Genetic forms of diabetes appear after 40 more often than many clinicians assume, yet routine clues rarely separate them from typical cases.
A large genetic analysis found monogenic diabetes in people diagnosed after age 40, but typical clinical signals were not reliable for spotting it. Many people with these genetic subtypes were on treatment that did not match their genotype. Tight clinical screening rules raised the hit rate but missed most cases.
Quick summary
- What the study found: Monogenic diabetes due to pathogenic variants in common genes occurred in later-onset diabetes, but clinical features largely overlapped with non-monogenic diabetes; many cases appeared mismatched to optimal therapy.
- Why it matters: A correct genetic label can enable precision therapy, including avoiding unnecessary medication or choosing a better drug class.
- What to be careful about: Simple clinical criteria (like low body mass index and family history) can miss the large majority of cases, so “rule-out” thinking is risky.
What was found
In the journal article MODY is prevalent in later-onset diabetes, has potential for targeted therapy but is challenging to identify, researchers analyzed whole-exome and clinical data from 51,619 people diagnosed with diabetes after age 40 across one United Kingdom cohort and one United States cohort.
They estimated monogenic diabetes prevalence at 0.52% in the United Kingdom cohort and 0.16% in the United States cohort. For subtypes with treatment implications (including GCK, HNF1A, HNF4A, ABCC8, and KCNJ11), prevalence was 1 in 234 in the United Kingdom cohort and 1 in 985 in the United States cohort.
GCK-related monogenic diabetes was most common, followed by HNF4A and lower-penetrance RFX6-related monogenic diabetes. “Lower-penetrance” means a variant is less likely to produce diabetes in every carrier, making pattern recognition harder.
What it means
The most actionable message is treatment mismatch. Among people with GCK-related monogenic diabetes, many received glucose-lowering drugs despite this subtype often being mild and biologically distinct.
For HNF1A, HNF4A, and ABCC8-related monogenic diabetes, most did not receive sulphonylureas. Sulphonylureas are an older class of medicines that stimulate insulin release and can be particularly effective for some genetic subtypes.
Where it fits
Clinically, monogenic diabetes after 40 did not “look” clearly different. The study compared monogenic diabetes against non-monogenic diabetes groups based on whether insulin was used from diagnosis, and the features overlapped substantially.
Across cohorts, only body mass index, hemoglobin A1c (a 2–3 month average blood glucose marker), and high-density lipoprotein cholesterol were consistently different. Even then, the differences were modest in practical terms, especially in the United States health-system cohort.
How to use it
Use this study as a caution against relying on a classic monogenic diabetes stereotype in midlife and older adults. Low body weight, a parent with diabetes, and not needing insulin may increase odds, but they are not safe filters.
Genetic testing decisions should be case-by-case when the result could change management. Examples include a strong multi-generation pattern, discordant clinical course, or when a younger affected family member could clarify the genetic story for the whole family.
Limits & what we still don’t know
Whole-exome sequencing misses promoter regions and mitochondrial variants, so prevalence estimates are minimums. The study also lacked type 1 diabetes biomarkers such as islet autoantibodies and C-peptide, which could help select candidates for testing.
The cohorts were predominantly of European ancestry, and only the ten most common monogenic diabetes genes were assessed. Some rarer forms and one gene (CEL) were not included.
Closing takeaway
Monogenic diabetes after age 40 is real, clinically blended into the broader diabetes population, and often treated without genotype guidance. If you restrict testing to “textbook” clinical profiles, you will miss most cases. The practical move is targeted testing when the expected treatment or family implications are high.
Data in this article is provided by PMC OAI-PMH.
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