diabetes - diagnosis,complication and monitoring by dr prabhash
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pathophysiology of diabetes and its complications. monitoring of diabetes, newer modalities for assessing blood glucoseTRANSCRIPT
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Diabetes Mellitus Dr. Prabhash
Bhavsar
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Blood Glucose Regulation
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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
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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 or action
Defect in proinsulin conversion, insulin- gene & receptor mutation etc.
Exocrine pancreatic defect Pancreatitis, cystic fibrosis etc.
Other endocrinopathies Glucagonoma, hyperthyroidism, cushing syndrome etc.
infections CMV, Coxsackie B etc.
Drugs Steroids, thyroxin, β adrenergic etc.
Genetic syndromes Down, turner etc.
iv Gestational Diabetes Mellitus
Diabetic care 25, 2003
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Pathogenesis of type1 DM
Genetic susceptibility
Environmental trigger
Autoimmunity
β cell destruction
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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.
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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.
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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.
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• 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.
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• 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.
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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
No acceptable T/t available to prevent the clinical onset of diabetes in autoantibody +ve individuals.Immunosuppresant therapy under development to prevent auotoimmunity
Known as latent autoimmune diabetes of adulthood (LADA)
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Pathogenesis of type2 DM
Genetic susceptibility
Environmental factors
InsulinResistance
Loss of β cell function
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Genetic Susceptibility
• Susceptibility of type2 DM is inherited.
• Mode of inheritance is complex.
• Concordance rate between identical twins is ~100%.
• Multigenic trait.
insulin receptor gene
• Mutation in GLUT 4 genes
glycogen synthase gene
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• 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.
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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>38
35≤
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Insulin resistance• Insulin resistance is decreased biological response to normal
concentration of Insulin.
• It is present in type2 DM and virtually all obese individuals.
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Factors causing insulin resistance
Pre-receptor Insulin autoantibodies
Primary defect in insulin signaling Insulin receptor mutationsLeprechaunism (complete)Ataxia telangectasia syndrome
Secondary to other endocrine disorders Cushing syndromeAcromegalyPheochromocytomaGlucagonomaHyperthyroidism
Secondary to other disorders Visceral obesityStress (infection, surgery, etc)Cytogenetic disorders (Down,Turner, Klinefelter)
Secondary to normal physiologic states PubertyPregnancyStarvation
Secondary to medications GlucocorticoidsThiazide diureticsOral contraceptiveProgesteroneblockers
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• 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 is-
Any 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
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Type1 Type2
Clinical Onset < 20 year >30 years
Normal or underweight
Obese mostly
↓ blood insulin levels Normal or increased
Autoantibodies +ve No (if +ve LADA)
Ketoacidosis is common
Hyperosmolar state common
Genetics 30% concordance in twins
~100%
HLA linked Not linked
pathogenesis Autoimmunity Insulin resistance
Severe insulin deficiency
Relative insulin deficiency
Islet cell histology
Insulitis NO
Marked atrophy and fibrosis
Focal atrophy with amyloidosis
Severe beta cell depletion
Mild beta cell depletionDr. Prabhash
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Complications of Diabetes Mellitus
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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
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Meal absorbed
Plasma fatty acid Plasma glucose Plasma amino acid
Fat breakdown
Fat storage
Glucose uptake
Glucose utilization
Aminoacid uptake
Protein breakdown
Liver Ketones glycogenolysis
gluconeogenesis
Plasma amino acid
Tissue loss
Brain interpret as starvation
polyphagia
hyperglycemia
Osmotic diuresis
dehydrationthirst polydipsia
Hypovolemia & Hypotension
Circulatory failure
Coma and
death
Plasma fatty acid
Tissue loss
Metabolic acidosisventilation
Anaerobic metabolism
Lactic acidosis
No insulin released
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Long term complications
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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.
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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.
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• 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.
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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.
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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
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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.
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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.
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others
• Microalbuminuria
• Evaluating complications- creat, lipid profile, ketone bodies, electrolytes, lactate etc.
• HOMA-IR = insulin (mU/L) * glucose (mg%) / 405
• C-peptide assessment.
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Thank you…