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figure 60-1 Human proinsulin and its conversion to insulin. The amino acid sequence of human proinsulin is shown. By proteolytic cleavage, four basic amino acids (residues 31, 32, 64, and 65) and the connecting peptide are removed, converting proinsulin to insulin. The sites of action of the endopeptidases PC2 and PC3 are shown.

figure 60-1 Human proinsulin and its conversion to insulin. The amino acid sequence of human proinsulin is shown. By proteolytic cleavage, four basic amino acids (residues 31, 32, 64, and 65) and the connecting peptide are removed, converting proinsulin to insulin. The sites of action of the endopeptidases PC2 and PC3 are shown.

Glucose, the principal stimulus to insulin secretion, is permissive for the action of many other secretagogues. Glucose provokes insulin secretion more effectively when taken orally than when administered intravenously because the oral route induces the release of GI hormones and stimulates vagal activity. Several GI hormones promote insulin secretion, the most potent of which are glucose-dependent insulinotropic peptide (GIP, also known as gastrointestinal inhibitory peptide) and glucagon-like peptide-1 (GLP-1).

Glucose-induced insulin secretion is biphasic: The first phase reaches a peak after 1—2 minutes and is short-lived; the second phase has a delayed onset but longer duration.

The resting fi cell is hyperpolarized, and its glucose-induced depolarization leads to insulin secretion. Glucose enters the fi cell by facilitated transport mediated by GLUT2, a specific subtype of glucose transporter. The sugar then is phosphorylated by glucokinase to yield glucose-6-phosphate (G-6-P). Its relatively high Km (10—20 mM) allows glucokinase to play an important regulatory role at physiological glucose concentrations. Glucokinase's role as a glucose sensor was validated by its association with type 2 maturity-onset diabetes of the young (MODY), a rare monogenic form of diabetes. These glucokinase mutations, which compromise its ability to phosphorylate glucose, raise the threshold for glucose-stimulated insulin release and eventually result in DM.

The increase in oxidizable substrates (e.g., glucose and G-6-P) enhances ATP production, thereby inhibiting an ATP-sensitive K+ channel. This decrease in K+ conductance causes Em to rise, opening a voltage-sensitive Ca2+ channel; Ca2+ then acts as the insulin secretagogue. The ATP-sensitive K+ channel in fi cells is an octamer composed of four Kir 6.2 and four SUR1 subunits. Both subunits contain nucleotide-binding domains; Kir 6.2 appears to mediate the inhibitory response to ATP; SUR1 binds ADP, the channel activator diazoxide, and the channel inhibitors (and promoters of insulin secretion) sulfonylureas and meglitinide.

distribution and degradation of insulin Insulin circulates in blood as a monomer, and its volume of distribution approximates the volume of extracellular fluid. Under fasting conditions, the pancreas secretes about 40 pg (1 unit) of insulin/h into the portal vein to achieve a concentration of insulin in portal blood of 2-4 ng/mL (50-100 punits/mL) and in the peripheral circulation of 0.5 ng/mL (12 punits/mL) or ~0.1 nM. After ingestion of a meal, there is a rapid rise in the concentration of insulin in portal blood, followed by a parallel but smaller rise in the peripheral circulation.

The plasma t1/2 of insulin normally is ~5-6 minutes but may be increased in diabetics who develop anti-insulin antibodies. The t1/2 of proinsulin is longer than that of insulin, and proinsulin accounts for ~10% of the immunoreactive insulin in plasma. Since proinsulin is only 2% as potent as insulin, the biologically effective concentration of insulin is lower than estimated by immunoassay. C peptide is secreted in equimolar amounts with insulin, but its molar concentration in plasma is higher because of its considerably longer t1/2 (~30 minutes).

Degradation of insulin occurs primarily in liver, kidney, and muscle. About 50% of the insulin that reaches the liver via the portal vein is destroyed and never reaches the general circulation. Insulin is filtered by the renal glomeruli and is reabsorbed by the tubules, which also degrade it. Severe impairment of renal function affects insulin clearance to a greater extent than does hepatic disease. Hepatic degradation of insulin operates near its maximal capacity and cannot compensate for diminished renal breakdown.

cellular actions of insulin Key insulin target tissues for regulation of glucose homeostasis are liver, muscle, and fat, but insulin also exerts potent regulatory effects on other cell types. Insulin stimulates intracellular use and storage of glucose, amino acids, and fatty acids and inhibits catabolic processes such as the breakdown of glycogen, fat, and protein. It does this by stimulating the transport of substrates and ions into cells, promoting the translocation of proteins between cellular compartments, activating and inactivating specific enzymes, and changing the amounts of proteins by altering the rates of transcription and mRNA translation (Figure 60-2).

Insulin receptor

exch GDP

Glucose

Gab1

exch GDP

MAP kinase

IRS proteins 1-4

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