Diabetes-risk Forecasts: Serum Calcium in Upper-Normal Range (>2.5 mmol/L) as a New Biomarker
Article Curator: Aviva Lev-Ari, PhD, RN
ClinicalTrials.gov identifier: NCT00005135
Other Study ID Numbers: | 1005 |
Study First Received: | May 25, 2000 |
Last Updated: | April 13, 2009 |
Insulin Resistance Atherosclerosis Study (IRAS)
sponsored by National Heart, Lung, and Blood Institute (NHLBI)
Clinical Trial had the following purpose:
To conduct a multicenter study of the relationship between insulin resistance and cardiovascular disease (CVD) and its risk factors in a tri-ethnic (African-American, Hispanic, and non-Hispanic white) population aged 40 to 69 years at baseline. Also, to identify the genetic determinants of insulin resistance and visceral adiposity.
Conditions
- Cardiovascular Diseases
- Atherosclerosis
- Diabetes Mellitus
- Heart Diseases
- Obesity
- Insulin Resistance
List of Investigators and Publications
Results of the Completed Clinical Trial
were presented at European Association for the Study of Diabetes (EASD) 49th Annual Meeting
September 23 – 27, 2013; Barcelona, Spain
http://www.medscape.com/viewcollection/32906
by Dr Carlos Lorenzo (University of Texas Health Science Center, San Antonio) in an interview with Heartwire
http://www.medscape.com/viewarticle/811536
Study Parameters
#1
Patient population
IRAS enrolled 863 nondiabetic subjects (age 40–69) at four centers. Insulin sensitivity and acute insulin response were measured at baseline and at regular intervals over a five-year follow-up period. Diabetes and IGT were defined by
- current fasting and
- two-hour plasma glucose criteria
- and/or use of glucose-lowering medications
Of the 863 subjects, the number of people in IRAS who fell into this high-calcium group was relatively small—about 15% to 17% of the study population.
- lower insulin sensitivity,
- impaired glucose tolerance (IGT), and the
- metabolic syndrome
#3
Tree Key factors involved in Calcium Regulation NOT studies by Insulin Resistance Atherosclerosis Study (IRAS)
The study did not address
- vitamin D – involved in calcium regulation
- parathyroid hormone levels – involved in calcium regulation
- physical-activity levels, which are also known to have an impact on serum calcium
#4
Study Results Highlights
- High concentrations of serum calcium—but not necessarily calcium intake—are associated with an increased risk of developing type 2 diabetes, results from the Insulin Resistance Atherosclerosis Study (IRAS) show. Moreover, calcium concentration appears to act independently of glucose, insulin secretion, and insulin resistance
- relationship between calcium concentration and incident diabetes was statistically significant but did not follow a linear relationship. Only subjects with the highest concentrations of calcium (>2.38 mmol/L) had a significantly increased risk of developing diabetes. After controlling for
- age,
- sex,
- race/ethnicity,
- family history of diabetes,
- body-mass index (BMI),
- plasma glucose levels,
- insulin-sensitivity index,
- acute insulin response,
- estimated glomerular filtration rate (eGFR), and
- diuretic drugs,
researchers found that only patients at the highest levels of serum calcium (>2.5 mmol/L) showed a statistically significant increase in incident diabetes.
- A similar, nonlinear relationship was seen between the highest category of serum calcium and impaired fasting glucose.
- Of note, in models that looked at albumin-adjusted calcium concentration as well as total calcium intake, no statistically significant relationship with five-year diabetes risk was seen
- In the past, explained Lorenzo, researchers have speculated that the link between calcium and diabetes is related to insulin resistance or insulin secretion. “Our study shows that people with serum calcium that is pretty much in the normal range, but in the upper-normal range—those people are at higher risk for diabetes. And that, most probably, is not related to their metabolic status defined by their obesity or their insulin resistance or their insulin secretion.”
- Calcium Intake Not Linked With Diabetes IncidenceThe findings on calcium intake are also important, he noted, since it shows that high calcium intake, per se, is not problematic; rather, it is the body’s ability to regulate calcium that seems to be at issue.
- Dr, Lorenzo suspect [serum calcium levels] won’t add much to their prediction equations, but “if you have someone in the clinic who has those levels of calcium, that person is going to be at higher risk for diabetes,” he concluded.
Other RELATED articles published on this Open Access Online Scientific Journal, include the following:
Critical Gene in Calcium Reabsorption: Variants in the KCNJ and SLC12A1 genes – Calcium Intake and Cancer Protection
MGH’s Largest-ever Genetic Study of Five Psychiatric Disorders: Variation in SNPs in Two Genes involved in Calcium-Channel Signaling
Calcium (Ca) supplementation (>1400 mg/day): Higher Death Rates from all Causes and Cardiovascular Disease in Women
Calcium Regulation Key Mechanism Discovered: New Potential for Neuro-degenerative Diseases Drug Development
Calcium dependent NOS induction by sex hormones: Estrogen
https://pharmaceuticalintelligence.com/2012/10/03/calcium-dependent-nos-induction-by-sex-hormones/
List of TEN articles on Dysfunction of Calcium Release Mechanism and Cardiovascular Diseases
Part I: Identification of Biomarkers that are Related to the Actin Cytoskeleton
Larry H Bernstein, MD, FCAP
Part II: Role of Calcium, the Actin Skeleton, and Lipid Structures in Signaling and Cell Motility
Larry H. Bernstein, MD, FCAP, Stephen Williams, PhD and Aviva Lev-Ari, PhD, RN
Part III: Renal Distal Tubular Ca2+ Exchange Mechanism in Health and Disease
Larry H. Bernstein, MD, FCAP, Stephen J. Williams, PhD and Aviva Lev-Ari, PhD, RN
Part IV: The Centrality of Ca(2+) Signaling and Cytoskeleton Involving Calmodulin Kinases and Ryanodine Receptors in Cardiac Failure, Arterial Smooth Muscle, Post-ischemic Arrhythmia, Similarities and Differences, and Pharmaceutical Targets
Larry H Bernstein, MD, FCAP, Justin Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN
Part V: Heart, Vascular Smooth Muscle, Excitation-Contraction Coupling (E-CC), Cytoskeleton, Cellular Dynamics and Ca2 Signaling
Larry H Bernstein, MD, FCAP, Justin Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN
Part VI: Calcium Cycling (ATPase Pump) in Cardiac Gene Therapy: Inhalable Gene Therapy for Pulmonary Arterial Hypertension and Percutaneous Intra-coronary Artery Infusion for Heart Failure: Contributions by Roger J. Hajjar, MD
Aviva Lev-Ari, PhD, RN
Part VII: Cardiac Contractility & Myocardium Performance: Ventricular Arrhythmiasand Non-ischemic Heart Failure – Therapeutic Implications for Cardiomyocyte Ryanopathy (Calcium Release-related Contractile Dysfunction) and Catecholamine Responses
Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN
Part VIII: Disruption of Calcium Homeostasis: Cardiomyocytes and Vascular Smooth Muscle Cells: The Cardiac and Cardiovascular Calcium Signaling Mechanism
Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN
Part IX: Calcium-Channel Blockers, Calcium Release-related Contractile Dysfunction (Ryanopathy) and Calcium as Neurotransmitter Sensor
Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN
Part X: Synaptotagmin functions as a Calcium Sensor: How Calcium Ions Regulate the fusion of vesicles with cell membranes during Neurotransmission
Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN
The study may have validity, but there are significant problems:
863 nondiabetic subjects (age 40–69)
Diabetes and IGT were defined by
current fasting and
two-hour plasma glucose criteria
and/or use of glucose-lowering medications
What about a HbA1c determined to exceed 6.3 or 6.1-6.3?
The study did not address
vitamin D – involved in calcium regulation – probably NOT relevant
it would be good to have information about intake of vit D supplements
24/25 and 1/25 vit D are regulated and the end result is the absorption of calcium from the small intestine (most of oral in take is absorbed)
parathyroid hormone levels – involved in calcium regulation – PTH is probably not relevant because the calcium levels would be quite a bit higher
physical-activity levels, which are also known to have an impact on serum calcium Probably not relevant because the 1/25 to 24/25 would adjust top activity needs
Only subjects with the highest concentrations of calcium (>2.38 mmol/L) had a significantly increased risk of developing diabetes. After controlling for
age,
sex,
race/ethnicity,
family history of diabetes,
body-mass index (BMI),
plasma glucose levels,
insulin-sensitivity index,
acute insulin response,
estimated glomerular filtration rate (eGFR), and
diuretic drugs,
researchers found that only patients at the highest levels of serum calcium (>2.5 mmol/L) showed a statistically significant increase in incident diabetes.
I don’t know that you can control for that many independent variables to account for variability in a population of 863 patients who are not diabetic at the start.
I also don’t know why they did a correction for albumin biding when there was so much substantial work at Hartford Hospital (1980s) in the ICU patients on ionized calcium, which is ACCURATELY measured. The critical care patient is a different patient, but the measurement of ionized calcium is now relatively easy.
I don’t know if these are clinic or hospitalized patients, and knowing whether there is dehydration or protein-energy malnutrition would help. The correction ios based on the equilibrium binding of ALB-Ca2+.
There is another consideration. – calcium, so abundant in the lean body mass, is actually an extracellular cation in equilibrium with intracellular divalent Mg2+. It has great importance in cell mobility, and in neural conductivity, and in muscle contraction.
Mg2+ is important, but we can’t so accurately measure the total body Mg2++, not reflected in the serum ULN, and metabolically important if deficient.
The authors of the paper acknowledge that the results are statistically significant, but there is no certatinty about the likelihood of later diabetes, or anything resembling a hazard ratio.
I would give credence to this report if they had 8,630 patients – at least, and then they could look at meaningful associations, and do linkage clustering. Alas, there is not much to consider.
We are on the same page again.
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