Morphologic and functional changes in sympathetic nerve relationships with pancreatic α-cells after destruction of β-cells in rats

M. Tominaga, H. Maruyama, Michael Vasko, D. Baetens, L. Orci, R. H. Unger

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Insulin-dependent diabetes mellitus (IDDM) in humans is accompanied by an attenuation of the response of glucagon to hypoglycemia. To identify an animal model of IDDM with α-cell unresponsiveness to glucopenia in which to pursue morphologic and in vitro functional investigation of the lesion, pancreases isolated from rats with IDDM induced by streptozocin (STZ) or occurring spontaneously in BB/W rats were perfused with buffer containing 150, 25, and 150 mg/dl of glucose. In both forms of IDDM the normal glucagon rise during glucopenia was markedly impaired, suggesting an abnormality comparable to that of human IDDM. Studies of the insular sympathetic apparatus were conducted in these rat models. Electron-microscopic examination of peri-insular nerve endings disclosed no discernible abnormality in either form of rat IDDM. However, morphometric analysis of contacts between [3H]norepinephrine-labeled sympathetic nerve terminals and α-cells in pancreases from STZ-induced diabetic (STZ-D) rats revealed a 65-70% reduction in direct contacts. An 80% reduction in the number of nerve endings (not labeled) in direct contact with α-cells was also noted in the BB/W diabetic rats. Norepinephrine reuptake, studied only in the STZ-D group, was not impaired. The availability of local endogenous norepinephrine to α-cells and their sensitivity to exogenous norepinephrine was determined by perfusing 2, 5, or 10 μg/ml of tyramine, a releaser of endogenous norepinephrine, and norepinephrine at a concentration that in pancreases from nondiabetic rats gave a quantitatively similar glucagon response. In STZ-D pancreases, the glucagon response to 10 μg/ml of tyramine was only 11.5% of normal, whereas the response to an equipotent concentration of norepinephrine (0.1 μM) was 55% of normal. These results are consistent with a reduction in both sensitivity to and availability of norepinephrine. The glucagon response of pancreases from BB/W diabetic rats to 10 μg/ml tyramine was 29% of normal, but this was not significantly less than the observed response to a comparable norepinephrine concentration. Consequently, in this group, reduced α-cell sensitivity to norepinephrine alone could have accounted for the reduced response to tyramine. The results suggest that 1) the sympathetic nerve endings are electron-microscopically intact in both spontaneous and insulin-dependent STZ-D rats; 2) there are fewer direct contacts between sympathetic nerve terminals and α-cells in both forms of diabetes; 3) sensitivity of α-cells to perfused norepinephrine is reduced in isolated pancreases of both spontaneously diabetic and STZ-D rats in proportion to reduction in baseline glucagon secretion; and 4) in the STZ-D group, but not in the BB/W diabetic group, there was evidence of reduced availability of locally released norepinephrine based on an α-cell response well below that of an equipotent norepinephrine concentration.

Original languageEnglish (US)
Pages (from-to)365-373
Number of pages9
JournalDiabetes
Volume36
Issue number3
StatePublished - 1987
Externally publishedYes

Fingerprint

Norepinephrine
Streptozocin
Glucagon
Type 1 Diabetes Mellitus
Pancreas
Tyramine
Nerve Endings
Inbred BB Rats
Electrons
Neurons
Hypoglycemia
Buffers
Animal Models
Insulin
Glucose

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Internal Medicine

Cite this

Morphologic and functional changes in sympathetic nerve relationships with pancreatic α-cells after destruction of β-cells in rats. / Tominaga, M.; Maruyama, H.; Vasko, Michael; Baetens, D.; Orci, L.; Unger, R. H.

In: Diabetes, Vol. 36, No. 3, 1987, p. 365-373.

Research output: Contribution to journalArticle

Tominaga, M. ; Maruyama, H. ; Vasko, Michael ; Baetens, D. ; Orci, L. ; Unger, R. H. / Morphologic and functional changes in sympathetic nerve relationships with pancreatic α-cells after destruction of β-cells in rats. In: Diabetes. 1987 ; Vol. 36, No. 3. pp. 365-373.
@article{8490fe1aacfe409297d3ee4d180fcdc8,
title = "Morphologic and functional changes in sympathetic nerve relationships with pancreatic α-cells after destruction of β-cells in rats",
abstract = "Insulin-dependent diabetes mellitus (IDDM) in humans is accompanied by an attenuation of the response of glucagon to hypoglycemia. To identify an animal model of IDDM with α-cell unresponsiveness to glucopenia in which to pursue morphologic and in vitro functional investigation of the lesion, pancreases isolated from rats with IDDM induced by streptozocin (STZ) or occurring spontaneously in BB/W rats were perfused with buffer containing 150, 25, and 150 mg/dl of glucose. In both forms of IDDM the normal glucagon rise during glucopenia was markedly impaired, suggesting an abnormality comparable to that of human IDDM. Studies of the insular sympathetic apparatus were conducted in these rat models. Electron-microscopic examination of peri-insular nerve endings disclosed no discernible abnormality in either form of rat IDDM. However, morphometric analysis of contacts between [3H]norepinephrine-labeled sympathetic nerve terminals and α-cells in pancreases from STZ-induced diabetic (STZ-D) rats revealed a 65-70{\%} reduction in direct contacts. An 80{\%} reduction in the number of nerve endings (not labeled) in direct contact with α-cells was also noted in the BB/W diabetic rats. Norepinephrine reuptake, studied only in the STZ-D group, was not impaired. The availability of local endogenous norepinephrine to α-cells and their sensitivity to exogenous norepinephrine was determined by perfusing 2, 5, or 10 μg/ml of tyramine, a releaser of endogenous norepinephrine, and norepinephrine at a concentration that in pancreases from nondiabetic rats gave a quantitatively similar glucagon response. In STZ-D pancreases, the glucagon response to 10 μg/ml of tyramine was only 11.5{\%} of normal, whereas the response to an equipotent concentration of norepinephrine (0.1 μM) was 55{\%} of normal. These results are consistent with a reduction in both sensitivity to and availability of norepinephrine. The glucagon response of pancreases from BB/W diabetic rats to 10 μg/ml tyramine was 29{\%} of normal, but this was not significantly less than the observed response to a comparable norepinephrine concentration. Consequently, in this group, reduced α-cell sensitivity to norepinephrine alone could have accounted for the reduced response to tyramine. The results suggest that 1) the sympathetic nerve endings are electron-microscopically intact in both spontaneous and insulin-dependent STZ-D rats; 2) there are fewer direct contacts between sympathetic nerve terminals and α-cells in both forms of diabetes; 3) sensitivity of α-cells to perfused norepinephrine is reduced in isolated pancreases of both spontaneously diabetic and STZ-D rats in proportion to reduction in baseline glucagon secretion; and 4) in the STZ-D group, but not in the BB/W diabetic group, there was evidence of reduced availability of locally released norepinephrine based on an α-cell response well below that of an equipotent norepinephrine concentration.",
author = "M. Tominaga and H. Maruyama and Michael Vasko and D. Baetens and L. Orci and Unger, {R. H.}",
year = "1987",
language = "English (US)",
volume = "36",
pages = "365--373",
journal = "Diabetes",
issn = "0012-1797",
publisher = "American Diabetes Association Inc.",
number = "3",

}

TY - JOUR

T1 - Morphologic and functional changes in sympathetic nerve relationships with pancreatic α-cells after destruction of β-cells in rats

AU - Tominaga, M.

AU - Maruyama, H.

AU - Vasko, Michael

AU - Baetens, D.

AU - Orci, L.

AU - Unger, R. H.

PY - 1987

Y1 - 1987

N2 - Insulin-dependent diabetes mellitus (IDDM) in humans is accompanied by an attenuation of the response of glucagon to hypoglycemia. To identify an animal model of IDDM with α-cell unresponsiveness to glucopenia in which to pursue morphologic and in vitro functional investigation of the lesion, pancreases isolated from rats with IDDM induced by streptozocin (STZ) or occurring spontaneously in BB/W rats were perfused with buffer containing 150, 25, and 150 mg/dl of glucose. In both forms of IDDM the normal glucagon rise during glucopenia was markedly impaired, suggesting an abnormality comparable to that of human IDDM. Studies of the insular sympathetic apparatus were conducted in these rat models. Electron-microscopic examination of peri-insular nerve endings disclosed no discernible abnormality in either form of rat IDDM. However, morphometric analysis of contacts between [3H]norepinephrine-labeled sympathetic nerve terminals and α-cells in pancreases from STZ-induced diabetic (STZ-D) rats revealed a 65-70% reduction in direct contacts. An 80% reduction in the number of nerve endings (not labeled) in direct contact with α-cells was also noted in the BB/W diabetic rats. Norepinephrine reuptake, studied only in the STZ-D group, was not impaired. The availability of local endogenous norepinephrine to α-cells and their sensitivity to exogenous norepinephrine was determined by perfusing 2, 5, or 10 μg/ml of tyramine, a releaser of endogenous norepinephrine, and norepinephrine at a concentration that in pancreases from nondiabetic rats gave a quantitatively similar glucagon response. In STZ-D pancreases, the glucagon response to 10 μg/ml of tyramine was only 11.5% of normal, whereas the response to an equipotent concentration of norepinephrine (0.1 μM) was 55% of normal. These results are consistent with a reduction in both sensitivity to and availability of norepinephrine. The glucagon response of pancreases from BB/W diabetic rats to 10 μg/ml tyramine was 29% of normal, but this was not significantly less than the observed response to a comparable norepinephrine concentration. Consequently, in this group, reduced α-cell sensitivity to norepinephrine alone could have accounted for the reduced response to tyramine. The results suggest that 1) the sympathetic nerve endings are electron-microscopically intact in both spontaneous and insulin-dependent STZ-D rats; 2) there are fewer direct contacts between sympathetic nerve terminals and α-cells in both forms of diabetes; 3) sensitivity of α-cells to perfused norepinephrine is reduced in isolated pancreases of both spontaneously diabetic and STZ-D rats in proportion to reduction in baseline glucagon secretion; and 4) in the STZ-D group, but not in the BB/W diabetic group, there was evidence of reduced availability of locally released norepinephrine based on an α-cell response well below that of an equipotent norepinephrine concentration.

AB - Insulin-dependent diabetes mellitus (IDDM) in humans is accompanied by an attenuation of the response of glucagon to hypoglycemia. To identify an animal model of IDDM with α-cell unresponsiveness to glucopenia in which to pursue morphologic and in vitro functional investigation of the lesion, pancreases isolated from rats with IDDM induced by streptozocin (STZ) or occurring spontaneously in BB/W rats were perfused with buffer containing 150, 25, and 150 mg/dl of glucose. In both forms of IDDM the normal glucagon rise during glucopenia was markedly impaired, suggesting an abnormality comparable to that of human IDDM. Studies of the insular sympathetic apparatus were conducted in these rat models. Electron-microscopic examination of peri-insular nerve endings disclosed no discernible abnormality in either form of rat IDDM. However, morphometric analysis of contacts between [3H]norepinephrine-labeled sympathetic nerve terminals and α-cells in pancreases from STZ-induced diabetic (STZ-D) rats revealed a 65-70% reduction in direct contacts. An 80% reduction in the number of nerve endings (not labeled) in direct contact with α-cells was also noted in the BB/W diabetic rats. Norepinephrine reuptake, studied only in the STZ-D group, was not impaired. The availability of local endogenous norepinephrine to α-cells and their sensitivity to exogenous norepinephrine was determined by perfusing 2, 5, or 10 μg/ml of tyramine, a releaser of endogenous norepinephrine, and norepinephrine at a concentration that in pancreases from nondiabetic rats gave a quantitatively similar glucagon response. In STZ-D pancreases, the glucagon response to 10 μg/ml of tyramine was only 11.5% of normal, whereas the response to an equipotent concentration of norepinephrine (0.1 μM) was 55% of normal. These results are consistent with a reduction in both sensitivity to and availability of norepinephrine. The glucagon response of pancreases from BB/W diabetic rats to 10 μg/ml tyramine was 29% of normal, but this was not significantly less than the observed response to a comparable norepinephrine concentration. Consequently, in this group, reduced α-cell sensitivity to norepinephrine alone could have accounted for the reduced response to tyramine. The results suggest that 1) the sympathetic nerve endings are electron-microscopically intact in both spontaneous and insulin-dependent STZ-D rats; 2) there are fewer direct contacts between sympathetic nerve terminals and α-cells in both forms of diabetes; 3) sensitivity of α-cells to perfused norepinephrine is reduced in isolated pancreases of both spontaneously diabetic and STZ-D rats in proportion to reduction in baseline glucagon secretion; and 4) in the STZ-D group, but not in the BB/W diabetic group, there was evidence of reduced availability of locally released norepinephrine based on an α-cell response well below that of an equipotent norepinephrine concentration.

UR - http://www.scopus.com/inward/record.url?scp=0023608774&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0023608774&partnerID=8YFLogxK

M3 - Article

VL - 36

SP - 365

EP - 373

JO - Diabetes

JF - Diabetes

SN - 0012-1797

IS - 3

ER -