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Biomedical subjects

R Cordera

Publications and source records attributed to R Cordera.

At least 19 recordsLinked to original sources
PubMed2004

Reduction of cardiovascular morbidity and mortality in type 2 diabetes. A rational approach to hypoglycemic therapy.

Type 2 diabetes mellitus is the single most important risk factor for the development of coronary artery disease. Unfortunately, the traditional therapeutic strategies for the treatment of hyperglycemia have proven to be ineffective in preventing cardiovascular complications. In recent years the number of available hypoglycemic agents has increased and considerable progress has been made regarding the comprehension of the pathophysiology of diabetes and its vascular complications. In the present article we firstly present benefits and risks of intensive vs standard hypoglycemic intervention, and the pros and cons of therapy targeted to postprandial hyperglycemia. Secondly, we discuss the cardiovascular effects of sulfonylurea agents and insulin, focusing on the role of intensive insulin treatment in the context of acute coronary syndromes. Thirdly, we review the epidemiological, clinical and experimental evidence linking insulin resistance and cardiovascular disease. Finally, we present the rationale and the role of metformin and thiazolidinedionetherapy in the prevention of cardiovascular complications. We conclude that the optimal use of the full spectrum of hypoglycemic agents has the potential to play a key role in the prevention of diabetes-related macrovascular complications.

Blood Glucose↗
PubMed2004

Long-term normalization of insulin sensitivity following biliopancreatic diversion for obesity.

OBJECTIVE: Assess insulin sensitivity and metabolic status of obese patients with stable weight loss at long term following biliopancreatic diversion (BPD). MATERIAL AND METHODS: The study was carried out in 36 nondiabetic severely obese patients undergoing BPD. Serum concentration of glucose, insulin and leptin were determined prior to and at 2 y following the operation. Insulin sensitivity was calculated according to the homeostatic model assessment (HOMA IR). RESULTS: At 2 y following BPD, weight loss in all subjects corresponded to a marked drop in serum leptin concentration and improvement of insulin sensitivity within physiological range. Following the operation, HOMA IR values were positively correlated with serum leptin concentration independently of body mass index values. DISCUSSION: The stable weight loss following BPD at long term is accompanied by a complete reversal of the preoperative insulin resistance. Serum leptin concentration and HOMA IR data were positively related only postoperatively, suggesting that the action of factors that could influence the relation between leptin and insulin action in the obese status can be reverted.

Adolescent↗
PubMed2003

The extracellular portion of the insulin receptor beta-subunit regulates the cellular trafficking of the insulin-insulin receptor complex. Studies on Chinese hamster ovary cells carrying the Cys 860-->Ser insulin receptor mutation.

OBJECTIVE: Chinese hamster ovary (CHO) cells transfected with human engineered insulin receptor (IR) cDNA to mutate Cys 860 to Ser (CHO-IR(C860S)) showed a defective insulin internalization without affecting insulin binding and IR autophosphorylation. Moreover, this mutation reduces insulin receptor substrate (IRS)-1 tyrosine phosphorylation and insulin-induced metabolic and mitogenic effects. Altogether, these observations support a role of the extracellular domain of IR beta-subunit in insulin and receptor intracellular targeting as well as in insulin signaling. DESIGN AND METHODS: This study assesses in more details the effect of IR(C860S) mutation on the trafficking of the insulin-IR complex. In particular, IR internalization, phosphorylation, dissociation and recycling, as well as insulin degradation and retroendocytosis have been investigated in CHO cells overexpressing either wild type (CHO-IR(WT)) or mutated IRs. RESULTS: the C860S mutation significantly decreases IR internalization both insulin stimulated and constitutive. In spite of a similar dissociation of internalized insulin-IR complex, recycling of internalized IR was significantly faster (half life (t(1/2)): 21 min vs 40 min, P<0.001) and more extensive (P<0.01) for IR(C860S) than for IR(WT). On the other hand, insulin degradation and retroendocytosis were superimposable in both cell lines. As expected, insulin-induced phosphorylation was similar in both IRs, however dephosphorylation was much more rapid and was greater (P<0.01) in CHO-IR(WT) as compared with CHO-IR(C860S) cells. CONCLUSIONS: Transmembrane and intracellular domain of IR seem to be determinants for IR internalization. Now we report that Cys 860 in the IR beta-subunit ectodomain may be of relevance in ensuring a proper internalization and intracellular trafficking of the insulin-IR complex.

Animals↗
PubMed2001

Cys 786 and Cys 776 in the posttranslational processing of the insulin and IGF-I receptors.

The extracellular regions of insulin and IGF-I receptors (IR and IGF-IR) contain fibronectin type III repeats with cysteine residues potentially involved in S==S bond. In this report we show that Cys 786 in the IR and the corresponding Cys 776 in the IGF-IR regulate proreceptor dimerization with high specificity. Both C786S insulin and C776S IGF-I proreceptors reach the monomeric 210-kDa step, but do not proceed further. Mature IR(C786S) and IGF-IR(C776S) expression on plasmamembrane is abolished. No retention of C786S IR precursor was detected in the endoplasmic reticulum, which is degraded by a nonlysosomal mechanism. The rearrangement of the remaining cysteines in the insulin receptor beta subunit ectodomain does not rescue dimerization of C786S insulin proreceptor. As observed in other transmembrane receptors, iuxtamembrane cysteines, specifically Cys 786 in the IR and Cys 776 in the IGF-IR, are critical for correct processing of proreceptors.

Animals↗
PubMed2001

Sulfonylurea treatment of type 2 diabetic patients does not reduce the vasodilator response to ischemia.

OBJECTIVE: Sulfonylureas block the activation of vascular potassium-dependent ATP channels and impair the vasodilating response to ischcmia in nondiabetic individuals, but it is not know whether this occurs in type 2 diabetic patients under chronic treatment with these drugs. Glimepiride, a new sulfonylurea, apparently has no cardiovascular interactions. The aim of our study was to compare the effect of the widely used compound glibenclamide, the pancreas-specific glimepiride, and diet treatment alone on brachial artery response to acute forearm ischemia. RESEARCH DESIGN AND METHODS: Brachial artery examination was performed by a high-resolution ultrasound technique on 20 type 2 diabetic patients aged mean +/- SD) 67 +/- 2 years and on 18 nondiabetic patients matched for age, hypertension, and dislipidemia. Diabetic subjects underwent three separate evaluations at the end of each 8-week treatment period, during which they received glibenclamide, glimepiride, or diet alone according to crossover design. Scans were obtained before and after 4.5 min of forearm ischemia. Postischemic vasodilation and hyperemia were expressed as percent variations in vessel diameter and blood flow. RESULTS: Postischemic vasodilation and hyperemia were, respectively, 5.42 +/- 0.90 and 331 +/- 38% during glibenclamide, 5.46 +/- 0.69 and 326 +/- 28% during glimepiride, and 5.17 +/- 0.64 and 357 +/- 35% during diet treatment (NS). These results were similar to those found in the nondiabetic patients (6.44 +/- 0.68 and 406 +/- 42%, NS). CONCLUSIONS: In type 2 diabetic patients, the vasodilating response to forearm ischemia was the same whether patients were treated with diet treatment alone or with glibenclamide or glimepiride at blood glucose-lowering equipotent closes.

Aged↗
PubMed2001

Phenotypic expression of familial hypobetalipoproteinemia in three kindreds with mutations of apolipoprotein B gene.

We report the clinical phenotype in three kindreds with familial heterozygous hypobetalipoproteinemia (FHBL) carrying novel truncated apolipoprotein Bs (apoBs) of different sizes (apoB-8.15, apoB-33.4 and apoB-75.7). In D.A. kindred, we found three carriers of a C-deletion in exon 10 leading to the synthesis of apoB-8.15 not detectable in plasma. They showed steatorrhea and fatty liver. In N.L. kindred, the proband is heterozygous for a nonsense mutation in exon 26, leading to the formation of apoB-33.4. He had premature cerebrovascular disease and fatty liver; two apoB-33.4 carriers in this kindred showed only fatty liver. In B.E. kindred, the proband is heterozygous for a T-deletion in exon 26, which converts tyrosine at codon 3435 into a stop codon, resulting in apoB-75.7. The proband, a heavy alcohol drinker, had steatohepatitis, whereas his teetotaller daughter, an apoB-75.7 carrier, had no detectable fatty liver. This study suggests that: i) fatty liver invariably develops in FHBL carriers of short and medium-size truncated apoBs (< apoB-48), but its occurrence needs additional environmental factors in carriers of longer apoB forms; ii) intestinal lipid malabsorption develops only in carriers of short truncated apoBs, which are not secreted into the plasma; and iii) cerebrovascular disease due to premature atherosclerosis may occur even in FHBL subjects.

Adult↗
PubMed2000

Serum leptin concentrations during the menstrual cycle in normal-weight women: effects of an oral triphasic estrogen-progestin medication.

OBJECTIVE: To investigate in normal-weight premenopausal women the relationship between circulating leptin and serum gonadotropins and gonadal steroids, during both spontaneous and pharmacologically induced menstrual cycles. DESIGN: Clinical longitudinal study. METHODS: Two groups of age-matched, normal-weight premenopausal volunteer women (groups I and II) were enrolled in this study. Women in group I were free of any hormonal treatment, while women in group II were taking a triphasic estrogen--progestin contraceptive preparation. Blood samples were collected daily in both groups after an overnight fast throughout a complete menstrual cycle. RESULTS: In the spontaneously cycling women, serum leptin concentration positively correlated with estradiol (P<0.03) and progesterone (P<0. 05) and was higher in the luteal than in the follicular phase (P<0. 05). However, a significant (P<0.03) short-lasting increase in circulating leptin was present in the late follicular phase of all subjects. In the women using hormonal contraception serum leptin remained unchanged throughout the cycle, along with constantly low values of circulating luteinizing hormone and follicle-stimulating hormone. CONCLUSIONS: In normal-weight premenopausal women serum leptin concentrations differ during the menstrual cycle in line with changes in gonadotropin and gonadal steroid concentrations, increasing in the luteal phase of the cycle after a peri-ovulatory peak. These findings suggest a permissive role for leptin with regard to the functioning of the corpus luteum.

Adult↗
PubMed1999

Evaluation of growth hormone administration in patients with chronic heart failure secondary to coronary artery disease.

We have examined the effects of 6 months of treatment with growth hormone (GH) (0.02 U/kg/day) in 10 patients with chronic postischemic cardiac failure. Ten patients matched for age, body mass index, functional class, and ejection fraction served as a control group. In the GH group, 1 patient died and 2 were withdrawn from the study because of arrhythmia or worsening of heart failure. In the control group, 1 patient died and 1 patient was withdrawn from the study because of progressive heart failure. Among GH patients, those with an unfavorable outcome had a greater left ventricular end-diastolic diameter (79, 82, and 88 mm) on entry to the study than patients without adverse events (range 62 to 72 mm). At the end of the study, the seven GH patients reported a feeling of well-being and had a significant increase in their exercise test duration (462 +/- 121 vs 591 +/- 105 seconds, p <0.05). Low baseline insulin-like growth factor-I values were increased with GH treatment (189 +/- 52 vs 100 +/- 22 ng/ml, p <0.01). GH did not change left ventricular diameters or wall thickness. A trend toward decreased serum triglyceride levels and adipose body tissue associated with an increase in high-density lipoproteins was observed in the GH group. In conclusion, our present data support previous suggestions that GH treatment exerts some beneficial effects in patients with chronic, stabilized, moderately severe heart failure, but may have deleterious effects in patients with more severe heart failure.

Aged↗
PubMed1999

Role of proline 193 in the insulin receptor post-translational processing.

AIMS/HYPOTHESIS: A point mutation, P193L, in the insulin receptor alpha subunit, has been previously identified in a patient affected by an extreme form of insulin resistance due to reduced insulin binding. In our study we investigated the cellular mechanisms by which P193L substitution causes a reduction of insulin receptor numbers on the cell surface. METHODS: Mutated insulin receptors have been generated and expressed in COS1 cells. Transcription as well as translation of P193L insulin receptor have been measured and compared with wild type insulin receptor. RESULTS: P193L insulin receptor is normally transcribed and progresses to the step of insulin proreceptor, which does not proceed to dimerization, resulting in the accumulation of the 210 kDa form. These findings suggest that the P193L insulin proreceptor is retained in the endoplasmic reticulum, where several molecular chaperones drive the folding of protein precursors. Therefore the interaction between mutated insulin receptor precursor and two endoplasmic reticulum resident chaperones (GRP78 and calnexin) were investigated. P193L insulin proreceptor co-immunoprecipitates with greater amounts of GRP78 and its interaction with calnexin is greatly delayed compared with wild type insulin receptor precursor. Co-transfection of wild type and mutated insulin receptors causes a considerable reduction of cell surface wild type insulin receptors. CONCLUSION/INTERPRETATION: P193 is critical for insulin proreceptor folding. The monomeric form of P193L insulin proreceptor is retained in the endoplasmic reticulum by a calnexin and GRP78 mediated mechanism that reduces mature insulin receptor expression on the cell surface.

Amino Acid Substitution↗
PubMed1999

Effects of dietary restriction on serum leptin concentration in obese women.

OBJECTIVE: To investigate the short- and long-term effects of dietary restriction on serum leptin in obese women and the role of the gastrointestinal system in the short-term regulation of leptin production. DESIGN: Clinical longitudinal study of anthropometric and serum leptin changes induced in obese women by a balanced 300 kcal/d very low calorie diet (VLCD), administered either orally or parenterally for 5 d, and by a balanced 900 kcal/d low calorie diet (LCD) lasting six months. SUBJECTS: 20 obese women (age: 38.1 +/- 12.7 y; body mass index (BMI): 40.2 +/- 8.3 kg/m2). RESULTS: Five days following VLCD, a modest, even if significant (P < 0.0001), fall of both body weight (BW) and BMI was observed, along with a dramatic (> 50%) highly significant (P < 0.0001) reduction of circulating serum leptin. Baseline and five-day anthropometric and biochemical findings were closely similar in the group of orally fed subjects, when compared with those of their parenterally fed counterparts. The baseline positive correlation between serum leptin and BMI (p = 0.533) increased (P < 0.05) at the end of the five day VLCD (p = 0.849). A further fall of BW and BMI was observed at day 30 (P < 0.001) and day 180 (P < 0.01) during the 900 kcal/d LCD, while the serum leptin concentration gradually increased until day 180 when it was only slightly but non significantly lower than at baseline. At the end of the study, the correlation between serum leptin and BMI was similar to the baseline (p = 0.562). CONCLUSIONS: Energy restriction causes a fall of serum leptin apparently not mediated by gastrointestinal signals and it seems not to affect the long-term regulatory pathways of circulating leptin.

Adult↗
PubMed1998

A nonsense mutation (R242X) in the branched-chain alpha-keto acid dehydrogenase E1alpha subunit gene (BCKDHA) as a cause of maple syrup urine disease. Mutations in brief no. 160. Online.

Mutation analysis of DNA from cultured amniocytes with absent branched-chain alpha-ketoacid dehydrogenase activity revealed a C to T transition producing a nonsense mutation (R242X) in exon 7 of the gene encoding the E1a subunit of this multienzme complex (BCKDHA). This pregnancy occured in a large consanguinous pedigree with mutiple individuals with maple syrup urine disease (MSUD). PCR amplification of the region surrounding exon 7 allowed the identification of this mutation as well as two other previously identified mutations which cause MSUD.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
PubMed1998

Role of IRS-1 and SHC activation in 3T3-L1 fibroblasts differentiation.

The early steps of 3T3-L1 fibroblasts differentiation to adipocytes are characterized by a proliferation phase, termed clonal expansion, that ends after the first 48 h of exposure of confluent cells to high doses of insulin, dexamethasone, 3-methyl-isobutylxanthine and FCS (differentiation mix). Since insulin is a key hormone for adipocyte conversion, and IRS-1 (insulin receptor substrate -1) and Shc (Src homology collagen)-proximal intracellular substrates of the insulin receptor-control cell proliferation, the aim of this study was to investigate the role of IRS-1 and Shc in the early steps of differentiation. At the end of clonal expansion, 48 h after induction of differentiation with differentiation mix, p66 Shc phosphorylation and IRS-1 amounts were reduced in those cells committed to fully differentiate. Conversely, in cells treated with insulin alone or dexamethasone alone (unable to be differentiated), p66 Shc and IRS-1 activities were maintained unaltered, compared to basal values. These observations suggest that the modifications of p66 Shc and IRS-1 in the first 48 h of 3T3-L1 conversion into adipocytes could play a role on this process, or alternatively they could represent an early cellular marker of differentiation.

1-Methyl-3-isobutylxanthine↗
PubMed1998

Serum leptin and weight loss in severely obese patients undergoing biliopancreatic diversion.

OBJECTIVE: To evaluate the influence of body fat and food intake on serum leptin concentration. DESIGN: Longitudinal study of a group of obese patients prior to and at, long term follow-up, after biliopancreatic diversion (BPD), when body weight was steadily reduced and food consumption was similar to or greater than preoperatively. RESULTS: In obese patients, very high serum leptin concentrations were found. Following the operation, with the body weight stable and normalized, a sharp fall of serum leptin concentration had occurred, with values returned to normal range. CONCLUSION: The changes in serum leptin concentration observed in the long term after weight loss are substantially accounted for by the loss of body fat and appear unrelated to the reduction of oral food intake.

Adolescent↗
PubMed1998

Cys860 in the extracellular domain of insulin receptor beta-subunit is critical for internalization and signal transduction.

The C860S mutation (IRC860S) in the extracellular domain of the insulin receptor beta-subunit has previously been shown to result in an inhibition of insulin receptor internalization. The present work aims at further dissecting the consequences of this mutation not only on insulin receptor internalization, but also on the signaling of the receptor. Following transfection of Chinese hamster ovary (CHO) cells with insulin receptors with the C860S mutation (CHO-IRC860S) and quantitative electron microscopic analysis of [125I]insulin localization in these cells, the inhibition of receptor internalization appears to be due to an inhibition of the lateral translocation of the receptor from microvilli to nonvillous domains of the cell surface. At 37 C, insulin-stimulated insulin receptor substrate-1 (IRS-1) phosphorylation is inhibited by 50% in CHO-IRC860S, whereas Shc phosphorylation remains unaffected. The inhibition of IRS-1 phosphorylation is still present when experiments are conducted at 4 C, a temperature at which insulin receptor internalization is prevented, suggesting that the defect in IRS-1 phosphorylation is not due to the reduced internalization of the receptor. In terms of biological effects, the mutation has negative consequences on insulin-stimulated c-fos expression and DNA synthesis as well as on glycogen synthase activity. Eventually, the events observed are specific for Cys860, as individual substitution of the two more proximal Cys residues (795 and 872) to Ser is not accompanied by any change in either insulin-induced insulin receptor internalization or IRS-1 phosphorylation. Thus, the present analysis of CHO-IRC860S 1) reveals that insulin receptor surface redistribution is not solely dependent on receptor autophosphorylation, 2) emphasizes that IRS-1 phosphorylation is not dependent on receptor internalization and can be triggered from microvilli, and 3) stresses divergent aspects between two of the major signaling pathways of the insulin receptor.

Amino Acid Sequence↗
PubMed1998

Toxic thyroid adenoma: absence of DNA mutations of the TSH receptor and Gs alpha.

DNA point mutations of the TSH receptor and of the alpha subunit of the stimulatory GTP-binding protein (Gs alpha) have been suggested as major causes of hyperfunctioning thyroid adenomas. However, significant differences in the prevalence of these mutations (from 0.3 to 84%) have been found in different populations. The present study was designed to evaluate further the presence of mutations in discrete fragments of cDNA encoding critical regions of the TSH receptor and of the Gs alpha involved in signal transduction and cAMP production. Genomic DNA extracted from 15 thyroid adenomas and surrounding quiescent thyroid tissues was used as a template to amplify four DNA fragments of TSH receptor and one DNA fragment of Gs alpha. TSH receptor and Gs alpha DNAs were analyzed by a number of techniques. We did not detect any mutations (new or previously described) in our patients. These results confirm that the causes of solitary toxic adenomas are protean, and only some of them may be somatic DNA point mutations. Since the clinical features of solitary toxic adenoma are homogeneous, it could be important to establish the specific molecular defect underlying each case, in order to follow up the patients and to assess their clinical evolution.

Adenoma↗
PubMed1996

The human skeletal muscle glycogenin gene: cDNA, tissue expression and chromosomal localization.

Glycogen synthesis is impaired in first degree relatives of subjects with non-insulin-dependent diabetes mellitus and genes relevant to this metabolic pathway are considered reasonable candidates in the pathogenesis of the disease. In skeletal muscle the de novo synthesis of glycogen in primed by an enzyme named glycogenin. We have cloned the glycogenin cDNA from human skeletal muscle mRNA: human glucogenin is a 333 amino acid protein exhibiting 93% identity with rabbit glycogenin. A single transcript of about 2.4 kb, prominent in skeletal muscle, was detected by Northern blot analysis. In situ hybridization unequivocally located the human glycogenin gene to chromosome 3q25.1. Furthermore, we mapped two intronless glycogenin-related sequences to human chromosomes 12 and 13.

Amino Acid Sequence↗
PubMed1996

Insulin-like growth factor-I and angiographically documented coronary artery disease.

In conclusion, we have reported an association between low IGF-I concentrations and CAD in relatively young men. This observation raises the possibility that IGF-I deficiency could be part of the polymetabolic syndrome. Whether a subnormal IGF-I production is due to growth hormone secretory abnormalities or to other metabolic reasons (e.g., insulin resistance or fat distribution, or both) is still unknown.

Adult↗