المؤلفون: Edgerton, Dale S., Moore, Mary C., Winnick, Jason J., Scott, Melanie, Farmer, Ben, Naver, Helle, Jeppesen, Claus B., Madsen, Peter, Kjeldsen, Thomas B., Nishimura, Erica, Brand, Christian L., Cherrington, Alan D.

المصدر: Diabetes; Nov2014, Vol. 63 Issue 11, p3946-3954, 9p, 2 Charts, 5 Graphs

مصطلحات موضوعية: INSULIN research, METABOLISM, FAT, GLUCOSE, GLUCAGON

مستخلص: Endogenous insulin secretion exposes the liver to three times higher insulin concentrations than the rest of the body. Because subcutaneous insulin delivery eliminates this gradient and is associated with metabolic abnormalities, functionally restoring the physiologic gradient may provide therapeutic benefits. The effects of recombinant human insulin (HI) delivered intraportally or peripherally were compared with an acylated insulin model compound (insulin-327) in dogs. During somatostatin and basal portal vein glucagon infusion, insulin was infused portally (PoHI; 1.8 pmol/kg/min; n = 7) or peripherally (PeHI; 1.8 pmol/kg/min; n = 8) and insulin-327 (Pe327; 7.2 pmol/kg/min; n = 5) was infused peripherally. Euglycemia was maintained by glucose infusion. While the effects on liver glucose metabolism were greatest in the PoHI and Pe327 groups, nonhepatic glucose uptake increased most in the PeHI group. Suppression of lipolysis was greater during PeHI than PoHI and was delayed in Pe327 infusion. Thus small increments in portal vein insulin have major consequences on the liver, with little effect on nonhepatic glucose metabolism, whereas insulin delivered peripherally cannot act on the liver without also affecting nonhepatic tissues. Pe327 functionally restored the physiologic portal-arterial gradient and thereby produced hepato-preferential effects. [ABSTRACT FROM AUTHOR]

: Copyright of Diabetes is the property of American Diabetes Association and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Nishizawa, Makoto, Shiota, Masakazu, Moore, Mary Courtney, Gustavson, Stephanie M., Neal, Doss W., Cherrington, Alan D.

المصدر: American Journal of Physiology: Regulatory, Integrative & Comparative Physiology; Apr2008, Vol. 294, pR1197-R1204, 8p, 2 Charts, 6 Graphs

مصطلحات موضوعية: NEUROPEPTIDES, NEUROPEPTIDE Y, GLUCOSE, METABOLISM, SOMATOSTATIN, GLUCAGON

مستخلص: We examined whether intraportal delivery of neuropeptide Y (NPY) affects glucose metabolism in 42-h-fasted conscious dogs using arteriovenous difference methodology. The experimental period was divided into three subperiods (P1, P2, and P3). During all subperiods, the dogs received infusions of somatostatin, intraportal insulin (threefold basal), intraportal glucagon (basal), and peripheral intravenous glucose to increase the hepatic glucose load twofold basal. Following P1, in the NPY group (n = 7), NPY was infused intraportally at 0.2 and 5.1 pmol·kg^-1·min^-1 during P2 and P3, respectively. The control group (n = 7) received intraportal saline infusion without NPY. There were no significant changes in hepatic blood flow in NPY vs. control. The lower infusion rate of NPY (P2) did not enhance net hepatic glucose uptake. During P3, the increment in net hepatic glucose uptake (compared with P1) was 4 ± I and 10 ± 2 µmol·kg^-1·min^-1 in control and NPY, respectively (P < 0.05). The increment in net hepatic fractional glucose extraction during P3 was 0.015 ± 0.005 and 0.039 ± 0.008 in control and NPY, respectively (P < 0.05). Net hepatic carbon retention was enhanced in NPY vs. control (22 ± 2 vs. 14 ± 2 µmol·kg^-1·min^-1, P < 0.05). There were no significant differences between groups in the total glucose infusion rate. Thus, intraportal NPY stimulates net hepatic glucose uptake without significantly altering whole body glucose disposal in dogs. [ABSTRACT FROM AUTHOR]

: Copyright of American Journal of Physiology: Regulatory, Integrative & Comparative Physiology is the property of American Physiological Society and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Moore, Mary Courtney, Satake, Shosuke, Lautz, Margaret, Neal, Doss W., Smith, Marta, Cherrington, Alan D., Soleimanpour, Scott A.

المصدر: Diabetes; Jan2004, Vol. 53 Issue 1, p32-40, 9p, 2 Charts, 6 Graphs

مصطلحات موضوعية: GLUCOSE, METABOLISM, LIVER, FATTY acids, DOGS, INSULIN, GLUCAGON, GLUCOSE metabolism, ANIMAL experimentation, BIOLOGICAL models, BLOOD sugar, COMPARATIVE studies, DYNAMICS, GLYCOGEN, HEPARIN, INTRAVENOUS therapy, LIVER blood-vessels, RESEARCH methodology, MEDICAL cooperation, RESEARCH, EVALUATION research, PHARMACODYNAMICS

مستخلص: We used tracer and arteriovenous difference techniques in conscious dogs to determine the effect of nonesterifled fatty acids (NEFAs) on net hepatic glucose uptake (NHGU). The protocol included equilibration ([3³H]glucose), basal, and two experimental periods (-120 to -30, -30 to 0, 0-120 [period 1], and 120-240 min [period 2], respectively). During periods 1 and 2, somatostatin, basal intraportal insulin and glucagon, portal glucose (21.3 µmol · kg[sup -1]· min[sup -1]), peripheral glucose (to double the hepatic glucose load), and peripheral nicotinic acid (1.5 mg · kg[sup -1] min[sup -1]) were infused. During period 2, saline (nicotinic acid INA], n = 7), lipid emulsion (NA plus lipid emulsion [NAL], n = 8), or glycerol (NA plus glycerol [NAG], n = 3) was infused peripherally. During period 2, the NA and NAL groups differed (P < 0.05) in rates of NHGU (10.5 ± 2.08 and 4.7 ± 1.9 µmol · kg[sup -1] · min[sup -1] )], respectively, endogenous glucose R[sub a] (2.3 ± 1.4 and 10.6 ± 1.0 µmol· kg[sup-1]· min[sup -1]), net hepatic NEFA uptakes (0.1 ± 0.1 and 1.8 ± 0.2 µmol · kg[sup -1] · min[sup -1]), net hepatic Β-hydroxybutyrate output (0.1 ± 0.0 and 0.4 ± 0.1 µmol· kg[sup -1] · min[sup -1]), and net hepatic lactate output (6.5 ± 1.7 vs. -2.3 ± 1.2 µmol · kg[sup -1]· min[sup -1]). Hepatic glucose uptake and release were 2.6 µmol · kg[sup -1] · min[sup -1] less and 3.5 µmol · kg[sup -1]· min[sup -1] greater, respectively, in the NAL than NA group (NS). The NAG group did not differ significantly from the NA group in any of the parameters listed above. In the presence of hyperglycemia and relative insulin deficiency, elevated NEFAs reduce NHGU by stimulating hepatic glucose release and suppressing hepatic glucose uptake. [ABSTRACT FROM AUTHOR]

: Copyright of Diabetes is the property of American Diabetes Association and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Nishizawa, Makoto, Moore, Mary Courtney, Shiota, Masakazu, Gustavson, Stephanie M., Snead, Wanda L., Neal, Doss W., Cherrington, Alan D.

المصدر: American Journal of Physiology: Endocrinology & Metabolism; May2003, Vol. 47 Issue 5, pE1027, 10p, 2 Charts, 12 Graphs

مصطلحات موضوعية: GLUCAGON-like peptide 1, METABOLISM

مستخلص: Arteriovenous difference and tracer ([3-³H]glucose) techniques were used in 42-h-fasted conscious dogs to identify any insulin-like effects of intraportally administered glucagonlike peptide 1-(7-36)amide (GLP-1). Each study consisted of an equilibration, a basal, and three 90-min test periods (P1, P2, and P3) during which somatostatin, intraportal insulin (3-fold basal) and glucagon (basal), and peripheral glucose were infused. Saline was infused intraportally in P1. During P2 and P3, GLP-1 was infused intraportally at 0.9 and 5.1 pmol·kg[sup -1]· min[sup -1] in eight dogs, at 10 and 20 pmol·kg[sup -1]·min[sup -1] in seven dogs, and at 0 pmol·kg[sup -1]·min[sup -1] in eight dogs (control group). Net hepatic glucose uptake was significantly enhanced during GLP-1 infusion at 20 pmol·kg[sup -1]·min[sup -1] [21.8 vs. 13.4 µmol· kg[sup -1]·min[sup -1] (control), P < 0.05]. Glucose utilization was significantly increased during infusion at 10 and 20 pmol·kg[sup -1]· min[sup -1] [87.3 ± 8.3 and 105.3 ± 12.8, respectively, vs. 62.2 ± 5.3 and 74.7 ± 7.4 µmol·kg[sup -1]·min[sup -1] (control), P < 0.05]. The glucose infusion rate required to maintain hyperglycemia was increased (P < 0.05) during infusion of GLP-1 at 5.1, 10, and 20 pmol·kg[sup -1]·min[sup -1] (22, 36, and 32%, respectively, greater than control). Nonhepatic glucose uptake increased significantly during delivery of GLP-1 at 5.1 and 10 pmol·kg[sup -1]·min[sup -1] (25 and 46% greater than control) and tended (P = 0.1) to increase during GLP-1 infusion at 20 pmol·kg[sup -1]·min[sup -1] (24% greater than control). Intraportal infusion of GLP-1 at high physiological and pharmacological rates increased glucose disposal primarily in nonhepatic tissues. [ABSTRACT FROM AUTHOR]

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المؤلفون: Edgerton, Dale S., Cardin, Sylvain, Pan, Catherine, Neal, Doss, Farmer, Ben, Converse, Margaret, Cherrington, Alan D.

المصدر: Diabetes; Nov2002, Vol. 51 Issue 11, p3151-3162, 12p, 1 Diagram, 5 Charts, 8 Graphs

مصطلحات موضوعية: INSULIN, GLUCONEOGENESIS, GLYCOLYSIS, GLYCOGEN, AMINO acid metabolism, ANIMAL experimentation, BIOLOGICAL models, COMPARATIVE studies, DOGS, DYNAMICS, GLUCAGON, HETEROCYCLIC compounds, HOMEOSTASIS, HORMONE antagonists, INTRAVENOUS therapy, LACTATES, LIVER, RESEARCH methodology, MEDICAL cooperation, METABOLISM, PYRIDINE, RESEARCH, SOMATOSTATIN, EVALUATION research, CHEMICAL inhibitors

مستخلص: The direct acute effects of insulin on the regulation of hepatic gluconeogenic flux to glucose-6-phosphate (G6P) in vivo may be masked by the hormone's effects on net hepatic glycogenolytic flux and the resulting changes in glycolysis. To investigate this possibility, we used a glycogen phosphorylase inhibitor (BAY R3401) to inhibit glycogen breakdown in the overnight-fasted dog, and the effects of complete insulin deficiency or a fourfold rise in the plasma insulin level were assessed during a 5-h experimental period. Hormone levels were controlled using somatostatin with portal insulin and glucagon infusion. After the control period, plasma insulin infusion 1) was discontinued, creating insulin deficiency; 2) increased fourfold; or 3) was continued at the basal rate. During insulin deficiency, glucose production and the plasma level and net hepatic uptake of nonesterified free fatty acids increased, whereas during hyperinsulinemia they decreased. Net hepatic lactate uptake increased sixfold during insulin deficiency and 2.5-fold during hyperinsulinemia. Net hepatic gluconeogenic flux increased more than fourfold during insulin deficiency but was not reduced by hyperinsulinemia. We conclude that in the absence of appreciable glycogen breakdown, an acute gluconeogenic effect of hypoinsulinemia becomes manifest, whereas inhibition of the process by a physiologic rise in insulin was not evident. [ABSTRACT FROM AUTHOR]

: Copyright of Diabetes is the property of American Diabetes Association and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Cardin, Sylvain, Walmsley, Konstantin, Neal, Doss W., Williams, Phillip E., Cherrington, Alan D.

المصدر: American Journal of Physiology: Endocrinology & Metabolism; Nov2002, Vol. 46 Issue 5, pE958, 7p, 3 Charts, 5 Graphs

مصطلحات موضوعية: VAGUS nerve, METABOLISM, GLUCAGON, SOMATOSTATIN

مستخلص: We determined if blocking transmission in the fibers of the vagus nerves would affect basal hepatic glucose metabolism in the 18-h-fasted conscious dog. A pancreatic clamp (somatostatin, basal portal insulin, and glucagon) was employed. A 40-min control period was followed by a 90-min test period. In one group, stainless steel cooling coils (Sham, n = 5) were perfused with a 37°C solution, while in the other (Cool, n -- 6), the coils were perfused with -20°C solution. Vagal blockade was verified by heart rate change (80 ± 9 to 84 ± 14 beats/min in Sham; 98 ± 12 to 193 ± 22 beats/min in Cool). The arterial glucose level was kept euglycemic by glucose infusion. No change in tracer-determined glucose production occurred in Sham, whereas in Cool it dropped significantly (2.4 ± 0.4 to 1.9 ± 0.4 mg · kg[SUP-1] · min[SUP-1]). Net hepatic glucose output did not change in Sham but decreased from 1.9 ± 0.3 to 1.3 ± 0.3 mg·[SUP-1] · kg[SUP-1].min[SUP-1] in the Cool group. Hepatic gluconeogenesis did not change in either group. These data suggest that vagal blockade acutely modulates hepatic glucose production by inhibiting glycogenolysis. [ABSTRACT FROM AUTHOR]

: Copyright of American Journal of Physiology: Endocrinology & Metabolism is the property of American Physiological Society and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Shiota, Masakazu, Moore, Mary Courtney, Galassetti, Pietro, Monohan, Michael, Neal, Doss W., Shulman, Gerald I., Cherrington, Alan D.

المصدر: Diabetes; Feb2002, Vol. 51 Issue 2, p469-478, 10p, 1 Chart, 8 Graphs

مصطلحات موضوعية: FRUCTOSE, HYPERGLYCEMIA, INSULIN resistance, ALANINE metabolism, BLOOD sugar analysis, GLUCOSE metabolism, GLYCERIN metabolism, ALANINE, ANIMAL experimentation, COMPARATIVE studies, DOGS, DUODENUM, GLUCAGON, GLUCOSE, GLYCERIN, HYPERINSULINISM, INGESTION, INTESTINES, LACTIC acid, LIVER, LIVER blood-vessels, RESEARCH methodology, MEDICAL cooperation, METABOLISM, RESEARCH, EVALUATION research, OSMOLAR concentration

مستخلص: Intraportal infusion of small amounts of fructose markedly augmented net hepatic glucose uptake (NHGU) during hyperglycemic hyperinsulinemia in conscious dogs. In this study, we examined whether the inclusion of catalytic amounts of fructose with a glucose load reduces postprandial hyperglycemia and the pancreatic beta-cell response to a glucose load in conscious 42-h-fasted dogs. Each study consisted of an equilibration (-140 to -40 min), control (-40 to 0 min), and test period (0-240 min). During the latter period, glucose (44.4 micromol x kg(-1) x min(-1)) was continuously given intraduodenally with (2.22 micromol x kg(-1) x min(-1)) or without fructose. The glucose appearance rate in portal vein blood was not significantly different with or without the inclusion of fructose (41.3 +/- 2.7 vs. 37.3 +/- 8.3 micromol x kg(-1) x min(-1), respectively). In response to glucose infusion without the inclusion of fructose, the net hepatic glucose balance switched from output to uptake (from 10 +/- 2 to 11 +/- 4 micromol x kg(-1) x min(-1)) by 30 min and averaged 17 +/- 6 micromol x kg(-1) x min(-1). The fractional extraction of glucose by the liver during the infusion period was 7 +/- 2%. Net glycogen deposition was 2.44 mmol glucose equivalent/kg body wt; 49% of deposited glycogen was synthesized via the direct pathway. Net hepatic lactate production was 1.4 mmol/kg body wt. Arterial blood glucose rose from 4.1 +/- 0.2 to 7.3 +/- 0.4 mmol/l, and arterial plasma insulin rose from 42 +/- 6 to 258 +/- 66 pmol/l at 30 min, after which they decreased to 7.0 +/- 0.5 mmol/l and 198 +/- 66 pmol/l, respectively. Arterial plasma glucagon decreased from 54 +/- 7 to 32 +/- 3 ng/l. In response to intraduodenal glucose infusion in the presence of fructose, net hepatic glucose balance switched from 9 +/- 1 micromol x kg(-1) x min(-1) output to 12 +/- 3 and 28 +/- 5 micromol x kg(-1) x min(-1) uptake by 15 and 30 min, respectively. The average NHGU (28 +/- 5 micromol x kg(-1) x min(-1)) and fractional extraction during infusion period (12 +/- 2%), net glycogen deposition (3.68 mmol glucose equivalent/kg body wt), net hepatic lactate production (3.27 mmol/kg), and glycogen synthesis via the direct pathway (68%) were significantly higher (P < 0.05) compared to that in the absence of fructose. The increases in arterial blood glucose (from 4.4 +/- 0.1 to 6.4 +/- 0.2 mmol/l at 30 min) and arterial plasma insulin (from 48 +/- 6 to 126 +/- 30 pmol/l at 30 min) were significantly smaller (P < 0.05). In summary, the inclusion of small amounts of fructose with a glucose load augmented NHGU, increased hepatic glycogen synthesis via the direct pathway, and augmented hepatic glycolysis. As a result, postprandial hyperglycemia and insulin release by the pancreatic beta-cell were reduced. In conclusion, catalytic amounts of fructose have the ability to improve glucose tolerance. [ABSTRACT FROM AUTHOR]

: Copyright of Diabetes is the property of American Diabetes Association and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Shiota, Masakazu, Galasetti, Pietro, Monohan, Michael, Neal, Doss W., Cherrington, Alan D., Shiota, M, Galassetti, P, Monohan, M, Neal, D W, Cherrington, A D

المصدر: Diabetes; Jun1998, Vol. 47 Issue 6, p867-873, 7p, 2 Charts, 11 Graphs

مصطلحات موضوعية: FRUCTOSE, PHYSIOLOGICAL effects of glucose, METABOLISM, PHYSIOLOGY

مستخلص: Fructose activates glucokinase by releasing the enzyme from its inhibitory protein in liver. To examine the importance of acute activation of glucokinase in regulating hepatic glucose uptake, the effect of intraportal infusion of a small amount of fructose on net hepatic glucose uptake (NHGU) was examined in 42 h-fasted conscious dogs. Isotopic ([3-3H] and [U-14C]glucose) and arteriovenous difference methods were used. Each study consisted of an equilibration period (-90 to -30 min), a control period (-30 to 0 min), and a hyperglycemic/hyperinsulinemic period (0-390 min). During the latter period, somatostatin (489 pmol x kg(-1) x min(-1)) was given, along with intraportal insulin (7.2 pmol x kg(-1) x min(-1)) and glucagon (0.5 ng x kg(-1) x min(-1)). In this way, the liver sinusoidal insulin level was fixed at four times basal (456 +/- 60 pmol/l), and liver sinusoidal glucagon level was kept basal (46 +/- 6 ng/l). Glucose was infused through a peripheral vein to create hyperglycemia (12.5 mmol/l plasma). Hyperglycemic hyperinsulinemia (no fructose) switched net hepatic glucose balance (micromoles per kilogram per minute) from output (11.3 +/- 1.4) to uptake (14.7 +/- 1.7) and net lactate balance (micromoles per kilogram per minute) from uptake (6.5 +/- 2.1) to output (4.4 +/- 1.5). Fructose was infused intraportally at a rate of 1.7, 3.3, or 6.7 micromol x kg(-1) x min(-1), starting at 120, 210, or 300 min, respectively. In the three periods, portal blood fructose increased from <6 to 113 +/- 14, 209 +/- 29, and 426 +/- 62 micromol/l, and net hepatic fructose uptake increased from 0.03 +/- 0.01 to 1.3 +/- 0.4, 2.3 +/- 0.7, and 5.1 +/- 0.6 micromol x kg(-1) x min(-1), respectively. NHGU increased to 41 +/- 3, 54 +/- 5, and 69 +/- 8 micromol x kg(-1) x min(-1), respectively, and net hepatic lactate output increased to 11.0 +/- 3.2, 15.3 +/- 2.7, and 22.4 +/- 2.8 micromol x kg(-1) x min(-1) in the three fructose periods, respectively. The amount of [3H]glucose incorporated into glycogen was equivalent to 69 +/- 3% of [3H]glucose taken up by the liver. These data suggest that glucokinase translocation within the hepatocyte is a major determinant of hepatic glucose uptake by the dog in vivo. [ABSTRACT FROM AUTHOR]

: Copyright of Diabetes is the property of American Diabetes Association and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Moore, Mary Courtney, Flakoll, Paul J., Po-Shiuan Hsieh, Pagliassotti, Michael J., Neal, Doss W., Monohan, Michael T., Venable, Carol, Cherrington, Alan D.

المصدر: American Journal of Physiology: Endocrinology & Metabolism; May98, Vol. 37 Issue 5, pE893, 10p, 4 Charts, 5 Graphs

مصطلحات موضوعية: GLUCOSE, KIDNEYS, METABOLISM, ABSORPTION

مستخلص: Presents information on a study designed to quantify the net hepatic glucose uptake (NHGU) during concomittant intraportal delivery of glucose and a mixture of gluconeogenic amino acids under specified conditions. Materials and methods of the study; Plasma insulin and glucagon concentrations; Hepatic blood flow, blood glucose metabolism and glucose infusion rates; Discussion of results.

المؤلفون: Rivera, Noelia¹, Ramnanan, Christopher J.¹, An, Zhibo¹, Farmer, Tiffany¹, Smith, Marta¹, Farmer, Ben¹, Irimia, Jose M.², Snead, Wanda¹, Lautz, Margaret¹, Roach, Peter J.², Cherrington, Alan D.¹

المصدر: Journal of Clinical Investigation. Dec2010, Vol. 120 Issue 12, p4425-4435. 11p. 3 Charts, 7 Graphs.

مصطلحات موضوعية: *DIABETES, *HYPOGLYCEMIA, *GLUCAGON, *GLYCOGEN, *INSULIN, *ANIMAL experimentation, *BIOCHEMISTRY, *BIOLOGICAL models, *CELLULAR signal transduction, *DOGS, *FATTY acids, *TYPE 1 diabetes, *LIVER, *PHENOMENOLOGY, *METABOLISM, *PHOSPHOTRANSFERASES, *RESEARCH funding, *GLYCOGENOLYSIS, *3-Hydroxybutyric acid

مستخلص: In individuals with type 1 diabetes, hypoglycemia is a common consequence of overinsulinization. Under conditions of insulin-induced hypoglycemia, glucagon is the most important stimulus for hepatic glucose production. In contrast, during euglycemia, insulin potently inhibits glucagon's effect on the liver. The first aim of the present study was to determine whether low blood sugar augments glucagon's ability to increase glucose production. Using a conscious catheterized dog model, we found that hypoglycemia increased glucagon's ability to overcome the inhibitory effect of insulin on hepatic glucose production by almost 3-fold, an effect exclusively attributable to marked enhancement of the effect of glucagon on net glycogen breakdown. To investigate the molecular mechanism by which this effect comes about, we analyzed hepatic biopsies from the same animals, and found that hypoglycemia resulted in a decrease in insulin signaling. Furthermore, hypoglycemia and glucagon had an additive effect on the activation of AMPK, which was associated with altered activity of the enzymes of glycogen metabolism. [ABSTRACT FROM AUTHOR]