No abstract

Objectives This study examined the natural history of the proinsulin to c-peptide (PI:C) ratio and its correlation with residual β-cell function in childhood new-onset type 1 diabetes (T1D). Reputedly, this ratio is a biomarker of β-cell endoplasmic reticulum (ER) stress. 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 one year, randomized, double-blind, placebo-controlled gamma aminobutyric acid (GABA) trial in new-onset T1D. Of the 99 participants in the primary study, aged 4-18 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 visit, 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, inferring escalating β-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 a 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 are undergoing progressive β-cell ER stress and aberrant proinsulin processing as evidenced by increasing PI:C ratios. Moreover, the PI:C ratio reflects a more aggressive β-cell onslaught the younger the age as well as diminished glycemic control.

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.