Handbook of Diabetes. Rudy Bilous

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 K_ATP channel (the sulfonylurea receptor, SUR‐1) and closing it. The K_ATP channel is an octamer that consists of four K⁺‐channel subunits (called Kir6.2) and four SUR‐1 subunits.

The incretin effect

There is a significant difference between the insulin secretory response to oral glucose compared with the response to intravenous glucose – a phenomenon known as the ‘incretin effect’ (Figure 5.13). The incretin effect is mediated by gut‐derived hormones, released in response to the ingestion of food, which augment glucose‐stimulated insulin release. In particular, there are two incretin hormones: glucagon‐like peptide‐1 (GLP‐1) and gastric inhibitory polypeptide (GIP). Both augment insulin secretion in a dose‐dependent fashion. GLP‐1 is secreted by L cells and GIP is secreted by K cells in the wall of the upper jejunum.

Figure 5.14 (a) The incretin effect is greatly diminished in patients with type 2 diabetes compared with normal subjects. This contributes to the impaired insulin secretory response observed in type 2 diabetes. (b) GLP‐1 has a trophic effect on pancreatic islets. Shown here is an islet from a db/db mouse before (left) and after (right) 2 weeks treatment with synthetic GLP‐1.

      Adapted from Stoffers et al. Diabetes 2000; 49: 741–748.

In patients with type 2 diabetes, GLP‐1 secretion is diminished (Figure 5.14). However, in contrast to GIP, GLP‐1 retains most of its insulinotropic activity. GIP secretion is maintained in type 2 diabetes, but its effect on the β cell is greatly reduced.

      GLP‐1 also suppresses glucagon secretion from pancreatic α cells and exerts additional effects on satiety and gastric emptying. There is also considerable interest in the trophic effects of GLP‐1 on β cells.

Insulin receptor signalling

Insulin exerts its main biological effects by binding to a cell surface insulin receptor, a glycoprotein that consists of two extracellular α subunits and two transmembrane β subunits. The receptor has tyrosine kinase enzyme activity (residing in the β subunits), which is stimulated when insulin binds to the receptor. The tyrosine kinase domain phosphorylates tyrosine amino acid residues on various intracellular proteins, such as insulin receptor substrate (IRS)‐1 and IRS‐2, and the β subunit itself (Figure 5.15) (autophosphorylation). The tyrosine kinase activity of the insulin receptor is essential for insulin action.

Post‐receptor downstream signalling events are complex but insulin binding to its receptor leads to phosphorylation of a number of intracellular proteins including IRS‐1 and IRS‐2 (Figure 5.16). Phosphorylated tyrosine residues on these proteins act as docking sites for the non‐covalent binding of proteins with specific ‘SH2’ domains, such as phospatidylinositol 3‐kinase (PI 3‐kinase), Grb2 and phosphotyrosine phosphatase (SHP2). Binding of Grb2 to IRS‐1 initiates a cascade that eventually activates nuclear transcription factors via activation of the proteins Ras and mitogen‐activated protein (MAP) kinase. IRS–PI 3‐kinase binding generates phospholipids that modulate other specific kinases and regulate insulin‐stimulated effects such as glucose transport, and protein and glycogen synthesis.

Figure 5.15 The insulin receptor and its structural domains. Many mutations have been discovered in the insulin receptor, some of which interfere with insulin’s action and can cause insulin resistance; examples are shown in the right column.

Figure 5.16 The insulin signalling cascade. Insulin binding and autophosphorylation of the insulin (and IGF‐1) receptor results in binding of the IRS‐1 protein to the β subunit of the insulin receptor via the IRS phosphotyrosine‐binding domain (PTB). There is then phosphorylation of a number of tyrosine residues (pY) at the C‐terminus of the IRS proteins. This leads to recruitment and binding of downstream signalling proteins, such as PI‐3 kinase, Grb2 and SHP2.

The family of GLUT transporters

Glucose is transported into cells by a family of specialised transporter proteins called glucose transporters (GLUTs) (Figure 5.17). The process of glucose uptake is energy independent.

      The best characterised GLUTs are:

       GLUT‐1: ubiquitously expressed and probably mediates basal, non‐insulin mediated glucose uptake.

       GLUT‐2: present in the islet β cell, and also in the liver, intestine, and kidney. Together with glucokinase, it forms the β cell’s glucose sensor and, because it has a high Km, allows glucose to enter the β cell at a rate proportional to the extracellular glucose level.

       GLUT‐3: together with GLUT‐1, involved in non‐insulin mediated uptake of glucose into the brain.

       GLUT‐4: responsible for insulin‐stimulated glucose uptake in muscle and adipose tissue, and thus the classic hypoglycaemic