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The presence of carbonic anhydrase (type V) was recently documented in rat and mouse pancreatic islet [3-cells by immunostaining and Western blotting. In the present study, the activity of carbonic anhydrase was measured in rat islet homogenates and shown to be about four times lower than in rat parotid cells. The pattern for the inhibitory action of acetazolamide on carbonic anhydrase activity also differed in islet and parotid cell homogenates, suggesting the presence of different isoenzymes. Na[N.sub.3] inhibited carbonic anhydrase activity in islet homogenates and both D-[U-[sup.14]C]glucose oxidation and glucose-stimulated insulin secretion. Acetazolamide (0.3-10.0 mM) also decreased glucose-induced insulin output but failed to affect adversely D-[U-[sup.14]C]glucose oxidation, although it inhibited the conversion of D-[5-[sup.3]H]glucose to [[sup.3]H]OH and that of D-[U-[sup.14]C]glucose to acidic metabolites. Hydrochlorothiazide (3.0-10.0 mM), which also caused a concentration-related inhibition of the secretory response, like acetazolamide (5.0-10.0 mM), decreased [H.sup.14]C[O.sup.-.sub.3] production from D-[U-[sup.14]C]glucose (16.7 mM). Acetazolamide (5.0 mM) did not affect the activity of volume-sensitive anion channels in [beta]-cells but lowered intracellular pH and adversely affected both the bioelectrical response to D-glucose and its effect on the cytosolic concentration of [Ca.sup.2+] in these cells. The lowering of cellular pH by acetazolamide, which could well be due to inhibition of carbonic anhydrase, might in turn account for inhibition of glycolysis. The perturbation of stimulus-secretion coupling in the [beta]-cells exposed to acetazolamide may thus involve impaired circulation in the pyruvate-malate shuttle, altered mitochondrial [Ca.sup.2+] accumulation, and perturbation of [Cl.sup.-] fluxes, resulting in both decreased bioelectrical activity and insulin release. acetazolamide; D-glucose metabolism; insulin secretion; bioelectrical activity; bicarbonate production doi: 10.1152/ajpendo.00631.2006

Abstract Background Women with rheumatoid arthritis (RA) have increased morbidity and mortality due to coronary heart disease. Chronic systemic inflammation is known to accelerate atherosclerosis and increase arterial stiffness in patients, but other mechanisms may also be involved. Biomarkers of oxidant stress, inflammation, insulinaemia and endothelial dysfunction were measured in blood and urine from 46 RA patients and 48 age-matched controls. Plaque formation and intima-medial thickness (IMT) were measured using B-mode carotid Doppler scan. Findings The prevalence of plaque was increased (p = 0.042) in RA patients between 50–59 years old compared to the same age group in controls. 8-isoprostane (p = 0.004), C-reactive protein (p < 0.001), interleukin-6 (p < 0.001), insulin (p = 0.035), adiponectin (p = 0.012), vascular cell adhesion molecule (VCAM) (p = 0.029) and E-selectin (p < 0.001) were all increased while selenium (p = 0.003) and LDL-cholesterol (p = 0.025) were both decreased in all RA patients. 8-isoprostane correlated with 10 year cardiac risk (r = 0.55, p < 0.001), VCAM with IMT (r = 0.37, p = 0.012) and E-selectin with rheumatoid factor titre (r = 0.43, p = 0.003) in RA patients. In the control group, age, carotid IMT, VCAM, systolic blood pressure and smoking status were all associated with plaque development whereas in RA patients only age was associated with plaque. Conclusion The burden of atherosclerosis is particularly increased in middle-aged women with RA. Patients with RA have increased levels of oxidant stress, inflammation, insulin and soluble adhesion molecules. As the association between classical risk factors was much weaker in RA patients compared to controls, these additional factors may be more important in the accelerated development of atheroma in RA.

Abstract The use of antipsychotic drugs is known to be associated with a number of adverse metabolic side effects, including diabetes mellitus. These side effects could be, at least in [...]

Background/aims: Pancreatic β-cell function is influenced by changes in cell volume. Such volume changes depend on water permeability of the plasma membrane, conferred in part by aquaporins. Islet cells express aquaporin 7 (AQP7), which is permeable to urea and glycerol in addition to water. We therefore investigated the effects of glycerol and urea on rat pancreatic β-cell function. Methods: Electrical activity and whole-cell current were studied using the perforated patch technique. Cell volume was measured by video-imaging and insulin release by radioimmunoassay. Aquaporin 7 expression was studied by RT-PCR, Western blot and double fluorescent immunolabelling. Results: The isosmotic addition of glycerol and urea resulted in depolarization of the plasma membrane and electrical activity, accompanied by β-cell swelling, activation of the volume-regulated anion channel (VRAC) and insulin release. However, the effects of glycerol, in contrast to urea, persisted throughout exposure to the osmolyte. Glycerol also caused β-cell activation when added hyperosmotically. A non-metabolizable glycerol analogue had comparable effects to urea on β-cells. The expression of AQP7 was demonstrated in rat β-cells. Conclusion: Glycerol and urea can activate β-cells via their rapid uptake across the β-cell plasma membrane, possibly via AQP7. This results in cell swelling, VRAC activation, electrical activity and insulin release. Glycerol appears to exert an additional effect, possibly related to its intracellular metabolism. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Medroxyprogesterone (MP) was used as the progestogen in randomized clinical trials of postmenopausal hormone replacement on cardiovascular risk. To attempt to understand the lack of benefit in these trials, we have examined the effects of MP and two other progestogens, the less androgenic desogestrel (DG) and the more androgenic norethisterone (NE), on cardiovascular risk factors against a background of oestrogen therapy.Thirty-four women were treated with conjugated equine oestrogens (CEE) 0·625 mg daily alone for 12 weeks, followed in random order by each of the three progestogens (DG 75 µg, MP 10 mg and NE 1 mg daily) given sequentially for three 12-week cycles while maintaining the same CEE treatment. We measured serum lipoproteins, paraoxonase activity, C-reactive protein (CRP), fibrinogen, fasting glucose and insulin levels at baseline, at the end of the oestrogen-only phase and at the end of each of the combined oestrogen and progestogen phases.The addition of progestogens to CEE maintained the oestrogen-induced reduction in apolipoprotein B (apo B) and lipoprotein (a)[Lp(a)], and further lowered total cholesterol (P < 0·01) and fibrinogen (P < 0·001). CEE raised serum triglyceride (P < 0·001) and CRP (P < 0·01) concentrations, which reverted towards pre-oestrogen levels with progestogens. Progestogens significantly reduced high density lipoprotein (HDL) cholesterol (P < 0·05). NE was associated with the greatest reduction in HDL cholesterol and apo A1, but was most effective in preserving paraoxonase activity and reducing the potentially unfavourable oestrogen-induced increases in triglycerides and CRP.Preconceptions that more androgenic progestogens necessarily have more unfavourable effects on cardiovascular risk factors may require revision. [ABSTRACT FROM AUTHOR]

Objective: Women with systemic lupus erythematosus (SLE) have increased risk of coronary heart disease (CHD) that is not fully explained by the classic CHD risk factors. Insulin resistance is an established risk factor for CHD in the general population. We compared insulin secretion and sensitivity in patients with SLE and healthy controls, and assessed the prevalence of the metabolic syndrome in women with SLE and its relation to circulating oxidized low density lipoprotein (ox-LDL)., Methods: Fasting insulin, glucose, and lipid profiles were measured in nondiabetic women with SLE (>or= 4 revised 1997 criteria) not undergoing antimalarial therapy (n = 44), and in age matched controls recruited from the hospital staff and the local community (n = 45). Using the Homeostatic Model Assessment equations, insulin sensitivity (HOMA-S) and pancreatic beta cell function (HOMA-B) were calculated from fasting insulin and glucose. The metabolic syndrome, defined according to the Adult Treatment Panel (ATP III) criteria, was determined in a consecutive series of 61 women with SLE., Results: Patients with SLE had significantly higher fasting insulin [median (range) 10 (2.8-38) vs 6.6 (3.1-26) mU/l; p < 0.01], higher pancreatic beta cell function (HOMA-B) [165 (54-1567) vs 111 (28-653); p < 0.01], and lower insulin sensitivity (HOMA-S) [0.46 (0.09-1.9) vs 0.73 (0.16-1.3); p < 0.01]. SLE patients also had significantly higher triglycerides (p < 0.01) and lower high density lipoprotein cholesterol (p < 0.01) than controls. HOMA-S did not correlate with disease activity or steroid therapy, but was associated with components of the insulin resistance syndrome. HOMA-S showed a significant negative correlation with levels of ox-LDL in patients, but not in controls. Eleven (18%) patients had the metabolic syndrome. Again, this was not related to current steroid therapy. SLE patients with the metabolic syndrome had no difference in LDL, but had significantly higher levels of ox-LDL., Conclusion: Nondiabetic patients with SLE have evidence of significant decrease in sensitivity to insulin, and overall this population has a high prevalence of the metabolic syndrome (18%). Insulin resistance in the context of SLE was not strongly related to current or recent steroid therapy; it was, however, associated with higher levels of ox-LDL. Insulin resistance may therefore represent an additional CHD risk factor in patients with SLE.

The use of antipsychotic drugs is known to be associated with a number of adverse metabolic side effects, including diabetes mellitus. These side effects could be, at least in part, the result of impaired islet cell function, although the underlying mechanisms are unknown. We have studied the effects of the atypical antipsychotic clozapine and of the conventional drug haloperidol on electrical and secretory activity in rat pancreatic beta-cells. At a low glucose concentration (4mM), clozapine (5microM) had little or no effect on membrane potential. However, at a stimulatory glucose concentration (16mM), clozapine was found to hyperpolarize the cell membrane potential, resulting in a complete inhibition of electrical activity. In contrast, haloperidol (5microM) was found to cause a marked depolarization of the membrane potential in the presence of both low and high concentrations of glucose. Clozapine and haloperidol were found, respectively, to increase and decrease-cell input conductance, an index of K(+) permeability. Single channel recordings indicated that changes in K(ATP) channel activity contributed towards these effects. Neither clozapine nor haloperidol affected basal insulin release, although clozapine inhibited glucose-induced insulin release. It is concluded that clozapine and haloperidol exert contrasting actions on electrical activity in rat pancreatic -cells as a result of opposing effects on K(+) permeability. These findings may relate to the increased incidence of diabetes associated with clozapine treatment.

We have investigated the effects of the ethacrynic acid derivative 4-(2-butyl-6,7-dichloro-2-cyclopentyl-indan-1-on-5-yl) oxobutyric acid (DCPIB), an inhibitor of the volume-sensitive anion channel (VSAC), on electrical activity and insulin secretion in rat pancreatic beta-cells. DCPIB inhibited whole-cell VSAC currents in beta-cells with IC50 values of 2.2 and 1.7 microM for inhibition of outward and inward currents, respectively. DCPIB also inhibited the VSAC at the single channel level in cells activated by glucose. In intact cells, DCPIB caused a net increase in beta-cell input conductance and evoked an outward current that was sensitive to inhibition by tolbutamide, suggesting KATP channel activation. However, no KATP channel activation was evident under conventional whole-cell conditions, suggesting that the drug might activate the channel in intact cells via an indirect mechanism, possibly involving nutrient metabolism. DCPIB suppressed glucose-induced electrical activity in beta-cells, hyperpolarised the cell membrane potential at a substimulatory glucose concentration and prevented depolarisation when the glucose concentration was raised to stimulatory levels. The suppression of electrical activity by DCPIB was associated with a marked inhibition of glucose-stimulated insulin release from intact islets. It is concluded that DCPIB inhibits electrical and secretory activity in the beta-cell as a combined result of a reciprocal inhibition of VSAC and activation of KATP channel activities, thus producing a marked hyperpolarisation of the beta-cell membrane potential.