ObjectivesTo evaluate the efficacy of two different formulations of glucagon given by three different routes (subcutaneous; SQ, rectal, intranasal; IN) for correcting insulin-induced hypoglycaemia in cats and to describe any adverse effects and compare the time required for administration by each route.MethodsA randomized, nonblinded, sham-controlled crossover study was conducted in six healthy cats, with a 7-day washout period between treatments. Hypoglycemia was induced using a continuous rate infusion (CRI) of rapid-acting Lispro insulin. Glucagon nasal powder (single-dose, ready-to-use) was given intranasally and rectally and compared to subcutaneous glucagon injection and intranasal sham control. Blood glucose concentration (BG) was measured from samples collected at baseline (T-15), after induction of hypoglycemia (T0), and at 5-minute intervals for 30 minutes (min), and then at 15 min intervals for 1 hour (h) following glucagon administration. Plasma glucagon and potassium (K+) concentrations were measured at T-15, T0, and T15 and T30 following glucagon administration. The time taken to prepare and administer each treatment was recorded.ResultsMedian BG was 2.6 mmol/L at T0 and increased significantly following glucagon administration by all routes, reaching peak median concentrations of 11.2 mmol/L (intranasal), 9.7 mmol/L (rectal), and 10.15 mmol/L (subcutaneous). Plasma glucagon concentrations increased markedly by T15, with the highest concentrations observed following intranasal administration (1562 pmol/L), followed by subcutaneous (191.7 pmol/L) and rectal (158 pmol/L) routes of administration. Plasma potassium decreased following insulin administration and increased modestly by T30 following glucagon administration by all routes. No serious adverse effects occurred following glucagon administration.Conclusions and Clinical ImportanceTransmucosal glucagon effectively restores BG towards baseline following insulin-induced hypoglycemia with minimal side effects. The IN route resulted in the highest plasma glucagon and BG concentrations compared to the rectal and subcutaneous routes of administration. Further studies are needed to quantify the efficacy and safety of transmucosal glucagon in diabetic cats in response to spontaneous insulin-induced hypoglycemia.

The speed of insulin therapy remains fundamentally constrained by the self-association of insulin into hexamers. Here, a materials-based strategy is introduced to stabilize HALQ, a monomeric insulin analog, using a non-interacting inulin-derived excipient (BN-Inu). BN-Inu markedly mitigates aggregation and maintains HALQ stability for 96 h under stress and for at least 30 days at room temperature. In a porcine model of diabetes, monomeric HALQ exhibits significantly accelerated absorption and a shorter duration of action than the ultrarapid insulin aspart Fiasp. This "fast-on, fast-off" profile is consistent with faster clearance from the subcutaneous depot, more closely synchronizes with endogenous prandial insulin physiology. Addition of clinically used absorption enhancers further accelerates its pharmacokinetic profile, producing a faster time-to-peak and reduced exposure relative to ultrarapid insulin lispro Lyumjev in this animal model. Furthermore, translation to human physiology was evaluated through pharmacokinetic modeling, which predicts that HALQ could reduce time-to-peak from 60 to 39 min and shorten duration of action from 143 to 84 min in humans. These simulations suggest the potential utility of achieving a step-change in the speed of insulin therapy. These findings demonstrate that monomer-stabilizing excipients enable next-generation ultrafast insulin formulations with the potential to improve glycemic control in diabetes.

Background/Objectives: Inflammatory bowel disease (IBD) represents a growing therapeutic challenge, and the identification of novel treatment strategies remains an unmet clinical need. Drug repurposing offers a pragmatic and cost-effective alternative to de novo drug development. This study aimed to identify candidate drugs for repurposing in IBD through inverse signal detection within a large spontaneous pharmacovigilance database. Methods: In this observational, retrospective pharmacovigilance study, data from the FDA Adverse Event Reporting System (FAERS) were analyzed using OpenVigil 2.1. Drugs inversely associated with IBD were identified based on a ROR < 1 and an adjusted p-value < 0.05. Candidates were subsequently filtered to exclude agents with implausible indications, unfavorable pharmacokinetic profiles, or recognized contraindications to use in IBD. Although this screening process yielded a broader set of repurposing candidates across multiple drug classes, the present study focused specifically on antidiabetic medications, which were subjected to a targeted literature review evaluating their immunomodulatory properties, anti-inflammatory mechanisms, and existing preclinical and clinical evidence in the context of IBD. Results: Of 3585 initial drug-event combinations evaluated, 73 candidates met predefined criteria for statistical significance, pharmacokinetic feasibility, and clinical relevance. Within this broader pool, ten antidiabetic agents which demonstrated meaningful inverse signal strength were selected for in-depth analysis: dulaglutide (ROR 0.181, 95% CI 0.136-0.242), insulin lispro (ROR 0.206, 95% CI 0.161-0.263), insulin glargine (ROR 0.246, 95% CI 0.205-0.295), insulin (ROR 0.340, 95% CI 0.295-0.390), insulin aspart (ROR 0.349, 95% CI 0.267-0.455), empagliflozin (ROR 0.400, 95% CI 0.311-0.514), liraglutide (ROR 0.419, 95% CI 0.319-0.552), metformin (ROR 0.446, 95% CI 0.407-0.489), sitagliptin (ROR 0.460, 95% CI 0.376-0.563), and semaglutide (ROR 0.622, 95% CI 0.507-0.764). The subsequent literature review discussed relevant immunomodulatory and anti-inflammatory properties for each of these agents, providing a mechanistic rationale for their potential therapeutic role in IBD. Conclusions: This study identifies antidiabetic drugs as plausible repurposing candidates for IBD, supported by both pharmacovigilance-derived inverse signals and a body of mechanistic and clinical literature suggesting shared pathophysiological pathways between the two conditions. However, it should be acknowledged that the clinical evidence supporting the therapeutic efficacy of several candidates remains variable or incomplete, and robust interventional data are largely lacking. Ultimately, the findings of this study generate testable hypotheses and highlight a set of candidate therapies that warrant dedicated experimental and clinical investigation, including well-designed prospective trials, to determine their true therapeutic potential in IBD management.

Type 2 diabetes mellitus is a highly prevalent chronic disease. In patients with comorbid psychiatric disorders, insulin may become a means of suicide due to its potentially lethal effects when overdosed. Continuous glucose monitoring (CGM) systems have proven effective for glycemic control, but their role in suicide prevention is less explored. We report the case of a 68-year-old woman with type 2 diabetes, borderline personality disorder, and major depressive disorder, who attempted suicide by injecting 90 units of lispro insulin and ingesting 12 tablets of lorazepam. The patient's daughter, monitoring her mother's glucose levels via CGM, detected a sudden hypoglycemic drop and intervened promptly, preventing a fatal outcome. The patient was treated in the emergency department with intravenous dextrose and supportive care, was later admitted to the ICU, and followed by psychiatric evaluation and pharmacological adjustments. Her psychiatric treatment plan was modified to reduce central nervous system depressants and reinforce outpatient psychiatric follow-up. At a one-month follow-up, the patient reported clinical improvement, denied suicidal ideation, and remained under psychiatric care. This case underscores the utility of CGM not only for glycemic control but also as an emergency detection tool in high-risk psychiatric patients, emphasizing the value of integrating digital health with psychiatric monitoring and family support.

In the year 2000 the first once daily long-acting bioengineered insulin analogue (LAIA), insulin glargine ('glargine'), a true basal insulin (BI), became available for clinical use. This led to the decline in the 50-year-old era and prominence of the intermediate-acting insulins, neutral protamine Hagedorn (NPH) and lente, requiring twice daily administration to control the basal metabolism of people with type 1 diabetes (T1DM) and type 2 diabetes (T2DM). This milestone bridged the gap between regimens involving unmodified human insulins of the previous century to those referred to as using 'designer insulins', with the introduction 4 years previously of the meal-time analogue, insulin lispro. The rapid gain in popularity of glargine is explained by its clinical benefits (once-daily dosing, titration to achieve improved pre-breakfast plasma glucose, with a lower risk of nocturnal hypoglycaemia compared to NPH, and less frequent blood glucose monitoring). These benefits correlate with the pharmacokinetic/pharmacodynamic characteristics of insulin glargine being closer to physiological BI supply. In T2DM glargine changed the paradigm of insulin substitution by embedding the concept of 'treating-to-target', by starting BI 'early', with focus on near-normal fasting plasma glucose prior to the introduction of prandial insulin, and more recently in combination with GLP-1 receptor agonists. These practices/principles have continued with the introduction of additional innovative LAIAs for once-daily or indeed weekly use. Today glargine remains in widespread worldwide use in people with T1DM and T2DM, is often the initial BI used, while it serves as a reference against which other LAIAs are tested in clinical trials.

Mothers with diabetes using insulin may nurse their infants. Exogenous insulin is excreted into breastmilk, including newer biosynthetic insulins (e.g., aspart, deglutec, detemir, glargine glulisine, lispro). Even direct administration of recombinant insulin orally to preterm infants is safe.[1] Insulin is a normal component of breastmilk and may decrease the risk of type 1 diabetes in breastfed infants.[2-5] Women taking insulin for type 2 diabetes have higher milk insulin levels than those controlled with diet alone.[6] Insulin requirements are reduced postpartum in women with type 1 diabetes,[7,8] although postpartum insulin requirements do not significantly differ between breastfeeding and non-breastfeeding women.[9] In general, insulin requirements are 30% to 50% lower than prepregnancy dosages immediately postpartum. Then the insulin requirements during breastfeeding average 21% lower than prepregnancy dosages, but there is wide variation.[8,10] In one study, insulin requirements were lower than prepregnancy dosage only during the first week postpartum: 54% of prepregnancy dosage on day 2 and 73% on day 3 postpartum. On day 7 postpartum, insulin dosage returned to prepregnancy requirements.[11] Another study found that dosage requirements did not return to normal for up to 6 weeks in some mothers.[12] A third study found that at 4 months postpartum, patients with type 1 diabetes who exclusively breastfed had an average of 13% lower (range -52% to +40%) insulin requirement than their prepregnancy requirement.[13] A retrospective case-control study found a 34% decrease in postpartum insulin requirement compare to preconception values. There was a nonsignificant trend towards lower requirements in exclusively breastfeeding mothers compared to partial or full formula feeding.[6] A small study found that mothers on insulin pumps were found to have an average basal insulin rates 14% lower and carbohydrate-to-insulin ratios were 10% higher than pre-pregnancy settings.[14] Breastfeeding appears to improve glucose postpartum glucose tolerance in mothers with gestational diabetes mellitus and in normal women.[15-17] A small, well-controlled study of women with type 1 diabetes mellitus using continuous subcutaneous insulin found that the average basal insulin requirement in women with type 1 diabetes who breastfed was 0.21 units/kg daily and the total insulin requirement was 0.56 units/kg daily. In similar women who did not breastfeed, the basal insulin requirement was 0.33 units/kg daily and the total insulin requirement was 0.75 units/kg daily. The 36% lower basal insulin requirement was thought to be caused by glucose use for milk production.[18] Lactation onset occurs later in patients with type 1 diabetes than in women without diabetes, with a greater delay in mothers with poor glucose control.[11,19] Mothers with type 1 diabetes also discontinue nursing at a higher rate during the first week postpartum.[20-22] Women with any form of diabetes during pregnancy had more problems with low milk supply than women without diabetes.[23] Once established, lactation persists as long in mothers with diabetes as in mothers without diabetes.[19,24] However, as in women without diabetes, smoking has a strong negative impact on lactation among mothers with type 1 diabetes.[13,25] Other factors that have been identified as causes of shorter duration of breastfeeding among type 1 diabetic patients are more frequent caesarean sections and earlier delivery.[26] Among patients with gestational diabetes, those treated with insulin have a delayed onset of lactogenesis II compared to those not treated with insulin.[27]

Recombinant insulin, used to treat diabetes, has an enormous impact on diabetes management. However, this essential hormone is prone to aggregation during transportation and storage, reducing its efficacy in glycemic control. To prevent insulin aggregation, here we repurposed an antifungal drug called Nystatin (Nys) identified through a virtual screening of 5500 FDA-approved drugs. Nys effectively inhibited the aggregation of insulin under physiological conditions. Nys-treated insulin was completely soluble, retained its native secondary structure, and was nontoxic to HEK293T cells. Notably, this drug completely abrogated fibrillation of fast-acting insulin formulations Aspart and Lispro, as well as slow-acting insulin, Glargine. The ability of insulin formulations to activate the insulin receptor was maintained after Nys treatment. The efficacy of Nys-treated formulations in maintaining glycemic control was further validated in a diabetic rat model. Thus, this FDA-approved drug has the potential to be used in commercial insulin formulations to maintain stability and activity while preventing its aggregation for an extended period.