Insulin amyloidosis poses challenges in diabetes therapy and biopharmaceuticals handling. Here, functionalized manganese-based nanoparticles (MnCO3@TEG, MnCO3@OAm, MnOHCO3@TEG, MnO2/Mn2O3@TEG, and Mn3O4@PG) were synthesized via solvothermal routes and evaluated in vitro using a fresh insulin aspart formulation (NovoRapid) and a separately aged insulin glargine formulation (Lantus). Structural and colloidal characterization (ATR-FTIR, XRD, TGA, DLS, zeta potential) confirmed phase purity and distinct surface profiles. In the fresh insulin aspart system, all nanoparticles extended the nucleation lag phase, with MnCO3@TEG delaying fibrillogenesis from 21.16 h to 105.41 h. In the aged insulin glargine system containing pre-existing ThT-positive aggregates, small, negatively charged nanoparticles (MnOHCO3@TEG, Mn3O4@PG) re-established a distinct lag phase and suppressed further aggregation. In the ThT decay assays, highly dispersed Mn3O4@PG produced the largest decrease in amyloid-associated fluorescence, to ~40% of the initial signal, whereas large clusters (MnO2/Mn2O3@TEG, 624 nm) produced a smaller decrease; limited access arising from steric effects is one possible explanation. Additionally, structural hydroxyl groups and high colloidal stability enabled MnOHCO3@TEG (-38.7 mV) to exhibit superior catalase-like H2O2 scavenging (42.27% inhibition at 250 μg/mL). Overall, fine-tuning nanoparticle size, surface charge, and core composition may offer a promising dual-action strategy for targeting insulin amyloidosis and associated oxidative stress across different stages of fibril formation, while further structural characterization and biological safety studies are needed to establish its therapeutic relevance.

Diabetes affects 589 million adults globally, 80% of whom live in low- and middle-income countries (LMICs). Although modern diabetes therapies such as sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1 RA) improve cardiovascular and renal outcomes and analog insulins help reduce risk of hypoglycemia, affordability remains a barrier to equitable access to these agents. This article analyzes how India has reduced the costs of modern diabetes therapies and improved affordability, pricing trends, regulatory frameworks, pharmaceutical manufacturing policies, and public distribution initiatives in India. India has achieved approximately 60%-90% price reductions for SGLT2i and GLP-1 RA following patent expiry, driven by strong generic competition, structured price regulation, and governmental support, leading to much greater access to these agents. Costs of insulin biosimilars of glargine are also much lower in India, making them more affordable. Cross-national price comparisons show 15- to 65-fold differences between Indian generic prices and U.S. list prices for selected agents. On the policy front, government initiatives like the Ayushman Bharat have considerably helped to increase accessibility for the poor and vulnerable sections of the society. Despite these advances, challenges remain, particularly in rural areas where modern therapies may still be unaffordable or unavailable. Moreover, due to multiple manufacturers providing generics, there could be differences in quality and pharmacokinetics, even between the branded generics. However, India's experience demonstrates that affordable access to modern diabetes medicines is achievable through coordinated pharmaceutical policy, regulatory efficiency, and enhanced manufacturing capacity, offering lessons for LMICs and high-income countries facing high drug costs.

Background/Objectives: Bedtime snacks are frequently used in youth with type 1 diabetes (T1D) to reduce nocturnal hypoglycemia risk; however, the optimal macronutrient composition remains uncertain, particularly in those treated with multiple daily injections (MDI). This randomized crossover study evaluated whether standardized whole-food bedtime snacks with different macronutrient profiles yield distinct overnight continuous glucose monitoring (CGM) patterns. Methods: Twelve children and adolescents with T1D using glargine/lispro-based MDI completed four bedtime snack protocols: carbohydrate-only (CHO), carbohydrate-plus-protein (CHO + PRO), carbohydrate-plus-fat (CHO + FAT), and carbohydrate-plus-fiber (CHO + FIB). Each snack was consumed for three consecutive nights at 21:00 without additional bolus insulin. Blinded CGM data were analyzed for 21:00-09:00 and for predefined postprandial intervals. Because no a priori sample size calculation was performed, the study was conducted as an exploratory pilot trial. Nights per snack were averaged before within-subject comparisons. Results: Overnight time in range (TIR; 70-180 mg/dL) varied across protocols (p = 0.014), with the highest TIR following CHO + PRO (85.8% ± 12.1%) and the lowest following CHO + FAT (70.9% ± 19.1%); however, adjusted whole-night pairwise comparisons were not statistically significant. Differences were more pronounced during the first 6 h following snack consumption, when CHO + PRO was associated with higher TIR than CHO + FAT (91.2% ± 7.6% vs. 71.4% ± 20.8%; adjusted p = 0.011). Moreover, CHO + PRO was associated with lower peak-to-nadir glucose amplitude than CHO + FAT (88.1 ± 24.9 vs. 123.9 ± 36.5 mg/dL; adjusted p = 0.041). Hypoglycemic and hyperglycemic event rates did not significantly differ across protocols. Conclusions: In children and adolescents with T1D using MDI, bedtime snack composition was associated with differences in early nocturnal glycemic stability. CHO + PRO demonstrated higher early night TIR and lower glucose amplitude than CHO + FAT; however, event-based safety outcomes did not significantly differ. Because only two pairwise comparisons remained significant after correction for multiple testing and the four snacks were not matched for energy content, these findings should be regarded as preliminary and hypothesis-generating; in particular, they do not demonstrate that any snack composition protects against nocturnal hypoglycemia. Confirmation is required in larger, adequately powered studies that include energy-matched snacks and a no-snack control condition.

In type 2 diabetes (T2DM), glucose-lowering is typically achieved by enhancing the capacity of the pancreatic beta-cells to compensate for ambient insulin resistance. Impaired processing of proinsulin, as reflected by an elevated ratio of fasting serum proinsulin to C-peptide (PI:C), is a marker of beta-cell stress but not compensation. Indeed, it is unclear whether enhancing proinsulin processing alone can improve glycemic control in T2DM. We thus sought to evaluate the impact of proinsulin processing on glucose-lowering in a recently reported clinical trial in which 90 adults with T2DM (mean A1c 6.5% ± 0.7%) were randomized to 8-wk treatment with 1) basal insulin glargine (Glar), 2) glargine plus thrice-daily meal insulin lispro (Glar/Lispro), or 3) glargine plus twice-daily administration of the glucagon-like peptide-1 receptor agonist exenatide (Glar/Exe). At baseline, after 8-wk treatment and again after subsequent 12-wk washout, participants underwent assessment of insulin sensitivity/resistance [Matsuda index; Homeostasis Model of Assessment of Insulin Resistance (HOMA-IR)], beta-cell compensation (Insulin Secretion-Sensitivity Index-2; insulinogenic index/HOMA-IR; ΔCpeptide0-120/Δglucose0-120 × Matsuda; ΔISR0-120/Δgluc0-120 × Matsuda), and proinsulin processing (fasting PI:C). At 8-wk, both A1c (6.2% ± 0.4% vs. 5.9% ± 0.5% vs. 5.8% ± 0.4%, P = 0.007) and fasting PI:C (0.013 ± 0.011 vs. 0.009 ± 0.006 vs. 0.008 ± 0.005, P = 0.01) progressively decreased from Glar to Glar/Lispro to Glar/Exe, with no differences between the groups in Matsuda index, HOMA-IR, or any of the four measures of beta-cell compensation. In mediation analyses, fasting PI:C emerged as the sole biologic mediator of the respective A1c treatment effects of Glar/Lispro (P = 0.03) and Glar/Exe (P = 0.01) vs. Glar. In conclusion, it thus emerges that glucose-lowering in T2DM may be achieved through improved proinsulin processing without better beta-cell compensation.NEW & NOTEWORTHY In this report, mediation analyses identify the fasting proinsulin-to-C-peptide ratio as a biologic determinant of the A1c treatment effect observed in a recently reported clinical trial in which the study interventions had no differential effect on pancreatic beta-cell compensation. These findings suggest that glucose-lowering may be achieved through improved proinsulin processing without better beta-cell compensation, supporting consideration of proinsulin biology as a potential novel therapeutic target in the management of type 2 diabetes.

People with type 2 diabetes in Asia have heterogeneous phenotypes but share common features of young age-at-diagnosis, low body mass index, low pancreatic beta-cell capacity, rapid decline in insulin secretion as well as visceral and ectopic fat excess. Cardiovascular diseases are the leading causes of mortality in people with diabetes. In clinical trial settings, despite receiving protocol-driven care, Asians had higher risk of chronic kidney disease than non-Asians. Aging and improved survival in people with diabetes continue to drive the epidemic of diabetes. People with old age, long disease duration and complications might benefit from both insulin to optimize glucose control and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for cardiovascular-renal protection. Complex therapies pose challenges in administration and adherence where fixed-dose combination such as basal insulin plus GLP-1 RA may improve safety, effectiveness and acceptability. In this narrative review, we summarized the efficacy and safety data from randomized controlled trials using iGlarLixi, a fixed-ratio combination of insulin glargine 100 U/mL (iGlar) and lixisenatide (Lixi), a short acting GLP-1 RA, studied widely in Asians. We discussed the guidelines on the use of this fixed-ratio combination illustrated by real-world case studies in older Asian adults with young-onset type 2 diabetes.