Walter S. Zawalich, Marc Bonnet-Eymard, and Kathleen C. Zawalich

Yale University School of Nursing, 100 Church Street South, New Haven, CT 06536-0740 USA

Received 2/24/97; Accepted 2/27/97; On-line 3/15/97

3. Multiple Effects of Glucose on the Pancreatic ß-cell

3.1 Acute Regulation of insulin release.

The release of insulin from the pancreatic ß-cell is dependent upon the interaction of a variety of signaling molecules with ß-cell signal transduction systems (1-3). It is commonly accepted that glucose is the primary physiologic regulator of ß-cell sensitivity and that it exerts multiple effects on ß-cell response patterns. At postprandial concentrations, it independently increases insulin secretion. Sustained, short-term (1 hour or less) glucose stimulation of rat islets results in a biphasic insulin secretory response (Figure 1) characterized by a transient first phase of release and a slowly rising and sustained second phase response that is, depending on the preparation and the glucose level, 30-60 fold greater than prestimulatory release rates (4-8). A qualitatively (9, 10) and quantitatively (11, 12) similar biphasic insulin secretory response to sustained glucose stimulation has been noted from human ß-cells studied with the hyperglycemic clamp methodologies, observations which lend credence to the concept that the biochemical signaling events which regulate insulin secretion from rat ß-cells are similar, if not identical, to the events which occur in human ß-cells. Thus it is not unreasonable to extrapolate findings made with rat islets to human islets. As will become evident later, similar extrapolations with mouse ß-cells must be cautiously made since pronounced species differences, which have been ignored in many instances, exist in the patterns of glucose-induced insulin secretion from mouse islets.

Figure 1. Biphasic Glucose-induced Insulin Secretion from Perifused Rat Islets but not Perifused Mouse Islets. Groups of rat (closed circles) or mouse (open circles) islets were collagenase isolated and perifused with 3mM glucose (G3) for 30 minutes prior to stimulation with 15mM glucose (G15). Note the characteristic biphasic insulin secretory response characterized by a rising second phase evoked from rat islets but the flat sustained response of mouse islets.

3.2 Fail-safe regulation of insulin secretion and time-dependent potentiation

In addition to stimulating a biphasic insulin secretory response, glucose also performs the role of a fail-safe regulator of secretion. For example, at glucose levels greater than 6mM acetylcholine (13) or cholecystokinin (CCK) (14) are potent stimulants for secretion but at hypoglycemic levels they fail to activate insulin exocytosis from the ß-cell. This, so-called permissive effect of glucose, is thought to be a result of glucose metabolism and the provision of adequate amounts of ATP to support a secretory response (1). The fact that other nutrient secretagogues that are well metabolized supply the same permissive signals supports this concept (15). Glucose stimulation of the ß-cell also sensitizes it to subsequent restimulation with a variety of agonists (4, 7, 16, 17). This response is induced by prior short-term stimulation with glucose and manifests itself in the heightened release of insulin during subsequent restimulation. Termed time-dependent potentiation (TDP), this phenomenon can be induced by agonists as structurally diverse as acetylcholine (18), cholecystokinin (19), alpha-ketoisocaproate (20), glyceraldehyde (21), monomethylsuccinate (15), methyl pyruvate (22) and, perhaps most importantly, by the PKC activator tetradecanoyl phorbol acetate (TPA) (23, 24). TDP may play a particularly important role in cephalic phase insulin secretion where vagally-derived acetylcholine may be responsible for its induction (25, 26).

3.3 Time-dependent suppression of insulin release

In addition to acutely regulating insulin secretion, acting as a fail-safe modulator when islets are stimulated with neurohumoral agonists or gut peptides like CCK, and inducing TDP, glucose exerts another additional important effect on the ß-cell. When chronically stimulated with high glucose, ß-cell insulin secretion fails. Termed the third phase of secretion by Grodsky and coworkers (27, 28), ß-cell desensitization is an inevitable consequence of sustained high glucose exposure (6). This process, also referred to as time-dependent suppression (TDS) of release (29), may be analogous to the ß-cell glucose toxicity noted in human diabetes and other animal models of glucose intolerance (30-32). The capacity to induce TDS of insulin secretion is not confined to glucose alone. It can be induced by sustained exposure to agonists as diverse as cholecystokinin (33), glucosamine (34), carbachol (35) and forskolin (36). What suppressed islets have in common is their inability to respond, in terms of increases in both PLC-mediated PI hydrolysis and insulin secretion, when subsequently challenged with high glucose (29). It should be emphasized that secretory failure is not the result of insulin depletion since desensitized islets still contain large amounts of insulin (6, 35, 37) and they will respond to an agonist which bypasses the lesion in PLC activation (15, 34).