Insulin Therapy In Type 1 DM H Delshad

Insulin Therapy In Type 1 DM H. Delshad M. D Endocrinologist Research Institute For Endocrine Sciences

INSULIN The most powerful agent we have to control glucose

First trial with Pancreatic extract Banting 1921 Charles Best and Frederick Banting

1923 Nobel price in Physiology/Medicine Banting Mac. Leod

Banting, s wedding day

Medical Sciences Building, at the University of Toronto In one of the most important advances in modern medicine, a team of investigators isolated and purified insulin in a building which stood on this site. On May 17, 1921, Frederick Banting, a young surgeon, and Charles Best, a recent graduate in physiology and biochemistry, began a series of experiments on pancreatic secretions in an attempt to find a treatment for "diabetes mellitus". Working under the general direction of J. J. R. Macleod, an expert in carbohydrate metabolism, they developed a promising antidiabetic extract. James Collip, a noted biochemist, then increased the purity and potency of the substance. Toronto's Historical Plaques

The miracle of Insulin With the first successful clinical test of insulin on a human diabetic on January 23, 1922, Banting, Best, Macleod and Collip ensured prolonged lives for millions of diabetics throughout the world. A 3 - year - old boy before and after 3 months of insulin therapy (1922).

Hypoglycemia and its treatment in 1920 s

Characteristics of first commercial insulin l 1 U/ml l Acidic l Bovine origin l Impure l Only short acting Academia Request : Longer acting insulin

Longer acting insulin l 1930: Insulin plus adrenalin l 1934: Zinc insulin crystallisation l 1936: Protraction with Protamin Academia Requirement: Purity

Purification / Higher Concentration l 1946 : Neutral Protamin Hagedorn(NPH) l 1951 : Neutral insulin solution l 1960 : Lente, Semilente, Mixed insulin Professor Hagedorn

NPH : Is the most important discovery for diabetes treatment since the discovery of insulin” P Joslin 1947

Gene technology– 1986 Transfer and cloning of the insulin gen 1990 Human insulin (Short- and long-acting and Mixed insulin )

- Academia Requirement : Simple Administration

1926 : The first pens

Diabetes care today

Types of Insulin Ø More than 20 types of insulin Ø Different time of onset and duration of action. Ø Among the criteria considered in choosing insulin are: How soon it starts working (onset) When it works the hardest (peak time) How long it lasts in the body (duration)

Available insulin injections Insulin Type Product Onset Peak Duration Novolog Apidra Humalog 10 -30 min. 0. 5 -3 h. 3 -5 h. Humulin R Novolin R 0. 5 -1 h. 2 -5 h. Up to 12 h. Humulin N Novolin N 1. 5 -4 h. 4 -12 h. Up to 24 h. Levemir Lantus 0. 75 -4 h. Minimal peak Up to 24 h. Rapid-Acting Aspart Glulisine Lispro Short-Acting Regular Intermediate-Acting NPH insulin Long-Acting Detemir Glargine

Insulin Analogues : 2000 Lispro Aspart Glulisine Glargine June 29 , 2010 , ADA 70 th Scientific Session : Ultrarapid = Technosfer ( Inhaled Insulin) Ultralong = Degludec Detemir

Conventional Insulins l REGULAR : Traditional Bolus insulin since 1921 l NPH : Traditional Basal insulin replacement since 1950 l Several well known limitations : * Absorption Variation : unfavorable plasma profiles * Duration of acton * Peak effect * Fasting hyperglycemia * Nocturnal hypoglycemia

Regular Insulin • • Exist in solution in hexameric form Onset of action : 0. 5 – 1 hour after SC It peaks 2 – 4 hours after SC The duration of action range 8 – 10 hours It peaks much later than the blood glucose rise Exerts its effect for too long Risk of hyperglycemia in the first 30 minutes and hypoglycemia many hours after meals

NPH Insulin Relative Insulin Effect • • • 0 2 4 6 Protamine molecule + human regular Slower absorption and longer duration of action Onset of action = 1 - 2 hours after SC It peaks 4 – 8 hours after SC The duration of action range 10 – 20 hours 8 10 12 Time (Hours) 14 16 18 20

Rapid Analogs Lispro Aspart Glulysine • • • Exist in solution in monomeric form Onset of action : up to 0. 5 hour after SC Peaks 1– 2 hours after SC The duration of action up to 4 hours Peak when the blood glucose rise No risk of hyper- or hypoglycemia

Long acting analogous Glargine & Detemir • Were designed to provide a reliable, constant basal insulin concentration to control basal metabolism. • They are more predictable than conventional insulins and allow simplified insulin-replacement strategies

Insulin Glargine A- chain has an Asparagine to Glycine substituiation at position A 21 Two positively charged Arginine are added at the C terminus of the B chain Gly A-Chain Substitution 1 5 10 15 20 Asn 1 5 10 15 20 B-Chain 25 Extension 30 Arg

Mechanism of Action Injection of an acidic solution (PH 4. 0) Clear Solution p. H 4 p. H 7. 4 Precipitation of insulin glargine in subcutaneous tissue (PH 7. 4) Precipitati on Dissolution Hexamers Dimers 10 -3 M 10 -5 M Monomers 10 -8 M Slow dissolution of free insulin glargin hexamers from micro precipitates (stabilized aggregates) Capillary Membrane Insulin in Blood Protracted action

PHARMACOKINETICS : Slow dissolution of the Glargine hexamers at the injection site results in a relatively constant release with no pronounced peak over a period of up to 24 hours. Onset of action = 2 hours Peak = flat Duration = 24 hours

Presentation of Glargine (Lantus) l Clear solution l Once-daily l Not dosing ● suitable for mixing with other insulins Pen delivery system

Insulin Detemir Ø A soluble derivative of human insulin Ø Threonine has been removed at position B 30 Ø A 14 -carbon fatty acid side-chain has been attached to position B 29

PHARMACOKINETICS : The fatty acid , enable Detemir to bind albumin in subcutaneous tissue and circulation. 98% of Detemir in the blood stream is albumin bound. Detemir distribute more slowly to peripheral target tissues. It dose not precipitate during administration or absorbtion. Protracted absorption may contribute to reduced variability in Detemie action. Onset of action = 2 hours Peak = flat Duration = 14 – 16 hours (dose dependent : 0. 4 IU/Kg , average 20 hours )

Insulin treatment regimens

Insulin Secretion After A Meal In Normal Individual

How is insulin normally secreted ? l Basal ( 50%) Breakfast Lunch Dinner serves to balance the rate of hepatic glucose production and peripheral uptake during Bolus overnight and prolonged periods between meals l Bolus Basal (50%) serves to control postprandial hyperglycemia in response to food intake Time of day

Insulin secretion in Type 1 and 2 DM Prandial Bolus Normal Type 1 Type 2 Bolus

Optimizing insulin therapy l The type of insulin l Insulin time action curves l Rational for selecting an insulin regimen - Conventional insulin regimen - Advanced insulin regimen ( intensive, multidose , flexible, functional, physiologic, basal-bolus )

Relative Insulin Effect Insulin Time Action Curves Rapid (Lispro, Aspart , Glulysine) Short (Regular) Intermediate (NPH) Long (Glargine) 0 2 4 6 8 10 12 Time (Hours) 14 16 18 20

Single insulin dose Is rarely able to achieve normoglycemia, Least effective regimen and rarely suitable - Occasionally in newly diagnosed T 1 DM - Diabetic patients with ESRD on dialysis

SINGLE INJECTION 120 NPH = 0. 5 -1. 0 U/kg Insulin concentration ( U/m. L) 100 B L D Bd (20 -30 IU) in the morning 80 60 40 Normal pattern NPH 20 0 6 8 AM 12 PM 18 Time of day (h) 24 AM 6

Twice-daily injection The most frequently used regimen NPH+ Regular insulin Starting dose : 0. 5 – 1 U/Kg (TDD) - 2/3 of TDD in the morning - 1/3 of TDD in the evening Frequent late afternoon and midnight hypoglycemia

Twice-daily injection 120 (Regular) Insulin concentration 100 (NPH) 80 60 Normal pattern 40 20 0 0 2 4 6 8 10 12 Time (Hours) 14 16 18 20

l. In many patients with type 1 diabetes, especially those with a long duration of diabetes, it may not be possible to achieve optimal glycemic control with two injections.

Multiple daily insulin injection l Is an effective diabetic treatment plan l Reduce wide and erratic excursions in blood glucose levels l Provides additional flexibility in a patient's daily routine l Bedtime NPH + Meal time Regular

Multiple daily insulin injection § Frequent monitoring of blood glucose § 3 or more daily injections of insulin § combined regular and intermediate- or long-acting § Adjusted to needs of individual patient 120 Regular 100 B 60 40 20 D Bd Insulin concentration 80 L Normal pattern Intermediate (NPH) 4 8 12 0 6 am 8 12 4 12 8 pm Time of day (h) 12 18 4 8 am 24 6

Determining initial insulin dosages for MDI l Bedtime l Meal NPH : 35 – 50 % TDD Boluses Regular ( % of TDD): - Breakfast = 20 – 25 % - Lunch = 10 – 15 % - Dinner = 15 – 20 %

Determining initial insulin dosages for MDI Total Daily Dose = 45 IU l Bedtime l Meal NPH : 45 X 0. 50= 22 IU Boluses Regular - Breakfast = 45 X 0. 20 = 9 IU - Lunch = 45 X 0. 15 = 7 IU - Dinner = 45 X 0. 15 = 7 IU

Making adjustment in insulin dosage l Based on blood glucose levels : 1800 ⁄ TDD = mg /dl of glucose which can be reduced with 1. 0 U of regular insulin ( 1. 0 U of Regular Insulin for 40 -50 mg/dl ) l Based on food intake : - 1. 0 U of Regular Insulin for every 15 gr. CAH (one starch exchange or equivalents = one fruit , one milk, two meats , three vegetables)

Conventional regimens problems Lack of flexibility Inadequate glycemia Fasting coverage of post-lunch hyperglycemia Nocturnal hypoglycemia

Conventional insulins do not replicate the pattern of basal and postprandial endogenous insulin secretion Breakfast Lunch Dinner Snack Split-mix twice-Daily Plasma levels Pre-Mixed twice-Daily Time of day Conventional insulins fail to meet the two fundamental features of normal insulin secretion

The new analogues are more predictable than conventional Insulins and allow simplified insulin replacement strategies. U/m. L Lispro, glulisine, or aspart or regular 100 Glargine 80 60 40 Normal pattern 20 0600 0800 1200 1800 Time of day 2400 Detemir 0600

Initial Dosing Guidelines for Insulin Glargine Type of Patient Insulin-naïve Switched from NPH once daily Switched from NPH Appropriate Glargine Dosage Initiate at 10 IU once daily , titrate appropriately Initiate at same dosage; titrate appropriately Reduced total daily dose by 20%-30% compared to NPH; titrate appropriately twice daily Titration of Glargine to a final dose range of 2 to 100 IU is suggested

Titrate basal insulin as long as FPG > target INITIATE • Bedtime or morning long-acting insulin OR • Bedtime intermediate-acting insulin Daily dose: 10 units or 0. 2 units/kg Check FPG daily • Increase dose by 2 units every 3 TITRATE days until FPG is (70– 130 mg/d. L) • If FPG is >180 mg/d. L, increase dose by 4 units every 3 days MONITOR Continue regimen and check Hb. A 1 c every 3 months In the event of hypoglycemia or FPG level < 70 mg/d. L • Reduce bedtime insulin dose by 4 units, or by 10% if >60 units