title: Arterial Calcification in Diabetes Mellitus: Preclinical Models and Translational Implications.
abstract: Diabetes mellitus increasingly afflicts our aging and dysmetabolic population. Type 2 diabetes mellitus and the antecedent metabolic syndrome represent the vast majority of the disease burden-increasingly prevalent in children and older adults. However, type 1 diabetes mellitus is also advancing in preadolescent children. As such, a crushing wave of cardiometabolic disease burden now faces our society. Arteriosclerotic calcification is increased in metabolic syndrome, type 2 diabetes mellitus, and type 1 diabetes mellitus-impairing conduit vessel compliance and function, thereby increasing the risk for dementia, stroke, heart attack, limb ischemia, renal insufficiency, and lower extremity amputation. Preclinical models of these dysmetabolic settings have provided insights into the pathobiology of arterial calcification. Osteochondrogenic morphogens in the BMP-Wnt signaling relay and transcriptional regulatory programs driven by Msx and Runx gene families are entrained to innate immune responses-responses activated by the dysmetabolic state-to direct arterial matrix deposition and mineralization. Recent studies implicate the endothelial-mesenchymal transition in contributing to the phenotypic drift of mineralizing vascular progenitors. In this brief overview, we discuss preclinical disease models that provide mechanistic insights-and point to challenges and opportunities to translate these insights into new therapeutic strategies for our patients afflicted with diabetes mellitus and its arteriosclerotic complications.
authors.affiliation: From the Division of Endocrinology, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX.
authors.forename: John N
authors.initials: JN
authors.lastname: Stabley
authors.affiliation: From the Division of Endocrinology, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX. dwight.towler@utsouthwestern.edu.
authors.forename: Dwight A
authors.initials: DA
authors.lastname: Towler
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001158:Arteries / Q000378:metabolism* / Q000473:pathology; D050197:Atherosclerosis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D003925:Diabetic Angiopathies / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D006949:Hyperlipidemias / Q000150:complications / Q000235:genetics; D008297:Male; D010641:Phenotype; D058226:Plaque, Atherosclerotic; D051381:Rats; D015398:Signal Transduction; D057170:Translational Research, Biomedical; D061205:Vascular Calcification / Q000209:etiology* / Q000378:metabolism / Q000473:pathology
keywords: amputation; arteriosclerosis; dementia; diabetes mellitus; vascular calcification