What biomarkers distinguish MODY from other diabetes subtypes? Sensitive to sulfonylureas or additional tips!

Diabetes is a highly prevalent heterogeneous disease, and appropriate treatment and timely diagnosis are fundamental to
diabetes management.
The American Diabetes Association's 2012 updated guidelines recommend classifying diabetes into four categories: T1D (type 1 diabetes), T2D (type 2 diabetes), gestational diabetes and other specific forms of diabetes
.
The "other specific form" contains a very rare form of monogenic diabetes called adult-onset diabetes mellitus (MODY)
in young adults.

This discrete form of non-insulin-dependent familial diabetes, first reported by Tattersal in 1974, is not suitable for a traditional diagnosis
based on hyperglycemia due to its mixed clinical manifestations.
MODY stands for a combination
of genetic, metabolic, and clinical heterogeneity.
There are 14 subtypes of MODY, depending on the gene and its mutations (deletions, splicing sites, nonsenses, etc.
).

Due to its complex clinical presentation, MODY is often misdiagnosed and improperly labeled T2D or T1D
.
However, through molecular diagnostic tests, MODY can be distinguished from other forms of diabetes
.
The diagnosis of MODY uses three marker genes: hepatocyte nuclear factor 4α (HNF4a), hepatocyte nuclear factor 1α (HNF1a), and glucokinase (GCK).

The use of molecular diagnostic tests relies on nonspecific clinical features such as family history, age of onset, etiology, and does not demonstrate realistic levels
of sensitivity and accuracy.
This study describes the use
of biomarkers in improving the diagnosis and clinical selection of MODY subjects for molecular identification.
The various biomarkers recommended for distinguishing and identifying MODY mutations are:

1.
hsCRP (highly sensitive c-reactive protein): as a marker of MODY3 (HNF1α).

It has 80 percent accuracy when it comes to distinguishing between MODY3 and T2D, but only 75 percent
when it comes to other types of diabetes.
If hsCRP were used alone to distinguish MODY3 from other types, there would be a lot of unnecessary genetic testing and false positive rates
.
hsCRP testing must be combined with other clinical tests to provide a clear differentiator
.

2.
Glutamate decarboxylase (GAD), insulinoma antigen 2 IA-2A, IA-2β: Differentiation of T1 autoimmune diabetes and young diabetes

In many studies, elevated levels of ICA (islet-specific antibodies) have been found to be a predictive marker
that distinguishes T1D from MODY diabetes.
Glutamate decarboxylase (GAD) and IA2 islet autoantibodies are important markers that distinguish T1D from other types of MODY (young diabetes
).
GAD and IA2 antibodies
were found in 1% of MODY cases and 80% of autoimmune T1D cases.
Seissler et al.
used recombinant antigens in 1998 to confirm the presence of IA-2, GAD65, and IA-2 autoantibodies
in T1D patients.

3.
Insulin autoantibodies (IAA) and zinc transporter-8 (ZnT8): distinguish between T1 diabetes and young diabetes

In addition to GAD and IA-I2, insulin autoantibodies (IAA) and zinc transporter-8 (ZnT8) are important biomarkers that distinguish T1D from early-onset diabetes
.
After extensive research and screening of overexpressed islet cell-specific molecules, ZnT8 was identified as an autoimmune marker for T1 diabetes
.

4.
Fucosylated plasma glycan-GP30 as a marker of HNF1α-MODY3

The HNF1a transcription factor caused by MODY is associated with the modification of fucose-containing plasma N-glycans, and low fucosylated GP30 plasma glycans were found in MODY patients with harmful HNF1a
alleles.
GP30 is more specific as a biomarker of harmful mutations in HNF1a than hs-CRP (80% vs.
69%)
.

5.
C peptides and sulfonylureas

C-peptide is a useful marker to distinguish MODY patients from autoimmune T1 diabetes
.
In autoimmune T1 diabetes, residual insulin secretion by pancreatic β cells is usually observed in the first two years of disease progression and completely disappears after five years, which results in a lower C-peptide value, while in MODY and T2DM, the C-peptide is preserved for a longer
time.

Sulfonylurea susceptibility
was reported before describing the gene mutation caused by MODY.
Sulfonylureas are indicated for MODY patients, regardless of the MODY mutation involved
.
Shepherd et al.
(2018) found that 36% of patients with HNF1a/HNF4a MODY mutations achieved HbA1c 7.
5%
through diet/sulfonylurea alone.
However, sensitivity to sulfonylurea is not a valid criterion
for the selection of participants for genetic testing.

In conclusion, while molecular diagnostic testing is beneficial, the key is to determine which patients are more likely to benefit
.
In the future, the continuous development of MODY biomarkers and clinical molecular testing will be reflected in clinical laboratory investigations, improving MODY's diagnostic capabilities
.

References: Firdous P, Nissar K, Masoodi SR, Ganai BA.
Biomarkers: Tools for Discriminating MODY from Other Diabetic Subtypes.
Indian J Endocrinol Metab.
2022 May-Jun; 26(3):223-231.
doi: 10.
4103/ijem.
ijem_266_21.