pathophysiology of diabetes and its complications. monitoring of diabetes, newer modalities for assessing blood glucose

1. Diabetes Mellitus
Dr. Prabhash Bhavsar

2. Blood Glucose Regulation

3. 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

4. Etiological Classification of DM
i
Type 1 Diabetes
Immune mediated β cell destruction,
idiopathic
ii
Type 2 Diabetes
Insulin resistance
iii
Genetic defect of β cell function
MODY
Genetic defect in insulin processing Defect in proinsulin conversion, insulinor action
gene & receptor mutation etc.
Exocrine pancreatic defect
Other endocrinopathies
Glucagonoma, hyperthyroidism, cushing
syndrome etc.
infections
CMV, Coxsackie B etc.
Drugs
Steroids, thyroxin, β adrenergic etc.
Genetic syndromes
iv
Pancreatitis, cystic fibrosis etc.
Down, turner etc.
Gestational Diabetes Mellitus
Diabetic care 25, 2003

5. Pathogenesis of type1 DM
Genetic
susceptibility
Environmental
trigger
Autoimmunity
β cell
destruction

6. Genetics
•
•
•
•
•
•
•
•
Susceptibility of type1 DM is inherited.
Mode of inheritance is complex.
Concordance rate between identical twins is 30%.
MHC on chromosome 6
Multigenic trait
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
DM.
INS VNTR also increases the risk.
Routine assessment of genetic markers is not recommended for
Δx and Mx.

7. Environmental factors
• Viruses such as rubella, mumps and coxsackie B have been
implicated.
• Autoimmunity to β cell is initiated by viral proteins.
• Genetic susceptibility determines the progression of β cell
destruction.

8. Autoimmunity
• Type1 DM results from cell mediated autoimmune destruction
of pancreatic β cell.
• 80-90% destruction of β cell is required to induce
symptomatic diabetes.
• Marker of β cell autoimmunity are circulating antibodies.
• They are present in the serum years before the onset of
hyperglycemia.

9. •
•
•
-
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
normal subjects.
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.

10. • 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.

11. Role of antibodies in Mx of Diabetes
Initial fasting hyperglycemia
detected
Presence of multiple
antibodies
85-90% of type1
DM
5-10% of type2
DM
1-2% of healthy subjects
have single autoantibody
Known as latent
autoimmune diabetes of
adulthood (LADA)
No acceptable T/t available to prevent the clinical onset of diabetes
in autoantibody +ve individuals.
Immunosuppresant therapy under development to prevent auotoimmunity

12. Pathogenesis of type2 DM
Genetic
susceptibility
Environmental
factors
Insulin
Resistance
Loss of
β cell function

13. Genetic Susceptibility
• 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
is ~100%.

14. • Genome
wide association studies – 17 genetic loci for type2
diabetes identified.
• Most of them are related to insulin secretion pathway and not the
insulin resistance.
• 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.
• So,
genes causing common forms of type2 DM are still
unknown.

15. Environmental factors
• Diet : high fat diet, excessive intake of free sugars
specially fructose.
• Exercise : Sedentary life style increases the risk of
diabetes.
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 :
BMI
Relative risk of developing
DM type2
30-34.9
20
23>
35≤
38

16. Insulin resistance
•
•
Insulin resistance is decreased biological response to normal
concentration of Insulin.
It is present in type2 DM and virtually all obese individuals.

18. Factors causing insulin resistance
Pre-receptor
Insulin autoantibodies
Primary defect in insulin signaling
Insulin receptor mutations
Leprechaunism (complete)
Ataxia telangectasia syndrome
Secondary to other endocrine disorders
Cushing syndrome
Acromegaly
Pheochromocytoma
Glucagonoma
Hyperthyroidism
Secondary to other disorders
Visceral obesity
Stress (infection, surgery, etc)
Cytogenetic disorders (Down,Turner,
Klinefelter)
Secondary to normal physiologic states
Puberty
Pregnancy
Starvation
Secondary to medications
Glucocorticoids
Thiazide diuretics
Oral contraceptive
Progesterone
blockers

19. • 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
DM
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
Insulin resistance
urinary albumin excretion ≥ 20 µg/min
or albumin : creatinine ratio ≥ 30 mg/g

20. Type1
Normal or increased
No (if +ve LADA)
Ketoacidosis is common
Hyperosmolar state common
30% concordance in twins
~100%
HLA linked
Not linked
Autoimmunity
Insulin resistance
Severe insulin deficiency
Islet cell histology
Obese mostly
Autoantibodies +ve
pathogenesis
>30 years
↓ blood insulin levels
Genetics
Onset < 20 year
Normal or underweight
Clinical
Type2
Relative insulin deficiency
Insulitis
NO
Marked atrophy and
fibrosis
Focal atrophy with amyloidosis
Severe beta cell depletion
Mild beta cell depletion
Dr. Prabhash

21. Complications of Diabetes Mellitus

22. 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

23. Meal absorbed
Plasma glucose
Plasma fatty acid
Plasma amino acid
No insulin released
Fat
breakdown
Fat
storage
Plasma
fatty acid
Glucose
uptake
Glucose
utilization
Aminoacid
uptake
Plasma
amino acid
Liver
Ketones glycogenolysis
gluconeogenesis
Tissue
loss
Brain interpret
as starvation
ventilation
Metabolic
acidosis
Protein
breakdown
Tissue
loss
hyperglycemia
polyphagia
Osmotic diuresis
Lactic
acidosis
Anaerobic
metabolism
thirst
Coma
and
death
dehydration
Hypovolemia & Hypotension
Circulatory failure
polydipsia

24. Long term complications

26. Diagnostic criteria for DM
Any one of the following is diagnostic
A. Glucose
1. Fasting plasma glucose ≥126 mg% or
2. Symptoms of hyperglycemia and
casual plasma glucose ≥200mg%
or
3. During an OGTT 2 hour plasma glucose ≥ 200mg%
B.
HbA1c ≥
6.5 mg%
Point of care assay should not be used for diagnosis.

27. Pre clinical screening of DM
•
Type1 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.

28. •
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.

29. Monitoring of blood glucose
•
SMBG:
-
With glucometer
-
Indications
(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
taken etc.
(5) determination of necessity for initiating insulin therapy in GDM
-
Should not be used for diagnosis.

30. 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

31. 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
use.

32. Monitoring long term glucose control
•
•
-
Glycated hemoglobin
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
goal
Estimated average glucose mg% = 28.7*HbA1c – 46.7
Altered life span of RBCs affect the result significantly.
Fructosamine
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.

33. others
• Microalbuminuria
• Evaluating complications- creat, lipid profile, ketone
bodies, electrolytes, lactate etc.
• HOMA-IR = insulin (mU/L) * glucose (mg%) / 405
• C-peptide assessment.

34. Thank you…