Exogenous Insulin in type 2 DM

Transcription

1 Exogenous Insulin in type 2 DM Russell Scott 2015

2 Part 1: Some basic biochemistry for Insulin absorption and action

3 MY CHECK LIST Factors influencing insulin action: Forgets to inject Amount given Timing of injection Needle length and depth Any retrograde spill Type of Insulin used Position used for injection Local tissue destruction Speed of uptake of Insulin Insulin binding in vivo Receptor uptake of Insulin Post receptor blocking Anti-insulin factors viz adrenaline, cortisol etc

4 Plasma Insulin (µu/ml) Peripheral Insulin Secretion Profile: what we are trying to emulate 75 Breakfast Lunch Dinner :00 8:00 12:00 16:00 20:00 24:00 4:00 Time 8:00 Adapted from White JR, Campbell RK, Hirsch I. Postgraduate Medicine. 2003;113:30-36.

5 Insulin replacement today has many deficiencies It is given peripherally not portally The crucial Insulin-glucagon communication network is destroyed in DM The gut GLP-1 network is also limited The Somatostatin network is non functional The neural network falls over with time

6 So physiological replacement of insulin is not feasible today The best we can do today is to supply insulin to the wrong place at the wrong time, and in the wrong dose

7 BUT: Portal levels are much more abrupt, exaggerated and wildly pulsatile and so all insulin replacement is completely non-physiological Arterialized ( ) and portal vein ( ) levels in 4 patients Song S H et al. JCEM 2000;85: by Endocrine Society

8 Insulins today Produced by recombinant technology Seldom use soluble insulin except iv Rapid absorbing: modified to reduce hexamer formation speeds absorption Long absorbing: Protamine mixture (NPH) slows absorption crystallization delays subcutaneous absorption

9 Hexameric Insulin

10 Insulin Formulations Prandial Rapid-absorbing analogs Aspart Insulin (NovoRapid) Lispro (Humalog) lisine (Apidra) Basal Intermediate-absorbing NPH (Neutral Protamine Hagedorn, Humulin-N Protophane Long-absorbing Insulin Glargine Detemir Insulin Fast-absorbing Regular (neutral) (Actrapid, Humulin-R) NOTE: I try to avoid the use of the term fast acting etc

11 Insulin Formulations Rapid-absorbing analogs plus Protamine suspension Aspart (NovoMix 30, + Flexpen ) LisPro (Humalog Mix 25, Mix 50) Soluble human insulin plus protamine suspension Actrapid - protamine 30/70, 40/60, 50/50 mixes» (Penmix 30, 40, 50) Mixtard 30 (10ml) Humulin R- protamine 30/70 mix (Humulin 30/70; 3ml, 10 ml)

12 All insulin vials or cartridges containing protamine need repeated agitation to ensure complete mixing viz: Humulin N Protaphane Humulin 30/70 Humalog mix 25, 50 Novo penmix insulin (30,40,50); Mixtard (only 10ml) Novomix30

13 A1 Lys Pro Thr Thr Arg Ala His His Asn B1 Asn Asn Ile Thr lle B20 A21 B28 B30 Human Insulin

14 Pro Lys Thr Thr Arg Ala His His Asn B1 Asn Asn Ile Thr lle A21 B28 A1 B30 B20 Insulin Lispro

15 Thr Lys Asp Thr Arg Ala His His Asn B1 Asn Asn Ile Thr lle A21 B28 Asp Pro Insulin Aspart A1 B30 B20

16 Pro Thr Thr Arg Ala His His Lys B1 Asn Asn Ile Thr lle A21 B28 A1 B30 B20 Insulin lisine Lys Asn

17 Rapid absorbing analogs Aspart substitutes b28 proline with aspartic acid Lispro reverses b29 lysine with b28 proline lisine substitutes b3 asparagine with Lysine and b29 lysine with glutamic acid

18 A1 Lys Pro Thr Thr Arg Ala His His Asn B1 Asn Ile Thr lle B20 A21 B28 B30 Insulin Glargine Arg Arg

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20 Glargine: a21 asparagine replaced with glycine and 2 arginines added at positions b31 and 32 Determir: insulin linked to myristic acid

21 Change in um Insulin Human Insulin Time-Action Patterns Normal insulin secretion at mealtime Theoretical representation of expected insulin release in nondiabetic subjects Baseline Level SC injection Time (hours)

22 Change in um Insulin Human Insulin Time-Action Patterns Normal insulin secretion at mealtime Regular insulin (human) Theoretical representation of profile associated with regular insulin (human) Baseline Level Time (hours) SC injection Need to inject 45 mins before meal to get in phase

23 Change in um Insulin Analog Insulin Time-Action Patterns Normal insulin secretion at mealtime Insulin analog Humalog or NovoRapid Theoretical representation of profile associated with insulin analog premix Baseline Level Time (hours) SC injection 20 mins to get in phase; 2-3 hours duration

24 Change in um Insulin NPH Insulin variation by day Normal insulin secretion at mealtime NPH insulin (human) Theoretical representation of profile associated with NPH insulin Baseline Level Time (hours) SC injection CV of absorption profile approaches 100%

25 Change in um Insulin Glargine Insulin Time-Action Patterns Normal insulin secretion at mealtime QD basal glargine insulin Theoretical representation of profile associated with basal analog insulin Baseline Level SC injection Time (hours) ~20% will have shorter absorption patterns; 2x daily works better in such people but still relatively peakless cf NPH and much lower CV

26 Truths: Insulin Insulin is absorbed variably in the same patient on different days The longer the action the greater the variability except for glargine and detemir Insulin is absorbed differently patient to patient Most insulin are absorbed differently at various anatomical sites External conditions of heat, stress, food, illness etc alter absorption parameters The volume injected alters absorption Local tissue proteases can destroy injected insulin All insulins cause antibody manufacture which may be high/low affinity..high/low capacity interfering with action Insulin sub-cut therapy is non-physiological and is a poor replacement option (so keep some B cells alive at all cost)

27 Insulin Myths : Rapid absorbing Insulin can be given with best effect a few minutes before food. Rapid acting, slow acting misleading terminology absorption is what is meant Long absorbing Insulins can always be given once daily for best effect Long absorbing insulins are completely peakless (Glargine is to all intents peakless; duration of plateau does vary however)

28 A snapshot of pharmacokinetics Property Glargine NPH End of action (viz all gone) 22 +/- 4 hrs 14 +/- 3 Onset 1.5 +/- 0.3 hrs 0.8 +/- 0.2 Duration of action /-3.7 hrs /-2.8 Anatomical site absorption variation No yes Peak Minimal (plateau) 4-8 hr Accumulation over time nil yes Mean +/- SEM in 20 subjects Diabetes 49: 2142, 2000

29 Questions and discussion