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.
Autonomic input is critical for the regulation of glucagon secretion to maintain blood glucose levels. Glucagon secretion is abnormal in patients with type 1 diabetes (T1D) and we hypothesize this results from dysfunctional sympathetic innervation of alpha-cells and may be present in at-risk autoantibody positive (AAb+) individuals. To characterize alpha-cell sympathetic innervation, pancreas tail samples were used from age-matched organ donors in three groups: controls (n=6), AAb+ (4), and T1D (4). Fresh frozen 40μm sections or 1-2 cm optically cleared samples were stained with markers for neuroendocrine cells (GCG, INS), total (NCAM)/ sympathetic nerves (tyrosine hydroxylase (TH)), and vascular smooth muscle cells (SMA) followed by confocal and Lightsheet imaging. To determine whether sympathetic fibers were decreased in AAb+ and/or T1D donors, TH+ fiber numbers were counted within islets and the percentage (%) of TH+ fibers/NCAM+ fibers determined. The TH+ fibers/islet were not significantly different between controls (1.5 ± 0.36, n=6), AAb+ (1.2 ± 0.27 (4)), and T1D (1.8 ± 0.57 (4)) donors (p = 0.07, ANOVA) with similar results for TH+ %. TH+ fibers were observed at alpha-cells in all donors. TH+ nerve densities were also similar between islets and exocrine regions between groups. Microarray analysis of single islet transcriptomes obtained using laser microdissection (n=120 islets, 13 control, 12 T1D) showed decreased expression of VMAT2 in insulin+ islets from T1D donors compared to control islets (p=0.047) while insulin- islets in T1D donors had significantly reduced VMAT2 levels compared to control islets (p<0.0001). These data indicate a potential direct mechanism by which the sympathetic nervous system may regulate alpha-cell glucagon secretion with dysregulation of a vesicular monoamine transporter that accumulates monoamines in synaptic vesicles in islets without beta-cells in T1D donors. Sympathetic innervation of alpha-cells could play a direct role in exacerbation of dysregulated glucagon secretion in T1D. Disclosure E.A. Butterworth: None. L.H. Nasif: None. K. Nasif: None. K.N. Carty: None. C.E. Mathews: None. M.A. Atkinson: Other Relationship; Self; Patent Issued. I.C. Gerling: None. M. Campbell-Thompson: None.
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