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Objective: Reparixin is an inhibitor of CXCR1/2 chemokine receptor shown to be an effective anti-inflammatory adjuvant in a pilot clinical trial in allotransplant recipients.Research Design and Methods: A phase 3, multicenter, randomized, double-blind, parallel-assignment study (NCT01817959) was conducted in recipients of islet allotransplants randomized (2:1) to reparixin or placebo in addition to immunosuppression. Primary outcome was the area under the curve (AUC) for C-peptide during the mixed-meal tolerance test at day 75 ± 5 after the first and day 365 ± 14 after the last transplant. Secondary end points included insulin independence and standard measures of glycemic control.Results: The intention-to-treat analysis did not show a significant difference in C-peptide AUC at both day 75 (27 on reparixin vs. 18 on placebo, P = 0.99) and day 365 (24 on reparixin vs. 15 on placebo, P = 0.71). There was no statistically significant difference between treatment groups at any time point for any secondary variable. Analysis of patient subsets showed a trend for a higher percentage of subjects retaining insulin independence for 1 year after a single islet infusion in patients receiving reparixin as compared with patients receiving placebo (26.7% vs. 0%, P = 0.09) when antithymocyte globulin was used as induction immunosuppression.Conclusions: In this first double-blind randomized trial, islet transplantation data obtained with reparixin do not support a role of CXCR1/2 inhibition in preventing islet inflammation-mediated damage. [ABSTRACT FROM AUTHOR]

Objective: The HypoCOMPaSS study was designed to test the hypothesis that successful avoidance of biochemical hypoglycemia without compromising overall glycemic control would restore sufficient hypoglycemia awareness to prevent recurrent severe hypoglycemia in the majority of participants with established type 1 diabetes. Before starting the study, we planned to investigate associations between baseline characteristics and recurrent severe hypoglycemia over 2 years' follow-up.Research Design and Methods: A total of 96 adults with type 1 diabetes and impaired awareness of hypoglycemia participated in a 24-week 2 × 2 factorial randomized controlled trial comparing insulin delivery and glucose monitoring modalities, with the goal of rigorous biochemical hypoglycemia avoidance. The analysis included 71 participants who had experienced severe hypoglycemia in the 12-month prestudy with confirmed absence (complete responder) or presence (incomplete responder) of severe hypoglycemia over 24 months' follow-up.Results: There were 43 (61%) complete responders and 28 (39%) incomplete responders experiencing mean ± SD 1.5 ± 1.0 severe hypoglycemia events/person-year. At 24 months, incomplete responders spent no more time with glucose ≤3 mmol/L (1.4 ± 2.1% vs. 3.0 ± 4.8% for complete responders; P = 0.26), with lower total daily insulin dose (0.45 vs. 0.58 units/24 h; P = 0.01) and greater impairment of hypoglycemia awareness (Clarke score: 3.8 ± 2.2 vs. 2.0 ± 1.9; P = 0.01). Baseline severe hypoglycemia rate (16.9 ± 16.3 vs. 6.4 ± 10.8 events/person-year; P = 0.002) and fear of hypoglycemia were higher in incomplete responders. Peripheral neuropathy was more prevalent in incomplete responders (11 [39%] vs. 2 [4.7%]; P < 0.001) with a trend toward increased autonomic neuropathy.Conclusions: Recurrent severe hypoglycemia was associated with higher preintervention severe hypoglycemia rate, fear of hypoglycemia, and concomitant neuropathy. [ABSTRACT FROM AUTHOR]

The article presents a study aimed at comparing the changes in glucose variability (GV) between multiple daily injections (MDI) and continuous subcutaneous insulin infusion (CSII) and between self-monitored blood glucose (SMBG) and real-time continuous glucose monitoring (RT-CGM) group in specific patient group with type 1 diabetes. The patient is said to have impaired awareness of hypoglycemia (IAH) or recurrent severe hypoglycemia (SH).

OBJECTIVE-Relative contributions of reversible b-cell dysfunction and true decrease in b-cell mass in type 2 diabetes remain unclear. Definitive rodent lineage-tracing studies have identified b-cell dedifferentiation and subsequent reprogramming to a-cell fate as a novel mechanism underlying b-cell failure. The aim was to determine whether phenotypes of b-cell dedifferentiation and plasticity are present in human diabetes. RESEARCH DESIGN AND METHODS-Immunofluorescence colocalization studies using classical endocrine and mesenchymal phenotypic markers were undertaken using pancreatic sections and isolated islets from three individuals with diabetes and five nondiabetic control subjects. RESULTS-Intraislet cytoplasmic coexpression of insulin and vimentin, insulin and glucagon, and vimentin and glucagon were demonstrated in all cases. These phenotypes were not present in nondiabetic control subjects. CONCLUSIONS-Coexpression of mesenchymal and a-cell phenotypic markers in human diabetic islet b-cells has been confirmed, providing circumstantial evidence for b-cell dedifferentiation and possible reprogramming to a-cells in clinical diabetes. [ABSTRACT FROM AUTHOR]

The authors respond to a commentary on their randomized controlled trial that assessed the hypoglycemia awareness in type 1 diabetes. Topics discussed include the argument against the conventional glucose self-monitoring or HypoCOMPASS protocol, the study's premise focusing on achievability within routine care and argument on the assertion that there was lack of glycemic benefit observed in subjects who used insulin pumps and continuous glucose monitoring (CGM).