AimsType 2 diabetes is associated with endothelial dysfunction leading to cardiovascular disease. CD34+ endothelial Progenitor Cells (EPCs) are responsible for endothelial repair and neo-angiogenesis and can be used as a cardiovascular disease risk biomarker. This study investigated whether the addition of saxagliptin, a DPP-IV inhibitor, to metformin, may reduce cardiovascular disease risk in addition to improving glycemic control in Type 2 diabetes patients.MethodsIn 12 week, double-blind, randomized placebo-controlled trial, 42 subjects already taking metformin 1–2 grams/day were randomized to placebo or saxagliptin 5 mg. Subjects aged 40–70 years with diabetes for < 10 years, with no known cardiovascular disease, BMI 25–39.9, HbA1C 6–9% were included. We evaluated EPCs number, function, surface markers and gene expression, in addition to arterial stiffness, blood biochemistries, resting energy expenditure, and body composition parameters. A mixed model regression to examine saxagliptin vs placebo, accounting for within-subject autocorrelation, was done with SAS (p < 0.05).ResultsAlthough there was no significant increase in CD34+ cell number, CD31+ cells percentage increased. Saxagliptin increased migration (in response to SDF1α) with a trend of higher colony formation count. MNCs cytometry showed higher percentage of CXCR4 double positivity for both CD34 and CD31 positive cells, indicating a functional improvement. Gene expression analysis showed an upregulation in CD34+ cells for antioxidant SOD1 (p < 0.05) and a downregulation in CD34− cells for IL-6 (p < 0.01). For arterial stiffness, both augmentation index and systolic blood pressure measures went down in saxagliptin subjects (p < 0.05).ConclusionSaxagliptin, in combination with metformin, can help improve endothelial dysfunction in early diabetes before macrovascular complications appear.Trial registration Trial is registered under clinicaltrials.gov, NCT02024477Electronic supplementary materialThe online version of this article (10.1186/s12933-018-0709-9) contains supplementary material, which is available to authorized users.

Background: Endothelial Progenitor cells (EPCs) has been shown to be dysfunctional in both type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) leading to poor regeneration of endothelium and renal perfusion. EPCs have been shown to be a robust cardiovascular disease (CVD) risk indicator. Cellular mechanisms of DPP4 inhibitors such as linagliptin (LG) on CVD risk, in patients with T2DM with established CKD has not been established. Linagliptin, a DPP4 inhibitor when added to insulin, metformin or both may improve endothelial dysfunction in a diabetic kidney disease (DKD) population. Methods: 31 subjects taking metformin and/or Insulin were enrolled in this 12 weeks, double blind, randomized placebo matched trial, with 5 mg LG compared to placebo. Type 2 diabetes subjects (30-70 years old), HbA1c of 6.5-10%, CKD Stage 1-3 were included. CD34+ cell number, migratory function, gene expression along with vascular parameters such as arterial stiffness, biochemistry, resting energy expenditure and body composition were measured. Data were collected at week 0, 6 and 12. A mixed model regression analysis was done with p value < 0.05 considered significant. Results: A double positive CD34/CD184 cell count had a statistically significant increase (p < 0.02) as determined by flow cytometry in LG group where CD184 is SDF1a cell surface receptor. Though mRNA differences in CD34+ve was more pronounced CD34-cell mRNA analysis showed increase in antioxidants (superoxide dismutase 2 or SOD2, Catalase and Glutathione Peroxidase or GPX) and prominent endothelial markers (PECAM1, VEGF-A, vWF and NOS3). Arterial stiffness measures such as augmentation Index (AI) (p < 0.04) and pulse wave analysis (PWV) were improved (reduced in stiffness) in LG group. A reduction in LDL: HDL ratio was noted in treatment group (p < 0.04). Urinary exosome protein examining podocyte health (podocalyxin, Wilms tumor and nephrin) showed reduction or improvement.

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Scope Low‐calorie sweetener (LCS) consumption is associated with metabolic disease in observational studies. However, physiologic mechanisms underlying LCS‐induced metabolic impairments in humans are unclear. This study is aimed at identifying molecular pathways in adipose impacted by LCSs. Methods and results Seven females with overweight or obesity, who did not report LCS use, consumed 12 ounces of diet soda containing sucralose and acesulfame‐potassium (Ace‐K) three times daily for 8 weeks. A subcutaneous adipose biopsy from the left abdomen and a fasting blood sample were collected at baseline and post‐intervention. Global gene expression were assessed using RNA‐sequencing followed by functional pathway analysis. No differences in circulating metabolic or inflammatory biomarkers were observed. However, ANOVA detected 828 differentially expressed annotated genes after diet soda consumption (p < 0.05), including transcripts for inflammatory cytokines. Fifty‐eight of 140 canonical pathways represented in pathway analyses regulated inflammation, and several key upstream regulators of inflammation (e.g., TNF‐alpha) were also represented. Conclusion Consumption of diet soda with sucralose and Ace‐K alters inflammatory transcriptomic pathways (e.g., NF‐κB signaling) in subcutaneous adipose tissue but does not significantly alter circulating biomarkers. Findings highlight the need to examine molecular and metabolic effects of LCS exposure in a larger randomized control trial for a longer duration.

Genetic modification, or gene transfer, represents a method of treatment for several diseases. It has been used extensively in the context of cardiovascular diseases; however, its role in the context of metabolic diseases, such as diabetes and obesity, has remained largely unexplored. In this chapter, we will review the use of adult stem cells, focusing on endothelial progenitor cells (EPCs) and mesenchymal stromal cells (MSCs), in the context of diabetes. We have highlighted the use of viral vectors, particularly DNA viruses, as a tool for genetic modification to help stem cells survive and resist apoptosis in a hyperglycemic environment. We then discuss genetic modification of EPCs and MSCs to treat complications of diabetes and obesity. Although there are several unanswered questions in the field of metabolic diseases, the future application of gene transfer technology along with genetic modification of stem cells prior to the therapy holds significant therapeutic promise.