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Abstract
Cells continually adjust their gene expression profiles in order to adapt to the availability of nutrients. Glucose is a major regulator of pxancreatic β-cell function and cell growth. However, the mechanism of β-cell adaptation to high levels of glucose remains uncertain. To identify the specific targets responsible for adaptation to high levels of glucose, the differentially expressed genes from primary rat islets treated with 3.3 and 16.7 mmol/l glucose for 24 h were detected by DNA microarray. The results revealed that the expression levels of genes that encode enzymes required for de novo cholesterol biosynthesis [3-hydroxy-3-methylglutaryl-CoA synthase 1 (Hmgcs1), 3-hydroxy-3-methylglutaryl-CoA reductase (Hmgcr), mevalonate (diphospho) decarboxylase (Mvd), isopentenyl-diphosphate δ-isomerase 1 (Idi1), squalene epoxidase (Sqle) and 7-dehydrocholesterol reductase (Dhcr7)] were significantly increased in islets treated with high levels of glucose compared with those in the islets treated with lower glucose levels. Quantitative polymerase chain reaction further confirmed that glucose stimulated the expression levels of these genes in a dose- and time-dependent manner. A similar result was obtained in islets isolated from rats subjected to 12, 24, 48 and 72 h of continuous glucose infusion. It has previously been recognized that cholesterol homeostasis is important for β-cell function. The present study provides, to the best of our knowledge, the first evidence for the involvement of the de novo cholesterol biosynthesis pathway in the adaptation of rat islets to high levels of glucose in vitro and in vivo.
Highlights
As a major global chronic health problem, type 2 diabetes affects 336 million people worldwide [1]
Western blot analysis revealed increased protein levels of hydroxy-3-methylglutaryl-CoA reductase (Hmgcr) (Fig. 1). These data demonstrate that high levels of glucose markedly increased the expression levels of various genes involved in cholesterol biosynthesis in rat islets
Numerous studies investigating the link between chronic high levels of glucose and pancreatic β‐cell lipid biosynthesis have focused on fatty acids (FAs)
Summary
As a major global chronic health problem, type 2 diabetes affects 336 million people worldwide [1]. It is critical to reveal the mechanism of β‐cell compensation and prevent the progression of β‐cell decompensation for the long‐term management of the disease Cells continually adjust their gene expression profiles in order to adapt to the availability of nutrients such as glucose [3,4]. The majority of nonproliferating, differentiated cells depend on the efficiency of ATP production through oxidative phosphorylation to maintain their integrity. These cells metabolize glucose to pyruvate through glycolysis following which they oxidize the majority of the pyruvate to CO2 through the tricarboxylic acid (TCA) cycle in the mitochondria [5]. Previous studies have reported that islets from mice with a specific inactivation of the ATP‐binding cassette transporter 1
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