Increased Plasma Glucagon Research Articles

Islet Auto‐Transplantation into an Omental or Splenic Site Results in a Normal Beta Cell but Abnormal Alpha Cell Response to Mild Non‐Insulin‐Induced Hypoglycemia

The present studies were designed to determine if totally pancreatectomized dogs that underwent islet auto-transplantation retained a functional pancreatic counterregulatory response to mild non-insulin-induced hypoglycemia. Six dogs underwent total pancreatectomy followed by islet auto-transplantation to spleen or omentum. The animals recovered and fasting plasma glucose and insulin levels were normal. Each study consisted of a 40-min control and 2-h test period. At the onset of the test period, a glycogen phosphorylase inhibitor was administered to create mild hypoglycemia. Plasma glucose in the transplanted dogs fell from 120 +/- 4 to 80 +/- 3 mg/dL, similar to the minimum in control dogs without islet auto-transplantation (108 +/- 2 to 84 +/- 5 mg/dL). The fall in plasma insulin was similar in both groups. Glucagon, however, rose in response to hypoglycemia in the control dogs (Delta24 +/- 7 pg/mL; p < 0.05), but failed to rise significantly in the transplanted dogs (Delta9 +/- 6 pg/mL). In fact, only 1 of 7 control dogs failed to increase plasma glucagon by at least 25%, whereas 4 of 6 transplanted dogs failed to do so. In conclusion, in conscious dogs with successfully auto-transplanted islets, the beta cell response to mild non-insulin-induced hypoglycemia was normal, whereas the alpha cell response was not.

Role of the Decrement in Intraislet Insulin for the Glucagon Response to Hypoglycemia in Humans

Animal and in vitro studies indicate that a decrease in beta-cell insulin secretion, and thus a decrease in tonic alpha-cell inhibition by intraislet insulin, may be an important factor for the increase in glucagon secretion during hypoglycemia. However, in humans this role of decreased intraislet insulin is still unclear. We studied glucagon responses to hypoglycemia in 14 nondiabetic subjects on two separate occasions. On both occasions, insulin was infused from 0 to 120 min to induce hypoglycemia. On one occasion, somatostatin was infused from -60 to 60 min to suppress insulin secretion, so that the decrement in intraislet insulin during the final 60 min of hypoglycemia would be reduced. On the other occasion, subjects received an infusion of normal saline instead of the somatostatin. During the 2nd h of the insulin infusion, when somatostatin or saline was no longer being infused, plasma glucose ( approximately 2.6 mmol/l) and insulin levels ( approximately 570 pmol/l) were comparable in both sets of experiments (both P > 0.4). In the saline experiments, insulin secretion remained unchanged from baseline (-90 to -60 min) before insulin infusion and decreased from 1.20 +/- 0.12 to 0.16 +/- 0.04 pmol . kg(-1) . min(-1) during insulin infusion (P < 0.001). However, in the somatostatin experiments, insulin secretion decreased from 1.18 +/- 0.12 pmol . kg(-1) . min(-1) at baseline to 0.25 +/- 0.09 pmol . kg(-1) . min(-1) before insulin infusion so that it did not decrease further during insulin infusion (-0.12 +/- 0.10 pmol . kg(-1) . min(-1), P = 0.26) indicating the complete lack of a decrement in intraislet insulin during hypoglycemia. This was associated with approximately 30% lower plasma glucagon concentrations (109 +/- 7 vs. 136 +/- 9 pg/ml, P < 0.006) and increments in plasma glucagon above baseline (41 +/- 8 vs. 67 +/- 11 pg/ml, P < 0.008) during the last 15 min of the hypoglycemic clamp. In contrast, increases in plasma growth hormone were approximately 70% greater during hypoglycemia after somatostatin infusion (P < 0.007), suggesting that to some extent the increases in plasma glucagon might have reflected a rebound in glucagon secretion. These results provide direct support for the intraislet insulin hypothesis in humans. However, the exact extent to which a decrement in intraislet insulin accounts for the glucagon responses to hypoglycemia remains to be established.

Loss of the Decrement in Intraislet Insulin Plausibly Explains Loss of the Glucagon Response to Hypoglycemia in Insulin-Deficient Diabetes

The intraislet insulin hypothesis for the signaling of the glucagon secretory response to hypoglycemia states that a decrease in arterial glucose --> a decrease in beta-cell insulin secretion --> a decrease in tonic alpha-cell inhibition by insulin --> an increase in alpha-cell glucagon secretion. To test this hypothesis in humans, a hyperinsulinemic- euglycemic ( approximately 5.0 mmol/l [90 mg/dl] x 2 h) and then a hypoglycemic ( approximately 3.0 mmol/l [55 mg/dl] x 2 h) clamp was performed in 14 healthy young adults on two occasions, once with oral administration of the ATP-sensitive potassium channel agonist diazoxide to selectively suppress baseline insulin secretion and once with the administration of a placebo. The decrement in plasma C-peptide during the induction of hypoglycemia was reduced by approximately 50% in the diazoxide clamps (from 0.3 +/- 0.0 to 0.1 +/- 0.0 nmol/l [0.8 +/- 0.1 to 0.4 +/- 0.1 ng/ml]) compared with the placebo clamps (from 0.4 +/- 0.0 to 0.1 +/- 0.0 nmol/l [1.2 +/- 0.1 to 0.4 +/- 0.1 ng/ml]) (P = 0.0015). This reduction of the decrement in intraislet insulin during induction of hypoglycemia caused an approximately 50% reduction (P = 0.0010) of the increase in plasma glucagon in the diazoxide clamps (from 29 +/- 3 to 35 +/- 2 pmol/l [102 +/- 9 to 123 +/- 8 pg/ml]) compared with the placebo clamps (from 28 +/- 2 to 43 +/- 5 pmol/l [98 +/- 7 to 151 +/- 16 pg/ml]). Baseline glucagon levels, the glucagon response to intravenous arginine, and the autonomic (adrenomedullary, sympathetic neural, and parasympathetic neural) responses to hypoglycemia were not altered by diazoxide. These data indicate that a decrease in intraislet insulin is a signal for the glucagon secretory response to hypoglycemia in healthy humans. The absence of that signal plausibly explains the loss of the glucagon response to falling plasma glucose concentrations, a key feature of the pathogenesis of iatrogenic hypoglycemia, in insulin-deficient (type 1 and advanced type 2) diabetes.

Neuropeptide Y Is Required for Hyperphagic Feeding in Response to Neuroglucopenia

To investigate the role played by the orexigenic peptide, neuropeptide Y (NPY), in adaptive responses to insulin-induced hypoglycemia, we measured hypothalamic, feeding, and hormonal responses to this stimulus in both wild-type (Npy+/+) and NPY-deficient (Npy-/-) mice. After administration of insulin at a dose (60 mU ip) sufficient to cause moderate hypoglycemia (plasma glucose levels, 40 +/- 3 and 37 +/- 2 mg/dl for Npy+/+ and Npy-/- mice, respectively; P = not significant), 4-h food intake was increased 2.5-fold in Npy+/+ mice relative to saline-injected controls. By comparison, the increase of intake in Npy-/- mice was far smaller (45%) and did not achieve statistical significance (P = 0.08). Hyperphagic feeding in response to insulin-induced hypoglycemia was therefore markedly attenuated in mice lacking NPY, and a similar feeding deficit was detected in these animals after neuroglucopenia induced by 2-deoxyglucose (500 mg/kg ip). A role for NPY in glucoprivic feeding is further supported by our finding that Npy mRNA content (measured by real-time PCR) increased 2.4-fold in the hypothalamus of Npy+/+ mice by 7 h after insulin injection. Unlike the feeding deficits observed in mice lacking NPY, the effect of hypoglycemia to increase plasma glucagon and corticosterone levels was fully intact in these animals, as were both the nadir glucose value and time to recovery of euglycemia after insulin injection (P = not significant). We conclude that NPY signaling is required for hyperphagic feeding, but not neuroendocrine responses to moderate hypoglycemia.

Hyperglucagonemia in patients with transjugular intrahepatic portosystemic stent-shunts (TIPS)

Background: Hyperglucagonemia has been described to be associated with insulin resistance in patients with liver cirrhosis. Portosystemic shunts may be involved in the etiology of hyperglucagonemia. To test this hypothesis we investigated peripheral plasma glucagon levels before and after portal decompression by transjugular intrahepatic portosystemic stent-shunts (TIPS). Methods: Glucagon, plasma glucose, HbA1c, C-peptide and insulin were determined in peripheral venous samples from 21 diabetic (D)- and 15 non-diabetic patients (ND; 3 treated with insulin, 3 with sulfonylurea, 9 with diet alone) with comparable clinical features (age, BMI, Child-Pugh-score, creatinine) before, 3 and 9 months after TIPS implantation. Results: Glucogon levels before TIPS were elevated in diabetics compared to non-diabetics (D: 145,4±52,1 vs. ND: 97,3±49,8 pg/ml; p=0,057). Three and nine months after TIPS implantation glucagon levels increased significantly in ND (183,9±80,3 and 176,2±93,4 pg/ml) but not in D (169,0±62,4 and 171,9±58,4 pg/ml). While plasma glucose, HbA1c and C-peptide were significantly higher in D than in ND, they did not change significantly three and nine months after TIPS implantation. Insulin was increased in D before TIPS (D: 31,8±15,9 vs. ND: 14,8±7,1 mU/l; p=0,0001). Three and nine months after TIPS insulin significantly increased in ND (26,6±14,7 and 23,2±10,9 vs. 14,8±7,1 mU/l before TIPS) but not in D. Liver and kidney function did not change with time. Conclusions: In non-diabetic cirrhotic patients TIPS implantation is followed by a significant increase of plasma glucagon. However this does not result in a worsening of glycemic control, apparently because of a simultaneous increase of insulin.

The role of corticosterone in the metabolic recovery after intrasplenic adrenal autotransplantation in rats.

Transplantation of adrenal cortical tissue may represent an alternative treatment to reestablish glucocorticoid secretion in adrenal insufficiency. In the present work, performed in adrenalectomized rats and adrenalectomized rats with a complete autotransplanted adrenal into the spleen, several hormones and biochemical parameters were measured and compared to control animals, in order to examine hormone interactions. Rats were sacrificed three weeks after surgery, and plasma and tissue samples were obtained for hormone and biochemical measurements. In adrenalectomized animals, plasma corticosterone, aldosterone and insulin levels were profoundly decreased, whereas in autotransplanted rats plasma corticosterone levels showed a partial recovery, aldosterone plasma concentrations remained low, and plasma insulin levels increased to values close to those of the controls. Both groups showed a marked elevation of plasma ACTH levels, as well as significantly increased plasma glucagon concentrations. In autotransplanted animals, most of the biochemical parameters, which were altered in adrenalectomized rats, returned to normal levels. These results suggest that increased glucagon levels in adrenalectomized and autotransplanted animals, may contribute to the marked increase of plasma ACTH, and could also be important in the recovery of plasma glucose and hepatic glycogen observed in autografted rats. Since high glucagon concentrations alone were unable to normalize carbohydrate levels in adrenalectomized animals, it appears that glucagon can act only in the presence of corticosterone.

Glucose regulates the release of orexin-a from the endocrine pancreas.

Orexins (hypocretins) are novel neuropeptides that appear to play a role in the regulation of energy balances. Orexin-A (OXA) increases food intake in rodents, and fasting activates OXA neurons in both the lateral hypothalamic area and gut. OXA is also found in the endocrine pancreas; however, little is known about its release or functional significance. In this study, we show that depolarizing stimuli evoke the release of OXA from rat pancreatic islets in a calcium-dependent manner. Moreover, OXA release is stimulated by low glucose (2.8 mmol/l), similar to glucagon secretion, and inhibited by high glucose (16.7 mmol/l). Fasting increases plasma OXA, supporting the idea that orexin is released in response to hypoglycemia. Cells that secrete glucagon and insulin contain OXA and both cell types express orexin receptors. OXA increases glucagon secretion and decreases glucose-stimulated insulin release from isolated islets. OXA infusion increases plasma glucagon and glucose levels and decreases plasma insulin in fasted rats. We conclude that orexin-containing islet cells, like those in the brain and gut, are glucosensitive and part of a network of glucose "sensing" cells that becomes activated when blood glucose levels fall. OXA may modulate islet hormone secretion to maintain blood glucose levels during fasting.

Characterization of new selective somatostatin receptor subtype-2 (sst2) antagonists, BIM-23627 and BIM-23454. Effects of BIM-23627 on GH release in anesthetized male rats after short-term high-dose dexamethasone treatment.

We here report a pharmacological characterization of two new somatostatin (SS) receptor subtype-2 (sst2) selective antagonists by evaluating their GH-releasing activity when administered, by different routes, in anesthetized adult rats and in freely moving 10-d-old rats. Moreover, we describe the effect of these SS antagonists on the GH response to GHRH after short-term high-dose dexamethasone (DEX) treatment in young male rats. BIM-23454 and BIM-23627, given iv, were able to counteract the SS-induced inhibition of GH secretion occurring after urethane anesthesia in a dose-dependent manner. In DEX-treated animals, the GH response to GHRH was partially blunted (5-min peak values, 270 +/- 50 ng/ml in saline-treated vs. 160 +/- 10 ng/ml in DEX-treated, P < 0.05); however, the simultaneous administration of BIM-23627 (0.2 mg/kg, iv) restored higher amplitude GH pulse, leading to a significantly higher overall mean GH response (area under the curve, 4200 +/- 120 ng/ml/30 min vs. 2800 +/- 100 ng/ml/30 min after GHRH alone; P < 0.05). The SS antagonists showed a reduced GH-releasing effect when administered sc or ip, likely attributable to decreased bioavailability, as compared with the iv route. SS antagonist administration also increased plasma glucagon, insulin, and glucose levels. Based on prior reports that sst2 tonically suppresses glucagon secretion, the antagonist most likely increased glucagon secretion from the pancreatic alpha-cells, with resultant increases in plasma glucose and then insulin.

Gender difference in the glucagon response to glucopenic stress in mice.

A gender difference in the glucagon response to insulin-induced hypoglycemia was previously demonstrated in humans. Whether this reflects a gender difference in autonomic activation or in pancreatic alpha-cell regulation is not known. We investigated the glucagon, epinephrine, and norepinephrine responses to neuroglycopenic stress induced by 2-deoxy-D-glucose (2-DG) or insulin in female and male mice. 2-DG increased plasma glucagon levels by 559 +/- 68% in females versus 281 +/- 46% in males (P < 0.01). Plasma levels of epinephrine or norepinephrine after 2-DG administration did not differ between genders. During insulin-induced hypoglycemia, the glucagon response was similarly higher in females (P < 0.001), whereas the plasma catecholamine response was higher in males (P < 0.05). In vivo, the glucagon response to carbachol or clonidine was higher in females (P < 0.05). In isolated islets, the glucagon response to carbachol (100 microM; P = 0.003) but not to clonidine (1 microM) was larger in females. We conclude that in addition to a larger alpha-cell mass (previously described in female mice), an increased sensitivity of the glucagon-producing alpha-cell to cholinergic activation contributes to the larger glucagon response to glucopenic stress in female mice.

Incubation Temperature Affects Plasma Insulin-Like Growth Factors in Embryos from Selected Lines of Turkeys

An experiment was conducted to test the hypothesis that incubator temperature may affect circulating insulin-like growth factors (IGF-I and IGF-II). In prior studies, growth of turkey embryos was altered by increasing incubator temperatures. Interestingly, the embryonic growth of a growth-selected line (F) was reduced, whereas embryos from an egg-production-selected line (E) did not alter embryonic growth but altered organogenesis. Growth of the F and E lines was altered experimentally in the current study by increasing incubator temperature from 36.8 to 37.2 C during the last 3 d of incubation. Embryonic blood samples were taken and analyzed for glucose, glucagon, IGF-I, and IGF-II concentrations.Increased incubator temperature elevated embryonic plasma glucose concentrations of all treatments compared to controls, which was accompanied by increased plasma glucagon concentration only in the E line embryos. Line and treatment interacted to affect IGF-I and IGF-II concentrations of embryo and hatchlings. Line E embryos increased IGF-I in response to the higher temperature, but controls did not; F embryos altered IGF-II in response to treatment, but controls did not. Alterations in IGF-I in E corresponded to growth responses, whereas IGF-II in F corresponded to metabolic responses. We concluded that changes in turkey embryo growth rates to incubator temperature involved changes in IGF-I. Additionally, IGF-II and glucagon are involved in intermediary metabolism during higher temperature exposure.

Corrigendum to: IGF-I is not a useful marker for nutritional status in the growing pig under commercial conditions

Plasma hormone concentrations were measured in gilts after fasting, long-term protein restriction, or supplementation. In 11-week-old pigs fasted overnight, plasma insulin, glucagon, gastrin, urea, and glucose were increased 30 min after re-feeding (P &lt; 0.05), whereas IGF-I did not change. In 16-week-old gilts fed a standard commercial diet [14.6% crude protein (CP)], or a high-protein diet (16.7% CP) for 4 weeks, the high-protein diet increased weight gain (13%; P &lt; 0.05) and carcass weight (4%; P &lt; 0.05), but did not alter plasma IGF-I, insulin, or glucagon. In 10-week-old gilts fed high-protein diets (19.4% and 18.3% CP), or low-protein diets (15.5% and 13.3% CP) for 12 weeks during the grower and finisher phases, respectively, the low-protein diet decreased weight gain (18%; P &lt; 0.001) and carcass weight (11%; P &lt; 0.01), with a marked increase in plasma glucagon (P &lt; 0.05), no change in insulin, and only a trend towards decreased IGF-I (P = 0.1). The pigs were more sensitive to altered dietary protein at 10 weeks of age than at 16 weeks. Plasma IGF-I was not responsive to the short-term effects of feeding or the long-term effects of dietary protein. Glucagon could provide a useful marker for nutritional status in young pigs, provided that time of feeding is taken into account.

IGF-I is not a useful marker for nutritional status in the growing pig under commercial conditions

Plasma hormone concentrations were measured in gilts after fasting, long-term protein restriction, or supplementation. In 11-week-old pigs fasted overnight, plasma insulin, glucagon, gastrin, urea, and glucose were increased 30 min after re-feeding (P &lt; 0.05), whereas IGF-I did not change. In 16-week-old gilts fed a standard commercial diet [14.6% crude protein (CP)], or a high-protein diet (16.7% CP) for 4 weeks, the high-protein diet increased weight gain (13%; P &lt; 0.05) and carcass weight (4%; P &lt; 0.05), but did not alter plasma IGF-I, insulin, or glucagon. In 10-week-old gilts fed high-protein diets (19.4% and 18.3% CP), or low-protein diets (15.5% and 13.3% CP) for 12 weeks during the grower and finisher phases, respectively, the low-protein diet decreased weight gain (18%; P &lt; 0.001) and carcass weight (11%; P &lt; 0.01), with a marked increase in plasma glucagon (P &lt; 0.05), no change in insulin, and only a trend towards decreased IGF-I (P = 0.1). The pigs were more sensitive to altered dietary protein at 10 weeks of age than at 16 weeks. Plasma IGF-I was not responsive to the short-term effects of feeding or the long-term effects of dietary protein. Glucagon could provide a useful marker for nutritional status in young pigs, provided that time of feeding is taken into account.

The 5-HT 2C/2B receptor agonist, m-chlorophenylpiperazine, increases plasma glucagon levels in rats

Effects of the 5-HT 2C/2B receptor agonist m-chlorophenylpiperazine (mCPP) on plasma glucagon levels were investigated in rats. mCPP dose dependently increased plasma glucagon levels. Hyperglucagonemia elicited by mCPP was prevented by the 5-HT 2A/2B/2C receptor antagonist, ritanserin, while the 5-HT 2A receptor antagonist, ketanserin, did not show any effect. Increases in glucagon levels induced by mCPP were inhibited by prior adrenodemedullation. These results indicate that increases in plasma glucagon levels induced by mCPP are mediated by the 5-HT 2C/2B receptor which in turn facilitates adrenaline release.

Liver Hyperplasia and Paradoxical Regulation of Glycogen Metabolism and Glucose-sensitive Gene Expression in GLUT2-null Hepatocytes: FURTHER EVIDENCE FOR THE EXISTENCE OF A MEMBRANE-BASED GLUCOSE RELEASE PATHWAY

We investigated the impact of GLUT2 gene inactivation on the regulation of hepatic glucose metabolism during the fed to fast transition. In control and GLUT2-null mice, fasting was accompanied by a approximately 10-fold increase in plasma glucagon to insulin ratio, a similar activation of liver glycogen phosphorylase and inhibition of glycogen synthase and the same elevation in phosphoenolpyruvate carboxykinase and glucose-6-phosphatase mRNAs. In GLUT2-null mice, mobilization of glycogen stores was, however, strongly impaired. This was correlated with glucose-6-phosphate (G6P) levels, which remained at the fed values, indicating an important allosteric stimulation of glycogen synthase by G6P. These G6P levels were also accompanied by a paradoxical elevation of the mRNAs for L-pyruvate kinase. Re-expression of GLUT2 in liver corrected the abnormal regulation of glycogen and L-pyruvate kinase gene expression. Interestingly, GLUT2-null livers were hyperplasic, as revealed by a 40% increase in liver mass and 30% increase in liver DNA content. Together, these data indicate that in the absence of GLUT2, the G6P levels cannot decrease during a fasting period. This may be due to neosynthesized glucose entering the cytosol, being unable to diffuse into the extracellular space, and being phosphorylated back to G6P. Because hepatic glucose production is nevertheless quantitatively normal, glucose produced in the endoplasmic reticulum may also be exported out of the cell through an alternative, membrane traffic-based pathway, as previously reported (Guillam, M.-T., Burcelin, R., and Thorens, B. (1998) Proc. Natl. Acad. Sci. U. S. A. 95, 12317-12321). Therefore, in fasting, GLUT2 is not required for quantitative normal glucose output but is necessary to equilibrate cytosolic glucose with the extracellular space. In the absence of this equilibration, the control of hepatic glucose metabolism by G6P is dominant over that by plasma hormone concentrations.

Effects of low-dose and high-dose glucagon and glucose production and gluconeogenesis in humans

The analysis of mass isotopomers in blood glucose and lactate can be used to estimate gluconeogenesis (Gneo), glucose production (GP), and, by subtraction, nongluconeogenic glucose release by the liver. At 6 AM, 18 normal subjects received a 7-hour primed constant infusion of [U-13C6] glucose. After a 3-hour baseline period (12 hours of fasting), somatostatin, insulin, hydrocortisone, growth hormone (GH), and glucagon were infused for 4 hours. Glucagon was infused at a low-dose (n = 6) or high-dose (n = 6) concentration for 4 hours and was compared with fasting alone (n = 6). Low-dose glucagon infusion increased plasma glucagon (64 +/- 3 v 44 +/- 7 ng/L, low glucagon v baseline). GP increased above baseline (15.5 +/- 0.5 v 13.8 +/- 0.5 micromol/kg/min, P < .05), which was also greater than fasting alone (11 .5 +/- 0.6 micromol/kg/min, P < .05). The elevation in GP was due to a near doubling of nongluconeogenic glucose release compared with fasting alone (8.3 +/- 0.6 v 4.7 +/- 0.5 micromol/kg/min, P < .01). High-dose glucagon infusion (125 +/- 25 ng/L) increased GP above baseline (15.8 +/- 0.6 v 13.5 +/- 0.5 micromol/kg/min, P < .05), which was also greater than fasting alone (11.5 +/- 0.6 micromol/kg/min, P < .05). The increase in GP was due to an increase in Gneo (8.5 +/- 0.5 v 6.8 +/- 0.7 micromol/kg/min, P < .05) and nongluconeogenic glucose release (7.4 +/- 0.5 v 4.7 +/- 0.4 micromol/kg/min, P < .05) compared with fasting. Low-dose glucagon increases GP only by stimulation of nongluconeogenic glucose release. High-dose glucagon increases GP by an increase in both Gneo and nongluconeogenic glucose release.

Effects of the 5-HT2A receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) on plasma glucose and glucagon levels of rats.

Effects of the 5-hydroxytryptamine (5-HT)2A receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) on plasma glucagon levels were studied in rats. Systemic injection of DOI induces significant increases in plasma glucagon levels. Hyperglucagonemia induced by DOI was dose-dependently prevented by the 5-HT2A receptor antagonist ketanserin. Adrenodemedullation abolished hyperglucagonemia elicited by DOI. Previous report demonstrated that the peripheral 5-HT2A receptor agonist induces hyperglycemia in rats but does not increase plasma glucagon levels at doses inducing hyperglycemia. Therefore, our findings suggest that DOI-induced glucagon release was elicited by stimulation of the central 5-HT2A receptor, which in turn increasing adrenaline release.

Regulation of messenger ribonucleic acid expression for gluconeogenic enzymes during glucagon infusions into lactating cows.

The effects of glucagon infusions on expression of mRNA for enzymes that regulate gluconeogenesis were studied in lactating cows. Normal cows and cows with fatty liver that were susceptible to ketosis were assigned to either glucagon-treated or control groups. Glucagon at 0 or 10 mg/d was infused for 14 d beginning at d 21 postpartum. In normal cows, glucagon infusions increased concentrations of both plasma glucagon and glucose, which caused plasma insulin to increase. Consequently, hepatic phosphoenolpyruvate carboxykinase mRNA decreased during wk 1 of glucagon infusions. Glucagon infusions into cows with fatty liver also increased plasma glucagon and glucose, but concentrations of plasma insulin and hepatic phosphoenolpyruvate carboxykinase mRNA did not change. More phosphoenolpyruvate carboxykinase mRNA was present in the livers of cows with fatty liver than in livers of normal cows. In a follow-up experiment with midlactation cows, 3.5-h infusions of glucagon at 14 mg/d increased plasma glucose and insulin and decreased plasma nonesterified fatty acids and hepatic glycogen. Hepatic phosphoenolpyruvate carboxykinase mRNA was decreased 41%, pyruvate carboxylase mRNA was increased 50%, but fructose-1,6-bisphosphatase mRNA did not change. We conclude that the expression of the hepatic phosphoenolpyruvate carboxykinase gene in normal cows is inhibited by insulin to balance elevated carbohydrate status during glucagon infusions; however, inhibited expression of hepatic phosphoenolpyruvate carboxykinase mRNA probably is not involved in the pathogenesis of lactation ketosis.

Hormone-related, muscle-specific changes in protein metabolism and fiber type profile after faba bean intake.

Male growing Wistar rats were fed, over 15 days, isoenergetic (16.72 +/- 0.49 MJ) and isoproteic (11%) diets containing either lactalbumin or raw Vicia faba L. (Vf) as the sole source of protein. Compared with pair-fed controls (PF), soleus muscles of Vf-fed rats showed increased (P < 0.05) synthesis and breakdown rates. In addition, the soleus of Vf-fed rats displayed a decrease (P < 0.05) in type I and an increase (P < 0.01) in type IIc fibers compared with that of PF animals. On the contrary, extensor digitorum longus muscles of both Vf-fed and PF rats showed an increase (P < 0.01) in type I and a reduction (P < 0.05) in type IIb fibers together with a decrease (P < 0.05) in the cross-sectional area of the latter fibers. Vf-fed rats exhibited a significant decrease in serum insulin (P < 0.05) and thyrotropin (P < 0.01) levels, together with an increase in plasma glucagon (P < 0.05) and 3,5,3'-triiodothyronine (P < 0.01) concentrations, compared with the PF group. Both Vf-fed and PF rats experienced an increase in corticosterone concentrations (P < 0.01 vs. control; P < 0.05 vs. PF). The muscle-specific changes in both protein metabolism and fiber type composition may partly depend on the hormonal changes that were observed after Vf intake.

The effects of a beef and fish meal on plasma amino acids, insulin and glucagon levels

In vivo studies have reported the effects of various protein meals on pancreatic hormone secretion. The purpose of the present investigation was to compare the plasma insulin, glucagon and amino acid variations in response to a beef or a fish meal with comparable amino acid content. It was found that the plasma insulin levels increased significantly more with the beef steak meal (from 46.2 ± 3.5 to 153.2 ± 12.6 pmol/l) than with the cod fillet (from 47.8 ± 3.1 to 104.2 ± 9.7). The increase in plasma glucagon following the beef meal (from 64.2 ± 8.1 to 139.4 ± 21.9) was not significantly different from that of the fish meal (from 64.2 ± 7.6 to 119.8 ± 17.8). The increase in plasma amino acids was comparable for both meals except for arginine and lysine which were higher with fish feeding and for histidine when beef was fed. The plama levels of histidine were 30 μmol/l compared to 10μmol/l for the fish meal. This difference may be related to the fact that carnosine, a dipeptide composed of histidine and beta-alanine, is found in high concentrations in beef muscles but is relatively absent in cod fillets. Postprandial studies on time-related variations of plasma histidine and on digestibility or rate of absorption of beef and fish meat are needed in order to identify the factor involved in the difference in insulin secretion between these two nutrients.

VITAMIN C ATTENUATION OF THE DEVELOPMENT OF TYPE I DIABETES MELLITUS BY INTERFERON-α

Interferon alpha (IFN-α) inhibits insulin release and may be cytotoxic to pancreatic islets. Increased free radical activity may be implicated in the cytotoxic action of IFN-α and development of diabetes mellitus. Therefore we measured markers of free radical activity (lipid peroxides and the non-peroxide-conjugated diene isomer of linoleic acid [PL-9,11-LA′]) along with some pancreatic variables in male albino rats treated with IFN-α, as well as the possible protective effect of two antioxidants, vitamin C and mannitol. Compared to untreated rats, it was shown that IFN-α induced an increase in plasma glucose. Pancreatic and serum insulin, as well as serum C-peptide, were increased after 1 week, then their levels were reduced after 2 weeks. Plasma lipid peroxides and (PL-9,11-LA′) were markedly elevated, while linoleic acid was reduced. These changes in the studied parameters were attributed, in part, to the superoxide and free radical generation during IFN-α treatment. Plasma glucagon was increased after 2 weeks. Administration of vitamin C along with IFN-α succeeded in modulating most of the altered parameters affected during IFN-α. The hyperglycaemic effect of IFN-α was greatly ameliorated and the negative effect on pancreatic and serum insulin and serum C-peptide were nearly abolished. The elevated levels of lipid peroxide and (PL-9,11-LA′) and the reduction in linoleic acid being normalised. The only persistent effect was the increase in plasma glucagon. Concurrent administration of mannitol with IFN-α caused no changes in the parameters studied compared to that induced by treatment with IFN-α alone.