Background Oral semaglutide is the first oral glucagon-like peptide-1 (GLP-1) receptor agonist for glycaemic control in patients with type 2 diabetes. Type 2 diabetes is commonly associated with renal impairment, restricting treatment options. We aimed to investigate the efficacy and safety of oral semaglutide in patients with type 2 diabetes and moderate renal impairment. Methods This randomised, double-blind, phase 3a trial was undertaken at 88 sites in eight countries. Patients aged 18 years and older, with type 2 diabetes, an estimated glomerular filtration rate of 30-59 mL/min per 1•73 m², and who had been receiving a stable dose of metformin or sulfonylurea, or both, or basal insulin with or without metformin for the past 90 days were eligible. Participants were randomly assigned (1:1) by use of an interactive web-response system, with stratification by glucose-lowering medication and renal function, to receive oral semaglutide (dose escalated to 14 mg once daily) or matching placebo for 26 weeks, in addition to background medication. Participants and site staff were masked to assignment. Two efficacy-related estimands were defined: treatment policy (regardless of treatment discontinuation or rescue medication) and trial product (on treatment without rescue medication) in all participants randomly assigned. Endpoints were change from baseline to week 26 in HbA1c (primary endpoint) and bodyweight (confirmatory secondary endpoint), assessed in all participants with sufficient data. Safety was assessed in all participants who received at least one dose of study drug. This trial is registered on ClinicalTrials.gov, number NCT02827708, and the European Clinical Trials Registry, number EudraCT 2015-005326-19, and is now complete.

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We have previously shown that hemizygous transgenic mice expressing human islet amyloid polypeptide (hIAPP) in pancreatic beta-cells have no diabetic phenotype, whereas in the homozygous state, they developed severe, early-onset hyperglycemia associated with impaired insulin secretion and beta-cell death. We investigated the possibility that when the hemizygous mice are crossed onto an obese, insulin-resistant strain such as agouti viable yellow (A(vy)/a), they would exhibit a phenotype more akin to human type 2 diabetes. The hIAPP-expressing A(vy) males (TG-Y) displayed fasting hyperglycemia at 90 days of age and by 1 year progressed to severe hyperglycemia relative to their nontransgenic counterparts. Plasma insulin concentrations and pancreatic insulin content dropped 10- to 20-fold, suggesting severe impairment of beta-cell function. Histopathological findings revealed beta-cell degeneration and loss consistent with the drop in the plasma insulin concentration. In addition, large deposits of IAPP amyloid were present in TG-Y islets. We conclude that in transgenic mice expressing hIAPP, insulin resistance can induce overt, slow-onset diabetes associated with islet amyloid and decreased beta-cell mass.

Objective: To examine the persistence of the original treatment effects 10 years after the Diabetes Control and Complications Trial (DCCT) in the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study. In the DCCT, intensive therapy aimed at nearnormal glycemia reduced the risk of microvascular complications of type 1 diabetes mellitus compared with conventional therapy.Methods: Retinopathy was evaluated by fundus photography in 1211 subjects at EDIC year 10. Further 3-step progression on the Early Treatment Diabetic Retinopathy Study scale from DCCT closeout was the primary outcome.Results: After 10 years of EDIC follow-up, there was no significant difference in mean glycated hemoglobin levels (8.07% vs 7.98%) between the original treatment groups. Nevertheless, compared with the former conven-tional treatment group, the former intensive group had significantly lower incidences from DCCT close of further retinopathy progression and proliferative retinopathy or worse (hazard reductions, 53%-56%; PϽ.001). The risk (hazard) reductions at 10 years of EDIC were attenuated compared with the 70% to 71% over the first 4 years of EDIC (PϽ.001). The persistent beneficial effects of former intensive therapy were largely explained by the difference in glycated hemoglobin levels during DCCT. Conclusion:The persistent difference in diabetic retinopathy between former intensive and conventional therapy ("metabolic memory") continues for at least 10 years but may be waning.

SUMMARY1. The effects of adrenaline on Ca distribution in isolated rat liver parenchymal cells were studied using a 45Ca exchange technique under steady-state conditions with respect to the net movement ofCa. 45Ca was initially introduced into the extracellular medium. The amount of cellular 45Ca was determined after separation ofthe cells from the medium by centrifugation through a solution which contained LaCl3 (to displace 45Ca bound to sites on the outside of the cell membrane) and silicon oil. At 1-3 and 2-4 mM-extracellular Ca, a stimulation of the initial rate of 45Ca exchange was observed in the presence of 10-7 M-adrenaline (or 10-6 M-phenylephrine) with a 7 % decrease, and no change, respectively, in the plateau of the exchange curve. The same degree of stimulation was observed when 45Ca was added at 1, 15, 30 or 45 min after the adrenaline.2. No stimulation of the initial rate of exchange was observed at 0-1 mMextracellular Ca, or at 2-4 mM-extracellular Ca in the presence of antimycin A and oligomycin. At 0'1 mM-Ca, a 60 % decrease in the plateau of the exchange curve was observed in the presence of adrenaline. The concentration of adrenaline (10-7 M) which caused half-maximal stimulation of the initial rate of 45Ca exchange at 1'3 mM-Ca was similar to that (2 x 10-7 M) which caused half-maximal decrease in the plateau at 0-1 mM-Ca.3. The addition of adrenaline to cells equilibrated with 45Ca at either 2-4 or 1-3 mM-Ca caused a transient loss of 45Ca followed by a return to a new steady state after 1 or 10 min, respectively. A loss of 45Ca was also observed at 0-1 mM-Ca, but the 45Ca content of the cells remained maximally depressed for at least 30 min.4. A non-linear least-squares iterative curve-fitting technique was used to demonstrate that (a) an equation which includes two exponential terms and (b) a parallel or series arrangement of three compartments of exchangeable Ca (the medium and two compartments associated with the cell) are consistent with each set of data obtained at 1-3 or 2-4 mM-Ca in the presence or absence ofadrenaline (or phenylephrine). G. J. BARRITT, J. C. PARKER AND J. C. WADSWORTH At 1P3 mM-Ca, the quantities of exchangeable Ca in the two kinetically defined cellular compartments were 0-04-0-07 and 034-4037 nmol per mg wet weight with rate constants for Ca outflow of 1P2-1P5 and 0-06-0-08 min-', respectively. 5. Analysis of the changes induced by adrenaline or phenylephrine showed that at 1-3 and 2-4 mM-extracellular Ca these agents caused a 75-150 % increase in the quantity ofexchangeable Ca in the small kinetically defined compartment and a 20 % decrease in the quantity of exchangeable Ca in the large kinetically defined compartment. These changes were mediated by an 80-160 % increase in the rate constant for the inflow of Ca from the medium to the small kinetically defined compartment, and either a 20-60 % decrease in the rate constant for inflow to, or a 20 % increase in the rate constant for outflow from, the large compartment.6. Replacement of the LaCl3 in the solution...