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Pdx1 (MODY4) Regulates Pancreatic Beta Cell Susceptibility to ER Stress

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Pdx1 (MODY4) Regulates Pancreatic Beta Cell Susceptibility to ER Stress Pdx1 (MODY4) regulates pancreatic beta cell susceptibility to ER stress Mira M. Sachdevaa, Kathryn C. Claiborna, Cynthia Khooa, Juxiang Yanga, David N. Groffa, Raghavendra G. Mirmirab, and Doris A. Stoffersa,1 aDepartment of Medicine, Division of Endocrinology, Diabetes, and Metabolism and Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, 415 Curie Boulevard, Philadelphia, PA 19104; and bDepartment of Pediatrics and the Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202 Edited by Gerald I. Shulman, Howard Hughes Medical Institute/Yale University, New Haven, CT, and approved August 24, 2009 (received for review May 5, 2009) Type 2 diabetes mellitus (T2DM) results from pancreatic ␤ cell Heterozygous mutations in Pdx1 are associated with type 2 failure in the setting of insulin resistance. Heterozygous mutations diabetes in humans, suggesting that Pdx1 plays a role in islet in the gene encoding the ␤ cell transcription factor pancreatic compensation for insulin resistance (14, 15). This hypothesis is duodenal homeobox 1 (Pdx1) are associated with both T2DM and supported by studies using genetic mouse models of insulin resis- maturity onset diabetes of the young (MODY4), and low levels of tance. In mice doubly heterozygous for the insulin receptor (IR) Pdx1 accompany ␤ cell dysfunction in experimental models of and insulin receptor substrate 1 (IRS-1), superimposed Pdx1 hap- glucotoxicity and diabetes. Here, we find that Pdx1 is required for loinsufficiency impairs both insulin secretion and compensatory ␤ compensatory ␤ cell mass expansion in response to diet-induced cell mass expansion, leading to worsened glucose tolerance (16); ϩ Ϫ insulin resistance through its roles in promoting ␤ cell survival and however, in the insulin resistant Glut4 / model, concurrent Pdx1 compensatory hypertrophy. Pdx1-deficient ␤ cells show evidence heterozygosity leads to hyperglycemia due to defects in insulin of endoplasmic reticulum (ER) stress both in the complex metabolic secretion with no impairment in ␤ cell mass expansion (17). The milieu of high-fat feeding as well as in the setting of acutely basis for the discrepancy regarding the role of Pdx1 in compensa- reduced Pdx1 expression in the Min6 mouse insulinoma cell line. tory expansion of ␤ cell mass in these genetic models of insulin Further, Pdx1 deficiency enhances ␤ cell susceptibility to ER stress- resistance has not been elucidated but may involve differences in associated apoptosis. The results of high throughput expression the sites and severity of insulin resistance. In particular, impaired ϩ/Ϫ ϩ/Ϫ microarray and chromatin occupancy analyses reveal that Pdx1 insulin responsiveness of the ␤ cell itself in the IR /IRS-1 regulates a broad array of genes involved in diverse functions of model may limit Pdx1-mediated compensatory ␤ cell mass expan- the ER, including proper disulfide bond formation, protein folding, sion. Further, these genetic models offer limited analogy to human and the unfolded protein response. These findings suggest that type 2 diabetes which is rarely caused by mutations in insulin Pdx1 deficiency leads to a failure of ␤ cell compensation for insulin response pathways. Therefore, we sought to define the role of Pdx1 ␤ resistance at least in part by impairing critical functions of the ER. in compensatory cell mass expansion using a mouse model of high-fat diet (HFD)-induced insulin resistance that more closely chromatin occupancy ͉ diabetes ͉ gene regulation ͉ islet compensation parallels the progression to type 2 diabetes in humans. The role of Pdx1 as a transcription factor regulating islet com- pensation suggests that the identification of direct Pdx1 transcrip- he pathogenesis of type 2 diabetes reflects a dynamic interaction tional targets will offer insights into the molecular mechanisms of Tbetween environmental influences and complex genetic pre- the islet response to insulin resistance that may be exploited disposition in which the development of insulin resistance, largely therapeutically to prevent or delay the progression of diabetes. To associated with obesity, is initially balanced by increased insulin this end, we performed high-throughput gene expression profiling ␤ production by the pancreatic cells. In some individuals, the and chromatin occupancy experiments in primary murine islets and increased demand for insulin eventually overwhelms the capacity of Min6 mouse insulinoma cells. The results of these studies comple- ␤ ␤ ϩ Ϫ the cell to respond, resulting in progressive cell dysfunction and mented the characterization of HFD-fed Pdx1 / mice to reveal ␤ overt diabetes. Indeed, cell compensation is considered the that Pdx1 regulates the susceptibility of pancreatic ␤ cells to critical determinant of whether impaired glucose tolerance will endoplasmic reticulum (ER) stress and ER stress-induced apopto- advance to frank diabetes (1). The islet compensatory response sis and uncovered a broad role for Pdx1 in transcriptional regulation consists of an increase in both insulin secretion and ␤ cell number. relevant to ER function. Patients with type 2 diabetes have reduced ␤ cell volume at autopsy, underscoring the importance of ␤ cell mass in maintaining glucose Results homeostasis (2). Notably, ␤ cell failure is not limited to type 2 Pdx1؉/؊ Mice Develop Diabetes in Response to HFD-Induced Insulin diabetes but rather is a common feature of most forms of diabetes, Resistance. We fed Pdx1ϩ/Ϫ male mice and their Pdx1ϩ/ϩ littermates including autoimmune type 1 diabetes, ketosis-prone diabetes, and a HFD starting at 4 weeks of age and followed them for 5 months. the monogenic, autosomal-dominant maturity onset diabetes of the young (MODY) syndromes (3). The ␤ cell-enriched pancreatic duodenal homeobox 1 (Pdx1) Author contributions: M.M.S., K.C.C., C.K., and D.A.S. designed research; M.M.S., K.C.C., gene, also known as Ipf1 (MODY4), encodes a transcription factor C.K., J.Y., and D.N.G. performed research; R.G.M. contributed new reagents/analytic tools; M.M.S., K.C.C., C.K., and D.A.S. analyzed data; and M.M.S. and D.A.S. wrote the paper. that critically regulates early pancreas formation and multiple ␤ Conflict of interest statement: D.A.S. is a coinventor on a patent entitled ‘‘Compositions aspects of mature cell function, including insulin secretion, and methods for detecting pancreatic disease’’ which covers the detection of Pdx1/Ipf1 mitochondrial metabolism, and cell survival (4–6). Pdx1 directly mutations in human disease, the royalties from which were $0 during the last 12 months. regulates expression of the insulin gene and other components of This article is a PNAS Direct Submission. the glucose-stimulated insulin secretion pathway (7, 8). Reduced The array data have been deposited in the Array Express database, http://www.ebi.ac.uk/ Pdx1 expression in the ␤ cell occurs in cellular models of glucose microarray-as/ae/ (accession no. E-MTAB-134). toxicity and accompanies the development of diabetes in complex 1To whom correspondence should be addressed. E-mail: [email protected]. genetic and environmental animal models of the disease, correlat- This article contains supporting information online at www.pnas.org/cgi/content/full/ ing low Pdx1 levels with ␤ cell failure (9–13). 0904849106/DCSupplemental. 19090–19095 ͉ PNAS ͉ November 10, 2009 ͉ vol. 106 ͉ no. 45 www.pnas.org͞cgi͞doi͞10.1073͞pnas.0904849106 Downloaded by guest on September 25, 2021 Fig. 1. Pdx1ϩ/Ϫ mice develop diabetes in response to HFD-induced insulin resistance. (A) Baseline glucose tolerance test and body weights of 3.5-week-old male Pdx1ϩ/Ϫ mice (n ϭ 16) and their wild-type Pdx1ϩ/ϩ littermates (n ϭ 15). GTT was performed aftera6hfast; P Ͻ 0.001 by ANOVA. (B) Weight gain profile of Pdx1ϩ/Ϫ ϩ ϩ mice and their littermate controls after randomization into HFD or normal chow (NC) groups. *, P Ͻ 0.05, **, P Ͻ 0.005 Pdx1 / HFD vs. NC; ‡, P Ͻ 0.05, ‡‡, P Ͻ 0.005 Pdx1ϩ/Ϫ HFD vs. NC. (C) Insulin tolerance test after 5 months on HFD or NC (by ANOVA, P Ͻ 0.005 Pdx1ϩ/ϩ HFD vs. NC; P ϭ 0.06 Pdx1ϩ/Ϫ HFD vs. NC; P ϭ ϩ ϩ ϩ Ϫ ϩ Ϫ 0.985 Pdx1 / HFD vs. Pdx1 / HFD). (D) Six-hour fasting blood glucose levels of mice 5 months in HFD or NC group. *, P Ͻ 0.001, Pdx1 / HFD vs. NC; ‡, P Ͻ 0.001, ‡‡, P Ͻ 0.00001 relative to diet-matched Pdx1ϩ/ϩ littermates. (E and F) IP glucose tolerance tests on mice fasted overnight after 1 month (E) and 4 months (F)on HFD or NC. In (E), P Ͻ 0.005 for Pdx1ϩ/Ϫ HFD vs. NC and P Ͻ 0.001 for all other pair-wise comparison groups by ANOVA. In (F), P Ͻ 0.0001 for all comparison groups by ANOVA. Glucose values of 600 mg/dL represent the upper limit of detection. (G) Acute insulin release in mice 3 months on HFD or NC. Plasma insulin was ϩ ϩ measured by ELISA after IP glucose injection. *, P Ͻ 0.05, **, P Ͻ 0.005 relative to time 0; ‡, P Ͻ 0.05, ‡‡, P Ͻ 0.01 relative to diet-matched Pdx1 / littermates; #, P Ͻ 0.05, ##, P Ͻ 0.01 relative to corresponding NC controls. For (B–G), n ϭ 8 mice per group, and data represent the mean Ϯ standard error. At baseline, body weights were comparable but Pdx1ϩ/Ϫ mice the context of diet-induced insulin resistance, Pdx1 is required for already displayed mild glucose intolerance (Fig. 1A). Although compensatory ␤ cell mass expansion. high-fat feeding induced similar weight gain (Fig. 1B) and an When comparing this finding with the published studies of Pdx1 equivalent degree of insulin resistance (Fig. 1C, P ϭ 0.985 by haploinsufficiency in genetic models of insulin resistance, our ANOVA for HFD-fed Pdx1ϩ/ϩ vs. HFD-fed Pdx1ϩ/Ϫ)inmiceof results thus far accorded with the IRϩ/Ϫ/IRS-1ϩ/Ϫ model, in which both genotypes, it caused severe hyperglycemia only in Pdx1ϩ/Ϫ the impaired ␤ cell mass expansion in IRϩ/Ϫ/IRS-1ϩ/Ϫ/Pdx1ϩ/Ϫ mice mice, with blood glucose levels Ͼ400 mg/dL after a 6-h fast (Fig.
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