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The incidence and prevalence of type 2 diabetes (T2D) continue to escalate at an unprecedented rate in the United States, particularly among populations with high rates of obesity. The impact of T2D on bone mass, geometry, architecture, strength, and resistance to fracture has yet to be incontrovertibly characterized because of the complex and heterogeneous nature of this disease. This study utilized skeletally mature male diabetic rats of the commonly used Zucker diabetic fatty (ZDF) and Zucker diabetic Sprague-Dawley (ZDSD) strains as surrogate models to assess alterations in bone attributable to T2D-like states. After the animals were euthanized, bone data were collected using dual-energy X-ray absorptiometry, peripheral quantitative tomography, and micro-CT imaging modalities and via three-point bending or compression mechanical testing methods. ZDF and ZDSD diabetic rats exhibited lower bone mineral densities, which coincided with declines in structural strength and increased fragility at the femoral midshaft and the L4 vertebral body in response to monotonic loading. Vertebral trabecular morphology was compromised in both diabetic rodent strains, and ZDSD diabetic rats exhibited additional phenotypic impairments to bone material properties at the spine. Because the metabolic origin of the T2D-like state that develops in the ZDSD rat strain is highly relevant to adult-onset diabetes, it is a particularly attractive novel model for future preclinical research.

Non-insulin-dependent diabetes mellitus (NIDDM) is attributed to a failure of pancreatic . cells to maintain insulin secretion at a level sufficient to compensate for underlying insulin resistance. In the ZDF rat, a model of

Metabolic syndrome and T2D produce significant health and economic issues. Many available animal models have monogenic leptin pathway mutations that are absent in the human population. Development of the ZDSD rat model was undertaken to produce a model that expresses polygenic obesity and diabetes with an intact leptin pathway. A lean ZDF rat with the propensity for beta-cell failure was crossed with a polygenetically obese Crl:CD (SD) rat. Offspring were selectively inbred for obesity and diabetes for >30 generations. In the current study, ZDSD rats were followed for 6 months; routine clinical metabolic endpoints were included throughout the study. In the prediabetic metabolic syndrome phase, ZDSD rats exhibited obesity with increased body fat, hyperglycemia, insulin resistance, dyslipidemia, glucose intolerance, and elevated HbA1c. As disease progressed to overt diabetes, ZDSD rats demonstrated elevated glucose levels, abnormal oral glucose tolerance, increases in HbA1c levels, reductions in body weight, increased insulin resistance with decreasing insulin levels, and dyslipidemia. The ZDSD rat develops prediabetic metabolic syndrome and T2D in a manner that mirrors the development of metabolic syndrome and T2D in humans. ZDSD rats will provide a novel, translational animal model for the study of human metabolic diseases and for the development of new therapies.