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F Barbetti

Publications and source records attributed to F Barbetti.

34 records · Page 2Linked to original sources
PubMed1992

Mutations in the insulin receptor gene in patients with genetic syndromes of insulin resistance and acanthosis nigricans.

Mutations of the insulin receptor gene have been identified in patients with genetic syndromes of insulin resistance associated with acanthosis nigricans. These mutations impair insulin responses by reducing the number of insulin receptors on the surface of target cells, or by reducing the receptor's ability to bind insulin or to undergo insulin-stimulated autophosphorylation, an important step in insulin action. Studies of mutant receptors expressed in transfection systems have contributed to our understanding of the structure-function relationships of the insulin receptor.

Acanthosis Nigricans↗
PubMed1992

Detection of mutations in insulin receptor gene by denaturing gradient gel electrophoresis.

Denaturing gradient gel electrophoresis (DGGE) has been used to screen for mutations in the insulin receptor gene. Each of the 22 exons was amplified by the polymerase chain reaction (PCR). For each exon, one of the two PCR primers contained a guanine-cytosine (GC) clamp at its 5' end. The DNA was analyzed by electrophoresis through a polyacrylamide gel containing a gradient of denaturants. Two geometries for the gels were compared; the gradient of denaturants was oriented either parallel or perpendicular to the electric field. The sensitivity of the technique was evaluated by determining whether DGGE succeeded in detecting known mutations and polymorphisms in the insulin receptor gene. With parallel gels, 12 of 16 sequence variants were detected. The use of perpendicular gels increased the sensitivity of detection so that all 16 sequence variants were successfully detected when DNA was analyzed by a combination of perpendicular and parallel gels. Furthermore, DGGE was used to investigate a patient with leprechaunism whose insulin receptor genes had not previously been studied. Two mutant alleles were identified in this patient. The allele inherited from the father had a mutation substituting alanine for Val-28; in the allele inherited from the mother, arginine was substituted for Gly-366.

Alanine↗
PubMed1991

Normal coding sequence of insulin gene in Pima Indians and Nauruans, two groups with highest prevalence of type II diabetes.

The nucleotide sequence of the insulin gene was determined in American Pima Indians and Micronesian Nauruans, two populations in whom the prevalence of non-insulin-dependent (type II) diabetes mellitus is the highest in the world. The insulin gene was amplified by the polymerase chain reaction to generate single-stranded DNA suitable for direct sequencing. The nucleotide sequences of the coding and adjacent regions of the insulin gene in six Pima Indians and two Nauruans with type II diabetes were identical to previously published insulin gene sequences of nondiabetic subjects.

Adult↗
PubMed1990

Growth hormone does not inhibit its own secretion during prolonged hypoglycemia in man.

In man, continuous infusion of GH-releasing hormone (GHRH) does not sustain GH secretion, unlike prolonged hypoglycemia. To further evaluate this difference in the stimulation of GH release we measured GH concentrations for 3 h during prolonged insulin-induced hypoglycemia and GHRH-(1-29)NH2 (100 micrograms/h) infusion in normal individuals. We also assessed the GH response to combined and separate administration of insulin and GHRH. Plasma GH levels increased during prolonged hypoglycemia and remained elevated for the third hour (22-24 micrograms/L). GH concentrations increased during GHRH infusion, peaked at 60 min (23.5 micrograms/L), and rapidly declined. Thus, our findings confirmed that prolonged hypoglycemia, unlike GHRH infusion, sustained elevated GH levels and that these high levels did not appear to influence GH secretion from the pituitary. Changes in FFA did not account for the sustained GH secretion. FFA levels initially declined during insulin infusion, but after 3 h of hypoglycemia they returned to near-basal values (basal, 0.1 +/- 0.02 g/L; 180 min, 0.09 +/- 0.02). The maximal GH concentration attained during the combined insulin and GHRH test was significantly higher than that with the insulin tolerance test or GHRH test (insulin plus GHRH, 71.9 +/- 13.5; insulin tolerance test, 34.2 +/- 2.9; P less than 0.025; GHRH test, 27.9 +/- 3.2; P less than 0.02), indicating an additive effect on GH secretion. These data suggest that insulin-induced hypoglycemia stimulates GH secretion through a mechanism partly independent of GHRH. The release from somatostatin inhibition and stimulation through other neuropeptides (e.g. galanin) is suggested as possible causes of hypoglycemia-induced GH secretion.

Adult↗
PubMed1990

Two unrelated patients with familial hyperproinsulinemia due to a mutation substituting histidine for arginine at position 65 in the proinsulin molecule: identification of the mutation by direct sequencing of genomic deoxyribonucleic acid amplified by polymerase chain reaction.

Mutations in the insulin gene can impair the bioactivity of the insulin molecule. Previously, two classes of mutations have been identified: 1) those that impair posttranslational processing of proinsulin to insulin, and 2) those that alter the structure of the insulin molecule, thereby reducing the affinity of the molecule for the insulin receptor. We have investigated two apparently unrelated patients, both of which have mutations that inhibit the conversion of proinsulin to insulin. By directly sequencing genomic DNA amplified by polymerase chain reaction, we have demonstrated that both patients are heterozygous for the same point mutation converting codon 65 from an arginine (CGT) to a histidine (CAT) codon. Because Arg65 is one of the two dibasic amino acids at the site of proteolytic cleavage between the insulin A-chain and C-peptide, this mutation explains the impairment in the cleavage of proinsulin to insulin. Interestingly, the same His65 mutation has been identified in the insulin gene of a Japanese kindred with familial hyperproinsulinemia. Thus, this mutation has occurred in three apparently unrelated kindreds from two different racial groups. This observation is consistent with the hypothesis that the dinucleotide sequence CpG, the first two nucleotides in the arginine (CGT) codon, is a "hot spot" for mutations.

Alleles↗
PubMed1989

Syndromes of autoimmunity and hypoglycemia. Autoantibodies directed against insulin and its receptor.

Humoral autoimmunity plays an important role in the pathogenesis of two forms of hypoglycemia. In one syndrome, antireceptor autoantibodies bind to the insulin receptor, mimic insulin action, and cause fasting hypoglycemia. In most patients with autoantibodies to the insulin receptor, there is other evidence of autoimmune disease as well. Interpretation of the standard tests used in evaluation of hypoglycemia may be confusing in these patients. For example, antireceptor antibodies may inhibit insulin binding, thereby inhibiting insulin clearance and elevating levels of plasma insulin. Nevertheless, because hypoglycemia suppresses beta-cell secretion, C-peptide levels are usually low. This constellation of data is consistent with surreptitious insulin injection. The most important laboratory test in the differential diagnosis is a direct assay for the presence of antibodies directed against the insulin receptor. Therapy with prednisone appears to alleviate the hypoglycemia rapidly, usually within 24 hours. This effect of prednisone appears to result from antagonism of the effects of antireceptor antibodies without actually lowering their titer. The natural history of this syndrome is that the antireceptor antibodies disappear and the syndrome resolves over a time course of several months to several years. In North America, the presence of anti-insulin antibodies in a hypoglycemic patient most commonly suggests that the patient has been immunized with exogenous insulin. However, some patients--especially in Japan--develop spontaneous autoantibodies directed against insulin. These antibodies can cause hypoglycemia, which is generally reactive in that it occurs several hours after a meal or a glucose challenge rather than in a fasting state. The most effective therapy is frequent small feedings and avoidance of large meals.

Autoantibodies↗
PubMed1988

Fecal lactate and ulcerative colitis.

Impaired metabolism of short-chain fatty acids, as well as a modified fecal ionogram, have been reported in ulcerative colitis. Fecal water samples from 62 patients with ulcerative colitis were analyzed in the present investigation to evaluate changes in SCFAs and lactic acid in relation to activity and severity of disease. Short-chain fatty acid levels were high in quiescent and mild disease (162.6 +/- 63.6 and 147.8 +/- 63.2 mM/L, respectively), but significantly decreased in the severe form (64.7 +/- 46.9 mM/L). Lactate showed a progressive increase from mild colitis (3.0 +/- 1.8 mM/L) to severe colitis (21.4 +/- 18.6 mM/L). It thus appears that mild colitis displayed a fecal pattern characterized by normal pH and bicarbonate, slightly impaired electrolyte handling, high short-chain fatty acid values, and only moderately increased lactate. Severe colitis, on the other hand, was characterized by low fecal pH, bicarbonate, and potassium, high sodium and chloride, low short-chain fatty acid levels, and very high lactate levels. A critical lowering of intraluminal pH, which shifts bacterial metabolism from short-chain fatty acid to lactate production, may be responsible for the intraluminal pooling of lactate.

Colitis, Ulcerative↗
PubMed1987

Dose-response effect of somatostatin-14 on human basal pancreatic hormones.

The effect of increased doses of Somatostatin-14 (3, 10, 30, 100, 300 micrograms/h) on basal release of insulin, pancreatic glucagon and pancreatic polypeptide (PP) was investigated on eight normal volunteers. Levels of Somatostatin-like immunoreactivity (SLI) was determined in order to correlate the increased SLI levels with the degree of islet hormone inhibition (r = 0.9947, p less than 0.01). By increasing the basal levels of SLI by one-third, a significant inhibition (p less than 0.01) of insulin, glucagon, and PP was noted (78.5, 78.6, 75.2%, respectively, on basal levels). The maximal effect was obtained with 300 micrograms/h for insulin, with 30 micrograms/h for glucagon and 100 micrograms/h for PP. In evaluating the relative inhibitory potency of somatostatin, expressed as ED50, the theoretic potency of somatostatin on each peptide had similar values, ranging from 30 to 10 micrograms/h. The present data show that a minimal peripheric increase in SLI is able to regulate basal islet pancreatic hormones.

Adult↗
PubMed1985

Amniotic membrane diffusion chambers: a new possibility for pancreatic islet transplantation.

In order to avoid the host foreign-body reaction which is probably responsible for the long-term failure of the artificial membrane diffusion chambers currently used for protecting the implanted islet tissue from rejection, we tested the human amniotic membrane as a possible new tool for enclosing transplanted islets of Langerhans. Bag-shaped chambers were made with human amniotic membranes and the diffusion of 125 I-Insulin out and of D-glucose into the chambers was measured. The diffusion patterns of insulin and glucose were shown to be better than those described for the best artificial membranes, the 50% diffusion being reached at min 42 for 125 I-Insulin and at min 11 for D-glucose. Moreover, it was shown that no lymphocytes diffused into the amniotic membrane chambers. These results, together with the already known characteristics of the human amniotic membrane, induce us to propose it as a suitable material for further experimental work in islet tissue transplantation.

Amnion↗
PubMed1982

Effects of somatostatin on established induced ketosis.

The metabolic effects of Somatostatin (SRIF) added to insulin were studied in five diabetic subjects with ketonuria induced by insulin withdrawal. In the same patients ketonuria was induced twice and they were randomly treated with insulin alone (10 units as a bolus + infusion 1 U/hr) until euglycemia was reached or with insulin (same criteria) + cyclic SRIF (100 micrograms/ hr i.v.) for ten hours. Treatment with insulin + SRIF significantly reduced both peak and cumulative hGH levels in contrast to insulin alone. Moreover, the percent decrease of glucagon was significantly greater during insulin + SRIF than with insulin alone. On the other hand, the beta-OH levels fell significantly more during insulin + SRIF than during insulin alone. Finally the prolactin plasma levels fell considerably when combined treatment was given but not when just insulin was administered.

3-Hydroxybutyric Acid↗
PubMedDate not supplied

Effects of somatostatin on insulin and glucagon in patients with insulinoma.

Effects of somatostatin on fasting and arginine-or tolbutamide-stimulated insulin release were studied in four patients with insulinoma. Somatostatin (bolus or bolus + infusion) reduced fasting insulin values in all patients; insulin response to tolbutamide was partially reduced in two patients; somatostatin bolus impaired the insulin response to arginine. Fasting glucagon levels and glucagon response to arginine were also reduced by somatostatin. These results indicate the potential usefulness of somatostatin in the diagnosis of insulinoma even if its effect on insulin is only partial.

Adenoma, Islet Cell↗
PubMedDate not supplied

[Sequential infusion of GHRH 1-29NH2, LHRH and TRH for evaluating the hypophyseal reserve. Comparison with Politest].

Fourteen patients with pituitary lesions and 6 normal subjects underwent the following tests: a) LHRH (100 mcg) + TRH (200 mcg) + Human Insulin (0.1 UI/kg) i.v. (Politest "A"); b) LHRH (100 mcg) + TRH (200 mcg) + GHRH 1-29NH2 (100 mcg) i.v. (Politest "B"); c) GHRH 1-29NH2 (100 mcg) i.v. (GHRH-TEST). FSH, LH and PRL, as assayed in patients and controls in response to Politest "A" and "B", revealed no significant differences between the tests. Plasma TSH values were significantly higher after Politest "B" in both patients and normals. The GH response after Politest "A" and "B" was similar in magnitude and concordant in 88.8% of cases.

Adenoma↗