Retrograde perfusion as a model for testing the relative effects of glucose versus insulin on the A cell.

Abstract

In order to determine whether the A cell may be directly suppressed by glucose in the absence of insulin, canine pancreata were perfused in vitro, both antegrade, through the arterial system and retrograde, through the venous system. Studies of the islet microvasculature have suggested that blood flows from the B cell core to the mantle; thus, the A cell may be tonically inhibited by intra-islet insulin. Retrograde perfusion may then be expected to prevent insulin from reaching the A cell, releasing it from inhibition.Retrograde perfusion with 88 mg/dl glucose markedly increased both insulin and glucagon secretion relative to antegrade levels. In a series of experiments, glucose concentrations were changed from 88 to 200 mg/dl. An antegrade glucose change resulted in increased insulin (134±21%; P < 0.0025) and decreased glucagon (-26±9%, P < 0.025) secretion. A retrograde glucose increase resulted in increased secretion of both insulin (91±15%; P < 0.0005) and glucagon (23±9%; P < 0.0125). To confirm that retrograde perfusion deprived the A cell of endogenous core derived, vascularly delivered insulin, possibly resulting in increased insulin sensitivity, 0.3 mU/ml exogenous porcine insulin was infused. Antegrade, 0.3 mU/mI insulin, had no effect on glucagon secretion (P < 0.250), while retrograde infusion of 0.3 mU/mI insulin significantly inhibited glucagon secretion (-31 + 8%; P < 0.0005).The results of our study support the concept that the direction of blood flow and of flow-dependent intra-islet hormone interactions are from the islet B cell core to the mantle. It was further concluded that the normal A cell may not be suppressed by glucose in the absence of insulin.

α- and β-Cell Responses to Small Changes in Plasma Glucose in the Conscious Dog

“…It should be remembered that insulin secretion decreased markedly in response to hypoglycemia. Anatomical and physiological studies (35)(36)(37)(38) suggest that blood in the islet flows from ␤-cells to ␣-cells, thereby exposing ␣-cells to high concentrations of intraislet insulin. It is possible, therefore, that the decrease in insulin secretion from ␤-cells lowered the level of the insulin concentration to which ␣-cells were exposed and, in turn, caused an increase in glucagon release.…”

Insulin modulation of glucagon secretion: The role of insulin and other factors in the regulation of glucagon secretion

“…[16][17][18] Several in vivo and ex vivo studies have revealed that insulin suppresses glucagon secretion. In insulinopenic animal models, exogenous insulin suppressed glucagon secretion, 14,19,20 while conversely, suppression of insulin action by infusion of an anti-insulin antibody increased glucagon release. 21 In humans, insulin has been reported to suppress glucagon secretion.…”

“…However, it should be noted that some reports indicate that somatostatin involvement in glucagon suppression during hyperglycemia may be less important than the contribution of β-cell secretion teleologically and in accordance with the direction of intra-islet microcirculation, namely β to α to δ. 14,15 Further investigation is necessary to dissect the intra-islet relationship of islet hormones.…”

Molecular Mechanism Underlying the Intra-Islet Regulation of Glucagon Secretion

“…It is likely that this distribution and arrangement of different islet cell types is teleologically important for physiological regulation between the cells since the blood flows from the center of the islets toward periphery; i.e. -cells to non--cells in the islet microcirculation system (Bonner- Weir and Orci, 1982;Stagner and Samols, 1986), suggesting that secreted insulin regulates hormone secretion from other islet cell types. This architecture is typically preserved in rodent islets, while in humans, non--cells are often observed both at the periphery and also seemingly in clusters within the center of islets (Cabrera et al, 2006).…”

“…In clinical studies in human type 1 diabetes patients whose -cell function is considered to be extinct (Asplin et al, 1981;Gerich et al, 1975), along with basic studies in insulinopenic animal models (Maruyama et al, 1984;Stagner and Samols, 1986;Weir et al, 1976), indicate Schematic image for the -cell-mediated suppression of glucagon secretion from -cells via a paracrine mechanism. The -cell secretes insulin, -amino-butyric acid (GABA), and zinc irons (Zn) which suppress glucagon secretion.…”