Diabetes is a group of Metabolic Disorders
characterized by Hyperglycemia resulting from defects
in insulin secretion, insulin action, or both.
-Diabetes Care Volume 37, Supplement 1, January 2014, S81
Etiological Classification of DM
Type 1 Diabetes
Immune mediated β cell destruction,
Type 2 Diabetes
Genetic defect of β cell function
Genetic defect in insulin processing Defect in proinsulin conversion, insulinor action
gene & receptor mutation etc.
Exocrine pancreatic defect
Glucagonoma, hyperthyroidism, cushing
CMV, Coxsackie B etc.
Steroids, thyroxin, β adrenergic etc.
Pancreatitis, cystic fibrosis etc.
Down, turner etc.
Gestational Diabetes Mellitus
Diabetic care 25, 2003
Susceptibility of type1 DM is inherited.
Mode of inheritance is complex.
Concordance rate between identical twins is 30%.
MHC on chromosome 6
INS gene on chr 11
other loci on chr 9
HLA – DQ & DR are most important determinant.
HLA – DQB1*0602 allele significantly reduces the risk of type1
INS VNTR also increases the risk.
Routine assessment of genetic markers is not recommended for
Δx and Mx.
• Viruses such as rubella, mumps and coxsackie B have been
• Autoimmunity to β cell is initiated by viral proteins.
• Genetic susceptibility determines the progression of β cell
• Type1 DM results from cell mediated autoimmune destruction
of pancreatic β cell.
• 80-90% destruction of β cell is required to induce
• Marker of β cell autoimmunity are circulating antibodies.
• They are present in the serum years before the onset of
Islet cell cytoplasmic antibodies (ICAs):
Against sialoglycoconjugate antigen present in the cytoplasm of all
endocrine cells of the pancreatic islets.
Detectable in 75-80% of newly diagnosed DM type1 and 0.5% of
Insulin autoantibody: detectable in
>90% of type1 DM developing before age 5.
<40% of type1 DM developing after age 12.
0.5 % of normal subjects.
Antibodies to glutamic acid decarboxylase 65KDa isoform:
60% of newly diagnosed type1 DM.
May be used to identify patients with apparent type2 DM who will
subsequently progress to type1.
• Insulinoma associated antigen (IA-2A & IA-2βA):
- Directed against tyrosin phosphatases
- Detected in >50% of newly diagnosed type1 DM.
• Zinc transporter (ZnT8):
- It is recently identified major autoantigen in type1 DM
- 60-80% of type1DM, <3% of type2 DM and <2% of controls.
Role of antibodies in Mx of Diabetes
Initial fasting hyperglycemia
Presence of multiple
85-90% of type1
5-10% of type2
1-2% of healthy subjects
have single autoantibody
Known as latent
autoimmune diabetes of
No acceptable T/t available to prevent the clinical onset of diabetes
in autoantibody +ve individuals.
Immunosuppresant therapy under development to prevent auotoimmunity
Pathogenesis of type2 DM
β cell function
• Susceptibility of type2 DM is inherited.
• Mode of inheritance is complex.
• Concordance rate between identical twins
• Multigenic trait.
insulin receptor gene
• Mutation in
GLUT 4 genes
glycogen synthase gene
wide association studies – 17 genetic loci for type2
• Most of them are related to insulin secretion pathway and not the
• Despite the well known fact that type 2 DM has strong genetic
association, only 5% of patients can be pinpointed with a genetic
defect with available information on gene association studies.
genes causing common forms of type2 DM are still
• Diet : high fat diet, excessive intake of free sugars
• Exercise : Sedentary life style increases the risk of
In a age, gender, BMI and family history matched study it
is observed that for every 500 Kcal increase in energy
expenditure there is 6% decrease in risk of type 2 DM.
• BMI :
Relative risk of developing
Insulin resistance is decreased biological response to normal
concentration of Insulin.
It is present in type2 DM and virtually all obese individuals.
Factors causing insulin resistance
Primary defect in insulin signaling
Insulin receptor mutations
Ataxia telangectasia syndrome
Secondary to other endocrine disorders
Secondary to other disorders
Stress (infection, surgery, etc)
Cytogenetic disorders (Down,Turner,
Secondary to normal physiologic states
Secondary to medications
• The insulin resistance syndrome (aka Syndrome X or
metabolic syndrome) is a constellation of clinical and lab
findings including hyperinsulinemia, insulin resistance,
dyslipidemia, obesity and hypertension.
• WHO criteria for diagnosis of metabolic syndrome isAny one of the following
Any two of the following
Blood pressure: ≥ 140/90
Impaired fasting glucose
TG >150 and HDL <35 M & < 40F
Impaired glucose tolerance
WHR >0.9 M & >0.85 F or BMI >30
urinary albumin excretion ≥ 20 µg/min
or albumin : creatinine ratio ≥ 30 mg/g
Normal or increased
No (if +ve LADA)
Ketoacidosis is common
Hyperosmolar state common
30% concordance in twins
Severe insulin deficiency
Islet cell histology
↓ blood insulin levels
Onset < 20 year
Normal or underweight
Relative insulin deficiency
Marked atrophy and
Focal atrophy with amyloidosis
Severe beta cell depletion
Mild beta cell depletion
Effect of insulin on metabolism
• Carbohydrate metabolism:
- ↑ glucose uptake in muscle and adipose tissues
- In liver : ↑ glycogenesis ↓ glycogenolysis & gluconeogenesis
• Fat metabolism:
- ↓ TG degradation by inhibiting lipoprotein lipase
- ↑ TAG synthesis in adipose tissues.
• Protein metabolism:
- ↑ AA entry into the cells
- ↑ protein synthesis by activating translational factors
Plasma fatty acid
Plasma amino acid
No insulin released
Hypovolemia & Hypotension
Diagnostic criteria for DM
Any one of the following is diagnostic
1. Fasting plasma glucose ≥126 mg% or
2. Symptoms of hyperglycemia and
casual plasma glucose ≥200mg%
3. During an OGTT 2 hour plasma glucose ≥ 200mg%
Point of care assay should not be used for diagnosis.
Pre clinical screening of DM
Screening is not recommended other than clinical studies.
Islet cell autoantibody detection may be useful in- (1) identifying
LADA (2) to screen non diabetic family member who wish to donate
kidney or part of pancreas fir transplantation (3) screening of women
with GDM to identify those at high risk of progression to type1 DM
(4) distinguishing type1 from type2 in children to institute insulin at
the time of diagnosis.
HLA typing is not recommended.
Glucose induced insulin secretion test is also not recommended for
routine clinical use.
Type 2 DM
All asymptomatic individuals over 45 years of age
Overweight children with any of the two following risk factors- (i)
type2 DM in of 1st or 2nd degree relative (ii) high risk race/ethnic group
(iii) have conditions associated with insulin resistance (iv) maternal
history of GDM……. Testing should be done every 3 years starting at
the age of 10.
Screening can be done using fasting glucose, 2 hour OGTT or HbA1c.
Monitoring of blood glucose
(1) patient under intense insulin therapy- 4-5 times a day.
(2) prevention and detection of hypoglycemia, especially in those who are
not able to recognize the early warning signs.
(3) avoidance of severe hyperglycemia especially when having medication
that alter insulin secretion and action
(4) adjusting the dose in response to life style modification, exercise, food
(5) determination of necessity for initiating insulin therapy in GDM
Should not be used for diagnosis.
Minimally invasive monitoring of blood glucose:
• Implanted sensors:
- CGMS- needle type of sensor, monitors glucose 1 to 5
minute from interstitial tissue fluid.
- Glucoday- microdialysis, every second
• Gluco watch biographer:
- Low level electric current moves glucose across the skin by
electroosmosis where measured by GOD
Noninvasive glucose monitoring
• Glucose has specific absorption at 1035nm
- Near infrared spectroscopy
- Raman scattering spectroscopy
- Photoacoustic spectroscopy
• All under active investigation and considerable success
has been achieved but none is FDA approved for clinical
Monitoring long term glucose control
Gives an idea of glucose control over past 3 months
Goal is to keep it below 7%.
Should be repeated every 6 months in patients meeting the treatment
Estimated average glucose mg% = 28.7*HbA1c – 46.7
Altered life span of RBCs affect the result significantly.
Proteins (other than Hb) with nonenzymatic attachment of glucose are
known as fructosamine.
Reflect glucose control over past 2-3 weeks.
Should not be done in patients with hypoalbuminemia.