Leaders in Pharmaceutical Business Intelligence (LPBI) Group

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

http://www.clinicaltrials.gov/ct2/show/NCT00005135?term=Insulin+Resistance+Atherosclerosis+Study&rank=1

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.

Cardiovascular disease and diabetes share many of the same risk factors and that calcium has also been linked with

• 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

Hypothesis was that serum calcium may also play some role in the development of diabetes

Dr. Lorenzo told heartwire:

Whether serum calcium plays a causative role in the development of diabetes or is a marker for other adverse processes remains unclear; “we can’t answer that question,”  “There is a relationship, but we can’t yet determine why this is happening.”

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

http://pharmaceuticalintelligence.com/2013/04/12/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

http://pharmaceuticalintelligence.com/2013/02/28/mghs-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

http://pharmaceuticalintelligence.com/2013/02/19/calcium-ca-supplementation-1400-mgday-higher-death-rates-from-all-causes-and-cardiovascular-disease-in-women/

Calcium Regulation Key Mechanism Discovered: New Potential for Neuro-degenerative Diseases Drug Development

http://pharmaceuticalintelligence.com/2013/01/17/calcium-regulation-key-mechanism-discovered-new-potential-for-neuro-degenerative-diseases-drug-development/

Calcium dependent NOS induction by sex hormones: Estrogen

http://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

http://pharmaceuticalintelligence.com/2012/12/10/identification-of-biomarkers-that-are-related-to-the-actin-cytoskeleton/

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

http://pharmaceuticalintelligence.com/2013/08/26/role-of-calcium-the-actin-skeleton-and-lipid-structures-in-signaling-and-cell-motility/

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

http://pharmaceuticalintelligence.com/2013/09/02/renal-distal-tubular-ca2-exchange-mechanism-in-health-and-disease/

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

http://pharmaceuticalintelligence.com/2013/09/08/the-centrality-of-ca2-signaling-and-cytoskeleton-involving-calmodulin-kinases-and-ryanodine-receptors-in-cardiac-failure-arterial-smooth-muscle-post-ischemic-arrhythmia-similarities-and-differen/

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

http://pharmaceuticalintelligence.com/2013/08/26/heart-smooth-muscle-excitation-contraction-coupling-cytoskeleton-cellular-dynamics-and-ca2-signaling/

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

http://pharmaceuticalintelligence.com/2013/08/01/calcium-molecule-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/

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

http://pharmaceuticalintelligence.com/2013/08/28/cardiac-contractility-myocardium-performance-ventricular-arrhythmias-and-non-ischemic-heart-failure-therapeutic-implications-for-cardiomyocyte-ryanopathy-calcium-release-related-contractile/

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

http://pharmaceuticalintelligence.com/2013/09/12/disruption-of-calcium-homeostasis-cardiomyocytes-and-vascular-smooth-muscle-cells-the-cardiac-and-cardiovascular-calcium-signaling-mechanism/

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

http://pharmaceuticalintelligence.com/2013/09/16/calcium-channel-blocker-calcium-as-neurotransmitter-sensor-and-calcium-release-related-contractile-dysfunction-ryanopathy/

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

http://pharmaceuticalintelligence.com/2013/09/10/synaptotagmin-functions-as-a-calcium-sensor-how-calcium-ions-regulate-the-fusion-of-vesicles-with-cell-membranes-during-neurotransmission/