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Case report, Monogenic diabetes, Neonatal diabetes mellitus, Variable clinical phenotype presentation, Incomplete penetrance, Sulfonylurea treatment Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations. Keywords: Case report; Monogenic diabetes; Neonatal diabetes mellitus; Sulfonylurea treatment; Variable clinical phenotype presentation; Incomplete penetrance EN Case report Monogenic diabetes Neonatal diabetes mellitus Sulfonylurea treatment Variable clinical phenotype presentation Incomplete penetrance 989 993 5 05/23/23 20230701 NES 230701 Introduction Neonatal diabetes mellitus (NDM) is a disorder of the glycemic status occurring in the first 6 months of life. [Extracted from the article]

Aim: In the pediatric diabetes clinic, patients with type 1 diabetes mellitus (T1D) account for more than 90% of cases, while monogenic forms represent about 6%. Many monogenic diabetes subtypes may respond to therapies other than insulin and have chronic diabetes complication prognosis that is different from T1D. With the aim of providing a better diagnostic pipeline and a tailored care for patients with monogenic diabetes, we set up a monogenic diabetes clinic (MDC). Methods: In the first 3 years of activity 97 patients with non-autoimmune forms of hyperglycemia were referred to MDC. Genetic testing was requested for 80 patients and 68 genetic reports were available for review. Results: In 58 subjects hyperglycemia was discovered beyond 1 year of age (Group 1) and in 10 before 1 year of age (Group 2). Genetic variants considered causative of hyperglycemia were identified in 25 and 6 patients of Group 1 and 2, respectively, with a pick up rate of 43.1% (25/58) for Group 1 and 60% (6/10) for Group 2 (global pick-up rate: 45.5%; 31/68). When we considered probands of Group 1 with a parental history of hyperglycemia, 58.3% (21/36) had a positive genetic test for GCK or HNF1A genes, while pick-up rate was 18.1% (4/22) in patients with mute family history for diabetes. Specific treatments for each condition were administered in most cases. Conclusion: We conclude that MDC maycontribute to provide a better diabetes care in the pediatric setting. [ABSTRACT FROM AUTHOR]

Group 1 consisted of 7 patients with non-autoimmune, sporadic PNDM, negative to the most common PNDM genes (i.e. KCNJ11, INS, ABCC8) or to a targeted panel of 27 monogenic diabetes genes (Supplementary Table 1). They found biallelic I ONECUT1 i mutations in 2 patients with syndromic, permanent neonatal diabetes mellitus (PNDM) from unrelated consanguineous families; family members carrying heterozygous I ONECUT1 i mutations showed hyperglycemia ranging from IFG to diabetes [[2]]. It is thus conceivable that in our patient G81D, coupled with another not yet identified variant in non coding regions of I ONECUT1 i or in another gene, contribute to causing PNDM. [Extracted from the article]

The original article can be found online at https://doi.org/10.1007/s00592-022-01972-2. Correction to: Monogenic diabetes clinic (MDC): 3-year experience Correction to: Acta Diabetologica https://doi.org/10.1007/s00592-022-01972-2 Author would like to update below listed corrections. [Extracted from the article]

Aims: Neonatal diabetes mellitus (NDM) is defined as hyperglycemia and impaired insulin secretion with onset within 6 months of birth. While rare, NDM presents complex challenges regarding the management of glycemic control. The availability of continuous subcutaneous insulin infusion pumps (CSII) in combination with continuous glucose monitoring systems (CGM) provides an opportunity to monitor glucose levels more closely and deliver insulin more safely. Methods: We report four cases of young infants with NDM successfully treated with CSII and CGM. Moreover, in two cases with Kir 6.2 mutation, we describe the use of CSII in switching therapy from insulin to sulfonylurea treatment. Results: Insulin pump requirement for the 4 neonatal diabetes cases was the same regardless of disease pathogenesis and c-peptide levels. No dilution of insulin was needed. The use of an integrated CGM system helped in a more precise control of BG levels with the possibility of several modifications of insulin basal rates. Moreover, as showed in the first two case-reports, when the treatment was switched from insulin to glibenclamide, according to identification of Kir 6.2 mutation and diagnosis of NPDM, the CSII therapy demonstrated to be helpful in allowing gradual insulin suspension and progressive introduction of sulfonylurea. Conclusions: During the neonatal period, the use of CSII therapy is safe, more physiological, accurate and easier for the insulin administration management. Furthermore, CSII therapy is safe during the switch of therapy from insulin to glibenclamide for infants with permanent neonatal diabetes mellitus. [ABSTRACT FROM AUTHOR]

Biallelic insulin receptor ( INSR) gene mutations cause congenital syndromes of severe insulin resistance (SIR) known as Donohue syndrome (DS) and Rabson–Mendenhall syndrome (RMS). At presentation, DS and RMS are difficult to differentiate since they share many clinical features; however, while patients with DS usually die within 1 year of birth, individuals classified as RMS can reach adult age. INSR mutations can be also found in pubertal females with hyperinsulinism, hyperandrogenism, and acanthosis nigricans (type A SIR). We studied the INSR gene in five subjects with congenital SIR and in a patient with type A SIR. Nine biallelic INSR gene mutations (eight novels, including an in-frame deletion of INSR signal peptide) were identified in patients with congenital SIR; a heterozygous, spontaneous INSR mutation was detected in the patient with type A SIR. Two probands, presenting severe hirsutism at birth, died at the age of 3 months and were classified as DS, while other 2, currently 2 and 3 years old, were diagnosed with RMS (patients 3 and 4). The fifth patient with congenital SIR died when 14 months old. Nephrocalcinosis, hyperaldosteronism, hyperreninemia, and hypokalemia, in the absence of hypertension, were discovered in patients 3 and 5 when 24 and 4 months old, respectively. Patient 3, now 3 years/3 months old, still shows hyperreninemic hyperaldosteronism requiring potassium supplementation. We conclude that renal abnormalities resembling antenatal Bartter’s syndrome type II, recently reported also by others, is a common observation in patients with congenital SIR. [ABSTRACT FROM AUTHOR]

The article presents the research that investigates the effectiveness of sensor-augmented insulin in the treatment of diabetes that is associated with insulin dominant gene mutations. The topics discussed include the implications of insulin gene mutations on diabetic patients, the use of continuous subcutaneous insulin infusion (CSII) on patients, and the measurement of C-peptides during the onset of diabetes.

Type 2 diabetes mellitus is a widespread disease, affecting millions of people globally. Although genetics and environmental factors seem to have a role, the cause of this metabolic disorder is largely unknown. Here we report a genetic flaw that markedly reduced the intracellular expression of the high mobility group A1 (HMGA1) protein, and adversely affected insulin receptor expression in cells and tissues from four subjects with insulin resistance and type 2 diabetes. Restoration of HMGA1 protein expression in subjects' cells enhanced INSR gene transcription, and restored cell-surface insulin receptor protein expression and insulin-binding capacity. Loss of Hmga1 expression, induced in mice by disrupting the Hmga1 gene, considerably decreased insulin receptor expression in the major targets of insulin action, largely impaired insulin signaling and severely reduced insulin secretion, causing a phenotype characteristic of human type 2 diabetes. [ABSTRACT FROM AUTHOR]

In eukaryotes, pyridoxal kinase (PDXK) acts in vitamin B6salvage pathway to produce pyridoxal 5′-phosphate (PLP), the active form of the vitamin, which is implicated in numerous crucial metabolic reactions. In Drosophila, mutations in the dPdxk gene cause chromosome aberrations (CABs) and increase glucose content in larval hemolymph. Both phenotypes are rescued by the expression of the wild type human PDXK counterpart. Here we expressed, in dPdxk1 mutant flies, four PDXK human variants: three (D87H, V128I and H246Q) listed in databases, and one (A243G) found in a genetic screening in patients with diabetes. Differently from human wild type PDXK, none of the variants was able to completely rescue CABs and glucose content elicited by dPdxk1 mutation. Biochemical analysis of D87H, V128I, H246Q and A243G proteins revealed reduced catalytic activity and/or reduced affinity for PLP precursors which justify this behavior. Although these variants are rare in population and carried in heterozygous condition, our findings suggest that in certain metabolic contexts and diseases in which PLP levels are reduced, the presence of these PDXK variants could threaten genome integrity and increase cancer risk. [ABSTRACT FROM AUTHOR]