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Liver glycogen is important for the counterregulation of hypoglycemia and is reduced in individuals with type 1 diabetes (T1D). Here, we examined the effect of varying hepatic glycogen content on the counterregulatory response to low blood sugar in dogs. During the first 4 hours of each study, hepatic glycogen was increased by augmenting hepatic glucose uptake using hyperglycemia and a low-dose intraportal fructose infusion. After hepatic glycogen levels were increased, animals underwent a 2-hour control period with no fructose infusion followed by a 2-hour hyperinsulinemic/hypoglycemic clamp. Compared with control treatment, fructose infusion caused a large increase in liver glycogen that markedly elevated the response of epinephrine and glucagon to a given hypoglycemia and increased net hepatic glucose output (NHGO). Moreover, prior denervation of the liver abolished the improved counterregulatory responses that resulted from increased liver glycogen content. When hepatic glycogen content was lowered, glucagon and NHGO responses to insulin-induced hypoglycemia were reduced. We conclude that there is a liver-brain counterregulatory axis that is responsive to liver glycogen content. It remains to be determined whether the risk of iatrogenic hypoglycemia in T1D humans could be lessened by targeting metabolic pathway(s) associated with hepatic glycogen repletion., Introduction In the fasted state, healthy humans are able to maintain their blood glucose levels within a very narrow range of approximately 85 to 100 mg/dl. When the glucose level [...]

In rodents, acute brain insulin action reduces blood glucose levels by suppressing the expression of enzymes in the hepatic gluconeogenic pathway, thereby reducing gluconeogenesis and endogenous glucose production (EGP). Whether a similar mechanism is functional in large animals, including humans, is unknown. Here, we demonstrated that in canines, physiologic brain hyperinsulinemia brought about by infusion of insulin into the head arteries (during a pancreatic clamp to maintain basal hepatic insulin and glucagon levels) activated hypothalamic Akt, altered STAT3 signaling in the liver, and suppressed hepatic gluconeogenic gene expression without altering EGP or gluconeogenesis. Rather, brain hyperinsulinemia slowly caused a modest reduction in net hepatic glucose output (NHGO) that was attributable to increased net hepatic glucose uptake and glycogen synthesis. This was associated with decreased levels of glycogen synthase kinase 3β (GSK3β) protein and mRNA and with decreased glycogen synthase phosphorylation, changes that were blocked by hypothalamic PI3K inhibition. Therefore, we conclude that the canine brain senses physiologic elevations in plasma insulin, and that this in turn regulates genetic events in the liver. In the context of basal insulin and glucagon levels at the liver, this input augments hepatic glucose uptake and glycogen synthesis, reducing NHGO without altering EGP., Introduction The ability of insulin to suppress hepatic glucose production (HGP) in vivo has been well defined (1), but the role of the CNS in this suppression remains controversial. The [...]

Hepatic glucagon action increases in response to accelerated metabolic demands and is associated with increased whole body substrate availability, including circulating lipids. The hypothesis that increases in hepatic glucagon action stimulate AMP-activated protein kinase (AMPK) signaling and peroxisome proliferator-activated receptor-[alpha] (PPAR[alpha] and fibroblast growth factor 21 (FGF21) expression in a manner modulated by fatty acids was tested in vivo. Wild-type ([gcgr.sup.+/+]) and glucagon receptor-null ([gcgr.sup.-/-]) littermate mice were studied using an 18-h fast, exercise, and hyperglucagonemic-euglycemic clamps plus or minus increased circulating lipids. Fasting and exercise in [gcgr.sup.+/+], but not [gcgr.sup.-/-] mice, increased hepatic phosphorylated AMPK[alpha] at threonine 172 ([MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII]) and PPAR[alpha] and FGF21 mRNA. Clamp results in [gcgr.sup.+/+] mice demonstrate that hyperlipidemia does not independently impact or modify glucagon-stimulated increases in hepatic AMP/ATP, [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII], or PPAR[alpha] and FGF21 mRNA. It blunted glucagon-stimulated acetyl-CoA carboxylase phosphorylation, a downstream target of AMPK, and accentuated PPAR[alpha] and FGF21 expression. All effects were absent in [gcgr.sup.-/-] mice. These findings demonstrate that glucagon exerts a critical regulatory role in liver to stimulate pathways linked to lipid metabolism in vivo and shows for the first time that effects of glucagon on PPARa and FGF21 expression are amplified by a physiological increase in circulating lipids. adenosine 5'-monophosphate-activated protein kinase; peroxisome proliferator-activated receptor-[alpha]; fibroblast growth factor 21 doi: 10.1152/ajpendo.00263.2010.

The hepatic energy state, defined by adenine nucleotide levels, couples metabolic pathways with energy requirements. This coupling is fundamental in the adaptive response to many conditions and is impaired in metabolic disease. We have found that the hepatic energy state is substantially reduced following exercise, fasting, and exposure to other metabolic stressors in C57BL/6 mice. Glucagon receptor signaling was hypothesized to mediate this reduction because increased plasma levels of glucagon are characteristic of metabolic stress and because this hormone stimulates energy consumption linked to increased gluconeogenic flux through cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) and associated pathways. We developed what we believe to be a novel hyperglucagonemic-euglycemic clamp to isolate an increment in glucagon levels while maintaining fasting glucose and insulin. Metabolic stress and a physiological rise in glucagon lowered the hepatic energy state and amplified AMP-activated protein kinase signaling in control mice, but these changes were abolished in glucagon receptor--null mice and mice with liver-specific PEPCK-C deletion. 129X1/Sv mice, which do not mount a glucagon response to hypoglycemia, displayed an increased hepatic energy state compared with C57BL/6 mice in which glucagon was elevated. Taken together, these data demonstrate in vivo that the hepatic energy state is sensitive to glucagon receptor activation and requires PEPCK-C, thus providing new insights into liver metabolism., Introduction The energy state in the cell is defined by adenine nucleotide levels and is critically coupled to nearly all metabolic processes (1). In the cell, the adenine nucleotides ATP, [...]

To determine the effect of nonesterified fatty acids (NEFA) on glucagon action, glucagon was infused intraportally (1.65 ng x [min.sup.-1] x [kg.sup.-1]) for 3 h into 18-h-fasted, pancreatic-clamped conscious dogs in the presence [NEFA + glucagon (GGN)] or absence (GGN) of peripheral Intralipid plus heparin infusion. Additionally, hyperglycemic (HG), hyperglycemic-hyperlipidemic (NEFA + HG), and glycerol plus glucagon (GLYC + GGN) controls were studied. Arterial plasma glucagon concentrations rose equally in GGN, NEFA + GGN, and GLYC + GGN but remained basal in hyperglycemic controls. Peripheral infusions of Intralipid and heparin increased arterial plasma NEFA concentrations equally in NEFA + GGN and NEFA + HG and did not change in other protocols. After 15 rain, glucagon infusion resulted in a rapid, brief increase in net hepatic glycogenolysis (NHGLY, mg x [min.sup.-1] x [kg.sup.-1]) of ~6.0 in GGN and GLYC + GGN but only increased by 3.8 [+ or -] 1.3 in NEFA + GGN. Thus increases in NHGLY, and consequently net hepatic glucose output (NHGO), were blunted by 40%, with no difference between the groups in the last 2.5 h of the study. NHGO and NHGLY did not significantly change in HG and NEFA + HG. Net hepatic gluconeogenic flux did not change in GGN, GLYC + GGN, or HG. However, Intralipid and heparin infusion resulted in similar increases in net hepatic gluconeogenic flux in NEFA + GGN and NEFA + HG. Thus elevated NEFA limit the initial increase in glucagon-stimulated HGO by blunting glycogenolysis, without having any effect on the gluconeogenic or glycogenolytic contributions or NHGO thereafter. nonesterified fatty acids; canine; gluconeogenesis; glycogenolysis; adenosine 3',5'-cyclic monophosphate doi: 10.1152/ajpendo.00043.2006

A portal venous 5-aminoimidazole-4-carboxamide-1-[beta]-D-fibofuranoside infusion that results in hepatic 5-aminoimidazole-4-carboxamide-1-[beta]-D-ribosyl-5-monophosphate (ZMP) concentrations of ~4 [micro]mol/g liver increases hepatic glycogenolysis and glucose output. ZMP is an AMP analog that mimics the regulatory actions of this nucleotide. The aim of this study was to measure hepatic AMP concentrations in response to increasing energy requirements to test the hypothesis that AMP achieves concentrations during exercise, consistent with a role in stimulation of hepatic glucose metabolism. Male C57BL/6J mice (27.4 [+ or -] 0.4 g) were subjected to 35 min of rest [sedentary (SED), n = 8], underwent short-term (ST, 35 min) moderate (20 m/min, 5% grade) exercise (n = 8), or underwent treadmill exercise under similar conditions but until exhaustion (EXH, n = 8). Hepatic AMP concentrations were 0.82 [+ or -] 0.05, 1.17 [+ or -] 0.11, and 2.52 [+ or -] 0.16 [micro]mol/g liver in SED, ST, and EXH mice, respectively (P < 0.05). Hepatic energy charge was 0.66 [+ or -] 0.01, 0.58 [+ or -] 0.02, and 0.33 [+ or -] 0.22 in SED, ST, and EXH mice, respectively (P < 0.05). Hepatic glycogen was 11.6 [+ or -] 1.0, 8.8 [+ or -] 2.2, and 0.0 [+ or -] 0.1 mg/g liver in SED, ST, and EXH mice, respectively (P < 0.05). Hepatic AMPK ([Thr.sup.172]) phosphorylation was 1.00 [+ or -] 0.14, 1.96 [+ or -] 0.16, and 7.44 [+ or -] 0.63 arbitrary units in SED, ST, and EXH mice, respectively (P < 0.05). Thus exercise increases hepatic AMP concentrations. These data suggest that the liver is highly sensitive to metabolic demands, as evidenced by dramatic changes in cellular energy indicators (AMP) and sensors thereof (AMP-activated protein kinase). In conclusion, AMP is sensitively regulated, consistent with it having an important role in hepatic metabolism. adenosine 5'-monophosphate; adenosine 5'-monophosphate-activated protein kinase; glycogen

This study aimed to test whether stimulation of net hepatic glucose output (NHGO) by increased concentrations of the AMP analog, 5-aminoimidazole-4-carboxamide-l-[beta]-D-ribosyl-5-monophosphate, can be suppressed by pharmacological insulin levels. Dogs had sampling (artery, portal vein, hepatic vein) and infusion (vena cava, portal vein) catheters and flow probes (hepatic artery, portal vein) implanted > 16 days before study. Protocols consisted of equilibration (- 130 to -30 min), basal (-30 to 0 min), and hyperinsulinemic-euglycemic (0-150 min) periods. At time (t) = 0 min, somatostatin was infused, and basal glucagon was replaced via the portal vein. Insulin was infused in the portal vein at either 2 (INS2) or 5 (INS5) mU*[kg.sup.-1]*[min.sup.-1]. At t = 60 min, 1 mg*[kg.sup.-1]*[min.sup.-1] portal venous 5-aminoimidazole-4-carbox-amide-l-[beta]-D-ribofuranoside (AICAR) infusion was initiated. Arterial insulin rose ~9- and ~27-fold in INS2 and INS5, respectively. Glucagon, catecholamines, and cortisol did not change throughout the study. NHGO was completely suppressed before t = 60 min. Intraportal AICAR stimulated NHGO by 1.9 [+ or -] 0.5 and 2.0 [+ or -] 0.5 mg*[kg.sup.-1]*[min.sup.-1] in INS2 and INS5, respectively. AICAR stimulated tracer-determined endogenous glucose production similarly in both groups. Intraportal AICAR infusion significantly increased hepatic acetyl-CoA carboxylase (ACC, [Ser.sup.79]) phosphorylation in INS2. Hepatic ACC ([Ser.sup.79]) phosphorylation, however, was not increased in INS5. Thus intraportal AICAR infusion renders hepatic glucose output insensitive to pharmacological insulin. The effectiveness of AICAR in countering the suppressive effect of pharmacological insulin on NHGO occurs even though AICAR-stimulated ACC phosphorylation is completely blocked. hepatic glucose production; glycogenolysis; AMP-activated protein kinase; adenosine 5'-monophosphate; 5-aminoimidazole-4-carboxamide-1-[beta]-D-ribosyl-5-monophosphate

Hepatic glucose fluxes and intracellular movement of glucokinase (GK) in response to increased plasma glucose and insulin were examined in 10-wk-old, 6-h-fasted, conscious Zucker diabetic fatty (ZDF) rats and lean littermates. Under basal conditions, plasma glucose (mmol/l) and glucose turnover rate (GTR; [micro]mol*[kg.sup.-1]*[min.sup.-1]) were slightly higher in ZDF (8.4 [+ or -] 0.3 and 53 [+ or -] 7, respectively) than in lean rats (6.2 [+ or -] 0.2 and 45 [+ or -] 4, respectively), whereas plasma insulin (pmol/l) was higher in ZDF (1,800 [+ or -] 350) than in lean rats (150 [+ or -] 14). The ratio of hepatic uridine 5'-diphosphate-glucose [sup.3]H specific activity to plasma glucose [sup.3]H specific activity ([[sup.3]H]UDP-G/[[sup.3]H]G; %), total hepatic glucose output ([micro]mol*[kg.sup.-1]*[min.sup.-1]), and hepatic glucose cycling ([micro]mol*[kg.sup.-1]*[min.sup.-1]) were higher in ZDF (35 [+ or -] 5, 87 [+ or -] 16, and 33 [+ or -] 10, respectively) compared with lean rats (18 [+ or -] 3, 56 [+ or -] 6, and 11 [+ or -] 2, respectively). [[sup.3]H]glucose incorporation into glycogen ([micro]mol glucose/g liver) was similar in lean (1.0 [+ or -] 0.7) and ZDF (1.6 [+ or -] 0.8) rats. GK was predominantly located in the nucleus in both rats. With elevated plasma glucose and insulin, GTR ([micro]mol*[kg.sup.-1]*[min.sup.-1]), [[sup.3]H]UDP-G/[[sup.3]H]G (%), and [[sup.3]H]glucose incorporation into glycogen ([micro]mol glucose/g liver) were markedly higher in lean (191 [+ or -] 22, 62 [+ or -] 3, and 5.0 [+ or -] 1.4, respectively) but similar in ZDF rats (100 [+ or -] 6, 37 [+ or -] 3, and 1.4 [+ or -] 0.4, respectively) compared with basal conditions. GK translocation from the nucleus to the cytoplasm occurred in lean but not in ZDF rats. The unresponsiveness of hepatic glucose flux to the rise in plasma glucose and insulin seen in prediabetic ZDF rats was associated with impaired GK translocation. liver; glucose flux; insulin; hyperglycemia

It was previously shown that glucagon and epinephrine have additive effects on both gluconeogenic and glycogenolytic flux. However, the changes in gluconeogenic substrates may have been limiting and thus may have prevented a synergistic effect on gluconeogenesis and a reciprocal inhibitory effect on glycogenolysis. Thus the aim of the present study was to determine if glucagon has a greater gluconeogenic and a smaller glycogenolytic effect in the presence of both epinephrine and clamped gluconeogenic precursors. Two groups (Epi and G + Epi + P) of 18-h-fasted conscious dogs were studied. In Epi, epinephrine was increased, and in G + Epi + P, glucagon and epinephrine were increased. Gluconeogenic precursors (lactate and alanine) were infused in G + Epi + P to match the rise that occurred in Epi. Insulin and glucose levels were also controlled and were similar in the two groups. Epinephrine and precursor administration increased glucagon's effect on gluconeogenesis (4.5-fold; P < 0.05) and decreased glucagon's effect on glycogenolysis (85%; P = 0.08). Thus, in the presence of both hormones, and when the gluconeogenic precursor supply is maintained, gluconeogenic flux is potentiated and glycogenolytic flux is inhibited. canine; gluconeogenesis; glycogenolysis; counterregulatory hormones; glucose production

Epinephrine increases net hepatic glucose output (NHGO) mainly via increased gluconeogenesis, whereas glucagon increases NHGO mainly via increased glycogenolysis. The aim of the present study was to determine how the two hormones interact in controlling glucose production. In 18-h-fasted conscious dogs, a pancreatic clamp initially fixed insulin and glucagon at basal levels, following which one of four protocols was instituted. In G + E, glucagon (1.5 ng*[kg.sup.-1]*[min.sup.-1]; portally) and epinephrine (50 ng*[kg.sup.-1].[min.sup.-1]; peripherally) were increased; in G, glucagon was increased alone; in E, epinephrine was increased alone; and in C, neither was increased. In G, E, and C, glucose was infused to match the hyperglycemia seen in G + E (~250 mg/dl). The areas under the curve for the increase in NHGO, after the change in C was subtracted, were as follows: G = 661 [+ or -] 185, E = 424 [+ or -] 158, G + E = 1,178 [+ or -] 57 mg/kg. Therefore, the overall effects of the two hormones on NHGO were additive. Additionally, glucagon exerted its full glycogenolytic effect, whereas epinephrine exerted its full gluconeogenic effect, such that both processes increased significantly during concurrent hormone administration. canine; gluconeogenesis; glycogenolysis; counterregulatory hormones

Research was conducted to study the effects of a selective rise in liver sinusoidal norepinephrine on hepatic glucose production (HGP). Doppler flow probes were utilized to estimate total hepatic blood flow while total glucose production was expressed using compartment models. Results indicated that the increase in glucose production caused by the norepinephrine release would lead to an increase in hepatic glycogenolysis.

Glucagon-like peptide-1 (GLP-1) is secreted from the L cell of the gut in response to oral nutrient delivery. To determine if endogenously released GLP-1 contributes to the incretin effect and postprandial glucose regulation, conscious dogs ( n = 8) underwent an acclimation period ( t = −60 to −20 min), followed by a basal sampling period ( t = −20 to 0 min) and an experimental period ( t = 0-320 min). At the beginning of the experimental period, t = 0 min, a peripheral infusion of either saline or GLP-1 receptor (GLP-1R) antagonist, exendin (9-39) (Ex-9, 500 pmol/kg/min), was started. At t = 30 min, animals consumed a liquid mixed meal, spiked with acetaminophen. All animals were studied twice (± Ex-9) in random fashion, and the experiments were separated by a 1-2-week washout period. Antagonism of the GLP-1R did not have an effect, as indicated by repeated-measures MANOVA analysis of the Δ AUC from t = 45-320 min of arterial plasma glucose, GLP-1, insulin, glucagon, and acetaminophen levels. Therefore, endogenous GLP-1 is not sufficient to alter postprandial glucose regulation in the dog. [ABSTRACT FROM AUTHOR]

AMP-activated protein kinase (AMPK) plays a key role in regulating metabolism, serving as a metabolic master switch. The aim of this study was to assess whether increased concentrations of the AMP analog, 5-aminoimidazole-4-carboxamide-1-β-D-ribosyl-5-monophosphate, in the liver would create a metabolic response consistent with an increase in whole-body metabolic need. Dogs had sampling (artery, portal vein, hepatic vein) and infusion (vena cava, portal vein) catheters and flow probes (hepatic artery, portal vein) implanted >16 days before a study. Protocols consisted of equilibration (-130 to -30 min), basal (-30 to 0 min), and hyperinsulinemic-euglycemic or -hypoglycemic clamp periods (0-150 min). At t = 0 min, somatostatin was infused and glucagon was replaced in the portal vein at basal rates. An intraportal hyperinsulinemic (2 mU ⋅ kg-1⋅ min-1) infusion was also initiated at this time. Glucose was clamped at hypoglycemic or euglycemic levels in the presence (H-AIC, n = 6; E-AIC, n = 6) or absence (H-SAL, n = 6; E-SAL, n = 6) of a portal venous 5-aminoimidazole-4-carboxamide-ribofuranoside (AICAR) infusion (1 mg ⋅ kg-1 ⋅ min-1) initiated at t = 60 min. In the presence of intraportal saline, glucose was infused into the vena cava to match glucose levels seen with intraportal AICAR. Glucagon remained fixed at basal levels, whereas insulin rose similarly in all groups. Glucose fell to 50 ± 2 mg/dl by t = 60 min in hypoglycemic groups and remained at 105 ± 3 mg/dl in euglycemic groups. Endogenous glucose production (Ra) was similarly suppressed among groups in the presence of euglycemia or hypoglycemia before t = 60 min and remained suppressed in the H-SAL and E-SAL groups. However, intraportal AICAR infusion stimulated Ra to increase by 2.5 ± 1.0 and 3.4 ± 0.4 mg ⋅ kg1 ⋅ min-1 in the E-AIC and H-AIC groups, respectively. Arteriovenous measurement of net hepatic glucose output showed similar results. AICAR stimulated hepatic glycogen to decrease by 5 ± 3 and 19 ± 5 mg/g tissue (P < 0.05) in the presence of euglycemia and hypoglycemia, respectively. AICAR significantly increased net hepatic lactate output in the presence of hypoglycemia. Thus, intraportal AICAR infusion caused marked stimulation of both hepatic glucose output and net hepatic glycogenolysis, even in the presence of high levels of physiological insulin. This stimulation of glucose output by AICAR was equally marked in the presence of both euglycemia and hypoglycemia. However, hypoglycemia amplified the net hepatic glycogenolytic response to AICAR by approximately fourfold. Diabetes 54:373-382, 2005 [ABSTRACT FROM AUTHOR]

Determines the effect of a selective rise in liver sinusoidal norepinephrine on hepatic glucose production. Arterial plasma levels of insulin and glucagon; Glucose utilization and clearance during basal and test periods; Stimulation of glycogenolysis.

Glucagon rapidly and profoundly stimulates hepatic glucose production (HGP), but for reasons that are unclear, this effect normally wanes after a few hours, despite sustained plasma glucagon levels. This study characterized the time course of glucagon-mediated molecular events and their relevance to metabolic flux in the livers of conscious dogs. Glucagon was either infused into the hepato-portal vein at a sixfold basal rate in the presence of somatostatin and basal insulin, or it was maintained at a basal level in control studies. In one control group, glucose remained at basal, whereas in the other, glucose was infused to match the hyperglycemia that occurred in the hyperglucagonemic group. Elevated glucagon caused a rapid (30 min) and largely sustained increase in hepatic cAMP over 4 h, a continued elevation in glucose-6-phosphate (G6P), and activation and deactivation of glycogen phosphorylase and synthase activities, respectively. Net hepatic glycogenolysis increased rapidly, peaking at 15 min due to activation of the cAMP/PKA pathway, then slowly returned to baseline over the next 3 h in line with allosteric inhibition by glucose and G6P. Glucagon's stimulatory effect on HGP was sustained relative to the hyperglycemic control group due to continued PKA activation. Hepatic gluconeogenic flux did not increase due to the lack of glucagon's effect on substrate supply to the liver. Global gene expression profiling highlighted glucagon-regulated activation of genes involved in cellular respiration, metabolic processes, and signaling, as well as downregulation of genes involved in extracellular matrix assembly and development. NEW & NOTEWORTHY Glucagon rapidly stimulates hepatic glucose production, but these effects are transient. This study links the molecular and metabolic flux changes that occur in the liver over time in response to a rise in glucagon, demonstrating the strength of the dog as a translational model to couple findings in small animals and humans. In addition, this study clarifies why the rapid effects of glucagon on liver glycogen metabolism are not sustained.

Regular exercise elicits adaptations in glucose and lipid metabolism that allow the body to meet energy demands of subsequent exercise bouts more effectively and mitigate metabolic diseases including fatty liver. Energy discharged during the acute exercise bouts that comprise exercise training may be a catalyst for liver adaptations. During acute exercise, liver glycogenolysis and gluconeogenesis are accelerated to supply glucose to working muscle. Lower liver energy state imposed by gluconeogenesis and related pathways activates AMP-activated protein kinase (AMPK), which conserves ATP partly by promoting lipid oxidation. This study tested the hypothesis that AMPK is necessary for liver glucose and lipid adaptations to training. Liver-specific AMPKα1α2 knockout ( AMPKα1α2 fl/fl +AlbCre ) mice and littermate controls ( AMPKα1α2 fl/fl ) completed sedentary and exercise training protocols. Liver nutrient fluxes were quantified at rest or during acute exercise following training. Liver metabolites and molecular regulators of metabolism were assessed. Training increased liver glycogen in AMPKα1α2 fl/fl mice, but not in AMPKα1α2 fl/fl +AlbCre mice. The inability to increase glycogen led to lower glycogenolysis, glucose production, and circulating glucose during acute exercise in trained AMPKα1α2 fl/fl +AlbCre mice. Deletion of AMPKα1α2 attenuated training-induced declines in liver diacylglycerides. In particular, training lowered the concentration of unsaturated and elongated fatty acids comprising diacylglycerides in AMPKα1α2 fl/fl mice, but not in AMPKα1α2 fl/fl +AlbCre mice. Training increased liver triacylglycerides and the desaturation and elongation of fatty acids in triacylglycerides of AMPKα1α2 fl/fl +AlbCre mice. These lipid responses were independent of differences in tricarboxylic acid cycle fluxes. In conclusion, AMPK is required for liver training adaptations that are critical to glucose and lipid metabolism. NEW & NOTEWORTHY This study shows that the energy sensor and transducer, AMP-activated protein kinase (AMPK), is necessary for an exercise training-induced: 1 ) increase in liver glycogen that is necessary for accelerated glycogenolysis during exercise, 2 ) decrease in liver glycerolipids independent of tricarboxylic acid (TCA) cycle flux, and 3 ) decline in the desaturation and elongation of fatty acids comprising liver diacylglycerides. The mechanisms defined in these studies have implications for use of regular exercise or AMPK-activators in patients with fatty liver.

The contribution of hormone-independent counterregulatory signals in defense of insulin-induced hypoglycemia was determined in adrenalectomized, overnight-fasted conscious dogs receiving hepatic portal vein insulin infusions at a rate 20-fold basal. Either euglycemia was maintained ( group 1 ) or hypoglycemia (≈45 mg/dl) was allowed to occur. There were three hypoglycemic groups: one in which hepatic autoregulation against hypoglycemia occurred in the absence of sympathetic nervous system input ( group 2 ), one in which autoregulation occurred in the presence of norepinephrine (NE) signaling to fat and muscle ( group 3 ), and one in which autoregulation occurred in the presence of NE signaling to fat, muscle, and liver ( group 4 ). Average net hepatic glucose balance (NHGB) during the last hour for groups 1-4 was -0.7 ± 0.1, 0.3 ± 0.1 ( P < 0.01 vs. group 1 ), 0.7 ± 0.1 ( P = 0.01 vs. group 2 ), and 0.8 ± 0.1 ( P = 0.7 vs. group 3 ) mg·kg -1 ·min -1 , respectively. Hypoglycemia per se ( group 2 ) increased NHGB by causing an inhibition of net hepatic glycogen synthesis. NE signaling to fat and muscle ( group 3 ) increased NHGB further by mobilizing gluconeogenic precursors resulting in a rise in gluconeogenesis. Lowering glucose per se decreased nonhepatic glucose uptake by 8.9 mg·kg -1 ·min -1 , and the addition of increased neural efferent signaling to muscle and fat blocked glucose uptake further by 3.2 mg·kg -1 ·min -1 The addition of increased neural efferent input to liver did not affect NHGB or nonhepatic glucose uptake significantly. In conclusion, even in the absence of increases in counterregulatory hormones, the body can defend itself against hypoglycemia using glucose autoregulation and increased neural efferent signaling, both of which stimulate hepatic glucose production and limit glucose utilization., (Copyright © 2017 the American Physiological Society.)

The postprandial state is characterized by a storage of nutrients in the liver, muscle, and adipose tissue for later utilization. In the case of a protein-rich meal, amino acids (AA) stimulate glucagon secretion by the α-cell. The aim of the present study was to determine the impact of the rise in glucagon on AA metabolism, particularly in the liver. We used a conscious catheterized dog model to recreate a postprandial condition using a pancreatic clamp. Portal infusions of glucose, AA, and insulin were used to achieve postprandial levels, while portal glucagon infusion was either maintained at the basal level or increased by three-fold. The high glucagon infusion reduced the increase in arterial AA concentrations compared with the basal glucagon level (-23%, P < 0.05). In the presence of high glucagon, liver AA metabolism shifted toward a more catabolic state with less protein synthesis (-36%) and increased urea production (+52%). Net hepatic glucose uptake was reduced modestly (-35%), and AA were preferentially used in gluconeogenesis, leading to lower glycogen synthesis (-54%). The phosphorylation of AMPK was increased by the high glucagon infusion (+40%), and this could be responsible for increasing the expression of genes related to pathways producing energy and lowering those involved in energy consumption. In conclusion, the rise in glucagon associated with a protein-rich meal promotes a catabolic utilization of AA in the liver, thereby, opposing the storage of AA in proteins., (Copyright © 2017 the American Physiological Society.)

A loss of glucose effectiveness to suppress hepatic glucose production as well as increase hepatic glucose uptake and storage as glycogen is associated with a defective increase in glucose phosphorylation catalyzed by glucokinase (GK) in Zucker diabetic fatty (ZDF) rats. We extended these observations by investigating the role of persistent hyperglycemia (glucotoxicity) in the development of impaired hepatic GK activity in ZDF rats. We measured expression and localization of GK and GK regulatory protein (GKRP), translocation of GK, and hepatic glucose flux in response to a gastric mixed meal load (MMT) and hyperglycemic hyperinsulinemic clamp after 1 or 6 wk of treatment with the sodium-glucose transporter 2 inhibitor (canaglifrozin) that was used to correct the persistent hyperglycemia of ZDF rats. Defective augmentation of glucose phosphorylation in response to a rise in plasma glucose in ZDF rats was associated with the coresidency of GKRP with GK in the cytoplasm in the midstage of diabetes, which was followed by a decrease in GK protein levels due to impaired posttranscriptional processing in the late stage of diabetes. Correcting hyperglycemia from the middle diabetic stage normalized the rate of glucose phosphorylation by maintaining GK protein levels, restoring normal nuclear residency of GK and GKRP under basal conditions and normalizing translocation of GK from the nucleus to the cytoplasm, with GKRP remaining in the nucleus in response to a rise in plasma glucose. This improved the liver's metabolic ability to respond to hyperglycemic hyperinsulinemia. Glucotoxicity is responsible for loss of glucose effectiveness and is associated with altered GK regulation in the ZDF rat., (Copyright © 2014 the American Physiological Society.)

The role of renal glucose production after an overnight fast and in response to different hormonal conditions has been debated. The aim of this study was to determine whether hyperglycemia, glucagon, or epinephrine can affect renal glucose production. In 18-hour fasted conscious dogs a pancreatic clamp initially fixed insulin and glucagon at basal levels, following which 1 of 4 protocols was instituted. In G+E glucagon (1.5 ng. kg(-1). min(-1); portally) and epinephrine (50 ng. kg(-1). min(-1); peripherally) were increased, in G glucagon was increased alone, in E epinephrine was increased alone, and in C neither were increased. In G, E, and C, glucose was infused to match the hyperglycemia in G+E (approximately 250 mg/dL). The average net renal glucose output during the last 2 hours was not different from the basal values in any group. Furthermore, the changes in unidirectional renal glucose production were not significantly different among groups. Therefore, after an overnight fast in the conscious dog, the kidneys do not significantly contribute to overall glucose production or respond to glucagon or epinephrine.