Maturity-onset diabetes of the young (MODY) is an autosomal dominantly inherited type of diabetes that results from heterozygous mutations in various transcription factors acting in the development and maturation of pancreatic β-cells. In addition, mutations in enzymes involved in glucose sensing of the β-cell have also been shown to result in early-onset diabetes. Characteristic features of MODY are autosomal inheritance, early onset of diabetes (with diagnosis generally before the age of 25 years), no signs related to the autoimmune process or insulin resistance, and preservation of endogenous insulin secretion.
MODY subtypes: gene mutations, pathophysiology, and clinical characteristics
| MODY | Gene | Pathophysiology | Clinical characteristics |
| 1 | HNF4A | Transcription factor; decreased insulin secretion | Rare (5%); neonatal hyperinsulinemia, low triglycerides, tendency for microvascular complications, sensitivity to sulfonylureas |
| 2 | GCK | Decreased glucose sensitivity due to phosphorylation defect; decreased glycogen storage | Common (30–50%); increased fasting glucose, increased likelihood of glucose < 55 mg/dL on oral glucose tolerance test; mild diabetes that generally does not require anti-diabetes medication |
| 3 | HNF1A | Transcription factor; decreased insulin secretion, progressive β-cell damage | Common (30–50%), high penetrance; glycosuria, microvascular complications, sensitivity to sulfonylurea |
| 4 | PDX1/IPF1 | Impaired pancreas development; homozygotes experience pancreas agenesis | Rare (1%); mean age at diagnosis 35 years, requires oral antidiabetes treatment (and insulin) |
| 5 | HNF1B | Transcription factor; decreased insulin secretion | Rare (5%); extra pancreatic signs (renal cysts or dysplasia, genital abnormalities in females, azoospermia in males) with diabetes; variable phenotype; requires insulin treatment |
| 6 | NEUROD1 | Abnormal development of β-cell functions | Very rare ( < 1%); adult-onset diabetes |
| 7 | KLF11 | Tumor-suppressor gene; decreased glucose sensitivity of β-cells | Very rare ( < 1%); phenotype resembling type 2 diabetes |
| 8 | CEL | Decreased endocrine and exocrine pancreas functions (pathophysiology?) | Very rare ( < 1%); typically autosomal dominant diabetes |
| 9 | PAX4 | Transcription factor affecting apoptosis and proliferation of β-cells | Very rare ( < 1%); possible ketoacidosis |
| 10 | INS | Heterozygous mutation of the insulin gene | Very rare ( < 1%); diabetes onset before 20 years of age; sulfonylurea or insulin treatment is generally required |
| 11 | BLK | Heterozygous mutation affecting insulin secretion | Very rare ( < 1%); increased penetrance with higher body mass indexes |
| 12 | ABCC8 | ATP-sensitive potassium channels dysfunction | Very rare ( < 1%); clinical phenotype is similar to HNF1A/4A-MODY |
| 13 | KCNJ11 | ATP-sensitive potassium channels dysfunction | Very rare ( < 1%); clinical phenotype is heterogenous |
| 14 | APPL1 | Adaptor protein | Impaired glucose-mediated insulin secretion. Hyperglycemia. Reduced beta cell survival |
References:
- Anık A, Çatlı G, Abacı A, Böber E. Maturity-onset diabetes of the young (MODY): an update. J Pediatr Endocrinol Metab. 2015 Mar;28(3-4):251-63. [Medline]
- Kant R, Davis A, Verma V. Maturity-Onset Diabetes of the Young: Rapid Evidence Review. Am Fam Physician. 2022 Feb 1;105(2):162-167. [Medline]
- Delvecchio M, Pastore C, Giordano P. Treatment Options for MODY Patients: A Systematic Review of Literature. Diabetes Ther. 2020 Aug;11(8):1667-1685. [Medline]
- Younis H, Ha SE, Jorgensen BG, Verma A, Ro S. Maturity-Onset Diabetes of the Young: Mutations, Physiological Consequences, and Treatment Options. J Pers Med. 2022 Oct 25;12(11):1762. [Medline]
Created Jun 08, 2023.
