insulin is a friend of diabetes

INSULIN IS A FRIEND OF DIABETES..

INTRODUCTION

Diabetes Mellitus is a syndrome complex of:

Hyperglycemia

Glycosuria

Hyperlipidemia

Negative nitrogen balance

India has largest no. of Diabetes pts. in world

No. of pts. with Diabetes Mellitus in India 40.9 millions

(2006)

Expected to rise to 69.9 million by 2025Diabetes Mellitus.www. mohfw.nic.in/NRHM/STG/PDF%20Content/STG%20Select%20Conditions/ Diabetes%20Mellitus.pdf

INTRODUCTION : HISTORY

Word “Diabetes” first used in 250 BC

Apollonius of Memphis coined name "diabetes” meaning "to go through" or siphon.

He observed: Disease drained more fluid than a person could consume

Gradually Latin word for honey, "mellitus" was added to diabetes because it made the urine sweet

INTRODUCTION

Two Types (Main):

Type I Diabetes Mellitus

Type II Diabetes Mellitus

Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 1997;20:1183–1197

TYPE 1 DIABETES:

Impaired or absent ß cell function:

insulin secretion

Normal insulin action:

insulin sensitivity

Insulin deficiency results in unacceptable blood glucose control

TYPE 2 DIABETES

Double Impairment

Impaired ß cell function:

insulin secretion

Impaired insulin action:

insulin resistance

Results in unacceptable blood glucose control

Alemzadeh R, Ali O. Diabetes Mellitus. In: Kliegman RM, ed. Kliegman: Nelson Textbook of Pediatrics . 19th ed. Philadelphia, Pa: Saunders;2011:chap 583

SYMPTOMS

Type 1 Diabetes:

Develop over a short period of time

People may be very sick by time of diagnosis

Type 2 Diabetes

Develops slowly

Some people with high blood sugar & have no symptoms

SYMPTOMS

Mild Neurovegetative

symptomsSweatingTremblingPalpitationsAnxietyTinglingPallor Hunger

Moderate to Severe Symptoms of

glucopeniaConfusion Visual disturbancesWeaknessSpeech disorderBehavioural disorderDrowsinessComaConvulsions

SCREENING

Recommended for:

Overweight children who have other risk factors for diabetes, starting at age 10 and repeated every 2 years

Overweight adults (BMI greater than 25) who have other risk factors

Adults over age 45, repeated every 3 years

DIAGNOSIS

Fasting blood glucose level: > 126 mg/dl

100 - 126 mg/dL are called impaired fasting glucose or pre-diabetes

Oral glucose tolerance test : Blood glucose level >200 mg/dl 2 hours after giving 75

mg of glucose orally

Hemoglobin A1c Test :

Normal: Less than 5.7%

Pre-diabetes: 5.7% - 6.4%

Diabetes: 6.5% or higher

TREATMENT

Treatment of Diabetes is a combination of :

Nutrition therapy :

Exercise :

Pharmacotherapy

TREATMENT

Nutrition :

Carbohydrate Intake: 55-60% of total calorie intake

Fat Intake : Maximum 30% or total calorie intake

Protein Intake : 10-20% of total calorie intake

Physical activity:

Adviced in both type I & type II Diabetes Mellitus

TREATMENT

Pharmacotherapy Treatment depends upon type of diabetes

Type I diabetes mellitus : Insulin therapy

Type II diabetes mellitus : Drug therapy

Drugs available to choose from

Sulphonylureas: Glimeperide, Glipizide, Glibenclamide

Biguanides : Metformin

α Glucosidase inhibitors : Acarbose , Miglitol

Thaizolidinediones : Rosiglitazone, Pioglitazone

Gestational diabetes mellitus : Insulin therapy

INSULIN-HISTORICAL PERSPECTIVE

EARLY DIABETES TREATMENTS

In 1000: Greek physicians recommended horseback riding to reduce excess urination

In 1800s: Bleeding, blistering, and doping were common

In 1915: Sir William Osler recommended opium

Overfeeding was commonly used to compensate for loss of fluids and weight

In early 1900s: a leading American diabetologist, Dr. Frederick Allen, recommended a starvation diet

EARLY RESEARCH 1798: John Rollo documented excess sugar in the

blood and urine

1813: Claude Bernard linked diabetes to glycogen metabolism

1869: Paul Langerhans, a German medical student, discovered islet cells in pancreas

1889: Joseph von Mehring and Oskar Minkowski created diabetes in dogs by removing the pancreas

1910: Sharpey-Shafer suggested a single chemical was missing from the pancreas. He proposed calling this chemical "insulin"

EARLY RESEARCH

In 1908, a young internist in Berlin, Georg Ludwig Zuelzer created a pancreas extract named acomatrol

After injecting acomatrol into dying diabetic patient, patient improved at first, but died when acomatrol was gone

Zuelzer filed an American patent in 1911 for a "Pancreas Preparation Suitable for the Treatment of Diabetes”

Disappointing results, however, caused his lab to be taken over by German military during World War I

INSULIN DISCOVERY

American scientist E. L. Scott was partially successful in extracting insulin with alcohol

A Romanian, R. C. Paulesco, made an extract from the pancreas that lowered the blood glucose of dogs

Some claim Paulesco may have been the first to discover insulin about 10 years before Banting & Best

Insulin was discovered by Banting & Best in 1921

1923 Nobel Prize for Medicine was awarded to Banting, Best & Macleod for discovery of insulin

Abel, J. J. (1926) Crystalline insulin. Proc. Natl. Acad. Sci. U. S. A. 12, 132–136

INSULIN DISCOVERY

Frederick G. Banting

Charles H. Best

BEFORE INSULIN

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

LEONARD THOMPSON 14 year old boy who first received Insulin

injections in Jan 1922

Abscesses developed & he became more acutely ill

However, his blood glucose had dropped enough to continue refining what was called "iletin” insulin

6 weeks later, a refined extract caused his blood glucose to fall from 520 to 120 mg/dL in 24 hours

Lived relatively healthy life for 13 years before dying of pneumonia (no Rx then) at 27

INSULIN PRODUCTION BEGINS

First produced as “Connaught” by the University of Toronto

First bottles contained U-10 insulin 3 to 5 cc were injected at a time Pain and abscesses were common until purer

U-40 insulin became available

IMPACT OF INSULIN ONLIFE EXPECTANCY BY 1940’S

Age at start of diabetes

50 30 10

Avg. age of death in 1897

58.0 34.1 11.3

Avg. age of death in 1945

65.9 60.5 45.0

Years Gained 8 26 34

Bliss, M. (1982) The Discovery of Insulin, The University of Chicago Press, Chicago, IL

INSULIN

INSULIN

Two chain polypeptide with 51 amino acid

Molecular weight - 6000 A chain – 21 amino acids

B chain – 30 amino acids

Goal of Insulin Therapy Reach the target HbA1C level with a low rate of

hypoglycemic episodes and the least amount of weight gain

Desired HbA1C level: < 7%

ENDOCRINE EFFECTS OF INSULIN

Effects on liver

Reversal of catabolic features of insulin deficiency

Inhibits glycogenolysis

Inhibits conversion of Fatty & Amino acids to keto acids

Promotes glucose storage as glycogen

Increases triglyceride synthesis

Increases VLDL formation

ENDOCRINE EFFECTS OF INSULIN

Effects on muscle

Increased protein synthesis

Increased amino acid transport

Increased ribosomal protein synthesis

Increased glycogen synthesis

Increases glucose transport

Induces glycogen syntheses & inhibits phosphorylase

ENDOCRINE EFFECTS OF INSULIN

Effects on adipose tissue

Increased triglyceride storage

Activation of lipoprotein lipase

Inhibition of intracellular lipase

Easterification of fatty acids

TYPES OF INSULIN

Short Acting

Regular ( Soluble ) Insulin

Intermediate Acting:

Neutral protamine hagedorn (NPH) or Isophane Insulin

Insulin zinc Suspension (Lente)

TYPES OF INSULIN

Long Acting:

Protamine zinc insulin

Insulin glargine

Insulin detemir

Rapid acting

Insulin lisipro

Insulin aspart

Insulin glulisine

SHORT ACTING INSULIN

Regular (Soluble) Insulin

Buffered solution of unmodified insulin stabilized by small amount of zinc

Effect within 30 min, peak - 2-3 hrs & lasts for 5-8 hours after subcutaneous injection

Self aggregation of molecules seen - delayed onset of action

To be administered 30-45 min before meals d/t ↑ risk of late postprandial hypoglyemia

SHORT ACTING INSULIN

Regular (Soluble) Insulin Only insulin to be adminstered intravenously

Delyed absorption

Dose dependent dution of action

Variability of absorption

Particularly useful in

t/t of Diabetic ketoacidosis

After Surgery

During acute infection

Use is declined

Martha S.Katzung basic & clinical Pharmacology; pancreatic harmones & antidiabetic drugs,Tata-McGraw Hill Publication ; pg744-751

SHORT ACTING INSULIN

INTERMEDIATE ACTING INSULIN

Neutral Protamine Hagedorn (NPH) or Isophane Insulin

Asorbption & Onset of action are delayed by :

Combining appropriate amounts of insulin & Protamine

Onset of action : 2- 5 hours

Duration of action : 4-12 Hours

Usually mixed with regular, lisipro, aspart or glulisine & given 2-4 times daily

Clinical use waning d/t adverse pharmacokinetic profile & variablity of absorption

INTERMEDIATE ACTING INSULIN

Insulin Zinc Suspension (Lente Insulin ) Two types :

Ultralente (Extended insulin zinc suspension)Large particles → Crystalline insoluble in waterLong acting than semilente

Semilente (Prompt insulin zinc suspension )Smaller Particles → AmorphousShort acting

Mixture of Ultralente & Lente in 7:3 ratio is Lente insulin → intermediate acting

LONG ACTING INSULIN

Protamine Zinc Insulin

Contains Excess of Protamine → complexed insulin is released more slowly after s.c injection

Rarely used now

LONG ACTING INSULIN

Insulin Glargine Soluble, peakless

first long-acting insulin analogue having amino acid modifications in both chains

A-chain, the asparagine at position 21 is substituted by glycine

B-chain is elongated at the C-terminus by addition of two arginine residues

Slow onset of action – 1-1.5 hrs

Duration of action – 11- 24 hrs

Precipitates in subcutaneous tissue after s.c. inj.

LONG ACTING INSULIN

Insulin Glargine

E.G.Hagenmeyer, P. K. Sch¨adlich, A. D. K¨oster, F.-W. Dippel,& B. H¨aussler, “Quality of life and treatment satisfactionin patients being treated with long-acting insulin analogues,” Deutsche Medizinische Wochenschrift, vol. 134, no. 12, pp. 565–570, 2009

LONG ACTING INSULIN

Insulin Detemir Most recently developed long acting insulin

analogue

Characterized by:

Acylation of myristic acid to the lysine residue at position 29 in the B-chain

Deletion of the last threonine (position 30) in the B-chain

Self –aggregation in subcutaneous tissue & reversible albumin binding

Dose dependent onset of action – 1-2 hrs

LONG ACTING INSULIN

Insulin Detemir Duration of action – 12 hrs

Given twice daily, Produces less hypoglycemia

J. Morales, “Defining the role of insulin detemir in basal insulin therapy,” Drugs, vol. 67, no. 17, pp. 2557–2584, 2007

RAPID ACTING INSULIN

Insulin Lisipro

First genetically engineered rapid-acting insulin analogue

Approved for clinical use in 1996

Reduced capacity of self association in solution d/t structural difference from human insulin in B chain →

Faster absorbed, with higher peak serum levels and shorter action duration in comparison to regular insulin

RAPID ACTING INSULIN

Insulin Lisipro

Improves postprandial leptin and grehlin regulation of type 1 diabetic patients

Needs to be injected immediately before or even after meal

Dose can be altered a/c to quantity of food consumed

Can be used in Gestational Diabetes

K. Eckardt and J. Eckel, “Insulin analogues: action profiles beyond glycaemic control,” Archives Physiol Biochem, vol. 114, no. 1, pp. 45–153, 2008

RAPID ACTING INSULIN

Insulin Lisipro

RAPID ACTING INSULIN

Insulin Aspart

differs from human insulin at position 28 where proline is substituted with aspartic acid →inhibits insulin self aggregation

absorbed twice as fast as human insulin

better glycaemic control when administered directly before a meal

reduced risk of nocturnal hypoglycaemia in pregnant women with type I diabetes

T. M. Chapman, S. Noble, and K. L. Goa, “Spotlight on nsulin aspart in type 1 and 2 diabetes mellitus,” Treatments in Endocrinology, vol. 2, no. 1, pp. 71–76, 2003

RAPID ACTING INSULIN

Insulin Aspart

RAPID ACTING INSULIN

Insulin Glulisine Most recent rapid-acting analogue, launched in

2004

Difference from human insulin

Asparagine at position 3 is substituted by lysine

Lysine at position 29 by glutamic acid

Glycemic control comparable to insulin lisipro

Pharmacokinetic & pharmacodynamic profile does not exhibit negative correlation with BMI & subcutaneous fat thickness R. H. A. Becker, “Insulin glulisine complementing basal insulins: a review of structure and activity,” Diabetes Technology and Therapeutics, vol. 9, no. 1, pp. 109–121, 2007

RAPID ACTING INSULIN

Insulin Glulisine

DURATION OF ACTION OF VARIOUS INSULIN PREPARATION

DURATION OF ACTION OF VARIOUS INSULIN PREPARATION

ROLE OF INSULIN IN TYPE I DM

As individuals with type 1 DM partially or completely lack endogenous insulin production,

Goal of insulin therapy is to design and implement insulin regimens that mimic physiologic insulin secretion

Administration of basal, exogenous insulin is essential for regulating Glycogen breakdown

Gluconeogenesis

Lipolysis

ketogenesis

ROLE OF INSULIN IN TYPE I DM (CONTD)

Target: To achieve glycemic control (Hb1Ac : < 7.0) &

To promote normal glucose utilization & storage

Insulin replacement should be appropriate to carbohydrate intake

Various insulin preparations available such as:

Short/Rapid/Long acting insulins

Mixed insulin preparations as described above

ROLE OF INSULIN IN TYPE I DM (CONTD)

Insulin Therapy

Doses:

0.5 units/kg = total daily dose

4x/day 40% NPH @ hs and 60% rapid acting analogue ac meals

30/70 Dose Calculation:Weight = 80 kg80 kg x 0.3 U/kg = 24 U2/3 in the AM = 16 Units1/3 at supper = 8 Units

ROLE OF INSULIN IN TYPE I DM (CONTD)

Dosage Changes:

Corresponds to most abnormal Blood Glucose value (pre-meal)

If all values are abnormal - start with fasting glycemia followed by lunch, supper and bedtime

Change the dose by increments of 1-4 U

No change of dose more than twice/week

Monitor for PATTERNS in hypoglycemia

Harrisons principle of internal Medicine, 17 th edition , Chapter 332, Endocrinology and metabolism; Diabetes mellitus: Tata McGraw Hill publication pg. 1324-386

ROLE OF INSULIN IN TYPE II DM

In type 2 diabetes mellitus, oral hypoglycemic agents & analogues of glucagon-like peptide-1 provide adequate glycemic control early in the disease

Insulin therapy becomes necessary for those with advanced disease

Some experts recommend electively starting insulin therapy in early diabetes

A common way to start is to add a once-daily dose of a long-acting insulin at bedtime (basal insulin) to patient’s antidiabetic regimen

ROLE OF INSULIN IN TYPE II DM (CONTD)

If Basal regimens do not control postprandial hyperglycemia then,

Long-acting (basal) insulin along with a rapid-acting (prandial or bolus) insulin before meals are given

In advanced stages of type II DM, Bolus insulin regimens of Lisipro, Aspart, Glulisine insulin are preferred

Premixed insulin preparations are not recommended

Most commonly NPH, Glargine, Detemir insulin preparations are usedMarwan Hamaty et al; Insulin treatment for type 2 diabetes: When to start, which to use; Cleveland clinical journal of medicien; 2011;78;5;pg 332-42

INSULIN DELIVERY SYSTEM

Standard Delivery Subcutaneous injection using conventional disposable

needles & syringes

Advantages:Maximal ability to “freemix” & adjust to patient need

Disadvantage:Multiple injections, need to carry inj. & bottlesVariable absorptionDifficult to distinguish between lisipro & glargine

( both being clear)

INSULIN DELIVERY SYSTEM

INSULIN DELIVERY SYSTEM

Portable Pen Injectors Developed to facilitate multiple subcutaneous

inactions of insulin

Contain cartridges of insulin & replaceable needle

Available for : Regular insulin

Insulin lisipro

Insulin aspart

Insulin glulisine

Insulin glargine

Insulin detemir

INSULIN DELIVERY SYSTEM

Portable Pen Injectors Well accepted by pts. As eliminates need to carry

syringes & needles

Advantages:Convinient, Less to carryEasy to distinguish (d/t different color of pens) Improves dosing accuracy

Disadvantages:Approximately 30% more costly per 1000 U

bottle of insulin Jennings AM, Lewis KS, Murdoch S, Talbot JF, Bradley C, Ward JD. Randomized trial comparing continuous subcutaneous insulin infusion and conventional insulin therapy in type II diabetic patients poorly controlled with sulfonylureas. Diabetes Care.1991;14:738-744

INSULIN DELIVERY SYSTEM

Insulin Pumps

AKA Contineous Subcutaneous Insulin Infusion Devices (CSII)

External open loop pumps for insulin delivery

Contains programmable pump → delivers individualized basal & bolus insulin replacement doses based on blood glucose level

INSULIN DELIVERY SYSTEM

Insulin Pumps Reminders to :

Test blood glucose after a bolusWarn when bolus delivery is not completedTest blood glucose following a low or high BGGive boluses at certain times of dayChange infusion site

Direct BG entry from meterEliminates errors in data transfer

G. Scheiner, R. J. Sobel, D. E. Smith, et al., “Insulin pump therapy guidelines for successful outcomes,” Diabetes Educator, vol. 35, supplement 2, pp. 29S–41S, 2009.

INSULIN DELIVERY SYSTEM

Insulin Pumps Advantages:

Fewer injections

Physiologic delivery with best glycemic control & fewest hypoglycemic events

Eliminates variable injection site absorption

Disadvantages:

Expensive

Additional training needed

Pt. must be aware of technical problems

INSULIN DELIVERY SYSTEM

INSULIN DELIVERY SYSTEM

Inhaled Insulins Marketed earlier , withdrawn later d/t deposition

in pharynx causing pharyngitis & pulmonary fibrosis

Two preparations approved by FDA earlier:EXUBERAAFREZZA

Both work like ultra short acting insulin Inhaled at meal time to control rapid rise of blood

glucose level Risk of hypoglycemia & weight gain

Justin Gillis (January 28, 2006). “Inhaled form of insulin is approved:.The Washington Post. Retrieved 2007-10-21

INSULIN REGIMENS

Intensive Insulin Therapy Described to most of pts. with type I DM

Total insulin requirement (U) = weight in pouds/4

= 0.55 * weight in Kg

Meals, Snacks & high blood sugar corrections are prescribed by formulas

Pt calculates amount of carbohydrate in meal/snacks, current plasma glucose & target glucose

Diurnal variations in insulin sensitivity accomodated by prescribing different basal rates & bolus insulin doses throught day

INSULIN REGIMENS

Conventional Insulin Therapy Prescribed only to some people with type II DM

Sliding Scale Regimen:

Regimen ranges from one injection per day to many injections per day

Regimen mainly based on intermediate/long acting insulin

Based on plasma glucose level before injection, short or rapid acting insulin can also be used

Action to control cardiovascular risks in diabetes study groups: Effects of intensive glucose lowering therapy in diabetes . N Engl J Med 2008;358;2545

INSULIN TREATMENT OF SPECIAL CIRCUMSTANCES

Emergency treatment of diabetic ketoacidosis (Diabetic Coma)

Seen in type I DM pts

Treated by Bolus dose of 0.1 U/kg I.V. short acting regular insulin f/b 0.1 U/kg/hr I.V. till glucose level falls to 300 mg/dl till pt regains consiousness

Fluid & Electrolyte management

INSULIN TREATMENT OF SPECIAL CIRCUMSTANCES

Treatment of Non ketotic hyperglycemic (hyperosmolar) ComaSeen in type II DM pts

Treated same as of Diabetic Coma with more aggressive Fluid & Electrolyte management