Evaluation of the Effect of Enteral Lipid Sensing on Endogenous Glucose Production in Humans

Administration of lipids into the upper intestine of rats has been shown to acutely decrease endogenous glucose production (EGP) in the preabsorptive state, postulated to act through a gut-brain-liver axis involving accumulation of long-chain fatty acyl-CoA, release of cholecystokinin, and subsequent neuronal signaling. It remains unknown, however, whether a similar gut-brain-liver axis is operative in humans. Here, we infused 20% Intralipid (a synthetic lipid emulsion) or saline intraduodenally for 90 min at 30 mL/h, 4 to 6 weeks apart, in random order, in nine healthy men. EGP was assessed under pancreatic clamp conditions with stable isotope enrichment techniques. Under these experimental conditions, intraduodenal infusion of Intralipid, compared with saline, did not affect plasma glucose concentration or EGP throughout the study period. We conclude that Intralipid infusion into the duodenum at this rate does not elicit detectable effects on glucose homeostasis or EGP in healthy men, which may reflect important interspecies differences between rodents and humans with respect to the putative gut-brain-liver axis.

Source Diabetes Pathophysiology http://ift.tt/1TUxJpG

Increased Efferent Cardiac Sympathetic Nerve Activity and Defective Intrinsic Heart Rate Regulation in Type 2 Diabetes

Elevated sympathetic nerve activity (SNA) coupled with dysregulated β-adrenoceptor (β-AR) signaling is postulated as a major driving force for cardiac dysfunction in patients with type 2 diabetes; however, cardiac SNA has never been assessed directly in diabetes. Our aim was to measure the sympathetic input to and the β-AR responsiveness of the heart in the type 2 diabetic heart. In vivo recording of SNA of the left efferent cardiac sympathetic branch of the stellate ganglion in Zucker diabetic fatty rats revealed an elevated resting cardiac SNA and doubled firing rate compared with nondiabetic rats. Ex vivo, in isolated denervated hearts, the intrinsic heart rate was markedly reduced. Contractile and relaxation responses to β-AR stimulation with dobutamine were compromised in externally paced diabetic hearts, but not in diabetic hearts allowed to regulate their own heart rate. Protein levels of left ventricular β₁-AR and G_s (guanine nucleotide binding protein stimulatory) were reduced, whereas left ventricular and right atrial β₂-AR and G_i (guanine nucleotide binding protein inhibitory regulatory) levels were increased. The elevated resting cardiac SNA in type 2 diabetes, combined with the reduced cardiac β-AR responsiveness, suggests that the maintenance of normal cardiovascular function requires elevated cardiac sympathetic input to compensate for changes in the intrinsic properties of the diabetic heart.

Source Diabetes Pathophysiology http://ift.tt/1VBErCJ

Bone Marrow Macrophages Contribute to Diabetic Stem Cell Mobilopathy by Producing Oncostatin M

Diabetes affects bone marrow (BM) structure and impairs mobilization of stem cells (SCs) into peripheral blood (PB). This amplifies multiorgan complications because BMSCs promote vascular repair. Because diabetes skews macrophage phenotypes and BM macrophages (BMM) prevent SC mobilization, we hypothesized that excess BMM contribute to diabetic SC mobilopathy. We show that patients with diabetes have increased M1 macrophages, whereas diabetic mice have increased CD169⁺ BMM with SC-retaining activity. Depletion of BMM restored SC mobilization in diabetic mice. We found that CD169 labels M1 macrophages and that conditioned medium (CM) from M1 macrophages, but not from M0 and M2 macrophages, induced chemokine (C-X-C motif) ligand 12 (CXCL12) expression by mesenchymal stem/stromal cells. In silico data mining and in vitro validation identified oncostatin M (OSM) as the soluble mediator contained in M1 CM that induces CXCL12 expression via a mitogen-activated protein kinase kinase-p38-signal transducer and activator of a transcription 3–dependent pathway. In diabetic mice, OSM neutralization prevented CXCL12 induction and improved granulocyte-colony stimulating factor and ischemia-induced mobilization, SC homing to ischemic muscles, and vascular recovery. In patients with diabetes, BM plasma OSM levels were higher and correlated with the BM-to-PB SC ratio. In conclusion, BMM prevent SC mobilization by OSM secretion, and OSM antagonism is a strategy to restore BM function in diabetes, which can translate into protection mediated by BMSCs.

Source Diabetes Pathophysiology http://ift.tt/1VBEs9R