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- Title
Pulsatility of Glucagon Counterregulation in STZ Diabetes Rat Model: Implications for Intrapancreatic Network Control of Glucagon Secretion.
- Authors
Farhy, Leon S.; Zhongmin Du; Qiang Zeng; Veldhuis, Paula P.; Johnson, Michael L.; Brayman, Kenneth L.; McCall, Anthony L.
- Abstract
Glucagon counterregulation protects against hypoglycemia; its decline prevents safe control of hyperglycemia but precise mechanisms underlying defects in type 1 diabetes are unknown. We combined experimental and mathematical approaches analyzing intrapancreatic mechanisms controlling glucagon counterregulation assuming an intraislet hormone network. We studied STZ-treated (80 mg/kg) male Wistar rats, which have a simplified islet network ([beta]-cell loss) and absence of glucagon counterregulation. Counterregulation was restored by in vivo intrapancreatic infusion of [alpha]-cell inhibitory signals (insulin or somatostatin) that were switched off at hypoglycemia. Frequent sampling allowed analysis of glucagon pulsatility by deconvolution. Feedback modeling using differential equations studied the dominant regulators in the glucagon control network. Pulsatile glucagon counterregulation was confirmed by deconvolution: average interpulse interval of 12.3 min (n=5; SD=2.4) and half-life of 1.3 min (n=5; SD=0.3). Mathematical modeling showed that putative interaction between [alpha] and [delta] cells can explain the specifics of the observed release profiles and the model-predicted response to a switch-off signal agrees with the experiments (see Figure). Mechanistically, the "switch-off" effect is interpreted as a rebound response of the [alpha]-[delta] cell network to disinhibition by [alpha]-cell suppressing signal. We showed that in STZ-treated rats, switch-off triggered secretion of glucagon is pulsatile suggesting that at least one [beta]-cell-independent intraislet feedback impacts glucagon counterregulation. The results confirm prior observations of the switch-off effect, by which insulin stimulates glucagon release. They demonstrate the utility of advanced mathematical modeling, which modifies the switch-off hypothesis by predicting that any [alpha]-cell suppressing signal (such as somatostatin) may exert similar regulatory control and trigger glucagon release upon disinhibition.
- Subjects
GLUCAGON; HYPOGLYCEMIA; DIABETES; INSULIN; SOMATOSTATIN; CELLS
- Publication
Diabetes, 2007, Vol 56, pA166
- ISSN
0012-1797
- Publication type
Article