Aquaporin 7 Is a β-Cell Protein and Regulator of Intraislet Glycerol Content and Glycerol Kinase Activity, β-Cell Mass, and Insulin Production and Secretion

Abstract

To investigate if intracellular glycerol content plays a role in the regulation of insulin secretion in pancreatic ␤ cells, we studied the expression of the glycerol channels, or aquaglyceroporins, encoded by the aquaporin 3 (Aqp3), Aqp7, and Aqp9 genes in mouse islets. We found expression of Aqp7 only, not that of Aqp3 or Aqp9, in the endocrine pancreas at both the mRNA (by reverse transcription-PCR) and protein (by immunohistochemistry) levels. Immunohistochemistry revealed a complete overlap between insulin and Aqp7 immunostaining in the pancreatic islet. Inactivation of Aqp7 by gene targeting produced viable and healthy mice. Aqp7 ؊/؊ mice harbored an increased intraislet glycerol concentration with a concomitant increase of the glycerol kinase transcript level and enzyme activity. The islet triglyceride content in the Aqp7 ؊/؊ mice was also increased compared to that in the Aqp7 ؉/؉ mice. Interestingly, Aqp7 ؊/؊ mice displayed reduced ␤-cell mass and insulin content but increased insulin-1 and insulin-2 mRNAs. The reduction of ␤-cell mass in Aqp7 ؊/؊ mice can be explained at least in part by a reduction in cell proliferation through protein kinase C and the c-myc cascade, with a reduction in the transcript levels of these two genes. Concomitantly, there was a decreased rate of apoptosis, as reflected by terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling and caspase 3 and Bax expression in Aqp7 ؊/؊ mice. Compared with Aqp7 ؉/؉ islets, islets isolated from Aqp7mice secreted insulin at a higher rate under basal low-glucose conditions and on exposure to a high (450 mg/dl) glucose concentration. Aqp7 ؊/؊ mice exhibited normal fasting blood glucose levels but elevated blood insulin levels. Their plasma glucose response to an intraperitoneal (i.p.) glucose tolerance test was normal, but their plasma insulin concentrations were higher than those of wild-type mice during the 2-h test. An i.p. insulin tolerance test showed similar plasma glucose lowering in Aqp7 ؊/؊ and Aqp7 ؉/؉ mice, with no evidence of insulin resistance. In conclusion, we found that pancreatic ␤ cells express AQP7, which appears to be a key regulator of intraislet glycerol content as well as insulin production and secretion.Glucose is the most important nutrient that regulates insulin secretion (21). In addition to its key role in insulin secretion, plasma glucose also regulates ␤-cell mass; in insulin-resistant states, the ␤-cell mass increases to provide sufficient insulin to keep the plasma glucose concentration in check. Therefore, glucose appears to play dual roles as a stimulus both for acute insulin secretion and for a compensatory increase in ␤-cell mass (8). Unlike glucose, glycerol, a triose sugar, has no apparent effect on insulin secretion (37, 39), though a closely related metabolite, glyceraldehyde, has a potent effect (1, 2). One reason that glycerol does not function as a signal for insulin secretion is that it appears not to be metabolized by pancreatic ␤ cells (37). Induced overexpression of glycerol kina...

Metabolic impact of the glycerol channels AQP7 and AQP9 in adipose tissue and liver

“…In both these lines, no effect on body weight or fat pad masses were detected, and neither were there any differences between KO and WT animals in the plasma levels of glycerol, FFA, or TGs (Matsumura et al 2007. Possible reasons for these variations could be due to different gene targeting strategies, different genetic backgrounds, or differences in collection and analysis of tissue samples.…”

“…Despite the apparent intracellular localization of AQP7, the AQP7 KO mice were reported to have a higher intra-islet glycerol and TG content with an increased activity of GlyK similar to that observed in WAT from the first KO line. This was accompanied by an increased secretion of insulin, increased p-insulin levels with no effect on p-glucose, and with no evidence of insulin resistance (Matsumura et al 2007). Owing to the wide expression profile of AQP7, the relative contribution of the different tissues to the phenotype of the total AQP7 KO mouse model seems difficult to define.…”

“…In parallel, it would also increase the need for other precursors than glycerol to support energy needs within muscle tissue. Finally, AQP7 has also been localized to pancreatic b-cells (Matsumura et al 2007, Best et al 2009). Despite the apparent intracellular localization of AQP7, the AQP7 KO mice were reported to have a higher intra-islet glycerol and TG content with an increased activity of GlyK similar to that observed in WAT from the first KO line.…”

Aquaglyceroporin-7 Overexpression in Women with the Polycystic Ovary Syndrome

“…Hibuse et al [11] demonstrated that Aqp 7-knockout mice developed insulin resistance after consumption of a high-fat/high-sucrose diet. Moreover, Aqp 7-knockout mice show hyperinsulinemia and increased pancreatic insulin-1 and insulin-2 transcript levels [26]. However, AQP7 does not correlate with either serum insulin levels or the HOMA IR from subcutaneous or visceral adipose tissue obtained from severely obese or type 2 diabetic humans [27].…”

Role of aquaporins in cell proliferation: What else beyond water permeability?

“…Accordingly, the reduction in b-cell mass observed in Aqp7 ¡/¡ mice can be explained at least in part by a reduction in cell proliferation through protein kinase C and the cmyc cascade, with a reduction in the transcript levels of the esponding two genes. 68 AQP9 is the primary route of hepatocyte glycerol uptake for gluconeogenesis. 69 In mouse memory T cells, it can act as a metabolic switch, enabling longterm survival of the cells by enabling triglyceride synthesis to build up an energetic reserve, allowing survival under nutrient-poor conditions.…”