Insulin is a hormone produced by the pancreas that regulates blood sugar levels. It allows the body to use and store carbohydrates from food. Without enough insulin, blood sugar levels rise and a person develops diabetes. There are different types of insulin that work in various timeframes to mimic the body's natural insulin release and keep blood sugar stable. Insulin is essential for diabetes treatment but requires careful dosing to avoid hypoglycemia from too much insulin or hyperglycemia from too little insulin. New delivery methods like insulin pens and pumps aim to more closely match a person's changing insulin needs.

1. INSULINDr.Nagula Praveen

2. Insulin is not a cure for diabetes; it is a treatment. It enables the diabetic to burn sufficient carbohydrates, so that proteins and fats may be added to the diet in sufficient quantities to provide energy for the economic burdens of life. — Sir Frederick Grant Banting'Diabetes and Insulin', Nobel Lecture, 15 September 1925. In Nobel Lectures: Physiology or Medicine, 1922-1941 (1965), 68.

3. Laughter is the best medicine - unless you're diabetic, then insulin comes pretty high on the list. Jasper Carrott

4. IntroductionIs a proteinSynthesised from the beta cells of islets of langerhans.Deficiency causes DIABETES MELLITUS.Gene located on chromosome 11.Name 'insulin'by J de meyer .-1907.Insulin –first hormone for which radioimmunoassay was developed.Name ''insulin'' is derived from word insula—meaning island---a latin word.Connaught initial nameNovo nordisk –since 1923

5. History1869---Paul Langerhans–two distinct group of cells in pancreas –acinar cells ,islets.1889---Minkowski---pancreactomized dogs—diabetes mellitus.1921—Frederick Grant Banting–insulin secreted was destroyed by proteolytic digestionCharles .H.Best, a fourth year medical student –ligated the pancreatic ductsLeonard Thompson, a 14 yr old was the first person to receive insulin .---11 JAN 1922J.M.Collip-who purified epinephrine,purified insulin also.Purified and crystallized –AbevAminoacid sequence by Sanger—1960Complete synthesis of protein-19633 dimensional structure—Hodgkins-1971NOBEL PRIZE in medicine or physiology-1923-Banting and Best,Mcleod and Collip

7. Best and Banting

9. BANTING AND BEST

10. Leonard thompson

11. V.SHESHAIH

12. Secretion of insulinΒ cells of islets of langerhans in the pancreas—secrete 110 AA chain ,single chain—PREPROINSULIN.Rough endoplasmic reticulum---24 AAterminal( NH2)of preproinsulin is cleaved off—PROINSULINDuring formation of PROINSULIN,the molecule folds,disulfide bonds are formedConverted to INSULIN-golgi complex.During conversion –4 basic AA are removed,remaining connector or C peptide removed byproteolysis.Insulin formed is stored in vesicles.Bound to zinc atoms.Exist in hexamer form.

13. Structure of insulin51 amino acids5808 daltons2 peptide chains A and BOne intrasubunit and two intersubunit disulphide bondsA-21 AA,B-30 AASlight difference in structure in speciesPorcine-one AABovine—3 AAC peptide differs in all.

14. Equimolar amounts of C peptide,insulin are released into the circulation.C peptide has no biological function.It is useful index of insulin secretion.Proinsulin-insulin by 2 Ca endopeptidasesPC2 lysine arginine—C-APC3 argininearginine –C-B

15. Structure of insulinConserved portions of insulin—3 disulfide bondsBoth ends of A chainC terminal residues of B chain

18. INSULIN STRUCTURE

19. Genetics of insulinSingle insulin gene –chromosome 11Close to IGF-1Single protein product in most species2 genes encode—rat,mice---two molecules differ from each other by 2 AA residuesin B chain.Several  helical regions in both A and B chains.Proinsulin –INS gene

20. Existence of insulinIsolated chains of insulin are inactive.In acid solution –dimersAt neutral Ph—exist as hexamers and with Zn.Insulin in solution exists as monomer,dimer,hexamerIntermediate,long acting insulins have hexamers are common 2 molecules of zn are incorporated in hexamer .Zn plays a role in crystallization.Monomer is active.

21. Pharmacology of insulin Introduction of insulin of human insulin,proinsulin gene into organisms—e.coli,yeast-recombinant DNA technology.Insulin ppt at ph—5.4—soluble at 2-31 U of insulin -38.5 ug of substance40 U and 100 U –40u/ml,100u/ml10 U for infantsT1/2—40 min

22. NN= SaccharomycesCerevisiaeEli lilly= non-disease producing strain of E.ColiSanofi= non-disease producing strain of E.Coli

23. Insulin receptorInsulin binds to N and C terminal of  subunit of the receptor.cysteine rich region in alpha subunit.Affinity towards receptor-effect on glucose metabolism.Insulin is a member of IGF s.IGF1,IGF2 –are similar to proinsulin ,concerned with growth,Cpeptides are not removed.IGF1 –somatomedin,growth promoting actions of insulin.Proinsulin has 2% metabolic potency of insulin,50% as potent for mitogenesis---atherosclerosis

25. hexamer

28. After injection

29. Regulation of insulin secretionPrinicipal stimulus for insulin secretion is the glucose.Sugar is more effective in provoking insulin secretion when taken orally than when taken IV –inc vagal activity.Stimulants—various nutrients-glucose,AA,FA,ketones. GI hormones pancreatic hormones autonomic neuro transmitters2 adrenergic receptor—inhibits insulin receptor.Β2 adrenergic receptor,vagal—release.Hypoxia,hypothermia,surgery,severe burns—suppress insulin secretion.2 antagonists—increases insulinB2 antagonists—decreases insulinHORMONES—GLP-1,GIP-inc insulinSimilarly gastrin,secretin,cholecystokinin,VIP,GRP,enteroglucagon

30. Insulin secretion is BIPHASIC.First phase—peak at 1-2 min,short lived.Second phase-delayed onset,long duration.Depends on intracellular calciumIntracelular Ca—increased by phospholipase C by Ach,cholecystokininInc c AMP-b adenylcyclase---GLUCAGON.Insulin circulates in blood as monomer.Distributed in ECF..Aminoacid which causes secretion of insulin –arginine.Glucokinase acts as glucose sensor.Glucose conc <90mg/dl—no insulin release

31. Rate of secretion in fasting—1U of insulin /hr into portal veinConc of insulin 2-4 ng/ml.50-10031U/ml-portal veinPeripheral circulation—0.5ng/ml,12U/ml.Goal of insulin therapy is to mimic this pattern –diificult to achieve with SC injection.T1/2-insulin 5-6 min in normal subjectsIncreased in diabetes Proinsulin -17 min C peptide -30 min serves as a marker of insulin secretion

32. degradationLiver,kidney,muscle50% insulin that reaches liver is destroyed.It is filtered by glomeruli-reabsorbed by tubules –degrade itRenal function impairement appears to affect the rate of disappearance of circulating insulin to a greater extent than hepatic diseaseDegraded in endosomes of liver.Thiolmetalloproteinases in liver,muscle,kidney,braininsulinase

33. Functions of insulinGlobally—Control of cellular intake of certain substance-glucose in muscle,adipose tissue.Increase of DNA replication and protein synthesisModification of activity of numerous enzymes.

34. Cellular levelIncreased glycogen synthesis.Increased fatty acid synthesis.Increased esterification of fatty acidsDecreased proteolysisDecreased lipolysisDecreased gluconeogenesisDecreased autophagyIncreased aminoacid uptakeIncreased potassium uptakeRelaxes arterial muscle tone,increases blood flow-micro arteriesIncreases HCL secretion in stomach.

35. Types of insulin20types of insulin products available in four basic forms,each with a different time of onset and duration of action.Which to choose is individulaisedChoosing insulin depends onOnset-how soon it starts workingpeak time-when it works the hardestDuration-how long it lasts in the body.Obesity affects the work of insulin in the body.extra fat tissue –more resistant to insulin.

36. Types of insulinFive different typesSome are clear in appearance .,some are cloudyRAPID ONSET-FAST ACTING INSULIN-novo rapid (insulin Aspart)humalog (Lispro) SHORT ACTING INSULIN—actrapid,Humulin,hypurin neutral(bovine)INTERMEDIATE ACTING INSULIN-cloudy—protamine or zinc addedProtamine—protaphane,humulinNPH.hypurinisophaneMIXED INSULIN—RAPID/INTERMEDIATE—novomix 30,humalog mix 25,mixtard 30/70,mixtard 20/8030/70—30% is short acting,70% long actingLONG ACTING INSULIN-lantus-(glargine).levemir(detemir)

38. Insulin sliding scaleNot recommended for subcutaneous injection 50U -50 ml NS Every one hour until the blood glucose level stabilisesRate of infusion adjusted as per blood sugar.<120mg/dl-no insulin120-200---2U/hr200-300—3U/hr300-500---5U/hr>500---7U/hr -JAPI october 2007

39. Somoygi phenomenonSomogyi effect is a rebounding high blood sugar that is a response to low blood sugar.It is due to counteracting hormones release –glucagon,adrenaline,cortisolFrequent monitoring of blood glucoseNight dose to be low compared to morning dose.

40. Dawns phenomenonEarly morning hyperglycemia without nocturnal hypoglycemia.It is due to counter regulatory hormonesNo need of insulin dose change.

41. Increasing requirementsInfection,stress,puberty,pregnancy,acromegaly,cushings syndrome.Lipohypertrophy at the site of injectionMalignanciesCompliance of the patient

42. Decreaesing requirementsImpending renal failureHoneymoon phase in type 1HypothyroidismAddisons diseaseHypopituitarismRemission of diabetes

43. In renal diseaseHalf of the sliding scale of insulin dose to be givenAs insulinase enzyme does not functionThe duration of insulin action increases.

44. Indications for insulin therapyType 1 diabetesWomen with diabetes who become pregnant or are breastfeedingTransiently in type 2 diabetes in special situations- renal & hepatic disease, pancreatitis, HHS, during surgery, infections etc. In type 2 diabetes, inadequately controlled on OADs

45. Side effects of insulin useHypoglycemiaWeight gainLocally-allergy infection abscessanaphylaxis

46. Insulin devicesInsulin syringesDelivery pensInsulin pumpsInsulin syringes—10ml insulin vials 30 unit—0.3 ml,50 unit-0.5 ml,100 unit-1mlNeedles -8mm to 13mm Use each syringe only once.Insulin pen-insulin catridge-3ml-300units fits into the device Disposable, reusable Durable pens are—Novopen3,Novopen demi,Innovo and HumaPen Pre filed disposable devices –innolet,flexpen and Novolet.

47. Insulin pumps-reservoir of insulin-infusion set worn outside the body—abdomen Only short or rapid acting insulin are used—mimics physiological patternInhaled insulin

48. Mode of administrationSubcutaneousIntravenousInhaledIntramuscular

49. Subcutaneous injection

50. Sites Rotation of injection site to prevent lipohypertrophy.Within one area.Abdomen has fastest rate of absorptionExercise increaseslipohypertrophydecreaseesRate of absorption after IM is faster.

51. Sites of injection

52. syringes1ml most common26-31 guage needle30 or 31 bend in single useNo sharing of needlesReuse is widely practicedInfection---poor hygeine,concurrent illness

53. Insulin syringe and vial

55. Timing of insulin30 min prior to meals Not to exceed 30 min in case of rapidly acting insulinsIntermediate acting insulin –bed time.

56. Insulin injectionCloudy insulin gently rolled in betweenPen needs to be rotated upside down for at least ten times before usingAir of volume equal to dose of insulin should be injected in vial.No use of alcohol may destroy silicon coating.90 angle—thin 45  Routine aspiration not neededEmbedded for 5 sec after complete depression--pens

58. Alternative routes—failedJet injectors—deliver high pressure stream of insulin.Useful in lipoatrophy.TransdermalIontophoresisLow frequency ultra soundTransferomes—phosphatidylcholine vesicles50% SC efficiency

59. IntranasalBioavailability is 8-15%Nasal irritation is commonHigh rates of treatment failure.Gelified nasal insulin OralEnteric—limited bioavailabilityToo large,hydrophilicOnly 0.5% reaches circulationBuccal—aerosol solutionPulmonary—large surface area—premeal deliveryLung cancer risk

61. Thank you

62. Types of insulin

63. Types of insulin and action

65. Regular insulinClear solution at neutral pH0.4% zinc added-hexamersPhenol or cresol-prevent growth of microorganismsOnset of action within 15-30 min after SC max activity-120 -150 minAction -6-8 hrsInsulin to be given 30-40 min prior to meals

66. indicationsIn case of type1 DM ,type 2 DM –DKA,HONK,Pregnancy,patients being taken up for surgery,acute illness.Controls post prandial blood glucose levels when used with long acting insulins.

67. NPH or isophane insulinAt hagedorn university in 1940.Protamine added in 1:6 ratio to regular insulinPhosphate buffer for neutral phZinc ,cresol.Peak of action at 5-7 hrsAction lasts for 12-15 hrs.Bed time to control FBS.Cloudy.

68. Lente insulinZinc in amounts 10 times to NPHAcetate as bufferInsoluble zinc insulin complexesSemilente---amorphous,biphasic absorptionUltralente—long acting crystalline suspensionCan’t be mixed with regular insulin.

69. Premixed formulations30:7050:5025:75Regular and NPH insulin

70. Rapidly acting insulins—insulin analoguesAnalogous to keep insulin in monomeric formOnly change in aminoacid sequence at a particular point.Action starts within 15 min after SC injection.Peaks at 60-90 minOver by 4 hrsPost prandial excursions curtailedNo delayed hypoglycemia.

71. Aspart

72. Aspart by Novo Nordisk as Novolog or NovorapidB28 ---proline is substituted by aspartic acid residue.Increased charge repulsion—no hexamersComponents-zinc-metal ion19.6g/mlbuffer-disodium hydrogen phosphate dihydrate1.25 mg/mlPreservative-- m cresol 1.72mg/ml Phenol 1.50mg/mlIsotoncity agent –glycerin and Nacl ph 7.2-7.6

73. NovoRapid (Insulin Aspart )ProPheGlyArgPheAspTyrGluB20ThrGlyAspCysLysB28B30ThrValAsnCysA21TyrLeuA1GlyAsnTyrIleGluLeuValLeuAlaGluGlnGluGlnTyrValLeuCysSerCysLeuIleSerThrCysHisSerGlyCysLeuB1HisGlnAsnValPhe

74. Lispro

75. LisproMarketed by Eli Lilly—HUMALOGFirst insulin analogue.Penultimate lysine and proline residues on the Cterminal end of B chain are reversed---no change in receptor binding.No formation of hexamersPost prandial excursions are controlled.

76. Glulisine

77. GlulisineMarketed by sanofiaventis. APIDRAAsparagine is replaced by lysine at B3Lysine replaced by glutamic acid at B293B-lysine-29B-glutamic acid-human insulin

79. Long acting insulin analoguesSteady basal insulin levelsGlargine –isoelectric at 7.4Clear and soluble at acidic phPpt after SC injectionAction >24 hrsDetemir—fatty acid chain attached to it.

80. Glargine

81. GlargineMarketed by sanofiaventis—LantusResembles basal insulin secretion of non diabetic pancreatic beta cells.Controls fast blood glucose.Glycine for asparagine at A21 and two arginine added to carboxy terminal of B chain.Formulated at acid pH—4.0Hexamers at pH-7.4Can be injected with I port

82. GlargineIn 2009 there was conflicting and confusing data regarding the link of glargine insulin and cancer developing risk.ADA –the avaailable data does not provide a cause for concern and that changes to the prescribing advice are therefore not necessary.

83. Detemir

84. C14 fatty acid chain(Myristic acid)PheGlyPheArgGluTyrThrGlyProCysLysValThrLysCysAsnA21B29LeuTyrGlyA1AsnTyrIleGluLeuValLeuAlaGluGluGlnGlnTyrValCysLeuLeuCysSerSerThrCysIleHisSerGlyCysLeuGlnHisAsnValPheB1Design of Insulin Detemir - 1LysB29(N-tetradecanoyl)des(threonine)human insulinDes-threonine myristic(mir) acid

85. DetemirMarketed by Novo Nordisk –LEVEMIRFatty acid myristic acid is bound to lysine aminoacid at B29.quickly absorbed—binds to Albumin—complexBetter control of blood glucose levelsAppreciable decrease in HbA1c levels--

86. levemirAlbumin binding: Makes Levemir therapy with a smooth and peakless profile throughout the day

87. Time-action profileUp to 24 hours Predictabilitylower within-patient variability than NPH and glargineGlycaemic controlBetter glycaemic control HypoglycaemiaLesser hypoglycaemia compared with NPH & glargineWeightNo undesirable weight gain shown in all studies

88. Premixed analogueProtamine insulin +rapidly acting analogues.

89. Strength of insulin40 U /ml –most widely usedWHO—all insulin across the globe to be U 100.StorageRefrigerated<2 and >30 CExcess agitation avoidedUsed for > 1 month –may lose potency.Away from sunlight.

90. Mixing insulinsglargine is not mixed with any other insulin.

91. Problems with syringes / vialsCumbersome procedureDifficult to transport and carry aroundInaccuracy in withdrawing the correct amount of insulinDifficulty in mixing insulinInsulin wastageStigma of injections and hence suggestion of ill-healthNeedle passes a rubber membrane and losses sharpness-more pain

92. Advantages with DevicesSimplicity - Simple to operate and injectAccuracy - A new superior standard in dose accuracyReliability - High quality materials and finishDiscreeteness - Non-medical, non-syringe designAll-in-one - Pen + insulin cartridge + needlesPortability - Small & compact, robust carrying case - with space for extra needles and cartridge

93. Device vs. Syringe

94. Prefilled penContain a built-in, single-use insulin cartridge LoadingRequire no loading by patientEase of usePortable, durable, & lightweight delivery systems patients who have difficulty handling the cartridges in reusable penspersons with busy schedulesshort - term therapy = GDM, Post-SurgeryEase of disposalare made of non-polluting plastic it breaks down into naturally occurring substances when burned industriallyit can be safely landfilled

95. FlexPen®Easy to usedialling dose; accurate / reliable

96. good control during injection

97. ‘can hear clicks’

98. minimal pressure required

99. can be administered with one handEasy to read (white font on black)numbers clearly visible

100. safer because mistakes less likelyConvenient; pre-filled / no re-loadingeasy to attach needles

101. easy to teachPortable and discreetcomes in carry case

102. FlexPen®FlexPen® is a unique dial-a-dose insulin pen. You can dial doses from 1 to 60 units inincrements of 1 unit

103. Single unit increment

104. Easy dial back

105. Large & easy to ready display

106. Max single dose-60 U

107. Virtually painless 31G needle FlexPen- Easy to use and teach

108. Design Characteristic of FlexPenThe FlexPen is a disposable, prefilled insulin delivery device— there is no insulin cartridge to change. The FlexPen is simply thrown away when the last of the insulin has been used, or at the end of the in-use time.

109. FlexPen Prefilled syringes are available with three insulin analog preparations: Levemir, NovoRapid, and NovoMix 30.Each FlexPen is named for the insulin it contains and is color branded for easy identification.

110. LevemirFlexPen = identified by green push button

111. NovoMix 30 FlexPen = identified by Blue push button

112. NovoRapidFlexPen = identified by orange push buttonDurable penPatient has to insert an insulin cartridge into pen's delivery chamber FlexibilityAllows greater flexibility for some patientsChanging types of insulin without needing to buy another pen if prescription changesEase of useDurable and easy to useDesigned for longer duration of use.With individual use - risk of infection is minimized

113. NOVO NORDISK

115. Insulin dose calculationCalculate total daily insulin TDI0.5 *WEIGHT (KG) or sum of current dosesEx—60 kg---30U.Total meal time insulin—lispro,aspart,regular60% 0f TDI18U-----three divided doses—breakfast,lunch.dinnerTotal basal insulin—NPH,glargine,ultrlente40% of TDI12U---bed time insulin

116. Insulin dosageDKABolus dose—IV 0.1U/kgIM-0.3U/kgThen 0.1U/kg/hrMild episodes of DKA—short acting insulin analoguesIV regular insulin to be used in infusion until acidosis resolves 0.05-0.1U/kg/hr.

117. Pre prandial insulin doseINSULIN /CARBOHYDRATE ratio1-1.5 U/10 gm of carbohydrateSupplemental or correcting insulin—1Uof insulin for every 50mg/dl of glucose over the preprandial glucose target.ExA 60kg male has FBG 0f 250 mg/dl,desired is 100mg/dl,the insulin dose is 60*(250-100)/150060(150/1500-----60*150/1500----6U

118. Twice daily regimensLong acting insulinNPH.regular insulin –morning,bed time.2/3 of insulin in the morning1/3 of insulin at bed timeTo prevent nocturnal hypoglycemia.FBG-prior evening long acting insulinPre lunch glucose—morning short acting insulinPre supper glucose-morning long acting insulin’Bed time—pre supper short acting insulin.Not an optimal regimen for 1 DM