Lactogens protect rodent and human beta cells against glucolipotoxicity-induced cell death through Janus kinase-2 (JAK2)/signal transducer and activator of transcription-5 (STAT5) signalling.

AIMS/HYPOTHESIS: A leading cause of type 2 diabetes is a reduction in functional beta cell mass partly due to increased beta cell death, triggered by stressors such as glucolipotoxicity (GLT). This study evaluates the hypothesis that lactogens can protect beta cells against GLT and examines the mechanism behind the pro-survival effect. METHODS: The effect of exogenous treatment or endogenous expression of lactogens on GLT-induced beta cell death was examined in INS-1 cells, and in rodent and human islets. The mechanism behind the pro-survival effect of lactogens was determined using an inhibitor, siRNAs, a dominant negative (DN) mutant, and Cre-lox-mediated gene deletion analysis. RESULTS: Lactogens significantly protect INS-1 and primary rodent beta cells against GLT-induced cell death. The pro-survival effect of lactogens in rodent beta cells is mediated through activation of the Janus kinase-2 (JAK2)/signal transducer and activator of transcription-5 (STAT5) signalling pathway. Lactogen-induced increase in the anti-apoptotic B cell lymphoma-extra large (BCLXL) protein is required to mediate its pro-survival effects in both INS-1 cells and primary rodent beta cells. Most importantly, lactogens significantly protect human beta cells against GLT-induced cell death, and their pro-survival effect is also mediated through the JAK2/STAT5 pathway. CONCLUSIONS/INTERPRETATION: These studies, together with previous work, clearly demonstrate the pro-survival nature of lactogens and identify the JAK2/STAT5 pathway as an important mediator of this effect in both rodent and human beta cells. Future studies will determine the effectiveness of this peptide in vivo in the pathophysiology of type 2 diabetes.

Systemic and acute administration of parathyroid hormone-related peptide(1-36) stimulates endogenous beta cell proliferation while preserving function in adult mice.

AIMS/HYPOTHESIS: A major focus in the treatment of diabetes is to identify factors that stimulate endogenous beta cell growth while preserving function. The first 36 amino acids of parathyroid hormone-related protein (PTHrP) are sufficient to enhance proliferation and function in rodent and human beta cells in vitro. This study examined whether acute and systemic administration of the amino-terminal PTHrP(1-36) peptide can achieve similar effects in rodent beta cells in vivo. METHODS: Adult male mice were injected with 40, 80 or 160 µg of PTHrP(1-36) per kg body weight or with vehicle for 25 days. Glucose and beta cell homeostasis, as well as expression of differentiation markers and cell cycle genes were analysed. RESULTS: All three doses of PTHrP(1-36) significantly enhanced beta cell proliferation in vivo at day 25, with 160 µg/kg PTHrP(1-36) increasing proliferation as early as day 5. Importantly, the two higher doses of PTHrP(1-36) caused a significant 30% expansion of beta cell mass, with a short-term improvement in glucose tolerance. PTHrP(1-36) did not cause hypercalcaemia, or change islet number, beta cell size, beta cell death or expression of differentiation markers. Analysis of islet G1/S cell cycle proteins revealed that chronic overabundance of PTHrP(1-139) in the beta cell significantly increased the cell cycle activator cyclin D2 and decreased levels of cyclin-dependent kinase 4 inhibitor (p16( Ink4a ) [Ink4a also known as Cdkn2a]), but acute treatment with PTHrP(1-36) did not. CONCLUSIONS/INTERPRETATION: Acute and systemic administration of PTHrP(1-36) increases rodent beta cell proliferation and mass without negatively affecting function or survival. These findings highlight the future potential therapeutic effectiveness of this peptide under diabetes-related pathophysiological conditions.

Pathophysiological mechanisms and consequences of cardiovascular calcifications: role of uremic toxicity.

SUMMARY: Chronic kidney disease (CKD) represents an accelerated model of the active cardiovascular calcification process. Recent data from our laboratory indicate the presence of a possible vascular remodeling leading to vascular calcification similar to that observed in bone tissue, and emphasize the role of uremic toxicity. Uremic serum not only induces differentiation of smooth muscle cells into an osteoblast-like phenotype but also inhibits the differentiation of monocyte-macrophages cells into osteoclasts. The imbalance between the two processes in vascular walls in favor of osteoblast-like formation could lead to calcification. Cardiovascular calcification may contribute to the high rate of cardiovascular disease in patients with CKD. However, uremic toxicity, which participates in the pathogenesis of cardiovascular calcification, seems to have independent effects on vascular walls, at least in the early stages of CKD. We recently reported that functional (i.e. endothelial dysfunction) rather than structural changes, including vascular calcification, may contribute to the aortic hemodynamic changes observed during early CKD. Uremic toxicity also appears to be associated with calcification of intracranial arteries. Knowledge concerning the pathogenesis and consequences of cardiovascular calcification derived from the uremic model therefore opens up new perspectives for pharmacologic treatments that may also help to prevent and/or treat cardiovascular calcification, and consequently cardiovascular mortality and morbidity, not only in CKD patients but also in the general population.

The pathophysiology of vascular calcification: are osteoclast-like cells the missing link?

There is increasing evidence to suggest that the initiation of vascular calcification is an active process involving vascular smooth muscle cell (VSMC) apoptosis and trans-differentiation into calcifying cells. This active process results in the deposition of an osteogenic extracellular matrix and may be exacerbated by a reduction in the levels of one or more native calcification inhibitors (such as fetuin A and pyrophosphate). Here, we present data which strongly suggest that the regression of vascular calcification might also be an active cellular process involving osteoclast-like cells. However, the presence of osteoclast like cells in the vascular wall is rather limited. To explain this rarity of osteoclast-like cells, we recently observed that the same factors, which promote the trans-differentiation of VSMCs into osteoblast-like cells are also capable of inhibiting the in vitro differentiation of monocytes/macrophages into osteoclast-like cells. An imbalance between osteoblast-like and osteoclast-like cell activities would therefore favour the occurrence of a pathological calcification process in vessel walls. Our new data are strongly evocative of a vascular remodelling process similar to that observed in bone tissue. To confirm this hypothesis, strategies for activating osteoclasts in the vascular wall (with a view to preventing or reversing vascular calcifications) are required.

Peer counselor program increases breastfeeding rates in Utah Native American WIC population.

Lack of breastfeeding promotion and support hinder successful breastfeeding. In this study, a breastfeeding peer counselor program improved both the initiation rate and duration of breastfeeding up to three months postpartum among Native American WIC participants. Trained peer counselors contacted subjects prenatally, and at one, two, and four to six weeks postpartum. Breastfeeding rates for the experimental group were compared to historical controls. Women in the peer counselor group who had complete data for three months (n = 41) had a higher rate of breastfeeding than the control group (n = 67) at initiation (84 percent vs. 70 percent; p = 0.05) and at three months postpartum (49 percent vs. 36 percent; p = 0.08).