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Biomedical subjects

Franco Folli

Publications and source records attributed to Franco Folli.

29 records · Page 2Linked to original sources
PubMed2003

Interaction between leptin and insulin signaling pathways differentially affects JAK-STAT and PI 3-kinase-mediated signaling in rat liver.

Chronic leptin treatment markedly enhances the effect of insulin on hepatic glucose production unproportionally with respect to body weight loss and increased insulin sensitivity. In the present study the cross-talk between insulin and leptin was evaluated in rat liver. Upon stimulation of JAK2 tyrosine phosphorylation, leptin induced JAK2 co-immunoprecipitation with STAT3, STAT5b, IRS-1 and IRS-2. This phenomenon parallels the leptin-induced tyrosine phosphorylation of STAT3, STAT5b, IRS-1 and IRS-2. Acutely injected insulin stimulated a mild increase in tyrosine phosphorylation of JAK2, STAT3 and STAT5b. Leptin was less effective than insulin in stimulating IRS phosphorylation and their association with PI 3-kinase. Simultaneous treatment with both hormones yielded no change in maximal phosphorylation of STAT3, IRS-1, IRS-2 and Akt, but led to a marked increase in tyrosine phosphorylation of JAK2 and STAT5b when compared with isolated administration of insulin or leptin. This indicates that there is a positive cross-talk between insulin and leptin signaling pathways at the level of JAK2 and STAT5b in rat liver.

Animals↗
PubMed2003

Long-term beneficial effect of islet transplantation on diabetic macro-/microangiopathy in type 1 diabetic kidney-transplanted patients.

OBJECTIVE: Our aim was to evaluate the long-term effects of transplanted islets on diabetic macro-/microangiopathy in type 1 diabetic kidney-transplanted patients. RESEARCH DESIGN AND METHODS: A total of 34 type 1 diabetic kidney-transplanted patients underwent islet transplantation and were divided into two groups: successful islet-kidney transplantation (SI-K; 21 patients, fasting C-peptide serum concentration >0.5 ng/ml for >1 year) and unsuccessful islet-kidney transplantation (UI-K; 13 patients, fasting C-peptide serum concentration <0.5 ng/ml). Patients cumulative survival, cardiovascular death rate, and atherosclerosis progression were compared in the two groups. Skin biopsies, endothelial dependent dilation (EDD), nitric oxide (NO) levels, and atherothrombotic risk factors [von Willebrand factor (vWF) and D-dimer fragment (DDF)] were studied cross-sectionally. RESULTS: The SI-K group showed a significant better patient survival rate (SI-K 100, 100, and 90% vs. UI-K 84, 74, and 51% at 1, 4, and 7 years, respectively, P = 0.04), lower cardiovascular death rate (SI-K 1/21 vs. UI-K 4/13, chi(2) = 3.9, P = 0.04), and lower intima-media thickness progression than the UI-K group (SI-K group: delta1-3 years -13 +/- 30 micro m vs. UI-K group: delta1-3 years 245 +/- 20 micro m, P = 0.03) with decreased signs of endothelial injuring at skin biopsy. Furthermore, the SI-K group showed a higher EDD than the UI-K group (EDD: SI-K 7.8 +/- 4.5% vs. UI-K 0.5 +/- 2.7%, P = 0.02), higher basal NO (SI-K 42.9 +/- 6.5 vs. UI-K 20.2 +/- 6.8 micro mol/l, P = 0.02), and lower levels of vWF (SI-K 138.6 +/- 15.3 vs. UI-K 180.6 +/- 7.0%, P = 0.02) and DDF (SI-K 0.61 +/- 0.22 vs. UI-K 3.07 +/- 0.68 micro g/ml, P < 0.01). C-peptide-to-creatinine ratio correlated positively with EDD and NO and negatively with vWF and DDF. CONCLUSIONS: Successful islet transplantation improves survival, cardiovascular, and endothelial function in type 1 diabetic kidney-transplanted patients.

Adult↗
PubMed2002

Obesity modulates the expression of haptoglobin in the white adipose tissue via TNFalpha.

Increase in adipose mass results in obesity and modulation of several factors in white adipose tissue (WAT). Two important examples are tumor necrosis factor alpha (TNFalpha) and leptin, both of which are upregulated in adipose tissue in obesity. In order to isolate genes differentially expressed in the WAT of genetically obese db/db mice compared to their lean littermates, we performed RNA fingerprinting and identified haptoglobin (Hp), which is significantly upregulated in the obese animals. Hp is a glycoprotein induced by a number of cytokines, LPS (Lipopolysaccharide), and more generally by inflammation. A significant upregulation of WAT Hp expression was also evident in several experimental obese models including the yellow agouti (/) A(y), ob/ob and goldthioglucose-treated mice (10-, 8-, and 7-fold, respectively). To identify the potential signals for an increase in Hp expression in obesity, we examined leptin and TNFalpha in vivo. Wild type animals treated with recombinant leptin did not show any alteration in WAT Hp expression compared to controls that were food restricted to the level of intake of the treated animals. On the other hand, Hp expression was induced in mice transgenically expressing TNFalpha in adipose tissue. Finally, a significant downregulation of WAT Hp mRNA was observed in ob/ob mice deficient in TNFalpha function, when compared to the ob/ob controls. These results demonstrate that haptoglobin expression in WAT is increased in obesity in rodents and TNFalpha is an important signal for this regulation.

Adipocytes↗
PubMed2002

Intracellular pathways mediating estrogen-induced cholangiocyte proliferation in the rat.

The aim of this study was to explore the intracellular signaling pathways involved in the stimulatory effects of estrogens on cholangiocyte proliferation. We investigated the tyrosine kinase-receptor pathway by evaluating the protein expression of total and phosphorylated mitogen-activated protein kinase (MAPK) isoform p44/p42 (e.g., extracellular signal-regulated kinase [ERK]1/2), the steroid-receptor coactivator Src and Shc (Src-homology/collagen protein). The study was performed in 3-week-old bile duct-ligated (BDL) rats, BDL rats treated with the antiestrogens, tamoxifen or Ici 182,780, and normal control rats. Proliferation was also evaluated in normal purified cholangiocytes treated with 17 beta estradiol in the presence or absence of tamoxifen, Ici 182,780, ERK, or Src inhibitors. After bile duct ligation, cholangiocyte proliferation was associated with a marked immunohistochemical nuclear positivity for phosphorylated (p)-ERK1/2, which was inhibited by in vivo treatment with tamoxifen or Ici 182,780. Protein expression of total and p-ERK1/2, and Shc in cholangiocytes isolated from BDL rats was markedly increased compared with controls and was inhibited by in vivo treatment with antiestrogens. In vitro, 17 beta estradiol-induced proliferation of isolated normal cholangiocyte was associated with increased (P <.01) protein expression of p-ERK1/2, Src, and Shc. Specific inhibitors of ER (Ici 182,780), ERK (U0125), and Src (PP2) inhibited in vitro 17 beta estradiol-induced cholangiocyte proliferation. In conclusion, this study showed that estrogens induced cholangiocyte proliferation by activating the Src/Shc/ERK pathway. This might suggest that pharmacologic modulation of ER, ERK, and/or Src could be proposed for the treatment of human pathology characterized by dysregulation of cholangiocyte proliferation.

Animals↗
PubMed2002

Antitumorigenic and antiinsulinogenic effects of calcitriol on insulinoma cells and solid beta-cell tumors.

Malignant insulinoma is a rare form of cancer with a poor prognosis because of metastatic dissemination and untreatable hypoglycemia. Effective chemotherapy of patients who are not cured by surgery is needed. Calcitriol has known anticancer properties on different neoplastic cell lines, but no data are available regarding its activity on tumorigenic pancreatic beta-cells. We analyzed the in vitro effects of calcitriol on the murine insulinoma cell line betaTC(3) and primary cultures of human isolated islets and benign insulinoma. The effect of in vivo calcitriol administration on insulinoma of recombinant insulin/Simian virus 40 oncogene-expressing transgenic mice was also investigated. In betaTC(3), calcitriol induced growth inhibition; apoptosis; down-regulation of insulin gene expression; and nongenomic activation of the MAPK pathway. MAPK kinase inhibitor (UO126) and staurosporine reduced calcitriol-mediated betaTC(3) death, and down-regulation of insulin gene transcription was prevented by staurosporine but not UO126. Calcitriol significantly decreased insulin release and mRNA levels of human islets and insulinoma cells. Finally, recombinant insulin/Simian virus 40 oncogene-expressing transgenic mice treated with calcitriol showed reduced insulinoma volumes because of increased apoptosis of adenomatous cells. Together, these findings provide the rationale for testing the efficacy of calcitriol in the treatment of patients with solid beta-cell tumors.

Animals↗
PubMed2002

Laparoscopic adjustable gastric banding for the treatment of morbid (grade 3) obesity and its metabolic complications: a three-year study.

Weight loss ameliorates arterial hypertension and glucose metabolism in obese patients, but the dietary approach is unsatisfactory because obesity relapses. Durable reduction of body weight, obtained through major nonreversible surgical procedures, such as jejunal and gastric bypass, allows improvement of glucose metabolism and arterial blood pressure in morbid (grade 3) obesity. Laparoscopic adjustable gastric banding (LAGB) is a minimally invasive and reversible surgical procedure that yields a significant reduction of gastric volume and hunger sensation. In this study, 143 patients with grade 3 obesity [27 men and 116 women; age, 42.9 +/- 0.83 yr; body mass index (BMI), 44.9 +/- 0.53 kg/m(2); normal glucose tolerance (NGT; n = 77); impaired glucose tolerance (IGT; n = 47); type 2 diabetes mellitus (T2DM; n = 19)] underwent LAGB and a 3-yr follow-up for clinical (BMI, waist circumference, waist to hip ratio, and arterial blood pressure) and metabolic variables (glycosylated hemoglobin, fasting insulin and glucose, insulin and glucose response to oral glucose tolerance test, homeostasis model assessment index, total and high-density lipoprotein cholesterol, triglycerides, uric acid, and transaminases). At baseline and 1 yr after LAGB, patients underwent computerized tomography and ultrasound evaluation of visceral and sc adipose tissue. One-year metabolic results were compared with 120 obese patients (51 men and 69 women; age, 42.9 +/- 1.11 yr; BMI, 43.6 +/- 0.46 kg/m(2); NGT, n = 66; IGT, n = 8; T2DM, n = 46) receiving standard dietary treatment. LAGB induced a significant and persistent weight loss and decrease of blood pressure. Greater metabolic effects were observed in T2DM patients than in NGT and IGT patients, so that at 3 yr glycosylated hemoglobin was no longer different in NGT and T2DM subjects. Clinical and metabolic improvements were proportional to the amount of weight loss. LAGB induced a greater reduction of visceral fat than sc fat. At 1-yr evaluation, weight loss and metabolic improvements were greater in LAGB-treated than diet-treated patients. We conclude that LAGB is an effective treatment of grade 3 obesity in inducing long-lasting reduction of body weight and arterial blood pressure, modifying body fat distribution, and improving glucose and lipid metabolism, especially in T2DM.

Adult↗
PubMed2002

Effects of carboxypeptidase E overexpression on insulin mRNA levels, regulated insulin secretion, and proinsulin processing of pituitary GH3 cells transfected with a furin-cleavable human proinsulin cDNA.

We recently developed two rat pituitary GH3 cell clones engineered to secrete human insulin (InsGH3). InsGH3 cells convert proinsulin into mature insulin, which is partially stored into a readily releasable pool of secretory granules. The efficiency of these processes, however, is relatively low in these cells, either in vitro or in vivo. This study was aimed at determining whether carboxypeptidase E (Cpe) overexpression can increase proinsulin processing and regulated secretion by InsGH3 clones. Indeed, in its membrane-bound form Cpe works as sorting receptor for the regulated secretory pathway of many hormones while, in its soluble form, Cpe takes part to the late step of insulin maturation. We obtained two Cpe-overexpressing cell lines from two different InsGH3 clones (InsGH3/C1 and C7). In the Cpe-overexpressing cell lines, derived from InsGH3 of clone 1 (InsGH3/C1-HACpe), in which the membrane-bound form of exogenous Cpe is accounted for by 90% of total Cpe immunoreactivity, we observed an increase in proinsulin gene expression, and in basal and stimulated insulin secretion compared with the original clone. In contrast, in the Cpe-overexpressing cell line derived from InsGH3 of clone 7 (InsGH3/C7-HACpe), where the exogenous membrane-bound form was only 60% of total Cpe, we detected a decrease in basal insulin release and a modest, albeit significant, increase in intracellular proinsulin processing. In conclusion, Cpe overexpression can increase regulated insulin secretion and proinsulin processing in InsGH3 cells; however, such improvements appear quantitatively and qualitatively modest.

Animals↗
PubMedDate not supplied

The multi-faceted cross-talk between the insulin and angiotensin II signaling systems.

Insulin and angiotensin II are hormones that play pivotal roles in the control of two vital and closely related systems, the metabolic and the circulatory systems, respectively. A failure in the proper action of each of these hormones results, to a variable degree, in the development of two highly prevalent and commonly overlapping diseases-diabetes mellitus and hypertension. In recent years, a series of studies has revealed a tight connection between the signal transduction pathways that mediate insulin and angiotensin II actions in target tissues. This molecular cross-talk occurs at multiple levels and plays an important role in phenomena that range from the action of anti-hypertensive drugs to cardiac hypertrophy and energy acquisition by the heart. At the extracellular level, the angiotensin-converting enzyme controls angiotensin II synthesis but also interferes with insulin signaling through the proper regulation of angiotensin II and through the accumulation of bradykinin. At an early intracellular level, angiotensin II, acting through JAK-2/IRS-1/PI3-kinase, JNK and ERK, may induce the serine phosphorylation and inhibition of key elements of the insulin-signaling pathway. Finally, by inducing the expression of the regulatory protein SOCS-3, angiotensin II may impose a late control on the insulin signal. This review will focus on the main advances obtained in this field and will discuss the implications of this molecular cross-talk in the common clinical association between diabetes mellitus and hypertension.

Angiotensin II↗
PubMedDate not supplied

Morphological and ultrastructural features of human islet grafts performed in diabetic nude mice.

Islet transplantation is a new therapeutic approach to type 1 diabetes mellitus. However, in several patients insulin levels are not restored and the glycemic control is inadequate. To clarify the cause of graft failure, the authors investigated with light and electron microscopy some human islet grafts before and after transplantation under the kidney capsule of streptozotocin-induced diabetic nude mice. In isolated islets, both pre- and post-transplantation, the endocrine component was scarcely represented, the beta/alpha cell ratio was reduced, and beta cells showed degenerative aspects such as apoptosis, immature secretory granules, and amylin fibrils deposition. The authors conclude that islet graft failure may be due to an insufficient beta cell mass related to their distress probably caused by anoxia and/or overstimulation.

Animals↗