FIG. 2.
A frequency-of-response histogram (a) and scatter plot (b) analysis summarizing the interaction of glucose and GLP-1 to depolarize β-cells. When initially challenged with 10 mM glucose the majority of cells exhibited a ⩽15mV depolarizing response, as indicated by either the fully shaded histogram bars in a, or the position of the triangles relative to the x-axis in b (where one triangle equals one cell except for the n = 4 cells triangle). When subsequently challenged with a combined application of 10 mM glucose and 10 nM GLP-1, the distribution of the histogram plot was shifted to the right (a, cross-hatched bars) and a subpopulation of β-cells labelled set 3 was rendered glucose competent (b, as indicated by the position of the triangles relative to the y-axis). In contrast, cells that comprised set 2 exhibited a dose-dependent depolarizing response to glucose over a concentration range of ~7–20 mM glucose and were constitutively glucose competent. Each illustration depicts results obtained from the same 25 cells. Test substances were applied for 30 s at 10-min intervals, and only cells exhibiting a resting membrane potential of at least −55 mV were included in the data analysis. More prolonged (3–5 min) application of 10 or 20 mM glucose (without GLP-1) to glucose-insensitive β-cells that comprised sets 1 and 3 did not significantly increase the magnitude of their depolarizing response. Such glucose resistance may reflect metabolic dysfunctions resulting from disaggregation of the islets and the loss of cell-to-cell contacts, or alternatively the loss of paracrine/endocrine influences that regulate glucose responsiveness.