Isoproterenol inhibits cyclic AMP-mediated but not insulin-mediated translocation of the GLUT4 glucose transporter isoform.

Isoproterenol is a beta adrenergic agonist whose effects have been attributed to the generation of cAMP. Previous studies have shown that it inhibits glucose transport in adipocytes without changing the number of insulin-responsive glucose transporters (GLUT4) on the cell surface. However, we have shown previously that cAMP stimulates translocation of GLUT4 to the cell surface in adipocytes (Kelada et al. J Biol Chem 267, 7021-7025, 1992). We therefore further investigated the mechanisms involved in isoproterenol regulation of glucose transport. Consistent with the effects of dibutyryl cAMP, we found that a low concentration of isoproterenol (10 nM) stimulated glucose transport and the translocation of GLUT4 from the low density microsomal fraction to the plasma membrane. By contrast, a higher concentration of isoproterenol (1 microM) did not stimulate transport or GLUT4 translocation and furthermore inhibited dibutyryl cAMP-stimulated GLUT4 translocation. This inhibitory effect was specific for cAMP since isoproterenol had no effect on insulin-stimulated GLUT4 translocation. We conclude that isoproterenol has a biphasic effect on glucose transport, mediated by acute translocation of GLUT4 at low concentrations and by inhibition of intrinsic activity at high concentration, both of which may be explained by effects of cAMP. It has a further cAMP-independent effect at high concentration to inhibit cAMP-mediated translocation of GLUT4.

Early decrease in GLUT4 protein levels in brown adipose tissue of New Zealand obese mice.

The aim of this study was to determine if the previously described insulin resistance in the New Zealand Obese (NZO) mouse is associated with a decrease in GLUT4 protein and if such changes occur early in the evolution of the syndrome. GLUT4 levels were measured in whole membranes isolated from a variety of tissues in 4 and 20-week-old NZO and control NZC mice by Western blotting using a specific antibody to the C terminal end of the protein. At 20 weeks of age, GLUT4 levels were lower in the NZO mice in brown and white adipose tissue, heart, diaphragm, red and white quadriceps, and red and white gastrocnemius, but not in soleus muscle. At 4 weeks of age, GLUT4 levels were 52% lower in BAT (3309 +/- 1006 vs 6951 +/- 1870 cpm P = 0.039) but were not lower in WAT, heart or red quadriceps. It is concluded that adult NZO mice have a decrease in GLUT4 levels in most insulin-sensitive tissues and that in BAT, this occurs at an early age.

Cyclic AMP acutely stimulates translocation of the major insulin-regulatable glucose transporter GLUT4.

Facilitated glucose transport across plasma membranes is mediated by a family of transporters (GLUT1-GLUT5) that have different tissue distributions and Km values for transport. It has been shown that insulin stimulates glucose transport in fat and muscle tissues by causing the redistribution of one of these proteins (GLUT4) from inside the cell to the plasma membrane. Previous studies have shown that agents that change cAMP levels are able to modulate glucose transport in fat cells. The aim of this study was to investigate the mechanisms responsible for modulation of glucose transport by cAMP. 2-Deoxyglucose transport and insulin-regulatable glucose transporter (GLUT4) immunoreactivity in plasma and low density microsomal membranes were measured in adipocytes incubated for 30 min with insulin or dibutyryl-cAMP (Bt2cAMP). Low concentrations of Bt2cAMP (10 microM) increased 2-deoxyglucose uptake by translocating GLUT4 from low density microsomal membranes to the plasma membranes. Bt2cAMP at 1000 microM inhibited glucose transport below basal but further increased translocation of GLUT4. The effect of Bt2cAMP on translocation was additive to that of 7 nM insulin. We conclude that in rat adipocytes, Bt2cAMP acutely translocates GLUT4 but inhibits its activity to transport glucose.

Patterns of Schistosoma haematobium egg distribution in the human lower urinary tract. III. Cancerous lower urinary tracts.

The distribution of S. haematobium eggs in urinary bladders containing tumors and removed at surgery has been studied; the majority of these tumors are well differentiated squamous cell carcinomas. The same three anatomic patterns of egg accumulation described in part I of this series (noncancerous lower urinary tracts) were found in these cancerous bladders, but, in addition, most of the tumors were surrounded by a collar of heavy S. haematobium egg deposition. The egg burdens in these collars were, on the average, twice the average egg burden in the remainder of the urinary bladder. These collars do not seem to be artifacts created by growth of the tumor and subsequent displacement of the adjacent normal tissue, creating a region of heavy egg concentrations; rather, these heavy S. haematobium egg concentrations seem to act as promoters of urothelial carcinogenesis.

Schistosomal polyposis of the urinary bladder.

Anatomic, clinical, and digestion analyses were done on 18 human urinary bladder polyps from patients with Schistosoma haematobium infections. Variations in histologic pattern conformed to stages in progression of the disease; most were from active cases with significant egg burdens. The data suggest that polypoid lesions of active schistosomiasis may persist as polyps in the inactive stage if antecedent active infection was heavy.

Studies on schistosomal rectal and colonic polyposis.

Anatomic and digestion studies were done on rectal and colonic schistosomal polyps from 30 patients. Results indicate that schistosomal colonic polyposis is principally due to high, localized egg burdens of Schistosoma mansoni or S. haematobium resulting in damage to the muscularis mucosa of the colon. Furthermore, atypically focal oviposition by S. mansoni is probably more important in genesis of rectocolonic polyposis than is schistosomiasis haematobium.

Schistosomal ulceration of the urinary bladder.

Clinical, anatomic and digestion studies were done in 91 surgically treated cases of bladder ulceration in Egyptian patients with urinary schistosomiasis. Most patients were rural male farmers; their mean age was 29 years. Symptoms were similar to uncomplicated urinary schistosomiasis except for suprapubic or perineal pain. Two clinicopathologic entities were noted: 1) sloughing of polypoid patches in early active disease; and 2) chronic schistosomal ulceration of the bladder occurring at sites of very heavy Schistosoma haematobium egg burdens. The gross appearance, location, size and shape are described. The cost of treatment and duration of hospitalization are noted.

Surgical pathology of schistosomal obstructive uropathy: a clinicopathologic correlation.

Schistosomal obstructive uropathy was studied by clinical, laboratory epidemiologic and pathologic analysis in 155 Egyptian patients treated surgically. Most patients were men; rural farmers or laborers. All had severe urinary schistosomiasis with heavy burdens of Schistosoma haematobium eggs in their urinary tracts. Schistosomal incomplete ureteral stenosis and schistosomal stenosis with ureterolithiasis were the most important obstructive lesions; these lesions were symmetrical and most frequent in the interstitial ureters decreasing proximally. The pathogenesis of these lesions is dependent upon focal destruction of ureteral muscle. The ureteral lesions proximal and consequent to schistosomal obstructive lesions are hydroureters resulting from active dilatation (due to increased hydrostatic pressure consequent to obstruction) and passive dilatation (due to loss of circular muscle action in sites of oviposition in the proximal ureter). Various combinations of these lesions with superimposed effects of bacterial infection and ureterolithiasis produce the spectrum of ureteral lesions attributable to urinary schistosomiasis.