Hypoglycemic effects of a β-agonist, Ro 16-8714, in streptozotocin-diabetic rats: Decreased hepatic glucose production and increased glucose utilization in oxidative muscles

Abstract Background and Aims The thyroid hormone (TH) plays an important role in glucose metabolism. Recently, we showed that the TH improves glycemia control by decreasing cytokines expression in the adipose tissue and skeletal muscle of alloxan-induced diabetic rats, which were also shown to present primary hypothyroidism. In this context, this study aims to investigate whether the chronic treatment of diabetic rats with T3 could affect other tissues that are involved in the control of glucose homeostasis, as the liver and kidney. Method Adult male Wistar rats were divided into nondiabetic, diabetic, and diabetic treated with T3 (1.5 ?g/100 g BW for 4 weeks). Diabetes was induced by alloxan monohydrate (150 mg/kg, BW, i.p.). Animals showing fasting blood glucose levels greater than 250 mg/dL were selected for the study. Results After treatment, we measured the blood glucose, serum T3, T4, TSH, and insulin concentration, hepatic glucose production by liver perfusion, liver PEPCK, GAPDH, and pAKT expression, as well as urine glucose concentration and renal expression of SGLT2 and GLUT2. T3 reduced blood glucose, hepatic glucose production, liver PEPCK, GAPDH, and pAKT content and the renal expression of SGLT2 and increased glycosuria. Conclusion Results suggest that the decreased hepatic glucose output and increased glucose excretion induced by T3 treatment are important mechanisms that contribute to reduce serum concentration of glucose, accounting for the improvement of glucose homeostasis control in diabetic rats.

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Hypoglycemia counterregulation in elderly humans: relationship to glucose levels

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1994.267.4.e497 ◽

1994 ◽

Vol 267 (4) ◽

pp. E497-E506 ◽

Cited By ~ 3

Author(s):

F. J. Ortiz-Alonso ◽

A. Galecki ◽

W. H. Herman ◽

M. J. Smith ◽

J. A. Jacquez ◽

...

Keyword(s):

Glucose Utilization ◽

Hepatic Glucose Production ◽

Severe Hypoglycemia ◽

Glucose Production ◽

Counterregulatory Hormones ◽

Glucose Levels ◽

Hepatic Glucose ◽

Consistent Increase ◽

Step Study ◽

Elderly Humans

This study was designed to define the effect of human aging on hypoglycemia counterregulatory mechanisms. A hyperinsulinemic (2 mU.kg-1.min-1) glucose clamp procedure was used to control glucose and insulin levels during stepwise lowering of plasma glucose. Counterregulatory hormones, hepatic glucose production (HGP), glucose utilization, and symptoms of hypoglycemia were studied in 13 healthy young [age 24 +/- 1 (SE) yr] and 11 healthy old (age 65 +/- 1 yr) nondiabetic volunteers on two occasions: 1) at matched euglycemia and 70 and 60 mg/dl (study 1) and 2) at matched euglycemia and 60 and 50 mg/dl (study 2). The old had consistently lower epinephrine (P < 0.005), glucagon (P < 0.02), cortisol (P < 0.05), and pancreatic polypeptide (P < 0.02) responses at the 60-mg/dl glucose step in study 1. However, these differences were no longer detectable at the more severe hypoglycemic stimulus of 50 mg/dl in study 2. A consistent increase in HGP occurred in both groups only at the 50-mg/dl glucose step (study 2) and was not different between young and old. There were also no differences in symptom responses between young and old. In summary, we found that elderly individuals have a subtle impairment of the glucose counterregulatory response during moderate hypoglycemia, but this impairment is no longer detectable during more severe hypoglycemia.

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Metformin improves peripheral but not hepatic insulin action in obese patients with type II diabetes

Acta Endocrinologica ◽

10.1530/acta.0.1200257 ◽

1989 ◽

Vol 120 (3) ◽

pp. 257-265 ◽

Cited By ~ 71

Author(s):

Ole Hother-Nielsen ◽

Ole Schmitz ◽

Per H. Andersen ◽

Henning Beck-Nielsen ◽

Oluf Pedersen

Keyword(s):

Type Ii Diabetes ◽

Insulin Action ◽

Glucose Utilization ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Metformin Treatment ◽

Obese Patients ◽

Type Ii ◽

Plasma Lactate ◽

Hepatic Glucose

Abstract. Nine obese patients with Type II diabetes mellitus were examined in a double-blind cross-over study. Metformin 0.5 g trice daily or placebo were given for 4 weeks. At the end of each period fasting and day-time postprandial values of plasma glucose, insulin, C-peptide and lactate were determined, and in vivo insulin action was assessed using the euglycemic clamp in combination with [3-3H]glucose tracer technique. Metformin treatment significantly reduced mean day-time plasma glucose levels (10.2 ± 1.2 vs 11.4 ± 1.2 mmol/l, P< 0.01) without enhancing mean day-time plasma insulin (43 ± 4 vs 50 ± 7 mU/l, NS) or C-peptide levels (1.26 ± 0.12 vs 1.38 ± 0.18 nmol/l, NS). Fasting plasma lactate was unchanged (1.57 ± 0.16 vs 1.44 ± 0.11 mmol/l, NS), whereas mean day-time plasma lactate concentrations were slightly increased (1.78 ± 0.11 vs 1.38 ± 0.11 mmol/l, P< 0.01). The clamp study revealed that metformin treatment was associated with an enhanced insulin-mediated glucose utilization (370 ± 38 vs 313 ± 33 mg · m−2 · min−1, P< 0.01), whereas insulin-mediated suppression of hepatic glucose production was unchanged. Also basal glucose clearance was improved (61.0 ± 5.8 vs 50.6 ± 2.8 ml · n−2 · min−1,, P< 0.05), whereas basal hepatic glucose production was unchanged (81 ± 6 vs 77 ± 4 mg · m−2 · min−1, NS). Conclusions: 1) Metformin treatment in obese Type II diabetic patients reduces hyperglycemia without changing the insulin secretion. 2) The improved glycemic control during metformin treatment was associated with an enhanced insulin-mediated glucose utilization, presumably in skeletal muscle, whereas no effect could be demonstrated on hepatic glucose production.

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Influence of prior exercise and liver glycogen content on the sensitivity of the liver to glucagon

Journal of Applied Physiology ◽

10.1152/jappl.2002.92.1.188 ◽

2002 ◽

Vol 92 (1) ◽

pp. 188-194 ◽

Cited By ~ 7

Author(s):

Victoria Matas Bonjorn ◽

Martin G. Latour ◽

Patrice Bélanger ◽

Jean-Marc Lavoie

Keyword(s):

Glucose Utilization ◽

Glycogen Content ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Liver Glycogen ◽

Hepatic Glycogen ◽

Prior Exercise ◽

Hepatic Glucose ◽

Increased Sensitivity ◽

Glucagon And Insulin

The purpose of the present study was to test the hypothesis that a prior period of exercise is associated with an increase in hepatic glucagon sensitivity. Hepatic glucose production (HGP) was measured in four groups of anesthetized rats infused with glucagon (2 μg · kg−1 · min−1 iv) over a period of 60 min. Among these groups, two were normally fed and, therefore, had a normal level of liver glycogen (NG). One of these two groups was killed at rest (NG-Re) and the other after a period of exercise (NG-Ex; 60 min of running, 15–26 m/min, 0% grade). The two other groups of rats had a high hepatic glycogen level (HG), which had been increased by a fast-refed diet, and were also killed either at rest (HG-Re) or after exercise (HG-Ex). Plasma glucagon and insulin levels were increased similarly in all four conditions. Glucagon-induced hyperglycemia was higher ( P < 0.01) in the HG-Re group than in all other groups. HGP in the HG-Re group was not, however, on the whole more elevated than in the NG-Re group. Exercised rats (NG-Ex and HG-Ex) had higher hyperglycemia, HGP, and glucose utilization than rested rats in the first 10 min of the glucagon infusion. HG-Ex group had the highest HGP throughout the 60-min experiment. It is concluded that hyperglucagonemia-induced HGP is stimulated by a prior period of exercise, suggesting an increased sensitivity of the liver to glucagon during exercise.

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Effects of sustained swimming on hepatic glucose production of rainbow trout

Journal of Experimental Biology ◽

10.1242/jeb.202.16.2161 ◽

1999 ◽

Vol 202 (16) ◽

pp. 2161-2166 ◽

Cited By ~ 6

Author(s):

D.S. Shanghavi ◽

J.M. Weber

Keyword(s):

Rainbow Trout ◽

Glucose Utilization ◽

Blood Glucose Concentration ◽

Hepatic Glucose Production ◽

Mammalian Species ◽

Glucose Production ◽

Glucose Kinetics ◽

Fourfold Increase ◽

Rainbow Trout Oncorhynchus Mykiss ◽

Hepatic Glucose

The rate of hepatic glucose production (R(a)glucose) was measured by continuous infusions of 6-[(3)H]glucose in live rainbow trout (Oncorhynchus mykiss) before, during and after swimming for 3 h at 1.5 body lengths s(−)(1) in a swim tunnel. Contrary to expectation, we found that sustained swimming causes a 33 % decline in the R(a),(glucose) of trout (from 7.6+/−2.1 to 5.1+/−1.3 (μ)mol kg(−)(1)min(−)(1), means +/− s.e.m., N=7), even though exercise of the same intensity elicits a two- to fourfold increase in all the mammalian species investigated to date. Measurements of catecholamine levels show that circulating [epinephrine] decreases by 30 % during exercise (from 4.7+/−0.3 to 3.3+/−0.4 nmol l(−)(1), N=8), suggesting that this hormone is partly responsible for controlling the decline in R(a)glucose. The inhibiting effect of swimming on hepatic glucose production persists for at least 1 h after the cessation of exercise. In addition, rainbow trout can maintain a steady blood glucose concentration throughout sustained exercise by closely matching hepatic glucose production with peripheral glucose utilization, even though this species is generally considered to be a poor glucoregulator. This study provides the first continuous measurements of glucose kinetics during the transition from rest to work in an ectotherm and it suggests that circulating glucose is not an important fuel for aerobic locomotion in trout.

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Evidence against important catecholamine compensation for absent glucagon counterregulation

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1991.260.2.e203 ◽

1991 ◽

Vol 260 (2) ◽

pp. E203-E212 ◽

Cited By ~ 2

Author(s):

P. De Feo ◽

G. Perriello ◽

E. Torlone ◽

C. Fanelli ◽

M. M. Ventura ◽

...

Keyword(s):

Plasma Glucose ◽

Glucose Utilization ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Plasma Glucagon ◽

Counterregulatory Hormones ◽

Exogenous Glucose ◽

Hepatic Glucose ◽

Clamp Study

To assess the counterregulatory role of glucagon and to test the hypothesis that catecholamines can largely compensate for an impaired glucagon response, four studies were performed in seven normal volunteers. In all studies, insulin was infused subcutaneously (15 mU.m-2.min-1) and increased circulating insulin approximately twofold to levels (26 +/- 1 microU/ml) observed with intensive insulin therapy. In study 1, plasma glucose fluxes (D-[3-3H]glucose) and plasma substrate and counterregulatory hormone concentrations were simply monitored; plasma glucose decreased from 87 +/- 2 mg/dl and plateaued at 51 +/- 2 mg/dl for 3 h. In study 2 [pituitary-adrenal-pancreatic (PAP) clamp], secretion of insulin and counterregulatory hormones (except for catecholamines) was prevented by somatostatin (0.5 mg/h i.v.) and metyrapone (0.5 g/4 h per os), and glucagon, cortisol, and growth hormone were reinfused to reproduce the concentrations of study 1. In study 3 (lack of glucagon response), the PAP clamp was performed with maintenance of plasma glucagon at basal levels, and glucose was infused whenever needed to reproduce plasma glucose concentration of study 2. Study 4 was identical to study 3, but exogenous glucose was not infused. The PAP clamp (study 2) reproduced glucose concentrations and fluxes observed in study 1. In studies 3 and 4, isolated lack of glucagon response did not affect glucose utilization but caused an early and persistent decrease in hepatic glucose production (approximately 60%) that caused plasma glucose to decrease to 38 +/- 2 mg/dl (P less than 0.01 vs. control 62 +/- 2 mg/dl), despite compensatory increases in plasma epinephrine. We conclude that, in a model of clinical hypoglycemia, glucagon's effect on hepatic glucose production is a dominant counterregulatory factor in humans and that its absence cannot be compensated for by increased epinephrine secretion.

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