Insulin stimulates fibroblast proliferation through calcium-calmodulin-dependent kinase II.

Insulin effects are mediated by multiple integrated signals generated by the insulin receptor. Fibroblasts, as most of mammalian cells, are a target of insulin action and are impor- tant actors in the vascular pathogenesis of hyperinsulinemia. A role for calcium-calmodulin-dependent kinases (CaMK) in insulin signaling has been proposed but has been under inves- tigated. We investigated the role of the CaMK isoform II in insulin signaling in human fibroblasts. A rapid and transient increase of intracellular calcium concentration was induced by insulin stimulation, followed by increase of CaMKII activity, via L type calcium channels. Concomitantly, insulin stimula- tion induced Raf-1 and ERK activation, followed by thymidine uptake. Inhibition of CaMKII abrogated the insulin-induced Raf-1 and ERK activation, resulting also in the inhibition of thymidine incorporation. These results demonstrate that in fibroblasts, insulin-activated CaMKII is necessary, together with Raf-1, for ERK activation and cell proliferation. This represents a novel mechanism in the control of insulin signals leading to fibroblast proliferation, as well as a putative site for pharmacological intervention

Insulin stimulates fibroblast proliferation through calcium-calmodulin-dependent kinase II.

Insulin effects are mediated by multiple integrated signals generated by the insulin receptor. Fibroblasts, as most of mammalian cells, are a target of insulin action and are impor- tant actors in the vascular pathogenesis of hyperinsulinemia. A role for calcium-calmodulin-dependent kinases (CaMK) in insulin signaling has been proposed but has been under inves- tigated. We investigated the role of the CaMK isoform II in insulin signaling in human fibroblasts. A rapid and transient increase of intracellular calcium concentration was induced by insulin stimulation, followed by increase of CaMKII activity, via L type calcium channels. Concomitantly, insulin stimula- tion induced Raf-1 and ERK activation, followed by thymidine uptake. Inhibition of CaMKII abrogated the insulin-induced Raf-1 and ERK activation, resulting also in the inhibition of thymidine incorporation. These results demonstrate that in fibroblasts, insulin-activated CaMKII is necessary, together with Raf-1, for ERK activation and cell proliferation. This represents a novel mechanism in the control of insulin signals leading to fibroblast proliferation, as well as a putative site for pharmacological intervention

Clinical outcomes of a digitally supported approach for self-management of type 2 diabetes mellitus

BackgroundSelf-management of Type 2 diabetes mellitus (T2D) is challenging. Regular self-monitoring of blood glucose and healthy lifestyles are required to improve glycometabolic control, thus delaying diabetes complications, and reducing hospitalizations. Digital technologies can empower patients in their disease management promoting self-management and motivation to change behaviors. We report the results of an exploratory trial aimed at evaluating the metabolic outcomes of using digital solutions for T2D self-management developed in the ProEmpower project, a European Commission funded Pre-Commercial Procurement.MethodsTwo digital solutions, DM4All and DiaWatch, which were codesigned with providers, patients, and caregivers, enabled the collection of clinical parameters by the patient using a smartphone integrated with the medical devices (glucometer, sphygmomanometer, scale, smart watch for heart rate monitoring and step counter). Data were automatically sent to the shared care plan allowing professionals to monitor adherence to treatment, set goals, and communicate more effectively with patients. At baseline and after an average follow-up of 8 months, glycosylated hemoglobin (HbA1c), body weight, blood pressure, and blood lipids were measured in 100 T2D patients using the ProEmpower solutions across different diabetes centers in Campania Region, age 45–79  years, both genders, and compared with a Control cohort of T2D patients (n = 100) with similar clinical characteristics and followed for a comparable period of observation in the same centers.ResultsAt baseline, the ProEmpower participants and the Control subjects were on average overweight, with a similar BMI in the two cohorts, and mean HbA1c was at acceptable levels (around 7.0%). After the 8 month exploratory trial, body weight, HbA1c, systolic and diastolic blood pressure, and plasma and LDL-cholesterol significantly decreased in the ProEmpower participants compared to baseline (p < 0.05 for all). The changes in systolic and diastolic blood pressure, and plasma and LDL-cholesterol were significantly different from those observed in the Control cohort (p < 0.05 for all).ConclusionThis pilot study showed positive effects on metabolic outcomes relevant to cardiovascular risk in T2D of adopting digital telemedicine self-monitoring solutions based on automation of measurements and coaching on healthy lifestyles promotion

Calmodulin-dependent kinase IV links Toll-like receptor 4 signaling with survival pathway of activated dendritic cells.

Microbial products, including lipopolysaccharide (LPS), an agonist of Toll-like receptor 4 (TLR4), regulate the lifespan of dendritic cells (DCs) by largely undefined mechanisms. Here, we identify a role for calcium-calmodulin–dependent kinase IV (CaMKIV) in this survival program. The pharmacologic inhibition of CaMKs as well as ectopic expression of kinase-inactive CaMKIV decrease the viability of monocyte-derived DCs exposed to bacterial LPS. The defect in TLR4 signaling includes a failure to accumulate the phosphorylated form of the cAMP response element-binding protein (pCREB), Bcl-2, and Bcl-xL. CaMKIV null mice have a decreased number of DCs in lymphoid tissues and fail to accumulate mature DCs in spleen on in vivo exposure to LPS. Although isolated Camk4(−/−) DCs are able to acquire the phenotype typical of mature cells and release normal amounts of cytokines in response to LPS, they fail to accumulate pCREB, Bcl-2, and Bcl-xL and therefore do not survive. The transgenic expression of Bcl-2 in CaMKIV null mice results in full recovery of DC survival in response to LPS. These results reveal a novel link between TLR4 and a calcium-dependent signaling cascade comprising CaMKIV-CREB-Bcl-2 that is essential for DC survival

A nutritional approach to the prevention of cancer: from assessment to personalized intervention

Among lifestyle factors, nutrition is one of the most important determinants of health, and represents a pivotal element of cancer risk. Nonetheless, epidemiological evidences of the relationship between several cancers and specific foods and nutrients is still inadequate, and solid conclusions are missing. Indeed, caloric restriction without malnutrition is associated to cancer prevention. Food may be also the primary route of exposure to contaminants such as metals, persistent organic pollutants, and pesticides. Exposuredisease associations and the interplay with genetic susceptibility requires further studies on genetic variation, environment, lifestyle, and chronic disease in order to eliminate and reduce associated health risks, thus contributing to improve health outcomes for the population. A primary nutritional approach for Active and Healthy Ageing (AHA) has been developed by the Nutrition group of the European Innovation Partnership (EIP) on AHA. The working group on lifestyles of the Italian Ministry of Health has developed a comprehensive approach to adequate nutrition using a consensus methodology to collect and integrate the available evidences from the literature and from the Italian experiences at the regional level, to raise the interest of other experts and relevant stakeholders to outline and scale-up joint strategies for a primary nutritional approach to cancer prevention