This document provides an overview of diabetes mellitus, including its definition, types, historical perspective, diagnosis, incidence and prevalence, anatomy and physiology, regulation of insulin and glucagon secretion, and blood glucose homeostasis. It discusses the key events in the discovery of insulin and its role in treating diabetes. The document also compares the phenotypes and genotypes of type 1 and type 2 diabetes and outlines the process of insulin secretion from beta cells in response to increased blood glucose levels.

1. DIABETES MELLITUS
BRIG (DR) AB KHARE (RETD)
ASSO. PROF (MED)

2. Diabetes Mellitus
Definition clinical syndrome characterised by increased plasma glucose.
• Mainly type 1 & type 2
1.Type 1--- autoimmune destruction of beta cells 2.Type 2 --- reduced sensitivity to insulin &
inability to increase production 3. MODY 4. gestational 5. neonatal diabetes 6. secondary diabetes
e.g . Endocrinopathies, steroid use etc
Problems
• Acute -- metabolic decompensation
• Chronic -- microvascular

3. Historical perspective

4. History of Diabetes
Wasting body , extreme thirst & frequent urination : 1922 first patient given
insulin
Glucosuria : black ants & flies attracted to urine ( ancient Hindu writings). 400
B.C., Sushruta ; sweet taste of urine ; key to Dx for centuries
250 B.C., term ‘diabetes’; Greek word ‘to syphon’. Areatus ; ‘liquefaction of flesh
& bones’
1674 : Diabetes Mellitus coined by Thomas Willis personal physician to King
Charles II : urine “ as if imbued with honey & sugar”

5. History of diabetes contd…
• Mid- 1800s treatment varied ; “fad” diet, opium, bleeding. ‘starvation diet’
added few years to life
• 1889 German Joseph von Mering & Oskar Minkowaski removed pancreas from
dogs  diabetes . A link established. Focus: pancreatic extract could treat !?
• Dr. Fredrick Banting, a surgeon in May 1921 in the lab of Professor John Mcloed
in Toronto, Canada with medical student Charles Best as his assistant. Tied
pancreatic duct- in July 1921 after several weeks extract given to a dog with
surgically removed pancreas. In the 2 hrs that followed blood sugar ↓&
condition improved.
• Dr. J. Collip ,a biochemist, drafted to purify extract & later Best carried this work.

6. Contd…
• A Young boy Leonard Thompson – first patient to receive insulin on Jan 11 ,
1922, aged 14 weighing 64 pounds was extremely ill. Lived for another 13 years
died due to pneumonia at the age 27 years.
• Over next 60 years : refined, purified, long acting & intermediate types
developed to provide flexibility
• Revolution : recombinant human DNA insulin in1978
• In1923. Banting & Mcloed : Nobel prize . Banting split his prize with Best &
Mcloed with Collip
• A Young boy Leonard Thompson – first patient to receive insulin on Jan 11 , 1922,
aged 14 weighing 64 pounds was extremely ill. Lived for another 13 years died
due to pneumonia at the age 27 years.
• Over next 60 years : refined, purified, long acting & intermediate types developed
to provide flexibility
• Revolution : recombinant human DNA insulin in1978
• In1923. Banting & Mcloed : Nobel prize . Banting split his prize with Best &
Mcloed with Collip
“Insulin is not a cure for diabetes; it is a treatment. It enables the diabetic to
burn sufficient carbohydrates, so that proteins and fats may be added to the diet
in sufficient quantities to provide energy for the economic burdens of life.”

7. Comparison of Type 1 and Type 2 Diabetes
PhenotypeOnset primarily in childhood and adolescence : Onset predominantly after
40 years of age*
Often thin or normal weight :Often obese
Prone to ketoacidosis : No ketoacidosis
Insulin administration required for survival : Insulin administration not required for
survival
Pancreas is damaged by an autoimmune attack : Pancreas is not damaged by an
autoimmune attack

8. Absolute insulin deficiency : Relative insulin deficiency and/or insulin resistance
Treatment: insulin injections : Treatment: (1) healthy diet and increased
exercise; (2) hypoglycemic tablets; (3) insulin injections
Genotype Increased prevalence in relatives : Increased prevalence in relatives
Identical twin studies: <50% concordance : Identical twin studies: usually above
70% concordance
HLA association: Yes : HLA association: No

9. Diabetes Mellitus
Diagnosis
• FBG ≥ 126 mg %
• After 2 hrs of glucose challenge ≥ 200 mg %
• HbA1C > 6.5%
IGT increased risk of macrovascular complications & developing dm later
Incidence World-- 415 million in 2015 & 642 million in 2040.
India --- 69.2 million in 2015 & 98 million in 2030 . 49%of world diabetics in 2017.
• Prevalence genetic factors & environmental like greater longevity , obesity
,unsatisfactory diet , sedentary life style , urbanisation , increased development.

10. Diabetes Mellitus
Anatomy &physiology
Regulation of insulin secretion
Insulin prime regulator of glucose
metabolism &
Storage .
Incretin effect

11. Diabetes Mellitus
• Insulin synthesized as
prohormone

12. DIABETES MELLITUS
INSULIN
SECRETION

13. Diabetes Mellitus
Regulation of glucagon
• Alpha cells 20% of islet cells
• Regulation –complex
• Insulin , GABA , Co-secreted Zn , somatostatin have role

14. Diabetes mellitus
Blood glucose homeostasis

15. Changes in key hormones after a meal. Changes in blood levels of glucose,
insulin, and glucagon after a carbohydrate-rich meal (ingested at time 0
minutes).

16. THE LIVER BUFFERS GLUCOSE LEVELS
• THE LIVER RECEIVES GLUCOSE-RICH BLOOD FROM THE DIGESTIVE TRACT VIA THE PORTAL VEIN.
• THE LIVER HAS A HIGH AMOUNT OF GLUT2 TRANSPORTERS THAT DO NOT NEED THE PRESENCE OF
INSULIN TO TRANSPORT GLUCOSE INTO THE LIVER CELLS. GLUT2 HAS A LOW AFFINITY FOR
GLUCOSE WHICH ENABLES A RAPID INFLUX OF GLUCOSE WHEN SUGAR LEVELS ARE HIGH.
THEREFORE, IN THE LIVER, LEVELS OF GLUCOSE INSIDE AND OUTSIDE THE CELL CAN BECOME
EQUAL (AN EQUILIBRIUM IS REACHED).
• THE FIRST STEP FOR TRAPPING GLUCOSE INSIDE THE CELL INVOLVES PHOSPHORYLATION TO
PRODUCE GLUCOSE-6-PHOSPHATE (G6P). THE LIVER DIFFERS FROM THE REST OF THE BODY IN
THAT IT USES THE ENZYME GLUCOKINASE, RATHER THAN HEXOKINASE. GLUCOKINASE CAN
PRODUCE G6P AT A FASTER RATE AND ALSO IS NOT INHIBITED BY ITS PRODUCT (THIS IS BECAUSE
IN THE LIVER, G6P CAN BE CHANNELED INTO MAKING GLYCOGEN).
• GLUCOSE AND INSULIN BOTH MODULATE METABOLIC ENZYMES IN SUCH A WAY THAT GLYCOGEN
FORMATION IS PROMOTED. THIS DRIVES FORWARD THE PROCESS OF BRINGING MORE GLUCOSE
INTO THE LIVER. INSULIN PROMOTES GLYCOGEN SYNTHESIS BY STIMULATING GLYCOGEN
SYNTHETASE AND INHIBITING GLYCOGEN PHOSPHORYLASE.

17. INSULIN SECRETION

19. THE INSULIN RECEPTOR IS A TYROSINE KINASE RECEPTOR AND IS COMPOSED OF A PAIR OF ALPHA
SUBUNITS AND A PAIR OF BETA SUBUNITS. INSULIN BINDS TO THE ALPHA SUBUNITS AND INDUCES A
CONFORMATIONAL CHANGE THAT IS TRANSMITTED TO THE BETA SUBUNITS THAT AUTO
PHOSPHORYLATE AND INITIATE A CASCADE OF PHOSPHORYLATION AND DEPHOSPHORYLATION
REACTIONS.

20. 1.Glucose is transported into the beta cell by type 2 glucose transporters (GLUT2). Once inside, the first
step in glucose metabolism is the phosphorylation of glucose to produce glucose-6-phosphate. This step is
catalyzed by glucokinase—it is the rate-limiting step in glycolysis, and it effectively traps glucose inside
the cell.
2.As glucose metabolism proceeds, ATP is produced in the mitochondria.
3.The increase in the ATP:ADP ratio closes ATP-gated potassium channels in the beta cell membrane.
Positively charged potassium ions (K+) are now prevented from leaving the beta cell.
4.The rise in positive charge inside the beta cell causes depolarization.
5.Voltage-gated calcium channels open, allowing calcium ions (Ca2+) to flood into the cell.
6.The increase in intracellular calcium concentration triggers the secretion of insulin via exocytosis.

21. • TO BE CONTD…..