Skeletal muscle microvascular exchange capacity is associated with hyperglycaemia in non-diabetic subjects with central obesity

Skeletal muscle microvascular exchange capacity is associated with hyperglycaemia in non-diabetic subjects with central obesit

Insulin vascular action in skeletal muscle is attenuated with insulin resistance and features of metabolic syndrome

Background and Aims: the relationship between total muscle blood flow,capillary recruitment and skeletal muscle insulin sensitivity remains unclear.The aim of this study was to investigate insulin-induced changes in musclemicrovascular blood flow using a novel non-invasive laser Doppler surfaceprobe in individuals with features of metabolic syndromeMaterials and Methods: twenty one volunteers (age range 37 – 67years;mean 51.5 ± 1.5y; 8 men) were recruited. All gave written informed consent.Blood flux in muscle and skin was measured by laser Doppler fluximetry(DRT4 Moor Instruments Ltd, UK) using a 785 nm, 20 mW, 4 mm separation(muscle) and a 1 mW, 0.5 mm separation (skin) probe placed above theanterior tibialis muscle. Measurements were made at rest and during areactive hyperaemia (RH) to arterial occlusion, before and during steppedhyperinsulinaemic euglycaemic clamp at low (0.2 mU/kg/min) and highdose insulin (1.5 mU/kg/ min). Insulin sensitivity was measured as the rate ofglucose disposal (M = mg/kg/min) during the steady state of the clamp.Results: resting blood flux in muscle and skin was 80±3 and 9±0.3 AU(arbitrary perfusion units), respectively. The insulin-induced increase inresting muscle blood flow was positively related to insulin sensitivity (r=0.45p<0.05). The relative increase in RH from baseline was negatively correlatedwith percentage body fat measured by DEXA (r=–0.59, p< 0.02).Conclusion: we conclude that insulin’s vascular action within skeletal muscle,as measured by non- invasive laser Doppler fluximetry, is attenuated withinsulin resistance and with increased body fat. We speculate that an impairedinsulin response within skeletal muscle microvasculature may contribute towhole body insulin resistance and to decreased glucose disposal by musclein these patient

Single-Cell Transcriptome Profiling of Mouse and hESC-Derived Pancreatic Progenitors

Summary: Human embryonic stem cells (hESCs) are a potential unlimited source of insulin-producing β cells for diabetes treatment. A greater understanding of how β cells form during embryonic development will improve current hESC differentiation protocols. All pancreatic endocrine cells, including β cells, are derived from Neurog3-expressing endocrine progenitors. This study characterizes the single-cell transcriptomes of 6,905 mouse embryonic day (E) 15.5 and 6,626 E18.5 pancreatic cells isolated from Neurog3-Cre; Rosa26mT/mG embryos, allowing for enrichment of endocrine progenitors (yellow; tdTomato + EGFP) and endocrine cells (green; EGFP). Using a NEUROG3-2A-eGFP CyT49 hESC reporter line (N5-5), 4,462 hESC-derived GFP+ cells were sequenced. Differential expression analysis revealed enrichment of markers that are consistent with progenitor, endocrine, or previously undescribed cell-state populations. This study characterizes the single-cell transcriptomes of mouse and hESC-derived endocrine progenitors and serves as a resource (https://lynnlab.shinyapps.io/embryonic_pancreas) for improving the formation of functional β-like cells from hESCs. : In this article, Krentz and colleagues characterize the single-cell transcriptome of E15.5 and E18.5 mouse pancreatic cells and hESC-derived endocrine cells. They identify pancreatic cell-type-specific genes in the mouse and compare hESC-derived endocrine cells to fetal mouse endocrine cells and human islets. Keywords: pancreas development, scRNA-seq, endocrine progenitors, Neurog3, hESCs, mT/mG, CyT49, diabetes, cell therap

DPP-4 inhibitors in the management of type 2 diabetes: A critical review of head-to-head trials.

Dipeptidyl peptidase-4 (DPP-4) inhibitors offer new options for the management of type 2 diabetes. Direct comparisons with active glucose-lowering comparators in drug-naive patients have demonstrated that DPP-4 inhibitors exert slightly less pronounced HbA(1c) reduction than metformin (with the advantage of better gastrointestinal tolerability) and similar glucose-lowering effects as with a thiazolidinedione (TZD; with the advantage of no weight gain). In metformin-treated patients, gliptins were associated with similar HbA(1c) reductions compared with a sulphonylurea (SU; with the advantage of no weight gain, considerably fewer hypoglycaemic episodes and no need for titration) and a TZD (with the advantage of no weight gain and better overall tolerability). DPP-4 inhibitors also exert clinically relevant glucose-lowering effects compared with a placebo in patients treated with SU or TZD (of potential interest when metformin is either not tolerated or contraindicated), and as oral triple therapy with a good tolerability profile when added to a metformin-SU or pioglitazone-SU combination. Several clinical trials also showed a consistent reduction in HbA(1c) when DPP-4 inhibitors were added to basal insulin therapy, with no increased risk of hypoglycaemia. Because of the complex pathophysiology of type 2 diabetes and the complementary actions of glucose-lowering agents, initial combination of a DPP-4 inhibitor with either metformin or a glitazone may be applied in drug-naive patients, resulting in greater efficacy and similar safety compared with either drug as monotherapy. However, DPP-4 inhibitors were less effective than GLP-1 receptor agonists for reducing HbA(1c) and body weight, but offer the advantage of being easier to use (oral instead of injected administration) and lower in cost. Only one head-to-head trial demonstrated the non-inferiority of saxagliptin vs sitagliptin. Clearly, more trials of direct comparisons between different incretin-based therapies are needed. Because of their pharmacokinetic characteristics, pharmacodynamic properties (glucose-dependent glucose-lowering effect) and good overall tolerability profile, DPP-4 inhibitors may have a key role to play in patients with renal impairment and in the elderly. The role of DPP-4 inhibitors in the therapeutic armamentarium of type 2 diabetes is rapidly evolving as their potential strengths and weaknesses become better defined mainly through controlled clinical trials

Dynamic Ins2 gene activity defines β-cell maturity states

Transcriptional and functional cellular specialization has been described for insulin-secreting β-cells of the endocrine pancreas. However, it is not clear whether β-cell heterogeneity is stable or reflects dynamic cellular states. We investigated the temporal kinetics of endogenous insulin gene activity using live cell imaging, with complementary experiments employing FACS and single cell RNA sequencing, in β-cells from Ins2GFP knock-in mice. In vivo staining and FACS analysis of islets from Ins2GFP mice confirmed that at a given moment, ~25% of β-cells exhibited significantly higher activity at the evolutionarily conserved insulin gene Ins2. Live cell imaging over days captured Ins2 gene activity dynamics in single β-cells. Autocorrelation analysis revealed a subset of oscillating cells, with mean oscillation periods of 17 hours. Increased glucose concentrations stimulated more cells to oscillate and resulted in higher average Ins2 gene activity per cell. Single cell RNA sequencing showed that Ins2(GFP)HIGH β-cells were enriched for markers of β-cell maturity. Ins2(GFP)HIGH β-cells were also significantly less viable at all glucose concentrations and in the context of ER stress. Collectively, our results demonstrate that the heterogeneity of insulin production, observed in mouse and human β-cells, can be accounted for by dynamic states of insulin gene activity. </p