Evidence that protecting pancreatic beta cells from chronic overstimulation to maintain glucose homeostasis has led to the concept of “beta cell rest” to preserve or restore beta cell function by temporarily inhibiting insulin secretion. Under normal circumstances this is unnecessary, but in obesity-linked glucose-intolerance and type 2 diabetic conditions beta cells could do with a break.
Normal Beta Cell Function
Normally insulin secretion is required postprandially, so that beta cells are only active a few hours a day and during others already get ”secretory respite.” However, beta cells are not completely asleep functionally because of the balance between insulin production and secretion: for about an hour after insulin secretion is turned off, a parallel up-regulation of insulin production lingers, insuring that the insulin secreted is efficiently replenished to keep the intracellular store of insulin optimal.
Pathologic Beta Cell Function
The situation differs considerably in obesity-linked glucose intolerance or type 2 diabetes. Here, beta cells work strenuously to meet the demand caused by insulin resistance. The resulting hyperinsulinemia is symptomatic of a hardworking beta cell. If accompanied by hyperglycemia, that functional beta cell mass, however hardworking, struggles to compensate, and beta cell dysfunction sets in. This exasperates the situation: beta cells become increasingly vulnerable to stress and exhaustion, eventually prompting loss of additional beta cells.
In this pathologic situation, hardworking beta cells essentially secrete insulin as soon as it is produced. Symptomatic of an obesity-linked glucose-intolerant/type 2 diabetes environment are overworked beta cells with insufficient time to convert fully newly synthesized proinsulin to mature insulin, secreting an increased proportion of less biologically active proinsulin. Also under these conditions (pro)insulin production can fail to keep pace with the high insulin demand, slowly (without therapeutic intervention) decreasing beta cell secretory capacity.
Therapeutically, protecting and preserving whatever functional beta cells remain in obesity-linked glucose intolerance and type 2 diabetes is key. Insulin sensitizers (e.g., thiazolidinediones), and diet and exercise, alleviate some insulin resistance and consequently take pressure off beta cells. Metformin also helps reduce circulating glucose levels and relieves some glucose-induced secretory demand. Incretin-based therapies, by inducing satiety, can reduce some metabolic demand on the beta cell as well. Also, by up-regulating insulin production in parallel to insulin secretion, GLP-1 analogs augment beta cell function positively by preserving beta cell secretory capacity.
Unfortunately, sulfonylureas lack this balanced effect on the beta cell. Yes, they are potent stimulators of insulin secretion, but an underappreciated fact is that sulfonylureas conversely inhibit proinsulin biosynthesis. Thus they accelerate decreasing beta cell secretory capacity and precipitate the move towards insulin replacement therapy. Of course, exogenous insulin-based therapies can help beta cells by supplementing endogenously secreted insulin.
Some intriguing experimental data suggest that diazoxide (which has an opposing effect of sulfonylureas) and other agents might temporarily inhibit insulin secretion without affecting proinsulin biosynthesis. Several studies indicate that this inhibition can rescue a degree of beta cell secretory capacity and restore normal insulin secretory patterns in type 2 diabetes. While not yet approved for clinical use, the counterintuitive idea of transiently inhibiting endogenous insulin secretion to instigate a period of beta cell rest may soon regain some therapeutic momentum.