Beta-Cell Dysfunction

Although abnormalities of insulin secretion in the pathophysiology of diabetes have often been neglected, they occur already early during the disease and can often already be demonstrated in subjects with normal glucose tolerance (first-degree relatives of type 2 diabetes).

Normal Insulin Secretion

After uptake of glucose pancreatic beta-cell glucose is rapidly degraded in oxidative glucose metabolism, leading to ATP formation. ATP is involved in beta-cell membrane depolarization.

The ADP/ATP ratio, the sulfonylurea receptor-1 (SUR 1) protein, which closes the adjacent potassium channel (potassium inward rectifier 6.2, KIR 6.2 channel). The closure of the potassium channels will decrease the membrane potential, which leads to opening of voltage-gated calcium channels; this induces the release of insulin-containing granules (Fig. 5). Upon stimulation with glucose, insulin is released with a short-lasting peak of a few minutes (so-called "first-phase") followed by a slowly evolving second phase; the second phase lasts as long as the plasma glucose level is elevated.

Insulin Secretion in Type 2 Diabetes

In patients with type 2 diabetes, plasma glucose levels are elevated; and consequently, fasting plasma insulin. Although the insulin levels sometimes increase slightly after a meal in patients with type 2 diabetes mellitus this is considerably less than normal.

In studies in which glucose levels have been raised by glucose infusions (hyperglycemic clamps) to comparable levels in diabetic subjects and controls, it has become clear that second-phase insulin secretion is roughly 25% (IGT) to 50% decreased in type 2 diabetes. First-phase secretion is generally completely lost. In normoglycemic first-degree relatives insulin secretion is also diminished but to a lower extent, presumably on a genetic basis.

It is suspected that upon acquaintance of insulin resistance (obesity, physical inactivity) the pancreas that has already lower secretory capabilities can adapt less than normal, which might lead to decreased glucose tolerance or diabetes.

FIGURE 5 Insulin secretion. Schematic representation of normal glucose-induced insulin secretion.
Abbreviations : ADP, adenosine dephosphate; ATP, adension triphosphate; IAAP, islet amyloid polypeptide.

It has been widely suggested that various mechanisms might further aggravate beta-cell insulin secretory dysfunction, among which glucose toxicity, lipotoxicity, and amyloid deposition.

Glucose Toxicity

Since over time insulin secretion appears to decrease in most patients, it has been proposed that glucose itself is toxic to beta cells.