Critical Role for 24-Hydroxylation in Homeostatic Regulation of Vitamin D Metabolism.

CONTEXT: The body has evolved homeostatic mechanisms to maintain free levels of Ca+2 and 1,25-dihydroxyvitamin D [1,25(OH)2D] within narrow physiological ranges. Clinical guidelines emphasize important contributions of PTH in maintaining this homeostasis. OBJECTIVE: To investigate mechanisms of homeostatic regulation of vitamin D (VitD) metabolism and to apply mechanistic insights to improve clinical assessment of VitD status. DESIGN: Crossover clinical trial studying participants before and after VitD3-supplementation. SETTING: Community. PARTICIPANTS: 11 otherwise healthy individuals with VitD-deficiency (25-hydroxyvitamin D [25(OH)D] ≤20 ng/mL). INTERVENTIONS: VitD3-supplements (50,000 IU once or twice a week depending on BMI, for 4-6 weeks) were administered to achieve 25(OH)D≥30 ng/mL. RESULTS: VitD3-supplementation significantly increased mean 25(OH)D by 2.7-fold and 24,25-dihydroxyvitamin D [24,25(OH)2D] by 4.3-fold. In contrast, mean levels of PTH, FGF23, and 1,25(OH)2D did not change. Mathematical modeling suggested that 24-hydroxylase activity was maximal for 25(OH)D≥50 ng/mL and achieved a minimum (∼90% suppression) with 25(OH)D<10-20 ng/mL. The 1,25(OH)2D/24,25(OH)2D ratio better predicted modeled 24-hydroxylase activity (h) (ρ=-0.85; p=0.001) compared to total plasma 25(OH)D (ρ=0.51; p=0.01) and the 24,25(OH)2D/25(OH)D ratio (ρ=0.37; p=0.3). CONCLUSIONS: Suppression of 24-hydroxylase provides a first line of defense against symptomatic VitD-deficiency by decreasing metabolic clearance of 1,25(OH)2D. The 1,25(OH)2D/24,25(OH)2D ratio provides a useful index of VitD status since it incorporates 24,25(OH)2D levels and therefore, provides insight into 24-hydroxylase activity. When VitD availability is limited, this suppresses 24-hydroxylase activity - thereby decreasing the level of 24,25(OH)2D and increasing the 1,25(OH)2D/24,25(OH)2D ratio. Thus, an increased 1,25(OH)2D/24,25(OH)2D ratio signifies triggering of homeostatic regulation, which occurs at early stages of VitD-deficiency.

Acute pharmacodynamic responses to sitagliptin: Drug-induced increase in early insulin secretion in oral glucose tolerance test.

DPP4 inhibitors are widely prescribed as treatments for type 2 diabetes. Because drug responses vary among individuals, we initiated investigations to identify genetic variants associated with the magnitude of drug responses. Sitagliptin (100 mg) was administered to 47 healthy volunteers. Several endpoints were measured to assess clinically relevant responses - including the effect of sitagliptin on glucose and insulin levels during an oral glucose tolerance test (OGTT). This pilot study confirmed that sitagliptin (100 mg) decreased the area under the curve for glucose during an OGTT (p = 0.0003). Furthermore, sitagliptin promoted insulin secretion during the early portion of the OGTT as reflected by an increase in the ratio of plasma insulin at 30 min divided by plasma insulin at 60 min (T30:T60) from mean ± SEM 0.87 ± 0.05 to 1.62 ± 0.36 mU/L (p = 0.04). The magnitude of sitagliptin's effect on insulin secretion (as judged by the increase in the T30:T60 ratio for insulin) was correlated with the magnitude of sitagliptin-induced increase in the area under the curve for intact plasma GLP1 levels during the first hour of the OGTT. This study confirmed previously reported sex differences in glucose and insulin levels during an OGTT. Specifically, females exhibited higher levels of glucose and insulin at the 90-180 min time points. However, we did not detect significant sex-associated differences in the magnitude of sitagliptin-induced changes in T30:T60 ratios for either glucose or insulin. In conclusion, T30:T60 ratios for insulin and glucose during an OGTT provide useful indices to assess pharmacodynamic responses to DPP4 inhibitors.

Whole genome sequence analysis of apparent treatment resistant hypertension status in participants from the Trans-Omics for Precision Medicine program.

Introduction: Apparent treatment-resistant hypertension (aTRH) is characterized by the use of four or more antihypertensive (AHT) classes to achieve blood pressure (BP) control. In the current study, we conducted single-variant and gene-based analyses of aTRH among individuals from 12 Trans-Omics for Precision Medicine cohorts with whole-genome sequencing data. Methods: Cases were defined as individuals treated for hypertension (HTN) taking three different AHT classes, with average systolic BP ≥ 140 or diastolic BP ≥ 90 mmHg, or four or more medications regardless of BP (n = 1,705). A normotensive control group was defined as individuals with BP < 140/90 mmHg (n = 22,079), not on AHT medication. A second control group comprised individuals who were treatment responsive on one AHT medication with BP < 140/ 90 mmHg (n = 5,424). Logistic regression with kinship adjustment using the Scalable and Accurate Implementation of Generalized mixed models (SAIGE) was performed, adjusting for age, sex, and genetic ancestry. We assessed variants using SKAT-O in rare-variant analyses. Single-variant and gene-based tests were conducted in a pooled multi-ethnicity stratum, as well as self-reported ethnic/racial strata (European and African American). Results: One variant in the known HTN locus, KCNK3, was a top finding in the multi-ethnic analysis (p = 8.23E-07) for the normotensive control group [rs12476527, odds ratio (95% confidence interval) = 0.80 (0.74-0.88)]. This variant was replicated in the Vanderbilt University Medical Center's DNA repository data. Aggregate gene-based signals included the genes AGTPBP, MYL4, PDCD4, BBS9, ERG, and IER3. Discussion: Additional work validating these loci in larger, more diverse populations, is warranted to determine whether these regions influence the pathobiology of aTRH.