Alloxan-induced diabetes exacerbates coronary atherosclerosis and calcification in Ossabaw miniature swine with metabolic syndrome
Abstract Background There is a preponderance of evidence implicating diabetes with increased coronary artery disease (CAD) and calcification (CAC) in human patients with metabolic syndrome (MetS), but the effect of diabetes on CAD severity in animal models remains controversial. We investigated whet...
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doaj-a1937202794c4805829c0e61c49b95242020-11-25T00:13:53ZengBMCJournal of Translational Medicine1479-58762018-03-0116111310.1186/s12967-018-1431-9Alloxan-induced diabetes exacerbates coronary atherosclerosis and calcification in Ossabaw miniature swine with metabolic syndromeJill K. Badin0Ayeeshik Kole1Benjamin Stivers2Victor Progar3Anisha Pareddy4Mouhamad Alloosh5Michael Sturek6Department of Cellular & Integrative Physiology, Indiana University School of MedicineDepartment of Cellular & Integrative Physiology, Indiana University School of MedicineDepartment of Cellular & Integrative Physiology, Indiana University School of MedicineDepartment of Cellular & Integrative Physiology, Indiana University School of MedicineDepartment of Cellular & Integrative Physiology, Indiana University School of MedicineDepartment of Cellular & Integrative Physiology, Indiana University School of MedicineDepartment of Cellular & Integrative Physiology, Indiana University School of MedicineAbstract Background There is a preponderance of evidence implicating diabetes with increased coronary artery disease (CAD) and calcification (CAC) in human patients with metabolic syndrome (MetS), but the effect of diabetes on CAD severity in animal models remains controversial. We investigated whether diabetes exacerbates CAD/CAC and intracellular free calcium ([Ca2+]i) dysregulation in the clinically relevant Ossabaw miniature swine model of MetS. Methods Sixteen swine, eight with alloxan-induced diabetes, were fed a hypercaloric, atherogenic diet for 6 months. Alloxan-induced pancreatic beta cell damage was examined by immunohistochemical staining of insulin. The metabolic profile was confirmed by body weight, complete blood panel, intravenous glucose tolerance test (IVGTT), and meal tolerance test. CAD severity was assessed with intravascular ultrasound and histology. [Ca2+]i handling in coronary smooth muscle (CSM) cells was assessed with fura-2 ratiometric imaging. Results Fasting and post-prandial blood glucose, total cholesterol, and serum triglycerides were elevated in MetS-diabetic swine. This group also exhibited hypoinsulinemia during IVGTT and less pancreatic beta cell mass when compared to lean and MetS-nondiabetic swine. IVUS analysis revealed that MetS-diabetic swine had greater percent wall coverage, percent plaque burden, and calcium index when compared to lean and MetS-nondiabetic swine. Fura-2 imaging of CSM [Ca2+]i revealed that MetS-nondiabetic swine exhibited increased sarcoplasmic reticulum Ca2+ store release and Ca2+ influx through voltage-gated Ca2+ channels compared to lean swine. MetS-diabetic swine exhibited impaired Ca2+ efflux. Conclusions Diabetes exacerbates coronary atherosclerosis and calcification in Ossabaw miniature swine with MetS, accompanied by progression of [Ca2+]i dysregulation in advanced CAD/CAC. These results recapitulate increased CAD in humans with diabetes and establish Ossabaw miniature swine as an animal model for future MetS/diabetes comorbidity studies.http://link.springer.com/article/10.1186/s12967-018-1431-9ObesityMetabolismAtherosclerosisIntravascular ultrasoundCalcium dysregulationCalcium index |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Jill K. Badin Ayeeshik Kole Benjamin Stivers Victor Progar Anisha Pareddy Mouhamad Alloosh Michael Sturek |
spellingShingle |
Jill K. Badin Ayeeshik Kole Benjamin Stivers Victor Progar Anisha Pareddy Mouhamad Alloosh Michael Sturek Alloxan-induced diabetes exacerbates coronary atherosclerosis and calcification in Ossabaw miniature swine with metabolic syndrome Journal of Translational Medicine Obesity Metabolism Atherosclerosis Intravascular ultrasound Calcium dysregulation Calcium index |
author_facet |
Jill K. Badin Ayeeshik Kole Benjamin Stivers Victor Progar Anisha Pareddy Mouhamad Alloosh Michael Sturek |
author_sort |
Jill K. Badin |
title |
Alloxan-induced diabetes exacerbates coronary atherosclerosis and calcification in Ossabaw miniature swine with metabolic syndrome |
title_short |
Alloxan-induced diabetes exacerbates coronary atherosclerosis and calcification in Ossabaw miniature swine with metabolic syndrome |
title_full |
Alloxan-induced diabetes exacerbates coronary atherosclerosis and calcification in Ossabaw miniature swine with metabolic syndrome |
title_fullStr |
Alloxan-induced diabetes exacerbates coronary atherosclerosis and calcification in Ossabaw miniature swine with metabolic syndrome |
title_full_unstemmed |
Alloxan-induced diabetes exacerbates coronary atherosclerosis and calcification in Ossabaw miniature swine with metabolic syndrome |
title_sort |
alloxan-induced diabetes exacerbates coronary atherosclerosis and calcification in ossabaw miniature swine with metabolic syndrome |
publisher |
BMC |
series |
Journal of Translational Medicine |
issn |
1479-5876 |
publishDate |
2018-03-01 |
description |
Abstract Background There is a preponderance of evidence implicating diabetes with increased coronary artery disease (CAD) and calcification (CAC) in human patients with metabolic syndrome (MetS), but the effect of diabetes on CAD severity in animal models remains controversial. We investigated whether diabetes exacerbates CAD/CAC and intracellular free calcium ([Ca2+]i) dysregulation in the clinically relevant Ossabaw miniature swine model of MetS. Methods Sixteen swine, eight with alloxan-induced diabetes, were fed a hypercaloric, atherogenic diet for 6 months. Alloxan-induced pancreatic beta cell damage was examined by immunohistochemical staining of insulin. The metabolic profile was confirmed by body weight, complete blood panel, intravenous glucose tolerance test (IVGTT), and meal tolerance test. CAD severity was assessed with intravascular ultrasound and histology. [Ca2+]i handling in coronary smooth muscle (CSM) cells was assessed with fura-2 ratiometric imaging. Results Fasting and post-prandial blood glucose, total cholesterol, and serum triglycerides were elevated in MetS-diabetic swine. This group also exhibited hypoinsulinemia during IVGTT and less pancreatic beta cell mass when compared to lean and MetS-nondiabetic swine. IVUS analysis revealed that MetS-diabetic swine had greater percent wall coverage, percent plaque burden, and calcium index when compared to lean and MetS-nondiabetic swine. Fura-2 imaging of CSM [Ca2+]i revealed that MetS-nondiabetic swine exhibited increased sarcoplasmic reticulum Ca2+ store release and Ca2+ influx through voltage-gated Ca2+ channels compared to lean swine. MetS-diabetic swine exhibited impaired Ca2+ efflux. Conclusions Diabetes exacerbates coronary atherosclerosis and calcification in Ossabaw miniature swine with MetS, accompanied by progression of [Ca2+]i dysregulation in advanced CAD/CAC. These results recapitulate increased CAD in humans with diabetes and establish Ossabaw miniature swine as an animal model for future MetS/diabetes comorbidity studies. |
topic |
Obesity Metabolism Atherosclerosis Intravascular ultrasound Calcium dysregulation Calcium index |
url |
http://link.springer.com/article/10.1186/s12967-018-1431-9 |
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