What are the causes of diabetes mellitus?

What Causes Diabetes Mellitus

Diabetes results from defects in insulin secretion, insulin action, or both, leading to chronic hyperglycemia that damages multiple organ systems. 1

Primary Pathogenic Mechanisms

The fundamental causes of diabetes involve two core defects that disrupt glucose metabolism:

Deficient Insulin Secretion

• Pancreatic β-cell dysfunction or destruction prevents adequate insulin production, ranging from complete absence to insufficient compensatory response 1
• The severity of β-cell impairment determines whether patients require exogenous insulin for survival 1
• Progressive β-cell failure occurs over time, with significant reduction already present at diagnosis in most cases 2

Insulin Resistance

• Diminished tissue responses to insulin occur at one or more points in the complex hormone action pathways, affecting carbohydrate, fat, and protein metabolism 1
• Target tissues (skeletal muscle, adipose tissue, liver) fail to respond appropriately to circulating insulin 3
• These two defects frequently coexist in the same patient, making it unclear which abnormality primarily causes the hyperglycemia 1

Type-Specific Etiologies

Type 1 Diabetes (5-10% of cases)

• Autoimmune destruction of pancreatic β-cells causes absolute insulin deficiency 1
• Serological markers include islet cell autoantibodies, anti-insulin antibodies, anti-GAD65 antibodies, and anti-IA-2/IA-2β antibodies present in 85-90% at diagnosis 4
• Genetic markers and HLA associations identify individuals at increased risk 1
• A minority have idiopathic forms with no evidence of autoimmunity, more common in African or Asian ancestry 1

Type 2 Diabetes (90-95% of cases)

• Combination of insulin resistance and inadequate compensatory insulin secretion characterizes this form 1
• Obesity itself causes significant insulin resistance, and most patients with type 2 diabetes are obese 1
• The specific etiologies remain incompletely understood, but autoimmune β-cell destruction does not occur 1
• Lifestyle factors—particularly overeating and physical inactivity—are the major clinical determinants 2
• Genetic susceptibility interacts with environmental factors including nutritious food availability and social determinants of health 3

Secondary Causes of Diabetes

Genetic Defects in β-Cell Function

• Maturity-onset diabetes of the young (MODY) results from monogenetic defects causing hyperglycemia before age 25 years 1
• Most common form involves mutations in hepatocyte nuclear factor (HNF)-1α on chromosome 12 1
• Glucokinase gene mutations on chromosome 7p create defective "glucose sensors" requiring higher glucose levels to trigger insulin secretion 1
• Mitochondrial DNA mutations (particularly position 3,243 in tRNA leucine gene) associate with diabetes and deafness 1

Genetic Defects in Insulin Action

• Insulin receptor mutations cause metabolic abnormalities ranging from hyperinsulinemia with modest hyperglycemia to severe diabetes 1
• Type A insulin resistance syndrome may present with acanthosis nigricans, virilization in women, and enlarged cystic ovaries 1
• Leprechaunism and Rabson-Mendenhall syndrome represent pediatric forms with extreme insulin resistance 1

Diseases of the Exocrine Pancreas

• Diffuse pancreatic injury from pancreatitis, trauma, infection, pancreatectomy, or carcinoma can cause diabetes when damage is extensive 1
• Cystic fibrosis and hemochromatosis damage β-cells and impair insulin secretion when sufficiently extensive 1
• Fibrocalculous pancreatopathy presents with abdominal pain, pancreatic calcifications, fibrosis, and calcium stones in exocrine ducts 1

Endocrinopathies

• Hormone excess states antagonize insulin action: growth hormone (acromegaly), cortisol (Cushing's syndrome), glucagon (glucagonoma), epinephrine (pheochromocytoma) 1
• Diabetes typically occurs in individuals with preexisting insulin secretion defects and resolves when hormone excess is corrected 1
• Somatostatinoma and aldosteronoma-induced hypokalemia inhibit insulin secretion 1

Drug- or Chemical-Induced Diabetes

• Multiple medications impair insulin secretion or action: corticosteroids, thiazide diuretics, beta blockers, estrogen therapy, antipsychotics, immunosuppressants, antiretroviral protease inhibitors 1, 5
• These agents may not cause diabetes independently but precipitate it in susceptible individuals with insulin resistance 1
• Certain toxins (Vacor rat poison, intravenous pentamidine) permanently destroy pancreatic β-cells, though such reactions are rare 1

Clinical Implications

The pathophysiology determines treatment approach: Type 1 diabetes requires insulin replacement for survival, while type 2 diabetes initially responds to lifestyle modifications (weight reduction, exercise) and oral glucose-lowering agents 1, 4

The degree of hyperglycemia reflects the severity of the underlying metabolic process and its treatment rather than the nature of the process itself 1. Progressive β-cell failure dictates the rate of worsening glycemic control regardless of treatment 2, emphasizing the importance of early intervention targeting both insulin resistance and impaired insulin secretion 6.