Pertussis Toxin Administered Spinally Induces a Hypoglycemic Effect on Normal and Diabetic Mice

Abstract

Background/Aims: To show whether intrathecal (i.t.) treatment with pertussis toxin (PTX) produces a hypoglycemic effect in ICR, db/db and streptozotocin-treated mice. Methods: The blood glucose level (BGL) was measured after i.t. treatment with PTX, AB₅ toxins and PTX subunits. Insulin or leptin levels were measured after PTX injection. The effect of PTX on the BGL was examined in adrenalectomized (ADX) mice. Glucose transporter (GLUT) levels were determined by Western blotting. Results: PTX attenuated the elevated BGL in the <smlcap>D</smlcap>-glucose-fed model in a long-term manner. Heat-labile toxin (HLT), HLT subunit B or Shiga toxin, which belong to the AB₅ toxins, administered i.t. did not affect the BGL. PTX A protomer (PTX-A) or PTX B oligomers (PTX-B) injected i.t. did not have an effect on the BGL as well. However, combined treatment with PTX-A and PTX-B subunits caused a hypoglycemic effect. The leptin level was gradually reduced by PTX for up to 6 days, without affecting the insulin level. PTX administered i.t. significantly decreased the BGL further in ADX mice. Moreover, GLUT-2 (hypothalamus and pituitary gland), GLUT-4 (muscle) and GLUT-3 (adrenal gland) expression levels were increased, whereas GLUT-1 (brain cortex, liver, muscle and spinal cord), GLUT-2 (liver) and GLUT-3 (brain cortex and pituitary gland) expression levels were decreased. Discussion: Our data suggest that PTX administered spinally produces a hypoglycemic effect in a long-term manner, and PTX-induced hypoglycemia appears to be mediated by the reduction in activity of the glucocorticoid system. Furthermore, PTX may modulate the insulin level during hypoglycemia. Among GLUTs, GLUT-4 in muscle, GLUT-2 in the liver, hypothalamus and pituitary gland as well as GLUT-1 in the adrenal gland may be responsible for PTX-induced hypoglycemia.

The activation of α2-adrenergic receptor in the spinal cord lowers sepsis-induced mortality

“…These results suggest that inhibitory G-protein located at the spinal cord appear to be involved in the production of hyperglycemia and protective effect by activations of α 2 -adrenergic receptors located in the spinal cord against sepsis+induced mortality. The inhibitory effect of PTX against clonidine-induced hyperglycemia is in line with our previous study [ 38 ]. It is suggested that blocking the effect of PTX against the hyperglycemic effect induced by clonidine appears to be responsible for antagonizing clonidine-induced protective effect against sepsis-induced mortality.…”

“…After brief sonication to shear DNA and reduce viscosity, the concentration of protein was determined with the detergent-compatible protein assay reagent (Bio-Rad Laboratories, USA) using bovine serum albumin as the standard. The western blot analysis was performed according to our previous study [ 38 42 ]. The membranes were then exposed to a Luminescent Image Analyzer (LAS-4000, Fuji Film Co., Japan) for the detection of light emission.…”

“…PTX inhibits glucose transport in perfused skeletal muscle [ 35 ], and also the treatment with PTX results in an inhibition of both insulin binding and glucose transport [ 36 ]. In addition, we and others have previously reported that PTX produces a long-term hypoglycemic effect [ 37 38 39 ]. However, the roles of spinally located PTX-sensitive G-proteins in the regulation of protective effect by clonidine against sepsis-induced mortality were examined in the present study.…”

Effect of pertussis toxin pretreated centrally on blood glucose level induced by stress

“…However, the present study was designed to find out the role of supraspinally and spinally located PTX sensitive G-proteins in blood glucose regulation under various types of stress conditions. We and others have previously demonstrated that PTX administered systemically or centrally exerts a hypoglycemic effect [254142]. In addition, i.t.…”

“…We have also recently reported In our previous studies, we have reported that i.t. administration with PTX causes hypoglycemia in a comprehensive manner and induced neuroprotection against the KA-induced hippocampal CA3 neuronal death by lowering the blood glucose level [2425]. Although PTX is involved in the regulation of the blood glucose level, However, the exact role of PTX-sensitive G-proteins in stress-induced hyperglycemia has not been well characterized yet.…”