Q1 LONG ANSWER 10M ★ High-yield

Classify diabetes mellitus. Differentiate type 1 from type 2 and describe the pathogenesis, morphology of complications and acute metabolic emergencies.

Pathology · 2nd Professional — Para-Clinical

Definition and Classification

Diabetes mellitus is a group of metabolic disorders characterised by hyperglycaemia resulting from defects in insulin secretion, insulin action, or both.

Feature	Type 1	Type 2
Share	About 5–10%	About 90%
Age at onset	Usually under 20; peak at puberty	Usually over 40, but falling; increasingly seen in the young in India
Body habitus	Normal or thin	Obese in 80%, especially central obesity
Mechanism	Autoimmune destruction of beta cells → absolute insulin deficiency	Insulin resistance with progressive beta cell failure → relative deficiency
Islet autoantibodies	Present — anti-GAD65, anti-islet cell, anti-insulin, IA-2	Absent
Genetics	HLA-DR3 and DR4 linked; twin concordance about 50%	Not HLA linked; twin concordance 60–90% — a stronger genetic component than type 1
Islet histology	Insulitis — lymphocytic infiltration; later beta cell depletion and islet atrophy	No insulitis; amyloid (amylin/IAPP) deposition; mild beta cell depletion
Ketoacidosis	Prone	Uncommon — tends to hyperosmolar non-ketotic states
Insulin requirement	Always, from onset	Often eventually, but not initially

Other specific types — MODY (autosomal dominant single-gene defects of beta cell function, presenting before 25 without antibodies), pancreatic disease (chronic pancreatitis, fibrocalculous pancreatic diabetes which is important in India, haemochromatosis, carcinoma), endocrine disease (Cushing, acromegaly, phaeochromocytoma), drugs (corticosteroids, thiazides), and gestational diabetes

Pathogenesis

Type 1 — genetic susceptibility (HLA-DQ, DR3/DR4) plus an environmental trigger, possibly viral or dietary → Loss of self-tolerance to beta cell antigens → T cell-mediated destruction with insulitis; autoantibodies are markers rather than the cause → Symptoms appear only when over 90% of beta cells are destroyed → type 2 — obesity and inactivity in a genetically susceptible person → insulin resistance — adipose tissue releases free fatty acids, TNF and resistin, and less adiponectin; muscle and liver respond poorly to insulin → Compensatory beta cell hyperplasia and hyperinsulinaemia maintain normal glucose for years → Beta cell exhaustion and failure — with islet amyloid deposition → overt diabetes

CLINICAL PEARL

Type 2 diabetes is a two-stage disease, and that explains its natural history. Insulin resistance comes first and is compensated for years by hyperinsulinaemia — which is why the condition is silent for so long and why up to half of patients already have complications at diagnosis. Hyperglycaemia appears only when the beta cell can no longer keep pace. Resistance is treatable by weight loss; beta cell loss is not.

Diagnostic Criteria

Test	Diabetes	Prediabetes
Fasting plasma glucose	126 mg/dL (7.0 mmol/L) or more	100–125 — impaired fasting glucose
2-hour value on 75 g oral glucose tolerance test	200 mg/dL (11.1 mmol/L) or more	140–199 — impaired glucose tolerance
HbA1c	6.5% or more	5.7–6.4%
Random glucose with classical symptoms	200 mg/dL or more	—

In the absence of unequivocal hyperglycaemia, the test must be repeated on a separate day to confirm
HbA1c reflects the preceding 8 to 12 weeks and needs no fasting, but is unreliable in anaemia, haemoglobinopathies, pregnancy, recent transfusion and renal failure — all common in India

Morphology of the Complications

Site	Lesion
Blood vessels — MACROvascular	Accelerated atherosclerosis — myocardial infarction (the commonest cause of death), stroke, peripheral vascular disease and gangrene
Blood vessels — MICROvascular	Hyaline arteriolosclerosis (affecting both afferent and efferent arterioles) and diffuse basement membrane thickening
Kidney	Diffuse and nodular (kimmelstiel–WILSON) glomerulosclerosis; papillary necrosis; pyelonephritis
Eye	Non-proliferative retinopathy (microaneurysms, dot and blot haemorrhages, hard exudates, cotton-wool spots) and proliferative retinopathy with neovascularisation; cataract and glaucoma
Nerves	Symmetrical distal sensorimotor polyneuropathy in a "glove and stocking" distribution; autonomic neuropathy (gastroparesis, postural hypotension, silent infarction, impotence); mononeuropathy
Pancreas	Type 1 — insulitis then islet atrophy. Type 2 — islet amyloid
Liver	Fatty change; non-alcoholic steatohepatitis
Skin and soft tissue	Necrobiosis lipoidica, infections, diabetic dermopathy

Acute Metabolic Complications

Feature	Diabetic ketoacidosis	Hyperosmolar hyperglycaemic state
Type	Chiefly type 1	Chiefly type 2, elderly
Glucose	Usually 300–600 mg/dL	Often above 600–1000 mg/dL
Ketones	Markedly raised	Absent or minimal — residual insulin suppresses lipolysis
Acidosis	Present — high anion gap metabolic acidosis	Absent or mild
Osmolality	Variable	Markedly raised
Clinical	Kussmaul breathing, acetone breath, vomiting, abdominal pain, dehydration	Profound dehydration, confusion, coma, focal neurological signs
Mortality	About 5%	Higher — 10 to 20%

Hypoglycaemia is the commonest acute complication of treatment, and may be more immediately dangerous than hyperglycaemia

Applied Aspects

India has one of the largest diabetic populations in the world, with earlier onset, lower body mass index at diagnosis, and a strong tendency to central obesity and insulin resistance — the "Asian Indian phenotype"
Screen annually for complications — fundus examination, urine albumin:creatinine ratio, foot examination with monofilament testing, and lipids. Most complications are silent until advanced
The diabetic foot results from neuropathy, ischaemia and infection together — loss of protective sensation permits unnoticed injury, poor perfusion prevents healing, and hyperglycaemia impairs neutrophil function. It is the commonest cause of non-traumatic amputation, and largely preventable by foot care
Infections are commoner and more severe — tuberculosis, mucormycosis, emphysematous pyelonephritis, malignant otitis externa; diabetes and tuberculosis aggravate each other, which matters greatly in India
Tight glycaemic control reduces MICROvascular complications clearly; macrovascular risk needs blood pressure, lipid and antiplatelet management as well
Gestational diabetes raises the risk of macrosomia, birth injury and neonatal hypoglycaemia, and predicts later type 2 diabetes in the mother — so postnatal follow-up matters
Never omit insulin in type 1 diabetes even when a patient is not eating — stopping it precipitates ketoacidosis, and basal insulin must continue
Foot examination takes two minutes and prevents amputations, yet is the most frequently omitted part of the diabetic review
Metformin remains first-line in type 2 diabetes; newer agents are chosen for their cardiovascular and renal benefits as much as for glucose lowering
Lifestyle intervention prevents progression from prediabetes more effectively than metformin in trials — which makes identifying impaired glucose tolerance worthwhile
Fibrocalculous pancreatic diabetes is a distinctively tropical form seen in young, thin patients in southern India, with pancreatic calculi, steatorrhoea and a high insulin requirement but resistance to ketosis

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