Towards better understanding of the contributions of overwork and glucotoxicity to the β‐cell inadequacy of type 2 diabetes

Abstract

Type 2 diabetes (T2D) is characterized by reduction of β-cell mass and dysfunctional insulin secretion. Understanding β-cell phenotype changes as T2D progresses should help explain these abnormalities. The normal phenotype should differ from the state of overwork when β-cells compensate for insulin resistance to keep glucose levels normal. When only mild hyperglycaemia develops, β-cells are subjected to glucotoxicity. As hyperglycaemia becomes more severe, so does glucotoxicity. β-Cells in all four of these situations should have separate phenotypes. When assessing phenotype with gene expression, isolated islets have artefacts resulting from the trauma of isolation and hypoxia of islet cores. An advantage comes from laser capture microdissection (LCM), which obtains β-cell-rich tissue from pancreatic frozen sections. Valuable data can be obtained from animal models, but the real goal is human β-cells. Our experience with LCM and gene arrays on frozen pancreatic sections from cadaver donors with T2D and controls is described. Although valuable data was obtained, we predict that the approach of taking fresh samples at the time of surgery is an even greater opportunity to markedly advance our understanding of how β-cell phenotype evolves as T2D develops and progresses.

VHL-mediated disruption of Sox9 activity compromises β-cell identity and results in diabetes mellitus

“…An adaptive expansion of b-cell mass may generate regions of hypoxia, as islets from ZDF rats display elevated levels of HIF target genes such as Ldha (Li et al 2006). Islets isolated from T2D patients have dysregulation of HIF components as well as the progenitor markers SOX9 and HNF6, among others (Gunton et al 2005;Weir et al 2009), indicating that in a subset of patients, hypoxia may impact the b-cell transcriptome.…”

“…Compromised expression of b-cell genes has been associated with b-cell dysfunction in several animal models (Laybutt et al 2003;Kjorholt et al 2005;Tweedie et al 2006). Loss of b-cell differentiation has been proposed as an end result of b-cell decompensation in T2D (Weir and Bonner-Weir 2004;Weir et al 2009). Although T2D is a diverse set of diseases, b-cell dedifferentiation due to either genetic or environmental insults (for instance, hypoxia) in a subset of patients may be a potential mechanism (Guo et al 2013).…”

Long term effects of the implantation of autologous bone marrow mononuclear cells for type 2 diabetes mellitus

“…As a result there have been many investigations into methods of preserving or recovering islet beta-cells and attempts to alter or delay the natural course of type 2 diabetes. Previous studies have shown that bone marrow stem cells can differentiate into islet cells [12][13][14] and can reduce blood glucose in animal models rendered diabetic by the use of streptozotocin [15][16][17]. Several studies of T1DM have also shown that autologous nonmyeloablative hematopoietic stem cell transplantation along with high-dose immunosuppression resulted in prolonged insulin independence in the majority of patients [18][19][20].…”

Effects of exercise on brain functions in diabetic animal models

“…Most of the T2DM animal models are characterized by the obese phenotype, which reflects the human condition where obesity is closely related to T2DM development [1] . The T2DM animal models are categorized according to the type of induction mechanism as follows: spontaneously obese models [1] , diet/nutrition induced obesity models [123,124] , nonobese models [125] , genetically induced models of β cell dysfunction [126] , and surgically induced diabetic animal models [127] . The T2DM rodent models are summarized in Table 2.…”