biological Insulin, synthesis, factors affecting synthesis, primary structure of insulin, different insulin preparations, mechanism of action of Insulin and pathway, physiological & biochemical effect of Insulin, Disorders related with insulin production, treatment strategy, Drugs Used to treat Diabetes Mellitus

1. Presenter: Dr Anurag Yadav
Dept Of Biochemistry, FMMC

2. Insulin
• Is a polypeptide hormone produce by β-cells
of langerhans of pancreas.
• It has profound influence on metabolism of
Carbohydrates, fat & proteins.
• It is considered as the anabolic hormone.
Dept Of Biochemistry, FMMC

3. • It was the first hormone to be isolated,
purified & synthesized.
• First hormone to be sequenced
• First hormone to be produced by recombinant
DNA technology.
Dept Of Biochemistry, FMMC

4. Structure
• Human Insulin contain 51 aminoacids,
arranged in TWO Polypeptide chains.
• Chain A = 21 AA
• Chain B = 30 AA
• Two Interchain Disulfide bridge = A7-B7 &
A20-B19.
• Intrachain Disulfide link in chain A = 6-11.
Dept Of Biochemistry, FMMC

5. Dept Of Biochemistry, FMMC

6. Synthesis
• Gene for protein synthesis
is located on Chr 11
• Produced from β-cell of
Langerhans of pancreas.
• Synthesis involve two
precursors
– Preproinsulin = 108AA
– Proinsulin = 86 AA
Dept Of Biochemistry, FMMC

7. • These are sequentially degraded to form the
active hormone Insulin and Connecting
peptide (C-Peptide)
• C-peptide has no biological activity, however
its estimation in plasma serves as the useful
index for endogenous production of insulin.
• In β-cells, Insulin combines with Zinc to form
a complex & stored in granules.
Dept Of Biochemistry, FMMC

8. Regulation of Insulin secretion
• About 40-50Units secreted daily by Human
pancreas.
• Normal value is = 20-30μU/mL
Dept Of Biochemistry, FMMC

9. Factors increasing the secretion
– Stimulating the
secretion
• Glucose
• Aminoacids
• GI Hormone (secretin,
gastrin, pancreozymin)
• Parasympatheic
stimulation
• Incretin hormone
– Inhibiting secretion
• Epinephrine
• Alp-ha adrenergic
stimulaion
Dept Of Biochemistry, FMMC

10. Mechanism of action of Insulin
Insulin receptor
mediated signal
transduction
Insulin
receptor
Signal
transduction
Insulin mediated
glucose
transport
Insulin mediated
enzyme
synthesis
Dept Of Biochemistry, FMMC

11. Mechanism of action
• The insulin signaling pathway provide an
excellent example for
Recognition
Hormone release
Signal generation
Effects
Surface receptor
and Tyrosine
kinase mediated
Dept Of Biochemistry, FMMC

12. Dept Of Biochemistry, FMMC

13. • Glucokinase
• Pyruvate kinase
• phosphofructokinase
• Acetyl CoA carboxylase
Insulin
induces
•Glyucose-6-P
•Phosphoenolpyruvate carboxykinase
•Fructose-6-P
Insulin
represses Dept Of Biochemistry, FMMC

14. Degradation of Insulin
• Half life is 4-5mins.
• A protease enzyme, namely insulinase
degrades Insulin (mainly found in liver and
kidney)
Dept Of Biochemistry, FMMC

15. Metabolism effects of insulin
Uptake
of
glucose
by
tissues
Glycoly
sis of
glucose
Hypogly
cemic
effect
Lipogen
esis
Anti-
lipotic
effect
Anti-
ketogeni
c effect
Dept Of Biochemistry, FMMC

16. Metabolism effects of insulin
• Glucose uptake by
tissues.
• Increase Glycolysis
(utilization).
• Decrease
gluconeogenesis.
Carbohydrate
Metabolism
• Favours synthesis of
TAG.
• Decrease lipolysis
(hormone sensitive
lipase)
• Reduce ketogenesis
(HMG CoA
synthetase).
• Increase utilization
of acetyl CoA in
Krebs Cycle.
Lipid
Metabolism
• Enhance protein
synthesis.
• Anabolic hormone
Protein
metabolism
Dept Of Biochemistry, FMMC

17. Disorders
• Diabetes mellitus
– Type I DM
– Type II DM
– Type 1.5 DM
Dept Of Biochemistry, FMMC

18. Resistance
• Insulin resistance (IR) is a pathological
condition in which cells fail to respond
normally to the hormone insulin.
• Measuring insulin resistance
– Hyperinsulinemic euglycemic clamp (Gold std)
– Modified insulin suppression test
– HOMA (homeostatic model assessment), QUICKI
(quantitative insulin sensitivity check index)
Dept Of Biochemistry, FMMC

19. Utility of test in assessing the Deficiency status
• Analysis for the Diagnosis & Monitoring of the
Diabetes status
– Blood Glucose (Fasting & PPBS)
– OGTC (Oral Glucose tolerance test)
– Glycated Hb (HbA1c)
– Urine Glucose
– Sr- Insulin, C-Peptide.
Dept Of Biochemistry, FMMC

20. Approaches to preventing Diabetes
Physical
activity
Life style
changes
Mental stress
handling
Hypoglycemic
Drugs/insulin
Dept Of Biochemistry, FMMC

21. Sulfonylureas
Glibenclami
de
Glipizide
Gliclazide
Glimepiride
Biguanides
Metformin
Phenylalanine
analogues
repaglinide,
Nateglinide
s
Thiazolidinedio
nes
Rosiglitazon
e
Pioglitazone
Insulin
Lispro/aspar
t (rapid
acting)
Regular
Dept Of Biochemistry, FMMC

22. Dept Of Biochemistry, FMMC

23. Dept Of Biochemistry, FMMC

24. • Reference
– Vasudevan-Textbook of Biochemistry
– Harper’s-Illustrated Biochemistry
– Gyton-Human Physiology
– Internet sources
Dept Of Biochemistry, FMMC