Islet Sympathetic Innervation and Islet Neuropathology in Patients with Type 1 Diabetes

Overview

Journal Sci Rep

Specialty Science

Date 2021 Mar 23

PMID 33753784

Citations 17

Authors

Martha Campbell-Thompson

Elizabeth A Butterworth

J Lucas Boatwright

Malavika A Nair

Lith H Nasif

Kamal Nasif

Andy Y Revell

Alberto Riva

Clayton E Mathews

Ivan C Gerling

Desmond A Schatz

Mark A Atkinson

Affiliations

Soon will be listed here.

Abstract

Dysregulation of glucagon secretion in type 1 diabetes (T1D) involves hypersecretion during postprandial states, but insufficient secretion during hypoglycemia. The sympathetic nervous system regulates glucagon secretion. To investigate islet sympathetic innervation in T1D, sympathetic tyrosine hydroxylase (TH) axons were analyzed in control non-diabetic organ donors, non-diabetic islet autoantibody-positive individuals (AAb), and age-matched persons with T1D. Islet TH axon numbers and density were significantly decreased in AAb compared to T1D with no significant differences observed in exocrine TH axon volume or lengths between groups. TH axons were in close approximation to islet α-cells in T1D individuals with long-standing diabetes. Islet RNA-sequencing and qRT-PCR analyses identified significant alterations in noradrenalin degradation, α-adrenergic signaling, cardiac β-adrenergic signaling, catecholamine biosynthesis, and additional neuropathology pathways. The close approximation of TH axons at islet α-cells supports a model for sympathetic efferent neurons directly regulating glucagon secretion. Sympathetic islet innervation and intrinsic adrenergic signaling pathways could be novel targets for improving glucagon secretion in T1D.

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References

Kakoki M, Bahnson E, Hagaman J, Siletzky R, Grant R, Kayashima Y . Engulfment and cell motility protein 1 potentiates diabetic cardiomyopathy via Rac-dependent and Rac-independent ROS production. JCI Insight. 2019; 4(12). PMC: 6629098. DOI: 10.1172/jci.insight.127660. View

Bolli G, Dimitriadis G, Pehling G, Baker B, Haymond M, Cryer P . Abnormal glucose counterregulation after subcutaneous insulin in insulin-dependent diabetes mellitus. N Engl J Med. 1984; 310(26):1706-11. DOI: 10.1056/NEJM198406283102605. View

Langmead B, Salzberg S . Fast gapped-read alignment with Bowtie 2. Nat Methods. 2012; 9(4):357-9. PMC: 3322381. DOI: 10.1038/nmeth.1923. View

Iglesias-Ara A, Zenarruzabeitia O, Buelta L, Merino J, Zubiaga A . E2F1 and E2F2 prevent replicative stress and subsequent p53-dependent organ involution. Cell Death Differ. 2015; 22(10):1577-89. PMC: 4563787. DOI: 10.1038/cdd.2015.4. View

Rickels M . Hypoglycemia-associated autonomic failure, counterregulatory responses, and therapeutic options in type 1 diabetes. Ann N Y Acad Sci. 2019; 1454(1):68-79. PMC: 6945804. DOI: 10.1111/nyas.14214. View

Amella C, Cappello F, Kahl P, Fritsch H, Lozanoff S, Sergi C . Spatial and temporal dynamics of innervation during the development of fetal human pancreas. Neuroscience. 2008; 154(4):1477-87. DOI: 10.1016/j.neuroscience.2008.04.050. View

Dominguez Gutierrez G, Gromada J, Sussel L . Heterogeneity of the Pancreatic Beta Cell. Front Genet. 2017; 8:22. PMC: 5337801. DOI: 10.3389/fgene.2017.00022. View

Unger R, Cherrington A . Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover. J Clin Invest. 2012; 122(1):4-12. PMC: 3248306. DOI: 10.1172/JCI60016. View

Tominaga M, Maruyama H, Vasko M, Baetens D, Orci L, Unger R . Morphologic and functional changes in sympathetic nerve relationships with pancreatic alpha-cells after destruction of beta-cells in rats. Diabetes. 1987; 36(3):365-73. DOI: 10.2337/diab.36.3.365. View

10.

Marselli L, Thorne J, Dahiya S, Sgroi D, Sharma A, Bonner-Weir S . Gene expression profiles of Beta-cell enriched tissue obtained by laser capture microdissection from subjects with type 2 diabetes. PLoS One. 2010; 5(7):e11499. PMC: 2903480. DOI: 10.1371/journal.pone.0011499. View

11.

Kitamura N, Mori Y, Hondo E, Baltazar E, Yamada J . An immunohistochemical survey of catecholamine-synthesizing enzyme-immunoreactive nerves and endocrine cells in the bovine pancreas. Anat Histol Embryol. 1999; 28(2):81-4. DOI: 10.1046/j.1439-0264.1999.00135.x. View

12.

Gerich J, Langlois M, Noacco C, KARAM J, FORSHAM P . Lack of glucagon response to hypoglycemia in diabetes: evidence for an intrinsic pancreatic alpha cell defect. Science. 1973; 182(4108):171-3. DOI: 10.1126/science.182.4108.171. View

13.

ITURRIZA F, Thibault J . Immunohistochemical investigation of tyrosine-hydroxylase in the islets of Langerhans of adult mice, rats and guinea pigs. Neuroendocrinology. 1993; 57(3):476-80. DOI: 10.1159/000126394. View

14.

Ahren B . Autonomic regulation of islet hormone secretion--implications for health and disease. Diabetologia. 2000; 43(4):393-410. DOI: 10.1007/s001250051322. View

15.

Romanska H, Bishop A, Lee J, Walsh F, Spitz L, Polak J . Idiopathic constipation is not associated with increased NCAM expression on intestinal muscle. Dig Dis Sci. 1996; 41(7):1298-302. DOI: 10.1007/BF02088550. View

16.

Mundinger T, Mei Q, Foulis A, Fligner C, Hull R, Taborsky Jr G . Human Type 1 Diabetes Is Characterized by an Early, Marked, Sustained, and Islet-Selective Loss of Sympathetic Nerves. Diabetes. 2016; 65(8):2322-30. PMC: 4955989. DOI: 10.2337/db16-0284. View

17.

Love J, Yi E, Smith T . Autonomic pathways regulating pancreatic exocrine secretion. Auton Neurosci. 2006; 133(1):19-34. DOI: 10.1016/j.autneu.2006.10.001. View

18.

Borelli M, Rubio M, Garcia M, Flores L, Gagliardino J . Tyrosine hydroxylase activity in the endocrine pancreas: changes induced by short-term dietary manipulation. BMC Endocr Disord. 2003; 3(1):2. PMC: 153518. DOI: 10.1186/1472-6823-3-2. View

19.

Damond N, Engler S, Zanotelli V, Schapiro D, Wasserfall C, Kusmartseva I . A Map of Human Type 1 Diabetes Progression by Imaging Mass Cytometry. Cell Metab. 2019; 29(3):755-768.e5. PMC: 6821395. DOI: 10.1016/j.cmet.2018.11.014. View

20.

Butterworth E, Dickerson W, Vijay V, Weitzel K, Cooper J, Atkinson E . High Resolution 3D Imaging of the Human Pancreas Neuro-insular Network. J Vis Exp. 2018; (131). PMC: 5912252. DOI: 10.3791/56859. View