Spotlight commentary—Insulin therapy: Future directions

This spotlight commentary article aims to summarize insulin-centred therapeutics, including those currently in use and those under research. Seetharaman et al. offer an extensive review marking over a century since insulin's discovery, tracing its unparalleled impact on diabetes mortality and morbidity reduction.1 As a crucial anabolic hormone, it is continuously secreted in small, basal amounts as a hexamer, with additional postprandial peaks resulting from its pulse-like secretion. When glucose enters the pancreatic beta cells, it causes insulin vesicles to fuse with the cell membrane, releasing insulin into the bloodstream. After secretion, circulating insulin binds to tyrosine-kinase receptors on various cells, particularly in adipose and muscle tissues, operating through two main signalling pathways. The PI3K/Akt pathway is essential for insulin's metabolic effects and regulates several processes, including glucose uptake through GLUT4 translocation, glycogen synthesis by inhibiting GSK-3 and protein synthesis via mTOR. This pathway is crucial for normoglycemia maintenance and cell survival.1 Complementing this broad overview, Inoue et al. emphasized the effects via incretin hormones, such as GLP-1 (glucagon-like peptide-1) and GIP (gastric inhibitory peptide), on insulin secretion. This mechanism increases postprandial insulin secretion while simultaneously suppressing glucagon secretion from alpha pancreatic cells. The discovery of ‘incretin effect’ has led to significant advancements in diabetes therapy and has transformed the diabetes treatment landscape by offering glucose-dependent insulinotropic effects, minimal hypoglycaemia risk and potential benefits on weight and beta cell preservation.2 As reviewed by Seetharaman et al., insulin remains a cornerstone of diabetes management, essential for T1DM due to absolute insulin deficiency and often required in advanced T2DM to achieve adequate glycaemic and HbA1c control.1 Recent research demonstrates additional clinical applications of insulin beyond diabetes management, including its use in the treatment of calcium channel blocker (CCB) poisoning. Isbister et al. provide a foundational review on CCB overdose management, underscoring the importance of a multimodal treatment approach driven by haemodynamic monitoring.3 They advocate early initiation of high-dose insulin (HDI) euglycemia therapy to bolster myocardial contractility, supplemented by catecholamines and vasopressors to stabilize patients in shock. Mégarbane and Rietjens consider HDI as a promising option for CCB overdose-induced myocardial suppression, although they note it may not be suitable as first-line treatment for all patients, and recommend combining it with vasopressors.4, 5 The probable mechanism of HDI action involves shifting energy metabolism from fatty acids to glucose utilization when carbohydrate availability is reduced because CCB decreases insulin secretion.4, 5 Chan et al. caution that HDI therapy can lead to sustained elevation of insulin concentrations, increasing the risk of hypoglycaemia and electrolyte disturbances and should be used cautiously. They also recommend the use of low-dose insulin (1–2 μ/kg) in patients with left ventricular dysfunction and to avoid HDI in patient with pre-existing obstructive cardiomyopathy.6 Additionally, they emphasize the difference between poisoning with dihydropyridines and nondihidropiridines and recommend starting treatment of CCB overdose with HDI alongside vasopressors which may improve brain perfusion, reduce fluid overload and limit peripheral vasodilation.6 In conclusion, HDI treatment should be adjusted to each patient's specific condition and symptoms because it is difficult to choose a single best treatment due to limited studies and common use of multiple therapies together in CCB overdose. Furthermore, article by Seetharaman et al. reviews different formulations of insulin that can be combined in various therapy regimens to customize treatment for each patient individually. The gold standard for treating T1DM is intensified insulin therapy, which mimics natural insulin secretion using basal and prandial insulins. Long-acting insulins like glargine or degludec are typically given once or twice daily, with doses adjusted based on morning glucose levels. This flexible approach improves adherence and glycaemic control, allowing for corrective bolus doses as needed. In contrast, premixed insulins offer less dosing flexibility. There are also advanced therapies, such as continuous subcutaneous insulin infusion (CSII). This way of dosing improves insulin absorption and reduces variability in insulin delivery that may otherwise occur.1 The study by Milder et al. highlights contemporary prescribing patterns and clinical decision-making in type 2 diabetes management. As metformin remains the cornerstone first-line therapy globally, understanding the optimal timing and choice of add-on therapies, such as insulin, is critical for addressing the progressive nature of T2DM and the challenge of sustained glycaemic control.7 The work by Koslover et al. further enhances understanding by detailing pharmacological principles of metformin, highlighting it as first line of treatment for T2DM.8 This approach is commonly referred to as basal oral therapy. Inoue et al. provide a rigorous model-based meta-analysis on the efficacy of incretin-based therapies and SGLT-2 inhibitors as add-ons to metformin in type 2 diabetes management, affirming their additive glycaemic benefits and positioning within treatment algorithms. The insulin therapy in both T1DM and T2DM is associated with complications such as hypoglycaemia and injection site reactions, including redness, swelling and lipodystrophy, with weight gain being another frequent side effect. Less common but more serious side effects are allergic reactions.1 As reviewed by Teo et al., one of the problems concerning insulin use is nonadherence among people with type 2 diabetes, which leads to poor glycaemic control and progression of T2DM.9 In this work, the author identified factors influencing medication nonadherence using the Capability, Opportunity, Motivation and Behaviour (COM-B) model. These factors include insulin injections, patient's understanding of diabetes, medication cost, poor healthcare provider relationship, habit and perceived lack of medication necessity.9 Despite existing insulin options for T1DM and T2DM, research continues into improved formulations and delivery systems, including pumps and artificial pancreas technologies. Novo Nordisk's ONWARDS phase 3 clinical trial evaluated Icodec, a once-weekly insulin. Approved in the EU in March 2024 as AWIQLI® for T2DM, Icodec showed greater HbA1c reduction than once-daily degludec in insulin-naive patients over 26 weeks, with no weight change, but a higher rate of hypoglycaemia.10 Insulin Icodec (AWIQLI®) represents the first approved insulin analogue intended for once-weekly dosing, which is anticipated to enhance medication adherence and, consequently, improve glycaemic control and long-term benefits.10 Insulin efsitora alfa is an investigational ultralong-acting immunoglobulin G (IgG) Fc-fusion insulin, with a pharmacokinetic half-life of 17 days.11 In a single-dose study involving patients with type 2 diabetes (T2D), a dose-dependent reduction in fasting plasma glucose levels was observed, which was maintained for at least 5 days. The glucose profiles remained consistent over time and were comparable to those using insulin glargine in a 6-week ascending dose study. Additionally, the same 6-week study reported fewer episodes of hypoglycaemia with insulin efsitora alfa (47%) compared to insulin glargine (54%).11 In 2023, the FDA approved the first allogeneic cellular therapy for treating type 1 diabetes: Lantidra (donislecel).12 This therapy involves infusing donor islet cells into the patient's pancreas to restore insulin production. It primarily targets individuals who experience severe hypoglycaemic episodes or have hypoglycaemia unawareness, offering a less invasive alternative to pancreas transplantation. The treatment has demonstrated long-term benefits, with approximately two-thirds of participants maintaining good glycaemic control up to 6 years later.13 Its safety profile is consistent with the typical risks associated with cellular therapies, notably long-term immunosuppression. In addition, beta cell transplantation using human embryotic stem cell (hESC)-derivated β offers a promising alternative to scare donor islet for T1DM treatment. Ongoing clinical trials suggest that these lab-grown insulin-producing cells could soon become an effective therapy for patients.1 Innovative oral insulin formulations have recently been developed, such as Fc receptor (FcRn)-targeted liposomes with a glucose-sensitive hyaluronic acid shell, enhancing postprandial glycaemic control and medication adherence. A notable example is IN-105 (Tregopil), a fast-acting oral insulin analogue by Biocon that reaches peak concentration in 20 min, with phase 2 and 3 studies showing a favourable safety profile and early postprandial effects similar to insulin aspart, though its late postprandial efficacy is reduced.14 Collectively, these articles summarize a wide range of insulin formulations already available, alongside the continued development of new therapeutics. As emphasized by Seetharaman et al., emerging therapies, such as small interfering RNA (siRNA) therapy, and anti-CD3 immunotherapy, are also being explored.1 In diabetes, siRNA-based therapies show promise by targeting genes involved in β-cell destruction, insulin resistance, and hepatic insulin action. As rapid progress is being made in treating other diseases, siRNA is emerging as a potential therapeutic option for diabetes, attracting increasing research interest.1 Open access publishing facilitated by Sveuciliste u Zagrebu, as part of the Wiley - National and University Library in Zagreb Consortium Croatian Academic and Research Libraries Consortium agreement.