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PHARMACOLOGY OF TYPE 1PHARMACOLOGY OF TYPE 1
DIABETES MELLITUS -DIABETES MELLITUS -
INSULININSULIN
Dr. CHANDANE R. D.Dr. C...
DIABETES MELLITUSDIABETES MELLITUS
Group of syndromes characterized byGroup of syndromes characterized by
hyperglycemia; a...
Classification of Diabetes MellitusClassification of Diabetes Mellitus
I) Type 1 DM ( IDDM )I) Type 1 DM ( IDDM )
a) Autoi...
Classification…….Classification…….
B) Diabetes Secondary to Pancreatic diseasesB) Diabetes Secondary to Pancreatic disease...
Symptoms Of DMSymptoms Of DM
Classical TriadClassical Triad
Polyuria - ↑urinationPolyuria - ↑urination
Polydipsia - ↑thirs...
DIAGNOSISDIAGNOSIS
Normal GTNormal GT Impaired GTImpaired GT DMDM
Fasting plasmaFasting plasma
glucose (mg/dl)glucose (mg/...
Type 1 DMType 1 DM Type 2 DMType 2 DM
Age at onsetAge at onset Childhood/pubertyChildhood/puberty Over age 35 yrsOver age ...
PATHOPHYSIOLOGY OF TYPE 1 DMPATHOPHYSIOLOGY OF TYPE 1 DM
A)A) AUTOIMMUNITYAUTOIMMUNITY--
Condition where ones own immune s...
C) ENVIRONMENTAL INFLUENCEC) ENVIRONMENTAL INFLUENCE
Viruses-Coxaschie B, Mumps, Rubella, ReovirusesViruses-Coxaschie B, M...
HONEYMOON PERIODHONEYMOON PERIOD
Due to b-cell reserve optimal function & initiation of insulinDue to b-cell reserve optim...
MANAGEMENT OF TYPE 1 DMMANAGEMENT OF TYPE 1 DM
EducationEducation
Diet and meal planningDiet and meal planning
Insulin the...
Diet and Meal planningDiet and Meal planning
Susrate and Charaka- 2,500 years agoSusrate and Charaka- 2,500 years ago
John...
INSULIN
HISTORY
1500 BC Sushruta – ayurveda Diabetes First Described
In Writing that flies and ants were attracted to urin...
Early Diabetes Treatments
1000- Greek physicians recommended
horseback riding to reduce excess urination
1800s- bleeding, ...
Early Research
1798- John Rollo - excess sugar in the blood and urine
1813-Claude Bernard linked diabetes to glycogen
meta...
Pancreas Extractors
1908- a young internist in Berlin, Georg Ludwig
Zuelzer created a pancreas extract named acomatrol.
Tr...
1922 BANTING & BEST1922 BANTING & BEST
Frederick Banting & Charles Best – ligate pancreaticFrederick Banting & Charles Bes...
Nobel PrizeNobel Prize
 1923 –1923 – Banting & MacleodBanting & Macleod nobel prize fornobel prize for
physiology /medici...
Structure & ChemistryStructure & Chemistry
PancreasPancreas –– Islets 2% of PancreasIslets 2% of Pancreas
CellsCells %isle...
Structure & Chemistry…..Structure & Chemistry…..
SpeciesSpecies AntigenicitAntigenicit
yy
A -ChainA -Chain B-ChainB-Chain
...
Biosynthesis & Storage of InsulinBiosynthesis & Storage of Insulin
 Human pancrea contain ~8mg insulin (200U) (1mg=28U)Hu...
INSULIN RELEASE
DEGRADATION OF INSULINDEGRADATION OF INSULIN
Insulin→Insulin→ EndogenousEndogenous Exogenous (s.c.)Exogenous (s.c.)
Liver ...
INSULIN RECEPTORSINSULIN RECEPTORS
Beta subunit has tyrosin kinaseBeta subunit has tyrosin kinase
Insulin bind toInsulin b...
Glucose Transporters (GLUT)Glucose Transporters (GLUT)
TransporTranspor
terter
TissueTissue GlucoseGlucose
(mmol/L)(mmol/L...
MECHANISM OF ACTIONMECHANISM OF ACTION
Insulin + ReceptorInsulin + Receptor
((αα subunit)subunit)
↓↓
Tyrosine kinase (Tyro...
Translocation of GLUT-glucose uptakeTranslocation of GLUT-glucose uptake
Insulin activate transcription facton – enhance D...
REGULATION OF INSULIN SECRETIONREGULATION OF INSULIN SECRETION
B) HORMONAL :-B) HORMONAL :-
Hormones like Growth Hormone,H...
C) NEURAL :-C) NEURAL :-
Islet- Sympathetic & Vagal n.Islet- Sympathetic & Vagal n.
1)1) αα-2 stimulation-↓ insulin releas...
PHARMACOLOGICAL ACTIONS OF INSULINPHARMACOLOGICAL ACTIONS OF INSULIN
LIVERLIVER ADDIPOSEADDIPOSE SKEL MUSCLESKEL MUSCLE
CH...
CLASSIFICATION OF INSULINCLASSIFICATION OF INSULIN
On Basis of duration of actionOn Basis of duration of action
TypeType A...
CONVENTIONAL PREPARATIONSCONVENTIONAL PREPARATIONS
Pork & Beef , Antigenic , Low costPork & Beef , Antigenic , Low cost
1)...
NEWER INSULINSNEWER INSULINS
ANTIGENICITY OF INSULINANTIGENICITY OF INSULIN
Electrophoresis –Electrophoresis –
A- high mol...
1)1) Enzymatic Modified Pathway – EMPEnzymatic Modified Pathway – EMP
Enzymatic conversion of porcine to human insulinEnzy...
2) CHAIN RECOMBINANT BACTERIA- CRB2) CHAIN RECOMBINANT BACTERIA- CRB
Organism of known fermentation – insert synthetic gen...
FeaturesFeatures Highly purifiedHighly purified ConventionalConventional
11 SpeciesSpecies PorcinePorcine Bovine/PorcineBo...
CHARACTERISTICS OF NEWER INSULINCHARACTERISTICS OF NEWER INSULIN
Absorbed faster, Gap between sc inj & food shorterAbsorbe...
INDICATIONS OF NEWER INSULINSINDICATIONS OF NEWER INSULINS
1.1. Newly diagnosed DM ptNewly diagnosed DM pt
2.2. Pt t/t int...
NEWER INSULINSNEWER INSULINS
1) Purified porcine1) Purified porcine
i) Short – Actrapidi) Short – Actrapid
ii) Intermediat...
NEWER INSULIN ANALOGUENEWER INSULIN ANALOGUE
SHORT ACTING:-SHORT ACTING:-
1) INSULIN ASP B10-1) INSULIN ASP B10-
-Substitu...
LONG ACTING –LONG ACTING –
1) NOVOSOL BASAL –1) NOVOSOL BASAL –
Contains Arginine, Glycine ThreonineContains Arginine, Gly...
ADVERSE REACTIONSADVERSE REACTIONS
1) HYPOGLYCEMIA-1) HYPOGLYCEMIA-
Most common, Occurs in any diabetic -Most common, Occu...
2) INSULIN ALLERGY & RESISTANCE2) INSULIN ALLERGY & RESISTANCE
Conventional insulin – contaminating proteinConventional in...
DRUG INTERACTIONSDRUG INTERACTIONS
1) Beta2 blocker inhibit compensatory mechanism - prolong1) Beta2 blocker inhibit compe...
USES OF INSULINUSES OF INSULIN
1) DIABETES MELLITUS-1) DIABETES MELLITUS-
Purpose-Purpose-
Restore metabolism to normalRes...
Regular insulin- sc before mealRegular insulin- sc before meal
Requirement – assess by BSL & Urine sugarRequirement – asse...
4) Premeal short acting & Long acting NPH/Lente at breakfast &4) Premeal short acting & Long acting NPH/Lente at breakfast...
2) DIABETIC KETOACIDOSIS2) DIABETIC KETOACIDOSIS
Infection (mc) Trauma, stroke, Pancreatitis, StressfulInfection (mc) Trau...
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....
3) Hyperosmolar Nonketotic (Hyperglycemia) Coma -3) Hyperosmolar Nonketotic (Hyperglycemia) Coma -
Type 2 DMType 2 DM
Dehy...
Pharmacology of Type 1 Diabetes mellitus insulin
Pharmacology of Type 1 Diabetes mellitus insulin
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Pharmacology of Type 1 Diabetes mellitus insulin

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  1. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 22. INSULIN RELEASE
  23. 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. 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. 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. 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. 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. 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. 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. 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. 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
  32. 32. 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)-
  33. 33. 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
  34. 34. 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
  35. 35. 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
  36. 36. 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
  37. 37. 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
  38. 38. 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
  39. 39. 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
  40. 40. 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
  41. 41. 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
  42. 42. 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
  43. 43. 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
  44. 44. 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
  45. 45. 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
  46. 46. 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
  47. 47. 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
  48. 48. 2) DIABETIC KETOACIDOSIS2) DIABETIC KETOACIDOSIS Infection (mc) Trauma, stroke, Pancreatitis, StressfulInfection (mc) Trauma, stroke, Pancreatitis, Stressful conditionsconditions
  49. 49. 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
  50. 50. 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
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