The mechanisms underlying immune deficiency in diabetes are largely unknown. In the present study, we demonstrate that diabetic mice are highly susceptible to polymicrobial sepsis due to reduction in rolling, adhesion, and migration of leukocytes to the focus of infection. In addition, after sepsis induction, CXCR2 was strongly downregulated in neutrophils from diabetic mice compared with nondiabetic mice. Furthermore, CXCR2 downregulation was associated with increased G-protein–coupled receptor kinase 2 (GRK2) expression in these cells. Different from nondiabetic mice, diabetic animals submitted to mild sepsis displayed a significant augment in α1-acid glycoprotein (AGP) hepatic mRNA expression and serum protein levels. Administration of AGP in nondiabetic mice subjected to mild sepsis inhibited the neutrophil migration to the focus of infection, as well as induced l-selectin shedding and rise in CD11b of blood neutrophils. Insulin treatment of diabetic mice reduced mortality rate, prevented the failure of neutrophil migration, impaired GRK2-mediated CXCR2 downregulation, and decreased the generation of AGP. Finally, administration of AGP abolished the effect of insulin treatment in diabetic mice. Together, these data suggest that AGP may be involved in reduction of neutrophil migration and increased susceptibility to sepsis in diabetic mice.

Mandibular trabecular bone shows a promising attempt of accurate detection of osteoporotic changes in some regions of the jaws. Fractal analysis and pixel intensity had strong positive correlation.

The present study was designed to determine the effect of chronic GH excess on forearm muscle glucose uptake and oxidation during the postabsorptive state and after an oral glucose challenge. Nine normal subjects and 10 nondiabetic acromegalic patients (5 of them with normal glucose tolerance) were studied after an overnight fast (12-14 h) and for 3 h after the ingestion of 75 g glucose. Peripheral glucose metabolism was analyzed by the forearm technique to estimate muscle exchange of substrate combined with indirect calorimetry. Decreased forearm glucose uptake was observed in the acromegalic patients compared to that in the normal subjects (380 +/- 84 vs. 709 +/- 56 mumol/100 mL forearm.3 h) with diminished nonoxidative glucose metabolism (262 +/- 81 vs. 572 +/- 53 mumol/100 mL forearm.3 h). The acromegalics with normal glucose tolerance also showed decreased forearm glucose uptake and nonoxidative glucose metabolism compared to normal subjects (271 +/- 124 vs. 709 +/- 56 and 133 +/- 110 vs. 572 +/- 53 mumol/100 mL forearm.3 h, respectively). Muscle glucose oxidation did not differ significantly in normal subjects, the entire group of acromegalic patients, and the acromegalics with normal glucose tolerance (137 +/- 18 vs. 118 +/- 22 vs. 138 +/- 34 mumol/100 mL forearm.3 h, respectively). Serum FFA levels and lipid oxidation rates were similar in the normal subjects and the acromegalic patients, and declined in a similar fashion after glucose ingestion. Insulin levels were significantly higher in acromegalic patients than in normal subjects before and after glucose loading. In conclusion, this study showed that the insulin resistance occurring in the presence of chronic GH excess is accompanied by impaired muscle glucose uptake and nonoxidative glucose metabolism, which are early derangements because they are also observed in acromegalic patients with normal glucose tolerance.

Second generation antipsychotics (SGAs) have been linked to metabolic and bone disorders in clinical studies, but the mechanisms of these side effects remain unclear. Additionally, no studies have examined whether SGAs cause bone loss in mice. Using in vivo and in vitro modeling we examined the effects of risperidone, the most commonly prescribed SGA, on bone in C57BL6/J (B6) mice. Mice were treated with risperidone orally by food supplementation at a dose of 1.25 mg/kg daily for 5 and 8 weeks, starting at 3.5 weeks of age. Risperidone reduced trabecular BV/TV, trabecular number and percent cortical area. Trabecular histomorphometry demonstrated increased resorption parameters, with no change in osteoblast number or function. Risperidone also altered adipose tissue distribution such that white adipose tissue mass was reduced and liver had significantly higher lipid infiltration. Next, in order to tightly control risperidone exposure, we administered risperidone by chronic subcutaneous infusion with osmotic minipumps (0.5 mg/kg daily for 4 weeks) in 7 week old female B6 mice. Similar trabecular and cortical bone differences were observed compared to the orally treated groups (reduced trabecular BV/TV, and connectivity density, and reduced percent cortical area) with no change in body mass, percent body fat, glucose tolerance or insulin sensitivity. Unlike in orally treated mice, risperidone infusion reduced bone formation parameters (serum P1NP, MAR and BFR/BV). Resorption parameters were elevated, but this increase did not reach statistical significance. To determine if risperidone could directly affect bone cells, primary bone marrow cells were cultured with osteoclast or osteoblast differentiation media. Risperidone was added to culture medium in clinically relevant doses of 0, 2.5 or 25 ng/ml. The number of osteoclasts was significantly increased by addition in vitro of risperidone while osteoblast differentiation was not altered. These studies indicate that risperidone treatment can have negative skeletal consequences by direct activation of osteoclast activity and by indirect non-cell autonomous mechanisms. Our findings further support the tenet that the negative side effects of SGAs on bone mass should be considered when weighing potential risks and benefits, especially in children and adolescents who have not yet reached peak bone mass.

Data about the impact of bariatric surgery (BS) and subsequent weight loss on bone are limited. The objective of the present study was to determine bone mineral density (BMD), bone remodeling metabolites and hormones that influence bone trophism in premenopausal women submitted to BS 9.8 months, on average, before the study (OGg, N = 16). The data were compared to those obtained for women of normal weight (CG, N = 11) and for obese women (OG, N = 12). Eight patients in each group were monitored for one year, with the determination of BMD, of serum calcium, phosphorus, magnesium, parathyroid hormone, 25-hydroxyvitamin D, insulin-like growth factor-I (IGF-I) and osteocalcin, and of urinary calcium and deoxypyridinoline. The biochemical determinations were repeated every three months in the longitudinal study and BMD was measured at the end of the study. Parathyroid hormone levels were similar in the three groups. IGF-I levels (CG = 332 ± 62 vs OG = 230 ± 37 vs OGg = 128 ± 19 ng/ mL) were significantly lower in the operated patients compared to the non-operated obese women. Only OGg patients presented a significant fall in BMD of 6.2% at L1-L4, of 10.2% in the femoral neck, and of 5.1% in the forearm. These results suggest that the weight loss induced by BS is associated with a significant loss of bone mass even at sites that are not influenced by weight overload, with hormonal factors such as IGF-I being associated with this process.

Objective To present an update on the diagnosis and treatment of hypoparathyroidism based on the most recent scientific evidence. Materials and methods The Department of Bone and Mineral Metabolism of the Sociedade Brasileira de Endocrinologia e Metabologia (SBEM; Brazilian Society of Endocrinology and Metabolism) was invited to prepare a document following the rules set by the Guidelines Program of the Associação Médica Brasileira (AMB; Brazilian Medical Association). Relevant papers were retrieved from the databases MEDLINE/PubMed, LILACS, and SciELO, and the evidence derived from each article was classified into recommendation levels according to scientific strength and study type. Conclusion An update on the recent scientific literature addressing hypoparathyroidism is presented to serve as a basis for the diagnosis and treatment of this condition in Brazil.

Phosphate is an active participant in energy metabolism, and its deficiency has been associated with changes in insulin sensitivity and glucose tolerance. In the present study, we have investigated insulin secretion and glucose tolerance in individuals with moderate and acute phosphate deprivation and in patients with chronic hypophosphatemia. The individuals with dietary phosphate deprivation, evidenced by a significant reduction in phosphaturia from 232.3 +/- 37.1 to 56.8 +/- 23.9 mmol/24 hours, but with normal serum levels of inorganic phosphorus, presented circulating glucose and insulin levels similar to those of the pre-dietary period during the oral and intravenous glucose tolerance tests. In contrast, patients with chronic hypophosphatemia (inorganic phosphorus < 0.65 mmol/l) presented in hyperinsulinemia during the postabsorptive state and during the early and late phases of insulin secretion after the oral and intravenous glucose stimulus. The physiological response of a fall in serum phosphate after glucose administration observed in individuals with chronic hypophosphatemia was similar to that of normal individuals. The presence of hyperinsulinemia both basally and after glucose stimulation, with normal glycemia, in phosphate-depleted individuals suggests that this condition is associated with reduced insulin sensitivity. However, severe phosphate deprivation is necessary for the manifestation of this undesirable association. The deviation of phosphate to the intracellular medium occurring after glucose administration in hypophosphatemic individuals is similar to that of normal individuals and explains the occurrence of severe hypophosphatemia in malnourished hypophosphatemic individuals when submitted to parenteral refeeding.

The skeleton harbors an array of lineage cells that have an essential role in whole body homeostasis. Adipocytes start the colonization of marrow space early in postnatal life, expanding progressively and influencing other components of the bone marrow through paracrine signaling. In this unique, closed, and hypoxic environment close to the endosteal surface and adjacent to the microvascular space the marrow adipocyte can store or provide energy, secrete adipokines, and target neighboring bone cells. Adipocyte progenitors can also migrate from the bone marrow to populate white adipose tissue, a process that accelerates during weight gain. The marrow adipocyte also has an endocrine role in whole body homeostasis through its varied secretome that targets distant adipose depots, skeletal muscle, and the nervous system. Further insights into the biology of this unique and versatile cell will undoubtedly lead to novel therapeutic approaches to metabolic and age-related disorders such as osteoporosis and diabetes mellitus.