Aims/hypothesis Genetic studies show coupling of genes affecting beta cell function to type 1 diabetes, but hitherto no studies on whether beta cell dysfunction could precede insulitis and clinical onset of type 1 diabetes are available. Methods We used 40-day-old BioBreeding (BB) DRLyp/Lyp rats (a model of spontaneous autoimmune type 1 diabetes) and diabetes-resistant DRLyp/+ and DR+/+ littermates (controls) to investigate beta cell function in vivo, and insulin and glucagon secretion in vitro. Beta cell mass was assessed by optical projection tomography (OPT) and morphometry. Additionally, measurements of intra-islet blood flow were performed using microsphere injections. We also assessed immune cell infiltration, cytokine expression in islets (by immunohistochemistry and qPCR), as well as islet Glut2 expression and ATP/ADP ratio to determine effects on glucose uptake and metabolism in beta cells. Results DRLyp/Lyp rats were normoglycaemic and without traces of immune cell infiltrates. However, IVGTTs revealed a significant decrease in the acute insulin response to glucose compared with control rats (1685.3 ± 121.3 vs 633.3 ± 148.7; p < 0.0001). In agreement, insulin secretion was severely perturbed in isolated islets, and both first- and second-phase insulin release were lowered compared with control rats, while glucagon secretion was similar in both groups. Interestingly, after 5–7 days of culture of islets from DRLyp/Lyp rats in normal media, glucose-stimulated insulin secretion (GSIS) was improved; although, a significant decrease in GSIS was still evident compared with islets from control rats at this time (7393.9 ± 1593.7 vs 4416.8 ± 1230.5 pg islet⁻¹ h⁻¹; p < 0.0001). Compared with controls, OPT of whole pancreas from DRLyp/Lyp rats revealed significant reductions in medium (4.1 × 10⁹ ± 9.5 × 10⁷ vs 3.8 × 10⁹ ± 5.8 × 10⁷ μm³; p = 0.044) and small sized islets (1.6 × 10⁹ ± 5.1 × 10⁷ vs 1.4 × 10⁹ ± 4.5 × 10⁷ μm³; p = 0.035). Finally, we found lower intra-islet blood perfusion in vivo (113.1 ± 16.8 vs 76.9 ± 11.8 μl min⁻¹ [g pancreas]⁻¹; p = 0.023) and alterations in the beta cell ATP/ADP ratio in DRLyp/Lyp rats vs control rats. Conclusions/interpretation The present study identifies a deterioration of beta cell function and mass, and intra-islet blood flow that precedes insulitis and diabetes development in animals prone to autoimmune type 1 diabetes. These underlying changes in islet function may be previously unrecognised factors of importance in type 1 diabetes development.

Dosing accuracy, activation force, maximum dose-setting torque, hold force, and injection time were determined for DuraTouch, a reusable insulin pen injector designed to optimize usability, across a range of insulin doses (1, 40, and 80 units) under various temperature and storage conditions. Additionally, a life-cycle assessment of DuraTouch was performed to determine its environmental impact. Dosing accuracy remained consistent across all conditions tested at each dose. Activation force, maximum dose-setting torque, hold force, and injection time remained comparable irrespective of test conditions. Per DuraTouch device per year, the total carbon footprint ranged from 482.2 g to 952.8 g of CO ₂ equivalents across geographical regions assessed, and the total plastic footprint was 0.47 kg including packaging, Penfill cartridge consumption, and use of NovoFine needles. These findings suggest that DuraTouch is suitable for use across a broad range of environments, and support its position as an alternative to disposable insulin pen injectors.

The global burden of diabetes continues to rise, resulting in a concomitant increase in the global demand for insulin replacement therapies. Subcutaneous insulin administration using pen injectors is one of the most common insulin delivery methods; these devices are often preferred over vial and syringe administration by individuals with diabetes owing to their convenience and ease of use, and by clinicians owing to enhanced user adherence and high dose accuracy. However, prefilled insulin pen injectors are commonly made of plastic and many are disposable; consequently, both their production and use are associated with a high carbon footprint and substantial medical waste through poor recycling infrastructures, posing a growing environmental concern. Historically, producing durable insulin pen injectors required high-quality metal components, which are more environmentally taxing despite being reusable. Conversely, plastic has a lower environmental footprint per unit but conventional plastic pen injectors have lacked durability, leading to greater consumption overall. Therefore, reusable insulin pen injectors that can be used repeatedly for several years, while also being easy to use and accurate, are essential for sustainable diabetes management. Novo Nordisk has developed several insulin pen injectors, such as NovoPen (NP) 4 (a reusable pen part of the NP family), FlexTouch (a disposable pen) and, more recently, DuraTouch (DT; a reusable pen). Here, we describe the technical attributes of DT using other pen injectors manufactured by Novo Nordisk as contextual comparators to illustrate how DT may meet users’ functional needs, while helping to reduce the environmental burden associated with the use of insulin pen injectors.

There is a preponderance for genes involved in ß-cell function among gene variants associated with future risk of type-2 diabetes (T2D). ß-cell function is controlled by metabolism of glucose, yielding signals triggering and amplifying insulin secretion. Perturbed ß-cell metabolism is a likely, albeit not proven, cause of T2D. We profiled metabolites in islets from T2D and non-diabetic donors, and found altered levels of mitochondrial metabolites in T2D. Analysis of genes encoding proteins localized to mitochondria (MitoCarta) by RNA-seq in an extended sample of islets revealed genes whose expression was associated with glycaemia- and/or BMI. Expression of two of these, α-methylacyl-CoA racemase (AMACR) and methylmalonyl-CoA mutase (MUT), was influenced by genetic variation (cis-eQTL). Silencing of AMACR and MUT in insulin-secreting cells reduced hormone secretion by 40-50%. In conclusion, by linking the metabolome to the transcriptome, we showed that perturbed mitochondrial metabolism is a feature of ß-cell dysfunction in T2D. [Supplementary material is available for this article.]