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Search for other papers by SIMON DUNMORE in
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Search for other papers by ANNE BELOFF-CHAIN in
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The perfused rat pancreas has been used to study the dynamics of insulin release during stimulation with a perifusate of the pituitary neurointermediate lobe (NIP) of genetically obese mice (ob/ob) and their lean litter-mates (+/+). It has been shown that the NIP of ob/ob mice is more active. The remainder of the study was carried out with NIP from ob/ob mice. The results showed that both phases of insulin release stimulated by 16·6 mm-glucose were increased by NIP. When the pancreas was first stimulated with NIP in the presence of 5·5 mm-glucose, followed by a high concentration of glucose, it responded to the latter with a normal biphasic response. If, however, the pancreas was stimulated first with glucose the response to NIP was refractory.
The results are discussed in relation to the possible significance of an insulin secretagogue from the pituitary pars intermedia in the hyperinsulinaemia associated with obesity.
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Search for other papers by M. A. CAWTHORNE in
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The pituitary glands from mice rendered obese by gold thioglucose treatment and by dietary manipulation, and pituitary glands from lean mice after a high food intake or a glucose load, were shown to stimulate insulin secretion from isolated pancreatic islets. The insulin releasing activity of pituitary glands from obese (ob/ob) mice was reduced by fasting for 24 and 48 h. Results obtained with pituitary glands from ob/ob and from lean ob/ + and + /+ mice suggest that the insulin releasing property manifests a gene dosage effect. Pituitary glands from 3-week-old (young) ob/ob mice stimulated insulin secretion to the same extent as pituitary glands from 3-month-old (adult) ob/ob mice. The pancreatic islets of young ob/ob mice were shown to be somewhat more responsive to stimulation by the pituitary factor than were lean ob/ + or + / + islets from this age group. The concept that high insulin level, partly under pituitary control, and high caloric intake may be interlinked and may, in combination, be a major factor in producing obesity is discussed. Furthermore, it is suggested that the pituitary insulin releasing factor may play a role in the early development of obesity in the animal models studied.
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Search for other papers by Anne Beloff-Chain in
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Search for other papers by M. A. Cawthorne in
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The influence of plasma from genetically obese (ob/ob) and lean (+/+) mice on insulin secretion has been studied by perifusion of collagenase-prepared pancreatic islets maintained for 48 h in culture. Insulin secretion was measured at 2-min intervals and plasma from the ob/ob mice not from the +/+ mice rapidly stimulated insulin release, reaching a maximum in 2–4 min and falling to basal levels in about 10 min. Experimental evidence is given indicating that the plasma insulin secretagogue is identical to β-cell-trophin, a peptide of the pituitary pars intermedia which stimulates insulin secretion. The evidence is based on (1) the antigenic properties of the peptides (both cross-react with a -COOH terminal ACTH antiserum raised to the 17–39 moiety of ACTH), (2) identical chromatographic separation on Biogel columns and on reverse-phase high pressure liquid chromatography and (3) the similarity of their insulin releasing action from perifused islets.
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Search for other papers by JANET HAWTHORN in
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SUMMARY
The influence of the pituitary gland of lean and genetically obese (ob/ob) mice on insulin secretion from microdissected pancreatic islets of lean and ob/ob mice has been studied by perifusing the pituitaries of these animals in series with the isolated islets and measuring insulin secretion at 5-min intervals over a period of 60 min.
It has been shown that the pituitary perifusate of both lean and obese mice stimulate insulin secretion from lean mouse islets but not from obese mouse islets. The maximum stimulation occurs in the first 10 min and with the lean mouse pituitaries returns to the basal level in about 20 min, whereas with the obese mouse pituitaries insulin secretion is about double that from the control islets even after 40 min.
A concentration of pure porcine ACTH equivalent to about three times the amount released from the pituitary gland under the experimental conditions used, caused only a small stimulation of insulin release. Possible interpretations of these findings and further lines of investigation are discussed.
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Search for other papers by K. A. ROOKLEDGE in
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Search for other papers by ANNE BELOFF-CHAIN in
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Search for other papers by J. D. LEVER in
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SUMMARY
The biochemical parameters of blood glucose, serum insulin and pancreatic insulin and glucagon were determined after single injections of the diabetogenic agent streptozotocin and in untreated animals from a strain of genetically obese mice and their lean litter-mates. Histological observations on α and β islet cells were also made in these animals by employing the phosphotungstic acid—haematoxylin and aldehyde—fuchsin staining techniques.
In untreated obese mice, endocrine hyperactivity was indicated by the presence of exceptionally large, highly vascular islets and by duct cell-islet metaplasia.
After streptozotocin injection, approximately half of the lean mice showed extensive β-cell necrosis and these animals became hyperglycaemic and hypoinsulinaemic with a much reduced pancreatic insulin over a long term. The remaining treated lean mice, whose biochemical parameters did not differ significantly from normal, showed little or no evidence of islet damage. The response of obese mice to streptozotocin treatment was less clear-cut than that of lean animals. Essentially similar histological changes were observed, though these were not consistently correlated with biochemical data. There was histological and biochemical evidence of islet cell recovery from the effects of the drug both in lean and in obese mice, and in all hyperglycaemic animals with initial severe islet damage a marked α-cell response was observed, namely an increased proportion of α cells and their random deployment throughout the islets.
