A Gly482Ser SNP within the coding region of human peroxisome proliferator activated receptor (PPAR)-γ coactivator-1 alpha (PGC-1α) is associated with type 2 diabetes (T2D) susceptibility and other metabolic diseases. It has been shown that the Serine expressing variant increases the relative risk of T2D; however, the functional significance of this single nucleotide polymorphism (SNP) has not yet been characterized. By cycloheximide chase, we determined that a Serine residue at amino acid position 482 decreases protein stability, compared to the 482Gly counterpart.
Canadian Journal of Diabetes
76 - Antiapoptotic Bcl-xL Preserves the Transcriptional, Morphological and Functional Integrity of β-Cell Mitochondria During Chronic Glucose Excess
Nutrient stress contributes to β-cell failure in type 2 diabetes. We previously reported that antiapoptotic Bcl-xL dampens β-cell glucose signalling. Here, we examined if Bcl-xL is important for β-cell mitochondrial homeostasis during prolonged exposure to excess glucose.
Heterogeneity within specific cell types is common and increasingly apparent with the advent of single-cell transcriptomics. Transcriptional and functional cellular specialization has been described for insulin-secreting β-cells of the endocrine pancreas, including so-called extreme β-cells exhibiting >2-fold higher insulin gene activity. However, it is not yet clear whether β-cell heterogeneity is stable or reflects dynamic cellular states. We investigated the temporal kinetics of endogenous insulin gene activity using live-cell imaging, with complementary experiments employing FACS and single-cell RNA sequencing, in β-cells from Ins2GFP knock-in mice.
Dietary carbohydrates raise blood glucose; as such, limiting carbohydrate intake improves glycemia in patients with T2D. Low carbohydrate intake (<25 g) allows the body to utilize fat as its primary fuel. As a consequence of increased fatty-acid oxidation, the liver produces ketones, of which β-hydroxybutyrate (βHB) is the most abundant, to serve as an alternative energy source. While βHB has a wide range of signalling functions outside of the pancreas, its effect on islet function remains understudied, especially in human islets.
The incidence of diabetes after organ transplantation (NODAT) has increased, in part due to calcineurin inhibitors, particularly tacrolimus (TAC). Voclosporin (VCS) is a next generation calcineurin inhibitor that causes less NODAT in clinical trials, but its effects on human beta cells are unknown. We compared the effects of TAC and VCS on the dynamics of insulin secretory function, the programmed cell death rate and the transcriptomic profile of isolated human islets. We studied 2 clinically relevant doses of TAC (10 ng/ml, 30 ng/ml) and VCS (20 ng/ml, 60 ng/ml), meant to approximate the trough and peak concentrations of each drug.
Type 2 diabetes (T2D) is characterized by progressive dysfunction and destruction of β-cells. Biological sex affects the risk of developing T2D: ∼40% more men develop T2D than premenopausal women. To gain insight into mechanisms underlying the male-biased risk of T2D, we used RNAseq to examine gene expression in 20-week male and female mice islets. Unbiased pathway analysis of islet RNAseq data revealed higher expression of genes that encode components of the cellular protein folding machinery in females compared with males.
81 - The Association of Albuminuria in Youth With Type 2 Diabetes With In-Utero Type 2 Diabetes Exposure Is Not Mediated Through Altered Renal Volume
Type 2 diabetes (T2D) diagnosed in youth is associated with early renal complications. We tested the hypothesis that in utero maternal diabetes exposure impacts the developing nephron mass resulting in smaller renal volume and early renal dysfunction.
82 - Effects of the Menstrual Cycle on Exercise Blood Glucose Responses to Exercise in Females With Type 1 Diabetes
To compare changes in blood glucose concentration during aerobic exercise performed in the follicular (FP) vs the luteal phase (LP) of the menstrual cycle in adult females with type 1 diabetes (FT1D).
83 - INS rs3842753 SNP Genotype Associated With Type 1 Diabetes Risk Modulates Insulin mRNA Expression Distribution in Single Nondiabetic Human Beta Cells
Type 1 diabetes (T1D) is characterized by the autoimmune destruction of insulin-secreting pancreatic beta cells. Variation upstream at the insulin (INS) locus: single DNA base changes rs689 (A > T) and rs3842753 (A > C), and shortening of a repetitive DNA sequence (Class III INS-VNTR > Class I INS-VNTR) occur in unison, contributing ∼10% of heritable risk.
84 - The HNF-1a G319S Gene Variant, Which Associates With Early-Onset Type 2 Diabetes (T2D) in Anishininiiwuk Youth, Affects Liver Metabolism and Endogenous Glucose Production in a Knock-In Mouse Model
Type 2 diabetes (T2D) diagnoses in the Anishininiiwuk (Oji-Cree) linguistic group of central Canada are among the highest in the world, and a genetic variant in the hepatic nuclear factor-1a (HNF-1a) gene, known as HNF-1a G319S, strongly associates with T2D in this population. HNF-1a is known to play an important role in the liver, and the liver plays a central role in controlling glucose homeostasis, but it is unclear how the G319S variant influences liver function. We hypothesize that the G319S variant promotes greater hepatic glucose production, which historically may have conferred an advantage during states of fasting, but, in modern times, promotes hyperglycemia and T2D.
Polycystic ovary syndrome (PCOS) is associated with poor sleep quality. In this secondary analysis of a 6-month exercise training randomized controlled trial in women aged 18-40 years with PCOS, our aims were: 1) to determine the proportion of participants with poor sleep quality, and 2) to evaluate the effect of high-intensity interval training (HIIT) and continuous aerobic exercise training (CAET) on sleep quality. Twenty-nine participants completed the Pittsburgh Sleep Quality Index (PSQI) pre- and postintervention: no-exercise control (n=9), HIIT (n=12) and CAET (n=8).
86 - Comparison of Maternal and Fetal Outcomes Using the 1-Step Vs 2-Step Canadian Diagnostic Strategies for GDM
The impact of the 2 Canadian diagnostic strategies for gestational diabetes mellitus (GDM) on maternal and neonatal complications need studying. Our objective is to compare these outcomes when using the 75 g 1-step oral glucose tolerance test (OGTT) vs the 50 g 2-step OGTT.
87 - Adverse Fetal and Neonatal Outcomes in Diabetic Pregnancies in Nova Scotia From 1988-2002 and 2003-2015
Pre-existing diabetes in pregnancy is related to adverse fetal and neonatal outcomes. We aimed to determine rates of these outcomes and changes over time among pregnancies associated with pre-existing diabetes in Nova Scotia (NS).
88 - Appropriateness of Clinical Indications for Ordering Thyroid-Stimulating Hormone in Noncritically Ill Adult Inpatients – A Modified Delphi Study
Thyroid-stimulating hormone (TSH) is ordered commonly among inpatients, but the possibility of nonthyroidal illness syndrome challenges interpretation. Our objective was to obtain Canadian consensus on appropriate indications for ordering TSH in the first 48 hours following presentation of a noncritically ill internal medicine patient.
89 - Thyroid Laboratory Testing and Management in Women on Thyroid Replacement Prior to Pregnancy and Associated Pregnancy Outcomes
To investigate: 1) the frequency and distribution of thyrotropin (TSH) testing and levothyroxine dosage adjustment by gestational age and 2) the relationship between “over”- or “under”-replacement of levothyroxine during pregnancy with adverse pregnancy outcomes among women using thyroid replacement prior to pregnancy.
90 - Evaluating the Risk of Malignancy (ROM) in Thyroid Nodules With Bethesda Category III and IV at St. Joseph’s Hospital, Hamilton Compared to the Malignancy Rates Reported in the Bethesda System
The Bethesda system standardized the reporting for thyroid fine needle aspiration (FNA) to provide an estimation of risk of malignancy (ROM) for each of its 6 categories. The prevalence of malignancy in thyroid nodules removed based on FNA diagnosis varies by institution and ranges 10-30% in Bethesda category III (BCIII) and 25-40% in Bethesda category IV (BCIV). The goal of this study is to determine the frequency of malignancy in thyroid nodules with BCIII and BCIV FNA result at St. Joseph's Hospital Hamilton.
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