Insulin Therapy in Type 1 Diabetes Mellitus

Professor of Pediatrics, Head of Diabetes Unit Ain Shams University, Cairo, Egypt.

Why are We Concerned about Diabetes?
Egypt will be the 10th. World wide

Ranking 1 2 3 4 5 6 7 8 9 10 Country India China USA Indonesia Japan Pakistan Russian Fed. Brazil Italy Bangladesh People with diabetes (millions) 31.7 20.8 17.7 8.4 6.8 5.2 4.6 4.6 4.3 3.2

2030 Country India China USA Indonesia Pakistan Brazil Bangladesh Japan Philippines Egypt People with diabetes(millions) 79.4 42.3 30.3 21.3 13.9 11.3 11.1 8.9 7.8 6.7

The worldwide diabetes market is experiencing exponential growth, especially with respect to type 2 diabetes, which has been described as a global epidemicv
Wild S et al. Diabetes Care 2004;27:1047–53

Lowering HbA1c reduces the risk of complications
Deaths related to diabetes


HbA 1c


Microvascular complications


Myocardial infarction

Stratton IM, et al. BMJ 2000; 321:405–412.

Treat To Target Guidelines Need For Progressive Treatment Strategy

Glucose control HbA1c (%) Mean FPG mmol/l (mg/dl) Mean postprandial PG mmol/l (mg/dl)
*12 hours postprandial; **2 hours postprandial.

Healthy <6 <5.6 (<100) <7.8 (<140)

ADA1 <7 57.2 (90130) <10* (<180)

AACE2 6.5 <6 (<110) <7.8** (<140)

IDF3 6.5 <6 (<110) <7.5** (<135)

PG=plasma glucose. Diabetes Association. Diabetes Care 2005;28(suppl 1):S14—36. 1.American Association of Clinical Endocrinologists. Endocr Pract 2002;8(suppl 1):43—84. 2.American International Diabetes Federation. Diabet Med 1999;16:716—30. 3.

Ideal therapy
Should include the following:

* Insulin. * Diet. * Exercise.

* Psychological management.
* Health education. * Home glucose monitoring.

Before Insulin….What‟s After?

Before insulin was discovered in 1921, everyone with type 1 diabetes died within weeks to years of its onset

JL on 12/15/22 and 2 mos later

Insulin Therapy in Type 1 Diabetes

is a must………

 Insulin

is the 1ry mode of therapy in type 1 diabetes
treatment must be started as soon as possible after diagnosis to prevent metabolic decompensation and diabetic ketoacidosis

 Insulin

 Most

children are prescribed human insulin because of their availability through modern manufacturing techniques using recombinant DNA technology and because of their low immunogenicity

Porcine or bovine preparations may be cheaper and more readily available in some parts of the world. They are not inferior in clinical efficacy to human insulin. They may have greater immunogenicity and high titer antibodies may alter pharmacodynamics by acting as insulin binding proteins

 Insulin


The most widely available insulin concentration is 100 IU/ml. It must be given by insulin syringes calibrated to the concentration of insulin being used
 Injection


1- Front of the thigh/ lateral thigh 2- Abdomen

3- Buttocks
4- Lateral aspect of arm

Storage of insulin :
. Insulin must never be frozen

. Unused insulin should be stored in a refrigerator (2-8C) . Direct sunlight damages insulin . After opening, an insulin vial

should be discarded after 3
months if kept at (2-8C)

Problems with injections
1- Local hypersensitivity reactions
2- Lipohypertrophy 3- Lipoatrophy 4- Painful injections 5- Leakage of insulin

6- Bruising and bleeding
7- Bubbles in insulin

Insulin Preparations
 Short
 Rapid

Acting Insulin (Regular)
- Acting Analogues - Acting (NPH) Insulin

 Intermediate  Premixed  Long  Long


- Acting Insulin Acting Analogues

Premixed insulins are popular in some countries particularly for prepubertal children on twice daily regimen. Although they reduce potential errors in drawing up insulin they remove the flexibility offered by separate adjustment of the two types

Pharmacokinetics of Current Insulin Preparations Compared With Insulin Glargine
Effective Duration 3 hr 3-6 hr 10-12 hr 18-20 hr 24 hr

Onset Insulin lispro Regular NPH/Lente Ultralente Insulin glargine <15 min 0.5-1 hr 2-4 hr 4 hr 1-2 hr

Peak 1 hr 2-3 hr 7-8 hr Varies Flat/Predictable

Barnett AH, Owens DR. Lancet. 1997;349:97-51. White JR, et al. Postgrad Med. 1997;101:58-70. Kahn CR, Schechter Y. In: Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 1990:1463-1495. Coates PA, et al. Diabetes. 1995;44(Suppl 1):130A.

Principles of insulin therapy

 To

provide sufficient insulin throughout the 24 hours to cover basal requirements. deliver higher bolus of insulin in an attempt to match the glycemic effect of meals.

 To

Insulin regimens
 Two

injections daily of a mixture of short and intermediate acting insulin (before breakfast and the main evening meal)
injections daily using a mixture of short and intermediate acting insulin before breakfast, short acting insulin alone before an afternoon snack or main evening meal, intermediate acting insulin before bed

 Three

 Basal-bolus

regimen of short acting insulin 20-30 min before main meals, intermediate or long acting insulin at bed time
regimen of rapid acting insulin analogue immediately before main meals, intermediate or long acting insulin at bed time, probably before breakfast and occasionally at lunch time

 Basal-bolus


Ideal Insulin Regimens Type 1 DM
The challenge is to •

Come as close as possible to normoglycemia and reduce hypoglycemia.

Minimizes nocturnal hypos

Optimize FBS

Minimizes late morning and afternoon hypos

Basal-Bolus Regimen

Intensive Insulin Therapy

Intensive glycemic control is the therapeutic approach
• That aims to achieve near normal glycemia.
• Reduce the risk of microvascular complications with intensive insulin therapy is associated with increase risk of hypoglycemia [specially nocturnal 55%].

Daily insulin dosage
 Dosage

depend on many factors such as: age, wt, stage of puberty, exercise, nutritional in take, results of blood glucose monitoring, etc…
the partial remission phase the daily insulin dose is <0.5 IU/kg/day. children 0.7-1 IU/kg/day puberty >1 IU/kg/day

 In

 Prepubertal  During

Insulin Therapy in Type 1 Diabetes
• Physiologic insulin delivery: – About half of insulin dose is “basal,” unrelated to meals – About half of insulin dose is required to utilize ingested carbohydrate, distributed approximately in proportion to carbohydrates in meals or snacks – Total dose in adults ~ 0.7- 0.9 U/kg/day, in adolescents up to 1.5 U/kg/day • Distinguish between “revising the regimen” and

“adjusting individual doses”:
• Revising the regimen means changing the usual dose on a recurring basis • Adjusting individual dose means one time only

Insulin Therapy in Type 1 Diabetes

Revising the regimen: • Change basal dose according to overnight BG profile (e.g. if BG rises, increase dose) • Change usual meal dose according to BG profile between meals or post-prandial BG • With practice, many patients can learn to revise the regimen Adjusting individual doses: • Each meal dose should be adjusted for current BG level (e.g. +1 unit/50 mg/dl) • Each meal dose may be adjusted for expected or planned carbohydrate intake (e.g. +/- 1 unit/15 gm carbohydrate) • Give written individual dose change schedules as a sliding scale or algorithm

Indications for Revising Insulin Regimen

• HbA1c > 7% • SMBG results erratic, or outside target range • Frequent hypoglycemia • Severe hypoglycemia without warning • Recurrent severe hypoglycemia • Symptoms of hyperglycemia


1) Insulin analogues
– Rapid-acting analogues.

– Long-acting analogues.
 

2) Oral insulin. 3) Inhaled insulin.

Rapid Acting Analogues

Limitations of Regular Human Insulin (RHI)

Properties of RHI:
– SC injection does not appropriately match the postprandial hyperglycaemic peak. – Slow onset of action with subcutaneous (SC) injection which lead to: – Late postprandial hypoglycaemia, if the meal is delayed.

– Nocturnal hypoglycaemia.
– Requires administration 30–45 minutes before any meal.

Wittlin SD, et al. In: Leahy JL, Cefalu WT, eds. Insulin Therapy:2002:73 –85

Ideal Rapid - Acting Analogue

Similar physiological properties to human insulin, with faster absorption & onset of action Faster absorption & higher concentration after SC. Injection compared to conventional insulin , thus more physiological action reduce post prandial glucose to greater extent. Give peak plasma concentration within 30 – 60 min. Rapid return to basal level by 180 min ( no delayed peak concentration)means less incidence of hypoglycemia Reduced tendency for self association or rapid dissociation. Improve patient convenience (pre & post meal).

 

 

Achieve the best glycemic control (post – prandial control). Diabetes care 1990 – 1991 & The Lancet 1997

Rapid Acting Analogues
Appearance: CLEAR
   

Onset: 15 minutes Peak: one hour Duration: 2-4 hours Examples: – Lispro (Humalog: Insulin analog) – Insulin Aspart (Novolog)

 

Administration: subcutaneous Usually given 5 minutes before the meal: – Peak coincides with postprandial rise in BS

Structure of insulin Lispro (LysB28, ProB29)
A-chain 1 1 6 7 11


7 B-chain

20 30 29 28
B29B28 Pro Lys

Asp Asp Pro Thr Tyr Phe Phe Gly Arg Glu Gly Cys Val Asn Glu Leu Gln Gln Cys Cys Thr Ser Ile Cys Ser Leu His Ser Gly Tyr Leu Tyr Leu Ala Glu


Lys Thr

Asn Cys Tyr

Val Glu










Rapid – Acting


Insulin lispro Insulin Aspart

B3Lys, B29Glu : HMR 1964

Insulin glulisine (Apidra)

Structure Difference How Insulin Glulisine is different?

Rapid-acting Insulin Glulisine ―Apidra‖
Insulin Glulisine: Replacement of Asparagine B3 with lysine and lysine B29 with glutamic acid

A chain



Ala Cys



20 S
Ile Gln

Thr Lys Pro

B chain


Asn His



15 25


His Gly Leu




Modified Human Insulin
Apidra (insulin glulisine [rDNA origin] injection) USPI. Sanofi Aventis 2004; EU SPC. Sanofi Aventis.

= Substitution

Insulin glulisine APIDRA®

The Only Rapid Insulin Analogue …
Without Zinc Zinc free reduce the formation of stable hexamers and obtain the fast acting properties (quick onset of action). An alternative stabilizer than zinc was needed. With Polysorbate 20 Stabilizer

•Improved physical stability in solution. •Inhibits the denaturation resulting from thermal &

mechanical stress. •Improved in-use stability. •No influence on the time-action profile of insulin glulisine.

APIDRA® (insulin glulisine) Rapid Onset of action

The two substitutions favour monomer formation and facilitate rapid absorption from the tissue following subcutaneous injection.

Hollemen F, et al. N Engl J Med 1997;337:176–83 (adapted from Brange 1988)

Insulin Glulisine “Apidra” Provides Rapid Onset & Short duration of action
Insulin glulisine Insulin lispro RHI


6 Glucose infusion rate (mg/kg/min) 4 2 0











Dosage=0.3 U/kg

Time (minutes)

Drugs of Today 2005, 41 (7): 433-440 Becker RHA, et al. Diabetes 2003;52:471-P

Rapid-Acting Analogs and RHI in Obese Subjects

GIR, 4

Glulisine Lispro Regular human insulin
N=18 BMI=30 kg/m2 to 40 kg/m2



2 1

0 0 60 120 240 Time, min * p< .05 GIR-t vs RHI and Lispro 20% 360 480 600

Dosage=0.3 U/kg GIR=Glucose Infusion Rate Frick AD et al. ADA 64th Scientific Sessions, 2004. Abstract 526.

Long acting analogues

The need for a 24 hour basal insulin
• To achieve near normal glycemia exogenous insulin must be delivered in a way that closely mimic normal physiologic insulin secretion: a) Continuous low level [basal insulin sec.] b) Stimulated sec. after meals [prandial insulin]
Reduce hepatic glucose production (more effective approach for glycemic control) Maintain glucose level for brain and other vital organs dependent on proper glucose utilization

• •

Which type Of Basal Insulin?
Attributes of an ideal basal insulin

Basal insulin should be characterised by:
– Peakless – 24-hour profile enabling once-daily dosing

– Good glycaemic control
– Less incidence of hypoglycaemia with proven long-term safety – Ability to easily titrate to targets – Minimal weight change – Improved quality of life and treatment satisfaction
3 2

International Diabetes Federation. Diabet Med 1999;16:716–730 Treat-to-target study. Riddle M, et al. Diabetes Care 2003;26:3080–3086

The Challenge is, The way the pancreas does it
Novel Basal Insulin
24-hour peakless profile of insulin glargine allows once-daily administration

1. Lantus® (insulin glargine) Approved Product Information 2. McKeage K et al. Drugs. 2001;61:1599-1624. 3. Kramer W. Exp Clin Endocrinol Diabetes. 1999;107(suppl 2):S52-S61.

Structure of Insulin Glargine





20 Asn







25 Extension


Arg Arg

• Modifications to human insulin chain – Substitution of glycine at position A21 – Addition of two arginines at position B30 – Unique release pattern from injection site

Absorption of Insulin Glargine
Sc Injection of Insulin Glargine Clear Solution PH 4.0 pH 7.4 Microprecipitates at neutral PH 7.4 Precipitation Dissolution Hexamers 10-3 M Dimers 10-5M Monomers 10-8 M “depot” of Insulin Glargine

Slow dissolution of free Glargine Hexamers Continuously released over 24 hours Once daily dose

Capillary Membrane Insulin in Blood

Insulin Glargine as an ideal basal insulin
• Reliable, constant basal insulin concentration to control basal metabolism.  Prolonged duration of action (24 hours) compared with NPH human insulin (14.5 hours).  Once-daily dosing  Safety Smooth peakless time-action profile  Lower risk of clinically hypoglycemic events  Clear Soluble with less interpersonal variation.  Consistent absorption from arm, leg and abdomen unlike other insulin formulations

Basal Insulin Profiles Glucose Infusion Rates

4 Glucose infusion (mg/kg/min) 3 2 1 0







12 Hours




Lepore et al. Diabetes 49: 2142-2148, 2000

Which type Of Basal Insulin? Look at all available basal insulins
Glucose infusion rate (mg/kg/min) 4 3 2 1 0 0 4 8 12 16 20 24 NPH Glucose infusion rate (µmol/kg/min) 24 Glucose infusion rate (mg/kg/min) 8 sc injection 6 30 4 2 0 0 NPH 0.3 IU/kg 4 8 12 16 20 24 Insulin detemir 0.4 IU/kg 20 10 0 40 Glucose infusion rate (µmol/kg/min)


20 16


12 8

Insulin glargine

4 0

Time (hours)
sc injection 0.3 IU/kg or CSII 0.3 IU/kg/24/h Lepore M, et al. Diabetes 2000;49:21428. Adapted from Plank J, et al. Diabetes Care 2005;28:1107–12.

Time (hours)

Plank et al 2005 (n=12)

216 180 s.c. insulin 0.35 U/Kg 12


10 8 6

144 108 72

Glargine Detemir

(N=24) Mean±SD


24 20 16 12 8 4 0

(Subjects with plasma glucose > 150 mg/dl) by time of study

100 84 67 50 33 17 0
16 18 20 22 24








Porcellati F et al., Diabetes 55 (Suppl.1): A130, 2006

Time (hours)

Subjects (%)

Subjects (N)



Ideal Insulin Regimens Type 1 DM
The challenge is to •

Come as close as possible to normoglycemia and reduce hypoglycemia.

Minimizes nocturnal hypos

Optimize FBS

Minimizes late morning and afternoon hypos

Basal-Bolus Regimen

Delivery System

Disadvantages of conventional subcutaneous injection: – Discomfort – Inconvenience – Systemic delivery – Inconsistent pharmacokinetics – Irreversible after injection Insulin pumps Insulin pen Systems in clinical testing: – Inhaled formulation

  

Insulin Pen Development

Development for reusable pens
Alpha disposable pen

OptiSet disposable pen

Omega Lite electronic reusable pen

Easy to teach

Simple and quick
Easy to use

Just dial and dose
Easy to inject 1,2

Easy-to-push, soft and gentle injection1

1. Clarke A, Spollett G. Expert Opin. Drug Deliv 2007; 4(2):165-174. 2. Haak T, et al. Clin Ther (2007) 29: (4) 2007.

Easy Accurate Efficacy SoloSTAR® is 100% accurate in the laboratory1 to ISO3 dose • accuracy standards is 100% accurate when used by patients2 • SoloSTAR® In a dose accuracy study with 60 patients, each delivering 6 • different doses, SoloSTAR® was 100% accurate2 to ISO3 laboratory dose accuracy standards
Lantus® 60 x 10 u 60 x 40 u 60 x 80 u
% of delivered doses within ISO standard Passes ISO standard

60 x 5 u 60 x 15 u 60 x 30 u

100% 100% 100%

  

% of delivered doses within ISO standard

Passes ISO standard

100% 100% 100%

  

―In a random sample hospitalized diabetic patients delivered very precisely insulin doses using both Lantus® SoloStar® and Apidra® SoloStar®‖ 2

1 Clarke A, Spollett G Expert Opinion in Drug Delivery 2007; 4(2): 165-174 2 Hermanns N, Diabetologie und Stoffwechsel, 2008, 3 (Supplementum 1) 3 Pen-injectors for medical use, EN ISO 11608-1:2000

Insulin Pumps

Mechanism: – Small externally worn device – Teflon catheter inserted into abdomen – Uses only rapid or short acting insulins – Continuous basal rate of insulin infuses
Implantable insulin pump

– Before each meal, patient administers a programmed bolus of insulin

Advantages: – Flexibility, No intermediate insulins used Disadvantages: – Pump dysfunction: • Dislodged, kinked, batteries out, etc.

– Numerous blood samples necessary
– Cost if insurance will not pay

Mini Med Continuous Glucose Monitoring System (CGMS)

Insulin Pumps (USA)

MiniMed insulin pumps  Paradigm

Disetronic Insulin pump

Animas Insulin Pump Implantable insulin pump

Alternative Insulin Delivery System

Pulmonary Approach

Insulin delivered through the oral cavity can also be considered to have its uptake in the pulmonary bed. However, the idea of pulmonary delivery of insulin is not a new idea, as the first report of inhaled insulin was noted in 1925.

The high permeability of the lung’s large surface area makes it an ideal route for the administration of insulin. The lung has hundreds of millions of alveoli that are richly vascularised and where drug absorption takes place

Exubera –Inhale Corporation Dry powder insulin inhaled

Inhaled Insulin

The rationale:  We know that medicine can be absorbed from the lung (e.g. Asthma Rx)  How big is the lung?

The pluses:

 It works (insulin is absorbed)

Oralin - Generex Corp. oral mucus membrane insulin application

 Insulin is absorbed in similar fashion to Humalog (Lyspro)  Consistent & reproducible action of the insulin  ~ action to Humalog/Novo-rapid

Inhaled Insulin

The negatives:
 Dose is ten times greater than normal insulin dose (only 10 percent is absorbed)  Where is the rest going (?swallowed, ?absorbed)  Buccal absorption is better  Still need an injection of basal insulin  Increased absorption if have upper respiratory tract infection or smoker

 Increased absorption if smoker
 ? Lung toxicity (2 of 4 studies showed impaired lung function)  2 patients found to have pulmonary fibrosis (by CT: ? There already)  How do we titrate the dose?

Intranasal Approach
Delivery of insulin using an intranasal approach was first suggested over 65 years ago, but it was not until the 1980s that this approach was seriously evaluated. Feasibility has been demonstrated, as intranasal insulin (60 or 120U) given pre-meal to 17 patients with type 2 diabetes and compared with placebo resulted in reductions in postprandial glucose at both 60 and 120 minutes.

Jet Injectors

This approach is appealing because of the lack of needles,but the discomfort associated with jet injectors is not reported to be less than that observed with injections.

Iontophoresis refers to transdermal delivery of insulin or other peptides by a direct electric current.
However, iontophoresis enhances the transdermal delivery of drug ions into the skin and surrounding tissues using low level electrical current.

Low-Frequency Ultrasound

It has been estimated that the permeability achieved by 1 hour of sonophoresis performed three times daily may allow for a typical daily dose of insulin (about 36U) to be delivered transdermally.

Transfersomes are lipid vesicles made of soybean of deformability, which makes them flexible enough to pass through pores much smaller than themselves.

Gastrointestinal Delivery

Insulin molecules lend to be too large and hydrophilic to cross the mucosa. Uptake of insulin via the gastrointestinal tract is limited by an extremely low bioavailability (i.e. 0.5%).

An additional limitation is the extensive enzymatic and chemical degradation of insulin within the enzymatic barrier of the gastrointestinal tract mucosa.

Buccal Delivery
Oral insulin delivery that relies upon uptake by the buccal mucosa and oropharynx appears to be feasible for more widespread clinical testing, as insulin appears to be rapidly absorbed into the systemic circulation with this approach.
Buccal insulin, therefore, has also demonstrated proof of concept; unfortunately, the studies to date demonstrating efficacy are presented as abstracts only, and safety and adverse effect profiles for this approach have not been presented for large numbers of subjects.

Insulin therapy in type 2 Diabetes

 The

emergence of type 2 diabetes in childhood and adolescence is alarming, especially as these patients progress to chronic complications, potentially at a very young age pausing a public health problem.

Proposed algorithm for the management of youth with T2DM (Silva Arslanian, 2007).

The recent advances in diabetes technology including:
 

newer and more powerful oral agents insulin analogs that provide a more physiological delivery of insulin insulin infusion devices accurate and less invasive methods of assessing glycemic control [offer great promise that improved, if not ideal, glycemic control and associated health-related benefits might be achieved, thus reducing or preventing the long-term complications of diabetes (Kenneth et al.,2005)]

 

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