DIABETES MELLITUS-1

Dr Chandrika D Nayak
Professor of Biochemistry
MMMC (Manipal Campus)

Dr Chandrika D Nayak, MMMC

OBJECTIVES
• Define diabetes mellitus (DM)
• Compare type 1 (T1DM) and type 2 (T2DM)
diabetes mellitus
• Biochemical basis for development of T1DM and
T2DM with emphasis on insulin resistance

Dr Chandrika D Nayak, MMMC

 Endocrine portion of
pancreas
Islets of Langerhans

Dr Chandrika D Nayak, MMMC

 INSULIN
• Is a peptide hormone *
• Is an anabolic hormone *
• Is the only hypoglycemic hormone*
• Contains 51 amino acids
• Has 2 chains: A: 21 amino acids & B: 30 amino acids
• Contains disulphide bridges
• Intrachain (A6 –A11)
• Interchain (A7 –B7 & A20- B19)
Dr Chandrika D Nayak, MMMC
Insulin structure

Dr Chandrika D Nayak, MMMC

 Regulation of insulin secretion

• Stimulus for insulin secretion

• Elevated blood glucose levels (β cells act as glucose sensors)*
• Elevated plasma amino acid levels especially arginine after a
protein rich meal
• GI hormones like GLP-1 and GIP (incretins) cause anticipatory rise
• Inhibition of insulin secretion
• Epinephrine released during stress, (vigorous exercise, hypoxia,
infections)
Dr Chandrika D Nayak, MMMC
 TYROSINE
MECHANSIM OF KINASE
ACTION OF 2nd
INSULIN messenger
system
Target cell

Tyr- P Tyr- P P

Insulin receptor Insulin receptor

substrate -1 (IRS-1) substrate -1 (IRS-1)

Cascade of protein phosphorylations & dephosphorylations

by kinases & phosphatases

Biological effects
Dr Chandrika D Nayak, MMMC
 Metabolic effects of insulin

• Glucose uptake by cells with GLUT-4 receptors

(skeletal & cardiac muscle, adipose tissue,
satiety centre of brain)
• On Carbohydrate metabolism
• On Lipid metabolism
• On Protein metabolism

Dr Chandrika D Nayak, MMMC

 Metabolic effects of INSULIN

+ Glycogenesis
- Glycogenolysis
+ Glycolysis
INSULIN
- Lipolysis
+ Fatty acid
synthesis
+ Protein synthesis
- Gluconeogenesis
+ Cholesterol synthesis
Dr Chandrika D Nayak, MMMC
 Diabetes mellitus (DM)

• Is a heterogenous group of multifactorial,

polygenic syndrome
• Is characterized by elevated fasting blood glucose
• Is caused by an absolute or relative deficiency of
insulin

Dr Chandrika D Nayak, MMMC

Diabetes mellitus is separated into 2 groups:

• Type 1 diabetes mellitus (T1D)

• Earlier was known as IDDM
• Usually onset is in childhood or puberty, but
symptoms develop rapidly
• Autoimmune destruction of -cells
• Plasma insulin levels low or absent
• < 10% of diagnosed diabetics
• Ketoacidosis- acute complication
• Treatment: insulin therapy, do not respond to oral
hypoglycemic drugs
Dr Chandrika D Nayak, MMMC
 CAUSE FOR T1D
• Genetic predisposition and a viral infection triggers
acutely
• Autoimmune attack on the  cells of the islets of
Langerhans
• Infiltration with activated T lymphocytes, leading to
insulitis
• Gradual depletion of  cells
• Symptoms appear abruptly on 80-90% loss of cells

Dr Chandrika D Nayak, MMMC

Type 2 diabetes mellitus (T2D)

• Earlier known as NIDDM

• > 90% of diagnosed diabetics
• Obesity is usually present
• Onset usually after 35 years of age & symptoms
develop gradually
• Plasma insulin levels: high in early stages and low to
absent in chronic stage

Dr Chandrika D Nayak, MMMC

• Insulin resistance combined with inability of
insulin production by -cells
• Hyperosmolar hyperglycemic coma is the
acute complication
• Treatment is usually by Diet, exercise & oral
hypoglycemic drugs and insulin
• Management of risk factors like weight
reduction, smoking cessation, blood pressure
control, treatment of dyslipidemia is essential

Dr Chandrika D Nayak, MMMC

 T2D
• Common in population
• Detected on routine screening tests
• Combination of insulin resistance & dysfunctional  cells
• Development of ketoacidosis is blunted by presence of insulin
though inadequate
• Strong genetic predisposition
• Most patients do not need insulin to sustain life
• Complication in elderly is hyperglycemia, dehydration ,
hyperosmolar coma
Dr Chandrika D Nayak, MMMC
• Insulin resistance
• Increases with weight gain & decreases with weight
loss
• Is decreased ability of target tissues to respond to the
normal levels of insulin
• In obese individuals is because
• Adipose tissue secretes proinflammatory cytokines
&  secretion of interleukin-6 (inflammation leads
to insulin resistance)
•  secretion of leptin (proinflammatory) and 
secretion of adinopectin (anti-inflammatory)
• Alone cannot lead to T2D
Dr Chandrika D Nayak, MMMC
• Insulin resistance
• Leads to hyperglycemia
•  hepatic glucose production by gluconeogenesis
•  glucose uptake by liver, muscle and adipose
tissue
• Leads to  plasma FFA
•  adipose tissue lipolysis
•  β oxidation of FFA (usually adinopectin increases
this, which is currently low levels here)

Dr Chandrika D Nayak, MMMC

1. Genetics
2. Obesity Insulin resistance
3. Sedentary
lifestyle
4. Ageing Hyperinsulinemia
5. 3-5% of
ladies who In combinaton with
had 1. Genetics
gestational
diabetes 2. Glucose toxicity
Decline of
3. Free fatty acid
-cell toxicity
function + 4. Proinflammatory
environment

T2D

Dr Chandrika D Nayak, MMMC