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Biomedical subjects

M Scavini

Publications and source records attributed to M Scavini.

At least 19 recordsLinked to original sources
PubMed2001

Insulin receptor antibodies inhibit insulin uptake by the liver: in vivo 123I-insulin scintigraphic scanning and in vitro characterization in autoimmune hypoglycemia.

BACKGROUND: Insulin receptor antibodies can induce severe hypoglycemia or insulin resistance in rare autoimmune syndromes. In vitro properties of these antibodies occasionally explain the clinical features of the syndrome, but direct evidence of their in vivo activity is poor. We studied a 58-year-old male with rheumatoid arthritis who presented with hypoglycemic coma. METHODS AND RESULTS: Antibodies were detected by inhibition of 125I-insulin binding to human insulin receptor-3T3 cells by the patient's serum. By immunofluorescence, they were immunoglobulin G of all four subclasses, immunoprecipitated insulin receptors from biotin-labeled cells, and triggered phosphorylation of the beta subunit of the insulin receptor. Insulin binding on the patient's red blood cells was markedly reduced. A biodistribution study after intravenous 123I-Tyr A14 insulin showed a marked inhibition of tracer uptake by the liver, reaching 10% of the injected dose (controls, mean +/- SD, 21.1 +/- 1.7%; n = 10). Time activity curves generated on the liver and on the heart were parallel, with a T1/2 of 11.5 minutes for both, suggesting that no specific uptake occurred in the liver, where tracer activity represented only the blood pool. Clearance of insulin from the blood was indeed slower than in controls and mainly occurred through the kidneys. Analysis of plasma 123I-insulin immunoreactivity and trichloroacetic acid precipitate showed that insulin degradation did not occur as in normal controls. CONCLUSIONS: In this patient with hypoglycemic syndrome, insulin receptor antibodies with in vitro insulin-like activity are capable of blocking in vivo the access of insulin to the liver receptor compartment, as directly demonstrated by the markedly altered biodistribution of intravenously injected 123I-insulin.

3T3 Cells↗
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

Z-2 microsatellite allele is linked to increased expression of the aldose reductase gene in diabetic nephropathy.

Epidemiological studies support the hypothesis that genetic factors modulate the risk for diabetic nephropathy (DN). Aldose reductase (ALDR1), the rate-limiting enzyme in the polyol pathway, is a potential candidate gene. The present study explores the hypothesis that polymorphisms of the (A-C)n dinucleotide repeat sequence, located 2.1 kb upstream of the transcription start site, modulate ALDR1 gene expression and the risk for DN. We conducted studies at two different institutions, the University of New Mexico Health Sciences Center (UNMHSC), and the Istituto Scientifico H San Raffaele (HSR). There were four groups of volunteers at UNMHSC: group I, normal subjects; group II, patients with insulin-dependent diabetes mellitus (IDDM) without DN; group III, IDDM with DN; and group IV, nondiabetics with kidney disease. At HSR we studied volunteers in groups I, II, and III. ALDR1 genotype was assessed by PCR and fluorescent sequencing of the (A-C)n repeat locus, and ALDR1 messenger ribonucleic acid (mRNA) was measured by ribonuclease protection assay in peripheral blood mononuclear cells. At UNMHSC we identified 10 alleles ranging from Z-10 to Z+8. The prevalence of the Z-2 allele among IDDM patients was increased in those with DN. Sixty percent of group III and 22% of group II were homozygous for Z-2. Moreover, 90% and 67% of groups III and II, respectively, had 1 or more copy of Z-2. In contrast, among nondiabetics, 19% of group IV and 3% of group I were homozygous for Z-2, and 69% and 32%, respectively, had 1 copy or more of Z-2. Among diabetics, homozygosity for the Z-2 allele was associated with renal disease [odds ratio (OR), 5.25; 95% confidence interval, 1.71-17.98; P = 0.005]. ALDR1 mRNA levels were higher in patients with DN (group III; 0.113 +/- 0.050) than in group I (0.068 +/- 0.025), group II (0.042 +/- 0.020), or group IV (0.015 +/- 0.011; P < 0.01). Among diabetics, ALDR1 mRNA levels were higher in Z-2 homozygotes (0.098 +/- 0.06) and Z-2 heterozygotes (0.080 +/- 0.04) than in patients with no Z-2 allele (0.043 +/- 0.02; P < 0.05). In contrast, among nondiabetics, ALDR1 mRNA levels in Z-2 homozygotes (0.034 +/- 0.04) and Z-2 heterozygotes (0.038 +/- 0.03) were similar to levels in patients without a Z-2 allele (0.047 +/- 0.03; P = NS). At HSR we identified eight alleles ranging from Z- 12 to Z+2. The prevalence of the Z-2 allele was higher in group III than in group II. In group III, 43% of the patients were homozygous for Z-2, and 81% had one copy or more of the Z-2 allele. In contrast, in group II, 4% were homozygous for Z-2, and 36% had one copy or more of the Z-2 allele. IDDM patients homozygous for Z-2 had an increased risk for DN compared with those lacking the Z-2 allele (OR, 18; 95% confidence interval, 2-159). IDDM patients who had one copy or more of Z-2 had increased risk (OR, 7.5; 95% confidence interval, 1.9-29.4) for DN compared with those without the Z-2 allele. These results support our hypothesis that environmental-genetic interactions modulate the risk for DN. Specifically, the Z 2 allele, in the presence of diabetes and/or hyperglycemia, is associated with increased ALDR1 expression. This interaction may explain the observed association between the Z-2 allele and DN.

Adult↗
PubMed1997

Long-term therapy of IDDM with an implantable insulin pump. The Implantable Insulin Pump Trial Study Group.

OBJECTIVE: To examine the long-term benefits and risks of treatment of IDDM with an implantable programmable insulin pump. RESEARCH DESIGN AND METHODS: Seventy-six patients with IDDM were studied at nine clinical centers. After 3-4 months of intensive subcutaneous therapy, the Infusaid Model 1000 pump was implanted, and insulin was delivered either intraperitoneally or intravenously for an average of 39.6 +/- 10 months (251 patient-years). Data was collected for glycemic control, lipid levels, weight gain, insulin requirements, adverse events, and quality of life. Sixty-three patients were also followed for 8.5 +/- 6.3 months (45 patient-years) after pump therapy was discontinued. RESULTS: Mean quarterly HbA1c fell with subcutaneous intensive therapy and remained stable on implantable pump therapy between 6.9 and 7.5%. Severe hypoglycemia was relatively rare, with only 4 episodes/100 patient-years of implantable pump therapy. This rate was significantly less than with subcutaneous intensive therapy before implantable pump initiation (33 episodes/100 patient-years) or after discontinuation of implantable pump therapy (36/100 patient-years) (P < 0.003). Weight did not increase significantly in the 1st year of therapy, but increased by 2.0 +/- 4.3 kg after 3 years of therapy. There were no significant differences in metabolic control or adverse events between intraperitoneal and intravenous insulin therapy except for minor differences in lipid levels and the more frequent development of catheter obstruction with intravenous delivery. Most pump slow-downs and catheter occlusions were corrected noninvasively. Quality of life, as measured by the Diabetes Control and Complications Trial instrument, showed high satisfaction and improved impact scores. CONCLUSIONS: Long-term implantable pump therapy maintained HbA1c in a range similar to intensive subcutaneous therapy, but with fewer episodes of severe hypoglycemia. Although pump and catheter occlusions remain a limitation, patient satisfaction with implantable pump therapy remains high.

Adult↗
PubMed1997

Catheter survival during long-term insulin therapy with an implanted programmable pump. The Implantable Insulin Pump Trial Study Group.

OBJECTIVE: To survey catheter complications and to analyze catheter survival during long-term intraperitoneal and intravenous insulin therapy with an implanted programmable pump with a sideport. RESEARCH DESIGN AND METHODS: Catheter occlusions were documented by measuring dynamic catheter resistance. Catheter migrations or breaks were demonstrated by X ray. When flushing the catheter with buffer solution through the sideport failed to clear the occlusion, catheters were replaced or laparoscopy was performed for the excision of fibrous tissue growth. Broken or migrated catheters were replaced. RESULTS: Occlusions were the most common catheter complications, and the majority of them (79% intraperitoneal and 84% intravenous) were cleared by flushing the catheter. Survival at 3 years was significantly higher for intraperitoneal catheters compared with intravenous catheters (60% intraperitoneal and 22% intravenous). CONCLUSIONS: Nonsurgical management of catheter occlusions contributed to extend catheter lifetime. Intraperitoneal catheters have a lower morbidity and a higher survival than intravenous catheters.

Catheters, Indwelling↗
PubMed1997

A method for assessing catheter patency in implanted pumps for long-term intraperitoneal insulin delivery.

Catheter complications are a common problem during long-term insulin therapy with implanted pumps. The purpose of this study was to test the feasibility of imaging intraperitoneal catheters with technetium (Tc) 99m in implantable devices for insulin delivery. Testing physical stability of an insulin/Tc 99 mixture did not show formation of insulin aggregates during a period up to 48 h on a rotating wheel. Five hundred microCurie (equal to 18 MBq) of Tc 99m were injected in the flush port of a pump for intraperitoneal insulin delivery implanted in patients with type I (insulin dependent) diabetes mellitus, and gamma camera images were obtained for 30 min. In patent catheters the tracer rapidly imaged the whole length of the catheter while in occluded catheters the tracer remained in the flush port, imaging only the portion of the catheter before the occlusion. In patent catheters in which insulin absorption was impaired, the tracer rapidly imaged the whole length of the catheter, but its removal from the peritoneum was delayed. Tc 99m imaging of intraperitoneal catheters for insulin delivery can be used to assess catheter patency and impaired delivery into the peritoneal cavity.

Catheterization↗
PubMed1996

Use of an integrated sideport for diagnosis and management of decreased flow rates in a programmable implanted insulin delivery system. Implantable Insulin Pump Trial Study Group.

The aim of this study was to develop procedures for the diagnosis and nonsurgical management of decreased insulin flow in an implantable programmable pump for long-term intraperitoneal or intravenous insulin delivery featuring a sideport. Patency of the catheter lumen was tested by measuring the time needed for sideport pressure to decrease by 50% after the injection of 0.1 ml of buffer solution. Pumping unit performances were assessed by measuring the volume of pump pulses after diverting the pump flow at the sideport. A catheter flush with buffer solution through the sideport was effective in clearing 79% of intraperitoneal and 84% of intravenous catheter occlusions. Washing the pumping unit with an alkaline solution after diverting pump flow at the sideport was effective in dissolving insulin aggregates inside the pumping unit and in restoring normal pump flow. These procedures were associated with a 1.3% rate of hypoglycemic episodes.

Buffers↗
PubMed1996

Insulin antibodies do not preclude optimization of metabolic control in women with IDDM during pregnancy.

OBJECTIVE: To evaluate whether the presence of insulin antibodies (IAs) may preclude the optimization of metabolic control during pregnancy and affect outcome in women with IDDM. RESEARCH DESIGN AND METHODS: IAs were measured by radiobinding assay in 44 women with IDDM referred to the Diabetes and Pregnancy Outpatients' Clinic during 46 pregnancies. Age, duration of IDDM, metabolic control (HbA1c, mean pre- and postprandial capillary blood glucose, frequency of hypo- or hyperglycemia), insulin requirement at 1st and 3rd trimester of pregnancy, BM1, and weight gain were recorded. Neonatal variables such as gestational age, weight, length, and the presence at birth of either hypoglycemia, hypocalcemia, or jaundice requiring phototherapy were also considered. RESULTS: IAs correlated positively with insulin requirement (P < 0.05) and negatively with HbA1c at term (P < 0.01). Patients with IA levels > or = 40% insulin binding (8 of 46) had a higher insulin requirement and lower preprandial capillary blood glucose at the beginning of pregnancy but not at term (P < 0.005), whereas they had lower HbA1c at term than did patients with low IA levels (P < 0.01). IA levels decreased slightly at term (P = 0.007). IA levels > or = 40% were not associated with a higher rate of hypo- or hyperglycemic episodes or with diabetic complications or thyreopathy. No correlation was found between 1A levels and any of the neonatal variables considered. CONCLUSIONS: The presence of IAs does not preclude optimization of metabolic control during pregnancy and is compatible with a favourable outcome.

Adult↗
PubMed1995

In vivo metabolic effects of insulin-like growth factor-I not mediated through the insulin receptor.

Patients with mutations affecting insulin receptor function may maintain some degree of metabolic control. The hypothesis has been put forth that in these patients, fuels may be metabolized through pathways (i.e. receptor activation) that become relevant in such abnormal conditions. The aim of our study was to evaluate the metabolic effects of insulin-like growth factor-I (IGF-I) in a 19-yr-old patient with homozygous mutation of the insulin receptor alpha-subunit. Her metabolic and hormonal features were marked hyperglycemia (11-33 mmol/L) and hyperinsulinemia (1000-2000 pmol/L); normal free fatty acids and lactate; low IGF-I; glycerol, alanine, and pyruvate below the normal range; and elevated beta-hydroxybutyrate. Unlike diabetic ketoacidosis, no triglyceride or protein breakdown was present, suggesting a compensatory mechanism, possibly sustained by the insulin concentration acting on IGF-I receptors. Subcutaneous administration of IGF-I (40, 80, and 120 micrograms/kg), although not affecting plasma glucose, resulted in a rapid decrease in free fatty acids and prevented the rise of beta-hydroxybutyrate levels compared to placebo. Therefore, IGF-I can exert direct metabolic effects in vivo, probably through activation of its own receptor, even at a concentration not affecting blood glucose levels. Furthermore, these findings are consistent with the hypothesis that IGF-I receptors may be activated by high insulin levels, providing lipid and protein regulation in patients with nonfunctional insulin receptors.

Adult↗
PubMed1995

Intraperitoneal insulin absorption after long-term intraperitoneal insulin therapy.

OBJECTIVE: To evaluate insulin absorption through the peritoneal membrane after long-term intraperitoneal insulin therapy using an implanted programmable device. RESEARCH DESIGN AND METHODS: Seven insulin-dependent diabetes mellitus (IDDM) patients implanted with a programmable pump were studied after 3 and 30 months of intraperitoneal insulin therapy. A 20-min square wave infusion of 15 IU of insulin was administered in the peritoneal space, and plasma glucose and plasma free insulin levels were monitored for 180 min. Hypoglycemia was prevented by intravenous glucose infusion. RESULTS: After 30 months of intraperitoneal insulin therapy, plasma free insulin profiles following the administration of insulin in the peritoneal space were similar to those observed at the beginning of this mode of therapy. CONCLUSIONS: In IDDM patients, intraperitoneal insulin absorption does not change after long-term intraperitoneal insulin therapy using an implanted device.

Adult↗
PubMed1993

Influence of meal ingestion on insulin profiles following intraperitoneal delivery.

This study evaluated the effect of meal ingestion on intraperitoneal insulin absorption in type I diabetic patients with an implanted pump for long-term intraperitoneal insulin delivery. On four separate occasions, patients (n = 7) were administered 15 IU insulin as a 20-minute square-wave infusion using their implanted device; hypoglycemia was prevented by intravenous infusion of 10% dextrose at a variable rate. Two studies were performed during fasting conditions (n = 2 fasting tests) and two studies after the administration of an 800-kcal standard meal (n = 2 postprandial tests). An insulin peak of 630 +/- 545.4 pmol/L (mean +/- SD) in fasting tests and 696 +/- 420.5 pmol/L in postprandial tests was reached in the peripheral circulation after 45 +/- 11.7 and 45 +/- 14.7 minutes, respectively, with no significant difference between the two experimental conditions. Areas under the insulin curves were not significantly different in fasting and postprandial tests (51,500 +/- 34,278 v 50,916 +/- 20,558 pmol/L.min-1, respectively; NS). In type I diabetic patients receiving long-term intraperitoneal insulin therapy, the increase in splanchnic blood flow following ingestion of a standard meal does not accelerate the appearance of insulin in the peripheral circulation.

Adult↗
PubMed1993

Peritoneal and subcutaneous absorption of insulin in type I diabetic subjects.

We and others have shown that in type I diabetes, ip insulin delivery results in lower free insulin levels than sc delivery. The aim of this study was to compare the rate of appearance of insulin in the peripheral circulation during ip and sc insulin administration in type I diabetes, in steady state and nonsteady state. To do this, we determined free insulin levels during ip or sc infusion as well as the impulse response of the insulin system after iv injection of a 6-nmol bolus of insulin. Twelve hours after a constant basal insulin infusion (5.5 +/- 1.4 nmol/h) was started, five C-peptide-negative type I diabetic subjects showed a lower systemic rate of appearance of insulin (expressed as a percentage of the administered dose) with ip than sc administration (27 +/- 6% vs. 40 +/- 10%; P < 0.001). In nonsteady state, when the infusion rate was increased from basal to 15 nmol/h (0-150 min) and subsequently to 42 nmol/h (150-300 min), the percent increase in insulin's systemic rate of appearance was higher with ip than sc infusion (P < 0.05 from 60-150 min; P < 0.01 from 150-300 min), indicating faster absorption. Thus, we conclude that insulin is more rapidly absorbed from the peritoneal cavity than from sc tissue. However, with ip administration, a sizable amount of insulin, once absorbed, is extracted before reaching the peripheral circulation, most likely by the liver. This is indirect evidence that ip insulin delivery results in a portal-peripheral insulin gradient in humans.

Adult↗
PubMed1992

Long-term implantation of a new implantable programmable insulin pump in two diabetic dogs.

A positive-pressure implantable programmable pump with an integrated sideport and a detachable catheter was tested for long-term intraperitoneal insulin delivery in 2 diabetic dogs. Programming and refilling of the pump was simple and presented no problems during 28 months of pump function. During pump therapy an acceptable degree of glycemic control was maintained. No catheter occlusion occurred, and no skin erosions or infections were observed. Insulin in the pump reservoir was stable. After 9.5 months of pump function, flow progressively decreased because of insulin precipitation in the valved accumulator. Solubilization of these precipitates using 0.1 N NaOH injected in the reservoir and drained through the sideport normalized pump delivery rates. We conclude that this device is safe for long-term intraperitoneal insulin delivery. The sideport enables discrimination between different causes of pump malfunction and allows for the safe use of an alkaline solution to remove insulin precipitates, thus avoiding pump explantation.

Animals↗
PubMed1989

Increased urinary prostaglandin excretion in galactose-fed rats.

Increased renal production of prostaglandins (PG) may contribute to the hyperfiltration that accompanies early diabetes. It was postulated that a putative metabolic abnormality of diabetes, ie, increased flux through the polyol pathway, stimulates renal PG production and that this phenomenon can be prevented by aldose-reductase inhibition. To test this hypothesis, the effects of polyol accumulation on urinary excretion rates (UER) of PGE2 and 6-keto-PGF1 alpha were studied, using the galactose-fed rat model. UER of PGE2 and 6-keto-PGF1 alpha were measured in three groups of weanling Wistar male rats. Group 1 was maintained on normal chow (n = 6), group 2 was fed chow supplemented with 30% galactose (n = 6), and group 3 received chow supplemented with 30% galactose and 0.7% sorbinil (n = 6). Ten 24-hour urine samples were obtained from each group between 151 and 240 days on the respective diets. UER of PGE2 (P less than .001) and 6-keto-PGF1 alpha (P less than .01) were higher in group 2 than in group 1. UER of PGE2 (NS) and 6-keto-PGF1 alpha (NS), respectively, were similar in groups 1 and 3. These data indicate that flux through the polyol pathway modulates the UER of PGE2 and 6-keto-PGF1 alpha. This phenomenon may contribute to the glomerular hyperfiltration of early diabetes.

6-Ketoprostaglandin F1 alpha↗
PubMed1988

Characterization of the carbamino adducts of insulin.

Carbon-13 (13C) nuclear magnetic resonance spectroscopy (NMR) is performed to characterize the formation of carbamino adducts between insulin and (13C) carbon dioxide over a range of pH values in the presence of a physiological concentration (23 mM) of sodium bicarbonate. The peaks from two of the carbamino adducts resonate at higher frequencies than the signal from bicarbonate, at 164.6 and 165.3 ppm, and are attributed to the adducts with the terminal amino groups of phenylalanine B1 and glycine A1. The intensities of these signals vary with the pH, with unique patterns. Over 6% of each terminal amino group exists as the carbamino adduct at the optimum pH values of 7.8 and 8.3. A unique third adduct resonates at 159.3 ppm, and is attributed to lysine B29. This adduct is present on 2% of the insulin molecules at pH 8.2, but has minimal intensity at pH 7.4. No signals from adducts are detected below pH 6.2, where the amino groups exist predominantly in the protonated form. Creation of the adducts is rapid and they are stable for over 4 wk at 37 degrees C. The narrow bandwidth of the resonance of the adduct (4.0-4.5 Hz) relative to the irreversible cyanate adduct is consistent with molecular forms of the carbamino adduct smaller than the 2-Zn-hexamer which is the preponderate form of clinically utilized U-100 insulin (i.e., 100 U/ml).

Animals↗
PubMedDate not supplied

Metabolic instability in type I diabetic patients. Studies on insulin absorption, hepatic production of metabolites and glucose counterregulation.

In order to investigate the causes underlying metabolic instability in type I diabetes mellitus, we studied 8 unstable (group 1) and 4 well-controlled (group 2) diabetic patients, matched for age and duration of diabetes. Subjects were connected overnight to an artificial pancreas and brought to normoglycemia. On the following morning, insulin administration was discontinued for 6 hours and both metabolic and hormonal studies were carried out during this period. After insulin withdrawal, group 1 showed a faster rise of blood glucose (peak: 324.63 +/- 24.93 vs 175.25 +/- 42.63 mg/dl, p less than 0.01), beta-OH-butyrate (peak: 2,273.25 +/- 415.78 vs 550.50 +/- 158.17 mumol/l, p less than 0.01), and glycerol (164.10 +/- 38.90 vs 28.25 +/- 10.6 mumol/l, p less than 0.01). C-peptide secretion increased in group 2 from 0.09 +/- 0.052 to 0.22 +/- 0.099 pmol/ml whereas it remained almost undetectable in group 1 (p less than 0.01, group 1 vs group 2). Growth hormone, cortisol and immunoreactive glucagon were not significantly different in the two groups at any time after insulin withdrawal. Free insulin, after repeated s.c. or i.m. injection of porcine monocomponent insulin (10 IU), was not different in the two groups. We concluded that type I diabetic patients showing severe metabolic instability produced more glucose, ketone bodies and glycerol after insulin withdrawal than control 'stable' patients. This difference could not be accounted for by an excessive secretion of counterregulatory hormones or by an erratic insulin absorption from the injection sites and may have been related to the degree of B-cell failure, as measured by the absence of C-peptide and/or to the degree of insulin resistance.

3-Hydroxybutyric Acid↗