H. Delshad M.D Endocrinologist Research Institute For Endocrine Sciences

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 MacLeod

BantingBanting,s wedding day

Medical Sciences Building, at the University of Toronto Toronto's Historical Plaques 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. insulin 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 anti- diabetic extract. James Collip, a noted biochemist, then increased the purity and potency of the substance.Frederick BantingCharles Bestdiabetes mellitusJ.J.R. MacleodJames Collip

A 3 - year - old boy before and after 3 months of insulin therapy (1922). 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. The miracle of Insulin

Hypoglycemia and its treatment in 1920s

1U/ml Acidic Bovine origin Impure Only short acting Academia Request : Longer acting insulin

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

1946 : Neutral Protamin Hagedorn(NPH) 1951 : Neutral insulin solution 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

 More than 20 types of insulin  Different time of onset and duration of action.  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)

Insulin TypeProductOnsetPeakDuration Rapid-Acting Aspart Glulisine Lispro Novolog Apidra Humalog min min min h h h. 3-5 h. 3-5 h. 3-5 h. Short-Acting RegularHumulin R Novolin R h.2-5 h.Up to 12 h. Intermediate-Acting NPH insulinHumulin N Novolin N h.4-12 h.Up to 24 h. Long-Acting Detemir Glargine Levemir Lantus h.Minimal peakUp to 24 h. Available insulin injections

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

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

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 Regular Insulin

Relative Insulin Effect Time (Hours) Protamine molecule + human regular Slower absorption and longer duration of action Onset of action = hours after SC It peaks 4 – 8 hours after SC The duration of action range 10 – 20 hours NPH Insulin

Rapid Analogs 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 Lispro Aspart Glulysine

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 A21 Two positively charged Arginine are added at the C terminus of the B chain

Mechanism of Action Clear Solution pH4 pH 7.4 Precipitation Dissolution Capillary Membrane Insulin in Blood HexamersDimersMonomers M10 -5 M10 -8 M Injection of an acidic solution (PH 4.0) Precipitation of insulin glargine in subcutaneous tissue (PH 7.4) Slow dissolution of free insulin glargin hexamers from micro precipitates (stabilized aggregates) Protracted action

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 PHARMACOKINETICS :

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

 A soluble derivative of human insulin  Threonine has been removed at position B30  A 14-carbon fatty acid side-chain has been attached to position B29 Insulin Detemir

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 ) PHARMACOKINETICS :

Insulin Secretion After A Meal In Normal Individual

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

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

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

Relative Insulin Effect Time (Hours) Long (Glargine) 1820 Intermediate (NPH)Short (Regular)Rapid (Lispro, Aspart, Glulysine) Insulin Time Action Curves

 Is rarely able to achieve normoglycemia, Least effective regimen and rarely suitable - Occasionally in newly diagnosed T1DM - Diabetic patients with ESRD on dialysis

SINGLE INJECTION AM PM NPH = U/kg (20-30 IU) in the morning NPH BLDBd Time of day (h) Insulin concentration (  U/mL) Normal pattern

 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

Time (Hours) (NPH)(Regular) Insulin concentration Normal pattern

In many patients with type1 diabetes, especially those with a long duration of diabetes, it may not be possible to achieve optimal glycemic control with two injections.

Is an effective diabetic treatment plan Reduce wide and erratic excursions in blood glucose levels Provides additional flexibility in a patient's daily routine 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 am pm am Intermediate (NPH) Regular BLDBd Time of day (h) Insulin concentration Normal pattern Multiple daily insulin injection

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

Total Daily Dose = 45 IU Bedtime NPH : 45 X 0.50= 22 IU Meal Boluses Regular - Breakfast = 45 X 0.20 = 9 IU - Lunch = 45 X 0.15 = 7 IU - Dinner = 45 X 0.15 = 7 IU Determining initial insulin dosages for MDI

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 mg/dl ) Based on food intake : U of Regular Insulin for every 15 gr. CAH (one starch exchange or equivalents = one fruit, one milk, two meats, three vegetables) Making adjustment in insulin dosage

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

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

Time of day Glargine Lispro, glulisine, or aspart or regular Normal pattern  U/mL Detemir The new analogues are more predictable than conventional Insulins and allow simplified insulin replacement strategies.

Type of Patient Type of Patient Appropriate Glargine Dosage Insulin-naïve Switched from NPH once daily Switched from NPH twice d aily twice d aily 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 appropri ately Initial Dosing Guidelines for Insulin Glargine Titration of Glargine to a final dose range of 2 to 100 IU is suggested

Check FPG daily In the event of hypoglycemia or FPG level < 70 mg/dL Reduce bedtime insulin dose by  4 units, or by 10% if >60 units Bedtime or morning long-acting insulin OR Bedtime intermediate-acting insulin Daily dose: 10 units or 0.2 units/kg INITIATE Increase dose by 2 units every 3 days until FPG is (70–130 mg/dL) If FPG is >180 mg/dL, increase dose by 4 units every 3 days TITRATE Continue regimen and check HbA 1c every 3 months MONITOR Titrate basal insulin as long as FPG > target

استخراج و طراحی اهداف انتهایی و تقویتی از ماتریس CP پس از تكميل ماتريس CP اولين قدم در استخراج اهداف ترمينال را طـــــرح سوالات هدايت‌كننده ( Leading Questions ) زير آغاز مي‌شود (به اسلایدهای بعد توجه کنید) بعد از پاسخ به اين سوالات بكمك قانون ABCD و چك‌ليست SMART و چك‌ليست تکمیلی آنها را بصورت اهداف واضح درآوريم