Vitamin B12 Ameliorates Diabetic complications: potential role of Circadian pathway and the NAMPT–NAD?–SIRT1 Pathway

Vitamin B12 is emerging as a potential therapeutic agent for diabetes-associated complications, with roles in redox balance, methylation, and mitochondrial function. Recent evidence suggests that B12 may also regulate circadian rhythms, which are closely linked to metabolic health. However, the connection between B12, circadian regulation, and protection against early diabetic liver and kidney damage remains unclear. Diabetic (Elmo1H/HIns2Akita/+) and non-diabetic (Elmo1HH) mice were treated with or without Vitamin B12 (10 mg/kg/day) in drinking water for 8 weeks, starting at 8 weeks of age. At 16 weeks, blood, liver, and kidney samples were collected for biochemical, transcriptomic, and histological analysis. Vitamin B12 significantly reduced serum triglycerides, improved mesangial expansion in kidneys, and improved liver cellular structure in diabetic mice. B12 also modulated circadian gene expression, downregulating Clock, Bmal1, and Npas2 (40–50%) while upregulating Cry1/2, Per1–3, Nr1d2, and Dbp in both liver and kidney (130–180%), regardless of diabetic status. Importantly, B12 significantly increased Nampt expression in the liver (p = 0.0062) and kidney (p = 0.0013) of diabetic mice, suggesting enhancement of the NAMPT–NAD?–SIRT1 axis, a key pathway for mitochondrial redox control and circadian stability. Additionally, B12 upregulated several solute carrier (SLC) transporters involved in nutrient and ion homeostasis. Together, these findings indicate that Vitamin B12 offers early protective effects against diabetic complications by improving metabolic balance and enhancing Nampt expression, supporting its potential role in preventing liver and kidney damage via circadian and NAD?-dependent mechanisms. Overall design: RNA Seq profiling of liver and kidney tissues of non-diabetic Elmo1H/HIns2+/+ and diabetic Elmo1H/HIns2Akita/+ mice were tretaed with and without vitamin B12 via drinking water.