Skeletal changes associated with the onset of type 2 diabetes in the ZDF and ZDSD rodent models

Abstract

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.

Delayed bone regeneration and low bone mass in a rat model of insulin-resistant type 2 diabetes mellitus is due to impaired osteoblast function

“…Interestingly, the suppressive effect of the diabetic microenvironment on osteogenic differentiation persists even after culture for up to 3 wk ex vivo. Our data are in accordance with earlier findings obtained in ZDF rats that demonstrated impaired bone mass and bone strength in diabetic ZDF rats (17,21) and provide a cellular explanation for these observations, which identify a predominant defect of osteoblastogenesis. This is in line with previous in vitro (9, 7) and in vivo studies involving rodent models of type 1 diabetes mellitus (2,18).…”

“…Data are represented as means Ϯ SE. rodent model of type 2 diabetes mellitus, since they recapitulate most features of poorly controlled type 2 diabetes mellitus in humans (17,21). Although hyperglycemia was consistently documented in diabetic rats, serum insulin levels after 21 wk were comparable as reported (27).…”

“…This may be, at least in part, due to the lack of appropriate rodent models of type 2 diabetes mellitus, which accounts for over 90% of diabetes mellitus in humans. Recently, two groups (17,21) have reported on the skeletal phenotype of Zucker diabetic fatty (ZDF) rats. Male ZDF rats start to develop obesity and type 2 diabetes mellitus at 9 wk of age after exposure to a high-fat and high-carbohydrate diet.…”

Wound Healing Delay in the ZDSD Rat

“…The Zucker diabetic Sprague dawley (ZDSD) rat is an animal model of type 2 diabetes and dietary obesity which develop subsequently to chronic dietary manipulation (9,10). ZDSD rats were developed by cross-breeding diet-induced obesity (DIO) rats derived from Sprague Dawley rats Crl:CD(SD) with ZDF +/+ lean rats.…”

Body Fat as a Regulator of Bone Mass: Experimental Evidence from Animal Models

“…For instance, the femora of fa/fa rats weigh less than those of their lean counterparts, and serum assays indicate that fa/fa rats have elevated parathyroid hormone levels and are hypercalciuric [26]. Consistent with these findings, other authors have found that Zucker rats show decreased total body BMD and BMC [28], decreased trabecular bone volume in the tibia and increased osteoclast surface [29], increased bone fragility and decreased bone strength [30], and lower percent ash content in the skeleton compared to lean rats [31].…”