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Explain diabetes Mellitus

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Diabetes Mellitus

Source: Robbins, Cotran & Kumar - Pathologic Basis of Disease, Chapter 24: The Endocrine System

Definition

Diabetes mellitus is a group of metabolic disorders sharing the common feature of hyperglycemia caused by defects in insulin secretion, insulin action, or - most commonly - both. Chronic hyperglycemia leads to secondary damage in multiple organ systems, especially the kidneys, eyes, nerves, and blood vessels.

Epidemiology

Affects >30 million people (>11% of the US population)
~1.9 million have Type 1; the vast majority (~90-95%) have Type 2
~96 million US adults have prediabetes
WHO estimates 422 million people with diabetes worldwide
7th leading cause of death in the USA
Total yearly cost in the US: ~$327 billion

Diagnosis (ADA/WHO Criteria)

Normal blood glucose: 70-120 mg/dL

Diabetes is diagnosed by any one of the following (confirmed on a separate day, except random glucose with symptoms):

Test	Diabetes	Prediabetes
Fasting plasma glucose	≥126 mg/dL	100-125 mg/dL
Random plasma glucose	≥200 mg/dL (with symptoms)	-
2-hr glucose (OGTT, 75g)	≥200 mg/dL	140-199 mg/dL
HbA1c	≥6.5%	5.7-6.4%

Classification

Type 1 Diabetes (T1D) - ~5-10%

Autoimmune destruction of pancreatic β-cells causing absolute insulin deficiency.

Most common in patients <20 years, but can occur at any age
Requires insulin for survival
Risk of diabetic ketoacidosis (DKA)
LADA (Latent Autoimmune Diabetes in Adults) is a slowly progressive adult form

Type 2 Diabetes (T2D) - ~90-95%

Combination of peripheral insulin resistance + relative insulin deficiency (inadequate β-cell compensatory response).

Most individuals are overweight/obese
Prevalence rising sharply in children and adolescents

Other Forms

Monogenic diabetes: MODY (Maturity-Onset Diabetes of the Young) - genetic defects in β-cell function or insulin action
Gestational diabetes: glucose intolerance first recognized during pregnancy
Secondary causes: pancreatitis, Cushing syndrome, acromegaly, drug-induced

Glucose Homeostasis (Normal)

Glucose is tightly regulated by three processes:

Hepatic glucose production (gluconeogenesis + glycogenolysis)
Peripheral glucose uptake (mainly skeletal muscle)
Insulin/glucagon balance

Fasting: low insulin, high glucagon → hepatic glucose release prevents hypoglycemia
Post-meal: insulin rises, glucagon falls → glucose uptake in muscle and fat

Insulin secretion from β-cells: triggered by rising blood glucose → glucose enters β-cell via GLUT2 → metabolized → ↑ATP/ADP ratio → closes K⁺-ATP channels → membrane depolarization → Ca²⁺ influx → insulin granule exocytosis (first-phase rapid, second-phase sustained)

Pathogenesis of Type 1 Diabetes

T1D is an autoimmune disease - immune effector cells attack endogenous β-cell antigens.

Genetic Susceptibility

HLA gene cluster contributes ~50% of genetic risk
90-95% of European patients carry HLA-DR3 or HLA-DR4 (vs ~40% of normal subjects)
40-50% of T1D patients are DR3/DR4 compound heterozygotes (vs 5% of normal subjects)
DR3 or DR4 + DQ8 haplotype = highest inherited risk
Other susceptibility genes: CTLA4, PTPN22, STAT3, AIRE mutations

Environmental Factors

Viral infections may trigger islet autoimmunity through molecular mimicry (viral epitopes cross-react with islet antigens)
Diet, gut microbiome, and hygiene hypothesis also implicated

Mechanisms of β-Cell Destruction

CD8⁺ cytotoxic T cells directly kill β-cells
CD4⁺ Th1 cells activate macrophages that produce cytokines damaging β-cells
Autoantibodies (anti-insulin, anti-GAD65, anti-IA-2) are markers of T1D but not primary effectors
Progressive loss of β-cell mass over years before clinical presentation

Pathogenesis of Type 2 Diabetes

Two central defects:

1. Insulin Resistance

Tissues (especially skeletal muscle, liver, adipose) fail to respond normally to insulin.

Key contributor - Obesity:

Development of Type 2 Diabetes - Obesity leads to insulin resistance via adipokines, FFAs, and inflammation, eventually causing β-cell failure

Free fatty acids (FFAs): Central adipose tissue is highly lipolytic; excess FFAs accumulate toxic lipid intermediates (DAG, ceramides) that impair insulin receptor signaling and activate inflammatory pathways. In the liver, attenuated insulin signaling unleashes phosphoenolpyruvate carboxykinase, driving excess gluconeogenesis.
Adipokines: Adipose tissue secretes hormones. Adiponectin (which improves insulin sensitivity) is reduced in obesity, worsening resistance.
Inflammation: Excess FFAs and glucose activate the inflammasome in macrophages and β-cells → IL-1β secretion → proinflammatory cytokine cascade → insulin resistance at peripheral tissues.

2. β-Cell Failure

Initially, β-cells compensate by secreting more insulin (hyperinsulinemia). Over time, sustained demands lead to:

β-cell exhaustion and reduced mass (partly from amyloid deposition - islet amyloid polypeptide/IAPP)
Glucotoxicity and lipotoxicity accelerate β-cell dysfunction
Eventually, insulin secretion is inadequate → frank hyperglycemia

Mechanisms of Vascular Complications (Common to T1D & T2D)

Three major biochemical pathways drive end-organ damage:

1. Advanced Glycation End-products (AGEs)

Glucose non-enzymatically glycates proteins and lipids → AGEs
AGEs bind RAGE receptors on endothelial cells, smooth muscle, macrophages → release of cytokines (TGF-β, VEGF), ROS, and procoagulant factors → basement membrane thickening, vascular injury

2. Protein Kinase C (PKC) Activation

Hyperglycemia → excess diacylglycerol (DAG) synthesis → PKC activation → overproduction of VEGF (retinopathy), TGF-β (glomerulosclerosis), and PAI-1 (thrombosis)

3. Polyol Pathway & Oxidative Stress

In insulin-independent tissues (nerves, lens, kidney, vessels): excess glucose → aldose reductase converts glucose to sorbitol (polyol pathway)
This depletes NADPH → impairs glutathione regeneration → ↑ oxidative stress
Sorbitol accumulation in the lens contributes to cataracts

Long-Term Complications

Macrovascular Disease

Most common cause of death in long-standing diabetes
2-4× higher risk of coronary artery disease
4× higher risk of dying from cardiovascular complications
Risk elevated even at the prediabetes stage
~75% of T2D patients have hypertension, which amplifies vascular damage
Diabetic dyslipidemia: ↑ triglycerides, ↑ LDL, ↓ HDL

Diabetic Nephropathy

Leading cause of end-stage renal disease in the USA
30-40% of all diabetic patients develop clinical nephropathy
Earliest sign: microalbuminuria (30-300 mg/day urinary albumin)
Progresses to macroalbuminuria → hypertension → ESRD
Morphology: glomerular basement membrane thickening, diffuse and nodular glomerulosclerosis (Kimmelstiel-Wilson nodules)

Diabetic Ocular Disease

60-80% of patients develop diabetic retinopathy - leading cause of adult blindness in the USA
Key lesion: neovascularization driven by VEGF
Also: cataracts (sorbitol), glaucoma

Diabetic Neuropathy

Most common complication: peripheral neuropathy (symmetric, distal sensorimotor)
Also: autonomic neuropathy (gastroparesis, orthostatic hypotension, impotence)
Affects up to 50% overall; up to 80% of those with disease >15 years

Infections

Impaired neutrophil function and poor tissue perfusion increase susceptibility
Foot infections → gangrene → leading cause of nontraumatic limb amputation

Acute Metabolic Complications

Feature	Diabetic Ketoacidosis (DKA)	Hyperosmolar Hyperglycemic State (HHS)
Type	Mainly T1D	Mainly T2D
Mechanism	Absolute insulin deficiency → lipolysis → ketones	Severe dehydration + hyperglycemia without significant ketosis
Blood glucose	Usually 250-600 mg/dL	Often >600 mg/dL
Ketones	Strongly positive	Minimal
pH	<7.3	Usually normal
Risk	Coma, death	Coma, death

Morphology Summary

Type	Pancreatic Changes
T1D	Insulitis (lymphocytic infiltrate), marked reduction in islet cell mass
T2D	Amyloid deposition in islets (IAPP/islet amyloid polypeptide), mild reduction in β-cell mass

Classic Triad of Symptoms

Symptom	Mechanism
Polyuria (excess urination)	Glucosuria → osmotic diuresis
Polydipsia (excess thirst)	Dehydration from osmotic diuresis
Polyphagia (excess hunger)	Impaired glucose utilization at cellular level
Weight loss (especially T1D)	Catabolism - muscle/fat breakdown for energy
Blurred vision	Osmotic changes in lens

Key Summary

T1D: Autoimmune → absolute insulin deficiency → requires exogenous insulin
T2D: Insulin resistance + relative insulin deficiency → begins with lifestyle/pharmacotherapy, may eventually need insulin
Complications arise from chronic hyperglycemia damaging blood vessels and nerves via AGEs, PKC activation, and oxidative stress
Severity of complications correlates directly with both the degree and duration of hyperglycemia - tight glycemic control demonstrably reduces end-organ damage

- Robbins, Cotran & Kumar Pathologic Basis of Disease, Chapter 24, pp. 997-1010

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