DIABETES MELLITUS

Definition
 It is a clinical syndrome characterized by hyperglycaemia due to absolute or relative insulin
deficiency/resistance or both.

Classification
 Type 1 Diabetes Mellitus: Type 1A (immune mediated) Type 1B (idiopathic)
 Type 2 Diabetes Mellitus
 Gestational diabetes mellitus (GDM)
 Maturity onset diabetes of the young (MODY)
 Genetic deficiency of beta cell development or its functions.
 Drug induced: Thiazides, phenytoin, OC pills, corticosteroids.
 Due to infections like cytomegalovirus, coxsackie B virus etc.
 Endocrinopathies: Acromegaly, Cushing’s syndrome, hyperthyroidism.

Pathogenesis
 Type 1 Diabetes Mellitus
o It is an autoimmune disorder.
o About 5-10% of all cases of DM.
o Destruction of beta cells of pancreas.
o Low or absent plasma insulin.
o Usually occurs in childhood or <40 years of age.
o High genetic susceptibility (HLA-DR3, HLA-DR4).
o Body weight is normal or wasted.
o Environmental factors: Viral infections may trigger islet cell destruction and
associated with mumps, rubella, coxackie B or cytomegalovirus.
o The autoimmune damage starts many years before the disease becomes
clinically evident.
 Type 2 Diabetes Mellitus
o It is a multifactorial disease.
o Characteristics: a) insulin resistance b) increased glucose production 3) impaired
insulin secretion/action 4) abnormal fat metabolism
o Age: Usually above 40 years. high genetic susceptibility.
o High risk factors: Obesity, sedentary life style, associated with hyperlipidaemia,
hypertension.
o There is failure of target (peripheral) tissues to insulin action.
o Consequences of insulin resistance: Decrease in glucose uptake. Reduce glycolysis.
Beta cell dysfunction or abnormalities.
o Dyslipidaemia also observed: Raised LDL, cholesterol, Low HDL.

Clinical features
 Type 1 Diabetes Mellitus or Insulin Dependent Diabetes Mellitus (IDDM)
o Symptoms: Triad of ‘Poly’: Polyuria, Polydipsia, Polyphagia. Others: weight loss,
weakness, fatigue, high blood glucose level
o High incidence of diabetes ketoacidosis (DKA).
 Type 2 Diabetes Mellitus or Non-Insulin Dependent Diabetes Mellitus (IDDM)
o Symptoms: Polyuria, Polydipsia, Polyphagia. unexplained weight loss, weakness.
o Recurrent infections , prolonged wound healing , genital pruritus ,fungal infections.
o Symptoms of complications like : nephropathy, Blurred vision, neuropathy, erectile
dysfunction, MI or angina.
o Less incidence of DKA. Insulin level is normal or high.
DIAGNOSTIC CRITERIA
1. Fasting blood glucose level: ≥ 125 mg/dL (Normal 70-100 mg/dL).
2. Random plasma glucose ≥200 mg/dL with classical signs and symptoms of DM.
3. Oral Glucose Tolerance Test (OGTT):
 A fasting blood glucose level is measured. Patient is given 75 g of glucose dissolved in
250-300 mL of water. A single venous sample of blood is collected 2 hours after glucose
administration and glucose level is estimated.
 Criteria for DM: If 2 hour plasma glucose level ≥200 mg/dL.
4. Glycosylated Hemoglobin (HbA1c)
HbA1C indicates blood glucose level over last 2-3 months. It has no relation with meals,
physical activity or diet. HbA1c >6.5 (48mmol/mol) is diagnostic.
5. Urine glucose, protein/creatinine ratio: To detect glycosuria and proteinurea
6. Microalbuminuria having risk of renal failure and CVS damage.
7. Serum creatinine: More serum creatinine level in diabetic nephropathy.
8. Insulin level: Either low or normal or high.
9. C-peptide: helps in deciding when to start insulin therapy.
10. Insulin antibody test.
11. GAD-65 antibody test: Common in newly diagnosed diabetic patients.
12. Markers for IDDM : Genetic markers, insulin autoantibodies, islet cell antibodies.

MANAGEMENT OF DIABETES MELLITUS

INSULIN
 Various insulin preparations are classified according to its duration of action.
 Used mainly in type 1 DM. Can be used in type 2 DM in some conditions like pregnancy,
surgery, infections and diabetic ketoacidosis.
Short acting
 Regular insulin
o Insulin molecule is stabilized by zinc and forms hexamer around insulin molecule.
Intermediate acting
1. Isophane insulin (Neutral Protamine Hagedorn or NPH)
2. Lente: Insulin zinc suspension
Long acting
1. Protamine zinc insulin (PZI)
o Excess protamine is added to insulin. So, slow release of insulin. Longer acting insulin.
2. Ultralente insulin
3. Insulin glargine.
 It has ‘Peakless’ action, which lasts for upto 24 h. Given once a day at bed time.
 Its pH is 4.0 (acidic); so, must not be mixed with other insulins.
 It normalizes fasting blood sugar.
Insulin analogues
a) Insulin Lispro
o Given s.c. 10-20 min before meal.
o Controls meal time hyperglycemia.
b) Insulin Aspart
o Fast and rapid action of insulin (same like lispro).
c) Insulin Glulisine: Similar to insulin lispro. Rapid dissociation and short acting. Used for
continuous subcutaneous insulin infusion (CSII) by a pump.
 Inhaled insulin: Afrezza: Manufactured for inhalation using a Technosphere technology.
Used along with long-acting insulin.
 Dose requirement of insulin: 0.6–0.7 U/kg/day, with a range of 0.4–1 U/kg/day.
 Sites: Abdomen is the preferred site for s.c. injection because insulin is absorbed 20 - 30% faster
than from the arm. Rotation of sites of injection is recommended to prevent lipohypertrophy or
lipoatrophy.
Adverse effects of insulin
1. Hypoglycemia: Most common and serious adverse effect.
2. Allergy: Due to histamine release itching, redness and urticaria
3. Local reaction: Lipodystrophy at injection site due to Ig-E. Lipohypertrophy can also occur.
4. Edema
5. Peripheral neuropathy.
6. Hepatomegaly
7. Formation of Anti-insulin antibodies
Insulin regimens
1. Split mixed regimen: Combination of regular + isophane (NPH) insulin added as 30:70 ratio
o 2/3 of total dose of insulin injected s.c. before breakfast.
o 1/3 of total dose of insulin injected s.c. before dinner.
2. Basal bolus regimen
o Insulin glargine (long acting) injected s.c. once a day before breakfast.
o Insulin lispro or aspart (ultrashort acting) injected s.c. before each major meal.

ORAL HYPOGLYCEMIC DRUGS

SULFONYLUREAS
 Sulfonylureas are oral hypoglycemic agents.
Classification
a. First generation: Tolbutamide, Chlorpropamide.
b. Second generation: Glibenclamide (Glyburide), Gliclazide, Glimepiride, Glipizide.
 Sulfonylureas (SU) blocks KATP channel sulfonylurea receptors. So degranulation of
insulin granules leads to insulin release.
 Second generation Sulfonylureas are commonly used. Usually combined with metformin
 Adverse effects : Hypoglycemia, Weight gain, Agranulocytosis,
BIGUANIDE : Metformin
 ↓ Hepatic and ↓ renal gluconeogenesis
 ↓ Glucose output from liver
 ↑ Glucose uptake and ↑ utilization of glucose
 ↓ Absorption of glucose from GIT
 Adverse effects: metallic taste, Lactic acidosis and Vit B12 deficiency
 Metformin is the first choice of drug for all type-2 DM. Especially, prescribed to obese
patients because it also causes weight loss. It reduces incidence of MI and stroke.
MEGLITINIDE ANALOGUES: Repaglinide, Nateglinide
 Block ATP sensitive K+ channels and stimulates first phase of insulin secretion
 Side effects: Dizziness, nausea, flu-like symptoms and joint pain.
 Preferred drug for patients of type-2 DM having high postprandial blood glucose level.
GLP-1 RECEPTOR AGONISTS: Exenatide, Liraglutide, Albiglutide
 Stimulate insulin release
 ↓ Glucagon release
 Used as an alternative to insulin in obese type-2 DM.
DIPEPTIDYL PEPTIDASE-4 (DDP-4) INHIBITORS: Sitagliptin, Vildagliptin, Saxagliptin
 Orally active inhibitor of DPP-4 → ↑ level of GLP-1 → stimulates GLP-1 receptors → ↑
insulin release
 Adverse effects: Nausea, rash, Nasopharyngitis
 Commonly used as an adjuvant drug in type II DM, not controlled by metformin/insulin.
THIAZOLINEDIONES : Pioglitazone
 It is an agonist to PPARγ in skeletal muscles and fat, ↑ Glucose entry into skeletal muscles
 May be used as monotherapy in mild type-2 DM along with diet and exercise.
  Adverse effects: Weight gain , hepatotoxicity, fracture and Risk of bladder cancer
Other drugs
 SGLT-2 inhibitors: Canagliflozin, Dapagliflozin, Empagliflozin, Remogliflozin.
 Dopamine (D2) agonist: Bromocriptine
 Alpha glucosidase inhibitors: Acarbose, Miglitol, Voglibose.
 Amylin analogue: Pramlintide.
 GLP-1 analogue: Exenatide, liraglutide, dulaglutide

COMPLICATIONS OF DIABETES MELLITUS

 Acute: Diabetic ketoacidosis, hyperosmolar hyperglycemic state and lactic acidosis.
 Chronic: Eye: Diabetic retinopathy, cataract, glaucoma. Neuropathy: Sensory , motor,
autonomic neuropathy. Renal: Nephropathy, chronic kidney disease.
 Macrovascular: Coronary artery disease, peripheral vascular disease, cerebrovascular disease.
 Others: Skin changes, recurrent infections and hearing loss.
A. Diabetic retinopathy
 It is one of the commonest complication in 60-80% of diabetics , about 15 years after
diagnosis.
 Hemorrhage and microaneurysm in retina.
 Retinal ischemia and exudates are seen.
 Poor vision and untreated cases leads to retinal detachment.
 Maculopathy leads to macular edema and loss of vision.
 Diagnosed by fundus fluorescein angiography and optical tomography.
 Treatment: Prevention by control of glucose level and BP. Retinopathy can be treated
by laser photocoagulation.
B. Cardiovascular complications
 Most common cause of mortality.
 Atherosclerosis is severe and occurs at early age.
 Myocardial infarction;. High risk of coronary artery disease (angina/MI).
 Gangrene of upper /lower limbs: May cause intermittent claudication.
 Cerebrovascular disease like stroke can occur.
C. Diabetic foot: Risk factors: Evidence of neuropathy, ischemia, foot ulcer or old aged patient.
Ranges from superficial ulcer, deeper ulcers, localised gangrene to entire foot gangrene.
Treatment : Inspect foot daily. Use crema/lotion to prevent dry skin. Avoid any injury in legs.
Consult doctor if any skin changes.

D. Diabetic nephropathy
 About 30-40% of all diabetic develop nephropathy.
 Leading cause of chronic kidney disease. Common in type 1 DM.
 Earlier stage: Glomerular hyperperfusion and renal hypertrophy develop gradually.
Leads to increase GFR and nephromegaly (enlarged kidney).
 During first 5 year: Thickening of glomerular basement membrane and progression of
glomerular hypertrophy can occur.
 Microalbuminuria: Urinary excretion of albumin (20-300 mg/day). It is also marker for
cardiovascular morbidity. Patients should be screened at the time of diagnosis and once a
year for presence of albuminuria. Gradually, rise in albuminuria (>300 mg/day) which is
irreversible. Fall in GFR, further worsen to chronic renal failure.
 Management
o Stop smoking and control lipid level. Strict control of diabetes
o Treat hypertension: High BP can accelerate nephropathy. Angiotensin converting
enzyme inhibitors or angiotensin receptor blocker can reduce BP (<140/90 mmHg).
They reduce microalbuminuria and further renal complications also.
o Other drugs like thiazide diuretics, calcium channel blocker, eplerenone, Aliskiren or
beta blocker can be given.
 o Oral antidiabetic drugs: Metformin is the first line drug.
o Low protein diet is beneficial. Fenofibrates or pentoxifylline can be used as an
alternative.

DIABETIC KETOACIDOSIS
 Diabetic ketoacidosis (DKA) is an emergency complication of diabetes mellitus.
 Common in type 1 diabetes mellitus.
 DKA is defined as the presence of a) Severe hyperglycaemia b) Ketosis (high ketone bodies)
c) Metabolic acidosis
Precipitating events
 Infection (Pneumonia, urinary tract infection, Gastroenteritis, Sepsis)
 Inadequate insulin administration
 Infarction (cerebral, coronary, mesenteric, peripheral)
 Drugs (thiazides, corticosteroids, cocaine)
 Pregnancy.

Flowchart 39.1 Pathophysiology of diabetic ketoacidosis

Insulin deficiency
↓
Activation of counterregulatory hormones like glucagon, catecholamines, growth hormone
↓
Fat breakdown generates acetyl co-A
↓
Acetyl co-A is converted to acetoacetic acid and beta-hydroxybutyric acid (ketone bodies)
↓ leads to
Development of DKA

Hyperglycemia causes osmotic diuresis Ketosis causes acidosis, vomiting & ketonuria
↓ ↓
Loss of electrolytes (K+, Na+, Ca2+) Loss of water, dehydration and hyperventilation
↓ ↓
Dehydration, hypotension and shock Less glucose entry into CNS

Impairment of consciousness

Symptoms
 Symptoms of uncontrolled diabetes : polyuria, polydipsia, thirst.
 Nausea/vomiting, weakness, weight loss, lethargy, anorexia and leg cramps
 Abdominal pain.
 Shortness of breath, blurred vision.
Physical findings
 Signs of dehydration: Dry skin and mucus membrane, Tachycardia, hypotension, cold
extremities and cyanosis.
 Tachypnoea / kussmaul respirations (deep, rapid hyperventilation)
 Fruity odour in breath.
 Abdominal tenderness.
 Signs of cerebral edema: Headache, seizures, bradycardia, hypertension and coma.
Investigations
 Very High plasma glucose level (>250 mg/dL).
  Blood:
o Complete blood count: Leucocytosis. ABG analysis
o Blood urea nitrogen (BUN): Usually raised. high C-reactive protein
o High anion gap and variable serum osmolarity. High Serum ketones
 Chest X ray
 Serum electrolytes
o Potassium (K+): Normal or raised in initially in spite of total body K+ level is low.
o Sodium (Na+) : Usually low if patient has repeated vomiting
o Bicarbonate: Low indicated severe metabolic acidosis.
o Phosphorous: May be high initially.
 Urine examination: high urinary ketones and glucose.
 ECG: To rule out myocardial infarction.
 Diagnostic criteria for DKA: Glucose level >250 mg/dL, arterial pH <7.3, bicarbonate
<15mEq/L and anion gap >12 mEq/L.
Treatment of DKA
 Fluid replacement
o Intravenous solutions are administered to replace fluid and electrolyte losses.
o Administer Normal saline (0.9% NaCl):
o During first hour: give 1-2 L.
o During second hour: give 1 L
o Following two hours: give 1 L
o Then switch to 0.45% NaCl if sodium level reaches to normal or high.
 Insulin
o Regular insulin should be infused i.v. via continuous infusion 0.1U/kg/h (7-8 U/h in
adults).
o Insulin must be not given if K+ level <3.3 mEq/L as it further reduces K+ level.
o When plasma glucose level reaches 250 mg/dL , decrease the insulin infusion 0.05-0.1
U/kg/h (3-6 U/h) and start dextrose 5-10% in intravenous fluid to prevent cerebral edema.
 Potassium replacement
o Hypokalaemia leads to cardiac arrhythmia.
o If K+ level >5.2 mEq/L: Do not give K+ infusion.
o If K+ level <3.3 mEq/L: Hold insulin and give K+ 20-30 mEq/h
o If K+ level 3.3-5.2mEq/L: Give K+ 20-30 mEq in each litre of i.v. fluid.
 Bicarbonate therapy
o If severe acidosis (If arterial pH <6.9), 100 ml of 7.5% bicarbonate in 400 mL of normal
saline and to be given i.v infusion slowly over 2 h .
 Phosphate infusion
o During insulin infusion, phosphate level may fall rapidly. But no additional treatment is
required.
 Treat infection: Intravenous antibiotics can be given according to culture and sensitivity
report.
Complications: Shock, Vascular thrombosis, Severe dehydration, Pulmonary Edema, Cerebral
Edema and Mental status changes

DIABETIC NEUROPATHY
 It involves the peripheral nervous system due to DM. It is a complication of DM.
A. Distal symmetric sensorimotor polyneuropathy
 Most common type of diabetic neuropathy.
 Involves motor and sensory functions of lower extremities.
Clinical features
 Numbness over legs or foot
  Sharp shooting or stabbing pain, Dull constant or boring pain.
 Tingling pins and needles, Hot or cold sensation
 Cramps, feeling of walking in cotton wool
 Loss of vibration, loss of tendon reflexes in lower limbs
 Loss of balance on walking or washing the face (washbasin sign).
 Involvement of other sensations like touch, pain, temperature, and proprioception.
 Later there is weakness and wasting of muscles
 Sequalae of neuropathy: Involvement of motor nerves to small muscles of feet. Gradually,
change in shape of foot and clawing of toes. These lead to callus formation under first
metatarsal head or on tip of toes. There is unrecognised trauma, blistering and ulceration. May
cause neuropathic arthropathy (Charcoat’s joint) in the ankle.
 Acute painful neuropathy
Pain is of rapid onset , severe and superficial described as burning , stinging or electrical
shock like pain. there is hyperesthesia. Pain worse at night.
B. Autonomic neuropathy
 Prevalence is difficult to ascertain.
 Affects CVS, GIT, urogenital, sudomotor, respiratory and pupillary function.
Clinical manifestations
 CVS: Increased heart rate, hypotension, sudden cardiac death.
 GIT: Abnormal esophageal motility, dysphagia, Gastroparesis, Diarrhea and constipation
 Urogenital: recurrent infection, Erectile dysfunction, difficulty in micturition, impotence
 Sudomotor: Anhidrosis, Gustatory sweating, fissures in feet.
 Pupil: Decreased pupil size, absent light reflexes
 Vasomotor: Cold feet, pedal edema
C. Asymmetrical motor diabetic neuropathy
 Usually develops in old patients.
 There is asymmetrical, severe and progressive weakness and atrophy of proximal
(quadriceps) muscles of lower limbs. Severe pain in the anterior aspect of leg, and
paraesthesia.
 Weight loss and muscle wasting. Reflexes may be diminished.
 The patient is severely ill and bed ridden.
D. Mononeuropathy
 Dysfunction of cranial nerve or peripheral nerves
 Isolated neuropathies affects 3rd, 6th, 4th, or 7th (Bell’s palsy)
 Occulomotor nerve palsy: Abrupt onset, retro orbital pain, ptosis and ophthalmoplegia
 Femoral or sciatic nerve may be involved.
E. Truncal radiculoneuropathy
 Abrupt onset. Pain over a focal area of chest/abdomen. Worse at night
 Characteristically thoracic and upper lumbar roots are involved.

Examination of neuropathy
 Autonomic function tests: Blood Pressure, Heart rate.
 Assessment of muscle power, sensations of temperature, vibration, joint position and pinprick
in lower limb or affected areas.
 Nerve conduction studies: reduction in amplitude of action potential.
 Vitamin B12 level should be measured.
Management
 Foot care. Strict glucose control
 Mononeuropathies are self-limiting. Do not require any treatment.
 For neuropathic pain: Antiepileptics (Gabapentin, pregabalin, carbamazepine, phenytoin,
valproic acid), Opioids (Tramadol), tri-cyclic antidepressants (imipramine, amitriptyline) . in
refractory cases, duloxetine can be given.
  Diarrhoea: Loperamide, broad spectrum antibiotic (tetracycline).
 Constipation: Bisacodyl, senna.
 Atonic bladder: Catheterization.
 Excessive sweating: oxybutynin, clonidine or glycopyrrolate cream.
 Topical capsaicin can be beneficial.
 Erectile dysfunction: Psychological counselling, sildenafil, vardenafil, tadalafil.
PG-E1 analogue alprostadil can be injected into corpus cavernosum.
 Alpha lipoic acid: Antioxidant. Improves neuropathic symptoms including pain.
 Aldose reductase inhibitor: Tolrestat.
 Methylcobalamin can be given.

OTHER TERMS
PREDIABETICS: Characterized by impaired glucose tolerance but blood sugar level does not reach
criteria for DM. following criteria:
1. Impaired fasting glucose (IFG): Fasting plasma glucose ≥100 but <125 mg/dL.
2. Impaired glucose tolerance (IGT): Plasma glucose between 140 and 200 mg/dL after 2
hour oral glucose.
3. HbA1C: Range between 5.7-6.4%

GESTATIONAL DIABETES MELLITUS (GDM)

 Defined as glucose intolerance or diabetes that develops as first time recognised during
pregnancy.
 Risk factors: history of gestational diabetes, obesity, particular ethnic groups.
 Importance of diagnosis
 Fetal risk if GDM: Intrauterine fetal death, polyhydramnios, respiratory distress ,
 Fetal macrosomia.
 Mother risk if GDM: Risk of preeclamsia, caesarean section.
 Diagnosis: fasting glucose level 85 mg/dL. Two hour after glucose level 140 mg/dL.
Oral glucose tolerance test (OGTT): Performed at 24-28 weeks of gestation. Method: 100 g
glucose is dissolved in 300-400 mL of water and consumed over 5 min.
 Management: Start insulin therapy. Dietary modifications should be done. Oral drugs for diabetes
are avoided.

HYPEROSMOLAR (NONKETOTIC) HYPERGLYCEMIC COMA

 Commonly seen in elderly patients of type 2 DM.
 High glucose level (>600 mg/dl) and high osmolarity (>320 mOsm/L).
 Precipitating factors: infections, stroke, MI, drugs like thiazides, immunosuppressives
, anticancers.
 Clinical features: Due to severe glycosuria, there is dehydration , less urine volume.
Confusion, stupor, coma, convulsion, infections, bleeding, pancreatitis.
 Treatment:
o I.V. regular insulin.
o Fluid replacement (about 10L) should be done as soon as possible.
o Potassium infusion if required and sodium bicarbonate if lactic acidosis.
o Infections: give antibiotics.
o Heparin is given i.v. to prevent thrombosis.