Bone marrow dysfunction in diabetes

Background. Diabetes mellitus (DM) increases cardiovascular disease (CVD) and this is attributed, at least in part, to shortage of vascular regenerative cells derived from the bone marrow (BM). Indeed, the BM harbours several subsets of progenitor cells for endothelial, smooth muscle cells and cardiomyocytes, which derive from a common CD34+ ancestor. Recent data from experimental models of type 1 and type 2 diabetes highlight BM pathologies that include microangiopathy, neuropathy, altered gene expression and niche dysfunction. Aims. The set of experiments herein described aim to portray the alterations of BM function in clinical and experimental diabetes. Methods. The approaches are diversified and include: 1) A prospective trial of direct BM stimulation with human recombinant granulocyte colony stimulating factor (G-CSF) in diabetic and non diabetic patients; 2) A meta-regression analysis of trials using G-CSF to stimulate cardiovascular repair in diabetic and non diabetic patients; 3) A study of stem/progenitor cell compartmentalization in the BM and peripheral blood (PB), in relation to diabetes; 4) An animal study to dissect the role of DPP-4 dysregulation in the impaired stem/progenitor cell mobilization induced by diabetes. Results. Part 1: in response to G-CSF, levels of CD34+ cells and other progenitor cell phenotypes increased in non DM subjects. DM patients had significantly impaired mobilization of CD34+, CD133+, CD34+CD133+ hematopoietic stem cells and CD133+KDR+ endothelial progenitors, independently of potential confounders. The in vivo angiogenic capacity of circulating mononuclear cells increased after hrG-CSF in non DM controls, but not in DM patients. DM was associated with inability to upregulate CD26/DPP-4 on CD34+ cells, which is required for the mobilizing effect of G-CSF. Part 2: for the meta-regression analysis 227 articles were screened, 96 were retrieved for evaluation and 24 retained for the analysis of the primary end-point. There was a strong negative correlation between prevalence of diabetes and achieved CD34+ cell levels after G-CSF stimulation (r=-0.68; p<0.0001), while there was no correlation with other traditional risk factors. A multiple regression analysis showed that the correlation between diabetes and mobilization was independent. In 13 articles reporting pre- and post-G-CSF cell counts, the increase in CD34+ cells was also negatively correlated with prevalence of diabetes (r=-0.82; p<0.0001). Part 3. PB and BM CD34+ cell counts were directly correlated, and that most circulating CD34+ cells were viable, non-proliferating and derived from the BM. Then, PB and BM CD34+ cell levels were analyzed in a 2-compartment model in 72 patients with or without cardiovascular disease. Self organizing maps showed that disturbed compartmentalization of CD34+ cells was associated with aging and cardiovascular risk factors, especially diabetes. High activity of DPP-4, a regulator of the mobilizing chemokine SDF-1α, was associated with altered stem cell compartmentalization. The role of DPP-4 in the BM mobilization response of diabetic rats was then assessed. Diabetes differentially affected DPP-4 activity in PB and BM and impaired stem/progenitor cell mobilization after ischemia or G-CSF administration. DPP-4 activity in the BM was required for the mobilizing effect of G-CSF, while in PB it blunted ischemia-induced mobilization. Indeed, DPP-4 deficiency restored ischemia (but not G-CSF) -induced stem cell mobilization and improved vascular recovery in diabetic animals. Conclusion. Evidences from multiple clinical and experimental approaches indicate that diabetes impairs the mobilization of stem/progenitor cells from the BM to PB. This primary BM defect is related to a maladaptive and tissue-specific DPP-4 dysregulatio

Continued efforts to translate diabetes cardiovascular outcome trials into clinical practice

Diabetic patients suffer from a high rate of cardiovascular events and such risk increases with HbA1c. However, lowering HbA1c does not appear to yield the same benefit on macrovascular endpoints, as observed for microvascular endpoints. As the number of glucose-lowering medications increases, clinicians have to consider several open questions in the management of type 2 diabetes, one of which is the cardiovascular risk profile of each regimen. Recent placebo-controlled cardiovascular outcome trials (CVOTs) have responded to some of these questions, but careful interpretation is needed. After general disappointment around CVOTs assessing safety of DPP-4 inhibitors (SAVOR, TECOS, EXAMINE) and the GLP-1 receptor agonist lixisenatide (ELIXA), the EMPA-REG Outcome trial and the LEADER trial have shown superiority of the SGLT2-I empagliflozin and the GLP-1RA liraglutide, respectively, on the 3-point MACE outcome (cardiovascular death, non-fatal myocardial infarction or stroke) and cardiovascular, as well as all-cause mortality. While available mechanistic studies largely support a cardioprotective effect of GLP-1, the ability of SGLT2 inhibitor(s) to prevent cardiovascular death was unexpected and deserves future investigation. We herein review the results of completed CVOTs of glucose-lowering medications and suggest a possible treatment algorithm based on cardiac and renal co-morbidities to translate CVOT findings into clinical practice

SGLT2 inhibitors and diabetic ketoacidosis: data from the FDA Adverse Event Reporting System

Sodium-glucose co-transporter-2 inhibitors (SGLT2i) are indicated for the treatment of type 2 diabetes and may also improve glucose control in type 1 diabetes. In 2015, regulatory agencies warned that SGLT2i may favour diabetic ketoacidosis (DKA). We provide a detailed analysis of DKA reports in which an SGLT2i was listed among suspect or concomitant drugs in the US Food and Drug Administration Adverse Event Reporting System (FAERS)

Diabetic retinopathy: a tool for cardiovascular risk stratification

Randomized, cross-sectional, and prospective studies have demonstrated that microvascular complications in patients with diabetes are not only the cause of blindness, renal failure and non-traumatic amputations, but also powerful predictors of cardiovascular complications. The pathophysiology of diabetic microvascular complications is determined by several factors including epigenetic modifications, and reduced release of circulating progenitor cells by the bone marrow. Identifying microvascular complications, in particular retinopathy, increases the ability to stratify patients in terms of cardiovascular risk. There may no longer be a rational to consider microangiopathy and macroangiopathy as entirely separate entities, but they should most likely be viewed as a continuum of the widespread vascular damage determined by diabetes mellitus

A PEDF-Derived Peptide Inhibits Retinal Neovascularization and Blocks Mobilization of Bone Marrow-Derived Endothelial Progenitor Cells

Proliferative diabetic retinopathy is characterized by pathological retinal neovascularization, mediated by both angiogenesis (involving mature endothelial cells) and vasculogenesis (involving bone marrow-derived circulating endothelial progenitor cells (EPCs)). Pigment epithelium-derived factor (PEDF) contains an N-terminal 34-amino acid peptide (PEDF-34) that has antiangiogenic properties. Herein, we present a novel finding that PEDF-34 also possesses antivasculogenic activity. In the oxygen-induced retinopathy (OIR) model using transgenic mice that have Tie2 promoter-driven GFP expression, we quantified Tie2GFP+ cells in bone marrow and peripheral blood by fluorescence-activated cell sorting (FACS). OIR significantly increased the number of circulating Tie2-GFP+ at P16, correlating with the peak progression of neovascularization. Daily intraperitoneal injections of PEDF-34 into OIR mice decreased the number of Tie2-GFP+ cells in the circulation at P16 by 65% but did not affect the number of Tie2-GFP+ cells in the bone marrow. These studies suggest that PEDF-34 attenuates EPC mobilization from the bone marrow into the blood circulation during retinal neovascularization

Longevity pathways and metabolic syndrome

The metabolic syndrome is becoming increasingly prevalent in the general population and carries significant incremental morbidity and mortality. It is associated with multi-organ involvement and increased all-cause mortality, resembling a precocious aging process. The mechanisms that account for this phenomenon are incompletely known, but it is becoming clear that longevity genes might be involved. Experiments with overactivation or disruption of key lifespan determinant pathways, such as silent information regulator (SIR)T1, p66Shc, and mammalian target of rapamycin (TOR), lead to development of features of the metabolic syndrome in mice. These genes integrate longevity pathways and metabolic signals in a complex interplay in which lifespan appears to be strictly dependent on substrate and energy bioavailability. Herein, we describe the roles and possible interconnections of selected lifespan determinant molecular networks in the development of the metabolic syndrome and its complications, describing initial available data in humans. Additional pathways are involved in linking nutrient availability and longevity, certainly including insulin and Insulin-like Growth Factor-1 (IGF-1) signaling, as well as FOXO transcription factors. The model described in this viewpoint article is therefore likely to be an oversimplification. Nevertheless, it represents one starting platform for understanding cell biology of lifespan in relation to the metabolic syndrome

Simvastatin Rapidly and Reversibly Inhibits Insulin Secretion in Intact Single-Islet Cultures

open10Epidemiological studies suggest that statins may promote the development or exacerbation of diabetes, but whether this occurs through inhibition of insulin secretion is unclear. This lack of understanding is partly due to the cellular models used to explore this phenomenon (cell lines or pooled islets), which are non-physiologic and have limited clinical transferability.openScattolini, Valentina; Luni, Camilla; Zambon, Alessandro; Galvanin, Silvia; Gagliano, Onelia; Ciubotaru, Catalin Dacian; Avogaro, Angelo; Mammano, Fabio; Elvassore, Nicola; Fadini, Gian PaoloScattolini, Valentina; Luni, Camilla; Zambon, Alessandro; Galvanin, Silvia; Gagliano, Onelia; Ciubotaru, CATALIN DACIAN; Avogaro, Angelo; Mammano, Fabio; Elvassore, Nicola; Fadini, GIAN PAOL

Oxytocin-Gly-Lys-Arg: A Novel Cardiomyogenic Peptide

Background: Oxytocin (OT), synthesized in the heart, has the ability to heal injured hearts and to promote cardiomyogenesis from stem cells. Recently, we reported that the OT-GKR molecule, a processing intermediate of OT, potently increased the spontaneous formation of cardiomyocytes (CM) in embryonic stem D3 cells and augmented glucose uptake in newborn rat CM above the level stimulated by OT. In the present experiments, we investigated whether OT-GKR exists in fetal and newborn rodent hearts, interacts with the OT receptors (OTR) and primes the generation of contracting cells expressing CM markers in P19 cells, a model for the study of early heart differentiation. Methodology/Principal Findings: High performance liquid chromatography of newborn rat heart extracts indicated that OT-GKR was a dominant form of OT. Immunocytochemistry of mouse embryos (embryonic day 15) showed cardiac OT-GKR accumulation and OTR expression. Computerized molecular modeling revealed OT-GKR docking to active OTR sites and to V1a receptor of vasopressin. In embryonic P19 cells, OT-GKR induced contracting cell colonies and ventricular CM markers more potently than OT, an effect being suppressed by OT antagonists and OTR-specific small interfering (si) RNA. The V1a receptor antagonist and specific si-RNA also significantly reduced OT-GKR-stimulated P19 contracting cells. In comparison to OT, OT-GKR induced in P19 cells less a-actinin, myogenin and MyoD mRNA, skeletal muscle markers. Conclusions/Significance: These results raise the possibility that C-terminally extended OT molecules stimulate C