What is the primary cause of type 2 diabetes mellitus?

Primary Cause of Type 2 Diabetes Mellitus

Type 2 diabetes is fundamentally caused by the combination of peripheral insulin resistance and relative insulin deficiency due to impaired beta-cell function, though the exact primary sequence remains debated. 1

Core Pathophysiologic Mechanisms

The American Diabetes Association defines type 2 diabetes as a condition where individuals have relative (rather than absolute) insulin deficiency combined with peripheral insulin resistance (decreased biological response to insulin). 1 While the specific etiologies are not fully known, autoimmune destruction of beta-cells does not occur. 1

The Dual Defect Model

Both defects are required for type 2 diabetes to manifest clinically:

• Insulin resistance primarily affects skeletal muscle glucose metabolism and is often the earliest detectable abnormality 2
• Beta-cell dysfunction manifests as a relative defect in glucose-stimulated insulin secretion that is insufficient to compensate for the insulin resistance 1
• As long as pancreatic beta cells can compensate for insulin resistance, glucose tolerance remains normal 2

Debate on Primary Event

There is ongoing debate about which defect occurs first:

• Traditional paradigm: Insulin resistance is the primary defect, leading to compensatory hyperinsulinemia and eventual beta-cell exhaustion 1, 2
• Alternative theory: Hyperinsulinemia may be the distinct first event, with primary factors being hypersecretion from beta cells and/or reduced hepatic insulin clearance 1
• Studies in Black African populations consistently show hyperinsulinemia as the most characteristic early feature, characterized by higher insulin secretion and lower insulin clearance 1

Major Contributing Factors

Obesity and Excess Weight

Excess weight is the single most important modifiable risk factor:

• Most (but not all) people with type 2 diabetes have overweight or obesity 1
• Excess weight itself causes insulin resistance 1
• Nine of 10 cases of type 2 diabetes are related to BMI in the overweight or obese range 1
• Even individuals without obesity by traditional criteria may have increased abdominal fat distribution, including visceral fat and ectopic fat deposition 1

Physical Inactivity

• Lack of physical activity is a major modifiable risk factor that increases diabetes risk 1
• Physical inactivity often precedes development of insulin resistance in offspring of type 2 diabetic patients 2

Genetic Predisposition

Type 2 diabetes has a stronger genetic component than type 1 diabetes:

• Strong family history in first-degree relatives is a major risk factor (more so than other known risk factors) 1
• Clustering in certain families and ethnic populations points to strong genetic background 2
• However, environmental factors are usually required to unmask the genes 2

Age

• Risk increases with age, with screening recommended starting at age 35 years for all patients 1

Racial and Ethnic Factors

Type 2 diabetes occurs more frequently in certain racial/ethnic subgroups:

• African American, Native American, Hispanic/Latino, and Asian American populations 1
• These disparities are driven by both genetic factors and social determinants of health 1

Other Risk Factors

• Prior gestational diabetes mellitus 1
• Polycystic ovary syndrome 1
• Hypertension 1
• Dyslipidemia 1
• Prediabetes (impaired fasting glucose or impaired glucose tolerance) 1

Clinical Implications

The progressive nature of beta-cell decline means:

• Early in disease course, insulin levels may appear normal or elevated, but glucose normalization fails due to relative insulin secretion defects 1
• Insulin resistance may improve with weight reduction, physical activity, and/or pharmacologic treatment but is seldom restored to normal 1
• Approximately one-third of patients with type 2 diabetes require insulin therapy during their lifetime due to progressive beta-cell failure 3

Important Caveats

• The pathophysiology may differ across populations, particularly in Black African populations who present with hyperinsulinemia as a primary feature 1
• Current understanding and clinical guidelines are largely based on studies of predominantly White European populations 1
• Type 2 diabetes develops as a consequence of interaction between genetic predisposition ("thrifty genes") and hostile affluent environment 2