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Chapter-1

Endocrinology LQ = Latest Questions PNQ = Prospective New Questions

I. Diabetes Mellitus (Hari. 18th ed., pg-2968)Definition: DM includes a group of metabolic disorder that share the phenotype of Hyperglycemia. Diagnosis: Diabetes is diagnosed by any of the following criteria.

1. Classical triad of Symptoms of DM (polyuria, polydipsia, weight loss) plus random blood glucose 200mg/dl.Q

2. Fasting plasma glucose 126mg/dl (LQ 2012). 3. Plasma glucose 200mg/dl 2hrs after an oral glucose tolerance test with 75gm of glucose4. HBA1C > 6.5% (Hari.18th ed. , Pg-2970, table 344.2)

Recent Advances HBA1C > 6.5% is a new diagnostic criteria for DM

Diagnostic criteria for evaluation of standard GTT (Ref. Hari. 18th ed. , Pg-2970, table 344.2)Normal Glucose tolerance Impaired Glucose tolerance

(prediabetic)Diabetes mellitus

Fasting plasma glucose (mg%) <100 100-125 126Two hours after glucose(mg%) <140 140 -199 200 Extra Edge

1. Impaired glucose tolerance on an oral GTT is indicated by 2 hrs after glucose load 140-199 mg/dl; fasting blood sugar< 126 mg/dl or HbA1C between 5.7 to 6.4 %. .

2. Fasting is defined as no caloric intake for at least 8 h. Normal FBS < 100 mg%3. 1 mmol/lit of blood sugar = 18 mg% of blood sugar

Important points1. Glycosuria + Ketonuria is seen only in diabetes. 2. Only glycosuria (without diabetes) is seen in a normal young adult, pregnancy, hyperthyroid.

(Note: In hyperthyroid it is known as alimentary glycosuria)3. Only ketonuria is seen in prolong starvation.4. Renal glycosuria is a benign condition, found in some young adults. Blood sugar is normal. No treatment required. It is

self limiting.

Monitoring glycaemic control: (Ref. Hari. 18th ed. , Pg - 2992)1. Glycated haemoglobin (= HbA1c)

a. HbA1c is produced by nonenzymatic condensation of glucose molecules with Hb molecule. b. In a normal adult HbA1c constitutes <5.6% of the total adult haemoglobin. c. Levels relate to mean glucose level over previous 8-12 wks (i.e RBC half-life).d. HbA1c is the single best parameter to know about long term diabetic control. (LQ 2012)

2. Fructosamine (glycated plasma protein) levels reflect diabetic control over 2-3 wks: may be used in pregnancy to assess shorter term control, and in patients with hemoglobinopathies which interfere with HbA1c tests.

Recent Advances (Ref. Hari. 18th ed., Pg - 2992)

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………………………………………………………………........... Medicine Text Book DBMI eAG (Estimated Average Glucose)

1. HBA1C should be measured in all individuals with DM during their initial evaluation and as part of their comprehensive diabetes care.

2. As the primary predictor of long-term complications of DM, the HBA1C should mirror, to a certain extent, the short-term measurements of Self monitoring of blood sugar (SMBG).

3. These two measurements are complementary in that recent intercurrent illnesses may impact the SMBG measurements but not the HBA1C.

4. Likewise, postprandial and nocturnal hyperglycemia may not be detected by the SMBG of fasting and preprandial capillary plasma glucose but will be reflected in the HBA1C.

5. In standardized assays, the HBA1C approximates the following mean plasma glucose values:6. HBA1C (%) to eAG (mg/dl)

a. 6.0% = 126 mg/dl b. 6.5% = 140 mg/dl c. 7.0% = 154 mg/dld. 7.5% = 169 mg/dl e. 8.0% = 183 mg/dl f. 8.5% = 197 mg/dlg. 9.0% = 212 mg/dl h. 9.5% = 226 mg/dl i. 10.0% = 240 mg/dl

A. Types of Diabetes

1. Ratio of type I & type II diabetes in India. = 5% : 95%2. Features that suggest Type - 1 DM (Ref. Hari.18th ed. , Pg-2972)

a. Patient has normal Weight or under weight Q b. Presence of autoantibodies: islet cell antibodies (lCA) and anti-glutamic acid decarboxylase (GAD) antibodies; Q

c. Ketonuria Q on urine dipstick.d. Family history may or may not be positivee. Autoimmune destruction of more than 80% of beta cells Q (Schmidt syndrome or polyglandular failure syndrome)f. Other autoimmune diseases (Thyroid disorders, Addison, RA etc. ) may be there Q

g. Serum insulin levels are low Q

h. HLA DR3, DR4 (LQ 2012)i. Main treatment is insulin.

3. Pathogensis of Type I diabetes- a. Autoimmunity.`

i. Diabetes mellitus type I is characterized by destruction of cells.ii. Autoimmunity is believed to be the major mechanism involved in destruction of Beta cells.

b. Idiopathic (type I B) some cases are idiopathic i.e. they have beta cell destruction without antibodies.

Recent AdvancesImmunologic markers in type 1 DM:

1. Islet cell autoantibodies (ICAs) 2. Antibody to insulin (IAA)3. Glutamic acid decarboxylase, (GAD) 4. Tyrosine phosphatase (IA-2 & IA- 2B) 5. Beta cell specefic zing transporter (ZnT – 8)

Prevention of type 1 DM: In patients with new-onset type 1 diabetes, treatment with anti-CD3 monoclonal antibodies.

Recent Advances Previously IDDM was considered to occur only in young patient. But now we have Latent autoimmune diabetes of adults (LADA) is a form of Type 1 DM,occuring in adults.

4. Features that suggest Type - 2 DM

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a. Patient has over Weight Q

b. No autoantibodies Q

c. Ketosis is uncommon. But Non ketotic hyper osmolar coma is common. Q

d. Family history strongly positive but not always positive.e. Insulin resistance is the main cause Q

f. Serum insulin levels are very high ( hyper insulinemia ) Q

g. Treatment include weight loss, oral drugs & insulin Q

5. Pathogenesis of Type II diabetes- The metaboic defects that characterize type 2 diabetes are:a. Decreased ability of peripheral tissues to respond to insulin (insulin resistance)b. Beta cell dysfunction that is manifested as inadequate insulin seretion in the face of insulin resistance and

hyperglycemia. c. Excessive hepatic glucose production

Recent advances in Pathology of Type II diabetes (PNQ)

1. Genes for type II diabetics that cause the insulin resistance and the beta cell failure- a gene on chromosome 2 encoding a cysteine protease, calpain –10, has been reported in some patient.

2. Several adipokines, secreted by fat cells, can affect insulin Action. 3. Example of adipokines 1. leptin 2. Adiponectin 3. TNF 4. Resistin

Extra Edge i. Adipokines which reduce insulin resistance - a. Leptin b. Adiponectin. ii. Adipokines which increase insulin resistance - a. TNF-alpha b. Resistin

B. Differences between different types of Diabetes Mellitus – Type 1 DM Type 2 DM

1. Age at onset - usually young Adults2. HLA association DR3, DR4 No HLA association 3. Body weight- Lean & thin Obese4. Family h/o - May or may not be there Strongly +ve (but not always positive)5. Presentation - Usually (Abrupt) Gradual or asymptomatic6. Insulin requirement Absolute, but drugs like AGI, OHA, later insulin. Pramlintide can be given7. Serum insulin level- Low High 8. Etiology Autoimmune, Insulin resistance, impaired insulin secretion

Recent Advances Other categories of Diabetes Mellitus (Newer types of diabetes.)

1. Potential Diabetes (PNQ): Person himself at present is non-diabetic but has a strong family history Q of type 2 diabetes.2. Latent Diabetes (PNQ): A person becomes diabetic under stressful conditions Q like pregnancy. Person again becomes non-

diabetic when stress is removed.3. Brittle Diabetes (PNQ): It is seen in children with type 1 diabetes. Some times patient’s sugar becomes very high leading to

DKA, sometimes patient goes into hypoglycemia Q.4. Acute Fulminant diabetes mellitus (PNQ)

a. It is acute onset diabetes, can occur in any age, occurs after viral infection. Serum insulin level are reduced but there are no antibodies against insulin or beta cell. (PNQ)

b. The viral infections associated with diabetes are :Mumps, Measles, Coxsackie virus, Cytomegalovirus, Rubella, EB virus

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5. Maturity onset diabetes of the young (MODY) is an autosomal dominant Q form of Type 2 DM affecting young people with a Definite positive family history. (AIPG 2012) a. There is impaired glucose – induced secretion of insulin. b. Six type of MODY have been described. Except for MODY 2, in which a glucokinase gene is defective, , all other

types involve mutations of a hepatocyte nuclear transcription factor (HNF) that regulates islet gene expression. (MODY 1,3,5 )

c. MODY-3 the most common form (AIIMS May 2013)– accounts for two-thirds of all MODY cases. It is due to HNF-1 alpha mutation.

d. Features of MODY:i. No antibodies ii. No obesity iii. Glucokinase gene defect Q iv. DKA uncommon Q

v. Insulinopenia Q vi. No hypertension vii. No Insulin resistance viii. No Hyperlipidemia6. Malnourished diabetes (PNQ)

It is seen in malnourished children. Serum insulin level are reduced but there are no antibodies against insulin or beta cell.But in these patients DKA is uncommon.

7. Latent autoimmune diabetes of adults (LADA) is a form of Type 1 DM, with slower progression to insulin dependence in elderly person. So in this case also serum insulin level is reduced & auto antibodies are there.

8. Tropical diabetes (LQ 2012)a. Tropical diabetes occurs in Tropical pancreatitis which is a type of chronic pancreatitis seen mainly in tropical

countries. It affects more commonly young people in southern India. b. It Involves the main pancreatic duct and results in large ductal calculi c. Aetiology Unknown, but SPINK1 mutation and environmental factors are likely, various environmental factor

supposed to cause tropical pancreatitis are: Malnutrition, Cassava, Infections (viral and Mycoplasma pneumoniae). d. Management Pain relief with analgesics and enzyme supplementation with proteases; control diabetes and

steatorrhoea; endotherapy coupled with stone fragmentation by extracorporeal shock wave lithotripsy for those who do not respond to medical therapy.

e. Surgical decompression of main pancreatic duct by lateral pancreato-jejunostomy for those with severe pain unresponsive to other therapy

9. Gestational Diabetes: This term includes gestational impaired glucose tolerance (GIGT) and gestational diabetes mellitus (GDM). These women are at risk of later developing diabetes, with Type 1 versus Type 2 diabetes mellitusGestational diabetes mellitus – It is defined as a. Fasting plasma glucose 126mg/dl

or b. After 100gm glucose- fasting 95(Carpenter/Clouston diagnostic criteria)

i. 1hr later plasma glucose 180mg/dl.orii. 2hr later plasma glucose 155mg/dl.or

iii. 3hr later plasma glucose 140mg/dl10. Mitochondrial Gene defects: Point mutations in mitochondrial DNA are associated with DM and deafness. A form of

IDDM, associated with mitochondrial mutations, is the wolfram syndrome. Wolfram syndrome is characterized by diabetes insipidus, DM, optic atrophy, and deafness – thus, the acronym DIDMOAD.

11. Genetic defects of insulin action: i. Leprechaunism ii. Rabson Mendenhall syndrome iii. Cystic fibrosis 12. AutoImmune disease having associated diabetes

a. Chronic lymphocytic thyroiditis (Hashimoto)b. Celiac disease c. Multiple endocrine deficiency syndrome

C. Other causes of diabetes

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………………………………………………………………........... Medicine Text Book DBMI Other causes of diabetes mellitus

1. Drug induced: steroids, thiazides Q, nicotinic acid Q , phenytoin Q, alpha IF Q, Protease inhibitor Q , beta agonist Q, clozapine Q. (Ref. Hari.18th ed., Pg-2969, table 344.1)

2. Pancreatic: pancreatitis Q; surgery (where >90% pancreas is removed); trauma: pancreatic destruction (hemochromatosis Q, cystic fibrosis) Q; pancreatic cancer . Fibrocalculous pancreatopathy/ Tropical calcific pancreatitis/Malnutrition related DM.

3. Endocrine: Cushing's disease; acromegaly (LQ 2012); pheochromocytoma; hyperthyroidism . Q Glucagonoma, Somatostatinoma (Note = In Addison disease (LQ 2012, hypoglycemia occurs)

Treatment of diabetes mellitus (Ref. Hari.18th ed., Pg-2990)1. Patient Education : For any obese type II diabetic patient initial therapy is diet therapy and exercise.

a. (Reduce weight to maintain normal BMI) i. BMI = body weight (kg) / height in meters2 Q

ii. BMI > 25 overweight

> 30 obese TABLE - Daily Caloric Requirement*

Body BuildActivity Level

Sedentary Moderately active Very activeObese 20 - 25 30 35

Normal 30 35 40Underweight 35 40 45 - 50

*Calories (kcal) required per kilogram of ideal body weight per day.

Recent Advances Yo-yo dieting (weight cycling). (Not Given in 18th edition of Harrison)In this process, the dieter is initially successful in weight loss but is unsuccessful in maintaining the loss long-term and begins to over eat again to gain the weight back. The dieter then again seeks to lose the regained weight and the cycle begins again.!!!

b. In Obesity down regulation of insulin receptors occurs in Type II diabetes.

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