Diabetes Mellitus Dr. Prabhash

Bhavsar

Blood Glucose Regulation

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

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

Pathogenesis of type1 DM

Genetic susceptibility

Environmental trigger

Autoimmunity

β cell destruction

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.

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.

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.

• 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.

• 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 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)

Pathogenesis of type2 DM

Genetic susceptibility

Environmental factors

InsulinResistance

Loss of β cell function

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

• 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.

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≤

Insulin resistance• 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

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

• 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

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

Complications of Diabetes Mellitus

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

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

Long term complications

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.

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.

• 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

• 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.

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 use.

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.

others

• Microalbuminuria

• Evaluating complications- creat, lipid profile, ketone bodies, electrolytes, lactate etc.

• HOMA-IR = insulin (mU/L) * glucose (mg%) / 405

• C-peptide assessment.

Thank you…