Clinical Pearls & Morning Reports
Published February 19, 2020
Monogenic diabetes is caused by alteration of a single gene. Types of monogenic diabetes include maturity-onset diabetes of the young, neonatal diabetes, and syndromic forms of diabetes. Read the Case Records of the Massachusetts General Hospital here.
Q: What are some of the features of maturity-onset diabetes of the young (MODY)?
A: MODY is an autosomal dominant condition characterized by primary pancreatic beta-cell dysfunction that causes mild diabetes that is diagnosed during adolescence or early adulthood. As early as 1964, the nomenclature “maturity-onset diabetes of the young” was used to describe cases that resembled adult-onset type 2 diabetes in terms of the slow progression to insulin use (as compared with the rapid progression in type 1 diabetes) but occurred in relatively young patients. Several genes cause distinct forms of MODY that have specific disease features that inform treatment, and thus MODY is a clinically important diagnosis. Most forms of MODY cause isolated abnormal glucose levels (in contrast to syndromic monogenic diabetes), a manifestation that has contributed to its frequent misdiagnosis as type 1 or type 2 diabetes.
Q: Which 3 genes are most often associated with MODY?
A: Although at least 13 genes have been associated with MODY, 3 genes — GCK, which encodes glucokinase, and HNF1A and HNF4A, which encode hepatocyte nuclear factors 1A and 4A, respectively — account for most cases. MODY associated with GCK (known as GCK-MODY) is characterized by mild, nonprogressive hyperglycemia that is present since birth, whereas the forms of MODY associated with HNF1A and HNF4A (known as HNF1A-MODY and HNF4A-MODY, respectively) are characterized by the development of diabetes, typically in the early teen years or young adulthood, that is initially mild and then progresses such that affected patients may receive insulin before diagnosis.
A: In patients with GCK-MODY, genetic variants reduce the function of glucokinase, the enzyme in pancreatic beta cells that functions as a glucose sensor and controls the rate of entry of glucose into the glycolytic pathway. As a result, reduced sensitivity to glucose-induced insulin secretion causes asymptomatic mild fasting hyperglycemia, with an upward shift in the normal range of the fasting blood glucose level to 100 to 145 mg per deciliter (5.6 to 8.0 mmol per liter), and also causes an upward shift in postprandial blood glucose levels, but with tight regulation maintained. This mild hyperglycemia is not thought to confer a predisposition to complications of diabetes, is largely unaltered by treatment, and does not necessitate treatment outside of pregnancy. In contrast to GCK-MODY, the disorders HNF1A-MODY and HNF4A-MODY result in progressive hyperglycemia that eventually leads to a need for treatment. Patients can often be treated with oral agents and discontinue insulin therapy started before the diagnosis of MODY. Of note, patients with HNF1A-MODY or HNF4A-MODY are typically sensitive to treatment with sulfonylureas but may also respond to glucagon-like peptide-1 receptor agonists.
A: It is possible for a patient to have type 1 or type 2 diabetes in addition to MODY, so affected patients should be screened for diabetes according to recommendations for the general population. In patients with GCK-MODY, the glycated hemoglobin level is typically below 7.5%, so a value rising above that threshold or a sudden large increase in the glycated hemoglobin level could indicate concomitant diabetes from another cause, which would need to be evaluated and treated.