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ABSTRACT: Net hepatic glucose uptake (NHGU) is an important contributor to postprandial glycemic control. We hypothesized that NHGU is reduced during normal pregnancy and in a pregnant diet-induced model of impaired glucose intolerance/gestational diabetes mellitus (IGT/GDM). Dogs (n = 7 per group) that were nonpregnant (N), normal pregnant (P), or pregnant with IGT/GDM (pregnant dogs fed a high-fat and -fructose diet [P-HFF]) underwent a hyperinsulinemic-hyperglycemic clamp with intraportal glucose infusion. Clamp period insulin, glucagon, and glucose concentrations and hepatic glucose loads did not differ among groups. The N dogs reached near-maximal NHGU rates within 30 min; mean ± SEM NHGU was 105 ± 9 µmol⋅100 g liver(-1)⋅min(-1). The P and P-HFF dogs reached maximal NHGU in 90-120 min; their NHGU was blunted (68 ± 9 and 16 ± 17 µmol⋅100 g liver(-1)⋅min(-1), respectively). Hepatic glycogen synthesis was reduced 20% in P versus N and 40% in P-HFF versus P dogs. This was associated with a reduction (>70%) in glycogen synthase activity in P-HFF versus P and increased glycogen phosphorylase (GP) activity in both P (1.7-fold greater than N) and P-HFF (1.8-fold greater than P) dogs. Thus, NHGU under conditions mimicking the postprandial state is delayed and suppressed in normal pregnancy, with concomitant reduction in glycogen storage. NHGU is further blunted in IGT/GDM. This likely contributes to postprandial hyperglycemia during pregnancy, with potential adverse outcomes for the fetus and mother.
Diabetes 12/2012; · 8.29 Impact Factor
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ABSTRACT: Portal vein glucose delivery (the portal glucose signal) stimulates glucose uptake by the liver, and a portal amino acid (AA) signal induces an increase in protein synthesis by the liver. During a meal both signals coexist and may interact. In this study, we compared the protein synthesis rates in the liver and muscle in response to portal or peripheral glucose infusion during intraportal infusion of a complete AA mixture. Dogs were surgically prepared with hepatic sampling catheters and flow probes. After a 42h fast, they underwent a 3h hyperinsulinemic (4x basal) hyperglucagonemic (3x basal) hyperglycemic (≈160 mg/dL) hyperaminoacidemic (hepatic load 1.5x basal; delivered intraportally) clamp (postprandial conditions). Glucose was infused either via a peripheral (PeG; n=7) or the portal (PoG; n=8) vein. Protein synthesis was assessed with a primed, continuous [(14)C] Leucine infusion. Net hepatic glucose uptake was stimulated by portal glucose infusion (+1 mg/kg/min, P<0.05), as expected, but hepatic fractional AA extraction and hepatic protein synthesis did not differ between groups. There was a lower arterial AA concentration in the PoG group (-19%, P<0.05) and a significant stimulation (+30%) of muscle protein synthesis, associated with increased p70S6 phosphorylation. Concomitant portal glucose and AA delivery enhances skeletal muscle protein synthesis in comparison to peripheral glucose and portal AA delivery. Enteral nutrition support may have an advantage over parenteral nutrition in stimulating muscle protein synthesis.
AJP Endocrinology and Metabolism 09/2012; · 4.75 Impact Factor
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Christopher J Ramnanan,
Guillaume Kraft,
Marta S Smith,
Ben Farmer,
Doss Neal, Phillip E Williams,
Margaret Lautz,
Tiffany Farmer,
E Patrick Donahue,
Alan D Cherrington,
Dale S Edgerton
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ABSTRACT: The importance of hypothalamic insulin action to the regulation of hepatic glucose metabolism in the presence of a normal liver/brain insulin ratio (3:1) is unknown. Thus, we assessed the role of central insulin action in the response of the liver to normal physiologic hyperinsulinemia over 4 h. Using a pancreatic clamp, hepatic portal vein insulin delivery was increased three- or eightfold in the conscious dog. Insulin action was studied in the presence or absence of intracerebroventricularly mediated blockade of hypothalamic insulin action. Euglycemia was maintained, and glucagon was clamped at basal. Both the molecular and metabolic aspects of insulin action were assessed. Blockade of hypothalamic insulin signaling did not alter the insulin-mediated suppression of hepatic gluconeogenic gene transcription but blunted the induction of glucokinase gene transcription and completely blocked the inhibition of glycogen synthase kinase-3β gene transcription. Thus, central and peripheral insulin action combined to control some, but not other, hepatic enzyme programs. Nevertheless, inhibition of hypothalamic insulin action did not alter the effects of the hormone on hepatic glucose flux (production or uptake). These data indicate that brain insulin action is not a determinant of the rapid (<4 h) inhibition of hepatic glucose metabolism caused by normal physiologic hyperinsulinemia in this large animal model.
Diabetes 09/2012; · 8.29 Impact Factor
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ABSTRACT: To assess the effects of different bariatric surgical procedures on the treatment of obesity and insulin resistance in high fat diet-induced obese (DIO) mice.
Bariatric surgery is currently considered the most effective treatment for morbid obesity and its comorbidities; however, a systematic study of their mechanisms is still lacking.
We developed bariatric surgery models, including gastric banding, sleeve gastrectomy, Roux-en-Y gastric bypass (RYGB), modified RYGB (mRYGB) and biliopancreatic diversion (BPD), in DIO mice. Body weight, body fat and lean mass, liver steatosis, glucose tolerance and pancreatic beta cell function were examined.
All bariatric surgeries resulted in significant weight loss, reduced body fat and improved glucose tolerance in the short term (4 weeks), compared with mice with sham surgery. Of the bariatric surgery models, sleeve gastrectomy and mRYGB had higher success rates and lower mortalities and represent reliable restrictive and gastrointestinal (GI) bypass mouse bariatric surgery models, respectively. In the long term, the GI bypass procedure produced more profound weight loss, significant improvement of glucose tolerance and liver steatosis than the restrictive procedure. DIO mice had increased insulin promoter activity, suggesting overactivation of pancreatic beta cells, which was regulated by the mRYGB procedure. Compared with the restrictive procedure, the GI bypass procedure showed more severe symptoms of malnutrition following bariatric surgery.
Both restrictive and GI bypass procedures provide positive effects on weight loss, fat composition, liver steatosis and glucose tolerance; however, in the long term, the GI bypass shows better results than restrictive procedures.
Annals of surgery 07/2011; 254(1):73-82. · 7.90 Impact Factor
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ABSTRACT: The effects of insulins detemir (Det) and glargine (Glar) on endogenous glucose production (EGP) and net hepatic glucose output (NHGO) were compared.
Arteriovenous difference and tracer ([3-(3) H]glucose) techniques were employed during a two-step hyperinsulinemic euglycaemic clamp in conscious dogs (6 groups, n = 5-6/group). After equilibration and basal sampling (0-120 min), somatostatin was infused and basal glucagon was replaced intraportally. Det or Glar was infused via portal vein (Po), peripheral vein (IV), or bilateral carotid and vertebral arteries (H) at 0.1 and 0.3 mU/kg/min (low Insulin; Glar vs. Det, respectively, 120-420 min) and 4× the low insulin rate (high insulin; 420-540 min).
NHGO and EGP were suppressed and glucose R(d) and infusion rate were stimulated similarly by Det and Glar at both Low and high insulin with each infusion route. Non-esterified fatty acid (NEFA) concentrations during low insulin were 202 ± 37 versus 323 ± 75 µM in DetPo and GlarPo (p < 0.05) and 125 ± 39 versus 263 ± 48 µM in DetIV and GlarIV, respectively (p < 0.05). In DetH versus GlarH, pAkt/Akt (1.7 ± 0.2 vs. 1.0 ± 0.2) and pSTAT3/STAT3 (1.4 ± 0.2 vs. 1.0 ± 0.1) were significantly increased in the liver but not in the hypothalamus.
Det and Glar have similar net effects on acute regulation of hepatic glucose metabolism in vivo regardless of delivery route. Portal and IV detemir delivery reduces circulating NEFA to a greater extent than glargine, and head detemir infusion enhances molecular signalling in the liver. These findings indicate a need for further examination of Det's central and hepatic effects.
Diabetes Obesity and Metabolism 05/2011; 13(9):832-40. · 3.38 Impact Factor
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ABSTRACT: Glucose metabolism was compared in dogs consuming a chow/meat diet throughout pregnancy (P group, n = 6) and dogs switched to a high-fat/high-fructose (HFF) diet during the 4th-5th gestational week (gestation ≃9 wk; P-HFF group; n = 6). An oral glucose tolerance test (OGTT; 0.9 g/kg) was administered in the 6th-7th gestational week, and a hyperinsulinemic [0-120 min: 1.8 pmol·kg(-1)·min(-1) (low insulin); 120-240 min: 9 pmol·kg(-1)·min(-1) (high insulin)] euglycemic clamp was performed the following week. Nonpregnant (NP) female dogs underwent OGTTs but not clamp studies. All P-HFF dogs exhibited impaired glucose tolerance (IGT) or gestational diabetes (GDM), but only one P dog had IGT. Insulin concentrations in P and P-HFF dogs were significantly lower than in NP dogs 30 and 60 min after the OGTT. Therefore, mean islet size and area were evaluated in P and NP dogs. These values did not differ between groups, and proliferating endocrine cells were rare in pregnancy. During exposure to high insulin, glucose infusion rate and hindlimb glucose uptake were ∼30% greater (P < 0.05) and net hepatic glucose output was more suppressed (-5.5 ± 6.1 vs. 7.8 ± 2.8 mg·100 g liver(-1)·min(-1), P < 0.05) in P than in P-HFF dogs. In conclusion, in the 2nd trimester the canine pancreas does not exhibit islet hypertrophy, hyperplasia, or neogenesis. Combined with the lack of pancreatic adaptation, a HFF diet during late pregnancy produces a canine model of IGT and GDM without hyperinsulinemia but exhibiting liver and muscle insulin resistance.
Journal of Applied Physiology 11/2010; 110(2):458-67. · 3.75 Impact Factor
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ABSTRACT: An adaptation to continuous total parenteral nutrition (TPN; 75% of nonprotein calories as glucose) is the liver becomes a major consumer of glucose with lactate release as a by-product. The liver is able to further increase liver glucose uptake when a small dose of fructose is acutely infused via the portal system. Glucagon, commonly elevated during inflammatory stress, is a potent inhibitor of glucose uptake by the liver during TPN. The aim was to determine if continuous fructose infusion could overcome the glucagon-mediated decrease in hepatic glucose uptake. Studies were performed in conscious, insulin-treated, chronically catheterized, pancreatectomized dogs that adapted to TPN for 33 hours. They were then assigned to 1 of 4 groups: TPN (C), TPN + fructose (4.4 μmol kg(-1) min(-1); F), TPN + glucagon (0.2 pmol kg(-1) min(-1); GGN), or TPN + fructose and glucagon (F + GGN) for an additional 63 hours (33-96 hours). Insulin, fructose, and glucagon were infused into the portal vein. During that period, all animals received a fixed insulin infusion of 0.4 mU·kg(-1)·min(-1) (33-96 hours); and the glucose infusion rates were adjusted to maintain euglycemia (6.6 mmol/L). Continuous fructose infusion was unable to further enhance net hepatic glucose uptake (in micromoles per kilogram per minute) (31.1 ± 2.8 vs 36.1 ± 5.0; C vs F), nor was it able to overcome glucagon-mediated decrease in net hepatic glucose uptake (10.0 ± 4.4 vs 12.2 ± 3.9; GGN vs F + GGN). In summary, continuous fructose infusion cannot augment liver glucose uptake during TPN; nor can it overcome the inhibitory effects of glucagon.
Metabolism: clinical and experimental 10/2010; 60(6):867-73. · 2.59 Impact Factor
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ABSTRACT: Insulin represses the expression of gluconeogenic genes at the mRNA level, but the hormone appears to have only weak inhibitory effects in vivo. The aims of this study were 1) to determine the maximal physiologic effect of insulin, 2) to determine the relative importance of its effects on gluconeogenic regulatory sites, and 3) to correlate those changes with alterations at the cellular level.
Conscious 60-h fasted canines were studied at three insulin levels (near basal, 4x, or 16x) during a 5-h euglycemic clamp. Pancreatic hormones were controlled using somatostatin with portal insulin and glucagon infusions. Glucose metabolism was assessed using the arteriovenous difference technique, and molecular signals were assessed.
Insulin reduced gluconeogenic flux to glucose-6-phosphate (G6P) but only at the near-maximal physiological level (16x basal). The effect was modest compared with its inhibitory effect on net hepatic glycogenolysis, occurred within 30 min, and was associated with a marked decrease in hepatic fat oxidation, increased liver fructose 2,6-bisphosphate level, and reductions in lactate, glycerol, and amino acid extraction. No further diminution in gluconeogenic flux to G6P occurred over the remaining 4.5 h of the study, despite a marked decrease in PEPCK content, suggesting poor control strength for this enzyme in gluconeogenic regulation in canines.
Gluconeogenic flux can be rapidly inhibited by high insulin levels in canines. Initially decreased hepatic lactate extraction is important, and later reduced gluconeogenic precursor availability plays a role. Changes in PEPCK appear to have little or no acute effect on gluconeogenic flux.
Diabetes 09/2009; 58(12):2766-75. · 8.29 Impact Factor
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ABSTRACT: Glucose, fat, and glucagon availability are increased in diabetes. The normal response of the liver to chronic increases in glucose availability is to adapt to become a marked consumer of glucose. Yet this fails to occur in diabetes. The aim was to determine whether increased glucagon and lipid interact to impair the adaptation to increased glucose availability. Chronically catheterized well controlled depancreatized conscious dogs (n = 21) received 3 days of continuous parenteral nutrition (TPN) that was either high in glucose [C; 75% nonprotein calories (NPC)] or in lipid (HL; 75% NPC) in the presence or absence of a low dose (one-third basal) chronic intraportal infusion of glucagon (GN; 0.25 ng.kg(-1).min(-1)). During the 3 days of TPN, all groups received the same insulin algorithm; the total amount of glucose infused (GIR) was varied to maintain isoglycemia ( approximately 120 mg/dl). On day 3 of TPN, hepatic metabolism was assessed. Glucose and insulin levels were similar in all groups. GIR was decreased in HL and C + GN ( approximately 30%) and was further decreased in HL + GN (55%). Net hepatic glucose uptake was decreased approximately 15% in C + GN, and HL and was decreased approximately 50% in HL + GN. Lipid alone or combined with glucagon decreased glucose uptake by peripheral tissues. Despite impairing whole body glucose utilization, HL did not limit whole body energy disposal. In contrast, glucagon suppressed whole body energy disposal irrespective of the diet composition. In summary, failure to appropriately suppress glucagon secretion adds to the dietary fat-induced impairment in both hepatic and peripheral glucose disposal. In addition, unlike increasing the percentage of calories as fat, inappropriate glucagon secretion in the absence of compensatory hyperinsulinemia limits whole body nutrient disposition.
AJP Endocrinology and Metabolism 03/2009; 296(5):E1172-8. · 4.75 Impact Factor
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ABSTRACT: Hepatic portal venous infusion of nitric oxide synthase (NOS) inhibitors causes muscle insulin resistance, but the effects on hepatic glucose disposition are unknown. Conscious dogs underwent a hyperinsulinemic (4-fold basal) hyperglycemic (hepatic glucose load 2-fold basal) clamp, with assessment of liver metabolism by arteriovenous difference methods. After 90 min (P1), dogs were divided into two groups: control (receiving intraportal saline infusion; n = 8) and LN [receiving N(G)-nitro-L-arginine methyl ester (L-NAME), a nonspecific NOS inhibitor; n = 11] intraportally at 0.3 mg x kg(-1) x min(-1) for 90 min (P2). During the final 60 min of study (P3), L-NAME was discontinued, and five LN dogs received the NO donor SIN-1 intraportally at 6 mug x kg(-1) x min(-1) while six received saline (LN/SIN-1 and LN/SAL, respectively). Net hepatic fractional glucose extraction (NHFE) in control dogs was 0.034 +/- 0.016, 0.039 +/- 0.015, and 0.056 +/- 0.019 during P1, P2, and P3, respectively. NHFE in LN was 0.045 +/- 0.009 and 0.111 +/- 0.007 during P1 and P2, respectively (P < 0.05 vs. control during P2), and 0.087 +/- 0.009 and 0.122 +/- 0.016 (P < 0.05) during P3 in LN/SIN-1 and LN/SAL, respectively. During P2, arterial glucose was 204 +/- 5 vs. 138 +/- 11 mg/dl (P < 0.05) in LN vs. control to compensate for L-NAME's effect on blood flow. Therefore, another group (LNlow; n = 4) was studied in the same manner as LN/SAL, except that arterial glucose was clamped at the same concentrations as in control. NHFE in LNlow was 0.052 +/- 0.008, 0.093 +/- 0.023, and 0.122 +/- 0.021 during P1, P2, and P3, respectively (P < 0.05 vs. control during P2 and P3), with no significant difference in glucose infusion rates. Thus, NOS inhibition enhanced NHFE, an effect partially reversed by SIN-1.
AJP Endocrinology and Metabolism 05/2008; 294(4):E768-77. · 4.75 Impact Factor
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ABSTRACT: Defects in insulin secretion and/or action contribute to the hyperglycemia of stressed and diabetic patients, and we hypothesize that failure to suppress glucagon also plays a role. We examined the chronic impact of glucagon on glucose uptake in chronically catheterized conscious depancreatized dogs placed on 5 days of nutritional support (NS). For 3 days of NS, a variable intraportal infusion of insulin was given to maintain isoglycemia (approximately 120 mg/dl). On day 3 of NS, animals received a constant low infusion of insulin (0.4 mU.kg-1.min-1) and either no glucagon (CONT), basal glucagon (0.7 ng.kg-1.min-1; BasG), or elevated glucagon (2.4 ng.kg-1.min-1; HiG) for the remaining 2 days. Glucose in NS was varied to maintain isoglycemia. An additional group (HiG+I) received elevated insulin (1 mU.kg-1.min-1) to maintain glucose requirements in the presence of elevated glucagon. On day 5 of NS, hepatic substrate balance was assessed. Insulin and glucagon levels were 10+/-2, 9+/-1, 7+/-1, and 24+/-4 microU/ml, and 24+/-5, 39+/-3, 80+/-11, and 79+/-5 pg/ml, CONT, BasG, HiG, and HiG+I, respectively. Glucagon infusion decreased the glucose requirements (9.3+/-0.1, 4.6+/-1.2, 0.9+/-0.4, and 11.3+/-1.0 mg.kg-1.min-1). Glucose uptake by both hepatic (5.1+/-0.4, 1.7+/-0.9, -1.0+/-0.4, and 1.2+/-0.4 mg.kg-1.min-1) and nonhepatic (4.2+/-0.3, 2.9+/-0.7, 1.9+/-0.3, and 10.2+/-1.0 mg.kg-1.min-1) tissues decreased. Additional insulin augmented nonhepatic glucose uptake and only partially improved hepatic glucose uptake. Thus, glucagon impaired glucose uptake by hepatic and nonhepatic tissues. Compensatory hyperinsulinemia restored nonhepatic glucose uptake and partially corrected hepatic metabolism. Thus, persistent inappropriate secretion of glucagon likely contributes to the insulin resistance and glucose intolerance observed in obese and diabetic individuals.
AJP Endocrinology and Metabolism 04/2007; 292(3):E928-35. · 4.75 Impact Factor
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ABSTRACT: We evaluated the effects of physiologic increases in insulin on hepatic and peripheral glucose metabolism in nonpregnant (NP) and pregnant (P; 3rd trimester) conscious dogs (n = 9 each) using tracer and arteriovenous difference techniques during a hyperinsulinemic euglycemic clamp. Insulin was initially (-150 to 0 min) infused intraportally at a basal rate. During 0-120 min (Low Insulin), the rate was increased by 0.2 mU x kg(-1) x min(-1), and from 120 to 240 min (High Insulin) insulin was infused at 1.5 mU x kg(-1) x min(-1). Insulin concentrations were significantly higher in NP than P during all periods. Matched subsets (n = 5 NP and 6 P) were identified. In the subsets, insulin was 7 +/- 1, 9 +/- 1, and 28 +/- 3 microU/ml (basal, Low Insulin, and High Insulin, respectively) in NP, and 5 +/- 1, 7 +/- 1, and 27 +/- 3 microU/ml in P. Net hepatic glucose output was suppressed similarly in both subsets (> or =50% with Low Insulin, 100% with High Insulin), as was endogenous glucose rate of appearance. During High Insulin, NP dogs required more glucose (10.8 +/- 1.5 vs. 6.2 +/- 1.0 mg x kg(-1) x min(-1), P < 0.05), and hindlimb (primarily skeletal muscle) glucose uptake tended to be greater in NP than P (18.6 +/- 2.5 mg/min vs. 13.6 +/- 2.0 mg/min, P = 0.06). The normal canine liver remains insulin sensitive during late pregnancy. Differing insulin concentrations in pregnant and nonpregnant women and excessive insulin infusion rates may explain previous findings of hepatic insulin resistance in healthy pregnant women.
AJP Regulatory Integrative and Comparative Physiology 02/2007; 292(1):R447-52. · 3.34 Impact Factor
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ABSTRACT: We examined net pancreatic norepinephrine (NE) spillover, pancreatic polypeptide (PP) release, and the decrement in C-peptide to identify factors involved in the blunted counterregulatory glucagon response in pregnancy. Conscious pregnant [pregnant hypoglycemic (Ph); 3rd trimester; n = 8] and nonpregnant [nonpregnant hypoglycemic (NPh); n = 6] dogs were studied during insulin-induced (approximately 12-fold basal insulin concentrations) hypoglycemia (plasma glucose 3.1 mM). Additional dogs were studied during hyperinsulinemic euglycemia [nonpregnant euglycemic (NPe), n = 4; pregnant euglycemic (Pe), n = 5; plasma glucose 6 mM]. Arterial glucagon concentrations declined similarly in NPe and Pe. Areas under the curve (AUCs) of the changes in glucagon and epinephrine were seven- and threefold greater in NPh than Ph (P < 0.05 between groups for both). Glucagon secretion fell below basal in NPe, Pe, and Ph but rose significantly in NPh. C-peptide declined 0.25 +/- 0.06, 0.12 +/- 0.11, 0.28 +/- 0.05, and 0.13 +/- 0.02 ng/ml in NPe, Pe, NPh, and Ph, respectively (P < 0.05, NPh vs. Ph). AUCs of NE spillover were 516 +/- 274, 265 +/- 303, 506 +/- 94, and -63 +/- 79 ng, respectively (P < 0.05, NPh vs. Ph). The AUC of PP release was approximately threefold greater in NPh than Ph (P < 0.05) but not different between euglycemic groups. The current evidence strongly suggests that the blunting of glucagon secretion during insulin-induced hypoglycemia in pregnancy is related to generalized impairment of a number of different signals, including parasympathetic and sympathoadrenal stimuli and altered sensing of circulating and/or intraislet insulin.
AJP Regulatory Integrative and Comparative Physiology 09/2006; 291(3):R788-95. · 3.34 Impact Factor
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ABSTRACT: To test whether pancreatic hormonal changes that occur during exercise are necessary for the postexercise enhancement of insulin-stimulated net hepatic glucose uptake, chronically catheterized dogs were exercised on a treadmill or rested for 150 min. At the onset of exercise, somatostatin was infused into a peripheral vein, and insulin and glucagon were infused in the portal vein to maintain basal levels (EX-Basal) or simulate the response to exercise (EX-Sim). Glucose was infused as needed to maintain euglycemia during exercise. After exercise or rest, somatostatin infusion was continued in exercised dogs and initiated in dogs that had remained sedentary. In addition, basal glucagon, glucose, and insulin were infused in the portal vein for 150 min to create a hyperinsulinemic-hyperglycemic clamp in EX-Basal, EX-Sim, and sedentary dogs. Steady-state measurements were made during the final 50 min of the clamp. During exercise, net hepatic glucose output (mg x kg(-1) x min(-1)) rose in EX-Sim (7.6 +/- 2.8) but not EX-Basal (1.9 +/- 0.3) dogs. During the hyperinsulinemic-hyperglycemic clamp that followed either exercise or rest, net hepatic glucose uptake (mg x kg(-1) x min(-1)) was elevated in both EX-Basal (4.0 +/- 0.7) and EX-Sim (4.6 +/- 0.5) dogs compared with sedentary dogs (2.0 +/- 0.3). Despite this elevation in net hepatic glucose uptake after exercise, glucose incorporation into hepatic glycogen, determined using [3-3H]glucose, was not different in EX-Basal and sedentary dogs, but was 50 +/- 30% greater in EX-Sim dogs. Exercise-induced changes in insulin and glucagon, and consequent glycogen depletion, are not required for the increase in net hepatic glucose uptake after exercise but result in a greater fraction of the glucose consumed by the liver being directed to glycogen.
Diabetes 01/2005; 53(12):3041-7. · 8.29 Impact Factor
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ABSTRACT: We determined whether intraportal caffeine infusion, at rates designed to create concentrations similar to that seen with normal dietary intake, would enhance net hepatic glucose uptake (NHGU) during a glucose load. Dogs (n = 15) were implanted with sampling and infusion catheters as well as flow probes >16 d before the studies. After a basal sampling period, dogs were administered a somatostatin infusion (0-150 min) as well as intraportal infusions of glucose [18 micromol/(kg . min)], basal glucagon [0.5 ng/(kg . min)], and insulin [8.3 pmol/(kg . min)] to establish mild hyperinsulinemia. Arterial glucose was clamped at 10 mmol/L with a peripheral glucose infusion. At 80 min, either saline (Control; n = 7) or caffeine [1.5 micromol/(kg . min); n = 8] was infused into the portal vein. Arterial insulin, glucagon, norepinephrine, and glucose did not differ between groups. In dogs infused with caffeine, NHGU was significantly higher than in controls [21.2 +/- 4.3 vs. 11.2 +/- 1.6 micromol/(kg . min)]. Caffeine increased net hepatic lactate output compared with controls [12.5 +/- 3.8 vs. 5.5 +/- 1.5 micromol/(kg . min)]. These findings indicate that physiologic circulating levels of caffeine can enhance NHGU during a glucose load, and the added glucose consumed by the liver is in part converted to lactate.
Journal of Nutrition 11/2004; 134(11):3042-6. · 3.92 Impact Factor
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ABSTRACT: The purpose of this study was to assess whether a prior bout of exercise enhances passive gut glucose absorption. Mongrel dogs had sampling catheters, infusion catheters, and a portal vein flow probe implanted 17 days before an experiment. Protocols consisted of either 150 min of exercise (n = 8) or rest (n = 7) followed by basal (-30 to 0 min) and a primed (150 mg/kg) intraduodenal glucose infusion [8.0 mg x kg-1x min-1, time (t) = 0-90 min] periods. 3-O-[3H]methylglucose (absorbed actively, facilitatively, and passively) and l-[14C]glucose (absorbed passively) were injected into the duodenum at t = 20 and 80 min. Phloridzin, an inhibitor of the active sodium glucose cotransporter-1 (SGLT-1), was infused (0.1 mg x kg-1 x min-1) into the duodenum from t = 60-90 min with a peripheral venous isoglycemic clamp. Duodenal, arterial, and portal vein samples were taken every 10 min during the glucose infusion, as well as every minute after each tracer bolus injection. Net gut glucose output in exercised dogs increased compared with that in the sedentary group (5.34 +/- 0.47 and 4.02 +/- 0.53 mg x kg-1x min-1). Passive gut glucose absorption increased approximately 100% after exercise (0.93 +/- 0.06 and 0.45 +/- 0.07 mg x kg-1 x min-1). Transport-mediated glucose absorption increased by approximately 20%, but the change was not significant. The infusion of phloridzin eliminated the appearance of both glucose tracers in sedentary and exercised dogs, suggesting that passive transport required SGLT-1-mediated glucose uptake. This study shows 1). that prior exercise enhances passive absorption of intraduodenal glucose into the portal vein and 2). that basal and the added passive gut glucose absorption after exercise is dependent on initial transport of glucose via SGLT-1.
Journal of Applied Physiology 10/2003; 95(3):1132-8. · 3.75 Impact Factor
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ABSTRACT: To determine if prior exercise enhances insulin-stimulated extraction of glucose by the liver, chronically catheterized dogs were submitted to 150 min of treadmill exercise or rest. After exercise or rest, dogs received portal glucose (18 micro mol x kg(-1) x min(-1)), peripheral somatostatin, and basal portal glucagon infusions from t = 0 to 150 min. A peripheral glucose infusion was used to clamp arterial blood glucose at 8.3 mmol/l. Insulin was infused into the portal vein to create either basal levels or mild hyperinsulinemia. Prior exercise did not increase whole-body glucose disposal in the presence of basal insulin (25.5 +/- 1.5 vs. 20.3 +/- 1.7 micro mol x kg(-1) x min(-1)), but resulted in a marked enhancement in the presence of elevated insulin (97.2 +/- 15.1 vs. 64.4 +/- 7.4 micro mol x kg(-1) x min(-1)). Prior exercise also increased net hepatic glucose uptake in the presence of both basal insulin (7.5 +/- 1.2 vs. 2.9 +/- 2.4 micro mol x kg(-1) x min(-1)) and elevated insulin (22.0 +/- 3.5 vs. 11.5 +/- 1.8 micro mol x kg(-1) x min(-1)). Likewise, net hepatic glucose fractional extraction was increased by prior exercise with both basal insulin (0.04 +/- 0.01 vs. 0.01 +/- 0.01 micro mol x kg(-1) x min(-1)) and elevated insulin (0.10 +/- 0.01 vs. 0.05 +/- 0.01). Hepatic glycogen synthesis was increased by elevated insulin, but was not enhanced by prior exercise. Although the increase in glucose extraction after exercise could be ascribed to increased insulin action, the increase in hepatic glycogen synthesis was independent of it.
Diabetes 09/2003; 52(8):1897-903. · 8.29 Impact Factor
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ABSTRACT: 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 degrees C solution, while in the other (Cool, n = 6), the coils were perfused with -20 degrees 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(-1). min(-1)). Net hepatic glucose output did not change in Sham but decreased from 1.9 +/- 0.3 to 1.3 +/- 0.3 mg. kg(-1). min(-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.
AJP Endocrinology and Metabolism 12/2002; 283(5):E958-64. · 4.75 Impact Factor
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ABSTRACT: To determine the contributions of transporter-mediated and passive absorption during an intraduodenal glucose infusion in a large animal model, six mongrel dogs had sampling catheters (portal vein, femoral artery, duodenum), infusion catheters (vena cava, duodenum) and a portal vein flow probe implanted 17 d before an experiment. Protocols consisted of a basal (-30 to 0 min) and an experimental (0-90 min) period. An intraduodenal glucose infusion of 44 micromol/(kg. min) was initiated at t = 0 min. At t = 20 and 80 min, 3-O-[3H]methylglucose and L-[14C]glucose (L-Glc) were injected intraduodenally. Phloridzin, an inhibitor of the Na+/K+ ATP-dependent transporter (SGLT1), was infused from t = 60 to 90 min in the presence of a peripheral isoglycemic clamp. Net gut glucose output was 21.1 +/- 3.0 micromol/(kg. min) from t = 0 to 60 min. Transporter-mediated glucose absorption was calculated using three approaches, which involved either direct measurements or indirect estimates of duodenal glucose analog radioactivities, to account for the assumptions and difficulties inherent to duodenal sampling. Values were essentially the same regardless of calculations used because transporter-mediated absorption was 89 +/- 1%, 90 +/- 2% and 91 +/- 2% of net gut glucose output. Phloridzin-induced inhibition of transporter-mediated absorption completely abolished passive absorption of L-Glc. We conclude that in dogs, transporter-mediated glucose absorption constitutes the vast majority of glucose absorbed from the gut and is required for passive glucose absorption. The method described here is applicable to investigation of the mechanisms of gut glucose absorption under a variety of nutritional, physiologic and pathophysiologic conditions.
Journal of Nutrition 08/2002; 132(7):1929-34. · 3.92 Impact Factor
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ABSTRACT: The present study was undertaken to determine whether an acute physiological increase in plasma cortisol level had significant effects on alanine metabolism and gluconeogenesis within 3 hours in conscious, overnight-fasted dogs. Each experiment consisted of an 80-minute tracer and dye equilibration period, a 40-minute basal period, and a 3-hour experimental period. A primed, continuous infusion of [3-3H]glucose and continuous infusions of [U-14C]alanine and indocyanine green dye were initiated at the start of the equilibration period and continued throughout the experiment. Dogs were studied with (1) a hydrocortisone infusion ([CORT] 3.0 μg · kg−1 · min−1, n = 5), (2) hydrocortisone infused as in CORT, but with pancreatic hormones clamped using somatostatin and basal intraportal replacement of insulin and glucagon (CLAMP + CORT, n = 5), or (3) saline infusion during a pancreatic clamp (CLAMP, n = 5). Glucose production and gluconeogenesis were determined using tracer and arteriovenous difference techniques. During CLAMP, all parameters were stable except for a modest 67% ± 6% increase in gluconeogenic conversion of alanine to glucose and a 53% ± 26% increase in gluconeogenic efficiency. When plasma cortisol levels were increased fourfold during CLAMP + CORT, there was no change in the concentration, production, or clearance of glucose. Gluconeogenic conversion of alanine to glucose increased 10% ± 34% and gluconeogenic efficiency increased 65% ± 43%, while net hepatic alanine uptake (NHAU) increased 60% ± 19% and hepatic fractional extraction of alanine increased 38% ± 12%. Cortisol did not cause an increase in the arterial glycerol level or net hepatic glycerol uptake. When plasma cortisol levels were increased and the pancreatic hormones were allowed to change (CORT), there was a transient but significant decrease in plasma insulin levels, while plasma glucagon levels remained unchanged. There was no change in the concentration, production (Ra), or clearance of glucose. However, gluconeogenic conversion of alanine increased 190% ± 59%, gluconeogenic efficiency increased 57% ± 43%, NHAO increased 75% ± 25%, and hepatic alanine fractional extraction increased 48% ± 6%. These changes were all statistically significant by the first 90 minutes of hydrocortisone infusion. In addition, there was a tendency for both net hepatic production of lactate and net hepatic uptake of glycerol to be elevated compared with the other two groups. These results suggest that an acute physiologic increase in plasma cortisol level can increase the gluconeogenic conversion of alanine to glucose by increasing both NHAU and hepatic fractional extraction of alanine. This increase in plasma cortisol level may also be associated with a transient decrease in plasma insulin level that may further promote gluconeogenesis.
Metabolism.
