Tutorial for MBBS: Insulin

Pharmacotherapy of  Diabetes Mellitus Insulin 15 June 2010

THE ENDOCRIN ENDOCRINE E PANCREAS PANCREAS 1 million islets of Langerhans 4 hormone-producing cells

Cell type

Hormone

Function

Alpha [A] cells

Glucagon

Hyperglycemic factor  

Beta [B] Cells

Insulin, Pro insulin, Amylin

Anabol Anabolic ic hormone hormone

Delta[D] Cells

Somatostatin

Universal inhibitor of   secretion

G Cells

Gastrin

Stim.Gastric secretion

F cell[PP cell]

Panc.Polypeptide

Digestion

Whatt is DM? Wha

Diab Diabetes etes mellitus Eleva Elevated blood glucose Associa Associated with with absent absent or ina inadequ dequa ate pa pancre ncrea atic insulin secretion With ith or with without concurrent impa impairment of  insulin action.

Expert Committee, 2003

Type 4

Type 3

Diab Diabetes etes mellitus -TYPES TYPE 1 

IDDM



Loss of  beta cells  deficiency of insulin

³Juvenile diabetes´ majority cases in children.

TYPE 2

 NIDDM 

Due to insulin resista resistance



[or reduced insulin sensitivity]



Comb ombined with with reduced insulin secretion

 TYPE 3 

Drug induced or other causes

 TYPE 4 

Gestational diabetes mellitus

INSULIN

Proinsulin

Two peptide pept ide chains A & B of  21 and 30 amino acids linked by disulfide bridges

Insulin Biosynth Biosynthesis [110AA] Preproinsulin (in RER)  [110-24AA] Proinsulin (Golgi Apparatus)  [51AA] Insulin + C Peptide[-35AA] Peptide[-35AA]  Stored in granules of  F cells Basal ra rate: 1U/h, o during meals

Control:Insulin Relea Release 



Neur eura al

Glucose

Adrenergic-a2

Incretins

 Adrenergic-b2

 Counter  regulatory

Chemic Ch emica al

Hormona Hormon al

GH Corticosteroids, Thyroxine Glucagon  Somatostatin 

Muscarinic [Vagal]



Insulin release from the pancreatic Beta cell by Glucose

First

phase- Within 2 minutes minutes Delayed phase

Role of ATP sensitive K + channels (K ATP) Hyperglycemia Hyperglycemia



o Intracellular ATP  Blockade of K ATP 

q Outflow of K +  Depola Depolariz rizati ation on of  cells cells  Ca2+ influx  Insulin Relea Release

Degra Degr adation of Insulin 

Endogenous:  ± Liver  ±  ± 60%, Kidney: 35-40%



Exogenous:  ± Liver  ±   ±  40%, Kidney- 60%



Plasma half-life: 5-6 min.

Insulin receptor  2 covalently linked heterodimers

The binding of an insulin molecule Mutual phosphorylation of tyrosin recidues

Activated Tyrosin kinases phosphorylates down stream proteins Further phosphorylates [IRS]

Insulin receptor  substrate

Translocation of of glucose transporters (especially GLUT 4) to the cell membrane with w ith increase in glucose uptake; Increased glycogen synthase activity and increased glycogen formation; Multiple effects on protein synthesis, lipolysis, and lipogenesis; and Activation of transcription factors that enhance DNA synthesis synthesis and cell growth and division.

Insulin receptors 

Glucocorticoids lower the affinity of  insulin receptors for insulin;



Growth hormone in excess increases this affinity slightly.



Aberrant serine and threonine phosphorylation of the insulin receptor subunits or IRS molecules may result in insulin resistance

Glucose transporters [GLUT]

Gluconeogenesis IN LIVER

Absorption

Glycogenolysis Insulin

[-] [-]

Processes add glucose [Hyperglycemia]

Blood

Processes utilize glucose [Hypoglycemia]

[+] Insulin [+]

Protein Synth. Synth. In Muscles

Peripheral utilization Lipogenesis

Endocrine effects of Insulin

Endocrine effects of Insulin«.

Endocrine effects of Insulin«.

Over view of Insulin action

Source and insulin prepera preperations Species

A Chain Chain

B Chain Chain

8th AA

10th AA

30th AA

Huma Human

THR

ILEU

THR  

Pork

THR

ILEU

ALA

B eef

ALA

VAL

ALA

Ana An alogs 1. 

Highly High ly pu puri rifi fied ed po pork rk Insulins Monocomponent Monocompone nt insulins

2. Human in ins sulin ins s  Recombninant DNA Technology[E.Coli, Yeast] 3. Insulin analogues Changing or replacing AA sequences 1. Lispro 2. Aspart 3. Glulisine 4. Gla larg rgin ine e 5. Det etem emir  ir 

Conventional prep. Conventional Impurities Antigenic Less expensive Replaced by 1. Hi High ghly ly pu puri rifi fied ed po pork rk Insulins 2. Human insulins 3. In Ins sul ulin in ana nalo logu gues es

Genetic engineering to produce human insulin

Insulin prepa preparations 

R apid acting insulins:  ± 



 ± 

Insulin aspart

 ± 

Insulin glulisine

Analogues

*Short acting insulins:  ± 



Insulin lispro

Regular insulin

*Intermedi Intermedia ate acting insulins:  ± Lente

insulin[Insulin Zinc suspension

 ± NPH

insulin [Isophane Insul nsulin in sus sus ensi ension on

*LongLong-a acting insulins:  ± 

Ultral Ultralent entee insuli insulin n

 ± 

Protamine Protamine Zinc Insulin Insulin (PZI) (PZI)

 ± 

Insulin Glargine

 ± 

Analogues

Insulin detemir 

*Premixed insulins:  ± 70%  NPH  ± 

+ 30% Regular 

50%  NPH + 50% Regular 

 ± 75%  NPH

+ 25% Lispro

*Anima *Anim al or hum uma an

Insulin prepa preparations R apid acting 

More ph physiologic pra prandia ndial insulin repla replacement - their rapid onset and ea early pea peak  k a ction - closely closely mim mimic ic norma normal action endogenous pra prandia ndial insulin secretion tha than n does regula regular insulin,



Can be ta Can taken immedia immediately before th the mea meal with without sacrificing glucose control.



Their dura duration of a of action is ra rarely more tha than n 4±5 hours, which ich decre decrea ases th the risk of la late postmea postmeal hypoglycemia ypoglycemia.



Lowest va vari riab ility of ab of absorption sorption [Monomers] ability



Preferred insulins insulins for use in continuous sub subcut cuta aneous insulin infusion [CSII] devices.

Insulin prepa preparations R apid acting

Lispro

Insulin prepa preparations R apid acting

Aspart

Insulin prepa preparations R apid acting

Glulysine

Insulin prepa preparations Short acting 

Recomb Recom bin ina ant DNA tech techniques, purified porcine



Effect appe ppea ars with within 30 min minut utes es - pe pea aks between 2 and 3 hours after s.c in jection  jection -la -lasts 5±8 hours.



Pra Pr andi ndia al hyperglycemi yperglycemia a and risk of la late hypoglycemi ypoglycemia a meals] [30-45 mts before mea



Only prepera preperation for i.v.use.

Insulin prepa preparations Intermedia Intermediate acting Lente insulin[Insulin Zinc suspension] NPH insulin [Isop Isopha hane ne Insulin suspension]

 ± Onset-1-2 Onset-1-2

h

Peak-6-12h  ± Peak ± Duration-1 Duration-18-24

Dose  ± Dose

related action profile

 ±Long

acting analogs are preferred

Long actingInsulin prepa prep arations  ± Onset-1-2 Onset-1-2

Peak  ± Peak

Detemir 

h

less

 ± Duration-1 Duration-18-24 THRThriiii

Glargine

THR

Myristic acid

Type

Appearance

Onset

Peak

Duration

R apid/S pid/Sh hort

Regular soluble

C le a r

0.5 ± 0. 0.7

1.5 ± 4

5 ± 8

Lispro

Cle a r

0.25

0.5 ± 1.5

2 ± 5

Aspart

C le a r

0.25

0.6± 0. 0.8

3 ± 5

Glulisine

C le a r

---

0.5 ± 1.5

1 ± 2.5 2.5

12 6± 12

18 ± 24 24

12 6± 12

18 ± 24 24

1 ± 2

Intermedia Intermedi ate  NPH

(isophane)

Lente

Cloudy

1 ± 2

Cloudy

Long

Ultralente

Cloudy

4 ±6

16± 18

20 ± 36

Protamine zinc

Cle a r

4 ±6

14 ± 20

24 ± 36

Glargine

Cle a r

2 ± 5

5 ± 24 24

18 ± 24 24

Detemir

C le a r

1 ± 2

4 ± 14 14

24 6± 24

Adverse Effects of Insulin: Hypoglycemia Hypoglycemi a 

Results from:  ± 

Delay in taking a meal

 ± 

Inadequate carbohydrate intake

 ± 

Unusual physical exertion

 ± 

Too large insulin doses

Symptoms 

Autonomic hypera yperactivity  ±   Sympathetic 

Tachycardia, palpitations, sweating, tremulousness

 ±   Parasympathetic:  Nausea, hunger 

 ± 

Convulsions / Coma

Adverse Effects of Insulin: Hypoglycemia Hypoglycemi a  ypoglycemia  H  

unawareness

Treatment:  ±  Glucose administration: administration: 



Fruit juice / Glucose gel / Sugar containing  beverage/food to eat at first sign If severe: 50% dextrose i.v. Carry identity card 

Adverse Effects of Insulin Insulin Allergy:  Noninsulin  Less  ?

protein contaminants

with purified insulin preparations

Anaphylaxis

Insulin Resista Resistance Requirement of > 200U/d 2 00U/da [Requirement ay] 





Acute:  ± 

Causes: Causes: Infections, tra trauma uma, surgery, stress (in stress corticosteroids oppose insulin action)

 ± 

Trea Tre ated by regula regular insulin

Chronic: Ch ronic:  ± 

Common in type II

 ± 

Cause: Cause: Antib Antibodies to conta contamina minating proteins wh which ich also bind insulin

 ± 

Trea Tre atmen tmentt- change hange to huma uman insulin

Reversib Reversi ble  ± 

Pregna Pregnancy

Adverse Effects of Insulin Insulin Lipodystroph Lipodystrophy 

Older insulin preparations  Repeated injections at the same site  Atrophy / Hypertrophy of subcutaneous fat



Atrophy not seen with newer human human insulin preparations, prepara tions, hypertrophy still a problem Injection of newer insulin into atrophic area  Restoration of normal contours

 ?



Sites of injection: Abdomen best,  K eep eep changing 

Insulin Edema Edema  Na+

retention, Weight gain

Unita Unit age of Insulin 

1 U = Amount required to reduce blood glucose by 45 mg% in a fasting rabbit



1mg=28units

Insulin Delivery Systems 

Disposab Disposable le needles and syringes: 27 G



Portab Portable le Pen In jectors  jectors



Jet in jectors  jectors



Continuous Sub Subcut cuta aneous Insulin Infusion: CSII  ±  M ost ost

physiologic insulin replacement 

 ±   Insulin

reservoir/ Program chip/  K eypad/ eypad/ Display screen

 ±   Excellent



Inha Inhaled led Insulin  ±  Absor bed  ±   Rapid  ± 



glycemic control eg, pregnancy through alveolar walls

onset of action / Short duration

? Pulmonary fi brosis/Pulmonary hypertension

Ora Or al insulin: Liposome enca encapsula psulated

Clinic linica al Uses of Insulin 

Type 1 diab diabetes etes mellitus



Type 2 diab diabetes etes mellitusmellitus-

 Not

controlled by ora oral agents

omplications:  Complica  To

Diab Diabetic etic ketoa ketoacidosis, Ga Gangrene,

tide over: Infection, Tra Trauma uma

Pregnancy  Pregna

Gestationa tional di diabetes abetes not controlled by [Gesta

diet alone] 

Emergency treatment of hyperkalemia: hyperkalemia: Insulin + glucose

Indica Indic ations of Huma Human Insulin 1. Insulin resistance 2. Allergy to to co conventional prepa preparations 3. In jection  jection site lipodystroph lipodystrophy 4. Short term term useuse- surgery surgery,, tr trauma uma 5. During pregnancy

Insulin regimens 

Intensive Insulin therapy-Based on formulaeCSII



Conve Conventio ntional nal-- For type 2



Spl circumstances



Principle:



Supply postprandial needs



Provide basal control

Glargine + 3 Analogs

2Long acting+2 Rapid or Short acting

CSII

Diab Di abetic etic Ketoa Ketoacidocis Diab abetic etic coma coma] [Di 

Precipitated by Precipita infection, tra traum uma a, stress in insulin dependent pa patients



Serious



Hypotension, sh shock, tachyc yca ardi rdia a, deh de hydr ydra ation, hyperventil yperventila ation, vomiting, coma coma

Treatment: 1. Regular insulin-I.V. 2. Bol olu us fol follo lowe wed d by infusion 3. i.v fluids. 4. Kcl ??? 5. NaHco3 6. Phosphate 7. Antibiotics

Drug intera interactions 

Beta blockers-



Inhibit comp mechanisms



Warning signs of hypoglycemia are masked



Thiazides, Furosemide, Corticosteroids, OCPs, reduce the effect of insulin



Salicylates, Li, increase insulin secretion

Insulin Delivery Systems

Disposable needles and syringes: 27 G

Portable Pen Injectors

Insulin Delivery Systems

 A device that uses high pressure instead of a needle to propel insulin through the skin and into the body.

Inhaled Insulin

Insulin Delivery Systems

Continuous Subcutaneous Insulin Infusion: CSII

Insulin Delivery Systems - Conti tinu nuo ous glucose sensor  monitors blood sugar  level 2 - Da Data ta tr tran ansm smit itte ted d for the computer  program to work out insulin dose 3 - In Ins sul uliin pum pump p delivers the dose 1

µArtificial

pancreas¶ Sensor activated pump