Monogenic, Secondary & Drug-Induced Diabetes

Maturity-onset diabetes of the young (MODY)

Recognizing MODY. MODY is a single-gene defect of β-cell function that accounts for roughly 1–2% of diabetes. Clues are autosomal dominant inheritance (often three affected generations), onset usually before age 25, a nonobese patient, absent islet autoantibodies, C-peptide still detectable years after diagnosis, and no ketoacidosis. Many patients carry a type 1 or type 2 label for years; genetic testing matters because the gene dictates therapy.

GCK-MODY. Heterozygous inactivating glucokinase mutations shift the glucose level at which β cells respond upward, so glucose is regulated normally but around a higher set point. The mild hyperglycemia is present from birth, is nonprogressive, and rarely causes complications, so drugs are usually unnecessary and barely change HbA1c. In pregnancy the fetal genotype matters: a fetus that did not inherit the mutation overgrows on maternal hyperglycemia and treatment is considered, whereas an affected fetus senses glucose like its mother and grows normally.

HNF1A- and HNF4A-MODY. These transcription-factor defects cause progressive loss of insulin secretion and the usual microvascular complications. HNF1A regulates SGLT2 in the proximal tubule, so glycosuria appears before marked hyperglycemia; it also drives CRP transcription, leaving high-sensitivity CRP unusually low. Both forms are exquisitely sensitive to low-dose sulfonylureas, which often replace insulin. HNF4A-MODY can announce itself at birth with macrosomia and transient hyperinsulinemic hypoglycemia.

Neonatal, mitochondrial and autoimmune variants

Neonatal diabetes. Diabetes diagnosed before 6 months of age is almost never autoimmune and should prompt genetic testing. The most common permanent causes are activating mutations of KCNJ11 (Kir6.2) or ABCC8 (SUR1): the K_ATP channel stays open, the β cell stays hyperpolarized, calcium never enters, and insulin is not released. High-dose oral sulfonylureas such as glyburide close the channel and usually allow insulin injections to stop. Severe KCNJ11 mutations also affect channels in brain and muscle, producing DEND syndrome (developmental delay, epilepsy, neonatal diabetes). Transient neonatal diabetes usually reflects 6q24 imprinting abnormalities and can recur later in life.

Mitochondrial diabetes. Maternally inherited diabetes and deafness is caused by the m.3243A>G mutation in the mitochondrial tRNA-Leu gene, the same variant that causes MELAS. Sensorineural hearing loss often precedes a progressive, insulin-deficient diabetes, and heteroplasmy makes severity variable within families. Metformin is avoided because of lactic acidosis risk. Wolfram syndrome (WFS1, autosomal recessive) also combines diabetes and deafness, with diabetes insipidus and optic atrophy.

Latent autoimmune diabetes of adults (LADA). LADA begins after about age 30, often in a lean patient, and is controlled without insulin for at least 6 months, but GAD65 antibodies reveal slowly progressive autoimmune β-cell destruction. Insulin becomes necessary within months to years, so the diagnosis should be considered when "type 2 diabetes" fails oral agents early; sulfonylureas are generally avoided.

Secondary diabetes: pancreas and hormones

Pancreatogenic (type 3c) diabetes. Chronic pancreatitis, cystic fibrosis, hemochromatosis (iron deposition in islets and liver, the "bronze diabetes"), pancreatic cancer and pancreatectomy destroy α cells along with β cells. Patients therefore lack glucagon as well as insulin, giving labile, hypoglycemia-prone diabetes, usually with exocrine insufficiency and steatorrhea. Cystic fibrosis–related diabetes is screened with a yearly oral glucose tolerance test from age 10, and new diabetes with weight loss in an older adult should prompt a search for pancreatic cancer.

Counter-regulatory hormone excess. Cortisol increases hepatic gluconeogenesis and causes insulin resistance (Cushing syndrome); GH promotes lipolysis and insulin resistance (acromegaly); catecholamines stimulate glycogenolysis and suppress insulin secretion through α2 receptors (pheochromocytoma); thyrotoxicosis causes milder hyperglycemia; and hypokalemia in primary aldosteronism impairs insulin release. Removing the hormone source often reverses the diabetes.

Islet-cell tumors. Glucagonoma, an α-cell tumor, causes diabetes with necrolytic migratory erythema (a migrating, blistering rash of the groin, perineum and legs), weight loss, deep venous thrombosis, stomatitis and depression. Somatostatinoma, a δ-cell tumor, causes diabetes with gallstones, steatorrhea and hypochlorhydria, because somatostatin inhibits insulin, CCK, pancreatic enzyme secretion and gastrin.

Drug-induced diabetes

Direct β-cell injury. Pentamidine lyses β cells: stored insulin spills out and can cause severe hypoglycemia in the first days, and the lost β-cell mass later leaves insulin-deficient diabetes that may be permanent. Checkpoint inhibitors (PD-1 or PD-L1 blockade) can unleash rapid autoimmune destruction of β cells, producing sudden severe hyperglycemia, often diabetic ketoacidosis at presentation, very low or undetectable C-peptide, and GAD65 antibodies in about half. The diabetes is permanent, requires lifelong insulin and does not respond to glucocorticoids.

Severe insulin resistance

Insulin receptor mutations. Mutations of INSR form a spectrum: Donohue syndrome (leprechaunism) with intrauterine growth restriction, elfin facies, extreme hyperinsulinemia and death in infancy; Rabson–Mendenhall syndrome of intermediate severity; and type A insulin resistance, usually seen in lean adolescent girls with hyperandrogenism and acanthosis nigricans.

Type B insulin resistance. Autoantibodies against the insulin receptor, typically in a woman with SLE or another autoimmune disease, cause extreme insulin resistance requiring thousands of units daily; some antibodies instead act as agonists and cause hypoglycemia. Immunosuppression is the treatment.

Lipodystrophy. Congenital or acquired loss of adipose tissue leaves too little leptin and nowhere to store fat, causing severe insulin resistance, fatty liver and marked hypertriglyceridemia; recombinant leptin (metreleptin) improves the metabolic picture.

Acanthosis nigricans, velvety hyperpigmented plaques of the neck, axillae and groin, forms when high insulin levels cross-activate IGF-1 receptors on keratinocytes and fibroblasts; it accompanies obesity and every severe insulin-resistance syndrome. Sudden, extensive acanthosis in a thin older adult suggests gastric adenocarcinoma.