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Biomedical subjects

G Pozza

Publications and source records attributed to G Pozza.

At least 19 recordsLinked to original sources
PubMed1998

Independence of dimethylamiloride-sensitive Li+ efflux pathways and Na+-Li+ countertransport in human erythrocytes.

The in vivo function of the erythrocyte Na+-Li+ countertransport (SLC) is unknown. Whether SLC may reflect an operational mode of the widespread Na+-H+ exchanger (NHE) or may otherwise be expression of an independent membrane transport, remains presently unclear. We explored the presence of 5-(N,N-dimethyl)-amiloride (DMA)-sensitive Li+ pathways in human erythrocytes where the activity of the Na+ pump, Na+-K+ cotransport and anion exchange were suitably inhibited. A total of 0.02 mM DMA had no effect on SLC as expected, but gave a significant inhibition of Li+ efflux into both Na+ and Na+-free media. This DMA-sensitive Li+ pathway, but not SLC, was significantly enhanced by hyperosmolar cell shrinkage, which is a characteristic feature of NHE. In conclusion, DMA-sensitive Li+ pathways, possibly mediated by NHE, are present in erythrocytes and coexist with the DMA-insensitive, SLC. This finding supports the notion that SLC is independent of amiloride-sensitive NHE.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1998

Improvement of glucose/insulin metabolism reduces hypertension in insulin-dependent diabetes mellitus recipients of kidney-pancreas transplantation.

There is increasing evidence that metabolic disorders are common in patients with hypertension. To evaluate the relationship between glucose/insulin metabolism and hypertension in diabetes, 61 hypertensive uremic insulin-dependent diabetes mellitus patients who were recipients of kidney or pancreas/kidney transplants were studied through a 1-year follow-up. Twenty of them received a kidney (K) transplant alone, 13 received a kidney and segmental pancreas (KSP), and 28 received a kidney and whole pancreas (KWP) with duodenocystostomy. All subjects received the same immunosuppressive treatment including steroids, azathioprine, and cyclosporine. The three groups of patients were comparable for biochemical parameters, clinical characteristic, cyclosporine levels, and renal function (creatinine < 2 mg/dl). The association between hypertension and type of transplant was evaluated according a global chi-square test, then the results were broken down into two components to test for differences in hypertension between KP versus K and KWP versus KSP groups. The improvement of hypertension rate was statistically associated with KP transplant the first week after surgery, at discharge, and 1 year after transplantation (hypertension% at 1 week: KWP = 75, KSP = 23 vs. K = 70, P = 0.004; at discharge: KWP = 39, KSP = 31 vs. K = 75, P = 0.017; at 1 yr: KWP = 44, KSP = 54 vs. K = 85, P = 0.02). One year after graft fasting, free immunoreactive insulin as well as glycosylated hemoglobin and glucose levels were statistically lower in the KP groups than in the K-alone recipients. The improvement of hypertension observed in KP recipients suggests a key role of glucose and insulin metabolism on pathogenesis of diabetic hypertension.

Adult↗
PubMed1998

Myocardial metabolism studied during warm blood antero-retrograde reperfusion in ischaemic human hearts.

We propose modified warm blood antegrade-retrograde reperfusion (WBARR) of arrested hearts as a metabolic model with which to study substrate exchange and energy metabolism during the recovery phase after 90 min of ischaemia in man. Eleven anaesthetized patients undergoing aorto-coronary bypass were studied during WBARR. The protocol was designed as follows: period 1, a warm blood reperfusion with potassium (3 min); period 2, a warm blood reperfusion without potassium (2 min). The perfusion flow rate averaged 250+/-2 ml/min at the beginning of period 1 and 218+/-19 ml/min at the beginning and at the end of period 2; the perfusion was performed antegradely and retrogradely in the arrested hearts. Samples were simultaneously taken from the coronary venous sinus (CVS) and from the aortic root needle (AR). At the beginning of WBARR lactate release was 85+/-44 micromol/min and at the end it had significantly decreased to 21+/-99 micromol/min (P<0.03). Simultaneously, non-esterified fatty acids (NEFA) and beta-hydroxy-butyrate were initially released (71+/-61 and 22+/-66 micromol/min, respectively), while at the end of the WBARR there was an uptake of both NEFA (20+/-22 micromol/min; P<0.01) and beta-hydroxy-butyrate (12+/-35 micromol/min; P=0.290). Alanine, glycerol and branched chain amino acid balance across the heart did not significantly change. In summary after 90 min of ischaemia the heart energy metabolism is mainly anaerobic and based on glucose consumption, with lactate, NEFA and amino acids, which are mainly released. After 5 min of WBARR (recovery from ischaemia), lactate release is significantly reduced and NEFA becomes the energy supply of the heart. In conclusion, (1) WBARR is a valuable method with which to study myocardial metabolism in anaesthetized humans and may be combined with the use of tracers; (2) the study of myocardial metabolism in arrested hearts eliminates the imprecisions arising from the noncontinuous coronary blood flow; (3) NEFA become an important source of energy utilized by human hearts in the recovery phase from ischaemia.

Adult↗
PubMed1998

Smaller, denser LDL particles are not a risk factor for cardiovascular disease in healthy nonagenarian women of the Cremona Population Study.

We evaluated LDL particle size and its relation with other established risk factors for cardiovascular disease in a group of healthy nonagenarian ( > or = 90 years) women participating in the Cremona Population Study. A group of younger healthy postmenopausal women (45-75 years) was used as control group. Nonagenarian women had significantly lower body mass index, systolic and diastolic blood pressure, and fasting insulin concentrations. Plasma total, LDL and HDL cholesterol, apo AI and apo B concentrations, and LpAI and LpAI:AII particles were significantly lower in the nonagenarian group as well. LDL particle size (262.7+/-0.9 vs. 270.1+/-1.1 A) was also lower in the nonagenarian group. The presence of the E4 isoform of apo E in the nonagenarian group resulted in significantly higher levels of plasma apo AI and LpAI:AII particles, and a trend toward larger LDL particles, and a lower diastolic blood pressure. In conclusion, smaller and denser LDL particles might not represent an important risk factor for cardiovascular disease in healthy nonagenarian women of the Cremona Population Study, characterised by a reduced number of LDL particles and other protective factors, like low systolic and diastolic blood pressure, body mass index, and plasma insulin levels.

Aged↗
PubMed1998

Imaging of the buffering effect of insulin antibodies in the autoimmune hypoglycemic syndrome.

Insulin autoimmune hypoglycemia is characterized by recurrent hypoglycemia and high levels of immunoreactive insulin in the presence of insulin autoantibodies. The mechanisms inducing hypoglycemia are largely unknown. An [123I]insulin scintigraphic scanning was performed to directly demonstrate the effect of antibodies on insulin biodistribution in one patient with this syndrome both before and after treatment. The patient had insulin autoantibodies IgG3 lambda, which had a single site dissociation constant (Kd = 10(-7) mol/L, by Scatchard analysis), a very fast dissociation rate of immune complexes, and a very rapid association of [125I]insulin. Insulin receptors on red blood cells were down-regulated. The [123I]insulin scintigraphic study imaged the buffering effect of antibodies on insulin bioavailability. [123I]Insulin was not removed from the blood, and no liver or kidney uptake of the hormone occurred. The frequency and severity of hypoglycemic episodes required treatment. Insulin antibody levels decreased and [123I]insulin biodistribution improved after treatment with plasmapheresis and prednisone. Improved hormone bioavailability was further evidenced by the reduction in the hypoglycemic delay after i.v. insulin from 90 min before any treatment to 60 min after plasmapheresis and 30 min after steroid administration. Glucose tolerance was normal after treatment. Plasmapheresis followed by steroid treatment can lower the insulin antibody concentration, abolish severe hypoglycemia, and improve insulin biodistribution and glucose tolerance in insulin autoimmune hypoglycemia.

Autoantibodies↗
PubMed1998

Long-term in vitro exposure to high glucose increases proinsulin-like-molecules release by isolated human islets.

The aim of this study was to determine the effect of long-term in vitro exposure to high glucose on the release and content of proinsulin and insulin in human islets. After 48 h culture in CMRL medium at 5.5 mM (control islets) and 16.7 mM glucose (experimental islets), islets were perifused and acutely stimulated with 16.7 mM glucose, followed by 3.3 mM glucose. Compared with control islets, experimental islets showed a higher basal release of true insulin and proinsulin-like-molecules (PLM), with no increase of true insulin and PLM release in response to 16.7 mM glucose, and a paradoxical true insulin release in response to 3.3 mM glucose; the PLM/total insulin ratio increased significantly after 16.7 mM glucose. Moreover these islets showed a decreased true insulin content and an increased PLM/total insulin ratio. Quantitative ultrastructural analysis of granules, supported by double gold immunostaining with monoclonal antibodies against proinsulin and insulin, showed an increased proinsulin to insulin ratio in beta-cells from experimental islets. These data support in vitro what was recently shown in vivo, and further confirm that culture in high glucose is a useful tool to mimic the effect of in vivo chronic hyperglycemia on human beta-cell function.

Adult↗
PubMed1997

Islet transplantation in IDDM patients.

This single-centre study investigated parameters that positively correlated with the success rate after islet allotransplantation in insulin-dependent diabetic (IDDM) patients. Twenty-one intrahepatic, fresh islet transplantations were performed in 20 IDDM patients (one patient had two transplants), after or simultaneous with kidney transplantation. The correlation between number and purity of transplanted islets and final outcome was investigated. One patient died of a cardiac arrest several hours after islet transplantation; this patient was not included in the follow-up analysis. Three patients (15%) experienced acute, irreversible, early failure of islet function, which was considered as a 'presumed rejection'. Nine patients (45%) achieved either complete insulin-independence (seven cases) or a reduction (> 50%) of exogenous insulin requirement (two cases), with sustained serum C-peptide secretion (0.89 +/- 0.04 nmol/l; duration: 21 +/- 7 months, range 2-58 months). Liver biopsy, performed 3 years after transplantation in one successful case, showed normal islets within the hepatic parenchyma. Eight cases (40%) did not show any metabolic effect of islet transplantation, with low serum C-peptide levels ('presumed function exhaustion'). Metabolic investigations performed in successful cases showed an early phase of insulin release after arginine, mild and reversible postprandial hyperglycaemia and normal HbA1c levels. Success of islet transplantation positively correlates with the number (p < 0.05) of the transplanted islets. Islet transplantation is a safe procedure, with 45% success rate, in terms of insulin-independence or relevant reductions of exogenous insulin requirement, although success can be transient.

Adult↗
PubMed1997

Amelioration of nerve conduction velocity following simultaneous kidney/pancreas transplantation is due to the glycaemic control provided by the pancreas.

Diabetic polyneuropathy is a common, disabling chronic complication of diabetes mellitus. Previous studies have suggested that combined pancreas-kidney transplantation can ameliorate nerve conduction. The relative contribution of the correction of hyperglycaemia and uraemia on nerve function is still a matter of debate. Nerve conduction velocity (NCV) was assessed before and after simultaneous pancreas and kidney transplantation, and before and after pancreas graft failure in five insulin-dependent diabetic (IDDM) patients affected by severe diabetic polyneuropathy. Sensory and motor NCV were recorded in five nerves and expressed as a cumulative index for each patient. Metabolic control was evaluated by fasting blood glucose and glycosylated haemoglobin levels. NCV index was below normal values before transplant: -3.8 +/- 0.7 (normal value: 0.89), improved 1 and 2 years after transplant: -3.1 +/- 1.3 and -2.6 +/- 0.9 (p = 0.0019), stabilised until pancreas failure and deteriorated to pre-transplant values 2 years after pancreas graft failure: -3.6 +/- 1.0 (p = 0.034). Fasting blood glucose levels worsened after pancreas graft failure. HbA1c levels, in the normal range during functioning pancreas graft (6.6 +/- 0.6%), deteriorated after its failure (8.0 +/- 0.6%, p = 0.04). Kidney function was preserved. These data support a positive effect of pancreas transplantation per se on NCV in IDDM subjects with diabetic polyneuropathy, thus demonstrating that metabolic control provided by a self-regulated source of insulin not only halts but also ameliorates nerve function, even if polyneuropathy is advanced.

Adult↗
PubMed1997

Glibenclamide: an old drug with a novel mechanism of action?

This review is meant to give to the readers an overview of the pharmacokinetics, pharmacodynamics, mechanism(s) of action and therapeutical indications of the sulfonylurea compound glibenclamide, which is a cardinal drug in the treatment of type 2 diabetes mellitus. Data produced in our own laboratory over the past 15 years will be presented, along with reference to the main literature in the field. As pharmacokinetics is concerned, special emphasis will be placed on the detrimental effect of hyperglycemia in the intestinal absorption of this class of drugs. Both beta-cell and extrapancreatic effects of glibenclamide will be highlighted. The mechanism of action of the drug consists in the inhibition of the ATP-sensitive K+ channels, which leads to depolarization of the cells and insulin secretion. Based on the same mechanism are also the extrapancreatic action of the drug at the liver, skeletal muscle, heart muscle and smooth muscle sites. The newly discovered possible physiological actions of the C-peptide molecule [suggesting a stimulatory effect of C-peptide on the Na+, K+ (ATPase) pump and on diabetic complications], cast a new light on all therapeutic approaches (like sulfonylurea class of compounds and whole pancreas or islet of Langerhans transplantation), which induce/replace both insulin and C-peptide secretion.

Adipose Tissue↗
PubMed1997

Glucose turnover and insulin clearance after growth hormone treatment in girls with Turner's syndrome.

The study was performed to elucidate, by means of a euglycemic-hyperinsulinemic clamp, whether insulin sensitivity, lipid levels, posthepatic insulin delivery, and insulin clearance are impaired in girls with Turner's syndrome in the absence of previous treatment (T0) and after 6 (T6) and 12 (T12) months of growth hormone (GH) therapy (GHT). The study was performed in six girls with Turner's syndrome and eight healthy girls. We found that previously untreated girls with Turner's syndrome had a normal insulin activity on glucose metabolism. GHT progressively and significantly decreased hepatic insulin sensitivity. In fact, residual hepatic glucose release (HGR), which was 19.6 +/- 4.7 mg/m2. min at T0, doubled at T6 (39.3 +/- 5.1 mg/m2.min) and showed a threefold increase at T12 (68.7 +/- 10.8 mg/m2.min, P < .05 v T0). On the contrary, GHT did not show an appreciable influence on peripheral insulin sensitivity. Insulin clearance was higher in girls with Turner's syndrome than in control girls at T0 (30.0 +/- 2.8 v 20.2 +/- 1.1 mL.kg-1.min-1). It decreased to normal values at T6 (18.2 +/- 2.0 mL.kg-1.min-1, P < .05 v T0) and remained at normal levels at T12 (23.8 +/- 2.9 mL.kg-1. min-1). The posthepatic insulin delivery rate significantly increased at T6 and T12, suggesting increased insulin secretion. In conclusion, we found that insulin-stimulated glucose turnover was normal in girls with Turner's syndrome before therapy. One year of GHT was successful in stimulating the growth rate, but significantly decreased the insulin suppressibility on HGR with only slight changes in peripheral insulin sensitivity. In addition, an increase in the insulin posthepatic delivery rate and a normalization of insulin clearance were present, probably to counteract hepatic insulin resistance.

Adolescent↗
PubMed1997

Modes of operation of an electroneutral Na+/Li+ countertransport in human skin fibroblasts.

An elevated activity of erythrocyte Na+/Li+ countertransport (SLC) is an intermediate phenotype of human essential hypertension, but cells other than erythrocytes have not been studied. Therefore, we have examined several transport modes of Na+/Li+ exchange in human skin fibroblasts. External Na+-stimulated Li+ efflux was 152 +/- 31 (SE) nmol x mg protein(-1) x min(-1) (n = 8). At intracellular pH 7.3, intracellular Na+-stimulated Li+ influx, intracellular Li+-stimulated Na+ influx, and external Li+-stimulated Na+ efflux were very similar, indicating the presence of a tightly coupled 1:1 SLC. This pathway was not affected by 5-(N,N-dimethyl)-amiloride and changes in the membrane potential, but phloretin and intracellular acidification (intracellular pH 6.8) were markedly inhibitory. Kinetic analyses of the external Na+ site also compared with SLC, although the internal site appeared to show a low affinity for Li+. We conclude that an SLC pathway similar to that in human erythrocytes is expressed in human skin fibroblasts.

Antiporters↗