For example, the HNF4A c.340C>T (p.Arg114Trp) (GenBank: NM_175914.4) variant associated with diabetes is <10% penetrant by the time an individual is 40 years old.
Mutations in the genes encoding the pancreatic K<sub>ATP</sub> channels can also lead to different types of diabetes (including neonatal diabetes mellitus (NDM) and Maturity Onset Diabetes of the Young, MODY), and defects in the solute carrier family 2 member 2 (<i>SLC2A2</i>) leads to diabetes mellitus as part of the Fanconi-Bickel syndrome.
HNF4α (hepatocyte nuclear factor 4α) is one of the master regulators of pancreatic β-cell development and function, and mutations in the <i>HNF4</i>α gene are well-known monogenic causes of diabetes.
Monogenic forms of diabetes like MODY and neonatal diabetes have paved the way for precision medicine in diabetes, as carriers of unique mutations require unique treatment.
Furthermore, studies of N-glycan alterations have successfully been used to identify individuals with rare types of diabetes (such as the HNF1A-MODY), and also to evaluate functional significance of novel diabetes-associated mutations.
HNF4α is a culprit gene product for a monogenic and dominantly-inherited form of diabetes, referred to as MODY1 (Maturity Onset Diabetes of the Young type 1).
Most (6/7) patients with HNF4A variants rapidly failed TODAY treatment across study arms (hazard ratio = 5.03, P = 0.0002), while none with GCK variants failed treatment.ConclusionThe finding of 4.5% of patients with monogenic diabetes in an overweight/obese cohort of children and adolescents with T2D suggests that monogenic diabetes diagnosis should be considered in children and adolescents without diabetes-associated autoantibodies and maintained C-peptide, regardless of BMI, as it may direct appropriate clinical management.
Subjects (N = 97) with diabetes onset ≤age 25, measurable C-peptide (≥0.1 ng/mL), and negative for all four diabetes autoantibodies were enrolled at a large academic center and tested for MODY 1-5 through Athena Diagnostics.
In those with HNF1A/HNF4A-MODY, a shorter diabetes duration, lower HbA<sub>1c</sub> and lower BMI at genetic diagnosis predicted successful treatment with sulfonylurea/diet alone, supporting the need for early genetic diagnosis and treatment change.
Eleven children with asymptomatic hyperglycemia and clinically suspected GCK-MODY were identified from the database of children with diabetes in the biggest children's hospital in South China.
We examined a total of 275 subjects having diabetes suspected to be MODY who were negative for mutations in MODY1-5 referred from 155 medical institutions throughout Japan.
Accurate genetic diagnosis directs management, such as no pharmacologic treatment for GCK-MODY, low-dose sulfonylureas for HNF1A-MODY and HNF4A-MODY, and high-dose sulfonylureas for K<sub>ATP</sub> channel-related diabetes.
Association of MODY genetic variants with diabetes incidence at a median of 3 years and measures of 1-year β-cell function, insulinogenic index, and oral disposition index.
Rats with STZ-induced diabetes who received GWBR supplementation exhibited decreased expression of sodium-dependent glucose transporter 1 (SGLT1) and glucose transporter (GLUT) 2 genes and proteins in the small intestine via decreases in hepatocyte nuclear factor (HNF)-1α, HNF-1β, and HNF-4α, transcriptional factors that are involved in the regulation of SGLT1 and GLUT2, compared with the rats with STZ-induced diabetes that did not receive GWBR supplements.
These results suggest that functional characterization of variants within MODY genes may overcome the limitations of bioinformatics tools for the purposes of presymptomatic diabetes risk prediction in the general population.
A total of 40 individuals with diabetes (1.8% of early onset sub-group and 0.6% of adult onset sub-group) were carriers of known pathogenic missense variants in the GCK, HNF1A, HNF4A, ABCC8, and INS genes.
In children and adolescents with diabetes, the presence of 2 risk alleles (DR3 and/or DR4) reduces the probability of MODY diagnosis, whereas the lack of risk alleles increases it.
Finally, we show that hepatocyte nuclear factor 4 alpha (HNF-4α) plays a key role in controlling hepatic CES2 expression in diabetes, obesity, or NASH.
Mutation p.T130I was associated with both early-onset and late-onset diabetes and caused downregulated HNF4A expression, whereas HNF1A polymorphisms p.I27L and p.S487N were associated with the age of diagnosis of diabetes.