β Cell transcription factors such as forkhead box protein O1 (FoxO1), v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MafA), pancreatic and duodenal homeobox 1, and neuronal differentiation 1, are dysfunctional in type 2 diabetes mellitus (T2DM). Posttransplant diabetes mellitus resembles T2DM and reflects interaction between pretransplant insulin resistance and immunosuppressants, mainly calcineurin inhibitors (CNIs). We evaluated the effect of tacrolimus (TAC), cyclosporine A (CsA), and metabolic stressors (glucose plus palmitate) on insulinoma β cells in vitro and in pancreata of obese and lean Zucker rats. Cells were cultured for 5 days with 100 μM palmitate and 22 mM glucose; CsA (250 ng/mL) or TAC (15 ng/mL) were added in the last 48 h. Glucose plus palmitate increased nuclear FoxO1 and decreased nuclear MafA. TAC in addition to glucose plus palmitate magnified these changes in nuclear factors, whereas CsA did not. In addition to glucose plus palmitate, both drugs reduced insulin content, and TAC also affected insulin secretion. TAC withdrawal or conversion to CsA restored these changes. Similar results were observed in pancreata of obese animals on CNIs. TAC and CsA, in addition to glucose plus palmitate, induced comparable inhibition of calcineurin and nuclear factor of activated T cells (NFAT); therefore, TAC potentiates glucolipotoxicity in β cells, possibly by sharing common pathways of β cell dysfunction. TAC-induced β cell dysfunction is potentially reversible. Inhibition of the calcineurin-NFAT pathway may contribute to the diabetogenic effect of CNIs but does not explain the stronger effect of TAC compared with CsA.

Very-low-dose insulin application and slow-motion reequilibration plus monitored substitution of electrolytes are the basic strategies in the treatment of severe DKA. In our view, small doses of infused insulin are the main reason for the safe results of this therapy program.

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ObjectiveThis study assesses the effectiveness of different interventions of knowledge transfer and behaviour modification to improve type 2 diabetes mellitus patients’ (T2DM) reported outcomes measures (PROMs) in the long-term. Design: open, community-based pragmatic, multicentre, controlled trial with random allocation by clusters to usual care (UC) or to one of the three interventions.ParticipantsA total of 2334 patients with uncomplicated T2DM and 211 healthcare professionals were included of 32 primary care centres.SettingPrimary Care Centers in Canary Islands (Spain).InterventionThe intervention for patients (PTI) included an educational group programme, logs and a web-based platform for monitoring and automated short message service (SMS). The intervention for professionals (PFI) included an educational programme, a decision support tool embedded into the electronic clinical record and periodic feedback about patients’ results. A third group received both PTI and PFI (combined intervention, CBI).Outcome measureCognitive-attitudinal, behavioural, affective and health-related quality of life (HQoL) variables.ResultsCompared with UC at 24 months, the PTI group significantly improved knowledge (p=0.005), self-empowerment (p=0.002), adherence to dietary recommendations (p<0.001) and distress (p=0.01). The PFI group improved at 24 months in distress (p=0.03) and at 12 months there were improvements in depression (p=0.003), anxiety (p=0.05), HQoL (p=0.005) and self-empowerment (p<0.001). The CBI group improved at 24 months in self-empowerment (p=0.008) and adherence to dietary recommendations (p=0.004) and at 12 months in knowledge (p=0.008), depression (p=0.006), anxiety (p=0.003), distress (p=0.01), HQoL (p<0.001) and neuropathic symptoms (p=0.02). Statistically significant improvements were also observed at 24 months in the proportion of patients who quit smoking for PTI and CBI (41.5% in PTI and 42.3% in CBI vs 21.2% in the UC group).ConclusionsAssessed interventions to improve PROMs in T2DM attain effectiveness for knowledge, self-empowerment, distress, diet adherence and tobacco cessation. PTI produced the most lasting benefits.Trial registration numberClinicalTrials.gov NCT01657227 (6 August 2012) https://clinicaltrials.gov/ct2/show/NCT01657227.