Vitamin D potentiation of metformin hepatoprotective activities: Concurrent targeting of carbohydrate enzymatic pathways and PCSK9/AGEs-regulated oxidative stress mechanisms in type 2 diabetic male Wistar rats

Abstract

Background: Emerging evidence indicates that metformin-based combination therapy may offer better glycemic control and improved tolerability compared to diabetes monotherapy. Building on this, vitamin D was considered a potential adjunct to metformin for managing type 2 diabetes. Although vitamin D is primarily recognized for its role in calcium regulation, it also appears to influence glucose metabolism and other non-skeletal functions. Therefore, this study was designed to evaluate the hepatoprotective effects of vitamin D and metformin in diabetic rats.

Methodology: Thirty (30) male Wistar rats were randomized into five treatment groups as follows: control, diabetes (DM) untreated, DM treated with vitamin D (25 µg/kg), DM treated with metformin (180 mg/kg), and DM treated with both vitamin D (25 µg/kg) and metformin (180 mg/kg). All treatments were via the oral route and lasted for 28 days.

Results: Vitamin D and/or metformin improved glucose and lipid imbalances caused by diabetes. These benefits were linked to enhanced activity of key liver enzymes involved in glucose metabolism, including hexokinase, phosphofructokinase, pyruvate kinase, glucose-6-phosphate dehydrogenase, G-6-phosphatase, and lactate dehydrogenase. Additionally, treatment with vitamin D and/or metformin counteracted diabetes-induced increases in pro-oxidant levels, restored both enzymatic and non-enzymatic antioxidant defenses, and reduced inflammation. This oxido-inflammatory response appeared to be connected to oxidative signaling mediated by proprotein convertase subtilisin/kexin type 9 (PCSK9), highlighting a potential mechanism underlying the protective effects of these therapies.

Conclusion: Vitamin D enhanced the antidiabetic effects of metformin by further improving the activity of carbohydrate-metabolizing enzymes and modulating PCSK9-mediated oxidative signaling. This suggests that vitamin D can boost metformin's efficacy in regulating glucose-lipid metabolism and reducing oxidative stress in diabetes.

Keywords: Antioxidant defense; Combination therapy; Glucose metabolism; Insulin resistance; Liver dysfunction; Type 2 diabetes complications.