INNODIA Master Protocol for the evaluation of investigational medicinal products in children, adolescents and adults with newly diagnosed type 1 diabetes

Background The INNODIA consortium has established a pan-European infrastructure using validated centres to prospectively evaluate clinical data from individuals with newly diagnosed type 1 diabetes combined with centralised collection of clinical samples to determine rates of decline in beta-cell function and identify novel biomarkers, which could be used for future stratification of phase 2 clinical trials. Methods In this context, we have developed a Master Protocol, based on the “backbone” of the INNODIA natural history study, which we believe could improve the delivery of phase 2 studies exploring the use of single or combinations of Investigational Medicinal Products (IMPs), designed to prevent or reverse declines in beta-cell function in individuals with newly diagnosed type 1 diabetes. Although many IMPs have demonstrated potential efficacy in phase 2 studies, few subsequent phase 3 studies have confirmed these benefits. Currently, phase 2 drug development for this indication is limited by poor evaluation of drug dosage and lack of mechanistic data to understand variable responses to the IMPs. Identification of biomarkers which might permit more robust stratification of participants at baseline has been slow. Discussion The Master Protocol provides (1) standardised assessment of efficacy and safety, (2) comparable collection of mechanistic data, (3) the opportunity to include adaptive designs and the use of shared control groups in the evaluation of combination therapies, and (4) benefits of greater understanding of endpoint variation to ensure more robust sample size calculations and future baseline stratification using existing and novel biomarkers

Allelic variation in exon 18 of the sulfonylurea receptor 1 (SUR1) gene, insulin secretion and insulin sensitivity in nondiabetic relatives of type 2 diabetic subjects.

BACKGROUND: We have previously observed associations of the T-allele of the exon 18 variant (ACC --> ACT; Thr759Thr) of the sulfonylurea receptor 1 (SUR1) gene with type 2 diabetes mellitus (T2DM). Here we assess beta-cell function and insulin sensitivity in carriers of different genotypes at this locus. METHODS: Pre-hepatic insulin secretion rates (ISR) derived by deconvolution of circulating C-peptide levels, and glucose clearance were assessed during graded infusions of intravenous glucose in CC-homozygous (n=6) and CT-heterozygous (n=6) nondiabetic relatives of CT-heterozygous type 2 diabetic subjects. RESULTS: Average ISR over the duration of the study, adjusted for sex, age, BMI and prevailing glucose levels, were lower in CT-heterozygous subjects as compared with CC-homozygous subjects (3.91 +/- 0.40 vs. 4.84 +/- 0.28 pmol/kg x min(-1); p=0.048). The correlation curves relating ISR to glucose levels were significantly different in the two groups (analyses of covariance p=0.029). Glucose clearance was similar in both groups. CONCLUSIONS: Insulin secretion rates, but not insulin sensitivity, assessed during graded infusion of glucose were mildly decreased in nondiabetic relatives of type 2 diabetic subjects, who carry the at risk T-allele of exon 18 variant of the SUR1 gene. These results suggest that the at-risk allele might have a small effect on pancreatic B-cell function and contribute to the development of T2DM in these families

Granulomatous hypophysitis: two case reports and literature review

Granulomatous hypophysitis (GRH) is extremely rare and commonly presents with chronic inflammatory of the enlarged pituitary gland. In our study, 66-year-old and 57-year-old women, both Chinese, were diagnosed with GRH presenting preoperatively definite imageology characters as pituitary adenoma. The 66-year-old woman presented with a year of headache, half a year of gradual decrease of visual acuity, and one month of right ptosis. Serum prolactin level was slightly elevated. Screening computed tomography (CT) scanning revealed typical low density mass found on the enlarged sella, which demonstrated invasive extension from the sella to the right cavernous sinus by contrast enhanced magnetic resonance imaging (MRI). Consequently, the patient was diagnosed with probable invasive pituitary adenoma. The other 57-year-old woman complained a light headache and had been previously treated as nonfunctional pituitary adenoma in other hospital. Finally these two patients underwent transsphenoidal microsurgery and were diagnosed with GRH according to postoperative histopathology. They then were treated with steroid. During the follow-up, the clinical symptoms such as headache, visual damage, and ptosis vanished, and the mass of the sellae dramatically shrank on repeated MR images. Clinically and radiologically, GRH is a rare sellar entity easily to be misdiagnosed as a pituitary adenoma. Trans-sphenoidal surgery can decompress the optical nerve or oculomotornerve as a therapeutic strategy, and support biopsy or further pathological diagnosis. However, the hormonal therapy should be emphasized both as diagnostic and therapeutic strategies. Conservative and tentative steroid treatment should be performed in preoperative period without acute nerve damage