Summary / Overview
- • “Diabetes” comes from Greek diabainein = “to pass through,” referring to excessive urination.
- • “Mellitus” (Latin: honey-sweet) was added because ancient physicians noticed sweet urine due to glycosuria.
- • Type 2 DM is the most common form—typically associated with insulin resistance + β-cell dysfunction.
- Historical Background
- • First clearly distinguished from Type 1 in the mid-20th century when insulin dependence patterns became understood.
- • Strong links identified with lifestyle, urbanization, and genetics, making it a modern global epidemic.
- Core Definition
- • Chronic metabolic disorder caused by insulin resistance + progressive β-cell failure → hyperglycemia.
- • Often asymptomatic for years, diagnosed during routine blood tests or after complications.
- • Preventable in many cases with lifestyle intervention
Etiology
- Genetic predisposition (strongest risk factor)
- • Strong family history → autosomal-polygenic pattern.
- • Multiple risk alleles identified (TCF7L2, FTO, KCNJ11, PPARG).
- • Heritability of T2DM exceeds that of Type 1 DM.
- Insulin resistance
- • Peripheral tissues (muscle, liver, adipose) fail to respond normally to insulin.
- • Leads to increased hepatic gluconeogenesis and reduced glucose uptake.
- β-cell dysfunction (progressive)
- • Chronic metabolic stress → β-cell exhaustion → inadequate insulin secretion.
- • Adipokines (TNF-α, IL-6, resistin) promote inflammation and insulin resistance.
Pathogenesis
- Insulin resistance develops in muscle, liver, and adipose tissue → decreased glucose uptake
- Pancreatic β-cells initially compensate by hypersecretion of insulin
- Chronic insulin resistance + β-cell overwork leads to progressive β-cell failure
- Visceral adiposity releases inflammatory cytokines (IL-6, TNF-α) → worsens insulin resistance
- Free fatty acids (lipotoxicity) impair β-cell insulin secretion and promote apoptosis
- Hepatic insulin resistance increases gluconeogenesis → fasting hyperglycemia
- Incretin defect (↓GLP-1, ↓GIP response) reduces post-meal insulin release
- Islet amyloid (amylin deposition) damages β-cells structurally and functionally
- Type 2 DM begins years before diagnosis. Insulin resistance appears first, driven largely by visceral fat and inflammatory mediators. β-cells respond by increasing insulin secretion, keeping glucose normal at early stages.
Symptoms
- Polyuria from osmotic diuresis caused by excess filtered glucose
- Polydipsia due to dehydration and increased serum osmolality
- Polyphagia despite hyperglycemia — cells cannot utilize glucose efficiently
- Fatigue from impaired glucose uptake in muscle and brain
- Blurred vision due to fluctuating lens osmotic status
- Recurrent infections — especially urinary tract, skin, and fungal infections
- Unintentional weight loss in late disease when insulin deficiency develops
- Paresthesias, burning feet — early peripheral neuropathy symptoms
- Nocturia due to persistent diuresis
- Post-prandial lethargy (“after-meal tiredness”) from glucose spikes
Clinical Features
- Insidious (slow) onset — symptoms develop gradually over years.
- Often detected incidentally during routine blood tests.
Insidious (slow) onset — symptoms develop gradually over years.
Often detected incidentally during routine blood tests.
• Overweight/central obesity (common phenotype)
• Acanthosis nigricans (marker of insulin resistance)
• Skin tags (acrochordons)
• Recurrent infections — candidiasis, skin infections, UTI
• Slow wound healing
• Fatigue, low energy
• Blurred vision (due to fluctuating glucose → lens swelling)
• Polydipsia / polyuria / nocturia
• Polyphagia with weight gain or unexplained weight loss in late-stage insulin deficiency
• Tingling, numbness, burning feet — early peripheral neuropathy
• Erectile dysfunction / reduced libido
• Menstrual irregularities (insulin resistance → hormonal imbalance)
• Hypertension and dyslipidemia commonly coexist (metabolic syndrome)
• Hepatic steatosis / NAFLD signs
• Often asymptomatic until complications appear (neuropathy, retinopathy, proteinuria)
TYPE 2 DIABETES MELLITUS
Complex, multifactorial metabolic disorder
T2DM develops due to a combination of insulin resistance and progressive β-cell dysfunction.
Genetic predisposition (strongest risk factor)
• Strong family history → autosomal-polygenic pattern.
• Multiple risk alleles identified (TCF7L2, FTO, KCNJ11, PPARG).
• Heritability of T2DM exceeds that of Type 1 DM.
Insulin resistance
• Peripheral tissues (muscle, liver, adipose) fail to respond normally to insulin.
• Leads to increased hepatic gluconeogenesis and reduced glucose uptake.
β-cell dysfunction (progressive)
• Chronic metabolic stress → β-cell exhaustion → inadequate insulin secretion.
• Loss of first-phase insulin release is an early hallmark.
Obesity and adipose dysfunction
• Visceral (central) obesity strongly linked.
• Adipokines (TNF-α, IL-6, resistin) promote inflammation and insulin resistance.
• Adiponectin (insulin-sensitizing hormone) is reduced.
Sedentary lifestyle
• Decreased muscle glucose utilization → increased insulin resistance.
Dietary factors
• Excess refined carbohydrates, sugary drinks, high glycemic load diet.
• High saturated fats → worsens insulin resistance.
Environmental and lifestyle factors
• Urbanization, stress, sleep deprivation, circadian disruption.
• Endocrine disruptors (BPA, phthalates) under investigation.
Age
Risk rises sharply after 40–45 years, but now seen in younger adults and adolescents.
Metabolic syndrome
• Central obesity
• Hypertension
• Dyslipidemia (↑TG, ↓HDL)
• Insulin resistance
—All increase T2DM risk.
Intrauterine and early life factors
• Low birth weight
• Gestational diabetes exposure
• Childhood obesity
—program future insulin resistance.
Certain medications
• Glucocorticoids
• Antipsychotics (olanzapine, clozapine)
• HIV protease inhibitors
• Thiazide diuretics (long-term)
Associated conditions
• PCOS (polycystic ovarian syndrome)
• NAFLD
• Sleep apnea
Not autoimmune (unlike Type 1 DM)
No islet autoantibodies are involved.
Insulin resistance develops in muscle, liver, and adipose tissue → decreased glucose uptake
Pancreatic β-cells initially compensate by hypersecretion of insulin
Chronic insulin resistance + β-cell overwork leads to progressive β-cell failure
Visceral adiposity releases inflammatory cytokines (IL-6, TNF-α) → worsens insulin resistance
Free fatty acids (lipotoxicity) impair β-cell insulin secretion and promote apoptosis
Hepatic insulin resistance increases gluconeogenesis → fasting hyperglycemia
Incretin defect (↓GLP-1, ↓GIP response) reduces post-meal insulin release
Islet amyloid (amylin deposition) damages β-cells structurally and functionally
Chronic hyperglycemia (glucotoxicity) impairs insulin gene expression
Oxidative & ER stress accelerate β-cell decline over years
Type 2 DM begins years before diagnosis. Insulin resistance appears first, driven largely by visceral fat and inflammatory mediators. β-cells respond by increasing insulin secretion, keeping glucose normal at early stages.
Over time, β-cells exhaust, lose mass and function, and insulin secretion becomes insufficient → hyperglycemia appears.
Islet amyloid deposition is characteristic of long-standing T2DM and correlates with declining C-peptide levels.
Origin & Naming
• “Diabetes” comes from Greek diabainein = “to pass through,” referring to excessive urination.
• “Mellitus” (Latin: honey-sweet) was added because ancient physicians noticed sweet urine due to glycosuria.
• Type 2 DM is the most common form—typically associated with insulin resistance + β-cell dysfunction.
Historical Background
• First clearly distinguished from Type 1 in the mid-20th century when insulin dependence patterns became understood.
• Strong links identified with lifestyle, urbanization, and genetics, making it a modern global epidemic.
Core Definition
• Chronic metabolic disorder caused by insulin resistance + progressive β-cell failure → hyperglycemia.
• Often asymptomatic for years, diagnosed during routine blood tests or after complications.
Key Facts
• Most common form of diabetes worldwide
• Caused by insulin resistance + β-cell exhaustion
• Strong genetic and lifestyle influences
• Preventable in many cases with lifestyle intervention
Polyuria from osmotic diuresis caused by excess filtered glucose
Polydipsia due to dehydration and increased serum osmolality
Polyphagia despite hyperglycemia — cells cannot utilize glucose efficiently
Fatigue from impaired glucose uptake in muscle and brain
Blurred vision due to fluctuating lens osmotic status
Recurrent infections — especially urinary tract, skin, and fungal infections
Unintentional weight loss in late disease when insulin deficiency develops
Paresthesias, burning feet — early peripheral neuropathy symptoms
Nocturia due to persistent diuresis
Post-prandial lethargy (“after-meal tiredness”) from glucose spikes
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