Prevailing hyperglycemia is critical in the regulation of glucose metabolism during exercise in poorly controlled alloxan-diabetic dogs

The separate impacts of the chronic diabetic state and the prevailing hyperglycemia on plasma substrates and hormones, in vivo glucose turnover, and ex vivo skeletal muscle (SkM) during exercise were examined in the same six dogs before alloxan-induced diabetes (prealloxan) and after 4–5 wk of poorly controlled hyperglycemic diabetes (HGD) in the absence and presence of ∼300-min phlorizin-induced (glycosuria mediated) normoglycemia (NGD). For each treatment state, the ∼15-h-fasted dog underwent a primed continuous 150-min infusion of [3-3H]glucose, followed by a 30-min treadmill exercise test (∼65% maximal oxygen capacity), with SkM biopsies taken from the thigh (vastus lateralis) before and after exercise. In the HGD and NGD states, preexercise hepatic glucose production rose by 130 and 160%, and the metabolic clearance rate of glucose (MCRg) fell by 70 and 37%, respectively, compared with the corresponding prealloxan state, but the rates of glucose uptake into peripheral tissues (Rdtissue) and total glycolysis (GF) were unchanged, despite an increased availability of plasma free fatty acid in the NGD state. Exercise-induced increments in hepatic glucose production, Rdtissue, and plasma-derived GF were severely blunted by ∼30–50% in the NGD state, but increments in MCRg remained markedly reduced by ∼70–75% in both diabetic states. SkM intracellular glucose concentrations were significantly elevated only in the HGD state. Although Rdtissue during exercise in the diabetic states correlated positively with preexercise plasma glucose and insulin and GF and negatively with preexercise plasma free fatty acid, stepwise regression analysis revealed that an individual's preexercise glucose and GF accounted for 88% of Rdtissue during exercise. In conclusion, the prevailing hyperglycemia in poorly controlled diabetes is critical in maintaining a sufficient supply of plasma glucose for SkM glucose uptake during exercise. During phlorizin-induced NGD, increments in both Rdtissue and GF are impaired due to a diminished fuel supply from plasma glucose and a sustained reduction in increments of MCRg.

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Regulation of glucose turnover and hormonal responses during electrical cycling in tetraplegic humans

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1996.271.1.r191 ◽

1996 ◽

Vol 271 (1) ◽

pp. R191-R199 ◽

Cited By ~ 10

Author(s):

M. Kjaer ◽

S. F. Pollack ◽

T. Mohr ◽

H. Weiss ◽

G. W. Gleim ◽

...

Keyword(s):

Heart Rate ◽

Plasma Glucose ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Glucose Turnover ◽

Hormonal Responses ◽

Hepatic Glucose ◽

Exercise Period ◽

Exercise Activity ◽

Beta Hydroxybutyrate

To examine the importance of blood-borne vs. neural mechanisms for hormonal responses and substrate mobilization during exercise, six spinal cord-injured tetraplegic (C5-T1) males (mean age: 35 yr, range: 24-55 yr) were recruited to perform involuntary, electrically induced cycling [functional electrical stimulation (FES)] to fatigue for 24.6 +/- 2.3 min (mean and SE), and heart rate rose from 67 +/- 7 (rest) to 107 +/- 5 (exercise) beats/min. Voluntary arm cranking in tetraplegics (ARM) and voluntary leg cycling in six matched, long-term immobilized (2-12 mo) males (Vol) served as control experiments. In FES, peripheral glucose uptake increased [12.4 +/- 1.1 (rest) to 19.5 +/- 4.3 (exercise) mumol.min-1.kg-1; P < 0.05], whereas hepatic glucose production did not change from basal values [12.4 +/- 1.4 (rest) vs. 13.0 +/- 3.4 (exercise) mumol.min-1.kg-1]. Accordingly, plasma glucose decreased [from 5.4 +/- 0.3 (rest) to 4.7 +/- 0.3 (exercise) mmol/l; P < 0.05]. Plasma glucose did not change in response to ARM or Vol. Plasma free fatty acids and beta-hydroxybutyrate decreased only in FES experiments (P < 0.05). During FES, increases in growth hormone (GH) and epinephrine and decreases in insulin concentrations were abolished. Although subnormal throughout the exercise period, norepinephrine concentrations increased during FES, and responses of heart rate, adrenocorticotropic hormone, beta-endorphin, renin, lactate, and potassium were marked. In conclusion, during exercise, activity in motor centers and afferent muscle nerves is important for normal responses of GH, catecholamines, insulin, glucose production, and lipolysis. Humoral feedback and spinal or simple autonomic nervous reflex mechanisms are not sufficient. However, such mechanisms are involved in redundant control of heart rate and neuroendocrine activity in exercise.

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Plasma free fatty acid turnover during insulin-induced hypoglycemia

American Journal of Physiology-Legacy Content ◽

10.1152/ajplegacy.1961.201.3.535 ◽

1961 ◽

Vol 201 (3) ◽

pp. 535-539 ◽

Cited By ~ 93

Author(s):

D. T. Armstrong ◽

R. Steele ◽

N. Altszuler ◽

A. Dunn ◽

J. S. Bishop ◽

...

Keyword(s):

Fatty Acid ◽

Free Fatty Acid ◽

Glucose Uptake ◽

Plasma Glucose ◽

Glucose Concentration ◽

Insulin Infusion ◽

Plasma Free Fatty Acid ◽

Plasma Glucose Concentration ◽

Free Insulin ◽

Adrenal Response

Plasma free fatty acid (FFA) concentration falls when an infusion of glucagon-free insulin is initiated in the normal unanesthetized dog in the postabsorptive state. Using C14 palmitate it was shown that the lowered FFA concentration is caused by decreased FFA production. This decreased FFA production accompanies increased glucose uptake by the tissues as demonstrated using C14 glucose. During slow insulin infusion, when plasma glucose concentration remains above 75 mg%, FFA production and concentration remain low. However, during more rapid insulin infusion, when plasma glucose concentration falls below 50 mg%, the initially lowered FFA production rebounds and FFA production and concentration exceed the preinsulin level. Glucose uptake always remains elevated during insulin infusion. Dibenzyline or guanethidine pretreatment blocks the rebound in FFA production. Thus decreased FFA production, due presumably to decreased FFA release by adipose tissue because of insulin-stimulated glucose uptake, can be overpowered by a sympatho-adrenal response to hypoglycemia during a continued infusion of insulin and a resulting continued increased glucose uptake.

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The synthetic human growth hormone fragment (32–38) increases glucose uptake in the conscious dog

Acta Endocrinologica ◽

10.1530/acta.0.1170457 ◽

1988 ◽

Vol 117 (4) ◽

pp. 457-462 ◽

Cited By ~ 7

Author(s):

Ralph W. Stevenson ◽

Nowell Stebbing ◽

Theodore Jones ◽

Keith Carr ◽

Peter M. Jones ◽

...

Keyword(s):

Glucose Uptake ◽

Plasma Glucose ◽

Insulin Action ◽

Hepatic Glucose Production ◽

Control Period ◽

Human Growth ◽

Glucose Production ◽

Independent Action ◽

Conscious Dog ◽

Hepatic Glucose

Abstract. hGH32-38 was tested to determine if the peptide could affect hepatic glucose production in the conscious dog under basal conditions (euglycemia) or if it could enhance glucose uptake when hyperglycemia was induced. hGH32-38 (1.6 nmol · kg−1 · min−1) or vehicle was infused in a cross-over design study into each of 4 conscious 16 h-fasted dogs for 3 h (0–180 min) following a 40 min control period. At 90 min, plasma glucose was raised to and maintained at 9.4 mmol/l by glucose infusion for 3 h (until 270 min). Neither hGH32-38 nor vehicle infusion had a significant effect on insulin and glucagon levels or on tracer determined ([3-3H]glucose) glucose production. As a result, neither treatment changed plasma glucose (5.72 ± 0.17 to 5.78 ± 0.17 mmol/l with hGH32-38; 5.50 ± 0.22 to 5.50 ± 0.17 mmol/l with vehicle). Induction of hyperglycemia (9.4 mmol/l) caused glucagon concentrations to fall similarly to about 50 ng/l with and without hGH32-38. Insulin rose to similar levels in both protocols, yet more glucose was required to maintain the same hyperglycemia with hGH32-38 (135– 180 min) (74.9 ± 12.7 vs 43.7 ± 7.1 μmol · kg−1 · min−1, P < 0.05). In summary, hGH32-38 significantly increased glucose disposition during hyperglycemia and this effect may be attributed to enhanced insulin action or to an insulin independent action of the peptide.

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Pentobarbital reduces basal liver glucose output and its insulin suppression in rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1990.258.4.e701 ◽

1990 ◽

Vol 258 (4) ◽

pp. E701-E707 ◽

Cited By ~ 10

Author(s):

P. W. Clark ◽

A. B. Jenkins ◽

E. W. Kraegen

Keyword(s):

Plasma Glucose ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Conscious State ◽

Hepatic Insulin Resistance ◽

Glucose Turnover ◽

Pentobarbital Anesthesia ◽

Hepatic Glucose ◽

Glucose Output ◽

Conscious Animals

Recent reports conflict on the effect that pentobarbital anesthesia has on basal glucose turnover in the rat. It is also unclear whether pentobarbital alters insulin suppressibility of hepatic glucose production (Ra). We examined these issues by performing basal and hyperinsulinemic euglycemic clamp studies in anesthetized and conscious animals. Ra and glucose utilization (Rd) were estimated using a steady-state infusion of 3-[3H]glucose. Pentobarbital anesthesia in normothermic rats transiently elevated plasma glucose but resulted in a sustained suppression of basal Ra (10.4 +/- 0.3 vs. conscious 13.2 +/- 0.9 mg.kg-1.min-1, P less than 0.05). In the insulin-stimulated state (110 mU/l), despite similar plasma glucose and insulin levels, clamp glucose infusion rate was significantly reduced in anesthetized animals (11.1 +/- 0.9 vs. conscious 23.6 +/- 1.3 mg.kg-1.min-1, P less than 0.001). This can be attributed to both a significantly lower insulin-stimulated Rd (15.4 +/- 1.3 vs. conscious 22.8 +/- 1.4 mg.kg-1.min-1, P less than 0.005) and reduced insulin suppression of Ra (4.3 +/- 0.8 vs. conscious -0.8 +/- 0.5 mg.kg-1.min-1, P less than 0.001; i.e., anesthetized 59% vs. conscious 100% reduction of basal Ra). Thus pentobarbital anesthesia significantly reduces basal Ra and induces hepatic insulin resistance (reduces Ra suppressibility). Pentobarbital effects are not dependent on induced hypothermia, but this exacerbates the metabolic perturbation. Caution should be used in extrapolating from the anesthetized to the conscious state.

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Effect of carbohydrate ingestion on glucose kinetics during exercise

Journal of Applied Physiology ◽

10.1152/jappl.1994.77.3.1537 ◽

1994 ◽

Vol 77 (3) ◽

pp. 1537-1541 ◽

Cited By ~ 83

Author(s):

G. McConell ◽

S. Fabris ◽

J. Proietto ◽

M. Hargreaves

Keyword(s):

Oxygen Uptake ◽

Glucose Uptake ◽

Plasma Glucose ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Glucose Kinetics ◽

Carbohydrate Ingestion ◽

Pulmonary Oxygen Uptake ◽

Hepatic Glucose ◽

Total Glucose

Six well-trained men (peak pulmonary oxygen uptake = 5.03 +/- 0.11 l/min) were studied during 2 h of exercise at 69 +/- 1% peak pulmonary oxygen uptake to examine the effect of carbohydrate (CHO) ingestion on glucose kinetics. Subjects ingested 250 ml of either a 10% glucose solution containing 6-[3H]glucose (CHO) or a sweet placebo every 15 min during exercise. Glucose kinetics were assessed by 6,6-[2H]glucose infusion corrected for gut-derived glucose in CHO. Plasma glucose was higher (P < 0.05) in CHO from 20 min. Total glucose appearance was higher in CHO due to glucose delivery from the gut (68 +/- 7 g), since hepatic glucose production was reduced by 51% (29 +/- 5 vs. 59 +/- 5 g). Glucose uptake was higher in CHO (96 +/- 7 vs. 60 +/- 6 g) with the ingested glucose supplying 67 +/- 4 g and, with the assumption that it was fully oxidized, accounted for 14 +/- 1% of total energy expenditure. In conclusion, CHO ingestion during prolonged exercise results in suppression of hepatic glucose production and increased glucose uptake. These effects appear to be mediated mainly by increased plasma glucose and insulin levels.

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Effects of glucose infusion on hepatic and muscle glycogenolysis in exercising dogs

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1981.240.5.e451 ◽

1981 ◽

Vol 240 (5) ◽

pp. E451-E457 ◽

Cited By ~ 1

Author(s):

B. Issekutz

Keyword(s):

Plasma Glucose ◽

Muscle Glycogen ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Glucose Infusion ◽

Molar Ratio ◽

Control Group ◽

Metabolic Clearance ◽

Indwelling Catheters ◽

Hepatic Glucose

Hepatic glucose production (Ra) and the rate of utilization of nonglucose sources (essentially muscle glycogen) were measured in dogs running on a treadmill (15%, 133 m/min) with indwelling catheters in the jugular vein and carotid artery. A mixture of [3-3H]glucose and [U-14C]glucose was used as tracer according to the principles of the primed constant-rate infusion techniques. Glucose was infused intravenously at a rate (12 mg.kg-1.min-1) about 20% higher than the endogenous glucose Ra in exercising dogs. Glucose infusion started either at the beginning of the run or midexercise. Plasma insulin (IRI), glucagon (IRG), and cAMP levels were measured. Exogenous glucose prevented the usual decline of both plasma glucose and IRI without causing hyperglycemia. Exercise increased the molar ratio of IRG/IRI from 0.7 to 1.4, and glucose infusion lowered it to the resting value. The rise of plasma cAMP was slowed significantly. Both the hepatic glucose Ra and intramuscular glycogenolysis were strongly inhibited and the metabolic clearance rate of glucose was increased by 60–100%. The ratio of the specific activities of [14C]lactate to [14C]glucose indicated that 75–95% of the lactate turnover arose from plasma glucose. The corresponding value in the control group was 40–50%. It is concluded that in prolonged exercise the decline of both plasma glucose and insulin play a major role in preserving glucose homeostasis, by limiting the glucose uptake of the working muscle and by helping to achieve an approximately equal contribution of the liver and the muscle glycogen for the elevated glycolysis.

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Glucose turnover in kelp bass (Paralabrax sp.): in vivo studies with [6-3H,6-14C]glucose

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1977.232.1.r66 ◽

1977 ◽

Vol 232 (1) ◽

pp. R66-R72 ◽

Cited By ~ 2

Author(s):

K. Bever ◽

M. Chenoweth ◽

A. Dunn

Keyword(s):

Plasma Glucose ◽

Hepatic Glucose Production ◽

Mean Transit Time ◽

Glucose Production ◽

In Vivo Studies ◽

Glucose Turnover ◽

Glucose Levels ◽

Hepatic Glucose ◽

Kelp Bass ◽

Carbon Recycling

[6-3H,6-14C]glucose was injected via an indwelling arterial cannula in free-swimming, fed, and fasted kelp bass to determine hepatic glucose production, peripheral glucose uptake, minimal glucose mass, mean transit time, and the percent of carbon recycling under the two different nutritional states. Mean plasma glucose levels remained unchanged in fed and fasted fish (48+/-8 vs. 43+/-8 mg/100 ml). During steady-state conditions, glucose replacement rates of fed and fasted fish determined with [6-3H]glucose are similar (0.035+/-0.006 vs. 0.025+/-0.003 mg/min per 100 g) and do not differ from rates determined with [6-14C]glucose (0.035+/-0.005 vs. 0.026+/-0.002). The minimal glucose masses and the mean transit tim-s determined with both isotopes are also similar suggesting that plasma glucose levels and glucose turnover are maintained in fish fasted up to 40 days with no apparent increase in carbon recycling. Nonsteady-state isotope experiments suggest that these fish can alter rates of hepatic glucose production and peripheral uptake in response to hyper- and hypoglycemia.

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Is the Peripheral Utilization of Glucose a Regulator of Hepatic Glucose Production and of Glycemia?

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y74-023 ◽

1974 ◽

Vol 52 (2) ◽

pp. 158-165 ◽

Cited By ~ 5

Author(s):

C. J. Achou ◽

G. Hetenyi Jr.

Keyword(s):

Plasma Level ◽

Inverse Relationship ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Glucose Consumption ◽

Glucose Turnover ◽

Metabolic Clearance ◽

Hepatic Glucose ◽

Normal Rat

The aim of the study was to examine the effect of an increase in peripheral uptake of glucose on its release by the liver in rats. If cross circulation is established between a normal and eviscerated rat, the turnover of glucose is elevated above that observed in single normal rat, indicating that the increase of glucose consumption from the system into which the liver releases glucose leads to an increase of the rate of glucose production. The duration of this compensation however is limited to about 90 min. Cross circulation established between diabetic and normal, non-eviscerated and eviscerated rats in different combinations demonstrated that the overall rate of glucose turnover is nearly identical in all such preparations although the level of glucose in the plasma is in inverse relationship to the metabolic clearance of glucose and is directly related to the amount of previously insulin-deprived tissues in the preparation. It appears that at least in such preparations the overall utilization rather than the plasma level of glucose is being regulated primarily.

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