. Author manuscript; available in PMC: 2018 Feb 1.

Published in final edited form as: Arterioscler Thromb Vasc Biol. 2016 Dec 22;37(2):205–217. doi: 10.1161/ATVBAHA.116.306258

Table 1.

Preclinical Models of Arterial Calcification in T1D and the T2D-MetS Spectrum

Model	Comments	References
C57BL/6J Mouse with Streptozotocin (STZ) Treatment	T1D. Aortic calcification and stiffness both quantified and increased. Osteogenic programs identified in other models activated. Comparison of mineralized vascular matrix ultrastructure with other models promises to be enlightening.	Ref. ²²
Wistar rat with STZ Treatment + Co-inducer - Warfarin+vitamin K (WVK) - Vitamin D and nicotine (VDN)	T1D. Femoral artery calcification noted as well as aortic calcification. Peripheral artery calcification often assessed in preclinical models but relevant to peripheral arterial disease. Disease responsive to modulation of RAGE/AGER and NADPH oxidase / Nox signaling.	Ref. ^{27, 28, 39, 40, 196}
ApoE−/− mouse with STZ treatment	T1D. Severe hypercholesterolemia Robust arterial calcification responses are observed. ApoE-null VSM cells are given to chondroid metaplasia. S100A12 transgene accelerates calcification in ApoE-null mice.	Ref. ^{45, 47, 100}
Ins2Akita/+ Mouse	T1D. Streptozotocin administration is not required to induce arterial calcification in this T1D model. Aortic calcification increased, stiffness to be characterized. Neuropathy is also induced. On LDLR−/− background diet-induced diabetes, hypercholesterolemia, & hypertriglyceridemia severe in both male & female animals, but arteriosclerosis has yet to be quantified in Ins2Akita/+;LDLR−/− mice.	Ref.^{30, 66, 197}
Male LDLR−/− Mouse with STZ Treatment	T1D. Atherosclerosis lesion more extensive after 2 weeks of diabetes. Aortic calcification and stiffness remain to be characterized.	Ref.^{198, 199}
Golden Syrian Hamster with STZ + High Fat Diet (HFD)	T1D. Nephropathy also arises in this model. Few publications, little physiological phenotypic data available.	Ref.^{200, 201}
Male LDLR−/− Mouse Fed High Fat Diet (HFD)	T2D – MetS spectrum. Severe hypercholesterolemia, modest fasting hypertriglyceridemia (~200 mg/dL), elevated free fatty acids, increased visceral and periaortic fat accumulation, hyperglycemia & hyperinsulinemia, increased HOMA-IR, and oxidative stress signaling regulated by OPN and Nox activity. Induced by high fat Western diet (Teklad 88137; 42% calories from fat). Aortic calcification and stiffness both quantified and increased. Regulated by canononical and noncanonical Wnt signals. Disease is induced in response to clinically relevant stimulus that promote VSM chondroid metaplasia and RAGE/AGER co-localization. Chondroid metaplasia is restrained by VSM OPN. Renal fibrosis induced via oxidized LDL signals. Modifiable with 5/6 nephrectomy to phenocopy arteriosclerotic disease in setting of T2D + renal insufficiency (chronic kidney disease – mineral and bone disorder, CKD-MBD). Latter is sensitive to renal and dietary phosphate metabolism. S100A/calgranulin proteins, key RAGE/AGER ligands that drive ectopic calcification, are increased by high fat diet.	Ref. ^{42, 67–69, 71, 72, 86, 89, 100, 101, 113, 121, 137, 202–207}
LDLR−/−;ApoB100/100;RIP1-IGF2Tg mouse	T2D-MetS spectrum. Similar to male LDLR−/− but more significant fasting hyperglycemia in both male and female mice, Western diet challenge performed in old animals. Severe hypercholesterolemia arises since all ApoB containing lipoproteins are now B100 only – and the LDLR is missing. Transgenic IGF2 expression in pancreatic beta cell from rat insulin promoter (RIP1) accelerates T2D with beta-cell failure upon dietary challenge. Extent of aortic calcification appears to track insulin resistance > hypercholesterolemia, fasting hyperglycemia.	Ref.^{107, 112}
db/db Mouse	T2D-MetS spectrum. Modest hypercholesterolemia, severe hypertriglyceridemia and visceral fat accumulation on Teklad rodent diet 8604 (14% calories from fat). In addition to nephropathy these leptin receptor –deficient mice also develop neuropathy (either on the C57BKS background, or on C57BL/6J with high fat diet to sustain hyperglycemia). Intriguing recent report of arterial stiffening without calcification in aged diabetic db/db mouse; genetic dietary conditions, composition, and basic metabolic profiling important to report to enable comparisons.	Ref.^{30, 63, 64, 126}
Ossabaw Island Hog	T2D – MetS spectrum. Modest hypercholesterolemia, hypertriglyceridemia, increased visceral fat accumulation, impaired glucose tolerance, and insulin-resistant. Early stages of coronary artery microcalcification by histology co-registered with ¹⁸F - PET/CT and ⁴¹Ca uptake. Epicardial fat surgically demonstrated to impact coronary disease processes.	Ref. ^{130, 131, 208–211}
Male Rhesus Macaque on High-Fat High-Sucrose Diet	T2D – MetS spectrum. Modest hypercholesterolemia, hypertriglyceridemia, increased visceral fat, hyperglycemia & hyperinsulinemia, increased HOMA-IR. Arterial calcification and stiffness are both increased, but arterial calcification assessed only histologically. Resveratrol supplementation over 2 years protective at doses of 80 mg to 480 mg daily (glass of red wine contains ~ 1 mg of resveratrol).	Ref. ¹³⁴
Watanabe (WHHL) Rabbit Fed High-Fructose High-Fat Diet	T2D – MetS spectrum. Severe hypercholesterolemia (in-frame LDLR deletion). Metabolic syndrome features similar to the male LDLR−/− model, e.g. hypertriglyceridemia, increased visceral fat, impaired glucose tolerance / increased HOMA-IR. While calcification is histologically increased, not rigorously quantified.	Ref. ²¹²