Translational development of ABCB5+ dermal mesenchymal stem cells for therapeutic induction of angiogenesis in non-healing diabetic foot ulcers.

BACKGROUND: While rapid healing of diabetic foot ulcers (DFUs) is highly desirable to avoid infections, amputations and life-threatening complications, DFUs often respond poorly to standard treatment. GMP-manufactured skin-derived ABCB5+ mesenchymal stem cells (MSCs) might provide a new adjunctive DFU treatment, based on their remarkable skin wound homing and engraftment potential, their ability to adaptively respond to inflammatory signals, and their wound healing-promoting efficacy in mouse wound models and human chronic venous ulcers. METHODS: The angiogenic potential of ABCB5+ MSCs was characterized with respect to angiogenic factor expression at the mRNA and protein level, in vitro endothelial trans-differentiation and tube formation potential, and perfusion-restoring capacity in a mouse hindlimb ischemia model. Finally, the efficacy and safety of ABCB5+ MSCs for topical adjunctive treatment of chronic, standard therapy-refractory, neuropathic plantar DFUs were assessed in an open-label single-arm clinical trial. RESULTS: Hypoxic incubation of ABCB5+ MSCs led to posttranslational stabilization of the hypoxia-inducible transcription factor 1α (HIF-1α) and upregulation of HIF-1α mRNA levels. HIF-1α pathway activation was accompanied by upregulation of vascular endothelial growth factor (VEGF) transcription and increase in VEGF protein secretion. Upon culture in growth factor-supplemented medium, ABCB5+ MSCs expressed the endothelial-lineage marker CD31, and after seeding on gel matrix, ABCB5+ MSCs demonstrated formation of capillary-like structures comparable with human umbilical vein endothelial cells. Intramuscularly injected ABCB5+ MSCs to mice with surgically induced hindlimb ischemia accelerated perfusion recovery as measured by laser Doppler blood perfusion imaging and enhanced capillary proliferation and vascularization in the ischemic muscles. Adjunctive topical application of ABCB5+ MSCs onto therapy-refractory DFUs elicited median wound surface area reductions from baseline of 59% (full analysis set, n = 23), 64% (per-protocol set, n = 20) and 67% (subgroup of responders, n = 17) at week 12, while no treatment-related adverse events were observed. CONCLUSIONS: The present observations identify GMP-manufactured ABCB5+ dermal MSCs as a potential, safe candidate for adjunctive therapy of otherwise incurable DFUs and justify the conduct of a larger, randomized controlled trial to validate the clinical efficacy. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03267784, Registered 30 August 2017, https://clinicaltrials.gov/ct2/show/NCT03267784.

Improving HbA1c Control in Type 1 or Type 2 Diabetes Using Flash Glucose Monitoring: A Retrospective Observational Analysis in Two German Centres.

INTRODUCTION: The aim of this study was to evaluate change in laboratory-measured HbA1c in patients with either type 1 diabetes (T1D) or type 2 diabetes (T2D) on insulin therapy following initiation of the FreeStyle Libre™ flash glucose monitoring system. METHODS: This was a retrospective observational study on adults with T1D or T2D on insulin, who were started on the FreeStyle Libre system as part of standard care. HbA1c was recorded at initiation and at 3-month intervals thereafter. RESULTS: The analysis included 131 patients with T1D and 176 patients with T2D on insulin. Mean HbA1c decreased significantly by 3 months following initiation of the FreeStyle Libre system, both in T1D (- 0.75%, p < 0.001) and in T2D (- 0.54%, p < 0.001). Reductions were maintained for 12 months. Change from 3 to 12 months was not significant either in T1D or T2D. Subgroup analysis showed significant reduction in patients with a baseline HbA1c > 7.5-10%, both in T1D (- 0.59%, p < 0.001) and in T2D on insulin (- 0.62%, p < 0.005) at 12 months. Reductions for subjects with HbA1c > 10% were - 4.66% in T1D and - 3.73% in T2D. No change was seen for subjects with a baseline HbA1c ≤ 7.5% (58 mmol/mol). Linear regression confirms that baseline HbA1c is strongly negatively correlated with subsequent change in HbA1c in T1D and in T2D. CONCLUSIONS: Patients with T1D or T2D show a reduction in HbA1c by 3 months following initiation of the FreeStyle Libre system. The mean fall in HbA1c at 3 months is strongly negatively correlated with starting HbA1c. This reduction is maintained over 12 months. The significant benefit is seen in patients with a starting HbA1c > 7.5% (58 mmol/mol).

Randomized Cross-Over Study Comparing Two Infusion Sets for CSII in Daily Life.

BACKGROUND: Continuous subcutaneous insulin infusion (CSII) therapy is a valuable option especially for people with type 1 diabetes. Although insulin infusion sets (IIS) are essential components of most insulin pump systems, only few studies have been conducted on their performance and safety. In this study 2 IIS with soft cannulas were compared. METHODS: In an open-label, randomized, crossover, multicenter 8-week study 80 type 1 diabetic subjects on CSII (20-74 years, mean 46.5 ± 12.9 years, 58.8% male) were enrolled to evaluate the use of 2 IIS. The Accu-Chek® FlexLink Plus (FL Plus) and the Accu-Chek® FlexLink infusion set (FL) were used 4 weeks each under real-life conditions at home. All patients had to record details about every IIS change in a diary. Insertion-related pain was assessed by means of a visual analogue scale (VAS). RESULTS: The mean pain noted during insertion was similar for both IIS (VAS 6.1 ± 6.4 mm for the FL Plus and 5.8 ± 6.3 mm for the FL, P = .92). 20.0% of the 895 IIS changes with FL Plus and 16.0% of the 854 with FL were unplanned. During the 4243 patient days of the study, 13 patients had adverse events. Among these, 2 serious adverse events occurred. Both serious events and 1 nonserious adverse event were considered as related to the IIS. Of the patients, 18.7% had kinked cannulas. Most patients were satisfied with both IIS. CONCLUSION: Both IIS are safe and effective. The 2 IIS did not differ from each other with respect to pain observed during insertion.

Evaluation of preference for a novel durable insulin pen with memory function among patients with diabetes and health care professionals.

BACKGROUND: Improving adherence to insulin treatment for better glycemic control remains a challenge in the management of diabetes. New technological aids are required to help support adherence. This study evaluated preference for the NovoPen(®) 5 (NP5), a durable insulin pen with memory function, compared with the HumaPen Luxura(®) (HPL) among patients with diabetes and health care professionals. METHODS: This crossover, multicenter usability study included insulin pen-experienced patients with diabetes and health care professionals treating patients with diabetes in Canada, China, and Germany. Participants evaluated NP5 and HPL in a randomized order by performing handling tasks in a usability test related to everyday use during a face-to-face interview. Tasks, pens, and preferences were assessed by completing a questionnaire comprised of rating and open-ended questions relating to confidence in everyday diabetes management. RESULTS: Overall, 300 patients with diabetes and 150 health care professionals participated in the study. Significantly more participants preferred NP5 (81%) to HPL (18%) (P < 0.001). Also, 82% of patients with diabetes had more confidence in NP5 for managing their daily injections versus 11% with HPL (P < 0.001), and 7% had no preference. Memory function was most helpful in giving patients with diabetes confidence about when they last injected (63%), how much insulin they last injected (62%) and improving diabetes management (55%). Participants gave higher ratings to NP5 than to HPL on all parameters relating to performing an injection (ease of handling, satisfaction when using the pen, convenience of using the pen day-to-day, quality of the pen, and the extent to which the pen meets their needs; P < 0.05 for all comparisons). CONCLUSION: NP5 was preferred to HPL by most participants. Significantly more patients with diabetes had more confidence for managing daily insulin injections when using NP5, the pen with a memory function.

Randomized forced titration to different doses of technosphere insulin demonstrates reduction in postprandial glucose excursions and hemoglobin A1c in patients with type 2 diabetes.

BACKGROUND: Individuals with type 2 diabetes mellitus have impairments in early insulin release, resulting in increased postprandial glucose excursions and suboptimal glycemic control. Studies with Technosphere Insulin (TI) indicate that it has rapid systemic absorption and a short duration of glucose-lowering activity, making it well suited for controlling postprandial glucose levels. METHODS: The goal of this phase 2b, prospective, multicenter, double-blind, placebo-controlled study was to characterize the dose response of four different doses (equivalent to 3.6, 7.3, 10.9, and 14.6 U subcutaneous regular human insulin) of prandial TI or Technosphere powder alone administered before each of three meals daily, in combination with insulin glargine over an 11-week treatment period, in patients with type 2 diabetes and suboptimal glycemic control. RESULTS: The study enrolled 227 patients. In all dose groups, TI demonstrated statistically significant dose-dependent reductions in hemoglobin A1c (HbA1c) versus baseline (-0.4, -0.5, -0.5, and -0.6 for 3.6, 7.3, 10.9, and 14.6 U equivalents, respectively; p < 0.05 in all groups), as well as versus placebo or Technosphere powder alone (-0.40, -0.67, -0.70, and -0.78 for 3.6, 7.3, 10.9, and 14.6 U equivalents, respectively; p < 0.04 in all groups). It reduced the postprandial maximum glucose concentration within each treatment group (statistically significant in all but the TI 3.6 U-equivalent group) and reduced the postprandial area under the glucose curve (statistically significant for the TI 10.9 and 14.6 U-equivalent groups) versus placebo. There were no cases of severe hypoglycemia, while mild/moderate hypoglycemia was observed most frequently in the highest dosage groups, as expected. Rates of cough were low and comparable among all groups. No clinically relevant changes in pulmonary function tests, body weight, or high-resolution computerized axial tomography and magnetic resonance imaging were observed. CONCLUSIONS: This study demonstrated that, over 11 weeks, TI plus basal insulin glargine is well tolerated and results in dose-dependent reductions in postprandial glucose and HbA1c levels.