The Impact of Low-dose Gliclazide on the Incretin Effect and Indices of Beta-cell Function

AIMS/HYPOTHESIS: Studies in permanent neonatal diabetes suggest that sulphonylureas lower blood glucose without causing hypoglycemia, in part by augmenting the incretin effect. This mechanism has not previously been attributed to sulphonylureas in patients with type 2 diabetes (T2DM). We therefore aimed to evaluate the impact of low-dose gliclazide on beta-cell function and incretin action in patients with T2DM. METHODS: Paired oral glucose tolerance tests and isoglycemic infusions were performed to evaluate the difference in the classical incretin effect in the presence and absence of low-dose gliclazide in 16 subjects with T2DM (hemoglobin A1c < 64 mmol/mol, 8.0%) treated with diet or metformin monotherapy. Beta-cell function modeling was undertaken to describe the relationship between insulin secretion and glucose concentration. RESULTS: A single dose of 20 mg gliclazide reduced mean glucose during the oral glucose tolerance test from 12.01 ± 0.56 to 10.82 ± 0.5mmol/l [P = 0.0006; mean ± standard error of the mean (SEM)]. The classical incretin effect was augmented by 20 mg gliclazide, from 35.5% (lower quartile 27.3, upper quartile 61.2) to 54.99% (34.8, 72.8; P = 0.049). Gliclazide increased beta-cell glucose sensitivity by 46% [control 22.61 ± 3.94, gliclazide 33.11 ± 7.83 (P = 0.01)] as well as late-phase incretin potentiation [control 0.92 ± 0.05, gliclazide 1.285 ± 0.14 (P = 0.038)]. CONCLUSIONS/INTERPRETATION: Low-dose gliclazide reduces plasma glucose in response to oral glucose load, with concomitant augmentation of the classical incretin effect. Beta-cell modeling shows that low plasma concentrations of gliclazide potentiate late-phase insulin secretion and increase glucose sensitivity by 50%. Further studies are merited to explore whether low-dose gliclazide, by enhancing incretin action, could effectively lower blood glucose without risk of hypoglycemia

Improving the quality of weekend medical handover on non-receiving medical hospital wards

INTRODUCTION: Handover is the system by which the responsibility for immediate and ongoing care is transferred between healthcare professionals and can be an area of risk. The Royal College of Physicians (RCP) has recommended improvement and standardisation of handover. Locally, national training surveys have reported poor feedback regarding handover at Glasgow Royal Infirmary. AIM: To improve and standardise handover from weekday to weekend teams. METHODS: The Plan–Do–Study–Act (PDSA) quality improvement framework was used. Interventions were derived from a driver diagram after consultation with relevant stakeholders. Four PDSA cycles were completed over a 4-month period: PDSA cycle 1—Introduction of standardised paper form on three wards. PDSA cycle 2—Introduction of electronic handover system on three wards. PDSA cycle 3—Expansion of electronic handover to seven wards. PDSA cycle 4—Expansion of electronic handover to all non-receiving medical wards. The outcome of interest was the percentage of patients with full information handed over based on a six-point scale derived from the RCP. Data were collected weekly throughout the study period. RESULTS: 18 data collection exercises were performed including 525 patients. During the initial phase there was an improvement in handover quality with 0/28 (0%) at baseline having all six points completed compared with 13/48 (27%) with standardised paper form and 21/42 (50%) with the electronic system (p<0.001). When the electronic handover form was expanded to all wards, the increased quality was maintained, however, to a lesser extent compared with the initial wards. CONCLUSION: A standardised electronic handover system was successfully introduced to downstream medical wards over a short time period. This led to an in improvement in the quality of handover in the initial wards involved. When expanded to a greater number of wards there was still an improvement in quality but to a lesser degree

Circulating tissue factor-positive procoagulant microparticles in patients with type 1 diabetes

Aim: To investigate the count of circulating tissue factor-positive (TF+) procoagulant microparticles (MPs) in patients with type 1 diabetes mellitus (T1DM). Methods: This case-control study included patients with T1DM and age and sex-matched healthy volunteers. The counts of phosphatidylserine-positive (PS+) MPs and TF(+)PS(+)MPs and the subgroups derived from different cell types were measured in the peripheral blood sample of the two groups using multicolor flow cytometric assay. We compared the counts of each MP between groups as well as the ratio of the TF(+)PS(+)MPs and PS(+)MPs (TF(+)PS(+)MPs/PS(+)MPs). Results: We recruited 36 patients with T1DM and 36 matched healthy controls. Compared with healthy volunteers, PS(+)MPs, TF(+)PS(+)MPs and TF(+)PS(+)MPs/PS(+)MPs were elevated in patients with T1DM (PS(+)MPs: 1078.5 +/- 158.08 vs 686.84 +/- 122.04/mu L, P &lt;0.001; TF(+)PS(+)MPs: 202.10 +/- 47.47 vs 108.33 +/- 29.42/mu L, P &lt;0.001; and TF(+)PS(+)MPs/PS(+)MPs: 0.16 +/- 0.04 vs 0.19 +/- 0.05, P = 0.004), mostly derived from platelet, lymphocytes and endothelial cells. In the subgroup analysis, the counts of total and platelet TF(+)PS(+)MPs were increased in patients with diabetic retinopathy (DR) and with higher HbA1c, respectively. Conclusion: Circulating TF(+)PS(+)MPs and those derived from platelet, lymphocytes and endothelial cells were elevated in patients with T1DM.De tre första författarna delar förstaförfattarskapet.</p

Low dose sulphonylurea plus DPP4 inhibitor lower blood glucose and enhance beta cell function without hypoglycaemia

Context: Low dose sulphonylureas have been found to augment the classical incretin effect, increase glucose sensitivity and late phase incretin potentiation.Objective: To evaluate potential synergy between low dose sulphonylurea plus DPP4 inhibitor.Design: Unblinded randomised crossover studySetting: Clinical Research Centre, University of DundeeParticipants: 30 participants with T2DM (HbA1c &lt; 64 mmol/mol) treated with diet or metformin.Intervention: Participants completed four, 14-day blocks in a random order: control, gliclazide 20 mg (SU), sitagliptin 100 mg (DPP4i), or combination (SUDPP4i). A mixed meal test was conducted after each intervention.Main Outcome Measure: The primary outcome was the effect of treatment on beta-cell glucose sensitivity. Secondary outcomes included frequency of glucose &lt;3 mmol/l on continuous glucose monitoring, sub-analyses by genotype (KNCJ11 E23 K), gender and body mass index.Results: SU combination with DPP4i showed additive effect on glucose lowering: Mean glucose AUC (mean 95% CI) (mmol/l) was: Control 11.5 (10.7–12.3), DPP4i 10.2 (9.4–11.1), SU 9.7 (8.9–10.5), SUDPP4i 8.7 (7.9–9.5) (p &lt; 0.001). Glucose sensitivity mirrored the additive effect (pmol min-1 m-2mM-1): Control 71.5 (51.1–91.9), DPP4i 75.9 (55.7–96.0), SU 86.3 (66.1–106.4), SUDPP4i 94.1 (73.9–114.3) (p = 0.04). The additive effect was seen in men but not women. Glucose time in range &lt;3 mmol/l on CGM (%) was unaffected: Control 1 (2-4), DPP4i 2 (3-6), SU 1 (0-4), SUDPP4i 3 (2–7) (p = 0.65)Conclusions: Low dose sulphonylurea plus DPP4i has potent glucose lowering effect through augmentation of beta cell function. A double-blind randomised controlled trial would formalise efficacy and safety of this combination, which may avoid negative aspects of SU

Low dose sulphonylurea plus DPP4 inhibitor lower blood glucose and enhance beta cell function without hypoglycaemia

Context: Low dose sulphonylureas have been found to augment the classical incretin effect, increase glucose sensitivity and late phase incretin potentiation.Objective: To evaluate potential synergy between low dose sulphonylurea plus DPP4 inhibitor.Design: Unblinded randomised crossover studySetting: Clinical Research Centre, University of DundeeParticipants: 30 participants with T2DM (HbA1c &lt; 64 mmol/mol) treated with diet or metformin.Intervention: Participants completed four, 14-day blocks in a random order: control, gliclazide 20 mg (SU), sitagliptin 100 mg (DPP4i), or combination (SUDPP4i). A mixed meal test was conducted after each intervention.Main Outcome Measure: The primary outcome was the effect of treatment on beta-cell glucose sensitivity. Secondary outcomes included frequency of glucose &lt;3 mmol/l on continuous glucose monitoring, sub-analyses by genotype (KNCJ11 E23 K), gender and body mass index.Results: SU combination with DPP4i showed additive effect on glucose lowering: Mean glucose AUC (mean 95% CI) (mmol/l) was: Control 11.5 (10.7–12.3), DPP4i 10.2 (9.4–11.1), SU 9.7 (8.9–10.5), SUDPP4i 8.7 (7.9–9.5) (p &lt; 0.001). Glucose sensitivity mirrored the additive effect (pmol min-1 m-2mM-1): Control 71.5 (51.1–91.9), DPP4i 75.9 (55.7–96.0), SU 86.3 (66.1–106.4), SUDPP4i 94.1 (73.9–114.3) (p = 0.04). The additive effect was seen in men but not women. Glucose time in range &lt;3 mmol/l on CGM (%) was unaffected: Control 1 (2-4), DPP4i 2 (3-6), SU 1 (0-4), SUDPP4i 3 (2–7) (p = 0.65)Conclusions: Low dose sulphonylurea plus DPP4i has potent glucose lowering effect through augmentation of beta cell function. A double-blind randomised controlled trial would formalise efficacy and safety of this combination, which may avoid negative aspects of SU