NEWER INSULINSanjay Singh

Moderator: Dr. Prabhat Agarwal

harrisons 19th edition

HUMAN INSULIN• Insulin is a 51-amino acid peptide hormone comprising two

polypeptide chains, the A and B chains,which are linked by disulphide bridge.

• Insulin is synthesized on the ribosomes of the rough endoplasmic reticulum (RER) as a single amino acid chain precursor molecule called preproinsulin

• After removal of the signal peptide, proinsulin is transferred from the RER to the Golgi apparatus, where soluble zinc-containing proinsulin hexamers are formed. The prohormone convertase enzyme,

• PC1/3, finally acts outside the Golgi apparatus to produce the mature insulin and connecting peptide (C-peptide).

harrisons 19 edition

• In the pancreatic islet, both insulin and C-peptide are released simultaneously in equimolar quantities by exocytosis in response to a number of stimuli, including glucose and amino acids.

• Proinsulin contains 86 amino acids, while insulin has 21 amino acids in the A chain and 30 in the B chain.

• One unit insulin is defined as the amount of insulin that will lower the blood glucose of the healthy 2kg rabbit that has fasted for 24 hours to 45mg/dl within 5 hrs*.

harrisons 19th edition

secretion• In response to nutrients following a meal, insulin is

secreted in a coordinated pulsatile fashion from the β-cells into the portal vein in a characteristic biphasic Pattern

• first there is an acute rapid ‘first phase’ release of insulin, lasting for a few minutes

• followed by a less intense more sustained ‘second phase’.

• Pancreatic β-cells also secrete 0.25–1.5 units of insulin/h during the fasting state. Although at a low-level, this background secretion accounts for over 50% of total daily insulin Production.

• The older commercial preparations were produced from beef and pork pancreas.

• They contained about 1% of other protein (proinsulin, polypeptides, pancreatic proteins, insulin derivatives etc.) which were potentially antigenic.

• They are no longer produced and have been replaced by highly purified pork/beef insulin, recombinant human insulin and insulin analogues.

• From the ESSENTIALS OF PHARMACOLOGY 7TH EDITION K.D TRIPATHI

Problems with conventional insulins• Normally, insulin concentration peaks at 30-45 minutes after a meal and

returns to basal level after 2-3 hrs. • The onset of action of regular insulin is too slow, its action peaks at 1-2 hrs

after an injection and the duration of action is too long i.e. 6 hrs.• This leads to post prandial hyperglycemia and late hypoglycemia. • It is therefore, recommended to administer regular human insulin 30-45

minutes before meals, which restricts patient lifestyle and compliance .• Similarly the available intermediate or long acting insulin preparation are

unable to provide continuous basal insulin for 24 hrs. • This causes premeal and fasting hyperglycemia and night hypoglycemia .

From the Department of Pharmacology, Christian Medical College and Hospital, Ludhiana,141008, India. Correspondence to : Dr. Dinesh.K. Badyal, Head, Department of Pharmacology CMC, Ludhiana India.REVIEW ARTICLEJasleen Kaur, Dinesh K. Badyal

Advantages of Insulin Analogues 1. They provide better control of sugars 2. They carry low risk of hypoglycemia Particularly

nocturnal hypoglycemia 3. They do not have to be injected half an hour before

meals 4. Compliance is improved with long acting analogues as

once a day the insulin 5. The need for snacks between meal may be reduced with

short acting analogues 6. Advantage in term of weight gain epically with detemir

insulin.From the Department of Pharmacology, Christian Medical College and Hospital, Ludhiana,141008, India. Correspondence to : Dr. Dinesh.K. Badyal, Head, Department of Pharmacology CMC, Ludhiana India.REVIEW ARTICLEJasleen Kaur, Dinesh K. Badyal

NEWER INSULINS

• Novel short or long acting insulin analogues also called ‘designer insulin’.

• The B chain 26-30 region is critical for insulin receptor recognition and has been the site preferred for structural alteration with the aim to modify the pharmacokinetic profile of insulin molecule.

• Major concern of all insulin analogues is their altered mitogenic properties and risk of carcinogenicity on long term.

Newer insulinsInsulins Date of approval indications

Insulin lispro (Humalog)(mrp 410 ; 10 ml)

June 14, 1996 In type I and type II diabetes mellitus along with long acting insulin

Insulin aspart (Novolog)(mrp 560; 3 ml)

June 07, 2000 In Type I and II adult DM along long acting insulin & in insulin pumps

Insulin glulisine (Apidra) April 26, 2004 In Type I and II adult DM and in insulin pumps

Insulin glargine (Lantus)(2400;1400)

April 20, 2000 In Type I and II DM

Insulin detemir(Levemir)Insulin degludec(tresiba)

June16, 2005 Sep.2015

In Type I

Inhaled Insulin (Exubera)

Inhaled Insulin (Afrezza)

June27, 2007

June 2014

Type I DM as add onto long acting Type II DM alone or along with oral antidiabetics or long acting insulin

Insulin PreparationsShort acting: • These have rapid onset and shorter duration of

action.• The peak of onset corresponds more closely

with the post prandial peak.• The shorter duration of action prevents the

incidence of hypoglycemia.

A. Lispro insulin• first recommended DNA analogue. • structurally modified human recombinant insulin• inversion of proline at position 28 with lysine at position 29.• change eliminates the ability to dimerize results in faster

absorption rates• administer 0 - 15 min pre-meal vs. 30 - 45 min• peak action in 0.5 - 1 h vs. 1.5 - 2 h.• Insulin lispro has been tested for use in pregnancy and

gestational diabetes.• It was found to be as effective as regular insulin and no

teratogenic effects were found

B.Insulin Aspart• Substitution of proline at 28 position with aspartic

acid.• This analogue also prevents the formation of

hexamers leading to rapid absorption from subcutaneous tissue than soluble insulin

• It has similar binding properties and mitogenecity characteristics as regular human insulin and has equivalent immunogenecity.

• Pregnancy cat B

C.Insulin Glulisine• Substitution of asparagine at position B3 by

lysine and lysine at position B 29 by glutamine. • It exerts its action by causing insulin receptor

substrate-2 (IRS-2) phosphorylation and also has antiapoptotic activity against cytokine and fatty acid induced â-cell destruction.

• Due to antiapoptotic activity, it counteracts autoimmune and lipotoxicity induced â-cell destruction.

• But insulin glulisine carry the risk of tumorogenecity due to increased binding to IGF-1 receptor and increases mitogenic activity

• early trial results indicate less “clumping” - may be insulin of choice

• Pregnancy cat C

LONG ACTING ANALOGUES : Ideal basal insulin has long duration of action and provide 24 hour control with minimum variation in absorption and has to be given once a day.

A.Insulin Glargine • It was the first long acting basal human insulin available in the market.• The structure was designed by substituting an asparagine residue with

a glycine at position 21 of the A-chain and elongating the B-chain at the C-terminus by addition of 2 arginine residues

• Modification of B-chain caused the pH to shift from 5.4 to 6.7 and makes it less soluble at physiological pH and more soluble at acidic pH. The glycine substitution of A chain of insulin glargine stabilizes the hexamer structure and therefore, contributing to delayed delivery from subcutaneous depot and maintaining its stability in acidic solution.

• Insulin glargine is not to be mixed with other insulin, as it becomes cloudy and results in alteration of pharmacokinetic and pharmacodynamics profile.

• It precipitates at physiological pH and absorbs slowly from injection site. Therefore, provides basal insulin that mimic insulin profile of healthy individual.

• It has slow onset of action and achieves a maximum effect after 4-6 hrs and this activity is maintained for 11-24 hours or longer.

• Insulin glargine has more affinity to the insulin growth factor 1 receptor (IGF- 1),therefore has increased mitogenic potency compared to human insulin in in-vitro studies.

• Pregnancy cat C

Initial dose

• Type 1 DM: Starting dose should be approx one third of the total daily insulin requirement.

• Short acting premeal insulin should be used to satisfy the remaining two thirds of the daily insulin requirements.

• Insulin glargine should be used in combination with a short acting or rapid-acting insulin.

• Usual daily maintenence range is 0.5-1 unit/kg/day.

• Type2 DM: starting dose who are not currently treated with insulin is 10 units (or 0.2 unit/kg) once daily.

Dosing considerations

• Indicates for once daily SC administrations; exhibits relatively constant glucose-lowering profile over 24 hrs.

• May be administered at any time during a day; should be administered SC only daily at the time every day.

• As with all insulins, injection sites should be rotated within the same region to reduce the risk of lipodystrophy.

• No clinical difference in insulin glargine absorption after abdominal, deltoid, or thigh SC administration.

Converting from other insulin

• If changing from a t/t regimen with an intermediate or long acting insulin to a regimen with insulin glargine, the amount and timing of shorter acting insulins and doses of any oral antidiabitics may need to be adjusted.

• From once daily NPH insulin to once daily insulin glargine: initial dose is the same as the dose of NPH that is being discontinued.

• From twice daily NPH insulin to once daily insulin glargine: initial dose is 80% of the total daily NPH dose that is being discontinued.

B. INSULIN DETEMIR

• Modifying insulin by binding to serum protein albumin prolongs the duration of action.

• It is a soluble basal insulin analogue at neutral pH. • It is created in which amino acid threonine at B 30 is

removed and acetylated with a 14-C fatty acid chain to lysine B29 which causes it to bind reversibly to albumin in plasma.

• Only free insulin detemir is biologically active and its slow dissociation from albumin results in delayed action.

• Its onset of action takes 1-2 hours and duration of action is for 24 hours.

• It is given twice daily to obtain a smooth basal insulin level.• Reduction in body weight is another advantage which may be

due to direct effect on hypothalamus.• But its lower affinity for insulin receptor necessitates higher

doses compared to human insulin.• It has low insulin receptor binding affinity and metabolic

potency so it is less potent in binding to IGF-1R & stimulating mitogenesis. Therefore, it has reduced risk of inducing tumours

Dosing

• Once daily dosage: administer SC with morning meal or at bedtime.

• Twice daily dosage: administer SC with morning meal and either with evening meal, at bedtime or 12 hr after the morning dose.

Initial dose • Type 1 DM: approx one third of the total daily

insulin requirement SC; rapid acting or short acting, premeal insulin should be used to satisfy the remainder of the daily insulin requirements; usual daily maintenance range is 0.4-0.6 unit/kg/day.

• Type2 DM: inadequately controlled on oral medication 10 units/day SC (or 0.1-0.2 unit/day) in evening or divided dose.

Conversion from other insulins

• If conversion from insulin glargine: change can be accomplished on a unit to unit basis.

• If converting from NPH insulin: change may be accomplished on a unit to unit basis; however, some patients with type 2 diabetes may require more insulin detemir than NPH insulin.

Dosing considerations

Dose adjustments:• Look for consistent pattern in blood sugars for

>3 days.• Same time each day: compare blood glucose

level with previous levels that time of day• Consider eating and activity patterns during

the day.

Rate of dose adjustments:• Adjust only 1 insulin dose at a time• Correct hypoglycemia 1st.• Correct highest blood sugar next.• If all blood sugars are high: correct morning fasting

blood glucose 1st .• Change insulin doses in small increments: Type1

diabetes 1-2 unit change; Type 2 diabetes resistant to diet and exercise 2-3 change.

INSULIN DEGLUDEC• Insulin degludec (INN/USAN) is an ultralong-acting basal insulin

analogue that was developed by Novo Nordisk under the brand name Tresiba.

• Insulin degludec is a modified insulin that has one single amino acid deleted in comparison to human insulin, and is conjugated to hexadecanedioic acid via gamma-L-glutamyl spacer at the amino acid lysine at position B29.

• It is administered via subcutaneous injection once daily to help control the blood sugar level of those with diabetes.

• It has a duration of action that lasts up to 40 hours (compared to 18 to 26 hours provided by other marketed long-acting insulins such as insulin glargine and insulin detemir), which would allow for a two or three times weekly administration.

Marketing Authorisation Holder and Manufacturer Novo Nordisk A/S Novo Allé DK-2880 Bagsværd, Denmark

INSULIN RYZODEG• Ryzodeg is a soluble insulin product

consisting of the basal insulin degludec and the rapid-acting prandial insulin aspart.

• Ryzodeg can be administered once- or twice-daily with the main meal(s).

OTHER NEWER INSULINAlbulin • It is the newest insulin analogues which is developed and

reported by Duttaroy et al, in 2005.• It is a single chain analogue produced in yeast or mammalian cell.• It consists of B and A chain of human chain linked by a

dodecapeptide linker and fused to NH(2) terminal of native human serum albumin. It has been shown in various studies that it has lower affinity to bind to insulin receptors.

• Albulin displays characteristics of a potent long- acting insulin analog that can be evaluated for use as a novel insulin therapy for patients with insulin-dependent diabetes.

Diabetes. 2005 Jan;54(1):251-8.Development of a long-acting insulin analog using albumin fusion technology.Duttaroy A1, Kanakaraj P, Osborn BL, Schneider H, Pickeral OK, Chen C, Zhang G, Kaithamana S, Singh M, Schulingkamp R, Crossan D, Bock J, Kaufman TE,Reavey P, Carey-Barber M, Krishnan SR, Garcia A, Murphy K, Siskind JK, McLean MA, Cheng S, Ruben S, Birse CE, Blondel O.

Inhaled Insulin • By pulmonary route drugs have faster onset of action, even faster than

i.v. route and large surface area of lungs causes more systemic absorption.

• If long-term safety and efficacy is confirmed, inhalation will become the first non-subcutaneous route of insulin administration for widespread clinical use.

• Exubera is first inhalational drug to be approved by FDA on Jan 2006.• Exubera is an insulin product for pulmonary delivery in powder form. • Bioavailability is just 10% compared to regular human insulin given by

subcutaneous route with duration of action of 5-10 hours.• Therefore, high doses of insulin have to be given about 8 times the

subcutaneous route to achieve glycemic control. The major problems are loss of drug with inhaler and mouth during inhalation, variation in absorption due to age related difference, respiratory tract infection and smoking.

• Other side effects are mild to moderate cough, shortness of breath, sore throat and dry mouth.

Enteral insulin:There are two technologies used to obtain enteral insulin.Emishere technologiesIt uses carriers to enable insulin resorption through membranes. After resorption the carrier seperates from insulin. Nobotex It has developed technology based on attachment of amphophilic oligomers to insulin resulting in resistance to enzymatic degradation. Insulin is absorbed into portal circulation, reaching high concentration in liver, which better mimics physiological secretion. FROM B.NOVAK, Z. METELKO / NEW TRENDS IN INSULIN THERAPY

Orally absorbed insulin(oralin)Generex has developing a aerosol containing insulin for buccal absorption , using an applicator similar to those used in asthma medications.

Transdermal insulins• Altea has developed trandermal patches for insulin delivery.• The electronic adhesive patch is first applied to the skin , vaporizing superficial

dermal cells and forming micropores for insulin to pass through, and then insulin patch is applied.

• It provide basal insulin delivery for 12 hrs.• Idea has developed Transferosulin , using particles called transformers.• Transformers are similar to lyposomes but are more deformable and can easier

pass through the skin.• Their membranes contain phospholipids and has hydrophilic core inside where

insulin is carried.

FROM B.NOVAK, Z. METELKO / NEW TRENDS IN INSULIN THERAPY

Other Routes • Pancreatic transplantation has also been tried but this

will remain limited to those patients receiving a kidney transplant and immunotherapy.

• Islet cell transplantation is at an early though encouraging stage following the availability of new less toxic immunosuppressive agents .

• Artificial pancreas 1. Medronic minimed(part of Medtronic Inc.) presented

initial results of artificial beta cell prototype studies at the 62nd scientific sessions of ADA.

2. It is a closed loop device consisting of implantable peritoneal insulin pump and glucose sensor implanted in the vena cava superior.

Insulin Delivery Devices

• Insulin syringes• External Insulin Pumps• Implantable Insulin Pumps• Insulin Pens• Insulin Injection Aids• Insulin Jet Injectors• Insulin Inhalers

FlexPen®

SoloStar® (sanofi aventis)

Examples of Insulin Pens

Pre-filled (Disposable)

Re-usable (uses insulin cartridges)

NovoPen® 4

HumaPen ®

Portable Pen Injector

Inhalation device or insulin

Insulin administration

Sites• Abdomen (fastest absorption & most

preferred)• Buttocks• Upper arm• Thigh-lateral & anterior aspects (slowest)• Rotate the site of injection around a selected

area

(Intermediate)

Types of insulin Type of Insulin

& Brand Names Onset Peak Duration Role in Blood Sugar Management

Rapid-ActingLispro 15-30 min. 30-90 min 3-5 hours Covers insulin needs for

meals eaten at the same time as the injection.Aspart 10-20 min. 40-50 min. 3-5 hours

Glulisine 20-30 min. 30-90 min. 1-2½ hours

Short-Acting

Regular 30 min- 60 min 2-5 hours 5-8 hours

Covers insulin needs for meals eaten within 30-60 minutes

Intermediate-Acting

NPH (N) 1-2 hours 4-12 hours 18-24 hours

Covers insulin needs for about half the day or overnight.

Types of insulin

Name of Insulin Onset Duration

Role in Blood Sugar

Management

Long-ActingLong-acting insulin covers insulin needs for about one full day.

Degludec 30-90 min No peak: insulin is

delivered at a steady

level.

Longer than 24 hours

Glargine 30-90 min Up to 24 hours

Detemir 1-120 min 20-24 hours

Types of insulin

Type of Insulin Onset Peak Duration Role in Blood Sugar Management

Pre-Mixed*

30/70 30 min. 2-4 hours 14-24 hours These products are generally taken two or three times a day before mealtime.50/50 30 min. 2-5 hours 18-24 hours

25/75 15 min. 30 min.-2½ hours 16-20 hours

InhalerExubera Banned

Afrezza With in min 12 to 15 min 2-3 hours Post prandial effects.

*Premixed insulins are a combination of specific proportions of intermediate-acting and short-acting insulin in one bottle or insulin pen (the numbers the brand name indicate the percentage of each type of insulin).

Thank you

Thanks to all