Diabetes-induced hepatic pathogenic damage, inflammation, oxidative stress, and insulin resistance was exacerbated in zinc deficient mouse model.

Abstract

OBJECTIVES:

Zinc (Zn) deficiency often occurs in the patients with diabetes. Effects of Zn deficiency on diabetes-induced hepatic injury were investigated.

METHODS:

Type 1 diabetes was induced in FVB mice with multiple low-dose streptozotocin. Hyperglycemic and age-matched control mice were treated with and without Zn chelator, N,N,N',N'-tetrakis (2-pyridylemethyl) ethylenediamine (TPEN), at 5 mg/kg body-weight daily for 4 months. Hepatic injury was examined by serum alanine aminotransferase (ALT) level and liver histopathological and biochemical changes.

RESULTS:

Hepatic Zn deficiency (lower than control level, p<0.05) was seen in the mice with either diabetes or TPEN treatment and more evident in the mice with both diabetes and TPEN. Zn deficiency exacerbated hepatic injuries, shown by further increased serum ALT, hepatic lipid accumulation, inflammation, oxidative damage, and endoplasmic reticulum stress-related cell death in Diabetes/TPEN group compared to Diabetes alone. Diabetes/TPEN group also showed a significant decrease in nuclear factor-erythroid 2-related factor 2 (Nrf2) expression and transcription action along with significant increases in Akt negative regulators, decrease in Akt and GSK-3β phosphorylation, and increase in nuclear accumulation of Fyn (a Nrf2 negative regulator). In vitro study with HepG2 cells showed that apoptotic effect of TPEN at 0.5-1.0 µM could be completely prevented by simultaneous Zn supplementation at the dose range of 30-50 µM.

CONCLUSIONS:

Zn is required for maintaining Akt activation by inhibiting the expression of Akt negative regulators; Akt activation can inhibit Fyn nuclear translocation to export nuclear Nrf2 to cytoplasm for degradation. Zn deficiency significantly enhanced diabetes-induced hepatic injury likely through down-regulation of Nrf2 function.

• Authors: Chi Zhang, Xuemian Lu, Yi Tan, Bing Li, Xiao Miao, Litai Jin, Xue Shi, Xiang Zhang, Lining Miao, Xiaokun Li, Lu Cai
• Journal: PloS one (PLoS One) Vol. 7 Issue 12 Pg. e49257 ( 2012) ISSN: 1932-6203 [Electronic] United States
• PMID: 23251339 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• GSK3B protein, human
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, mouse
• Proto-Oncogene Proteins c-akt
• Glycogen Synthase Kinase 3
• Zinc

Topics

• Animals
• Apoptosis
• Cell Line, Tumor
• Diabetes Mellitus, Experimental (metabolism, pathology)
• Disease Models, Animal
• Down-Regulation
• Glycogen Synthase Kinase 3 (metabolism)
• Glycogen Synthase Kinase 3 beta
• Humans
• Hyperglycemia (metabolism, pathology)
• Inflammation (metabolism, pathology)
• Insulin Resistance (physiology)
• Liver (metabolism, pathology)
• Male
• Mice
• Oxidative Stress (physiology)
• Phosphorylation
• Proto-Oncogene Proteins c-akt (metabolism)
• Zinc (deficiency)