Abstract
Although the effects of cadmium (Cd) on the development of diabetes have been extensively investigated, the relationship between Cd exposure and the severity of established diabetes is unclear. Herein, we investigate the effects of long-term exposure to Cd in a streptozotocin-induced mouse model of type-2 diabetes mellitus (T2DM) and the underlying mechanism. C57BL/6 Mice were divided into the following four groups: (1) control group; (2) Cd-exposed group; (3) diabetic group; (4) Cd-exposed diabetic group. Cd exposure was established by the administration of 155 ppm CdCl2 in drinking water. After 25 weeks of treatment, serum fasting glucose and insulin were measured. Meanwhile, the liver and pancreas specimens were sectioned and stained with Hematoxylin and eosin. Gluconeogenesis, glycolysis, lactate concentration, and fibrosis in liver were evaluated. Clinical signs attributable to diabetes were more apparent in Cd-exposed diabetic mice, while no effects of Cd exposure were found on non-diabetic mice. Cd exposure significantly decreased fasting blood glucose (FBG) levels in diabetic group. We further demonstrated that the glycolysis related hepatic enzymes, pyruvate kinase M2 (PKM-2) and lactic dehydrogenase A (LDHA) were both increased, while the gluconeogenesis related hepatic enzymes, phosphoenolpyruvate-1 (PCK-1) and glucose-6-phosphatase (G6Pase) were both decreased in Cd exposed diabetic mice, indicating that Cd increased glycolysis and inhibited gluconeogenesis in diabetic model. Moreover, lactate accumulation was noted accompanied by the increased inflammation and fibrosis in the livers of diabetic mice following Cd exposure. Cd exposure disturbed glucose metabolism and exacerbated diabetes, providing a biological relevance that DM patients are at greater risk when exposed to Cd.
Highlights
Diabetes mellitus (DM) is a major contributor to morbidity, mortality, and disability, which represents a critical public health issue[1]
We further demonstrated that the glycolysis related hepatic enzymes, pyruvate kinase M2 (PKM-2) and lactic dehydrogenase A (LDHA) were both increased, while the gluconeogenesis related hepatic enzymes, phosphoenolpyruvate-1 (PCK-1) and glucose-6-phosphatase (G6Pase) were both decreased in Cd exposed diabetic mice, indicating that Cd increased glycolysis and inhibited gluconeogenesis in diabetic model
Lactate accumulation was noted accompanied by the increased inflammation and fibrosis in the livers of diabetic mice following Cd exposure
Summary
Diabetes mellitus (DM) is a major contributor to morbidity, mortality, and disability, which represents a critical public health issue[1]. DM is genetic and environmentally-related [2]. Environmental pollutants, such as heavy metals, have been implicated as contributing to the pathogenesis of DM. Cadmium (Cd) is an environmental pollutant and has been associated with DM [3, 4]. Prior research in animal models identified a dysregulation of glucose metabolism, a relationship between Cd exposure and increased blood glucose levels [5, 6]. We further suggested that urinary Cd levels in humans were positively associated with DM [12]. A cohort study suggested that individuals with high levels of urine Cd and plasma CRP (creactive protein) were at developing type-2 diabetes (T2DM) [13].
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