(T2DM) is increasing, creating a need for T2DM animal models for the study of disease pathogenesis, prevention, and treatment. The purpose of this project was to develop a rat model of T2DM that more closely models the pathophysiology of T2DM in humans. The model was created by crossing obese Sprague-Dawley rats with insulin resistance resulting from polygenic adult-onset obesity with Zucker diabetic fatty-lean rats that have a defect in pancreatic ␤-cell function but normal leptin signaling. We have characterized the model with respect to diabetes incidence; age of onset; longitudinal measurements of glucose, insulin, and lipids; and glucose tolerance. Longitudinal fasting glucose and insulin data demonstrated progressive hyperglycemia (with fasting and fed glucose concentrations Ͼ250 and Ͼ450 mg/dl, respectively) after onset along with hyperinsulinemia resulting from insulin resistance at onset followed by a progressive decline in circulating insulin concentrations, indicative of ␤-cell decompensation. The incidence of diabetes in male and female rats was 92 and 43%, respectively, with an average age of onset of 6 mo in males and 9.5 mo in females. Results from intravenous glucose tolerance tests, pancreas immunohistochemistry, and islet insulin content further support a role for ␤-cell dysfunction in the pathophysiology of T2DM in this model. Diabetic animals also exhibit glycosuria, polyuria, and hyperphagia. Thus diabetes in the UC Davis-T2DM rat is more similar to clinical T2DM in humans than in other existing rat models and provides a useful model for future studies of the pathophysiology, treatment, and prevention of T2DM. diabetic rodent model; hyperglycemia; insulin; ␤-cell TYPE 2 DIABETES MELLITUS (T2DM) is a devastating metabolic disease presently affecting at least 16 million people in the United States alone (33, 49). The prevalence of T2DM is also increasing in children and adolescents (42). With the increasing incidence of T2DM, the identification of preventative measures has become crucial, necessitating the development of effective preclinical models for studying approaches for both diabetes prevention and treatment.The most commonly used rodent models of T2DM include the Zucker diabetic fatty (ZDF) rat, the Otsuka Long Evans Tokushima fatty (OLETF) rat, and the db/db mouse, all of which exhibit obesity-associated insulin resistance and impaired ␤-cell function, resulting in diabetes (5, 25, 38). While these animal models have contributed substantially to understanding the pathophysiology and treatment of T2DM and its complications, the basic mechanisms underlying the pathogenesis of diabetes in these models do not correspond with what occurs in most human patients with T2DM. These differences in etiology are likely to hinder effective translational research.Obesity and insulin resistance in most animal models of T2DM result from monogenic mutations that are rare in human and animal populations and present multiple problems in terms of applying these models to clinical T2DM. For example, mutat...

Acylation-stimulating protein (ASP) acts as a paracrine signal to increase triglyceride synthesis in adipocytes. In mice, C3 (the precursor to ASP) knock-out (KO) results in ASP deficiency and leads to reduced body fat and leptin levels yet they are hyperphagic. In the present study, we investigated the mechanism for this energy repartitioning. Compared with wild-type (WT) mice, male and female C3(؊/؊) ASP-deficient mice had elevated oxygen consumption (VO 2 ) in both the active (dark) and resting (light) phases of the diurnal cycle: ؉8.9% males (p < 0.05) ؉9.4% females (p < 0.05). Increased physical activity (movement) was observed during the dark phase in female but not in male KO animals. Female WT mice moved 16.9 ؎ 2.4 m whereas KO mice moved 30.1 ؎ 5.4 m, over 12 h, ؉78.4%, p < 0.05). In contrast, there was no difference in physical activity in male mice, but a repartitioning of dietary fat following intragastric fat administration was noted. This was reflected by increased fatty acid oxidation in liver and muscle in KO mice, with increased UCP2 (inguinal fat) and UCP3 (muscle) mRNA expression (p ‫؍‬ 0.005 and 0.036, respectively). Fatty acid uptake into brown adipose tissue (BAT) and white adipose tissue (WAT) was reduced as reflected by a decrease in the fatty acid incorporation into lipids (BAT ؊68%, WAT ؊29%. The decrease of FA incorporation was normalized by intraperitoneal administration of ASP at the time of oral fat administration. These results suggest that ASP deficiency results in energy repartitioning through different mechanisms in male and female mice. Acylation-stimulating protein (ASP)1 is an adipocyte-derived protein that has potent anabolic effects on human adipose tissue where it increases glucose uptake and non-esterified fatty acid (NEFA) storage (1, 2) via translocation of glucose transporters (GLUT1, GLUT3, and GLUT4) from intracellular sites to the cell surface (3, 4) and activation of diacylglycerol acyltransferase (DGAT) (2). These effects appear to be mediated through specific cell surface binding (5, 6) resulting in activation of a signal pathway that includes protein kinase C (7). In addition, ASP has been shown to inhibit hormone-sensitive lipase in adipocytes, independently and additively to insulin (8). There is a differentiation-dependent increase in ASP binding and ASP response in human adipocytes (1). The major site of action of ASP is adipocytes, as determined by competitive binding, stimulation of triglyceride synthesis, enhanced glucose transport, and transporter translocation (5).ASP is identical to C3adesArg, a cleavage product of complement C3. Cleavage of complement C3 is mediated through the alternate complement pathway via the interaction of C3, factor B, and adipsin that generates C3a. Rapid cleavage of the Cterminal arginine of C3a by carboxypeptidase N generates ASP (9). Adipocytes are one of the few cells capable of producing all three factors (factor B, adipsin, and C3) that are required for the production of ASP (10). ASP production increases consequent to a...

What is osteoporosis? Osteoporosis is a decrease in bone density and strength, resulting in increased susceptibility to bone fractures. Osteoporosis is a debilitating disease most commonly found in postmenopausal women; however, men are also at risk for this disease. In the United States, 8 million women and 2 million men have osteoporosis. 1 Osteoporosis cannot be cured; it can only be prevented or its progression delayed. Mean bone density essentially remains the same between the ages of 30 and the onset of menopause. Afterward, women lose 2 to 5 percent of bone mass each year until approximately 5 years after menopause, at which time bone loss becomes more gradual. 2

What function does calcium have in the body? Calcium is a mineral used for numerous functions, including building bones and teeth, muscle contraction, blood clotting, maintenance of cell membranes, and nerve transmission. 1 Because most of the calcium in the body is found in the skeleton, calcium' s critical function in maintaining bone health receives much attention. What are the effects of calcium deficiency? Adequate intake of calcium is essential for maximizing bone density. Therefore, an inadequate intake of calcium can adversely influence bone formation and may contribute to osteoporosis. Osteoporosis is a decrease in bone density and strength that results in increased susceptibility to bone fractures. It is a debilitating disease most commonly found in postmenopausal women; however, men are also at risk for this disease. In the United States osteoporosis affects an estimated 35 percent of postmenopausal Caucasian women. 2 Osteoporosis cannot be cured; it can only be prevented or its progression delayed. The best ways to prevent the disease are to build strong bones early in life by eating a well-balanced, calcium-rich diet, and by making weight-bearing exercise a regular routine. How much calcium should be consumed each day?

The human body needs enough energy (calories) and nutrients to work properly and to maintain good health. In the last few years, health experts have concluded that the quality of life may be improved through healthy eating habits and regular exercise. Healthy eating is based on nutrient needs from a variety of foods over several days. Remember, moderation is the key.The following recommendations for healthy living have been adapted from the 2005 Dietary Guidelines for Americans, 1 directed at people aged 2 years and over. These guidelines recommend that most Americans eat less, exercise more, and make sensible food choices. 1