This ppt is important for UG MBBS, PG Pharmacology and any other person interested in Pharmacotherapy of Diabetes Mellitus.

1. PHARMACOLOGY OF TYPE 1PHARMACOLOGY 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

2. DIABETES MELLITUSDIABETES MELLITUS
Group of syndromes characterized byGroup of syndromes characterized by
hyperglycemia; altered metabolism of lipid,hyperglycemia; altered metabolism of lipid,
CHO & Proteins and increase risk ofCHO & 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

3. 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 mutationgene mutation
iii)iii) MODY-3: Hepatic nuclear factor 1MODY-3: Hepatic nuclear factor 1αα gene mutationgene 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) Insulinb) Insulin gene mutationgene mutation
c) Insulin receptor gene mutationc) Insulin receptor gene mutation

4. 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 Diseasei) 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)

5. Symptoms Of DMSymptoms Of DM
Classical TriadClassical Triad
Polyuria - ↑urinationPolyuria - ↑urination
Polydipsia - ↑thirst & fluid intakePolydipsia - ↑thirst & fluid intake
Polyphagia - ↑appetitePolyphagia - ↑appetite
↑↑BSL→incomplete reabsorption in prox. Renal tubuli→ GlycosuriaBSL→incomplete reabsorption in prox. Renal tubuli→ Glycosuria
→↑→↑ osmotic pressure of urine →↓reabsorption of water →polyuriaosmotic 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 ofvomitting & Abdominal pain, altered state of
consciousness, coma, deathconsciousness, coma, death

6. DIAGNOSISDIAGNOSIS
Normal GTNormal GT Impaired GTImpaired GT DMDM
Fasting plasmaFasting plasma
glucose (mg/dl)glucose (mg/dl)
< 100< 100 100 -125100 -125 >> 126126
2hrs after glucose2hrs after glucose
load (mg/dl)load (mg/dl)
< 140< 140 >> 140-199140-199 >> 200200
HbA1c – Glycosylated Hb/glycated Hb/glycoHbHbA1c – Glycosylated Hb/glycated Hb/glycoHb
6% or more abnormal6% or more abnormal
In DM Good glycemic control 6.5-7% HbA1cIn DM Good glycemic control 6.5-7% HbA1c
Reflects avg. BSL over preceding 90 daysReflects 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

7. Type 1 DMType 1 DM Type 2 DMType 2 DM
Age at onsetAge at onset Childhood/pubertyChildhood/puberty Over age 35 yrsOver age 35 yrs
Nutritional status atNutritional status at
time of onsettime of onset
UndernourishedUndernourished Obesity presentObesity present
PrevalencePrevalence 10-20%10-20% 80-90%80-90%
GeneticGenetic
predispositionpredisposition
ModerateModerate Very strongVery strong
DefectDefect Beta cells destroyedBeta cells destroyed
eliminating insulineliminating insulin
productionproduction
Inadequate insulinInadequate insulin
production,production,
Insulin resistanceInsulin resistance
KetoacidosisKetoacidosis FrequentFrequent AbsentAbsent
Anti islet cellAnti islet cell
antibodyantibody
>80%>80% <5%<5%

8. PATHOPHYSIOLOGY OF TYPE 1 DMPATHOPHYSIOLOGY OF TYPE 1 DM
A)A) AUTOIMMUNITYAUTOIMMUNITY--
Condition where ones own immune system attackCondition where ones own immune system attack
structure in one’s own bodystructure in one’s own body
Circulating antibodies against b-cells and insulinCirculating antibodies against b-cells and insulin
Cytoplasmic & membrane bound Ag IAAS GAD HSP etcCytoplasmic & membrane bound Ag IAAS GAD HSP etc
InsulitisInsulitis
Both humoral & cell-mediated immunity are stimulatedBoth humoral & cell-mediated immunity are stimulated
triggered by reaction to infectiontriggered by reaction to infection
B)B) GENETIC FACTORSGENETIC FACTORS
Ethnic differences, Familial clustering, High concordanceEthnic 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

9. 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-

10. HONEYMOON PERIODHONEYMOON PERIOD
Due to b-cell reserve optimal function & initiation of insulinDue 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 toObserved in 50-60% of newly diagnosed patients & it can last up to
one year but it always ends.one year but it always ends.

11. 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 planMeal plan

Sick-day managementSick-day management

12. Diet and Meal planningDiet and Meal planning
Susrate and Charaka- 2,500 years agoSusrate and Charaka- 2,500 years ago
John Rollo -eighteenth centuryJohn Rollo -eighteenth century
Frederick Allen -modern history of the diabetic dietFrederick Allen -modern history of the diabetic diet
Regular meal plans with calorie exchange options areRegular meal plans with calorie exchange options are
encouraged.encouraged.
50-60% of required energy to be obtained from complex50-60% of required energy to be obtained from complex
carbohydrates.carbohydrates.
Distribute carbohydrate load evenly during the day preferablyDistribute 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.

13. INSULIN
HISTORY
1500 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

14. 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

15. 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."

16. 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

17. 1922 BANTING & BEST1922 BANTING & BEST
Frederick Banting & Charles Best – ligate pancreaticFrederick Banting & Charles Best – ligate pancreatic
duct extract islets with alcohol and acid-↓BSL in dogduct extract islets with alcohol and acid-↓BSL in dog
Leonard Thompson- age14-year wt 64 lb injectedLeonard Thompson- age14-year wt 64 lb injected
their extract - blood glucose to fall from 520 to 120their extract - blood glucose to fall from 520 to 120
mg/dL in 24 hoursmg/dL in 24 hours
Leonard lived a relatively healthyLeonard lived a relatively healthy
life for 13 years before dyinglife 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

18. Nobel PrizeNobel Prize
 1923 –1923 – Banting & MacleodBanting & Macleod nobel prize fornobel 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

19. 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-peptideInsulin C-peptide
AmylinAmylin
Amylin- modulate appetiteAmylin- 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

20. Structure & Chemistry…..Structure & Chemistry…..
SpeciesSpecies AntigenicitAntigenicit
yy
A -ChainA -Chain B-ChainB-Chain
88thth
aaaa 1010thth
aaaa 3030thth
aaaa
HumanHuman LeastLeast ThreonineThreonine IsoleucineIsoleucine ThreonineThreonine
PorkPork NegligibleNegligible ThreonineThreonine IsoleucineIsoleucine AlanineAlanine
BeefBeef HighHigh AlanineAlanine ValineValine AlanineAlanine
Human Insulin – Human sequence insulin as primary structureHuman 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

21. 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 translationalmRNA 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 form
2 Zn + 6 Insulin mol2 Zn + 6 Insulin mol

22. INSULIN RELEASE

23. DEGRADATION OF INSULINDEGRADATION OF INSULIN
Insulin→Insulin→ EndogenousEndogenous 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: 60-90Meals peak value: 60-90 μμU/mlU/ml

24. INSULIN RECEPTORSINSULIN RECEPTORS
Beta subunit has tyrosin kinaseBeta subunit has tyrosin kinase
Insulin bind toInsulin bind to αα subunitsubunit
High specificity & affinityHigh specificity & affinity

25. Glucose Transporters (GLUT)Glucose Transporters (GLUT)
TransporTranspor
terter
TissueTissue GlucoseGlucose
(mmol/L)(mmol/L)
FunctionsFunctions
GLUT 1GLUT 1 All tissue specillyAll tissue specilly
red cells & brainred cells & brain
1-21-2 Basal uptake of glucoseBasal 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

26. MECHANISM OF ACTIONMECHANISM OF ACTION
Insulin + ReceptorInsulin + Receptor
((αα subunit)subunit)
↓↓
Tyrosine kinase (Tyrosine kinase (ββ
subunit)subunit)
↓↓
Activate IRSActivate IRS
↓↓
Activation of Phosphatidyl inositol 3 kinase pathway & MAPActivation 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

27. Translocation of GLUT-glucose uptakeTranslocation of GLUT-glucose uptake
Insulin activate transcription facton – enhance DNAInsulin activate transcription facton – enhance DNA
synthesis, cell growth and divisionsynthesis, cell growth and division
Stimulate NaStimulate Na++
-K-K++
ATPase increase pump activity - KATPase increase pump activity - K++
accumalationaccumalation

28. REGULATION OF INSULIN SECRETIONREGULATION OF INSULIN SECRETION
B) HORMONAL :-B) HORMONAL :-
Hormones like Growth Hormone,Hormones like Growth Hormone,
Corticosteroids, ThyroxinCorticosteroids, 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 releasebeta 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 phaseGlucose induce 1st phase within 2 min f/b 2nd phase
sustainedsustained

29. 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 intracellularinsulin release (IP3/DAG)→↑Ca intracellular
Primary central site – HypothalamusPrimary central site – Hypothalamus
Stimulation of Ventrolat nu →↑ insulin releaseStimulation of Ventrolat nu →↑ insulin release
Stimulation of Ventromed nu →↓ insulin releaseStimulation of Ventromed nu →↓ insulin release

30. PHARMACOLOGICAL ACTIONS OF INSULINPHARMACOLOGICAL ACTIONS OF INSULIN
LIVERLIVER ADDIPOSEADDIPOSE 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 ofInhibt flow of
gluconeogenicgluconeogenic
precursor to liverprecursor to liver
(Glycerol)(Glycerol)
2.↑Glycogen synth2.↑Glycogen synth
3.↓Gluconeogenesis3.↓Gluconeogenesis 3.3.Inhibt flow gluconeoInhibt 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

31. CLASSIFICATION OF INSULINCLASSIFICATION OF INSULIN
On Basis of duration of actionOn Basis of duration of action
TypeType Appea-Appea-
-rance-rance
AddedAdded
proteinsproteins
Action in hrsAction in hrs
OnsetOnset PeakPeak DurationDuration
RAPID ACTINGRAPID ACTING
1.Regular soluble Insulin1.Regular soluble Insulin ClearClear 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

33. 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 ppInj. just before meal early pp hyperglycemia & late pp
hypoglycemiahypoglycemia
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 CrystallineAmorphous 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)-

34. 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

35. 1)1) Enzymatic Modified Pathway – EMPEnzymatic Modified Pathway – EMP
Enzymatic conversion of porcine to human insulinEnzymatic conversion of porcine to human insulin
Alanine replaced by ThreonineAlanine replaced by Threonine
Crude insulinCrude 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

36. 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 lysingCulture 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

37. FeaturesFeatures Highly purifiedHighly purified ConventionalConventional
11 SpeciesSpecies PorcinePorcine Bovine/PorcineBovine/Porcine
22 PurificationPurification ChromatographyChromatography RecrystallizationRecrystallization
33 PurityPurity Proinsulin foldProinsulin fold Proinsulin & other prProinsulin & other pr
44 ImmunogenicityImmunogenicity LessLess MoreMore
55 PH of solublePH of soluble
insulininsulin
NeutralNeutral Acidic (2.5-3.5)Acidic (2.5-3.5)
66 MixibilityMixibility PossiblePossible Not possibleNot possible
77 CompatibilityCompatibility CompatibleCompatible Less CompatibleLess Compatible

38. 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-soDuratio & 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

39. 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 conventionalPt develop insulin resistance to conventional
preparationspreparations
7.7. Rapidly progressive microagiopathyRapidly progressive microagiopathy
8.8. During pregnancyDuring pregnancy

40. 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

41. 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 lysineSequence 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 replaceLysine replace aspargine at B23 & Glutamic acid replace
lysine at B29lysine at B29

42. 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 req
2) INSULIN GLARGINE –2) INSULIN GLARGINE –
Contains Arginine at carboxyterminus of B chain, GlycineContains 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 hypoglycemia
3) INSULIN DETEMIR – Fatty Acid acetylated insulin3) INSULIN DETEMIR – Fatty Acid acetylated insulin
Most recent, Threonine dropped from B30 & Mysteric acid isMost 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 >24hrsOnset of action 1-2 Hrs Duration >24hrs

43. 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 anxietyCounter regulatory sympathetic regulation- sweating anxiety
palpitation tremorpalpitation 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 unawarenessHypoglycemic 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

44. 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 ofLipohypertrophy- enlarge subcut fat-→ lipogenic action of
high local conc. Insulinhigh local conc. Insulin
T/t- To change site of inj regularlyT/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

45. DRUG INTERACTIONSDRUG INTERACTIONS
1) Beta2 blocker inhibit compensatory mechanism - prolong1) Beta2 blocker inhibit compensatory mechanism - prolong
hypoglycemia, mask warning signs , ↑BPhypoglycemia, mask warning signs , ↑BP
2) Thiazide, Furosemide, corticosteroid, Salbutamol, OC2) 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

46. USES OF INSULINUSES OF INSULIN
1) DIABETES MELLITUS-1) DIABETES MELLITUS-
Purpose-Purpose-
Restore metabolism to normalRestore metabolism to normal
Prevent death & alleviate symptomsPrevent death & alleviate symptoms
Prevent acute & chronic complicationsPrevent acute & chronic complications
Achieve biochemical controlAchieve biochemical control
DM controlled by diet & exerciseDM controlled by diet & exercise
need insulin whenneed insulin when
Not controlled by diet & exerciseNot controlled by diet & exercise
OHA prim/sec failure or not toleratedOHA prim/sec failure or not tolerated
Under wt ptUnder wt pt
Any DM complicationAny DM complication
Temporary tide over infection, Trauma, Surgery, Pregnancy,Temporary tide over infection, Trauma, Surgery, Pregnancy,
Perioperative monitoringPerioperative monitoring

47. Regular insulin- sc before mealRegular insulin- sc before meal
Requirement – 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/day
Regimens-Regimens-
1) Typical split mixed regimen- reg/lispro/aspart & intemediate1) Typical split mixed regimen- reg/lispro/aspart & intemediate
acting (NPH/Lente) twice daily before breakfast & dinneracting (NPH/Lente) twice daily before breakfast & dinner
2) In above evening dose of NPH/Lente is delayed at bed time2) In above evening dose of NPH/Lente is delayed at bed time
3) Long acting insulin Glargine OD for basal coverage & rapid3) Long acting insulin Glargine OD for basal coverage & rapid
acting at meal timeacting at meal time

48. 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

49. 2) DIABETIC KETOACIDOSIS2) DIABETIC KETOACIDOSIS
Infection (mc) Trauma, stroke, Pancreatitis, StressfulInfection (mc) Trauma, stroke, Pancreatitis, Stressful
conditionsconditions

50. Treatment-Treatment-
1) Insulin- regular insulin, 0.1-0.2 U/kg iv bolus f/b 0.1 U/kg/hr1) 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 NSStabilize 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 Klost, intracellular store replace, after insulin K++
driven intracellularly →Hypokalemiadriven 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>7.24) Sodium Bicarbonate- 50 meq till PH>7.2
5) Phosphate – 5-10 meq/hr5) Phosphate – 5-10 meq/hr
6) Antibiotics & other support T/t of ppt cause6) Antibiotics & other support T/t of ppt cause

51. 3) Hyperosmolar Nonketotic (Hyperglycemia) Coma -3) Hyperosmolar Nonketotic (Hyperglycemia) Coma -
Type 2 DMType 2 DM
Dehydration, Glycosuria → diuresis, hemoconc.→↓ urineDehydration, Glycosuria → diuresis, hemoconc.→↓ urine
output→↑BSL >800mg/dl→↑plasma osmolarity >350mosm/Loutput→↑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. JAJUThank You to Dr. J. B. JAJU
for guidance & supportfor guidance & support