α Cell Function and Gene Expression Are Compromised in Type 1 Diabetes
Marcela Brissova, Rachana Haliyur, Diane Saunders, Shristi Shrestha, Chunhua Dai, David M Blodgett, Rita Bottino, Martha Campbell-Thompson, Radhika Aramandla, Gregory Poffenberger, Jill Lindner, Fong Cheng Pan, Matthias G von Herrath, Dale L Greiner, Leonard D Shultz, May Sanyoura, Louis H Philipson, Mark Atkinson, David M Harlan, Shawn E Levy, Nripesh Prasad, Roland Stein, Alvin C Powers, Marcela Brissova, Rachana Haliyur, Diane Saunders, Shristi Shrestha, Chunhua Dai, David M Blodgett, Rita Bottino, Martha Campbell-Thompson, Radhika Aramandla, Gregory Poffenberger, Jill Lindner, Fong Cheng Pan, Matthias G von Herrath, Dale L Greiner, Leonard D Shultz, May Sanyoura, Louis H Philipson, Mark Atkinson, David M Harlan, Shawn E Levy, Nripesh Prasad, Roland Stein, Alvin C Powers
Abstract
Many patients with type 1 diabetes (T1D) have residual β cells producing small amounts of C-peptide long after disease onset but develop an inadequate glucagon response to hypoglycemia following T1D diagnosis. The features of these residual β cells and α cells in the islet endocrine compartment are largely unknown, due to the difficulty of comprehensive investigation. By studying the T1D pancreas and isolated islets, we show that remnant β cells appeared to maintain several aspects of regulated insulin secretion. However, the function of T1D α cells was markedly reduced, and these cells had alterations in transcription factors constituting α and β cell identity. In the native pancreas and after placing the T1D islets into a non-autoimmune, normoglycemic in vivo environment, there was no evidence of α-to-β cell conversion. These results suggest an explanation for the disordered T1D counterregulatory glucagon response to hypoglycemia.
Keywords: alpha cells; glucagon; human; insulin; pancreatic islet; type 1 diabetes.
Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
Figures
![Figure 1. T1D β Cells in Recent-Onset…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6368357/bin/nihms963683f1.jpg)
Figure 2. T1D α Cells in Recent-Onset…
Figure 2. T1D α Cells in Recent-Onset T1D Have Reduced Glucagon Secretion and Dysregulated Gene…
Figure 3. T1D α Cells Do Not…
Figure 3. T1D α Cells Do Not Show Evidence of α-to-β Cell Reprogramming in Normoglycemic,…
Figure 4. Genes Critical to α Cell…
Figure 4. Genes Critical to α Cell Function Are Differentially Expressed in T1D α Cells
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- β Cells Persist in T1D Pancreata Without Evidence of Ongoing β-Cell Turnover or Neogenesis.Lam CJ, Jacobson DR, Rankin MM, Cox AR, Kushner JA. Lam CJ, et al. J Clin Endocrinol Metab. 2017 Aug 1;102(8):2647-2659. doi: 10.1210/jc.2016-3806. J Clin Endocrinol Metab. 2017. PMID: 28323930 Free PMC article.
- Epigenetic-mediated reprogramming of pancreatic endocrine cells.Mathiyalagan P, Keating ST, Al-Hasani K, El-Osta A. Mathiyalagan P, et al. Antioxid Redox Signal. 2015 Jun 1;22(16):1483-95. doi: 10.1089/ars.2014.6103. Epub 2015 Mar 18. Antioxid Redox Signal. 2015. PMID: 25621632 Review.
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- Human alpha cell transcriptomic signatures of types 1 and 2 diabetes highlight disease-specific dysfunction pathways.Bosi E, Marchetti P, Rutter GA, Eizirik DL. Bosi E, et al. iScience. 2022 Sep 3;25(10):105056. doi: 10.1016/j.isci.2022.105056. eCollection 2022 Oct 21. iScience. 2022. PMID: 36134336 Free PMC article.
-
- Alkorta-Aranburu G, Sukhanova M, Carmody D, Hoffman T, Wysinger L, Keller-Ramey J, Li Z, Johnson AK, Kobiernicki F, Botes S, et al. Improved molecular diagnosis of patients with neonatal diabetes using a combined next-generation sequencing and MS-MLPA approach. J. Pediatr. Endocrinol. Metab. 2016;29:523–531. - PubMed
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- Balamurugan AN, Chang Y, Fung JJ, Trucco M, Bottino R. Flexible management of enzymatic digestion improves human islet isolation outcome from sub-optimal donor pancreata. Am. J. Transplant. 2003;3:1135–1142. - PubMed
-
- Bolli G, de Feo P, Compagnucci P, Cartechini MG, Angeletti G, Santeusanio F, Brunetti P, Gerich JE. Abnormal glucose counterregulation in insulin-dependent diabetes mellitus. Interaction of anti-insulin antibodies and impaired glucagon and epinephrine secretion. Diabetes. 1983;32:134–141. - PubMed
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- Adolescent
- Adult
- Animals
- Case-Control Studies
- Cellular Reprogramming
- Child
- Diabetes Mellitus, Type 1 / genetics*
- Female
- Gene Expression Regulation*
- Glucagon / metabolism
- Glucagon-Secreting Cells / metabolism*
- Glucagon-Secreting Cells / pathology
- Humans
- Insulin Secretion
- Insulin-Secreting Cells / metabolism
- Insulin-Secreting Cells / pathology
- Male
- Mice
- Middle Aged
- Phenotype
- Tissue Donors
- Transcription Factors / metabolism
- Young Adult
- Transcription Factors
- Glucagon
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The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.
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![Figure 2. T1D α Cells in Recent-Onset…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6368357/bin/nihms963683f2.jpg)
Figure 3. T1D α Cells Do Not…
Figure 3. T1D α Cells Do Not Show Evidence of α-to-β Cell Reprogramming in Normoglycemic,…
Figure 4. Genes Critical to α Cell…
Figure 4. Genes Critical to α Cell Function Are Differentially Expressed in T1D α Cells
- Pancreatic Alpha-Cells Contribute Together With Beta-Cells to CXCL10 Expression in Type 1 Diabetes.Nigi L, Brusco N, Grieco GE, Licata G, Krogvold L, Marselli L, Gysemans C, Overbergh L, Marchetti P, Mathieu C, Dahl Jørgensen K, Sebastiani G, Dotta F. Nigi L, et al. Front Endocrinol (Lausanne). 2020 Sep 15;11:630. doi: 10.3389/fendo.2020.00630. eCollection 2020. Front Endocrinol (Lausanne). 2020. PMID: 33042009 Free PMC article.
- Converting Adult Pancreatic Islet α Cells into β Cells by Targeting Both Dnmt1 and Arx.Chakravarthy H, Gu X, Enge M, Dai X, Wang Y, Damond N, Downie C, Liu K, Wang J, Xing Y, Chera S, Thorel F, Quake S, Oberholzer J, MacDonald PE, Herrera PL, Kim SK. Chakravarthy H, et al. Cell Metab. 2017 Mar 7;25(3):622-634. doi: 10.1016/j.cmet.2017.01.009. Epub 2017 Feb 16. Cell Metab. 2017. PMID: 28215845 Free PMC article.
- β Cells Persist in T1D Pancreata Without Evidence of Ongoing β-Cell Turnover or Neogenesis.Lam CJ, Jacobson DR, Rankin MM, Cox AR, Kushner JA. Lam CJ, et al. J Clin Endocrinol Metab. 2017 Aug 1;102(8):2647-2659. doi: 10.1210/jc.2016-3806. J Clin Endocrinol Metab. 2017. PMID: 28323930 Free PMC article.
- Epigenetic-mediated reprogramming of pancreatic endocrine cells.Mathiyalagan P, Keating ST, Al-Hasani K, El-Osta A. Mathiyalagan P, et al. Antioxid Redox Signal. 2015 Jun 1;22(16):1483-95. doi: 10.1089/ars.2014.6103. Epub 2015 Mar 18. Antioxid Redox Signal. 2015. PMID: 25621632 Review.
- Alpha cell dysfunction in type 1 diabetes.Yosten GLC. Yosten GLC. Peptides. 2018 Feb;100:54-60. doi: 10.1016/j.peptides.2017.12.001. Peptides. 2018. PMID: 29412832 Review.
- Human pancreatic capillaries and nerve fibers persist in type 1 diabetes despite beta cell loss.Richardson TM, Saunders DC, Haliyur R, Shrestha S, Cartailler JP, Reinert RB, Petronglo J, Bottino R, Aramandla R, Bradley AM, Jenkins R, Phillips S, Kang H; Human Pancreas Analysis Program; Caicedo A, Powers AC, Brissova M. Richardson TM, et al. Am J Physiol Endocrinol Metab. 2023 Mar 1;324(3):E251-E267. doi: 10.1152/ajpendo.00246.2022. Epub 2023 Jan 25. Am J Physiol Endocrinol Metab. 2023. PMID: 36696598
- Human alpha cell transcriptomic signatures of types 1 and 2 diabetes highlight disease-specific dysfunction pathways.Bosi E, Marchetti P, Rutter GA, Eizirik DL. Bosi E, et al. iScience. 2022 Sep 3;25(10):105056. doi: 10.1016/j.isci.2022.105056. eCollection 2022 Oct 21. iScience. 2022. PMID: 36134336 Free PMC article.
-
- Alkorta-Aranburu G, Sukhanova M, Carmody D, Hoffman T, Wysinger L, Keller-Ramey J, Li Z, Johnson AK, Kobiernicki F, Botes S, et al. Improved molecular diagnosis of patients with neonatal diabetes using a combined next-generation sequencing and MS-MLPA approach. J. Pediatr. Endocrinol. Metab. 2016;29:523–531. - PubMed
-
- Balamurugan AN, Chang Y, Fung JJ, Trucco M, Bottino R. Flexible management of enzymatic digestion improves human islet isolation outcome from sub-optimal donor pancreata. Am. J. Transplant. 2003;3:1135–1142. - PubMed
-
- Bolli G, de Feo P, Compagnucci P, Cartechini MG, Angeletti G, Santeusanio F, Brunetti P, Gerich JE. Abnormal glucose counterregulation in insulin-dependent diabetes mellitus. Interaction of anti-insulin antibodies and impaired glucagon and epinephrine secretion. Diabetes. 1983;32:134–141. - PubMed
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
- Research Support, U.S. Gov't, Non-P.H.S.
- Adolescent
- Adult
- Animals
- Case-Control Studies
- Cellular Reprogramming
- Child
- Diabetes Mellitus, Type 1 / genetics*
- Female
- Gene Expression Regulation*
- Glucagon / metabolism
- Glucagon-Secreting Cells / metabolism*
- Glucagon-Secreting Cells / pathology
- Humans
- Insulin Secretion
- Insulin-Secreting Cells / metabolism
- Insulin-Secreting Cells / pathology
- Male
- Mice
- Middle Aged
- Phenotype
- Tissue Donors
- Transcription Factors / metabolism
- Young Adult
- Transcription Factors
- Glucagon
- R01 DK090570/DK/NIDDK NIH HHS/United States
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The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.
National Library of Medicine
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Bethesda, MD 20894
![Figure 3. T1D α Cells Do Not…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6368357/bin/nihms963683f3.jpg)
Figure 4. Genes Critical to α Cell…
Figure 4. Genes Critical to α Cell Function Are Differentially Expressed in T1D α Cells
- Pancreatic Alpha-Cells Contribute Together With Beta-Cells to CXCL10 Expression in Type 1 Diabetes.Nigi L, Brusco N, Grieco GE, Licata G, Krogvold L, Marselli L, Gysemans C, Overbergh L, Marchetti P, Mathieu C, Dahl Jørgensen K, Sebastiani G, Dotta F. Nigi L, et al. Front Endocrinol (Lausanne). 2020 Sep 15;11:630. doi: 10.3389/fendo.2020.00630. eCollection 2020. Front Endocrinol (Lausanne). 2020. PMID: 33042009 Free PMC article.
- Converting Adult Pancreatic Islet α Cells into β Cells by Targeting Both Dnmt1 and Arx.Chakravarthy H, Gu X, Enge M, Dai X, Wang Y, Damond N, Downie C, Liu K, Wang J, Xing Y, Chera S, Thorel F, Quake S, Oberholzer J, MacDonald PE, Herrera PL, Kim SK. Chakravarthy H, et al. Cell Metab. 2017 Mar 7;25(3):622-634. doi: 10.1016/j.cmet.2017.01.009. Epub 2017 Feb 16. Cell Metab. 2017. PMID: 28215845 Free PMC article.
- β Cells Persist in T1D Pancreata Without Evidence of Ongoing β-Cell Turnover or Neogenesis.Lam CJ, Jacobson DR, Rankin MM, Cox AR, Kushner JA. Lam CJ, et al. J Clin Endocrinol Metab. 2017 Aug 1;102(8):2647-2659. doi: 10.1210/jc.2016-3806. J Clin Endocrinol Metab. 2017. PMID: 28323930 Free PMC article.
- Epigenetic-mediated reprogramming of pancreatic endocrine cells.Mathiyalagan P, Keating ST, Al-Hasani K, El-Osta A. Mathiyalagan P, et al. Antioxid Redox Signal. 2015 Jun 1;22(16):1483-95. doi: 10.1089/ars.2014.6103. Epub 2015 Mar 18. Antioxid Redox Signal. 2015. PMID: 25621632 Review.
- Alpha cell dysfunction in type 1 diabetes.Yosten GLC. Yosten GLC. Peptides. 2018 Feb;100:54-60. doi: 10.1016/j.peptides.2017.12.001. Peptides. 2018. PMID: 29412832 Review.
- Human pancreatic capillaries and nerve fibers persist in type 1 diabetes despite beta cell loss.Richardson TM, Saunders DC, Haliyur R, Shrestha S, Cartailler JP, Reinert RB, Petronglo J, Bottino R, Aramandla R, Bradley AM, Jenkins R, Phillips S, Kang H; Human Pancreas Analysis Program; Caicedo A, Powers AC, Brissova M. Richardson TM, et al. Am J Physiol Endocrinol Metab. 2023 Mar 1;324(3):E251-E267. doi: 10.1152/ajpendo.00246.2022. Epub 2023 Jan 25. Am J Physiol Endocrinol Metab. 2023. PMID: 36696598
- Human alpha cell transcriptomic signatures of types 1 and 2 diabetes highlight disease-specific dysfunction pathways.Bosi E, Marchetti P, Rutter GA, Eizirik DL. Bosi E, et al. iScience. 2022 Sep 3;25(10):105056. doi: 10.1016/j.isci.2022.105056. eCollection 2022 Oct 21. iScience. 2022. PMID: 36134336 Free PMC article.
-
- Alkorta-Aranburu G, Sukhanova M, Carmody D, Hoffman T, Wysinger L, Keller-Ramey J, Li Z, Johnson AK, Kobiernicki F, Botes S, et al. Improved molecular diagnosis of patients with neonatal diabetes using a combined next-generation sequencing and MS-MLPA approach. J. Pediatr. Endocrinol. Metab. 2016;29:523–531. - PubMed
-
- Balamurugan AN, Chang Y, Fung JJ, Trucco M, Bottino R. Flexible management of enzymatic digestion improves human islet isolation outcome from sub-optimal donor pancreata. Am. J. Transplant. 2003;3:1135–1142. - PubMed
-
- Bolli G, de Feo P, Compagnucci P, Cartechini MG, Angeletti G, Santeusanio F, Brunetti P, Gerich JE. Abnormal glucose counterregulation in insulin-dependent diabetes mellitus. Interaction of anti-insulin antibodies and impaired glucagon and epinephrine secretion. Diabetes. 1983;32:134–141. - PubMed
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
- Research Support, U.S. Gov't, Non-P.H.S.
- Adolescent
- Adult
- Animals
- Case-Control Studies
- Cellular Reprogramming
- Child
- Diabetes Mellitus, Type 1 / genetics*
- Female
- Gene Expression Regulation*
- Glucagon / metabolism
- Glucagon-Secreting Cells / metabolism*
- Glucagon-Secreting Cells / pathology
- Humans
- Insulin Secretion
- Insulin-Secreting Cells / metabolism
- Insulin-Secreting Cells / pathology
- Male
- Mice
- Middle Aged
- Phenotype
- Tissue Donors
- Transcription Factors / metabolism
- Young Adult
- Transcription Factors
- Glucagon
- R01 DK090570/DK/NIDDK NIH HHS/United States
- UC4 DK104211/DK/NIDDK NIH HHS/United States
- UC4 DK108120/DK/NIDDK NIH HHS/United States
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![Figure 4. Genes Critical to α Cell…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6368357/bin/nihms963683f4.jpg)
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Source: PubMed