Biology subjects

Peter, D. C.

Publications and source records attributed to Peter, D. C..

3 recordsLinked to original sources

bioRxiv2021

Independent mechanisms underlie the protective effect of dietary polyunsaturated fatty acid supplementation and G&alphaz deficiency on the early type 1 diabetes phenotype of Non-obese diabetic (NOD) mice

Non-obese diabetic (NOD) mice deficient in Gz alpha subunit (Gz) are protected from developing hyperglycemia, even with early islet insulitis similar to wild-type mice. Similarly, wild-type (WT) NOD mice are protected from glucose intolerance when fed a diet enriched in eicosapentaneoic acid (EPA). In the beta-cell, Prostaglandin EP3 receptor (EP3), whose primary endogenous ligand is the arachidonic acid (AA) metabolite, prostaglandin E2, is specifically coupled to Gz. In this work, we tested whether dietary EPA supplementation, thereby reducing systemic PGE2 levels, would complement Gz loss in the NOD mouse model. WT and Gz-null NOD mice were fed an AA-enriched diet, EPA-enriched diet, or control diet upon weaning. After 12 weeks of diet feeding, glucose tolerance tests were performed and pancreatic islets and whole pancreas collected for ex vivo analyses, with the longer-term effect of an EPA-enriched diet on splenic T-cell populations quantified via flow cytometry. Our results reveal a polyunsaturated fatty acid-enriched diet, whether AA or EPA, improves wild-type NOD glucose tolerance by the same magnitude as Gz loss, but through almost completely different physiological and cellular mechanisms. Our results shed critical light on future research into novel pharmacological and dietary adjuvant therapies for T1D.

physiology↗

bioRxiv2021

The protection of Gαz-null NOD mice from hyperglycemia is sexually dimorphic and only partially β-cell autonomous

The mechanisms that underlie the {beta}-cell pathophysiology of Type 1 Diabetes (T1D) are not fully understood. Our group has defined the unique heterotrimeric G protein alpha-subunit, Gz, as a key negative regulator of {beta}-cell signal transduction pathways. Non-obese diabetic (NOD) mice lacking Gz throughout the body are protected from developing T1D-like hyperglycemia. To determine whether this phenotype is {beta}-cell autonomous, we generated and validated a {beta}-cell-specific Gz knockout ({beta}KO) on the NOD background and characterized the phenotype of female and male cohorts. Long-term hyperglycemia incidence was lower in Gz {beta}KO mice as compared to wild-type (WT) controls, but, unlike global Gz knockout mice, this protection was incomplete. While young male and female Gz {beta}KO NOD mice had improved glucose tolerance, WT NOD males were significantly less glucose tolerant than females, and only female Gz {beta}KO mice retained improved glucose tolerance at 28-29 weeks of age. Conversely, {beta}-cell-specific Gz loss only influenced insulitis in 28-29-week old male NOD mice, a phenotype correlating directly with body burden of glucose during oral glucose challenge. Using surrogates for {beta}-cell function and apoptosis, the partial penetrance of euglycemia in Gz {beta}KO NOD was best explained by an early failure to up-regulate {beta}-cell proliferation. We conclude {beta}-cell Gz is an important regulator of the sexually-dimorphic T1D-like phenotype of NOD mice. Yet, other factors must be important in imparting full protection from the disease.

physiology↗

bioRxiv2021

Human islet expression levels of Prostaglandin E2 synthetic enzymes, but not prostaglandin EP3 receptor, are positively correlated with markers of β-cell function and mass in non-diabetic obesity

Elevated islet production of prostaglandin E2 (PGE2), an arachidonic acid metabolite, and expression of Prostaglandin E2 Receptor subtype EP3 (EP3) are well-known contributors to the {beta}-cell dysfunction of type 2 diabetes (T2D). Yet, many of the same pathophysiological conditions exist in obesity, and little is known about how the PGE2 production and signaling pathway influences non-diabetic beta-cell function. In this work, plasma arachidonic acid and PGE2 metabolite levels were quantified in a cohort of non-diabetic and T2D human subjects to identify their relationship with glycemic control, obesity, and systemic inflammation. In order to link these findings to processes happening at the islet level, cadaveric human islets were subject to gene expression and functional assays. Interleukin-6 (IL-6) and cyclooxygenase-2 (COX-2) mRNA levels, but not those of EP3, positively correlated with donor body mass index (BMI). IL-6 expression also strongly correlated with the expression of COX-2 and other PGE2 synthetic pathway genes. Insulin secretion assays using an EP3-specific antagonist confirmed functionallyrelevant up-regulation of PGE2 production. Yet, islets from obese donors were not dysfunctional, secreting just as much insulin in basal and stimulatory conditions as those from non-obese donors as a percent of content. Islet insulin content, on the other hand, was increased with both donor BMI and islet COX-2 expression, while EP3 expression was unaffected. We conclude up-regulated islet PGE2 production may be part of the {beta}-cell adaption response to obesity and insulin resistance that only becomes dysfunctional when both ligand and receptor are highly expressed in T2D.

pharmacology and toxicology↗