Among the most widely used animal models in obesity-induced type 2 diabetes mellitus (T2DM) research are the congenital leptin- and leptin receptor-deficient rodent models. These include the leptin-deficient ob/ob mice and the leptin receptor-deficient db/db mice, Zucker fatty rats, Zucker diabetic fatty rats, SHR/N-cp rats, and JCR:LA-cp rats. After decades of mechanistic and therapeutic research schemes with these animal models, many species differences have been uncovered, but researchers continue to overlook these differences, leading to untranslatable research. The purpose of this review is to analyze and comprehensively recapitulate the most common leptin/leptin receptor-based animal models with respect to their relevance and translatability to human T2DM. Our analysis revealed that, although these rodents develop obesity due to hyperphagia caused by abnormal leptin/leptin receptor signaling with the subsequent appearance of T2DM-like manifestations, these are in fact secondary to genetic mutations that do not reflect disease etiology in humans, for whom leptin or leptin receptor deficiency is not an important contributor to T2DM. A detailed comparison of the roles of genetic susceptibility, obesity, hyperglycemia, hyperinsulinemia, insulin resistance, and diabetic complications as well as leptin expression, signaling, and other factors that confound translation are presented here. There are substantial differences between these animal models and human T2DM that limit reliable, reproducible, and translatable insight into human T2DM. Therefore, it is imperative that researchers recognize and acknowledge the limitations of the leptin/leptin receptor-based rodent models and invest in research methods that would be directly and reliably applicable to humans in order to advance T2DM management.

Coronary artery calcium (CAC), a measure of subclinical coronary heart disease (CHD), may be useful in identifying asymptomatic persons at risk of CHD events. The current study included 10,746 adults who were 22-96 years of age, were free of known CHD, and had their CAC quantified by electron-beam tomography at baseline as part of a preventive medical examination at the Cooper Clinic (Dallas, Texas) during 1995-2000. During a mean follow-up of 3.5 years, 81 hard events (CHD death, nonfatal myocardial infarction) and 287 total events (hard events plus coronary revascularization) occurred. Age-adjusted rates (per 1,000 person-years) of hard events were computed according to four CAC categories: no detectable CAC and incremental sex-specific thirds of detectable CAC; these rates were, respectively, 0.4, 1.5, 4.8, and 8.7 (trend p<0.0001) for men and 0.7, 2.3, 3.1, and 6.3 (trend p=0.02) for women. CAC levels also were positively associated with rates of total CHD events for women and men (trend p<0.0001 each). The association between CAC and CHD events remained significant after adjustment for CHD risk factors. CAC was associated with CHD events in persons with no baseline CHD risk factors and in younger (aged <40 years) and older (aged >65 years) study participants. These findings show that CAC is associated with an increased risk of CHD events in asymptomatic women and men.

1-123 metaiodobenzylguanidine (MIBG) is a new radiopharmaceutical with properties that allow the characterization of the sympathetic innervation of several organ systems. In this study, we used MIBG with tomographic imaging to evaluate noninvasively the differences in myocardial sympathetic innervation in 14 healthy volunteers and 16 patients with severe dilated cardiomyopathy (CM). Initial (15-minute) images demonstrated no significant differences in MIBG concentration in the hearts of patients with CM and of healthy volunteers. However, the myocardial retention of MIBG was significantly reduced in the patients with CM. Expressed as the percent washout from 15 to 85 minutes, the patients with CM had a 28 ± 12% washout rate compared with 6 8% in the controls (p

Summaryonly a limited number of anti-diabetic drugs are in clinical use for humans, most of which have adverse health effects, but little impact on disease progression, and none of which cures t2DM or clearly prolongs life.the purpose of this review is to examine the underlying molecular, biological, and physiological differences -from gene regulation to whole-animal and population levels -that help explain why rodents do not serve as reliable models for studying human t2DM. this review will also address how researchers may overcome this translational barrier by employing a wide range of human-based investigational methods that will promote human-relevant discoveries while reducing -and eventually replacing -the use of animals in t2DM research.

SYNOPSISMultiple neuroprotective agents have shown benefit for the treatment of acute spinal cord injury (SCI) in animal studies. However, clinical trials have, thus far, been uniformly disappointing. This review explores reasons for discrepancies between promising animal studies and disappointing clinical trials and potential barriers to extrapolation of research results from animals to humans. The three major barriers disclosed are: differences in injury type between laboratory-induced SCI and clinical SCI, difficulties in interpreting functional outcome in animals, and inter-species and interstrain differences in pathophysiology of SCI. These barriers can impair the effectiveness of animal models of SCI to predict human outcomes. While some of these barriers can be overcome, others are inherent to the animal models.