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R J Denver and C S Nicoll

Abstract

We investigated the influence of and interactions among pancreatic hormones on the secretion of insulin-like growth factor-I (IGF-I) and IGF-binding proteins (IG-FBPs) by treating primary hepatocytes from young male Long–Evans rats with insulin or glucagon in combination with rat GH (rGH). The concentration of IGF-I secreted into the medium was estimated by radioimmunoassay after formic acid-acetone cryoextraction, and secreted IGFBPs were analysed by Western ligand blot and immunoblot; accumulation of IGF-I mRNA was analysed by Northern blot. Both insulin (0·1–100 nmol/l) and rGH (0·5, 5 and 50 pmol/l) produced a dose-dependent stimulation of IGF-I secretion over a 24-h incubation period. In contrast, glucagon (0·1–100 nmol/l) inhibited IGF-I production in a dose-related manner. Glucagon (10 nmol/l) also inhibited IGF-I secretion stimulated by rGH (5 pmol/l) and insulin (10 nmol/l). Northern blot analysis of total RNA isolated from rat hepatocytes revealed that rGH (5 pmol/l) elevated IGF-I mRNA levels, glucagon (10 nmol/l) alone had no effect on this parameter, but glucagon significantly reduced IGF-I transcript accumulation in response to rGH. IGFBPs secreted by rat hepatocytes run in two molecular weight ranges on SDS-PAGE: ∼ 25 kDa (IGFBP-4) and ∼29–31 kDa (IGFBP-1 and -2); the predominant hormonally regulated IGFBP was identified as IGFBP-1. Insulin produced a dose-dependent inhibition of production of IGFBP-1, while glucagon was stimulatory; when given together at an equivalent concentration (1 nmol/l), the effects of insulin were dominant to glucagon on IGFBP-1. These observations provide support for significant opposite roles for the pancreatic hormones, insulin and glucagon, in the regulation of liver IGF-I and IGFBP-1 production. As the production of pancreatic hormones is influenced by nutritional status, these polypeptides may mediate the effects of changing nutritional state on the hormonal control of protein anabolism and glucose homeostasis by directly influencing the circulating level of liver-derived IGF-I and its binding proteins.

Journal of Endocrinology (1994) 142, 299–310

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RM Ortiz, DP Noren, CL Ortiz, and F Talamantes

After nursing, pups of the northern elephant seal (Mirounga angustirostris) are approximately 46% body fat and rely almost entirely on the oxidation of their large fat stores to sustain their metabolism for the ensuing 8-12 week postweaning fast, which is a natural component of their life history. Thus, fasting pups provide an ideal opportunity to examine the hormonal alterations associated with prolonged food deprivation in a naturally adapted model. Cortisol, ghrelin, glucagon, growth hormone (GH), insulin-like growth factor-I (IGF-I), insulin, blood urea nitrogen (BUN), glucose and non-esterified fatty acids (NEFA) were examined in 20 male and 20 female pups blood sampled early (<1 week postweaning) and late (6-8 weeks postweaning) during the fast. Mean cortisol, ghrelin, GH, and glucagon increased 1.8-, 1.8-, 1.4-, and 2.3-fold between early and late periods, while mean IGF-I and insulin decreased 97% and 38%, respectively. NEFA increased 2.3-fold, while BUN and glucose decreased 46% and 11%, respectively. NEFA was significantly and positively correlated with cortisol and GH; individually; however, when the relationship was examined as a multiple regression the correlation improved suggesting that cortisol and GH act synergistically to promote lipolysis during the fast. GH and BUN were negatively and significantly correlated between early and late fasting suggesting that GH may promote protein sparing as well. The decrease in glucose may be responsible for stimulating glucagon, resulting in the maintenance of relative hyperglycemia. The increases in cortisol, ghrelin, glucagon, and GH suggest that these hormones may be integral in mediating the metabolism of seal pups during prolonged fasting.

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Jennifer H Stern, Gordon I Smith, Shiuwei Chen, Roger H Unger, Samuel Klein, and Philipp E Scherer

Hyperglucagonemia, a hallmark in obesity and insulin resistance promotes hepatic glucose output, exacerbating hyperglycemia and thus predisposing to the development type 2 diabetes. As such, glucagon signaling is a key target for new therapeutics to manage insulin resistance. We evaluated glucagon homeostasis in lean and obese mice and people. In lean mice, fasting for 24 h caused a rise in glucagon. In contrast, a decrease in serum glucagon compared to baseline was observed in diet-induced obese mice between 8 and 24 h of fasting. Fasting decreased serum insulin in both lean and obese mice. Accordingly, the glucagon:insulin ratio was unaffected by fasting in obese mice but increased in lean mice. Re-feeding (2 h) restored hyperglucagonemia in obese mice. Pancreatic perfusion studies confirm that fasting (16 h) decreases pancreatic glucagon secretion in obese mice. Consistent with our findings in the mouse, a mixed meal increased serum glucagon and insulin concentrations in obese humans, both of which decreased with time after a meal. Consequently, fasting and re-feeding less robustly affected glucagon:insulin ratios in obese compared to lean participants. The glucoregulatory disturbance in obesity may be driven by inappropriate regulation of glucagon by fasting and a static glucagon:insulin ratio.

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GM Portela-Gomes and A Hoog

Insulin-like growth factor II (IGF-II) appears to play an important role during fetal life in cell growth and differentiation in several organs, including the pancreas. In the present study we investigated the cellular localization of IGF-II in human fetal pancreas at 16, 18 and 22 embryonic weeks and compared it with adult pancreas. Single and double immunofluorescence methods were used to study co-localization of IGF-II with the four major islet hormones - insulin, glucagon, somatostatin, pancreatic polypeptide - and with islet amyloid polypeptide (IAPP). Distinct IGF-II immunoreactive (IR) cells were found in the endocrine, but not in the exocrine, pancreas. The intensity of IGF-II immunoreactivity was more pronounced in the fetal than in the adult pancreas. In fetal pancreas IGF-II immunoreactivity was observed in virtually all insulin-IR cells and in subsets of the glucagon, somatostatin and IAPP cells. In the adult pancreas, IGF-II immunoreactivity was found in insulin/IAPP cells only. Our results suggest a broader effect of IGF-II in fetal endocrine pancreatic cells than in the adult.

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H. Vilhardt, T. Krarup, J. J. Holst, and P. Bie

ABSTRACT

Injections and infusions of oxytocin into conscious dogs caused an increase in plasma concentrations of glucose, insulin and glucagon. When blood glucose was clamped at a raised level the injection of oxytocin still increased insulin and glucagon concentrations in plasma. Infusion of somatostatin suppressed plasma concentrations of glucagon and insulin but did not prevent oxytocin-induced increments in blood glucose. Injection of oxytocin still caused a marked release of glucagon, whereas the insulin response was greatly diminished. When endogenous insulin and glucagon secretion was suppressed by infusion of somatostatin and glucose levels were stabilized by concomitant infusions of glucagon and insulin, injections of oxytocin did not alter blood glucose concentrations. It is concluded that the increase in blood glucose following the administration of oxytocin is secondary to the release of glucagon and that oxytocin exerts a direct stimulatory effect on glucagon and possibly insulin secretion.

J. Endocr. (1986) 108, 293–298

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F Bertuzzi, C Berra, C Socci, A M Davalli, G Pozza, and A E Pontiroli

Abstract

Hyperglucagonemia is commonly found in insulin-dependent as well as in non-insulin-dependent diabetes mellitus, and is likely to be caused by absolute or relative insulin deficiency. The aim of the present study was to evaluate whether a chronic glucagon exposure (1·0 μm for 4 h) modifies the insulin response to acute stimuli with glucagon (1·0 μm), arginine (10·0 mm) and glucose (16·7 mm), or the glucagon response to arginine and glucose, in human islets. Chronic exposure to glucagon did not affect the insulin response to glucose and arginine, but inhibited its response to glucagon (44·6 ± 9·3 vs 168·6 ± 52·3 pg/islet per 20 min, P<0·05); the latter effect was not observed when exposure to glucagon was discontinuous (2·0 μm glucagon alternated with control medium for 30 min periods). The chronic exposure to glucagon also reduced the glucagon response to arginine (−4·9 ± 5·7 vs 19·9 ± 7·9 pg/islet per 20 min, P<0·05) without affecting the inhibition of glucagon release exerted by glucose. These data indicate that chronic exposure to glucagon desensitizes pancreatic α and β cells in response to selected stimuli.

Journal of Endocrinology (1997) 152, 239–243

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A L Pierce, J T Dickey, L Felli, P Swanson, and W W Dickhoff

Igf1 and Igf2 stimulate growth and development of vertebrates. Circulating Igfs are produced by the liver. In mammals, Igf1 mediates the postnatal growth-promoting effects of growth hormone (Gh), whereas Igf2 stimulates fetal and placental growth. Hepatic Igf2 production is not regulated by Gh in mammals. Little is known about the regulation of hepatic Igf2 production in nonmammalian vertebrates. We examined the regulation of igf2 mRNA level by metabolic hormones in primary cultured coho salmon hepatocytes. Gh, insulin, the glucocorticoid agonist dexamethasone (Dex), and glucagon increased igf2 mRNA levels, whereas triiodothyronine (T3) decreased igf2 mRNA levels. Gh stimulated igf2 mRNA at physiological concentrations (0.25×10−9 M and above). Insulin strongly enhanced Gh stimulation of igf2 at low physiological concentrations (10−11 M and above), and increased basal igf2 (10−8 M and above). Dex stimulated basal igf2 at concentrations comparable to those of stressed circulating cortisol (10−8 M and above). Glucagon stimulated basal and Gh-stimulated igf2 at supraphysiological concentrations (10−7 M and above), whereas T3 suppressed basal and Gh-stimulated igf2 at the single concentration tested (10−7 M). These results show that igf2 mRNA level is highly regulated in salmon hepatocytes, suggesting that liver-derived Igf2 plays a significant role in salmon growth physiology. The synergistic regulation of igf2 by insulin and Gh in salmon hepatocytes is similar to the regulation of hepatic Igf1 production in mammals.

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T Leinskold, TE Adrian, U Arnelo, J Larsson, and J Permert

Insulin-like growth factor-I (IGF-I) has been demonstrated to exert a nitrogen sparing effect, both experimentally and in patients after abdominal surgery. IGF-I is a major mediator for the anabolic effects of growth hormone (GH). Whether elevated circulating IGF-I levels are the sole mediator of the anabolic effects following GH has not been clarified. IGF-I influences glucose metabolism, both through its own specific receptor and by activating the insulin receptor, and has also been proposed to influence pancreatic islet secretion directly. In the present study, the postoperative effects of IGF-I on plasma levels of other gastrointestinal and pancreatic islet hormones and growth factors were measured in patients after abdominal surgery. Fifteen patients who were candidates for large bowel resection were randomly divided into two groups: IGF-I-treated (n=8) and placebo-treated (n=7). The IGF-I group received daily two s.c. injections of human recombinant IGF-I (80 microg/kg body weight) for five days, beginning on the morning of the first postoperative day. The other group received placebo injections. Fasting plasma levels of gastrointestinal growth factors (epidermal growth factor, transforming growth factor-alpha, IGF-II), gastrointestinal hormones (gastrin, enteroglucagon, peptide YY), and islet hormones (insulin, islet amyloid polypeptide (IAPP) and pancreatic glucagon) were determined by RIA preoperatively and after five days of treatment. No significant effects of IGF-I on other growth factors or gastrointestinal hormones were seen. A marked increase in plasma insulin postoperatively compared with the preoperative levels (42+/-3 vs 61+/-5 pM, P<0.05) was seen in the placebo group, whereas the postoperative levels in the IGF-I-treated patients remained unchanged (44+/-3 vs 45+/-4 pM). A similar pattern was observed for IAPP and cortisol concentrations. No differences in glucagon concentrations were seen. In conclusion, these results suggest that IGF-I does not influence production of other gastrointestinal hormones thought to be involved in alimentary growth or pancreatic glucagon. In contrast, IGF-I caused a marked reduction of insulin and IAPP secretion. The inhibition of beta-cell secretion could be direct or, alternatively, could involve an improvement in postoperative insulin resistance, perhaps by reducing serum cortisol.

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P. R. Flatt, C. J. Bailey, and K. D. Buchanan

This study examines the role of glucagon in the pathogenesis of the obese hyperglycaemic (ob/ob) syndrome in mice. Plasma C-terminal immunoreactive glucagon concentrations were measured in fed and fasted ob/ob mice at different ages between 5–40 weeks, and in 20-week-old mice after the administration of established stimulators and inhibitors of glucagon secretion. Plasma glucagon concentrations were inappropriately raised irrespective of age, nutritional status and the accompanying prominent changes in plasma glucose and insulin concentrations. Glucose suppressed plasma glucagon in the fed but not the fasted state, suggesting a dependence on the marked hyperinsulinaemia associated with feeding. Administration of 0·25 units insulin/kg to fasted mice failed to affect plasma glucagon and glucose concentrations. Increasing the dose to 100 units/kg restored the normal suppressive actions of insulin. Fasted mice showed an exaggerated glucagon response to arginine but not to the parasympathomimetic agent pilocarpine. Fed mice displayed normal plasma glucagon responses to the sympathomimetic agents noradrenaline and adrenaline. Administration of insulin antiserum or 2-deoxy-l-glucose raised plasma glucagon concentrations of fed mice. Contrary to the lack of suppression by glucose in the fasted state, heparin-induced increase in free fatty acids reduced plasma glucagon concentrations. This study demonstrates inappropriate hyperglucagonaemia and defective A-cell function in ob/ob mice. The extent of the abnormality is exacerbated by fasting and appears to result from insensitivity of the A-cell to the normal suppressive action of insulin.

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J. C. EDWARDS, K. ASPLUND, and G. LUNDQVIST

SUMMARY

A solid phase radioimmunoassay for glucagon was specially modified in order to overcome the problems involved in the measurement of glucagon release from incubated pieces of pancreas. The modified immunoassay procedure was used to study glucagon release from pieces of pancreas taken from newborn rats aged from 1 to 20 days. The glucagon content of rat pancreas was also measured during this period.

It was found that glucagon release from rat pancreas was stimulated by arginine and inhibited by octanoic acid at 1 and 2 days of age. However, glucagon release at 3 days of age was low, and between 3 and 7 days of age glucagon release could not be inhibited by octanoic acid or stimulated by arginine. At 10 and 20 days of age, the stimulatory action of arginine and the inhibitory action of octanoic acid were again noted. Glucagon release, measured at several ages, was not significantly affected by changes in glucose concentration. The glucagon content of the rat pancreas rose to a maximum at 5 days of age and then decreased gradually over a period of 90 days.

It is suggested that the low rate of glucagon release between 3 and 7 days of age may be a result of the high levels of blood fatty acids and ketone bodies found in the rat during this period.