Cell lineages of the early human gonad commit to one of the two mutually antagonistic organogenetic fates, the testis or the ovary. Some individuals with a 46,XX karyotype develop testes or ovotestes (testicular or ovotesticular disorder of sex development; TDSD/OTDSD), due to the presence of the testis-determining gene, SRY. Other rare complex syndromic forms of TDSD/OTDSD are associated with mutations in pro-ovarian genes that repress testis development (e.g. WNT4); however, the genetic cause of the more common non-syndromic forms is unknown. Steroidogenic factor-1 (known as NR5A1) is a key regulator of reproductive development and function. Loss-of-function changes in NR5A1 in 46,XY individuals are associated with a spectrum of phenotypes in humans ranging from a lack of testis formation to male infertility. Mutations in NR5A1 in 46,XX women are associated with primary ovarian insufficiency, which includes a lack of ovary formation, primary and secondary amenorrhoea as well as early menopause. Here, we show that a specific recurrent heterozygous missense mutation (p.Arg92Trp) in the accessory DNA-binding region of NR5A1 is associated with variable degree of testis development in 46,XX children and adults from four unrelated families. Remarkably, in one family a sibling raised as a girl and carrying this NR5A1 mutation was found to have a 46,XY karyotype with partial testicular dysgenesis. These unique findings highlight how a specific variant in a developmental transcription factor can switch organ fate from the ovary to testis in mammals and represents the first missense mutation causing isolated, non-syndromic 46,XX testicular/ovotesticular DSD in humans.

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Autoantibodies directed against tyrosine phosphatase IA-2 antibody (IA-2 Ab) are diagnostic for autoimmune type 1 diabetes. Conventional assays target the intracellular domain of IA-2. Among patients with ketosis-prone diabetes (KPD), characterized by presentation with diabetic ketoacidosis (DKA), >60% of adults lack three classic islet autoantibodiesdIA-2, GAD65, and ZnT8 Absdassociated with type 1 diabetes. We aimed to determine whether apparently autoantibodynegative ("A2") KPD patients possess occult IA-2 Ab directed against fulllength IA-2 (IA-2FL) or its extracellular domain (IA-2EC). RESEARCH DESIGN AND METHODS We developed an assay that targets IA-2FL and IA-2EC and used it to analyze 288 subjects with A2 KPD. RESULTS Ten A2 KPD patients were positive for IA-2EC Ab (3.5%), and three were also positive for IA-2FL Ab (1.0%), similar to frequencies in type 1 and type 2 diabetes. CONCLUSIONS Measurement of IA-2FL Ab and IA-2EC Ab improves the accuracy of the Ab classification of KPD patients. Ketosis-prone diabetes (KPD) is a heterogenous syndrome characterized by presentation with diabetic ketoacidosis (DKA) and classified by the presence or absence of islet autoantibodies ("A+" or "A2") and presence or absence of b-cell functional reserve ("b+" or "b2") (1,2). Distinct from patients with type 1 diabetes, patients with KPD often present when older, have fewer recurrences of DKA, and can often discontinue insulin treatment while maintaining glycemic control (3). More than 60% of KPD adult patients lack evidence of islet autoimmunity (i.e., are A2) by testing for the presence of autoantibodies against the 65-kDa isoform of glutamate decarboxylase (GAD65), zinc transporter T8 (ZnT8), and the neuroendocrine autoantigen IA-2 (or ICA512) (1,2,4). Constructs used in conventional IA-2 autoantibody assays include intracellular fragments, but not the extracellular domain (IA-2EC), which has recently been investigated as a target for IA-2-specific autoantibodies (5). We reported that 1% of patients with autoimmune type 1 diabetes are positive only for the IA-2EC antibody (Ab), as were 4.7% of 258 patients with type 2 diabetes (5,6). Furthermore, we reported that full-length IA-2 (IA-2FL

Compared with control participants, KPD patients have increased arginine availability in the euglycemic state, indicating a higher requirement. This is compromised during hyperglycemia, with an inadequate supply of arginine to sustain metabolic functions such as insulin secretion. Exogenous arginine administration restores a normal insulin secretory response.

Background:We explored the association of C-peptide (marker of secreted insulin), proinsulin and proinsulin ⁄C-peptide ratio (PI/C) (markers of beta-cell endoplasmic reticulum [ER] stress) with undercarboxylated (uOC) and carboxylated osteocalcin (cOC) and their ratio (uOC/cOC) in children with recently diagnosed type 1 (T1D) or type 2 diabetes (T2D), and the correlation of these variables with partial remission (PR) in children with T1D.Methods: Demographic and clinical data of children with new-onset diabetes (n = 68; median age = 12.2 years; 33.8% non-Hispanic White, 45.6% Hispanic/Latino, 16.2% African American and 4.4% other) were collected at diagnosis and during the first (V1), second (V2) and third clinical visits at 9.0, 32.0 and 175.7 weeks, respectively.Serum proinsulin, C-peptide, uOC and cOC values were measured 7.0 weeks after diagnosis. PR was defined as insulin dose-adjusted HbA1c (IDAA1c) ≤9. Results:In children with new-onset T1D with DKA (33.3%) or T2D (29.4%), Spearman's correlation coefficient revealed a positive association between the C-peptide levels and both uOC and uOC/cOC ratio. In T1D (n = 48), both higher serum C-peptide levels and low PI:C ratio were associated with higher BMI percentile (β = 0.02, P = .001; β = −0.01, P = .02, respectively) and older age at diagnosis (β = 0.13, P = .001; β = −0.12, P = .001, respectively). Furthermore, in children with T1D, C-peptide levels at V1 correlated with IDAA1c ≤ 9 at V1 (P = .04).Conclusion: C-peptide levels are associated with a higher uOC and uOC/cOC ratio in paediatric diabetes. In new-onset T1D children, older age and higher BMI were associated with lower beta-cell stress and higher preserved function, which was predictive of PR on follow-up. K E Y W O R D SC-peptide, diabetes, osteocalcin, paediatrics