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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- Abstract: Diabetes x
- Abstract: Islets x
- Abstract: Insulin x
- Abstract: BetaCells x
- Abstract: Pancreas x
- Abstract: Obesity x
- Abstract: Glucose x
- Abstract: Hyperglycemia x
- Abstract: Hypoglycemia x
- Abstract: Insulinoma x
- Abstract: Glucagon x
- Abstract: IGF* x
RM Ortiz, DP Noren, CL Ortiz and F Talamantes
R J Denver and C S Nicoll
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
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.
H. Vilhardt, T. Krarup, J. J. Holst and P. Bie
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
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.
F Bertuzzi, C Berra, C Socci, A M Davalli, G Pozza and A E Pontiroli
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
SJ Fisher, ZQ Shi, HL Lickley, S Efendic, M Vranic and A Giacca
At supraphysiological levels, IGF-I bypasses some forms of insulin resistance and has been proposed as a therapeutic agent in the treatment of diabetes. Unfortunately, side effects of high-dose IGF-I (100-250 microg/kg) have precluded its clinical use. Low-dose IGF-I (40-80 microg/kg), however, shows minimal side effects but has not been systematically evaluated. In our previous study under conditions of declining glucose, low-dose IGF-I infusion was more effective in stimulating glucose utilization, but less effective in suppressing glucose production and lipolysis than low-dose insulin. However, under conditions of hyperglycemia, we could not observe any differential effects between high-dose infusions of IGF-I and insulin. To determine whether the differential effects of IGF-I and insulin are dose-related or related to the prevailing glucose level, 3 h glucose clamps were performed in the same animal model as in the previous studies, i.e. the moderately hyperglycemic (175 mg/dl) insulin-infused depancreatized dog, with additional infusions of low-dose IGF-I (67.8 microg/kg, i.e. 29.1 microg/kg bolus plus 0.215 microg/kg( )per min infusion; n=5) or insulin 49.5 mU/kg (9 mU/kg bolus plus 0.45 mU/kg per min; n=7). As in the previous study under conditions of declining glucose, low-dose IGF-I had significant metabolic effects in vivo, in our model of complete absence of endogenous insulin secretion. Glucose production was similarly suppressed with both IGF-I and insulin, by 54+/-3 and 56+/-2% s.e. (P=NS) respectively. Glucose utilization was stimulated to the same extent (IGF-I 5.2+/-0.2, insulin 5.5+/-0.3 mg/kg per min, P=NS). Glucagon, free fatty acid, glycerol, alanine and beta-hydroxybutyrate, were suppressed, while lactate and pyruvate levels were raised, similarly with IGF-I and insulin. We conclude that: (i) differential effects of IGF-I and insulin may be masked under hyperglycemic conditions, independent of the hormone dose; (ii) low-dose IGF-I has no selective advantage over additional insulin in suppressing glucose production and lipolysis, nor in stimulating glucose utilization during hyperglycemia and subbasal insulin infusion when insulin secretion is absent, as in type 1 diabetes mellitus.
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.
Wanbao Yang, Hui Yan, Quan Pan, James Zheng Shen, Fenghua Zhou, Chaodong Wu, Yuxiang Sun and Shaodong Guo
Glucagon promotes hepatic glucose production maintaining glucose homeostasis in the fasting state. Glucagon maintains at high level in both diabetic animals and human, contributing to hyperglycemia. Mitochondria, a major place for glucose oxidation, are dysfunctional in diabetic condition. However, whether hepatic mitochondrial function can be affected by glucagon remains unknown. Recently, we reported that FOXO1 is an important mediator in glucagon signaling in control of glucose homeostasis. In this study, we further assessed the role of FOXO1 in the action of glucagon in the regulation of hepatic mitochondrial function. We found that glucagon decreased the heme production in a FOXO1-dependent manner, suppressed heme-dependent complex III (UQCRC1) and complex IV (MT-CO1) and inhibited hepatic mitochondrial function. However, the suppression of mitochondrial function by glucagon was largely rescued by deleting the Foxo1 gene in hepatocytes. Glucagon tends to reduce hepatic mitochondrial biogenesis by attenuating the expression of NRF1, TFAM and MFN2, which is mediated by FOXO1. In db/db mice, we found that hepatic mitochondrial function was suppressed and expression levels of UQCRC1, MT-CO1, NRF1 and TFAM were downregulated in the liver. These findings suggest that hepatic mitochondrial function can be impaired when hyperglucagonemia occurs in the patients with diabetes mellitus, resulting in organ failure.
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.