The phosphatidylinositol 3 kinase (PI3K) pathway regulates fundamental cellular processes such as metabolism, proliferation, and survival. A central component in this pathway is the p85α regulatory subunit, encoded by PIK3R1. Using whole-exome sequencing, we identified a heterozygous PIK3R1 mutation (c.1945C>T [p.Arg649Trp]) in two unrelated families affected by partial lipodystrophy, low body mass index, short stature, progeroid face, and Rieger anomaly (SHORT syndrome). This mutation led to impaired interaction between p85α and IRS-1 and reduced AKT-mediated insulin signaling in fibroblasts from affected subjects and in reconstituted Pik3r1-knockout preadipocytes. Normal PI3K activity is critical for adipose differentiation and insulin signaling; the mutated PIK3R1 therefore provides a unique link among lipodystrophy, growth, and insulin signaling.

OBJECTIVE-Mutations in the insulin (INS) gene can cause neonatal diabetes. We hypothesized that mutations in INS could also cause maturity-onset diabetes of the young (MODY) and autoantibody-negative type 1 diabetes.RESEARCH DESIGN AND METHODS-We screened INS in 62 probands with MODY, 30 probands with suspected MODY, and 223 subjects from the Norwegian Childhood Diabetes Registry selected on the basis of autoantibody negativity or family history of diabetes.RESULTS-Among the MODY patients, we identified the INS mutation c.137GϾA (R46Q) in a proband, his diabetic father, and a paternal aunt. They were diagnosed with diabetes at 20, 18, and 17 years of age, respectively, and are treated with small doses of insulin or diet only. In type 1 diabetic patients, we found the INS mutation c.163CϾT (R55C) in a girl who at 10 years of age presented with ketoacidosis and insulindependent, GAD, and insulinoma-associated antigen-2 (IA-2) antibody-negative diabetes. Her mother had a de novo R55C mutation and was diagnosed with ketoacidosis and insulindependent diabetes at 13 years of age. Both had residual ␤-cell function. The R46Q substitution changes an invariant arginine residue in position B22, which forms a hydrogen bond with the glutamate at A17, stabilizing the insulin molecule. The R55C substitution involves the first of the two arginine residues localized at the site of proteolytic processing between the B-chain and the C-peptide. M olecular genetic studies of monogenic forms of diabetes such as maturity-onset diabetes of the young (MODY) and neonatal diabetes have provided important insight into the pathophysiology and have led to improved diagnosis and treatment (1-7). In type 1 diabetes, immune-mediated destruction of the pancreatic ␤-cells plays an important role in the pathogenesis (8). However, some type 1 diabetic children do not present with signs of autoimmunity and are classified as having autoantibody-negative type 1 diabetes, also denoted idiopathic or type 1b diabetes (9 -11). Recently, we observed that heterozygous missense mutations in the insulin gene (INS) can cause permanent neonatal diabetes (12). The majority of these mutations occurred de novo. Moreover, this phenomenon has been noted in previous studies of KCNJ11 and ABCC8 in patients with neonatal diabetes and is in accordance with the sporadic nature of permanent neonatal diabetes. CONCLUSIONS-OurWe hypothesized that INS mutations might also cause MODY and could explain some cases of apparent type 1 diabetes. The aim of the present study was therefore to search for INS mutations in patients with MODY of unknown etiology as well as in selected patients from the Norwegian Childhood Diabetes Registry. RESEARCH DESIGN AND METHODSPhysicians refer subjects to the Norwegian MODY Registry based on at least two of the following criteria: first-degree relative with diabetes, onset of diabetes before 25 years of age in at least one family member, insulin level Ͻ0.5 units ⅐ kg Ϫ1 ⅐ day Ϫ1 , diabetes diagnosed between age 25 and 40 years of age, or unusual ...

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To relate the vitamin D metabolism in puberty to sex, sexual maturation, and, indirectly, to growth velocity and cessation of growth, the plasma level of 25-hydroxy vitamin D, 1,25-dihydroxyvitamin D [1,25-(OH)2D], 24,25-dihydroxyvitamin D [24,25-(OH)2D], and 25,26-(OH)2D were measured in 191 adolescents representing all stages of puberty. In girls, 1,25-(OH)2D3 increased from age 11 yr to a peak at 12 yr of age (P less than 0.0005) and then decreased. In boys, the increase occurred between 13--14 yr of age (P less than 0.005), with a subsequent decline. When the 1,25-(OH)2D concentrations were related to the stage of puberty, the girls showed a maximal increase between stages 1 and 2 (P less than 0.0005), with a peak at stage 3, whereas the boys had a significant increase from stage 2 to a peak at stage 3 (P less than 0.01). In both sexes, there were subsequent significantly decreasing values to stage 4 through stage 5. The ratio of 24,25-(OH)2D to 25-hydroxyvitamin D varied inversely with the 1,25-(OH)2D concentration, with the lowest value at age 12 yr in both sexes, followed by a gradual increase to a plateau at age 15 yr in girls and 17 yr in boys. It appears that the hormones of the vitamin D system add another dimension to the endocrinology of growth and puberty.

Plasma concentrations of 25-hydroxyvitamin D (25-OHD), 1,25-dihydroxyvitamin D (1,25-(OH)2D), and 24,25-dihydroxyvitamin D (24,25-(OH)2D) were determined in 17 children with vitamin D deficiency rickets before therapy was started. Thirteen of them also had these tests repeated during treatment. The median 25-OHD concentration was at the lower limit of the reference range before, but increased distinctly within one week of treatment with 1 700-4 000 IU vitamin D per day (17 vs. 37 nmol/l, p less than 0.01). 24,25-(OH)2D was undetectable in twelve of the patients before therapy. Detectable concentrations were in the range of 1.7 to 3.5% of the corresponding 25-OHD levels throughout the study, and the two metabolites were closely correlated (r = 0.84, p less than 0.0005). The median 1,25-(OH)2D concentration was near the average of the reference range before, but increased to well above the upper limit of normal within one week of treatment (121 vs. 368 pmol/l, p less than 0.01). The levels were largely normal after 10 weeks of therapy, as were the plasma concentrations of calcium, phosphate, and alkaline phosphatase. Parathyroid activity, as judged by serum parathyroid hormone or urinary cyclic AMP concentrations, was stimulated in 11 of 12 children studied prior to treatment. It is concluded that there may be no clear-cut differences between normal nad rachitic values of the different vitamin D metabolites under practical clinical conditions. A low 25-OHD level combined with evidence of a stimulated parathyroid activity, and a rise of 1,25-(OH)2D levels to supernormal values following a few days of vitamin D therapy may be diagnostic clues.

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Serum concentrations of 25-hydroxyvitamin D (25-OHD) and 1,25-dihydroxyvitamin D [1,25-(OH)2D] of vitamin D2 and D3 origin were determined separately in 10 women before vitamin intake in early pregnancy, and repeated in maternal and cord serum obtained at delivery after 20 to 30 wk of vitamin D2 supplementation in a dose of 400 IU/day. Before supplementation 25-OHD2 and 1,25-(OH)D2D2 were present in just traceable or nondetectable concentrations, but the levels increased in all to a mean +/- 1 SD of 7.3 +/- 3.7 ng/ml and 37.2 +/- 18.1 pg/ml, respectively (p less than 0.0025), by the time of delivery. At delivery the total 25-OHD and 1,25-(OH)2D levels were always lower in the cord than in the maternal serum (30.7 +/- 14.2 versus 20.1 +/- 9.1 ng/ml, and 90.1 +/- 31.2 versus 37.3 +/- 11.6 pg/ml, p less than 0.0025). The paired concentrations of 25-OHD were closely related (r = 0.89, p less than 0.0005), while the association for 1,25-(OH)2D was not statistically significant (r = 0.53, p less than .01). The 25-OHD of D2 and D3 origin accounted for a similar proportion of the total 25-OHD in the maternal and cord serum (ratio of 25-OHD2 to 25-OHD3: 0.40 +/- 0.28 versus 0.45 +/- 0.29, p = NS), as did the respective 1,25-(OH)2D metabolites [ratio of 1,25-(OH)2D2 to 1,25-(OH)2D3: 0.73 +/- 0.35 versus 0.90 +/- 0.50, p = NS].(ABSTRACT TRUNCATED AT 250 WORDS)