Calcium Intake is Associated to Changes in the Interplay between Bone, Pancreas and Fat Tissue in the Control of Glucose Homeostasis- Experimental Study

Research Article

Austin J Nutr Metab. 2019; 6(1): 1063.

Calcium Intake is Associated to Changes in the Interplay between Bone, Pancreas and Fat Tissue in the Control of Glucose Homeostasis- Experimental Study

Marotte C1, Bonanno MS1, Zeni Coronel M1, Avendaño ME2, Pita Martín de Portela ML3 and Zeni SN1*

¹Metabolic Bone Diseases Laboratory, Immunology, Genetic and Metabolism Institute (INIGEM), School of Pharmacy and Biochemistry, Clinical Hospital “José de San Martín”, Buenos Aires University (UBA)/ National Council for Scientific and Technologic Research (CONICET), Argentina

²Department of Images Diagnostic I, School of Dentistry, Cuyo National University, Rio Negro, Argentina

³Food Science and Nutrition Department, School of Pharmacy and Biochemistry, Buenos Aires University (UBA), Buenos Aires, Argentina

*Corresponding author: Prof. Dr. Zeni SN, Metabolic Bone Diseases Laboratory, INIGEM CONICET-UBA, Clinical Hospital “José de San Martín”, Av. Córdoba 2351 8° piso, CP 1120, CABA, Buenos Aires, Argentina; TEL/ FAX: 541159508972; Email: snzeni@hotmail.com

Received: September 09, 2019; Accepted: October 10, 2019; Published: October 17, 2019

Abstract

Background: Bone remodeling, insulin levels and fat mass interrelationship in glucose homeostasis control was evaluated in Weaning Normal (W) and Obese (O) rats fed High (H), Normal (N) or Low (L) Ca intakes.

Methods: Glucose, Cholesterol (Chol), HDL-Chol, Triglyceride (TGL), Ca, P, insulin, Osteocalcin (OCN) and collagen C-telopeptide (CTX), body composition, BMD, BMC, body Ca and P content, perigonadal plus retroperitoneal fat (PG+RP) and liver weight were determined and HOMA-IR calculated.

Results: WHCa reached the highest body fat, PG+RP and the highest CTX levels (p‹0.05); WNCa had the lowest liver weight. WLCa reached the lowest body protein content (p‹0.05) and the highest glucose, insulin and HOMA-IR (p‹0.05). WLCa and WHCa had similar Chol levels but higher than WNCa; TGL increased and OCN decreased as dietary Ca content increased (p‹0.05). OLCa presented the highest body fat, Chol and OCN levels but the lowest HDLChol levels (p‹0.05); ONCa had the highest body protein percentage (p‹0.05). OHCa had the lowest CTX levels (p‹0.05). PG+RP, liver weight, glucose, insulin and HOMA-IR decreased as dietary Ca content increased (p‹0.05). O groups reached higher adipose PG+RP fat, liver weight, glucose, insulin, Chol, TGL and HOMA-IR and lower OCN, CTX and body protein content than their matched-W groups (p‹0.05).

Conclusion: The relative amount of dietary Ca to P may regulate energy metabolism and bone turnover, insulin and body fat interplay in glucose homeostasis control. However, the mechanisms differ in physiological conditions or in the presence of metabolic abnormalities of energy dysregulation such as obesity and T2-diabetes.

Keywords: Osteocalcin; Bone Resorption; Insulin; Body Fat

Abbreviations

OCN: Osteocalcin; BGP: Gamma-Carboxyglutamic Acid- Containing Protein; GLA: Gamma-carboxyglutamic acid; Ca: Calcium; InsR: Osteoblastic Insulin Receptor; OPG: Osteoprotegerin; RANK: Receptor Activator of Nuclear Factor-Kappa B; RANKL: Receptor Activator of Nuclear Factor-Kappa B Ligand; CNS: Central Nervous System; T2DM: Type 2 Diabetes Mellitus; BMD: Bone Mineral Density; CaI: Ca Intake; NCa: Normal Ca Diet; HCa: High Ca Diet; LCa: Low Ca Diet; BW: Body Weight; PG: Perigonadal Fat; RP: Retroperitoneal Fat; Pi: Inorganic Phosphorus; Chol: Total Cholesterol; HDL Chol: Higth Density Lipoprotein Cholesterol; TGL: Triglyceride; 25OHD: 25 hydroxyvitamin D; b-ALP: Serum Bone Alkaline Phosphatase; CTX: C-Terminal Telopeptide of Type I Collagen; tsBMC: Total Skeleton Bone Mineral Content; tsBMD: Total Skeleton Bone Mineral Density; BMD: Bone Mineral Content, SE: Standard Error; W: Wistar Rats; O: IIMb/β Obese Rats; PTH: Parathormone; 2ºHPT: Secondary Hyperparathyroidism; MS:Metabolic Syndrome).

Introduction

One of the energy metabolism regulations appears to occur through the interplay between bone, fat tissue and pancreas. According to literature, these organs maintain glucose homeostasis through the interaction between bone turnover markers, insulin and leptin levels.

Osteocalcin (OCN) is a non-collagenous protein secreted by osteoblasts/osteocytes. The negative charge of Gammacarboxyglutamic acid (GLA) residues increases OCN Calcium (Ca)- binding properties, resulting in an association with hydroxyapatite in bone extracellular matrix. In clinical practice, OCN used to be used as a bone formation marker and more broadly, of bone remodeling. Bone matrix acidification performed by osteoclasts resorbing activity induces OCN bioactivation, which loses Ca affinity and is released into bloodstream. OCN bioactive form may regulate energy metabolism stimulating insulin synthesis and secretion by the pancreatic β cells, and insulin sensitivity and glucose utilization in peripheral tissues [1]. Transgenic OCN-deficient mice are fat, insulin resistant, glucose intolerant, and hyperlipidemic [2]. Ferron et al. demonstrated that OCN production and bioavailability are under insulin control [3].

Osteoblastic Insulin Receptor (InsR) is required for osteoblast survival, proliferation, and differentiation. Insulin signalling in osteoblasts regulates Runx2 expression, OCN production and decreases the expression of Osteoprotegerin (OPG). The latter increases osteoclastic activity. The acidic environment in the resorption lacuna increases OCN bioavailability [3]. Many factors regulate the positive feedback loop between the osteoblastic insulin signalling and OCN in pancreatic β cells.

Leptin plays an essential role on energy metabolism. Leptin secretion correlates positively with adipose tissue mass, and thereby it monitors overall energy availability. Leptin inhibits insulin secretion through a direct effect on pancreatic β cells and induces the indirect suppression of insulin signalling in osteoblasts via Central Nervous System (CNS) [4]. These observations establish the tight metabolic link between osteoblasts, pancreatic β cells and adipocytes Falta el punto.

Energy metabolism dysregulation is associated with intracellular lipid accumulation and excess of body adipose tissue storage that results in several comorbidities [5]. Type 2 Diabetes Mellitus (T2DM) is the most significant obesity-associated metabolic disorder, characterized by insulin resistance, hyperglycemia, dyslipidemia and alterations in hormonal signalling systems both, in CNS and peripheral nervous system [6]. Moreover, T2DM patients have an increased risk of bone fragility and fractures, regardless of having Bone Mineral Density (BMD) increase [7]. One of the main factors involved in T2DM-derived bone fragility would be bone quality deterioration due to bone turnover suppression [8].

There is no doubt about the negative effect of low Ca Intake (CaI) on bone mass. Furthermore, according to literature, it also appears to induce energy dysregulation by affecting insulin secretion and lipogenesis [9,10]. Our group evidenced the obesogenic effect of Ca insufficiency in rats fed a low Ca diet, which presented an increase in fat mass accumulation and a negative effect in lipid profile, but these alterations were more evident when animals were prone to obesity [11]. Moreover, epidemiological studies determined that obesity and T2DM incidence was likely to be inversely associated with the increase in dietary Ca [12].

The results of our previous paper led us to postulate that Ca amount supplied by the diet may mediate, at least in part, glucose homeostasis through changes in bone, pancreas and fat mass interplay. Besides, abnormalities in insulin secretion, fat mass accumulation and bone remodeling because of T2DM could additionally affect the possible effect of CaI on energy metabolism. On these bases, the present experimental report evaluated in vivo the interaction of bone remodeling, insulin levels and fat mass in glucose homeostasis in normal Wistar rats and in obese/T2DM rats fed three different dietary Ca contents. The results of this interrelationship were also compared between the two strains of rats.

Materials and Methods

Diets

Three experimental isocaloric diets were prepared according to American Institute of Nutrition Rodent Diets Recommendations settled in 1993 (AIN-93G) [13]. Diet composition was identical, except for Ca content. Normal Ca diet (NCa) contained 0.5% Ca, providing Ca requirement for rodents; High Ca diet (HCa) contained 0.9% Ca, exceeding Ca recommendations by 50% and Low Ca diet (LCa) contained 0.2% Ca, contributing by 40% of Ca recommendations (Table 1).