Proinsulin to C-Peptide Ratio in the First Year After Diagnosis of Type 1 Diabetes.

OBJECTIVE: The proinsulin to C-peptide (PI:C) ratio is reputedly a biomarker of ß-cell endoplasmic reticulum (ER) stress. OBJECTIVE: This study examined the natural history of the PI:C ratio and its correlation with residual ß-cell function in childhood new-onset type 1 diabetes (T1D). Over the first year of T1D, the temporal trend in fasting and nutrient-stimulated PI data is limited. METHODS: PI was a secondary pre-planned analysis of our 1-year, randomized, double-blind, placebo-controlled gamma aminobutyric acid (GABA) trial in new-onset T1D. Of the 99 participants in the primary study, aged 4 to 18 years, 30 were placebo. This study only involved the 30 placebo patients; all were enrolled within 5 weeks of T1D diagnosis. A liquid mixed meal tolerance test was administered at baseline and 5 and 12 months for determination of C-peptide, PI, glucose, and hemoglobin A1C. RESULTS: Both the fasting (P = 0.0003) and stimulated (P = 0.00008) PI:C ratios increased from baseline to 12 months, indicating escalating ß-cell ER stress. The baseline fasting PI correlated with the fasting change in C-peptide at 12 months (P = 0.004) with a higher PI correlating with greater decline in C-peptide. Patients with an insulin-adjusted A1C >9% (hence, not in remission) had higher fasting PI:C ratios. Younger age at diagnosis correlated with a higher PI:C ratio (P = 0.04). CONCLUSION: Children with new-onset T1D undergo progressive ß-cell ER stress and aberrant proinsulin processing, as evidenced by increasing PI:C ratios. Moreover, the PI:C ratio reflects more aggressive ß-cell onslaught with younger age, as well as diminished glycemic control.

Hepatic endoplasmic reticulum calcium fluxes: effect of free fatty acids and KATP channel involvement.

As a common sequel to obesity, plasma and intracellular free fatty acid (FFA) concentrations are elevated and, as a consequence, manifold disturbances in metabolism may ensue. Biochemical processes in the cytosol and organelles, such as mitochondria and endoplasmic reticulum (ER), can be disturbed. In the ER, the maintenance of a high calcium gradient is indispensable for viability. In sarcoplasmic reticulum, selective FFA can induce ER stress by disrupting luminal calcium homeostasis; however, there are limited studies in hepatic microsomes. Our studies found that FFA has a noxious effect on rat hepatic microsomal calcium flux, and the extent of which depended on the number of double bonds and charge. Furthermore, insofar as the FFA had no effect on microsomal calcium efflux, their inhibitory action primarily involves calcium influx. Finally, other cationic channels have been found in hepatic ER, and evidence is presented of their interaction with the Ca2+ ATPase pump.

Fragile Bones Secondary to SMURF1 Gene Duplication.

Studies on mice have shown that the Smad Ubiquitin Regulatory Factor-1 (SMURF1) gene negatively regulates osteoblast function and the response to bone morphogenetic protein in a dose-dependent fashion (Chan et al. in Mol Cell Biol 27(16):5776-5789, https://doi.org/10.1128/MCB.00218-07, 2007; Yamashita et al. in Cell 121(1):101-113, https://doi.org/10.1016/j.cell.2005.01.035, 2005). In addition, a tumorigenic role for SMURF1 has been implicated due to the interference with apoptosis signals (Nie et al. in J Biol Chem 285(30):22818-22830, https://doi.org/10.1074/jbc.M110.126920, 2010; Wang et al. in Nat Commun 5:4901, https://doi.org/10.1038/ncomms5901, 2014). A 10-year-old girl with a history of severe developmental delay, infantile seizures, and B-cell lymphoma, in remission for approximately 3.5 years, was referred to the metabolic bone clinic for fractures and low bone mineral density. Array comparative genomic hybridization revealed a pathogenic microduplication in chromosome 7 at bands 7q21.3q22.1 that encompasses the SMURF1 gene. The clinical features of this child are congruous with the phenotype as ascribed excess Smurf1 mutations in mice. This is the first case description of osteoporosis in a child secondary to a microduplication involving SMURF1 gene.

Community-acquired serious bacterial infections in the first 90 days of life: a revisit in the era of multi-drug-resistant organisms.

BACKGROUND: Infants in the first 90 days of life are more prone to develop serious bacterial infections (SBIs). Multi-drug-resistant organisms (MDROs) are emerging as important pathogens causing SBIs. We reviewed the epidemiology of SBIs in infants 0-90 days old and compared the clinical features, laboratory values and final outcome for SBIs due to MDROs vs. non-MDROs. METHODS: Episodes of culture-proven SBIs (bacteremia, urinary tract infections, or meningitis) with age at onset of 0-90 days during a 7-year period were retrospectively reviewed. Health care-associated infections were excluded. We collected demographics, clinical features, and laboratory and microbiology data. We compared clinical characteristics, laboratory data, microbiologic results and final outcome for SBIs due to MDROs vs. non-MDROs. RESULTS: Ninety-four episodes (88 patients) including bacteremia (42.6%), urinary tract infections (54.3%) and meningitis (3.1%) were caused by Gram-negative bacteria (67%), and Gram-positive bacteria (33%). Escherichia coli, Klebsiella pneumoniae and GBS were the most common causes. MDROs caused SBIs in 39 patients (44.3%). SBIs due to MDROs were associated with more delay in providing targeted antimicrobial therapy compared to non-MDROs (74.4% vs. 0%, P ≤ 0.001), but no difference in case-fatality rate (12.8% vs. 12.2%, P = 1.0). Clinical features or basic laboratory values were not statistically different between the two groups. CONCLUSIONS: The bacteriology of SBIs in the first 90 days of life is changing to include more MDROs, which causes more delay in providing targeted antimicrobial therapy. Awareness of the local epidemiology is crucial to ensure appropriate antibiotics are provided in a timely manner.