Cellular and Molecular Characterization of a Feline Insulinoma

Abstract

Background: Insulinoma is an autonomous insulin-secreting islet cell neoplasm that is rarely diagnosed in cats. The clinical and pathological aspects of feline insulinoma have been described previously, but the molecular characteristics of these tumors have not been investigated.Objectives: The study objectives were to characterize peptide hormone production and determine expression of selected genes involved in glucose metabolism and insulin secretion in a feline insulinoma.Methods: Immunohistochemistry and RT-PCR were used to examine hormone and gene expression, respectively, by insulinoma cells.Results: Immunohistochemistry examination indicated that the tumor cells expressed insulin, chromogranin A, and somatostatin but not glucagon or pancreatic polypeptide. The tumor expressed several genes characteristic of pancreatic beta cells (b cells) including insulin (INS), glucose transporter 2 (GLUT2), and glucokinase (GCK). The tumor also expressed hexokinase 1 (HK1), a glycolytic enzyme not normally expressed in b cells. GCK expression was higher in the insulinoma than in normal pancreas from the same cat. The GCK : HK1 ratio was 420-fold higher in insulinoma tissue than in normal pancreas.Conclusions and Clinical Importance: The feline insulinoma produced several peptide hormones and expressed genes consistent with a b-cell phenotype. The pattern of hexokinase gene expression in tumor cells differed from that of normal pancreas. These findings suggest insulinoma cells may have an increased sensitivity to glucose that could contribute to the abnormal insulin secretory response observed at low serum glucose concentrations.

Normal Glucose Metabolism in Carnivores Overlaps with Diabetes Pathology in Non-Carnivores

“…GCK activity in normal feline pancreas has yet to be confirmed. However, in a cat with a functional insulin-producing tumor and hypoglycemia, tumor GCK expression was nearly 17 times greater than normal pancreatic tissue from the same cat, suggesting a relationship between the magnitude of GCK expression and insulin secretion, similar to that observed in in vitro overexpression studies (7). Feline islets also express numerous other genes with roles in insulin signaling (67).…”

“…GCK mRNA has been detected in the feline pancreas (7, 35, 66) and in an insulin-producing pancreatic tumor from a cat (7). GCK activity in normal feline pancreas has yet to be confirmed.…”

“…GCK mutations cause a monogenetic form of human non-insulin dependent diabetes known as Maturity Onset Diabetes in the Young (MODY). Each MODY subtype (there are five subtypes) results from mutation of a gene involved in glucose metabolism; GCK mutations cause MODY type 2 (MODY2), which account for as many as 60% of all MODY cases (7). Along with its causative role in MODY-GCK, a monogenic form of diabetes, GCK has long been suspected as a candidate gene with a role in the development of other forms of diabetes mellitus, too.…”

Nutritional regulation of glucokinase: a cross-species story

“…Given that the glycogen-storage pathway is also very low in the cat (131) , then carbohydrates will be stored as lipids through de novo lipogenesis with the consistent associated pathophysiological complications, diabetes included (122) . In contrast to the situation observed in the liver, nutrient-sensing machinery seems to be present in feline pancreatic tissue, where the activity and expression of GK are comparable with those of other mammalian species (127) . Glucokinase in carnivorous species: the example of the dog.…”

Cloning and characterization of feline islet glucokinase

“…Recent studies have shown that the feline liver does not express mRNA for GK [5] or GKRP [6], which suggests that reduced expression of genes involved in glucose-sensing is responsible for the low GK enzyme activity observed in early studies. Although GK mRNA expression has been documented in the feline pancreas [5,7], expression and activity of the feline pancreatic GK isoform has not been studied in depth. Given the central role of pancreatic GK as glucose-sensor for insulin-producing islet cells and the requirement for GK in normal glucose metabolism and insulin secretion, detailed knowledge about GK expression and function may improve understanding of feline carbohydrate metabolism.…”