Diabetogenic polypeptide from human pituitaries similar to that excreted by proteinuric diabetic patients

Louis, Lawrence H.; Conn, Jerome W.

doi:10.1016/0026-0495(72)90014-5

Cited by 27 publications

(8 citation statements)

References 7 publications

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“…Also, this same group reported (6) that 20-kDa hGH lacked the acute insulin-like property of 22-kDa hGH, since the 20-kDa hGH variant failed to produce hypoglycemia and increase plasma free fatty acids when administered to hypophysectomized rats and did not increase glucose uptake or oxidation to CO2 by isolated rat adipose tissue when added in vitro. These observations have led to the conclusion that, unlike 22-kDa hGH, the 20-kDa variant lacks significant diabetogenic and insulin-like activities. The explanation proposed is that the active site(s) for these properties of hGH reside in the region of the amino acid deletion or because conformational changes in the molecule resulting from the deletion interfere with the expression of these properties (5, 7).…”

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confidence: 99%

“…Unfortunately, 22-kDa hGH itself exhibits little diabetogenic activity under these conditions. At least 2 days of treatment with growth hormone are required (21,22) to produce hyperglycemia and glucose intolerance in the dog. Thus, it is not surprising that native 20-kDa hGH did not cause hyperglycemia and glucose intolerance in the dog 10 hr after its administration (5).…”

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confidence: 99%

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Biosynthetic 20-kilodalton methionyl-human growth hormone has diabetogenic and insulin-like activities.

Kostyo¹,

Cameron²,

Olson³

et al. 1985

Proc. Natl. Acad. Sci. U.S.A.

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The anterior pituitary gland produces a 20-kilodalton (kDa) variant of human growth hormone (hGH) that differs from the predominant 22-kDa form of hGH in that amino acid residues 32-46 are deleted. Previous work has suggested that the 20-kDa variant possesses the full growth-promoting and lactogenic activities of 22-kDa hGH but lacks its intrinsic diabetogenic and insulin-like activities. In the present study, recombinant DNA techniques were used to prepare biosynthetic 20-kDa hGH, and some of the biological properties of the purified hGH variant were examined. The biosynthetic 20-kDa hGH variant was found to share the propensity for aggregation exhibited by its native counterpart. Moreover, like the native variant, biosynthetic 20-kDa hGH possessed full growth-promoting activity in the weight gain test in hypophysectomized rats. However, contrary to previous work suggesting that native 20-kDa hGH lacks diabetogenic and insulin-like activities, biosynthetic 20-kDa hGH was found to have substantial diabetogenic activity when administered chronically to ob/ob mice and to possess approximately 20% the in vitro insulin-like activity of biosynthetic 22-kDa hGH on isolated epididymal adipose tissue of hypophysectomized rats. The diabetogenic and insulin-like activities of biosynthetic 20-kDa hGH cannot be ascribed to contamination of the hormone preparation with the 22-kDa form of hGH or with other diabetogenic or insulin-like pituitary peptides. Therefore, the results strongly suggest that diabetogenic and insulin-like activities are also intrinsic properties of the 20-kDa variant of hGH.A 20-kilodalton variant of human growth hormone (20-kDa hGH) has been isolated from human pituitary glands (1) and has been found to differ from the predominant 22-kilodalton form of hGH (22-kDa hGH) in that residues 32-46 are deleted (2, 3). The variant is produced in the human pituitary, because the nucleotide sequence encoding residues 32-46 is sometimes excised during the processing of hGH pre-mRNA to hGH mRNA (4). As a consequence, approximately 5-10%1 of the hGH present in the human pituitary is 20-kDa hGH (1). Physicochemical studies of 20-kDa hGH (3) suggest that its conformation is similar but not identical to that of 22-kDa hGH.The 20-kDa variant of hGH has been reported (1, 5) to have growth-promoting activity in the hypophysectomized rat equivalent to that of 22-kDa hGH. Moreover, its lactogenic activity in the pigeon crop sac assay equals that of 22-kDa hGH (1). On the other hand, Lewis et al. (5) reported that 20-kDa hGH lacked diabetogenic activity, in that it failed to produce hyperglycemia and glucose intolerance in dogs, when administered 10 hr prior to a glucose tolerance test. Also, this same group reported (6) that 20-kDa hGH lacked the acute insulin-like property of 22-kDa hGH, since the 20-kDa hGH variant failed to produce hypoglycemia and increase plasma free fatty acids when administered to hypophysectomized rats and did not increase glucose uptake or oxidation to CO2 by isolated rat adipose tissue wh...

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confidence: 99%

mentioning

confidence: 99%

Biosynthetic 20-kilodalton methionyl-human growth hormone has diabetogenic and insulin-like activities.

Kostyo¹,

Cameron²,

Olson³

et al. 1985

Proc. Natl. Acad. Sci. U.S.A.

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“…All peptides produce hyperglycemia and resistance to exogenous insulin when injected into dogs and humans. After purification to homogeneity, all exhibit similar physicochemical and biological properties (5).…”

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confidence: 99%

“…The evidence that the pituitary peptide is not growth hormone or a fragment is: first, that it has no growth-promoting activity (6); second, no fragment of growth hormone with diabetogenic activity was isolated when growth hormone was subjected to the same isolation and purification procedures as the peptide (7); and third, there was little or no immunological crossreactivity between growth hormone antiserum and the peptide (5,8). Evidence also suggests that this peptide is not adrenocorticotrophic hormone (3) or prolactin (4).…”

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confidence: 99%

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Anti-Insulin Actions of a Bovine Pituitary Diabetogenic Peptide on Glycogen Synthesis

Miller¹,

Larner²

1972

Proc. Natl. Acad. Sci. U.S.A.

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The site(s) of action of a bovine pituitary diabetogenic peptide that produces hyperglycemia and hyperinsulinemia in vivo (dogs or humans) was investigated in vitro. When rat diaphragms were incubated with the peptide in the presence of insulin, the peptide depressed insulin-mediated (a) glucose uptake, (b) glycogen synthesis, and (c) glycogen synthase activation (conversion of D to I form). Incubation with the peptide alone resulted in small increases in (a), (b), and (c). Insulin-mediated glycogen synthase kinase inactivation was inhibited when both insulin and peptide were present (d), whereas glycogen synthase kinase activity was lowered by the peptide alone. High doses of insulin completely reversed inhibitory effects of the peptide on glycogen synthesis. Therefore, the hyperglycemic and anti-insulin properties of this peptide in vivo can possibly be explained by the partial blocking action of the peptide on insulin-mediated glucose uptake and glycogenesis.In 1963, Louis et al.(1) first reported the isolation of a polypeptide exhibiting diabetogenic and anti-insulin properties from urine of human lipoatrophic diabetics. This peptide was not found in the urine of normal subjects. A similar peptide was subsequently isolated from urine of proteinuric diabetic patients without lipoatrophy (2), as well as from adenohypophyses of beef (3), sheep, pigs (4), and humans (5). All peptides produce hyperglycemia and resistance to exogenous insulin when injected into dogs and humans. After purification to homogeneity, all exhibit similar physicochemical and biological properties (5).The evidence that the pituitary peptide is not growth hormone or a fragment is: first, that it has no growth-promoting activity (6); second, no fragment of growth hormone with diabetogenic activity was isolated when growth hormone was subjected to the same isolation and purification procedures as the peptide (7); and third, there was little or no immunological crossreactivity between growth hormone antiserum and the peptide (5, 8). Evidence also suggests that this peptide is not adrenocorticotrophic hormone (3) or prolactin (4). Therefore, the suggestion has been made that this is a novel pituitary peptide (7).Since the biological effects of the peptide in vivo suggested an action antagonistic to insulin, we decided to examine this question directly in vitro. We have investigated the mechanism of action in terms of the well established stimulation by insulin of glucose uptake, glycogen synthesis, and the two enzyme perturbations that regulate the latter biochemical action. In the present paper we demonstrate that in addition to blocking each of these four actions of insulin in isolated rat diaphragm, the peptide alone acts as a weak positive effector 2774 on these same four parameters, suggesting that it may act very early in the sequence of actions initiated by insulin. METHODS AND MATERIALSMale Wistar rats (140-180 g) were decapitated and their diaphragms were dissected either with or without the rib cage. The diaphragms were place...

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Growth hormone and metabolism

Press¹

1988

Diabetes Metab. Rev.

122

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Diabetogenic polypeptide from human pituitaries similar to that excreted by proteinuric diabetic patients

Cited by 27 publications

References 7 publications

Biosynthetic 20-kilodalton methionyl-human growth hormone has diabetogenic and insulin-like activities.

Biosynthetic 20-kilodalton methionyl-human growth hormone has diabetogenic and insulin-like activities.

Anti-Insulin Actions of a Bovine Pituitary Diabetogenic Peptide on Glycogen Synthesis

Growth hormone and metabolism

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