Serum Calcium Concentrations, Chronic Inflammation and Glucose Metabolism: A Cross-Sectional Analysis in the Andhra Pradesh Children and Parents Study (APCaPS)

ORIGINAL RESEARCH CURRENT DEVELOPMENTS IN NUTRITION Nutritional Epidemiology and Public Health Serum Calcium Concentrations, Chronic Inflammation and Glucose Metabolism: A Cross-Sectional Analysis in the Andhra Pradesh Children and Parents Study (APCaPS) Sharon E Cox ,3 Prabhakaran D,1,2,4 ,2,5 and Preet K Dhillon1 1 Centre for Chronic Conditions and Injuries, Public Health Foundation of India, Gurgaon, Haryana, India; London School of Hygiene and Tropical Medicine, London, UK; 3 Public Health Foundation of India, Gurgaon, Haryana, India; 4 Centre for Chronic Disease Control, Haryana, India; and 5 School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki, Japan 2 ABSTRACT Background: Evidence suggests a role for elevated serum calcium in dysregulated glucose metabolism, linked through low-level chronic inflammation. Objectives: We investigated the association of elevated serum calcium concentrations (corrected for albumin) with markers of dysregulated glucose metabolism and type II diabetes and tested if these associations were accounted for by chronic inflammation in a rural Indian population. Methods: A cross-sectional analysis of participants aged 40–84 y from the Andhra Pradesh Children and Parents Study (APCaPS; n = 2699, 52.2% women) was conducted. Comprehensive information on household, sociodemographic, and lifestyle factors; medical and family history; physical measurements; blood measurements including fasting plasma glucose (FPG), fasting insulin (FI), serum calcium, albumin, phosphorous, vitamin D (in a subset), and creatinine were analyzed. Additionally, in a random sample of healthy participants (n = 1000), inflammatory biomarkers (interleukins 6 and 18, soluble intercellular adhesion molecule 1, adiponectin, and high-sensitivity C-reactive protein) were measured and an inflammatory score (IScore) calculated. Results: After adjustments for sociodemographics, lifestyle factors, and anthropometry the highest calcium quartile (Q4 compared with Q1) was associated with FI (β = 1.4 µU/ml; 95% CI: 1.2, 1.5 µU/ml; P-trend < 0.001), the homeostasis model assessment for insulin resistance (HOMA-IR) (β = 1.4; 95% CI: 1.2, 1.5; P-trend < 0.001), and was modestly associated with FPG (β = 2.1 mg/dL; 95% CI: −0.9, 5.2 mg/dL; P-trend = 0.058) and prevalent type II diabetes (OR = 1.6; 95% CI: 1.0, 2.6; P-trend= 0.020). In the healthy subgroup, the association of the highest calcium quartile was similar for FI and HOMA-IR. Additional adjustment with IScore did not alter the associations. Further, in a subset, all these associations were independent of endogenous regulators of calcium metabolism (serum vitamin D, phosphorus, and creatinine). Independently, after accounting for potential confounders, the highest IScore quartile (Q4 compared with Q1) was positively associated with FPG, FI, HOMA-IR, and prevalent prediabetes, and also with serum calcium concentrations in men. Conclusions: Elevated serum calcium was positively associated with markers of dysregulated glucose metabolism and prevalent type II diabetes in a rural Indian population. Chronic inflammation did not mediate this association but was independently associated with markers of dysregulated glucose metabolism. Inflammation might be responsible for elevated serum calcium concentrations in men. Curr Dev Nutr 2019;3:nzy085. Keywords: calcium, glucose metabolism, insulin resistance, type II diabetes, prediabetes, chronic inflammation, India, APCaPS Copyright © American Society for Nutrition 2018. All rights reserved. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits noncommercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact Manuscript received June 4, 2018. Initial review completed August 6, 2018. Revision accepted October 23, 2018. Published online October 25, 2018. This study was funded by Wellcome Trust Strategic Award 084774 and European Commission Strategic Award (FP-7) and Department of Bio-Technology, India (BT/PR6172/FNS/20/609/2012). KS was supported by a Wellcome Trust Capacity Strengthening Strategic Award Extension phase to the Public Health Foundation of India and a consortium of UK universities (WT084754/Z/08/A), and this work was part of her MSc (Epidemiology) thesis dissertation submitted to London School of Hygiene and Tropical Medicine. The Wellcome Trust had no role in the design, data collection, analysis, or publication of the manuscript. The authors declare no potential conflicts of interest. Supplemental Material, Supplemental Figures 1-2 and Supplemental Tables 1–3 are available from the “Supplementary data” link in the online posting of the article and from the same link in the online table of contents at https://academic.oup.com/cdn/. Address correspondence to KS (e-mail: ). Abbreviations used: APCaPS, Andhra Pradesh Children and Parents Study; COPD, chronic obstructive respiratory disease; CVD, cardiovascular disease; DALY, disability-adjusted life-year; FPG, fasting plasma glucose; FI, fasting insulin; hsCRP, high-sensitivity C-reactive protein; IScore, inflammatory score; PAL, physical activity level; PTH, parathyroid hormone; sICAM-1, soluble intercellular adhesion molecule 1; SLI, Standard of Living Index. ; 1 Krithiga Shridhar,1 Sanjay Kinra,2 Ruby Gupta,1 Shweta Khandelwal 2 Shridhar et al. Introduction Methods The analyses in this study used data from the third follow-up of APCaPS (2010–12), a prospective cohort study established through long-term follow-up of the Hyderabad Nutrition Trial (1987–90). Brief details of the study design are included as Supplemental Material along with a participant flow chart and venn diagram (Supplemental Figure 1-2). A total of 6944 out of a potential 10,213 individuals participated during this phase. This included adults born between 1987 and 1990, their parents, and household members. Our analysis included men and women aged ≥40 y (n = 2699) from the third follow-up phase. Comprehensive information on household, sociodemographic, socioeconomic, lifestyle factors, medical and family history, as well as physical measurements (anthropometrics and blood pressure) were collected. Fasting blood samples (8 h) were collected, and biochemical concentrations of FPG and FI, and serum concentrations of nutrients including calcium, phosphorus as well as vitamin D in a subset (n = 1713), along with full blood count, and kidney function tests (e.g., serum creatinine, albumin) were measured. Vitamin D data were available for adults born between 1987 and 1990 and their parents (n = 1713/2699), but were not available for other members of the household or community. Inflammatory biomarkers IL-6, IL-18, soluble intercellular adhesion molecule 1 (sICAM-1), adiponectin, and highsensitivity C-reactive p (...truncated)