A gene expression network model of type 2 diabetes links cell cycle regulation in islets with diabetes susceptibility

Abstract

Insulin resistance is necessary but not sufficient for the development of type 2 diabetes. Diabetes results when pancreatic beta-cells fail to compensate for insulin resistance by increasing insulin production through an expansion of beta-cell mass or increased insulin secretion. Communication between insulin target tissues and beta-cells may initiate this compensatory response. Correlated changes in gene expression between tissues can provide evidence for such intercellular communication. We profiled gene expression in six tissues of mice from an obesity-induced diabetes-resistant and a diabetes-susceptible strain before and after the onset of diabetes. We studied the correlation structure of mRNA abundance and identified 105 co-expression gene modules. We provide an interactive gene network model showing the correlation structure between the expression modules within and among the six tissues. This resource also provides a searchable database of gene expression profiles for all genes in six tissues in lean and obese diabetes-resistant and diabetes-susceptible mice, at 4 and 10 wk of age. A cell cycle regulatory module in islets predicts diabetes susceptibility. The module predicts islet replication; we found a strong correlation between 2H2O incorporation into islet DNA in vivo and the expression pattern of the cell cycle module. This pattern is highly correlated with that of several individual genes in insulin target tissues, including Igf2, which has been shown to promote beta-cell proliferation, suggesting that these genes may provide a link between insulin resistance and beta-cell proliferation.

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

“…Moreover, we confirmed a reduction of Stx1a protein in GK islets. Similarly, several ciliary/basal body genes have been shown to be misregulated in pancreatic islets of another diabetes model, ob/ ob mice 54 , further supporting a role for cilia in T2DM. In summary, our data strongly suggest a link between ciliary dysfunction and T2DM susceptibility.…”

Inhibition or Ablation of p21-activated Kinase (PAK1) Disrupts Glucose Homeostatic Mechanisms in Vivo

“…Since PAK1 preferentially signals through cofilin and is downstream of Rac1, this implicates a role for PAK1 in F-actin reorganization in the process of GLUT4 vesicle translocation in skeletal muscle cells. Interestingly, mRNA levels of PAK1 but not of Rac1, are significantly reduced in soleus and gastrocnemius skeletal muscle from obese diabetes-susceptible BTBR mice, at both 4 and 10 weeks of age (38). Since the BTBR ob mouse is not yet diabetic at 4 weeks, changes in gene expression at this time are proposed to be potential causes rather than consequences of hyperglycemia.…”

Elevation of transcription factor Islet-1 levels in vivo increases β-cell function but not β-cell mass

“…To understand the pathophysiology of diabetes, gene expression analyses of multiple tissues, including pancreatic islets, have been performed in different physiological conditions of altered β-cell function. 1,2 By analyzing changes in gene expression under different conditions such as obesity, strain and age, Keller and colleagues have detected a decrease of Islet-1 (Isl-1) expression in the islets of obese diabetic mice. 1 Similarly, aging can induce a distinct gene expression program in mouse islets, leading to a decrease in the expression of a small number of genes, including Isl-1.…”