Islet gene expression and function in type 2 diabetes; studies in the Goto‐Kakizaki rat and humans

Abstract

Defective b-cell function with resulting impairment of glucose-stimulated insulin release is a critical factor in the pathogenesis of type 2 diabetes. Accumulated studies in pancreatic islets of the spontaneously diabetic GotoKakizaki (GK) rat suggest that this is a useful animal model of type 2 diabetes. The GK rat is non-obese, and abnormal glucose regulation develops early in life in association with impaired insulin secretion. There are some differences in islet morphology and function reported between different GK rat colonies. In addition to reduction of b-cell mass, a number of b-cell defects have been described with possible relevance for the reduced insulin secretion. Interestingly, some of these defects have also been shown in isolated islets from type 2 diabetic humans. The polygenic nature of diabetes heredity in the GK rat may well resemble the genetic basis in the majority of patients with type 2 diabetes. Here, we review studies concerning b-cell function and islet gene expression in the GK rat and compare it with the limited number of investigations on similar topics in isolated islets from patients with type 2 diabetes.

Ciliary dysfunction impairs beta-cell insulin secretion and promotes development of type 2 diabetes in rodents

“…7). In addition and as reported previously 50 , we observed a reduction of Stx1a levels in GK rats compared with Wistar controls. The seeming discrepancy between loss of function and increased expression levels could indicate a compensatory mechanism in reaction to impairment of ciliary/basal body integrity.…”

“…GK rats from the Stockholm colony manifest a marked glucose intolerance with hyperglycemia, mainly due to impaired glucose-stimulated insulin secretion. At the age studied (2-3 months), b-cell density and relative volume of islet endocrine cells are similar to those of age-matched control Wistar rats 50 . At the time of the experiment, blood glucose levels were elevated (n ¼ 10, 7.2 to 10.2 mM) compared with Wistar controls (n ¼ 12, 5.1-6.4 mM).…”

“…We have found that ciliary/basal body defects lead to pre-diabetic phenotypes in vitro and in vivo, but to establish a link between primary cilia and diabetes, we tested for ciliary dysfunction in diabetic GotoKakizaki (GK) rats 50,51 . GK rats from the Stockholm colony manifest a marked glucose intolerance with hyperglycemia, mainly due to impaired glucose-stimulated insulin secretion.…”

Therapeutic properties of VO(dmpp)2 as assessed by in vitro and in vivo studies in type 2 diabetic GK rats

“…After 120 min of the glucose load, plasma insulin levels were not statistically different from the basal ones at 0 min, but the group treated with VO(dmpp) 2 showed a significant decrease when compared to 30 min. Importantly, VO(dmpp) 2 treated GK rats have shown plasma insulin levels similar to placebo treated W rats, demonstrating the efficiency of VO(dmpp) 2 to improve the glucose tolerance with less insulinresistance in diabetic GK rats [58,59]. These results show that GK rats treated with VO(dmpp) 2 recover from a glucose load with a profile similar to W rats, presenting blood glucose values significantly lower than those from GK control.…”

ARA290 Improves Insulin Release and Glucose Tolerance in Type 2 Diabetic Goto-Kakizaki Rats

“…Impaired β-cell function and insulin secretion play a primary role in type 2 diabetes (1,2). Although the mechanisms behind impaired insulin secretion may reside in inherited defects related to β-cell development and metabolism, immunological events such as low-grade inflammation and apoptosis may also contribute to β-cell dysfunction.…”