Critical Reduction in β-Cell Mass Results in Two Distinct Outcomes over Time

Abstract

We have proposed that hyperglycemia-induced dedifferentiation of ␤-cells is a critical factor for the loss of insulin secretory function in diabetes. Here we examined the effects of the duration of hyperglycemia on gene expression in islets of partially pancreatectomized (Px) rats. Islets were isolated, and mRNA was extracted from rats 4 and 14 weeks after Px or sham Px surgery. Px rats developed different degrees of hyperglycemia; low hyperglycemia was assigned to Px rats with fed blood glucose levels less than 150 mg/dl, and high hyperglycemia was assigned above 150 mg/dl. ␤-Cell hypertrophy was present at both 4 and 14 weeks. At the same time points, high hyperglycemia rats showed a global alteration in gene expression with decreased mRNA for insulin, IAPP, islet-associated transcription factors (pancreatic and duodenal homeobox-1, BETA2/NeuroD, Nkx6.1, and hepatocyte nuclear factor 1␣), ␤-cell metabolic enzymes (glucose transporter 2, glucokinase, mitochondrial glycerol phosphate dehydrogenase, and pyruvate carboxylase), and ion channels/pumps (Kir6.2, VDCC␤, and sarcoplasmic reticulum Ca 2؉ -ATPase 3). Conversely, genes normally suppressed in ␤-cells, such as lactate dehydrogenase-A, hexokinase I, glucose-6-phosphatase, stress genes (heme oxygenase-1, A20, and Fas), and the transcription factor c-Myc, were markedly increased. In contrast, gene expression in low hyperglycemia rats was only minimally changed at 4 weeks but significantly changed at 14 weeks, indicating that even low levels of hyperglycemia induce ␤-cell dedifferentiation over time. In addition, whereas 2 weeks of correction of hyperglycemia completely reverses the changes in gene expression of Px rats at 4 weeks, the changes at 14 weeks were only partially reversed, indicating that the phenotype becomes resistant to reversal in the long term. In conclusion, chronic hyperglycemia induces a progressive loss of ␤-cell phenotype with decreased expression of ␤-cell-associated genes and increased expression of normally suppressed genes, these changes being present with even minimal levels of hyperglycemia. Thus, both the severity and duration of hyperglycemia appear to contribute to the deterioration of the ␤-cell phenotype found in diabetes.Pancreatic ␤-cells maintain specialized pathways of metabolism that efficiently couple the secretion of insulin to circulating glucose levels (1, 2). With the increased demand of insulin resistance and obesity, an adaptation in ␤-cell mass and secretion can keep glucose levels within a narrow range (3-5). The failure of ␤-cells to adequately adapt to increased demand is fundamental to the pathogenesis of all forms of diabetes. We have hypothesized that abnormal ␤-cell function in diabetes is due to the loss of the unique expression pattern of genes that optimize glucose-induced insulin secretion (GIIS) 1 and insulin synthesis (5).The development of the endocrine pancreas and the maintenance of ␤-cell differentiation is regulated by a network of transcription factors, which includes pancreatic and duodenal homeob...

Exercise and dexamethasone oppositely modulate β-cell function and survival via independent pathways in 90% pancreatectomized rats

“…Thus, consistent with Taylor's results, our data revealed that DEX and exercise expanded b-cell mass via two independent mechanisms, contributing to the modulation of b-cell function in order to compensate for insulin resistance. Consistent with our results, Px rats exhibited abnormalities in b-cell function and mass, even though b-cell area and small b-cell clusters were increased (Laybutt et al 2003). The mechanism that impairs b-cell function and mass due to insulin resistance has not yet been clarified.…”

“…Another possible mechanism to reduce b-cell mass is decreased expression of transcription factors, which are important for islet development, such as PDX-1, Neuro D and hepatic nuclear factor-1a (HNF-1a) (Laybutt et al 2003). Several studies have demonstrated that mRNA levels of these transcription factors were reduced by 50-60% in Px rats with 120 mg/dl glucose levels after 4 weeks from pancreatectomy (Jonsson et al 1994, Stoffers et al 1997.…”

The Fas pathway is involved in pancreatic β cell secretory function

“…According to this hypothesis, long-term adaptation of the ␤ cells to conditions of increased demand may be triggered by limited hyperglycemic excursions (35). These excursions elicit ␤ cell production of IL-1␤ (6) followed by Fas upregulation (3,7). At low concentrations of IL-1␤ and in the presence of FLIP, Fas engagement leads to ␤ cell proliferation (36) and enhanced function via NF-B and PDX-1, as shown in the present study.…”

“…Fas (CD95) is a cell surface receptor that plays a central role in the regulation of death in many cell types, including ␤ cells, and may be implicated in the development of type 1 and type 2 diabetes (3)(4)(5). Glucose-induced ␤ cell apoptosis in human islets involves IL-1␤-mediated up-regulation of Fas and subsequent interaction with the constitutively expressed Fas ligand (FasL) on neighboring ␤ cells (3,(6)(7)(8). Fas/FasL interaction leads to cleavage of procaspase-8, the most upstream caspase in the Fas apoptotic pathway.…”

Type 1, type 1.5, and type 2 diabetes: NOD the diabetes we thought it was

“…Furthermore, it is becoming increasingly apparent that many factors classically deemed type 1 diabetesspecific are also integral to the process of ␤ cell failure in type 2 diabetes patients. These include the effect of IL-1␤, Fas, and nuclear factor-B, endoplasmic reticulum stress, and increased expression of c-Myc (19)(20)(21)(22). Interestingly, polymorphisms in the Fas pathway have been associated recently with type 2 diabetes (23).…”