A Review of Islet of Langerhans Degeneration in Rodent Models of Type 2 Diabetes

Abstract

Type 2 diabetes mellitus (TTDM) is characterized by progressive loss of glucose control through multifactorial mechanisms. The search for an understanding of TTDM has relied on animal models since the realization of the importance of the pancreas in controlling plasma glucose concentration. Rodent models of TTDM are developed to express hyperglycemia and not islet degeneration per se. Degeneration of the islets of Langerhans with β-cell loss is secondary to insulin resistance and is regarded as the more important lesion. Despite this, differences between models are seen in the development and progression of islet degeneration. Assessing the differences between the models is important to appreciate the various aspects of TTDM and understand their advantages as well as their deficiencies. Relevant animal models of TTDM provide opportunities to investigate important physiological and cell biological processes that may ultimately lead to development of targeted therapies. This article reviews the importance, advantages, and limitations of rodent models of TTDM in relation to the histopathological changes that characterize islet degeneration. Pathophysiological mechanisms that contribute to islet degeneration are also discussed and are placed into the context of changes in islet histological appearances.

Experimental models of diabetes mellitus

“…The Goto Kakizaki (GK) rat is skinny, diabetic rat developed in Japan in 1975 from Wistar species (6). Both insulin resistance and impaired insulin secretion are present in this model (32).…”

“…The most important factor for the disorder of insulin secretion is the dysfunction of glucose metabolism connected with a deficiency of enzymes that control oxidative glycolysis (6). The GK rat develops some features that can be compared with the complications of diabetes seen in humans (1).…”

“…The Zucker Fatty (ZF) rat has a defect of a gene that codes for leptin receptors (fa/fa), resulting in the development of obesity and hypertension with associated renal and cardiovascular disease (6). The Zucker Fatty Diabetic Rat (ZDF) has the identical genetic mutation and, additionally, a mutation which leads to the spontaneous development of hyperglycemia in males during the 7 th -10 th week (41).…”

“…Leptin suppresses insulin secretion and controls food intake. The fa/fa mutation of the leptin receptor results in insulin resistance with severe glucose intolerance (6). ZF and ZDF rats are hyperphagic due to the reduction in leptin signalling that results in obesity (6).…”

“…Toxicity of the streptozotocin on beta-cells is complex and includes genetic and non-genetic mechanisms (6). Nitric oxide (NO) and other free radicals influenced by streptozotocin result in spontaneous lesions of the DNA chain (7).…”