Physiological Regulation Of Insulin Secretion Research Articles

Insulinotropin: glucagon-like peptide I (7-37) co-encoded in the glucagon gene is a potent stimulator of insulin release in the perfused rat pancreas.

Insulin secretion is controlled by a complex set of factors that include not only glucose but amino acids, catecholamines, and intestinal hormones. We report that a novel glucagon-like peptide, co-encoded with glucagon in the glucagon gene is a potent insulinotropic factor. The glucagon gene encodes a proglucagon that contains in its sequence glucagon and additional glucagon-like peptides (GLPs). These GLPs are liberated from proglucagon in both the pancreas and intestines. GLP-I exists in at least two forms: 37 amino acids GLP-I(1-37), and 31 amino acids, GLP-I(7-37). We studied the effects of synthetic GLP-Is on insulin secretion in the isolated perfused rat pancreas. In the presence of 6.6 mM glucose, GLP-I(7-37) is a potent stimulator of insulin secretion at concentrations as low as 5 X 10(-11) M (3- to 10-fold increases over basal). GLP-I(1-37) had no effect on insulin secretion even at concentrations as high as 5 X 10(-7) M. The earlier demonstration of specific liberation of GLP-I(7-37) in the intestine and pancreas, and the magnitude of the insulinotropic effect at such low concentrations, suggest that GLP-I(7-37) participates in the physiological regulation of insulin secretion.

Effect of rat hypothalamic extract administration on insulin secretion in vivo.

Supernatants obtained from extracts of both the ventrolateral (VLH) and ventromedial (VMH) hypothalamus of normal rats were found to promote insulin secretion when injected in vivo to normal rats. Catecholamines, acetylcholine, and enkephalins can be excluded as potential candidates in producing the effects of VLH extract administration, since pretreatment of recipient rats with their respective specific blockers (i.e. phentolamine, propranolol, atropine, and naloxone) did not prevent the increase in plasma insulin levels observed after the injection of VLH extracts. In contrast, atropine and propranolol reduced by about 50% the rise in plasma insulin levels that followed the injection of VMH extracts. When extracts of VLH or VMH were partially purified, the insulin-releasing activity was found to correspond, in both cases, to compounds of low molecular weight (i.e. 3600 or lower). Furthermore, digestion of partially purified VLH extracts with trypsin or collagenase markedly decreased their in vivo insulin-promoting activity, suggesting a possible polypeptidic nature of the factor(s) involved. The presence of hypothalamic factor(s), which may conceivably be involved in physiological regulation of insulin secretion, is therefore suggested. This is in keeping with analogous results obtained by other laboratories using different species and experimental conditions.

Insulin in blood and insulin antibodies

T HIS presentation is concerned with the state of insulin in plasma rather than the physiologic regulation of insulin secretion. Our own studies on the concentrations of immunoassayable insulin in blood in hyperglycemic and hypoglycemic states have recently been summarized elsewhere [ 7-31. Since insulin in blood has never been extracted and recovered in amounts sufficient to permit its chemical characterization we have, unfortunately, no acceptable definition for “blood insulin.” When we speak of insulin in blood, or rather of insulin in plasma (since there is no evidence that insulin is present in blood cells), we refer only to the inference of the existence of insulin by virtue of the presence of some activity in the plasma that mimics the action of insulin in one or more specific systems. This activity may be exhibited biologically in the whole animal or on tissues in zo furthermore, plasma from depancreatized animals is devoid of insulin activity [5,73,74] and the virtual absence of plasma insulin activity has frequently been observed in insulin-dependent diabetic subjects [ 751. However, there is a serious lack of proportionality when insulin activity is measured in successive dilutions of plasma [ 76-781; assays in diluted plasma yield values often several hundred per cent higher than predicted from undiluted plasma. This result has been interpreted by some [ 77,79,20] as due to the presence, in whole plasma, of insulin inhibitors whose effects are more readily diluted out than the plasma insulin. If this is the correct explanation, it would seem that the truer estimate of insulin concentration should be given by the diluted plasma; yet the hemidiaphragm assay is generally carried out in whole plasma. Wardlaw and Moloney [27] measured glycogen synthesis, rather than glucose uptake, by the mouse diaphragm using partial neutralization by insulin antiserum to increase sensitivity over a small range. This method has been employed by Davidson et al. [22] to measure insulin in pancreas and plasma after treatment with hy-