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Purpose: The management of type 2 diabetes mellitus patients has changed over the past decade, and a large number of antidiabetic drug treatment options are now available. This complexity poses challenges for healthcare professionals and may result in potentially inappropriate prescriptions of antidiabetic drugs in patients with type 2 diabetes mellitus which can be limited using screening tools. The effectiveness of explicit tools such as lists of potentially inappropriate prescriptions has been widely demonstrated. The aim was to set up nominal groups of healthcare professionals from several disciplines and develop a list of explicit definition of potentially inappropriate prescriptions of antidiabetic drugs. Methods: In a qualitative, nominal-groups approach, 30 diabetologists, general practitioners, and pharmacists in France developed explicit definitions of potentially inappropriate prescriptions of antidiabetic drugs in patients with type 2 diabetes mellitus. A nominal group technique is a structured method that encourages all the participants to contribute and makes it easier to reach an agreement quickly. Each meeting lasted for two hours. Results: The three nominal groups comprised 14 pharmacists, 10 diabetologists, and 6 general practitioners and generated 89 explicit definitions. These definitions were subsequently merged and validated by the steering committee and nominal group participants, resulting in 38 validated explicit definitions of potentially inappropriate prescriptions of antidiabetic drugs. The definitions encompassed four contexts: (i) the temporary discontinuation of a medication during acute illness (n = 9; 24%), (ii) dose level adjustments (n = 23; 60%), (iii) inappropriate treatment initiation (n = 3; 8%), and (iv) the need for further monitoring in the management of type 2 diabetes mellitus (n = 3; 8%). Conclusion: The results of our qualitative study show that it is possible to develop a specific list of explicit definitions of potentially inappropriate prescriptions of antidiabetic drugs in patients with type 2 diabetes mellitus by gathering the opinions of healthcare professionals caring for these patients. This list of 38 explicit definitions necessitates additional confirmation by expert consensus before use in clinical practice. [ABSTRACT FROM AUTHOR]

BACKGROUND: Maturity-onset of the young (MODY) is a clinically heterogeneous form of diabetes characterized by an autosomal-dominant mode of inheritance, an onset before the age of 25 years, and a primary defect in the pancreatic beta-cell function. Approximately 30% of MODY families remain genetically unexplained (MODY-X). Here, we aimed to use whole-exome sequencing (WES) in a four-generation MODY-X family to identify a new susceptibility gene for MODY. METHODOLOGY: WES (Agilent-SureSelect capture/Illumina-GAIIx sequencing) was performed in three affected and one non-affected relatives in the MODY-X family. We then performed a high-throughput multiplex genotyping (Illumina-GoldenGate assay) of the putative causal mutations in the whole family and in 406 controls. A linkage analysis was also carried out. PRINCIPAL FINDINGS: By focusing on variants of interest (i.e. gains of stop codon, frameshift, non-synonymous and splice-site variants not reported in dbSNP130) present in the three affected relatives and not present in the control, we found 69 mutations. However, as WES was not uniform between samples, a total of 324 mutations had to be assessed in the whole family and in controls. Only one mutation (p.Glu227Lys in KCNJ11) co-segregated with diabetes in the family (with a LOD-score of 3.68). No KCNJ11 mutation was found in 25 other MODY-X unrelated subjects. CONCLUSIONS/SIGNIFICANCE: Beyond neonatal diabetes mellitus (NDM), KCNJ11 is also a MODY gene ('MODY13'), confirming the wide spectrum of diabetes related phenotypes due to mutations in NDM genes (i.e. KCNJ11, ABCC8 and INS). Therefore, the molecular diagnosis of MODY should include KCNJ11 as affected carriers can be ideally treated with oral sulfonylureas.

IntroductionPotentially inappropriate prescriptions (PIPs) of antidiabetic drugs (ADs) (PIPADs) to patients with type 2 diabetes mellitus (T2DM) have been reported in some studies. The detection of PIPs in electronic databases requires the development of explicit definitions. This approach is widely used in geriatrics but has not been extended to PIPADs in diabetes mellitus. The objective of the present literature review was to identify all explicit definitions of PIPADs in patients with T2DM.Materials and methodsWe performed a systematic review of the literature listed on Medline (via PubMed), Scopus, Web of Science, and, Embase between 2010 and 2021. The query included a combination of three concepts ("T2DM" AND "PIPs" AND "ADs") and featured a total of 86 keywords. Two independent reviewers selected publications, extracted explicit definitions of PIPADs, and then classified the definitions by therapeutic class and organ class.ResultsOf the 4,093 screened publications, 39 were included. In all, 171 mentions of PIPADs (corresponding to 56 unique explicit definitions) were identified. More than 50% of the definitions were related to either metformin (34%) or sulfonylureas (29%). More than 75% of the definitions were related to either abnormal renal function (56%) or age (22%). In addition, 20% (n = 35) mentions stated that biguanides were inappropriate in patients with renal dysfunction and 17.5% (n = 30) stated that sulfonylureas were inappropriate above a certain age. The definitions of PIPADs were heterogeneous and had various degrees of precision.ConclusionOur results showed that researchers focused primarily on the at-risk situations related to biguanide prescriptions in patients with renal dysfunction and the prescription of sulfonylureas to older people. Our systematic review of the literature revealed a lack of consensus on explicit definitions of PIPADs, which were heterogeneous and limited (in most cases) to a small number of drugs and clinical situations.

Males and females responses to gestational overnutrition set the stage for subsequent sex-specific differences in adult onset non communicable diseases. Placenta, as a widely recognized programming agent, contibutes to the underlying processes. According to our previous findings, a high-fat diet during gestation triggers sex-specific epigenetic alterations within CpG and throughout the genome, together with the deregulation of clusters of imprinted genes. We further investigated the impact of diet and sex on placental histology, transcriptomic and epigenetic signatures in mice. Both basal gene expression and response to maternal high-fat diet were sexually dimorphic in whole placentas. Numerous genes showed sexually dimorphic expression, but only 11 genes regardless of the diet. In line with the key role of genes belonging to the sex chromosomes, 3 of these genes were Y-specific and 3 were X-specific. Amongst all the genes that were differentially expressed under a high-fat diet, only 16 genes were consistently affected in both males and females. The differences were not only quantitative but remarkably qualitative. The biological functions and networks of genes dysregulated differed markedly between the sexes. Seven genes of the epigenetic machinery were dysregulated, due to effects of diet, sex or both, including the Y- and X-linked histone demethylase paralogues Kdm5c and Kdm5d, which could mark differently male and female epigenomes. The DNA methyltransferase cofactor Dnmt3l gene expression was affected, reminiscent of our previous observation of changes in global DNA methylation. Overall, this striking sexual dimorphism of programming trajectories impose a considerable revision of the current dietary interventions protocols.