Renzo Cordera

Insulin-like growth factor-1 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.

Effects of biliopanceratic diversion on type 2 diabetes in patients with BMI 25 to 35.

Objective:Biliopancreatic diversion (BPD) resolves type 2 diabetes in near totality of morbidly obeses [BMI (body mass index) ≥35 kg/m2]. However, studies of BPD effect in BMI range 25.0 to 34.9 kg/m2, including about 90% of diabetic patients, are lacking. Materials and Methods:If BPD effects are independent of weight changes, they should be maintained in patients who, being mildly obese or overweight, will lose little or no weight after operation. Thirty type 2 diabetic patients with BMI 25 to 34.9 were submitted to BPD and monitored 12 months. Thirty-eight diabetic patients selected from a large database, kept 1 year on medical therapy, served as controls. Results:Nineteen male and 11 female. Mean age 56.4 ± 7.4 years, weight 84.8 ± 11.1 kg, BMI 30.6 ± 2.9 kg/m2, waist circumference 104 ± 9.4 cm, diabetes duration 11.2 ± 6.9 years, HbA1c 9.3±1.5. Twelve patients on insulin. Fifteen (2 F) with BMI < 30 (mean: 28.1). No mortality or major adverse events occurred. BMI progressively decreased, stabilizing around 25 since the fourth month, without excessive weight loss. One year after BPD, mean HbA1c was 6.3%±0.8, with 25 patients (83%) controlled (HbA1c⩽7%) on free diet, without antidiabetics, and the remaining improved. Acute insulin response to intravenous glucose had increased from 1.2 ± 2.9 to 4.2 ± 4.4 &mgr;IU/mL. Diabetes resolution correlated positively with BMI. HbA1c decreased at 1 year in the control group, along with an overall increased amount of antidiabetic therapy. Conclusions:BPD improves or resolves diabetes in BMI 25 to 35 without causing excessive weight loss, its action being on insulin sensitivity and beta-cell function. The strikingly different response between morbidly obese and low BMI patients might depend on different beta-cell defect. ClinicalTrials.gov Identifier: NCT00996294

Restoration of Acute Insulin Response in T2DM Subjects 1 Month After Biliopancreatic Diversion

Objective: Biliopancreatic diversion (BPD) restores normal glucose tolerance in a few weeks in morbid obese subjects with type 2 diabetes, improving insulin sensitivity. However, there is less known about the effects of BPD on insulin secretion. We tested the early effects of BPD on insulin secretion in obese subjects with and without type 2 diabetes.

Direct inhibition of hexokinase activity by metformin at least partially impairs glucose metabolism and tumor growth in experimental breast cancer

Emerging evidence suggests that metformin, a widely used anti-diabetic drug, may be useful in the prevention and treatment of different cancers. In the present study, we demonstrate that metformin directly inhibits the enzymatic function of hexokinase (HK) I and II in a cell line of triple-negative breast cancer (MDA-MB-231). The inhibition is selective for these isoforms, as documented by experiments with purified HK I and II as well as with cell lysates. Measurements of 18F-fluoro-deoxyglycose uptake document that it is dose- and time-dependent and powerful enough to virtually abolish glucose consumption despite unchanged availability of membrane glucose transporters. The profound energetic imbalance activates phosphorylation and is subsequently followed by cell death. More importantly, the “in vivo” relevance of this effect is confirmed by studies of orthotopic xenografts of MDA-MB-231 cells in athymic (nu/nu) mice. Administration of high drug doses after tumor development caused an evident tumor necrosis in a time as short as 48 h. On the other hand, 1 mo metformin treatment markedly reduced cancer glucose consumption and growth. Taken together, our results strongly suggest that HK inhibition contributes to metformin therapeutic and preventive potential in breast cancer.

High-molecular weight adiponectin isoforms increase after biliopancreatic diversion in obese subjects.

Objective: Our objective was to test the effect of biliopancreatic diversion (BDP) in adiponectin multimerization. Adiponectin, the major protein secreted by adipose tissue, circulates in plasma in different isoforms. The most clinically relevant oligomers are high‐molecular weight (HMW) multimers and low‐molecular weight (LMW) trimers. Contrasting data on the effect of weight loss on adiponectin isoforms have been reported.

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.

Alterations in the autonomic control of heart rate variability in patients with anorexia or bulimia nervosa: Correlations between sympathovagal activity, clinical features, and leptin levels

Changes in body composition, hormone secretions, and heart function with increased risk of sudden death occur in eating disorders. In this observational clinical study, we evaluated sympathovagal modulation of heart rate variability (HRV) and cardiovascular changes in response to lying-to-standing in patients with anorexia (AN) or bulimia nervosa (BN) to analyze: a) differences in autonomic activity between AN, BN, and healthy subjects; b) relationships between autonomic and cardiovascular parameters, clinical data and leptin levels in patients with eating disorders. HRV, assessed by power spectral analysis of R-R intervals, blood pressure (BP) and heart rate (HR) were studied by tilt-table test in 34 patients with AN, 16 with BN and 30 healthy controls. Autonomic and cardiovascular findings were correlated with clinical data, and serum leptin levels. Leptin levels were lowered in AN vs BN and healthy subjects (p<0.0001), but both AN and BN patients showed unbalanced sympathovagal control of HRV due to relative sympathetic failure, prevalent vagal activity, impaired sympathetic activation after tilting, independently from their actual body weight and leptin levels. No significant correlations were obtained between HRV data vs clinical data, BP and HR findings, and leptin levels in eating disorders. Body mass indices (BMI) (p<0.02), and leptin levels (p<0.04) correlated directly with BP values. Our data showed alterations of sympathovagal control of HRV in eating disorders. These changes were unrelated to body weight and BMI, diagnosis of AN or BN, and leptin levels despite the reported effects of leptin on the sympathetic activity.

IGF-I induces caveolin 1 tyrosine phosphorylation and translocation in the lipid rafts

Caveolin 1, a component of caveolae, regulates signalling pathways compartmentalization interacting with tyrosine kinase receptors and their substrates. The role of caveolin 1 in the Insulin Receptor (IR) signalling has been well investigated. On the contrary, the functional link between caveolin 1 and IGF-I Receptor (IGF-IR) remains largely unknown. Here we show that (1) IGF-IR colocalizes with caveolin 1 in the lipid rafts enriched fractions on plasmamembrane in R-IGF-IR(WT) cells, (2) IGF-I induces caveolin 1 phosphorylation at the level of tyrosine 14, (3) this effect is rapid and results in the translocation of caveolin 1 and in the formation of membrane patches on cell surface. These actions are IGF-I specific since we did not detect caveolin 1 redistribution in insulin stimulated R(-) cells overexpressing IRs.

Recovery of Insulin Sensitivity in Obese Patients at Short Term After Biliopancreatic Diversion

OBJECTIVE To gain insight into the specific mechanisms by which biliopancreatic diversion (BPD) can improve insulin action. MATERIALS AND METHODS Nondiabetic severely obese patients (n=20) undergoing BPD were included. Waist-to-hip ratio and serum concentration of glucose, insulin, and leptin were determined before, at 4-day, and at 2 months after the operation. Insulin sensitivity was calculated according to the homeostatic model assessment (HOMA IR). RESULTS A marked increase of insulin sensitivity was observed by the fourth day after the operation; at the second postoperative month, when body weight was still in the obese range and the food intake was substantially similar to the preoperative one, a further improvement of insulin action towards normality was found. Moreover, before BPD HOMA IR data were independently correlated both to BMI and waist-to-hip ratio values, whereas at 2 months after the operation data were in positive correlation only with the BMI. DISCUSSION In obese patients, BPD seems to achieve recovery of insulin sensitivity by specific mechanisms independent of weight loss: the main causes of this sharp improvement might be both the intramyocellular fat depletion and the interruption of enteroinsular axis.

Metformin Impairs Glucose Consumption and Survival in Calu-1 Cells by Direct Inhibition of Hexokinase-II

The anti-hyperglycaemic drug metformin has important anticancer properties as shown by the direct inhibition of cancer cells proliferation. Tumor cells avidly use glucose as a source for energy production and cell building blocks. Critical to this phenotype is the production of glucose-6-phosphate (G6P), catalysed by hexokinases (HK) I and II, whose role in glucose retention and metabolism is highly advantageous for cell survival and proliferation. Here we show that metformin impairs the enzymatic function of HKI and II in Calu-1 cells. This inhibition virtually abolishes cell glucose uptake and phosphorylation as documented by the reduced entrapment of 18F-fluorodeoxyglucose. In-silico models indicate that this action is due to metformin capability to mimic G6P features by steadily binding its pocket in HKII. The impairment of this energy source results in mitochondrial depolarization and subsequent cell death. These results could represent a starting point to open effective strategies in cancer prevention and treatment.