Genotype phenotype relationship in subjects with HNF-1 beta MODY and mitochondrial diabetes and deafness: Study of optimal diabetes treatment and establishment of biomarkers of disease

Aims: HNF1B-MODY and MIDD are rare forms of monogenic diabetes where the appropriate treatment guidelines are poorly established. MIDD can often be misdiagnosed as Type 1 or Type 2 Diabetes and small non-coding RNAs (sncRNAs) have huge potential as a MIDD biomarker due to its abundance in serum and plasma. The aim of this study is to establish the genotype/phenotype correlations of HNF1B-MODY and MIDD and to identify potential sncRNAs as MIDD biomarkers to differentiate from other forms of diabetes. Methods: Twelve HNF1B-MODY subjects and 50 MIDD subjects were phenotyped in detail. A 2-hour oral glucose tolerance test was performed to establish insulin secretory response. We also investigated the diagnostic potential of tiRNA 5’ValCAC (alone and in combination with miR-23b-3p) identified from small-RNA sequencing studies in MIDD subjects compared to T1DM, T2DM and healthy controls. Results: Four HNF1B subjects demonstrating marked insulin deficiency. 5 subjects on insulin were trialled on sulphonylurea therapy and none were successfully weaned off insulin. 8/10 subjects required insulin. In MIDD, we found both insulin deficiency and insulin resistance play a role in diabetes development. 3/7 subjects on sulphonylureas progressed to insulin therapy. 1/6 subjects managed to wean off insulin to sulphonylurea and 23/34 MIDD subjects required insulin therapy. Serum levels of 5’ValCAC were reduced in MIDD and Type 2 diabetes subjects compared to controls. Type 2 diabetes subjects had higher serum levels of miR-23b-3p compared to all other subjects. Receiver Operating Characteristic analysis showed the potential of 5’ValCAC and miR-23b-3p as MIDD biomarkers, with the combination showing excellent separation from type 2 diabetes subjects.
Conclusions: Early initiation of insulin therapy would be suitable to achieve glycaemic control in both HNF1B and MIDD subjects.The combined use of 5’ValCAC and mir-23b-3p as serum biomarkers could help differentiate between MIDD subjects and Type 2 diabetes subjects.