Insulin recent updates final

ppt insulin

1. RECENT UPDATES ON INSULINS Dr Meeta Amit Burande MBBS, MD (Pharmacology), D Diabetology (Australia), Fellow in Diabetes (UK) Professor & Head, Department of Pharmacology , D Y P Medical College, D Y Patil Deemed to be University , Kolhapur Consultant Diabetologist , Surya Multispecialty Hospital , Kolhapur Webinar conducted by Medical Pharmacologist Society

2. DIABETES Diabetes is the relative deficiency of the insulin, which may be either due to absolute decrease in insulin secretion (Type 1) or due to increase insulin requirement/ resistance (Type 2).

3. INSULIN First treatment discovered and still most effective and safest therapeutic option Insulin in english from insula means island By species of origin it is of three types: human, porcine and bovine. Pork insulin is more homologous to human insulin. Insulin is the polypeptide hormone synthesized in pancreatic beta cell as per- proinsulin and get stored in secretary vesicle as proinsulin with the help of C-peptide. It is secreted in blood along with C-peptide. Insulin was bioassayed in rabbit blood but now it is assayed by chemical method also.

4. HISTORY Barron noticed endocrine pancreas not affected by bile duct ligation. Banting used the observation for isolation of islets Insulin was discovered in 1921 by Banting,Best , collip and Macleod and awarded noble in1923 NPH introduced in 1946 by Hagedorn Hallas at Novonordisk develop insulin zn i.e. Lente . 1955- sanger described molecular structure of insulin and species differences, awarded nobel in 1958 1970 – purification methods developed and neutral insulin was produced Yalow developed radioimmunoassys , nobel in 1978 Ulrich cloned the insulin gene in 1997,and first commercially available human insulin was made in novonordisk in 1981 and 1984 with saccharomyces cerevesiae (Baker yeast) 1982, gentically eingeeneered insulin was made by el lily in E coli

5. Insulin productions Animal insulin – not available now Bovine and porcine – both – monoporcine Pancreas- frozen- acid ethanol/water extraction – neutralization – acidification – evaporation – salting Bovine – differs in A8,A10and B30 Porcine – B30 Human insulin – Semisynthetic – converting porcine to human by enzymatic replacemnet of B30 alanine to threonine Genetically engineered - E coli or saccharomyces cerevesiae Human insulin chain recombinant material (CRB) Genetically engineered human insulin ( HMge ) Insulin analogues

6. Regulation of secretion Insulin is secreted continuously under the basal condition at the rate of 1U/hour. It is interrupted by the pulse of secretion at meals. It is regulated by different stimuli i.e. Chemical – increase blood sugar level, amino acids like arginine , leucine , guanosine etc. secretion is in 2 phase: early and delayed Hormonal – growth hormone, steroids, thyroids has insulin resistant action. They inhibits the release of insulin or increase the resistance in tissue to insulin. Neural – alpha 2 receptor decrease the insulin release, beta 2 stimulation decrease the insulin release, cholinergic muscarinic activation increase insulin release. Increased insulin secretion in reactive hypoglycemia, persistant hyperinsulinomic hypoglycemia of infancy, insulinoma

7. Insulin synthesis Insulin gene- at p13on short arm of chromosome 11 3 exons and 2 introns Synthesised in beta cells, yolk sac and fetal liver Other tissues – negative regulatory element Insulin gene transplantation !!

8. Transcription of code: Chro­mosome 11 coding for insulin and are transcribed to mRNA in the nucleus. 2. Translation of the code: Polypeptide syn­thesis is initiated with the formation of N-terminal signal peptide (leading se­quence) 3. Synthesis of preproinsulin : Further elon­gation resulting in the for­mation of preproinsulin . It is constituted by 109 amino acid residues and mol. wt. is 11.5 kdt . 4. Separation of signal sequence: N-terminal signal peptide is hydrolysed away by signal peptidase and pro- insulin is formed Pro-insulin consists of 86 amino acid residues and its mol. wt. is about 9 kd . 5. Transfer of pro-insulin: Pro-insulin is trans­ported from GER to the Golgi complex. 6. Splitting of pro-insulin: In Golgi cisternae pro-insulin is hydrolysed by trypsin like peptidase to yield a 53 amino acid insu­lin precursor and pro-c-peptide has 33 amino acids. 7. Formation of insulin: In the Golgi com­plex about 95% of the pro-insulin is con­verted to active insulin. Insulin synthesis

9. Release of insulin

10. Actions of insulin Increase glucose transport from blood to tissue Formation of muscle proteins Lipid synthesis ( Lipogenesis ) Increased activity of lipoprotein lipase in blood vessels so decrease serum VLDL and chylomicrons Reduction in hepatic glucose output Mitogenic action i.e. proliferation of endothelial cells in blood vessels.

11. Mechanism of action Insulin act on membrane bound heteroreceptor with tyrosine kinase enzymatic activity.

12. Pharmacokinetics Orally given destructed in GIT so given parenterally . It is distributed extracellularly and metabolized in liver and kidney. Normally secreted insulin is highly metabolized in liver with plasma half life of 5 minutes.

13. Preparations of insulin Ultra short acting – Insulin lispro , Insulin Aspart , insulin glusiline Short acting – Regular insulin Intermediate acting – NPH & Lente Insulin Long acting - PZI, Glargine & Detemir Premixed insulins – NPH & Regular, Lispro & LPL, NPA & Aspart etc. Lispro protamine / lispro – 50/50, 75/35 Protamine / aspart – 70/30

14. Highly purified insulins Conventional preparations contain impurities and are more antigenic. So they are purified by different methods like Gel filtration – single peak insulin Ion exchange chromatography – highly purified and monocomponent insulin

15. Human insulins Produced by recombinant DNA technology i.e. proinsulin recombinant bacterial, precurasor yeast recombinant, enzymatic modification of porcine insulin. Human insulin are specially indicated in – insulin resistance allergy to conventional preparations lipodystrophy at injection site short term use like surgery, trauma, infection, ketoacidosis preganacy

16. Insulin analogues Insulin lispro : reversing praline and lysine at 28 and 29 for beta chain. Form hexamers that dissociate very rapidly Insulin aspart : praline of B 28 is replaced by aspart . So it reduces the aggregation Insulin glulisine : replace aspargine at B23 by lysine and lysine at B29 by glutamic acid Insulin glargine : long acting with 2 additional arginine at B chain. It is soluble at acidic pH but precipitates at neutral pH so depot in subcutaneous tissue on injection. It releases slowly and give peakless profile in blood. Given once a day to control fasting blood sugar level Insulin detemir : it is highly protein bound long acting insulin that dissociate from the binding site slowely . Significantly less weight gain as compared to NPH

17. Insulin degludec: slow release following injection Insulin degludec multi- hexamers Zinc diffuses slowly causing individual hexamers to disassemble, releasing monomers Subcutaneous depot Zn 2+ Monomers are absorbed from the depot into the circulation

18. 20 Basal Insulin Prandial Boluses Insulin 0hr 24hr BG mg/dl Physiologic Insulin Therapy

19. 21 Time Activity of Human Insulins

20. Pharmacodynamics of NPH versus Glargine Insulin Lepore, et al. Diabetes 1999; 48 (suppl 1): A97 Bolli et al. The Lancet • Vol 356 • August 5 2000 Plasma glucose Glucose infusion rate

21. Biologic activity over 24-hours more consistent for basal insulin analogs GIR = Glucose Infusion Rate Heise et al. Diabetes 2004; 53 (6): 1614-1620 Insulin detemir

22. 24 Insulin Bolus Dosage Amount to “cover” food eaten - Usually calculated as 1 unit per x number gms of carbohydrate - For example: 6 units needed to cover 60 gms CHO if using 1 unit per 10 gms CHO (60/10 = 6) Amount to lower blood sugar to target range - Usually calculated according to sliding scale or correction factor - Sliding scale: give units of insulin for each range of BG - Correction factor: Blood glucose level – target blood glucose/correction factor = units insulin to be given - Ex: BG=150 (actual) minus Target BG (100) = 50 divided by Correction factor (50) = 1 unit insulin needed Add together to get Insulin Bolus Dosage

23. www.diabetesclinic.ca 25 Two injections/day Blood Glucose (mmols) 8am noon 6pm 2am 4am 8am Time R or H + N in AM R or H + N at Supper 10- 8- 6- 4- 2-

24. www.diabetesclinic.ca 26 Three injections/day Blood Glucose (mmols) 8am noon 6pm 2am 4am 8am Time R or H + N in AM R or H at Supper N before bed 10- 8- 6- 4- 2-

25. www.diabetesclinic.ca 27 Four injections/day Blood Glucose (mmols) 8am noon 6pm 2am 4am 8am Time R or H at every meal N or U once or twice/day 10- 8- 6- 4- 2-

26. www.diabetesclinic.ca 28 Continuous Infusion Blood Glucose (mmols) 8am noon 6pm 2am 4am 8am Time 10- 8- 6- 4- 2-

27. New insulin delivery devices insulin syringes, pen devices, inhaled insulin, insulin pumps, implantable pumps, external artificial pancreas, liposomal delivery

28. 30 Insulin Syringes Sizes – 30, 50, 100 units Disposable-

29. 31 Insulin Pen: Devices Prefilled pens Reusable (cartridge) pens Auto injectors Dual chamber catridge

30. 32 Insulin Pump Therapy Based on what body does naturally - Small amounts of insulin all the time (basal insulin) - Extra doses to cover each meal or snack (bolus insulin) Rapid or Short-Acting Insulin- analogues preferred due to less crystalization in plastic tubes Precision, and Flexibility

31. 33 What is an Insulin Pump? Battery operated device about the size of a pager Reservoir filled with insulin Computer chip with user control of insulin delivery Worn 24 hours per day Delivers one type of insulin Temporarily disconnected from cannula in place at time of bathing etc. What Pumps Do Bolus for food intake and to correct high blood glucose levels. Many pumps will calculate bolus dosages. Delivers pre-determined amount of basal insulin throughout the day. Some blood glucose meters communicate with pump.

32. Uses Diabetes mellitus Indication for insulin therapy are – OHA failure – it may be primary or secondary OHA contraindications i.e. pregnancy, hepatic failure, renal failure, stress, allergy to OHA etc. Metabolic emergencies i.e. DKA, HONK etc. Overt hyperglycemia i.e. fasting BSL is more than 300 mg % at diagnosis Underweight patients

33. Insulin requirement of diabetes in children Stages - Stage of metabolic recovery -1.5 to 3 u/kg/day – occurs at the time of diagnosis. Very high requirement due to high bsl , high stress hormones and compensatory hyperphagia . Partial remission or honeymoon phase - drops to 0.3 to 0.5 U/kg/day due to decreased stress, inflammation and glucotoxicity , 1 to 2 unit per day ! Intensification – after 3 to 12 months due to continued beta cell destruction Total diabetes – usually after 2 years of initial diagnosis After 8 yrs of age – should inject themselves

34. Insulin in patients doing ramdan fasting paradoxical risk of food excess after the hours of fasting. individualized education improved safety during Ramadan in terms of decreasing hypoglycemic events, improved diabetes control, and prompted weight loss. premixed insulin can be given with the sunset meal and half the usual evening dose to be used with the predawn meal ( suhoor ) Long-acting insulin-like glargine can be given as a single injection and this can be administered with short-acting insulin or metformin . Before ramadan Fasting 100 to 180 no change in total dose per day

35. Special cases Diabetes in elderly – many complications, reduced vision and financial constraints, prefer simple regimens, less dose due to ckd and risk of hypo and cognitive dysfunction Diabetes and pregnancy – requirement increases gradually from 0.7 to 1 unit/ kg till last trimester, split bbf in two portions, start premix at bbf , Regular nph npl , lispro aspart

36. Quantity for insulin initiation – 0.6 – 0.7 U/ Kg – average dose 1-2 U/kg – obese patients Fasting BSL/ 10

37. Insulin resistance When requirement is increased more than 200 U per day insulin resistance is developed. It may be Acute – Infection, trauma, surgery, emotional stress, corticosteroids Ketoacidosis Chronic – Chronic diabetics treated for years with animal insulin IRS1 PC1 K121Q region gene polymorphism Combined therapy approach to type 2 DM

38. Side effects – Hypoglycemia: most frequent and commonly seen in labile diabetes although can occur in any diabetic. The symptoms are secondary to sympathetic stimulation and neuroglucopenic symptoms in CNS. It is treated by i.v ./oral glucose. Oedema : due to sodium retention but short lived. Insulin neuritis – osmotic change in nerve fibres , resolve in 1-2 months Transient visual disturbances – due to difference in sugar lowerin rate in acqous humor and lens. It get corerected spontaneously with time. Local reactions (hypertrophy or atrophy): more common with impure insulins Allergy: more common with impure and animal preparations. Neutral on CV risk and Carcinogenesis – evidence by ORIGIN trial outcome reduction with initial glargine intervention

39. Drug interactions Beta blockers prolong hypoglycemia as well as mask the symptoms of hypoglycemia. Thiazides , CCBs increase the blood sugar level Acute alcohol decrease the BSL. Aspirin and lithium may increase the hypoglycemia Vitamin D improved beta cell function Pioglitazone and insulin drugs which decrease insulin requirement drugs which need increased insulin requirement

40. Upcoming insulins Reverse split insulin – more lispro / aspart and less NPL Ultrafast acting analogues – combination of insulin lispro with recombinant human hyaluronidase (rhuPH20) Glargine U 300 – flatter pharmacokinetic and pharmacodynamic profile Hepatoselective insulin – LY2605541 – Insulin lispro with PEG at B28 lysine 17 time less binding to IR and 32 times less binding to IGF as compare to lispro – less mitogenic profile Half life 24 hrs, duration of action 36 hrs, unaltered in renal disease Preferential hepatic function-mimic endogenous secretion – raised liver enzyme !! Idegasp / degludecplus / Rhyzodeg – premixed with aspart Degludec with liraglutide

41. Inhalational insulin- Affrezza Faster absorption Pfizer marketed in 2006 Mannkind – in 2014 with sanoffi till 2016 than continued alone – prefilled catrige of 4,8 or 12 unit Alkrems with eli lilly and aradygm with Novonordisk "appears to be as effective, but no better than injected short-acting insulin. The additional cost is so much more that it is unlikely to be cost-effective.“ "failed to gain acceptance among patients and physicians“ – difficult metered dosing, not portable label restriction for patients having asthma, active lung cancer or COPD. May be promoted as add on to oral medications in type 2 Along with basal in type 1

42. Insulin Transdermal Patch H2O2 responsive vesicles integrated with transcutaneous patches for glucose mediated insulin delivery I-port It includes a built-in inserter, which gives quick, virtually painless application. Only a soft flexible tube, called a cannula stays under the skin. Once applied, insulin is injected through the port instead of skin . It is small and discrete, and sticks like a Band-Aid

43. Transpalntation , Gene therapy, Stem cells Pancreatic transplantation along with renal transplantation Islet transplantation – immunosuppressive drugs are different ! Mixed bone marrow chimerism Costimulatory blockade Vaccination to make them more tolerant Porcine insulin producing cell line – but no human Pancreatic ductal cell to be differentiated as beta cell Bone marrow derived stem cell transplanted in type 1 Genetically developed human pancreatic beta cell is developed

44. Practical information Vial can be kept in room temperature Not to be kept in check in bag – will be ineffective due to freezing Fastest abdomen/ gluteal / bracheal /femoral Now can be taken without skin pinch due to lesser length of needle Rotate particular injection in particular region To reduce pain –inject after spirit is dried and at room temp, change needle After Giving Insulin -Check site for leakage, Correction doses, Meal/snack doses, Timeliness in relation to eating, Supervision of food amount

45. Thank you Resources https :// www.pharmacychoice.com/article/the-return-of-inhaled-insulin.cfm https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4477152 / https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5629872 / https:// www.acs.org/content/acs/en/pressroom/presspacs/2017/acs-presspac-january-18-2017/toward-a-smart-patch-that-automatically-delivers-insulin-when-needed.html https:// www.medtronicdiabetes.com/products/i-port-advance G & G, Tripathy , RSSDI text book of Diabete s, Harrsons etc and journals