2.51-2.5

INTERMEDIATE ACTINGINTERMEDIATE ACTING

1.1.NPHNPH(Neut protamine (Neut protamine hagedorn)hagedorn)

CloudyCloudy ProtamiProtami 1-21-2 6-126-12 18-2418-24

2.Lente (IZS)2.Lente (IZS) CloudyCloudy NoneNone 1-21-2 6-126-12 18-2418-24

LONG ACTINGLONG ACTING

1.Prota Zn Insulin1.Prota Zn Insulin CloudyCloudy ProtamiProtami 4-64-6 14-2014-20 24-3624-36

2.Insulin Glargine2.Insulin Glargine ClearClear NoneNone 2-52-5 5-125-12 18-2418-24

3.Ultralente3.Ultralente CloudyCloudy NoneNone 4-64-6 16-1816-18 20-3620-36

CONVENTIONAL PREPARATIONSCONVENTIONAL PREPARATIONS

Pork & Beef , Antigenic , Low costPork & Beef , Antigenic , Low cost

1) Regular (soluble) Insulin- stabilizes by Zn, form Hexamers1) Regular (soluble) Insulin- stabilizes by Zn, form Hexamers

Inj. just before meal early pp hyperglycemia & late pp Inj. just before meal early pp hyperglycemia & late pp hypoglycemia hypoglycemia

2) Lente Insulin- Insulin Zn Suspension two types in 7:3 ratio2) Lente Insulin- Insulin Zn Suspension two types in 7:3 ratio

Ultralente- Extended IZS Semilente- Prompt IZSUltralente- Extended IZS Semilente- Prompt IZS

Amorphous Crystalline Amorphous Crystalline

Large particle Small particleLarge particle Small particle

Long acting Short actingLong acting Short acting

3) Isophane-(NPH) Neutral protamine hagedorn3) Isophane-(NPH) Neutral protamine hagedorn

4) Protamine Zn Insulin(PZI)- 4) Protamine Zn Insulin(PZI)-

NEWER INSULINSNEWER INSULINS

ANTIGENICITY OF INSULINANTIGENICITY OF INSULIN

Electrophoresis –Electrophoresis –

A- high mol wt contaminantA- high mol wt contaminant

B- Proinsulin & intermediate product of proinsulinB- Proinsulin & intermediate product of proinsulin

C- Insulin MonomersC- Insulin Monomers

Antigenicity – A&B Component – eliminate →purified C insulinAntigenicity – A&B Component – eliminate →purified C insulin

Animal insulin production – need large no. of animalsAnimal insulin production – need large no. of animals

DNA Technology research – identical to human insulinDNA Technology research – identical to human insulin

1)1) Enzymatic Modified Pathway – EMPEnzymatic Modified Pathway – EMPEnzymatic conversion of porcine to human insulinEnzymatic conversion of porcine to human insulinAlanine replaced by ThreonineAlanine replaced by Threonine

Crude insulin Crude insulin ↓ ↓ TranspeptidationTranspeptidation

Threonine esterThreonine ester ↓ ↓ Trypsin organic solventTrypsin organic solvent

Human insulin esterHuman insulin ester↓ ↓

Gel filtration at low PH (remove trypsin)Gel filtration at low PH (remove trypsin)↓ ↓

Anion exchange chromatographyAnion exchange chromatography (remove unconverted porcine insulin)(remove unconverted porcine insulin)

↓↓

Cleavage & human insulin esterCleavage & human insulin ester↓↓

Chromatography (human insulin ester)Chromatography (human insulin ester)↓↓

Human monocomponent insulinHuman monocomponent insulin

2) CHAIN RECOMBINANT BACTERIA- CRB2) CHAIN RECOMBINANT BACTERIA- CRB

Organism of known fermentation – insert synthetic geneOrganism of known fermentation – insert synthetic gene

sequence of DNA for derived protein- by plasmidsequence of DNA for derived protein- by plasmid

Culture this organism-synthesized protein harvested by lysing Culture this organism-synthesized protein harvested by lysing

bacteria –purified & chemical conversion E.colibacteria –purified & chemical conversion E.coli

3) PROINSULIN RECOMBINANT BACTERIA- 3) PROINSULIN RECOMBINANT BACTERIA-

Pronsulin gene inserted same way – proinsulin chains cleavedPronsulin gene inserted same way – proinsulin chains cleaved

by carboxypeptidase E – human insulin & C-peptide- purifiedby carboxypeptidase E – human insulin & C-peptide- purified

Features Features Highly purifiedHighly purified Conventional Conventional

11 Species Species PorcinePorcine Bovine/PorcineBovine/Porcine

22 Purification Purification ChromatographyChromatography Recrystallization Recrystallization

33 PurityPurity Proinsulin foldProinsulin fold Proinsulin & other prProinsulin & other pr

44 ImmunogenicityImmunogenicity Less Less More More

55 PH of soluble PH of soluble insulininsulin

Neutral Neutral Acidic (2.5-3.5)Acidic (2.5-3.5)

66 MixibilityMixibility Possible Possible Not possibleNot possible

77 Compatibility Compatibility CompatibleCompatible Less CompatibleLess Compatible

CHARACTERISTICS OF NEWER INSULINCHARACTERISTICS OF NEWER INSULIN

Absorbed faster, Gap between sc inj & food shorterAbsorbed faster, Gap between sc inj & food shorter

Duratio & onset of action –shorter-fasting hypoglycemia-so Duratio & onset of action –shorter-fasting hypoglycemia-so inj given post dinnerinj given post dinner

More pure more effectiveMore pure more effective

Neutral PH-more stable mixing & less painfullNeutral PH-more stable mixing & less painfull

Potency – more on wt basisPotency – more on wt basis

Less AntigenicLess Antigenic

Not cause LipodystrophyNot cause Lipodystrophy

Now cost is lowNow cost is low

Disadvantage:-Disadvantage:-

Hypoglycemic unawarenessHypoglycemic unawareness

INDICATIONS OF NEWER INSULINSINDICATIONS OF NEWER INSULINS

1.1. Newly diagnosed DM ptNewly diagnosed DM pt

2.2. Pt t/t intermittently with insulin – surgery infection etcPt t/t intermittently with insulin – surgery infection etc

3.3. Immunological insulin resistanceImmunological insulin resistance

4.4. Allergic or local reaction to animal insulinAllergic or local reaction to animal insulin

5.5. Pt developed insulin induced lipodystrophyPt developed insulin induced lipodystrophy

6.6. Pt develop insulin resistance to conventional Pt develop insulin resistance to conventional preparationspreparations

7.7. Rapidly progressive microagiopathyRapidly progressive microagiopathy

8.8. During pregnancyDuring pregnancy

NEWER INSULINSNEWER INSULINS

1) Purified porcine1) Purified porcine

i) Short – Actrapidi) Short – Actrapid

ii) Intermediate – Lentard (Lente), Insultard (NPH)ii) Intermediate – Lentard (Lente), Insultard (NPH)

iii) Premixed – Mixtard (30/70)iii) Premixed – Mixtard (30/70)

2) Human Insulin2) Human Insulin

i) Short – Actrapidi) Short – Actrapid

ii) Intermediate – Monotard (Lente), Insultard (NPH)ii) Intermediate – Monotard (Lente), Insultard (NPH)

iii) Long – Ultratard (Ultralente)iii) Long – Ultratard (Ultralente)

iv) Premixed – Mixtard (30/70)iv) Premixed – Mixtard (30/70)

3) Penfills3) Penfills

i) Short – Actrapid HMi) Short – Actrapid HM

ii) Intermediate – Insultard HMii) Intermediate – Insultard HM

iii) Premixed – Mixtard 10HM, 20HM, 40HM, 50HMiii) Premixed – Mixtard 10HM, 20HM, 40HM, 50HM

NEWER INSULIN ANALOGUENEWER INSULIN ANALOGUE

SHORT ACTING:-SHORT ACTING:-

1) INSULIN ASP B10- 1) INSULIN ASP B10-

-Substituting aspartic acid for histidine at B10 -Substituting aspartic acid for histidine at B10 -mitogenic experimentally -mitogenic experimentally

2) INSULIN LISPRO- 2) INSULIN LISPRO-

First genetically engineered – clinical useFirst genetically engineered – clinical use

Sequence of proline at B28 & lysine at B29 reversed to lysine Sequence of proline at B28 & lysine at B29 reversed to lysine at B28 & proline at B29 ( Lis Pro)at B28 & proline at B29 ( Lis Pro)

3) INSULIN ASPART –3) INSULIN ASPART –

Proline of B28 replaced by Aspartic acidProline of B28 replaced by Aspartic acid

4) INSULIN GLUISINE-4) INSULIN GLUISINE-

Lysine replace aspargine at B23 & Glutamic acid replace Lysine replace aspargine at B23 & Glutamic acid replace lysine at B29lysine at B29

LONG ACTING –LONG ACTING –1) NOVOSOL BASAL – 1) NOVOSOL BASAL – Contains Arginine, Glycine ThreonineContains Arginine, Glycine Threonine Low bioavailability, so high doses reqLow bioavailability, so high doses req2) INSULIN GLARGINE –2) INSULIN GLARGINE – Contains Arginine at carboxyterminus of B chain, Glycine Contains Arginine at carboxyterminus of B chain, Glycine

replaces arginine at A21replaces arginine at A21 Peakless effect given ODPeakless effect given OD Fasting & interdigestive BSL ↓ irrespective of time of dayFasting & interdigestive BSL ↓ irrespective of time of day Not mixable , Not control mealtime glycemiaNot mixable , Not control mealtime glycemia Lower night time hypoglycemiaLower night time hypoglycemia3) INSULIN DETEMIR – Fatty Acid acetylated insulin3) INSULIN DETEMIR – Fatty Acid acetylated insulin Most recent, Threonine dropped from B30 & Mysteric acid is Most recent, Threonine dropped from B30 & Mysteric acid is

attached to B29 Lysine, Less hypoglycemiaattached to B29 Lysine, Less hypoglycemia Onset of action 1-2 Hrs Duration >24hrs Onset of action 1-2 Hrs Duration >24hrs

ADVERSE REACTIONSADVERSE REACTIONS

1) HYPOGLYCEMIA-1) HYPOGLYCEMIA- Most common, Occurs in any diabetic -Most common, Occurs in any diabetic - Inadvertent inj of large doses, Missing meal, Inadvertent inj of large doses, Missing meal, Vigourous exerciseVigourous exercise Counter regulatory sympathetic regulation- sweating anxiety Counter regulatory sympathetic regulation- sweating anxiety

palpitation tremor palpitation tremor Neuroglycopenic symptoms – dizziness, headache, visual dist, Neuroglycopenic symptoms – dizziness, headache, visual dist,

hunger, fatigue, weakness, muscular incoordination, ↓BPhunger, fatigue, weakness, muscular incoordination, ↓BP Hypoglycemic unawareness Hypoglycemic unawareness When BSL <40 mg/dl- mental confusion, abnormal behaviour, When BSL <40 mg/dl- mental confusion, abnormal behaviour,

seizure coma & deathseizure coma & death Irreversible neurological deficitIrreversible neurological deficit Treatment:- Glucose oral, ivTreatment:- Glucose oral, iv Glucagon 0.5-1mg iv/ Adr 0.2 mg scGlucagon 0.5-1mg iv/ Adr 0.2 mg sc

2) INSULIN ALLERGY & RESISTANCE2) INSULIN ALLERGY & RESISTANCE

Conventional insulin – contaminating proteinConventional insulin – contaminating protein

IgE mediated , hypersensitivityIgE mediated , hypersensitivity

Urticaria, angioedema & anaphylaxisUrticaria, angioedema & anaphylaxis

3) LIPOATROPHY & LIPOHYPERTROPHY-3) LIPOATROPHY & LIPOHYPERTROPHY-

atrophy- immune response to insulinatrophy- immune response to insulin

Lipohypertrophy- enlarge subcut fat-→ lipogenic action of Lipohypertrophy- enlarge subcut fat-→ lipogenic action of high local conc. Insulin high local conc. Insulin

T/t- To change site of inj regularly T/t- To change site of inj regularly

purified human insulinpurified human insulin

4) INSULIN EDEMA- 4) INSULIN EDEMA-

Dependant edema – sodium retentionDependant edema – sodium retention

DRUG INTERACTIONSDRUG INTERACTIONS

1) Beta2 blocker inhibit compensatory mechanism - prolong 1) Beta2 blocker inhibit compensatory mechanism - prolong

hypoglycemia, mask warning signs , ↑BPhypoglycemia, mask warning signs , ↑BP

2) Thiazide, Furosemide, corticosteroid, Salbutamol, OC -2) Thiazide, Furosemide, corticosteroid, Salbutamol, OC -↑BSL↑BSL

3) Alcohol ppt hypoglycemia3) Alcohol ppt hypoglycemia

4) Salicylate Lithium, Theophylline – hypoglycemia accentuate4) Salicylate Lithium, Theophylline – hypoglycemia accentuate

USES OF INSULINUSES OF INSULIN

1) DIABETES MELLITUS-1) DIABETES MELLITUS-

Purpose- Purpose- Restore metabolism to normalRestore metabolism to normalPrevent death & alleviate symptomsPrevent death & alleviate symptomsPrevent acute & chronic complications Prevent acute & chronic complications Achieve biochemical controlAchieve biochemical control

DM controlled by diet & exercise DM controlled by diet & exercise need insulin whenneed insulin when

Not controlled by diet & exercise Not controlled by diet & exercise OHA prim/sec failure or not toleratedOHA prim/sec failure or not toleratedUnder wt ptUnder wt ptAny DM complicationAny DM complicationTemporary tide over infection, Trauma, Surgery, Pregnancy, Temporary tide over infection, Trauma, Surgery, Pregnancy, Perioperative monitoringPerioperative monitoring

Regular insulin- sc before mealRegular insulin- sc before mealRequirement – assess by BSL & Urine sugarRequirement – assess by BSL & Urine sugar Type 1 – 0.4-0.8 U/kg/dayType 1 – 0.4-0.8 U/kg/day Type 2- 0.2-1.6 U/kg/dayType 2- 0.2-1.6 U/kg/dayRegimens- Regimens- 1) Typical split mixed regimen- reg/lispro/aspart & intemediate 1) Typical split mixed regimen- reg/lispro/aspart & intemediate

acting (NPH/Lente) twice daily before breakfast & dinneracting (NPH/Lente) twice daily before breakfast & dinner2) In above evening dose of NPH/Lente is delayed at bed time2) In above evening dose of NPH/Lente is delayed at bed time3) Long acting insulin Glargine OD for basal coverage & rapid 3) Long acting insulin Glargine OD for basal coverage & rapid

acting at meal timeacting at meal time

4) Premeal short acting & Long acting NPH/Lente at breakfast & 4) Premeal short acting & Long acting NPH/Lente at breakfast & bed timebed time

Goal- Fasting BSL – 90-120 mg/dlGoal- Fasting BSL – 90-120 mg/dl

PP - < 150 mg/dl, HbA1c < 7% / <6.5%PP - < 150 mg/dl, HbA1c < 7% / <6.5%

Less disciplined- Fasting-140 mg/dl, PP- 200-250 mg/dlLess disciplined- Fasting-140 mg/dl, PP- 200-250 mg/dl

2) DIABETIC KETOACIDOSIS2) DIABETIC KETOACIDOSIS

Infection (mc) Trauma, stroke, Pancreatitis, Stressful Infection (mc) Trauma, stroke, Pancreatitis, Stressful conditionsconditions

Treatment-Treatment-

1) Insulin- regular insulin, 0.1-0.2 U/kg iv bolus f/b 0.1 U/kg/hr 1) Insulin- regular insulin, 0.1-0.2 U/kg iv bolus f/b 0.1 U/kg/hr infusion, fall in BSL 10% per hr adequateinfusion, fall in BSL 10% per hr adequate

when BSL 300mg/dl – 2-3U/hr , after full conscious sc therapywhen BSL 300mg/dl – 2-3U/hr , after full conscious sc therapy

2) IV Fluids- correct dehydration2) IV Fluids- correct dehydration

NS 1L/hr, ↓ 0.5L/4hr depend on dehydration, NS 1L/hr, ↓ 0.5L/4hr depend on dehydration,

Stabilize pt (BP HR) ½ NS Stabilize pt (BP HR) ½ NS

when BSL 300mg/dl 5% Glucose in ½ NS – when BSL 300mg/dl 5% Glucose in ½ NS –

i. BSL ↓ before ketones clearedi. BSL ↓ before ketones cleared

ii. For restore depleted hepatic glycogenii. For restore depleted hepatic glycogen

3) KCl- 400 meq K3) KCl- 400 meq K++ lost, intracellular store replace, after insulin K lost, intracellular store replace, after insulin K++ driven intracellularly →Hypokalemia driven intracellularly →Hypokalemia

After 4hr 10-20meq/hr add to iv fluidAfter 4hr 10-20meq/hr add to iv fluid

4) Sodium Bicarbonate- 50 meq till PH>7.2 4) Sodium Bicarbonate- 50 meq till PH>7.2

5) Phosphate – 5-10 meq/hr 5) Phosphate – 5-10 meq/hr

6) Antibiotics & other support T/t of ppt cause6) Antibiotics & other support T/t of ppt cause

3) Hyperosmolar Nonketotic (Hyperglycemia) Coma -3) Hyperosmolar Nonketotic (Hyperglycemia) Coma -

Type 2 DMType 2 DM

Dehydration, Glycosuria → diuresis, hemoconc.→↓ urine Dehydration, Glycosuria → diuresis, hemoconc.→↓ urine output→↑BSL >800mg/dl→↑plasma osmolarity >350mosm/L output→↑BSL >800mg/dl→↑plasma osmolarity >350mosm/L → coma, death→ coma, death

T/t – like ketoacidosis, Faster fluid replacement reqT/t – like ketoacidosis, Faster fluid replacement req

prone to thrombosis- prophylactic heparinprone to thrombosis- prophylactic heparin

Thank You to Dr. J. B. JAJU Thank You to Dr. J. B. JAJU for guidance & supportfor guidance & support