Читать книгу Handbook of Diabetes - Rudy Bilous - Страница 31
Insulin secretion
ОглавлениеGlucose is the main stimulator of insulin release from the β cells, and insulin secretion occurs in a characteristic biphasic pattern – an immediate ‘first phase’ response that lasts only a few minutes, followed by a more gradual sustained ‘second phase’ (Figure 5.11). The first phase of insulin release involves a small, readily releasable pool of granules fusing with the plasma membrane. Of particular importance is the observation that first‐phase insulin secretion is lost in patients with type 2 diabetes.
Various types of fuels, hormones, and neurotransmitters regulate insulin secretion. Glucose is the most important regulator and glucose stimulates insulin secretion by mechanisms that depend upon the metabolism of glucose and other nutrients in the β cells. A triggering pathway involves closure of ATP‐sensitive potassium channels (KATP channels), cellular depolarisation, an influx of calcium through voltage‐dependent calcium channels and an increase in intracellular calcium concentration. Simultaneously, a metabolic amplifying pathway augments the stimulatory effect of calcium on the exocytosis of insulin‐containing granules. The second messenger cAMP is an important amplifier of insulin secretion triggered by Ca2+ elevation in the β cells.
Glucose enters the β cell by facilitated diffusion via GLUT‐2 transporters. It is then phosphorylated by the enzyme glucokinase, which acts as the ‘glucose sensor’ that couples insulin secretion to the prevailing glucose concentration (Figure 5.12). Glycolysis and mitochondrial metabolism of glucose produce adenosine triphosphate (ATP), which leads to the closure of the KATP channels. This in turn causes depolarisation of the β cell plasma membrane, leading to an influx of extracellular calcium through cell‐surface voltage‐gated channels. The increase in cytosolic calcium triggers translocation of insulin granules and exocytosis.
Figure 5.11 (a) The biphasic glucose‐stimulated release of insulin from pancreatic islets. (b) The glucose–insulin dose–response curve for islets of Langerhans.
Figure 5.12 The mechanism of glucose‐stimulated insulin secretion from the β cell. The structure of the KATP channel is shown in the inset.
Figure 5.13 The classic experiment illustrating the incretin effect in normal subjects who were studied on two separate occasions. On one occasion, they were given an oral glucose load and on the second occasion an IV glucose bolus was administered in order to achieve identical venous plasma glucose concentration‐time profiles on the two study days (left panel). The insulin secretory response (shown by C‐peptide) was significantly greater after oral compared with IV glucose (right panel).
Adapted from Nauck et al. J Clin Endocrinol Metab 1986; 63: 492–498.
Sulfonylureas stimulate insulin secretion by binding to a component of the KATP channel (the sulfonylurea receptor, SUR‐1) and closing it. The KATP channel is an octamer that consists of four K+‐channel subunits (called Kir6.2) and four SUR‐1 subunits.