I-9. Pathogenesis of Type 2 diabetes mellitus

2型糖尿病の発症機序

Overview

Target tissues stop responding to insulin (insulin resistance) → relative insulin deficiency. β-cells compensate by overproducing insulin (hyperinsulinemia), eventually leading to a slow decline of β-cells.

Type 2 Diabetes Mellitus

Non-insulin-dependent (NIDDM), adult onset:

>90% of diabetics, adult onset (>35 yrs, peak 45–64), with obesity/overweight and physical inactivity. Mild or asymptomatic, no ketoacidosis, insulin resistance (relative deficiency), and slow β-cell depletion.

Genetic & Environmental Factors

Genetic: many susceptibility loci, with very high twin concordance (72%). Lifetime risk: everyone 30%, one diabetic parent 40%, two 70%.
- TCF7L2 polymorphism strongly associated: TCF7L2 normally ↑GLP-1 expression (GLP-1 helps insulin store energy), and the SNP blocks TCF7L2 → ↓GLP-1 action → inhibits insulin secretion.
Environmental triggers: excess energy intake + obesity, fast-absorbing processed foods, sedentary lifestyle. Risk ↑ with other metabolic abnormalities (prediabetes, hypertension, hypercholesterolemia, hypertriglyceridemia).

Risk Factors

Non-modifiable: age (~25% above 80, rising above 50), urban/rural setting.
Modifiable: body weight, diet, physical inactivity, education, hypertension, hypercholesterolemia.

Natural History

Genetic + environment → insulin resistance, then β-cells ↑mass/secretion to compensate → normal glucose (mild macrovascular injury/AS already begins).
Prediabetes: β-cells exhaust → ↓secretion. High glucose → glucotoxicity kills β-cells, while ↓PKA inhibition → ↑hepatic FFA release → lipotoxicity. Microvascular complications develop, seen with macrovascular injury/AS in overt T2DM.

Insulin Resistance (3 target tissues)

Skeletal muscle: ↓glucose uptake, ↑FA oxidation.
Liver: ↑gluconeogenesis (↑hepatic glucose output), ↑triglyceride/VLDL secretion.
Adipose tissue: lipolysis not inhibited → FFA released as substrate for hepatic TAG/VLDL. Fat is the most insulin-responsive tissue — hence in T1DM (no insulin) extreme lipolysis → ketoacidosis, whereas T2DM (some insulin) → no ketoacidosis.

Molecular mechanisms

Reduced insulin-signaling cascade, mainly via interference at IRS (insulin receptor substrate):
- Ectopic fat: ↑DAG + ↑ceramide → PKC → inhibits IRS.
- Inflammation: ↑TNF-α + DAMPs → NF-κB/MAPK/JNK → inhibits IRS.
- Glucocorticoids/11β-HSD1: activates cortisol → JNK → blocks IRS.

β-Cell Biology

Insulin secretion

Glucose → GLUT2 into β-cell → glycolysis → ATP → closes K_ATP channels → depolarization → opens voltage-dependent Ca²⁺ channels → ↑[Ca²⁺] → insulin exocytosis. GLP-1/GIP add a cAMP signal. (Phase 1 is rapid, Phase 2 sustained via oxidative phosphorylation.)

Glucotoxicity

Excess glucose → oxidative stress → JNK → ↓insulin production. ↓insulin → no FOXO1 inhibition → ↓β-cell survival, ↑apoptosis.
Short-term hyperglycemia stimulates β-cells, while long-term hyperglycemia induces β-cell death.

Diagnosis

T2DM often lacks classic signs → needs two separate abnormal glucose tests.
Thresholds: fasting ≥7.0 mmol/L, random ≥11.1 mmol/L, postprandial ≥11.1 mmol/L at 2 h (75 g OGTT), HbA1c ≥ 6.5% (single test, advantage).
Aggressive treatment/lifestyle change can achieve remission in some patients.

Screening & prediabetes

Population screening via OGTT (75 g, 2 h) or HbA1c.
IFG (impaired fasting glucose): fasting 6.1–6.9 mmol/L. IGT (impaired glucose tolerance): OGTT 120 min ≥7.8 mmol/L.

Treatment

Metformin
Sulfonylureas
GLP-1 receptor agonist

一問一答

▶What is the core pathophysiology of Type 2 diabetes?

Target tissues stop responding to insulin (insulin resistance) → relative insulin deficiency; β-cells compensate with hyperinsulinemia, eventually leading to slow β-cell decline.

▶What are the defining features of Type 2 diabetes?

>90% of diabetics, adult onset (>35 yrs, peak 45–64), associated with obesity/inactivity, mild or asymptomatic, no ketoacidosis, insulin resistance (relative deficiency), and slow β-cell depletion.

▶How strong is the genetic contribution to T2DM?

Very high — twin concordance 72%; lifetime risk is 30% generally, 40% with one diabetic parent, and 70% with two.

▶How does the TCF7L2 polymorphism contribute to T2DM?

TCF7L2 normally increases GLP-1 expression (which helps insulin store energy); the SNP blocks TCF7L2 → ↓GLP-1 action → inhibited insulin secretion.

▶What are the three insulin-resistant target tissues and their changes?

Skeletal muscle (↓glucose uptake, ↑FA oxidation), liver (↑gluconeogenesis, ↑TAG/VLDL secretion), and adipose tissue (uninhibited lipolysis → FFA release).

▶Why does T1DM cause ketoacidosis but T2DM usually does not?

Fat is the most insulin-responsive tissue; T1DM (no insulin) causes extreme lipolysis → ketoacidosis, whereas T2DM (some insulin) suppresses enough lipolysis to avoid ketoacidosis.

▶What molecular mechanisms cause insulin resistance at the IRS level?

Ectopic fat (↑DAG + ceramide → PKC), inflammation (TNF-α + DAMPs → NF-κB/MAPK/JNK), and glucocorticoids/11β-HSD1 (cortisol → JNK) all inhibit the insulin receptor substrate (IRS).

▶Describe the mechanism of glucose-stimulated insulin secretion.

Glucose enters the β-cell via GLUT2 → glycolysis → ↑ATP → closes K_ATP channels → depolarization → opens voltage-gated Ca²⁺ channels → ↑[Ca²⁺] → insulin exocytosis (GLP-1/GIP add a cAMP signal).

▶What is glucotoxicity in T2DM?

Excess glucose → oxidative stress → JNK → ↓insulin production; ↓insulin removes FOXO1 inhibition → ↓β-cell survival and ↑apoptosis (long-term hyperglycemia kills β-cells).

▶What is the natural history of T2DM?

Genetic + environmental factors → insulin resistance with compensatory β-cell hypersecretion (normoglycemia, early atherosclerosis) → prediabetes (β-cell exhaustion, glucotoxicity, lipotoxicity) → overt T2DM with micro/macrovascular complications.

▶What are the diagnostic thresholds for T2DM?

Fasting ≥7.0 mmol/L, random ≥11.1 mmol/L, 2-h postprandial ≥11.1 mmol/L (75 g OGTT), or HbA1c ≥6.5%; usually requires two separate abnormal tests.

▶How are IFG and IGT defined?

IFG (impaired fasting glucose): fasting 6.1–6.9 mmol/L; IGT (impaired glucose tolerance): OGTT 120-min ≥7.8 mmol/L.

▶What is the first-line stepwise pharmacological treatment of T2DM?

1) Metformin, 2) sulfonylureas, 3) GLP-1 receptor agonist.

▶What are the modifiable and non-modifiable risk factors for T2DM?

Non-modifiable: age, urban/rural setting. Modifiable: body weight, diet, physical inactivity, education, hypertension, hypercholesterolemia.

▶How does lipotoxicity arise in prediabetes/T2DM?

Reduced PKA inhibition → ↑hepatic FFA release → lipotoxicity, which along with glucotoxicity contributes to β-cell loss.

▶How does short-term vs long-term hyperglycemia affect β-cells?

Short-term hyperglycemia stimulates β-cells (more insulin), while long-term hyperglycemia induces β-cell death.

▶What environmental factors trigger T2DM?

Excess energy intake with obesity, fast-absorbing processed foods, and a sedentary lifestyle; risk rises with prediabetes, hypertension, hypercholesterolemia, and hypertriglyceridemia.

▶Can T2DM go into remission?

Yes — aggressive treatment and lifestyle change can achieve remission in some patients.

▶Why does the liver worsen hyperglycemia and dyslipidemia in T2DM?

Hepatic insulin resistance increases gluconeogenesis (↑glucose output) and increases triglyceride/VLDL secretion.

▶How are populations screened for T2DM and prediabetes?

Via OGTT (75 g, 2 h) or HbA1c.