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Diabetes Mellitus

Definition: DM includes a group of metabolic disorder that share the phenotype of Hyperglycemia.

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 glucose
  4. 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%)



= 126

Two hours after glucose(mg%)


140 -199



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 points:
  1. 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. No treatment required. Blood sugar is normal. It is self limiting.

Monitoring glycaemic control:
 (Ref. Hari. 18th ed. , Pg - 2992)

  1. Glycated haemoglobin (= HbA1c)
    1. HbA1c is produced by nonenzymatic condensation of glucose molecules with Hb molecule.
    2. In a normal adult HbA1c constitutes <5.6% of the total adult haemoglobin.
    3. Levels relate to mean glucose level over previous 8-12 wks (i.e RBC half-life).
    4. 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)

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)
    1. 6.0% = 126 mg/dl
    2. 6.5% = 140 mg/dl
    3. 7.0% = 154 mg/dl
    4. 7.5% = 169 mg/dl
    5. 8.0% = 183 mg/dl
    6. 8.5% = 197 mg/dl
    7. 9.0% = 212 mg/dl
    8. 9.5% = 226 mg/dl
    9. 10.0% = 240 mg/dl

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)
    1. Patient has normal Weight or under weight Q
    2. Presence of autoantibodies: islet cell antibodies (lCA) and anti-glutamic acid decarboxylase (GAD) antibodies; Q
    3. Ketonuria Q on urine dipstick.
    4. Family history may or may not be positive
    5. Autoimmune destruction of more than 80% of beta cells Q ­­ (Schmidt syndrome or polyglandular failure syndrome)
    6. Other autoimmune diseases (Thyroid disorders, Addison, RA etc. ) may be there Q
    7. Serum insulin levels are low Q
    8. HLA DR3, DR4 (LQ 2012)
    9. Main treatment is insulin.
  3. Pathogensis of Type I diabetes-
    1. Autoimmunity.'
      1. Diabetes mellitus type I is characterized by destruction of ß cells.
      2. Autoimmunity is believed to be the major mechanism involved in destruction of Beta cells.
    2. Idiopathic (type I B) some cases are idiopathic i.e. they have beta cell destruction without antibodies.
Recent Advances:
Immunologic 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.

  1. Features that suggest Type - 2 DM
    1. Patient has over Weight Q
    2. No autoantibodies Q
    3. Ketosis is uncommon. But Non ketotic hyper osmolar coma is common. Q
    4. Family history strongly positive but not always positive.
    5. Insulin resistance is the main cause Q
    6. Serum insulin levels are very high ( hyper insulinemia ) Q
    7. Treatment include weight loss, oral drugs & insulin Q 
  2. Pathogenesis of Type II diabetes-
    The metaboic defects that characterize type 2 diabetes are:
    1. Decreased ability of peripheral tissues to respond to insulin (insulin resistance)
    2. Beta cell dysfunction that is manifested as inadequate insulin seretion in the face of insulin resistance and hyperglycemia.
    3. 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. TNFα
    4. Resistin


Extra Edge
  1. Adipokines which reduce insulin resistance - 
    1. Leptin
    2. Adiponectin.
  2. Adipokines which increase insulin resistance –
    1. TNF-alpha
    2. Resistin

Differences between different types of Diabetes Mellitus

Type 1 DM Type 2 DM
(1) Age at onset -   usually young Adults
(2) HLA association DR3, DR4 No HLA association
(3) Body weight-     Lean & thin Obese
(4) Family h/o   -    May or may not be there Strongly +ve (but not always positive)
(5) Presentation -   Usually (Abrupt) Gradual or asymptomatic
(6) Insulin requirement Absolute, but drugs like AGI,
Pramlintide can be given
OHA, later insulin.
(7) Serum insulin level- Low High
(8) Etiology Usually Autoimmune,
Some are idiopathic  
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)
    1. 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.&nbsp; (PNQ)
    2. The viral infections associated with diabetes are :­
      Mumps, Measles, Coxsackie virus, Cytomegalovirus, Rubella, EB virus
  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)
    1. There is impaired glucose – induced secretion of insulin.
    2. 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 )
    3. 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
    4. Features of MODY:
      1. No antibodies           
      2. No obesity   
      3. Glucokinase gene defect Q
      4. DKA uncommon Q
      5. Insulinopenia Q
      6. No hypertension
      7. No Insulin resistance
      8. No Hyperlipidemia
  6. 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)
    1. 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.
    2. It Involves the main pancreatic duct and results in large ductal calculi
    3. 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).
    4. 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.
    5. 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 mellitu
    Gestational diabetes mellitusIt is defined as
    1. Fasting plasma glucose 126mg/dl
    2. After 100gm glucose- fasting 95 (Carpenter/Clouston diagnostic criteria)
      1. 1hr later plasma glucose 180mg/dl.or
      2. 2hr later plasma glucose 155mg/dl.or
      3. 3hr later plasma glucose 140mg/dl
  10. 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:
    1. Leprechaunism
    2. Rabson Mendenhall syndrome
    3. Cystic fibrosis
  12. AutoImmune disease having associated diabetes
    1. Chronic lymphocytic thyroiditis (Hashimoto)
    2. Celiac disease
    3. Multiple endocrine deficiency syndrome

Other causes of diabetes

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.
    1. (Reduce weight to maintain normal BMI)
      1. BMI =  body weight (kg) / height in meters2 Q
      2. BMI  > 25 overweight
                >30 obese

TABLE - Daily Caloric Requirement*


Body Build

Activity Level


Moderately active

Very active


20 - 25










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.!!!

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

Downregulation & upregulation of insulin receptor

Downregulation is the process by which a cell decreases the quantity of a cellular component, such as RNA or protein, in response to an external variable. An increase of a cellular component is called upregulation.

Mechanism: The Insulin Receptor

The process of downregulation occurs when there are elevated levels of the hormone insulin in the blood.


At high plasma insulin levels, the number of surface receptors for insulin is gradually reduced by the accelerated rate of receptor internalization and degradation brought about by increased hormonal binding.

The process of downregulation can be counteracted by weight loss. Which leads to increase insulin receptors.
(c) Avoid food of high glycemic index (LQ 2012) (i.e. any food like sugar, glucose powder etc. which are absorbed immediately in GIT and raised blood sugar very fast). 

  1. Glycemic index of various foods. 




Corn Flakes, carrots, potatoes (mashed), maltose, honey, idli.


Bread (whole meal), millets, rice (white), broad beans, potato (new), uppama

60 –69%

Bread (white), paratha (Wheat), rice (brown, unhusked), shredded wheat, beetroot, banana, raisins, sprouted green gram, sucrose.


Buck wheat, noodles (white), peas (frozen), pongal sweet corn, potato chips.


Noodles (whole mal), porridge oats (dahlia), beans, potato (sweet), oranges (juice), peas (dried), bengal gram, black gram.


Black-eyed peas, apple, skimmed milk, curd/yogurt, tomato soup, ice cream


Kidney beans, lentils (all daals), fructose, rajmaah


Soyabeans, groundnuts

NB: Cornflake is a food of very high glycemic index.


Note: This table is given in 22nd edition of Park Page 568 in different style. But above given table is much better hence I have not changed it.

  1. Oral hypoglycemics
    1. Metformin.
      1. It has got anorexic effect so it causes loss of body weight.
      2. It is the drug of choice for obese type II diabetes. It does not cause hypoglycemia.Q
      3. SE - nausea and diarrhoea.
      4. It should not be used in CRF, liver failure & alcoholics (due to risk of lactic acidosis).
      5. MCQ: Metformin therapy does not need plasma level monitoring.Q
      6. Prolong use can cause Vit B12 deficiency.
    2. Sulfonylurea.
      1. These are insulin secretogogue.
      2. Act on ATP sensitive k+ channel (Hari-18th Pg-2995).
      3. They act by release of pre formed insulin from pancreas.
      4. They can cause hypoglycemia and weight gain. Q  

Example :

  1. Short acting: Tolbutamide
  2. Medium acting: Gliclazide
  3. Long acting: Glibenclamide, Chlorpropamide, Glimepiride

  1. Thiazolidinediones:
    1. It increases Insulin sensitivity.
    2. It acts on PPAR gamma nuclear receptor.
    3. Can cause ovulation in PCOS (Ref. Hari.18th ed., Pg-2998)
    4. S/E: Fluid retention (Can precipitate heart failure), hepatotoxicity.    

Example: Rosiglitazone, Pioglitazone


Recent advances:
Recently Rosiglitazone has been banned in many countries because it causes increase mortality due to CHF.

  1. Acarbose (alpha-glucosidase inhibitor)
    1. Decreases breakdown of starch to sugar in GIT.
    2. They are very good drug for post prandial hyperglycemia.
    3. S/E: Flatulence, abdominal distension/pain, diarrhoea.
  2. Meglitinide (Nateglinide, repaglinide). (sulfonylurea receptor binder):
    1. Increases beta-cell insulin release (insulin secretogogue).
    2. They target post-prandial hyperglycemia (t1/2 is short).
    3. They may have a role in those with irregular mealtimes if glycaemic control is poor.  
Recent Advances :

 Recently Bromocriptine has been approved as an antidiabetic drug. 

  1. It improves glycemic control and glucose tolerance in obese type 2 diabetic patients.
  2. Both reductions in fasting and postprandial plasma glucose levels appear to contribute to the improvement in glucose tolerance.
  3. The bromocriptine-induced improvement in glycemic control is associated with enhanced maximally stimulated insulin-mediated glucose disposal.
Extra Edge:

Anti diabetic drugs which do not cause hypoglycemia (AIIMS Nov 08)
1. Metformin
2. Alpha glucosidase inhibitor    
3. Pioglitazone          
4. DPP- IV inhibitor


Recent Advances (Ref. Hari.18th ed. , Pg-2997)


New concepts and new drugs in diabetes. (PNQ)

  1. Incretin effect (Physiology) (PNQ)
    1. Normally when anybody eats food it causes increased insulin secretion.
    2. In a new study it is seen that normal people who take oral glucose tend to have higher serum insulin level as compared to those normal people to whom glucose was given intravenous although blood sugar was same in both the groups of people. It is because oral glucose causes release of some polypeptide from the intestine which raise serum insulin level (insulinotropic polypeptide).
    3. These polypeptide include GLP- 1, GIP
    4. These two polypeptide are degraded by DPP - IV Enzyme

Pharmacology: (PNQ)


  1. New anti diabetic drugs which raise GLP -1 and GIP
    1. Exenatide (Injection)
    2. Liraglutide (Injection)
  2. New anti diabetic drugs which raised GLP1 and GIP level by inhibiting DPP – IV (DPP – IV inhibitors) (PNQ)
    1. Sitagliptin (Oral)
    2. Vildagliptin (Oral)
    3. Saxagliptin
    4. Ritagliaptin
    5. Alogliaptin 

Profound hypoglycemia is not a feature of DPP IV inhibitors. (LQ 2012)

  1. Amylin effect  (Physiology): (PNQ)
    1. Normally when we eat food, intestine secretes amylin  
    2. Amylin reduces glucagon secretion and slows down the gastric emptying.

Pharmacology: (PNQ)


New anti diabetic drugs which increases amylin secretion (Amylin agonist)


  1. Pramlintide (Injection)

Recent Advances: Newer drugs:

  1. Colesevelam (Ref. Hari.18th ed. , Pg-2996,2998, table 344.11)
    1. It is a bile acid sequestrant
    2. It bind bile acids but mechanism of glucose lowering not known.   
    3. Side Effect: Constipation, dyspepsia, abdominal pain, nausea, Increases tri-glycosides, intestinal obstruction
  2. Renal glucose transporter inhibitors (Sodium Glucose-2 inhibitors). Following drugs are not given in Harrison 18th edition also!!!)
    1. Phlorozin                            
    2. Dapagliflozin     
    3. Sergliflozin                   
    4. Remogliflozin  
  3. Resveratrol
    1. A natural compound found in grape skin that mimics some of the effects of dietary restriction, increases longevity and improves health
    2. The mechanisms responsible for life span expansion are "food" sensors typically activated in situations of food shortage, such as IGF (insulin-like growth factor)/insulin and the TOR (target of rapamycin) pathways.
    3. Accordingly, a reduction in food intake without malnutrition extends the life span by 10–50%
  4. Imeglimin is an oral anti-diabetic. It inhibit hepatic gluconeogenesis, increase muscle glucose uptake, and restore normal insulin secretion. It of a new class of anti-diabetic. It is a new drug. (Not given in 18th edition of Harrisons).
    Action: Imeglimin is mainly an indirect activator of AMP-kinase

Drugs which can be used in both type I and type II diabetes (LQ 2012)
1. Acarbose                                
2. Pramlintide                
3. Insulin

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