Mechanism of Action on Insulin Secretion and Other Hormones
The effects of somatostatin are mediated by high-affinity binding to membrane receptors on target tissues. Five different somatostatin receptor subtypes that belong to a superfamily of G-protein coupled receptors are identified and assigned numbers (SSTR1–SSTR5) according to their order of discovery.14 Octreotide, lanreotide, and vapreotide have high binding affinity for subtype SSTR2, a lower affinity for SSTR5 and SSTR3, and almost no affinity for SSTR1 and SSTR4.45 The pancreas contains all five subtypes, but in mice SSTR5 is more prevalent in the β-cells and SSTR2 is more prevalent in the α-cells in animal studies.69 SSTR5 is found in many tissues, including the brain, pituitary, stomach, intestine, thyroid, and adrenal gland; SSTR2 is found in the brain, pituitary, stomach, liver, kidney, lung, intestine, spleen, thymus, uterus, prostate, and adrenal gland.45,50,58,69 A variety of pituitary and gastroenteropancreatic tumors contain varying percentages of the SSTR subtypes. Recently in comparison to studies in mice SSTR2 was found to be the functionally dominant somatostatin receptor in human pancreatic β- and α-cells.36
Octreotide, similar to the natural hormone somatostatin, but with a longer duration of action, is a potent inhibitor of growth hormone, glucagon, and insulin. It also suppresses the response of luteinizing hormone to gonadotropin releasing hormone; decreases splanchnic blood flow; and inhibits the release of serotonin, gastrin, vasoactive intestinal peptide, secretin, motilin, thyroid-stimulating hormone, and pancreatic polypeptide.54
Experiments in both healthy human volunteers and an isolated perfused canine pancreas model demonstrate the ability of somatostatin to inhibit glucose-stimulated insulin release.2,26 Experiments using a whole-cell patch clamp technique on a hamster β-cell line suggest that somatostatin inhibits insulin secretion by a G-protein–mediated decrease in calcium entry through voltage-dependent Ca2+ channels.34 No evidence indicates that somatostatin inhibits insulin release by promoting K+ efflux through KATP channels at physiologic concentrations as do the oral hypoglycemics (Fig. 53–2).22,47,56 Instead somatostatin, like epinephrine, stimulates a pertussis toxin sensitive Gi-coupled receptor that inhibits adenylate cyclase and production of cyclic adenosine monophosphate (cAMP), decreasing intracellular calcium and thereby reducing insulin secretion.32 Simultaneous distal reduction in phosphorylation of specific proteins may also be involved in reducing insulin secretion.22,32,43 This latter mechanism appears to be independent of Ca2+.22,32 More recent experiments in human pancreatic β- and α-cells indicate somatostatin agonism via SSTR2 hyperpolarizes human β-cells and decreases depolarized evoked exocytosis in both α- and β-cells via several mechanisms.36 First, increased current through G-protein gated inward rectifying potassium (GIRK, Kir3.x) channels can be demonstrated. This effect is independent of the ATP-sensitive K+ (KATP) channel, and thus it remains effective when the KATP channel is antagonized by an oral sulfonylurea. Second, somatostatin inhibits a depolarization leak current (mediated by an as yet unidentified channel). Third, somatostatin reduced voltage-gated P/Q-type Ca2+ currents. Lastly, somatostatin directly inhibited calcium dependent exocytosis.
Activation of SSTR5 on the β-cell of the pancreas also reduces insulin biosynthesis.22 One study in human volunteers confirms the ability of somatostatin to inhibit the increased insulin response to both glucose and glucagon.26 Intravenous (IV) infusion of 1 g of tolbutamide over 2 minutes caused insulin concentrations to rise and serum glucose concentration to drop sharply. Similarly, in the presence of somatostatin and tolbutamide, administration of IV glucagon caused a rise in glucose concentration without the expected subsequent glucose stimulated rise in insulin. The effects of somatostatin were short lived. Within 5 minutes of stopping the somatostatin, the insulin releasing effects of tolbutamide continued, and within 15 minutes the serum glucose concentration fell. Peak insulin concentrations were achieved within 25 minutes.
Studies comparing octreotide to somatostatin in rats and monkeys demonstrate that octreotide is 1.3 times as potent as somatostatin in inhibiting insulin secretion by 50%. Likewise, compared with somatostatin, octreotide was 45 times more potent in inhibiting growth hormone secretion and 11 times more potent in inhibiting glucagon release.7 Comparable results were found using a hyperglycemic glucose clamp technique.39 Octreotide blocks the counterregulatory response to the effects of 0.1 unit/kg IV insulin by preventing an increase in glucagon and growth hormone. The effects of octreotide on the responses of adrenocorticotropin, cortisol, prolactin, luteinizing hormone, and follicle-stimulating hormone to insulin-induced hypoglycemia all remained intact.47 In contrast, growth hormone20 and thyroid stimulating hormone are significantly inhibited.47
Lanreotide and vapreotide are very long-acting, FDA approved somatostatin analogs. However, their use in sulfonylurea induced insulin secretion is not warranted based on the time action profiles of the sulfonylureas.
The pharmacokinetics of IV and subcutaneous (SC) octreotide were studied in eight healthy adult volunteers.41 Subjects received 25, 50, 100, and 200 μg IV octreotide over 3 minutes and 50, 100, 200, and 400 μg SC octreotide in random order. Following IV administration, the distribution half-life averaged 12 minutes, and the elimination half-life ranged from 72 ± 22 minutes to 98 ± 37 minutes and was linear. Vi (volume of distribution of the central compartment) was dose dependent and increased from approximately 5.7 L at 25, 50, and 100 μg IV to 10 L at 200 μg IV doses.41 The Vd (volume of distribution determined by area under the curve) ranged from 18 ± 6 L to 30 ± 30 L and showed no dose dependency.41 Approximately 30% of elimination was renal, and this was reduced in the elderly and in those with chronic kidney disease.54
After SC administration, bioavailability was 100%, and peak concentrations were achieved within 30 minutes with an absorption half-life of 5 to 12 minutes. The elimination half-life was 88 to 102 minutes. Peak serum concentrations after SC administration ranged from 2.4 ng/mL at doses of 50 μg to 23.5 ng/mL at doses of 400 μg. After IV administration, peak serum concentrations ranged from 9.6 ng/mL at doses of 50 μg to 27.8 ng/mL at doses of 200 μg.41
The pharmacokinetics in patients with pathologic conditions may differ from the pharmacokinetics in healthy volunteers as exemplified by a lower peak concentration and a higher steady state Vd in patients with acromegaly.54 In patients with reduced kidney function and those with liver cirrhosis and fatty liver disease, the half-life ranges from 2.5 to 3.7 hours depending on the extent of impairment. The half-life in the elderly is also prolonged by about 50%.54
The duration of action of octreotide is variable. When used for tumor suppression, the duration may last up to 12 hours.54 The duration of action for inhibition of insulin secretion is unknown but presumed to be somewhere between 6 to 12 hours.