Publications by authors named "Alessia Gravina"

32 Publications

Hypoimmune induced pluripotent stem cell-derived cell therapeutics treat cardiovascular and pulmonary diseases in immunocompetent allogeneic mice.

Proc Natl Acad Sci U S A 2021 07;118(28)

Division of Cardiothoracic Surgery, Department of Surgery, Transplant and Stem Cell Immunobiology Laboratory, University of California, San Francisco, CA 94143;

The emerging field of regenerative cell therapy is still limited by the few cell types that can reliably be differentiated from pluripotent stem cells and by the immune hurdle of commercially scalable allogeneic cell therapeutics. Here, we show that gene-edited, immune-evasive cell grafts can survive and successfully treat diseases in immunocompetent, fully allogeneic recipients. Transplanted endothelial cells improved perfusion and increased the likelihood of limb preservation in mice with critical limb ischemia. Endothelial cell grafts transduced to express a transgene for alpha1-antitrypsin (A1AT) successfully restored physiologic A1AT serum levels in mice with genetic A1AT deficiency. This cell therapy prevented both structural and functional changes of emphysematous lung disease. A mixture of endothelial cells and cardiomyocytes was injected into infarcted mouse hearts, and both cell types orthotopically engrafted in the ischemic areas. Cell therapy led to an improvement in invasive hemodynamic heart failure parameters. Our study supports the development of hypoimmune, universal regenerative cell therapeutics for cost-effective treatments of major diseases.
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http://dx.doi.org/10.1073/pnas.2022091118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285900PMC
July 2021

The SIRPα-CD47 immune checkpoint in NK cells.

J Exp Med 2021 03;218(3)

Department of Surgery, Division of Cardiothoracic Surgery, Transplant and Stem Cell Immunobiology Lab, University of California, San Francisco, San Francisco, CA.

Here we report on the existence and functionality of the immune checkpoint signal regulatory protein α (SIRPα) in NK cells and describe how it can be modulated for cell therapy. NK cell SIRPα is up-regulated upon IL-2 stimulation, interacts with target cell CD47 in a threshold-dependent manner, and counters other stimulatory signals, including IL-2, CD16, or NKG2D. Elevated expression of CD47 protected K562 tumor cells and mouse and human MHC class I-deficient target cells against SIRPα+ primary NK cells, but not against SIRPα- NKL or NK92 cells. SIRPα deficiency or antibody blockade increased the killing capacity of NK cells. Overexpression of rhesus monkey CD47 in human MHC-deficient cells prevented cytotoxicity by rhesus NK cells in a xenogeneic setting. The SIRPα-CD47 axis was found to be highly species specific. Together, the results demonstrate that disruption of the SIRPα-CD47 immune checkpoint may augment NK cell antitumor responses and that elevated expression of CD47 may prevent NK cell-mediated killing of allogeneic and xenogeneic tissues.
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http://dx.doi.org/10.1084/jem.20200839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7802363PMC
March 2021

The H-Y Antigen in Embryonic Stem Cells Causes Rejection in Syngeneic Female Recipients.

Stem Cells Dev 2020 09 25;29(18):1179-1189. Epub 2020 Aug 25.

Transplant and Stem Cell Immunobiology Lab, Department of Surgery, University of California, San Francisco, California, USA.

Pluripotent stem cells are promising candidates for cell-based regenerative therapies. To avoid rejection of transplanted cells, several approaches are being pursued to reduce immunogenicity of the cells or modulate the recipient's immune response. These include gene editing to reduce the antigenicity of cell products, immunosuppression of the host, or using major histocompatibility complex-matched cells from cell banks. In this context, we have investigated the antigenicity of H-Y antigens, a class of minor histocompatibility antigens encoded by the Y chromosome, to assess whether the gender of the donor affects the cell's antigenicity. In a murine transplant model, we show that the H-Y antigen in undifferentiated embryonic stem cells (ESCs), as well as ESC-derived endothelial cells, provokes T- and B cell responses in female recipients.
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http://dx.doi.org/10.1089/scd.2019.0299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7482111PMC
September 2020

Genetic activation of Nrf2 reduces cutaneous symptoms in a murine model of Netherton syndrome.

Dis Model Mech 2020 06 1;13(5). Epub 2020 Jun 1.

Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, 8093 Zurich, Switzerland

Netherton syndrome is a monogenic autosomal recessive disorder primarily characterized by the detachment of the uppermost layer of the epidermis, the It results from mutations in the gene, which codes for a kallikrein inhibitor. Uncontrolled kallikrein activity leads to premature desquamation, resulting in a severe epidermal barrier defect and subsequent life-threatening systemic infections and chronic cutaneous inflammation. Here, we show that genetic activation of the transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nfe2l2/Nrf2) in keratinocytes of knockout mice, a model for Netherton syndrome, significantly alleviates their cutaneous phenotype. Nrf2 activation promoted attachment of the and concomitant epidermal barrier function, and reduced the expression of pro-inflammatory cytokines such as tumor necrosis factor α and thymic stromal lymphopoietin. Mechanistically, we show that Nrf2 activation induces overexpression of secretory leukocyte protease inhibitor (Slpi), a known inhibitor of kallikrein 7 and elastase 2, in mouse and human keratinocytes and , respectively. In the Spink5-deficient epidermis, the upregulation of Slpi is likely to promote stabilization of corneodesmosomes, thereby preventing premature desquamation. Our results suggest pharmacological NRF2 activation as a promising treatment modality for Netherton syndrome patients.This article has an associated First Person interview with the first author of the paper.
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http://dx.doi.org/10.1242/dmm.042648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286291PMC
June 2020

A Cryoinjury Model to Study Myocardial Infarction in the Mouse.

J Vis Exp 2019 09 19(151). Epub 2019 Sep 19.

Transplant and Stem Cell Immunobiology Lab, University Heart Center; Department of Surgery, Transplant and Stem Cell Immunobiology Lab, University of California San Francisco; Cardiovascular Research Center (CVRC) and DZHK German Center for Cardiovascular Research; Cardiovascular Surgery, University Heart Center;

The use of animal models is essential for developing new therapeutic strategies for acute coronary syndrome and its complications. In this article, we demonstrate a murine cryoinjury infarct model that generates precise infarct sizes with high reproducibility and replicability. In brief, after intubation and sternotomy of the animal, the heart is lifted from the thorax. The probe of a handheld liquid nitrogen delivery system is applied onto the myocardial wall to induce cryoinjury. Impaired ventricular function and electrical conduction can be monitored with echocardiography or optical mapping. Transmural myocardial remodeling of the infarcted area is characterized by collagen deposition and loss of cardiomyocytes. Compared to other models (e.g., LAD-ligation), this model utilizes a handheld liquid nitrogen delivery system to generate more uniform infarct sizes.
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http://dx.doi.org/10.3791/59958DOI Listing
September 2019

De novo mutations in mitochondrial DNA of iPSCs produce immunogenic neoepitopes in mice and humans.

Nat Biotechnol 2019 10 19;37(10):1137-1144. Epub 2019 Aug 19.

Department of Surgery, Division of Cardiothoracic Surgery, Transplant and Stem Cell Immunobiology Lab, University of California, San Francisco, San Francisco, CA, USA.

The utility of autologous induced pluripotent stem cell (iPSC) therapies for tissue regeneration depends on reliable production of immunologically silent functional iPSC derivatives. However, rejection of autologous iPSC-derived cells has been reported, although the mechanism underlying rejection is largely unknown. We hypothesized that de novo mutations in mitochondrial DNA (mtDNA), which has far less reliable repair mechanisms than chromosomal DNA, might produce neoantigens capable of eliciting immune recognition and rejection. Here we present evidence in mice and humans that nonsynonymous mtDNA mutations can arise and become enriched during reprogramming to the iPSC stage, long-term culture and differentiation into target cells. These mtDNA mutations encode neoantigens that provoke an immune response that is highly specific and dependent on the host major histocompatibility complex genotype. Our results reveal that autologous iPSCs and their derivatives are not inherently immunologically inert for autologous transplantation and suggest that iPSC-derived products should be screened for mtDNA mutations.
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http://dx.doi.org/10.1038/s41587-019-0227-7DOI Listing
October 2019

Hypoimmunogenic derivatives of induced pluripotent stem cells evade immune rejection in fully immunocompetent allogeneic recipients.

Nat Biotechnol 2019 03 18;37(3):252-258. Epub 2019 Feb 18.

Department of Surgery, Division of Cardiothoracic Surgery, Transplant and Stem Cell Immunobiology-Lab, University of California San Francisco, San Francisco, CA, USA.

Autologous induced pluripotent stem cells (iPSCs) constitute an unlimited cell source for patient-specific cell-based organ repair strategies. However, their generation and subsequent differentiation into specific cells or tissues entail cell line-specific manufacturing challenges and form a lengthy process that precludes acute treatment modalities. These shortcomings could be overcome by using prefabricated allogeneic cell or tissue products, but the vigorous immune response against histo-incompatible cells has prevented the successful implementation of this approach. Here we show that both mouse and human iPSCs lose their immunogenicity when major histocompatibility complex (MHC) class I and II genes are inactivated and CD47 is over-expressed. These hypoimmunogenic iPSCs retain their pluripotent stem cell potential and differentiation capacity. Endothelial cells, smooth muscle cells, and cardiomyocytes derived from hypoimmunogenic mouse or human iPSCs reliably evade immune rejection in fully MHC-mismatched allogeneic recipients and survive long-term without the use of immunosuppression. These findings suggest that hypoimmunogenic cell grafts can be engineered for universal transplantation.
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http://dx.doi.org/10.1038/s41587-019-0016-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6419516PMC
March 2019

Sibutramine and L-carnitine compared to sibutramine alone on insulin resistance in diabetic patients.

Intern Med 2010 13;49(16):1717-25. Epub 2010 Aug 13.

Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy.

Objective: To evaluate the effects of one year of treatment with sibutramine plus L-carnitine compared to sibutramine on body weight, glycemic control, and insulin resistance state in type 2 diabetic patients.

Methods: Two hundred and fifty-four patients with uncontrolled type 2 diabetes mellitus (T2DM) [glycated hemoglobin (HbA(1c)) >8.0%] in therapy with different oral hypoglycemic agents or insulin were enrolled in this study and randomised to take sibutramine 10 mg plus L-carnitine 2 g or sibutramine 10 mg in monotherapy. We evaluated at baseline, and after 3, 6, 9, and 12 months these parameters: body weight, body mass index (BMI), glycated hemoglobin (HbA(1c)), fasting plasma glucose (FPG), post-prandial plasma glucose (PPG), fasting plasma insulin (FPI), homeostasis model assessment insulin resistance index (HOMA-IR), total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C), high density lipoprotein-cholesterol (HDL-C), triglycerides (Tg), retinol binding protein-4 (RBP-4), resistin, visfatin, high sensitivity-C reactive protein (Hs-CRP).

Results: There was a decrease in body weight, BMI, HbA(1c), FPI, HOMA-IR, and RBP-4 in both groups, even when the values obtained with sibutramine plus L-carnitine were lower than the values obtained in sibutramine group. There was a faster decrease of FPG, PPG, TC, LDL-C, resistin and Hs-CRP with sibutramine plus L-carnitine even when no differences between the two groups were obtained. Furthermore, only sibutramine plus L-carnitine improved Tg, and visfatin.

Conclusion: Sibutramine plus L-carnitine gave a faster improvement of lipid profile, insulin resistance parameters, glycemic control, and body weight compared to sibutramine.
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http://dx.doi.org/10.2169/internalmedicine.49.3401DOI Listing
May 2011

Comparison of orlistat treatment and placebo in obese type 2 diabetic patients.

Expert Opin Pharmacother 2010 08;11(12):1971-82

University of Pavia, Department of Internal Medicine and Therapeutics, 27100 Pavia, Italy.

Aim: To evaluate the effects of 1-year treatment with orlistat compared with placebo on different inflammatory parameters in type 2 obese diabetic patients.

Materials And Methods: Two hundred and fifty-four type 2 diabetic patients were randomized to take orlistat 120 mg three times a day or placebo for 12 months. We evaluated at baseline and after 3, 6, 9 and 12 months: leptin, tumor necrosis factor (TNF)-alpha, adiponectin (ADN), vaspin and high-sensitivity C-reactive protein (HS-CRP), body weight, waist circumference, body mass index (BMI), lipid profile, glycemic profile, fasting plasma insulin (FPI) and homeostasis model assessment insulin resistance index (HOMA-IR).

Results: Regarding inflammatory parameters, there was a significant improvement of ADN and TNF-alpha, and a faster decrease of leptin and HS-CRP in the orlistat group compared with the control group. We also recorded a significant reduction of body weight and BMI with orlistat, but not with placebo. A faster improvement of glycemic profile and FPI was obtained with orlistat compared with the controls. Also, there was a significant reduction of lipid profile with orlistat, not reached with placebo.

Conclusions: Orlistat was more effective than placebo in ameliorating inflammatory parameters such as ADN and TNF-alpha, and anthropometric parameters.
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http://dx.doi.org/10.1517/14656566.2010.493557DOI Listing
August 2010

Differential effects of candesartan and olmesartan on adipose tissue activity biomarkers in type II diabetic hypertensive patients.

Hypertens Res 2010 Aug 27;33(8):790-5. Epub 2010 May 27.

Department of Internal Medicine and Therapeutics, University of Pavia, PAVIA, Italy.

The aim of this study is to compare the effects of candesartan and olmesartan on insulin sensitivity-related parameters, before and after antihypertensive therapy. After a 4-week washout placebo period, 194 hypertensive (diastolic blood pressure (DBP) > or =80 mm Hg and systolic blood pressure (SBP) > or =130 mm Hg) patients with well-controlled type II diabetes were randomized to receive either 8 mg of candesartan once a day (o.d.) or 10 mg olmesartan o.d. and titrated after 1 month to 16 mg candesartan o.d. or 20 mg olmesartan o.d., respectively; the treatment period had a 1-year duration. We evaluated body weight, body mass index, SBP, DBP, glycated hemoglobin, fasting plasma glucose, M value, adiponectin (ADN), resistin (r), retinol-binding protein 4, visfatin, vaspin and high-sensitivity C-reactive protein (Hs-CRP) at their baseline values and after 6 and 12 months of treatment. We observed no variation in body weight or glycemic profile for either treatment. SBP and DBP were significantly reduced by both treatments (from 144+/-8/88+/-6 to 126+/-5/77+/-4 mm Hg by candesartan (P<0.001) and from 145+/-9/89+/-7 to 128+/-7/79+/-5 mm Hg by olmesartan (P<0.001)) without any difference between them. Retinol binding protein-4, r, and the vaspin value decreased in the candesartan group but not in olmesartan group. The M value, visfatin and ADN increased with candesartan, whereas no significant variations were observed with olmesartan. Both treatments resulted in a similar reduction in Hs-CRP. Although both therapies resulted in similar reductions in blood pressure, candesartan therapy was more effective than olmesartan therapy in improving insulin sensitivity.
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http://dx.doi.org/10.1038/hr.2010.85DOI Listing
August 2010

Effects of combination of sibutramine and L-carnitine compared with sibutramine monotherapy on inflammatory parameters in diabetic patients.

Metabolism 2011 Mar 27;60(3):421-9. Epub 2010 Apr 27.

Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy.

The aim of the study was to evaluate the effects of 12-month treatment with sibutramine plus L-carnitine compared with sibutramine alone on body weight, glycemic control, insulin resistance, and inflammatory state in type 2 diabetes mellitus patients. Two hundred fifty-four patients with uncontrolled type 2 diabetes mellitus (glycated hemoglobin [HbA(1c)] >8.0%) in therapy with different oral hypoglycemic agents or insulin were enrolled in this study and randomized to take sibutramine 10 mg plus L-carnitine 2 g or sibutramine 10 mg in monotherapy. We evaluated at baseline and after 3, 6, 9, and 12 months these parameters: body weight, body mass index, HbA(1c), fasting plasma glucose, postprandial plasma glucose, fasting plasma insulin, homeostasis model assessment of insulin resistance index, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, leptin, tumor necrosis factor-α, adiponectin, vaspin, and high-sensitivity C-reactive protein. Sibutramine plus L-carnitine gave a faster improvement of fasting plasma glucose, postprandial plasma glucose, lipid profile, leptin, tumor necrosis factor-α, and high-sensitivity C-reactive protein compared with sibutramine alone. Furthermore, there was a better improvement of body weight, HbA(1c), fasting plasma insulin, homeostasis model assessment of insulin resistance index, vaspin, and adiponectin with sibutramine plus L-carnitine compared with sibutramine alone. Sibutramine plus L-carnitine gave a better and faster improvement of all the analyzed parameters compared with sibutramine alone without giving any severe adverse effect.
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http://dx.doi.org/10.1016/j.metabol.2010.03.010DOI Listing
March 2011

Effects of a standardized oral fat load on vascular remodelling markers in healthy subjects.

Microvasc Res 2010 Jul 29;80(1):110-5. Epub 2010 Mar 29.

Department of Internal Medicine and Therapeutics, University of Pavia, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.

The most adequate way to experimentally reproduce the post-prandial lipemia condition appears to be the administration of a standardized oral fat load (OFL) to fasting patients. We studied the effects of a standardized OFL on markers of vascular remodelling in healthy subjects. We enrolled 286 Caucasians aged >or= 18 of either sex. The OFL was given after a 12-h fast. Blood samples were drawn before and 3, 6, 9 and 12h after the fat load. The following parameters were evaluated: body mass index (BMI), blood glucose (BG), systolic blood pressure (SBP), diastolic blood pressure (DBP), lipid profile, nitrites and nitrates, adiponectin (ADP), metalloproteinase-2 (MMP-2) and metalloproteinase-9 (MMP-9). High density lipoprotein-cholesterol (HDL-C) decrease was present in subjects after 6h. Triglycerides (Tg) change was observed after 6h. Nitrites/nitrates variation was observed after 6 and 9h during OFL. Adiponectin level was decreased after 6 and 9h during OFL. Both MMP-2 and MMP-9 levels were higher after 6h during OFL. We observed that nitrites/nitrates and ADP significantly decreased and MMP-2 and MMP-9 significantly increased after a standardized OFL. Other studies need to confirm the direct acute effects of post-prandial lipemia on vascular damage.
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http://dx.doi.org/10.1016/j.mvr.2010.03.012DOI Listing
July 2010

Modification of vascular and inflammation biomarkers after OGTT in overweight healthy and diabetic subjects.

Microvasc Res 2010 Mar 14;79(2):144-9. Epub 2010 Jan 14.

Department of Internal Medicine and Therapeutics, University of Pavia, Fondazione IRCCS Policlinico S. Matteo, Pavia, P. le C. Golgi, 2 - 27100 PAVIA, Italy.

We evaluated the effect of an oral glucose tolerance test (OGTT) on the level of biomarkers of vascular remodelling. We enrolled 256 Caucasian overweight healthy subjects (H) and 274 overweight type 2 diabetic patients (D). All patients underwent basal measurements of blood glucose (BG), nitrites/nitrates, adiponectin (ADP), matrix metalloproteinase-2 (MMP-2), and matrix metalloproteinase-9 (MMP-9) before and after OGTT. Nitrites/nitrates decrease was present after 60, 90, 120, and 180 min in both groups. Nitrite/nitrate levels were decreased at baseline, after 30 and 60 min in D group compared to H group. ADP decrease was present after 90, 120, and 180 min, in both groups. ADP levels were lower in D group than in H group during OGTT. MMP-2 increase was present after 60, 90, and 120 min in H group, while MMP-2 increase was observed after 90, 120, and 180 min in D group. MMP-2 levels were higher in D group than in H group during OGTT. MMP-9 increase was present in H group after 60, 90, 120, and 180 min, while MMP-9 increase was observed after 90, 120, and 180 min in D group. MMP-9 levels were higher in D group than in H group during OGTT. Postprandial glycemia induces an acute increase in biomarkers of vascular remodelling.
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http://dx.doi.org/10.1016/j.mvr.2010.01.002DOI Listing
March 2010

Candesartan effect on inflammation in hypertension.

Hypertens Res 2010 Mar 15;33(3):209-13. Epub 2010 Jan 15.

Department of Internal Medicine and Therapeutics, University of Pavia, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy.

The aim of this study was to evaluate the effect of candesartan on inflammatory biomarkers in hypertensive patients with and without type 2 diabetes mellitus after a standardized oral fat load (OFL). A total of 219 patients were enrolled: 106 patients were assigned to the non-diabetic hypertensive (NH) group, and 113 to the diabetic hypertensive (DH) group. All patients received candesartan therapy for 6 months and underwent a standardized OFL at baseline and after 6 months of therapy. We evaluated systolic blood pressure (SBP) and diastolic blood pressure (DBP), blood glucose (BG), triglycerides (Tg), soluble intercellular adhesion molecule-1 (sICAM-1), interleukin-6 (IL-6) and high-sensitivity C reactive protein (Hs-CRP). At baseline, glycated hemoglobin, homeostasis model assessment insulin resistance index, BG, fasting plasma insulin, Tg, sICAM-1, IL-6 and Hs-CRP in the DH group were significantly higher, whereas high-density lipoprotein-cholesterol value was significantly lower compared to NH group. After 6 months of candesartan therapy, sICAM-1, IL-6 and Hs-CRP were significantly lower compared to baseline in both groups; furthermore, there was a significant decrease of SBP and DBP values in both groups. After the OFL administered at baseline, there was an increase of Tg, sICAM-1, IL-6 and Hs-CRP in both groups. After the OFL administered after 6 months of therapy, instead, there was no significant variation of BG, Tg or sICAM-1 value in both groups, whereas there was an increase of IL-6 and Hs-CRP compared to time 0. We observed that candesartan treatment attenuated the inflammatory answer in both groups of patients, even if more efficiently in nondiabetic ones.
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http://dx.doi.org/10.1038/hr.2009.212DOI Listing
March 2010

Modulation of adipokines and vascular remodelling markers during OGTT with acarbose or pioglitazone treatment.

Biomed Pharmacother 2009 Dec 13;63(10):723-33. Epub 2009 Oct 13.

Department of Internal Medicine and Therapeutics, University of Pavia, Fondazione IRCCS Policlinico S. Matteo, P.le C. Golgi 2, 27100 PAVIA, Italy.

Adipose tissue secretes biologically active mediators as adipokines. We evaluate the effect of pioglitazone and acarbose on adipokines and vascular remodelling markers during an oral glucose tolerance test (OGTT). Height and body weight, BMI, glycemic and lipid profile, blood pressure, Nitrites/nitrates, ADP, resistin, MMP-2, and MMP-9 were evaluated at titration beginning, after 3, 6 months, and at the study end in 473 type 2 diabetic patients. BMI and weight increased after full treatment with pioglitazone respect to acarbose. HbA(1c) decreased after titration period with pioglitazone compared to baseline and to acarbose, and after full treatment with pioglitazone compared to the end of titration period and to acarbose. FPG decreased after full treatment with pioglitazone compared to the end of titration period. PPG decreased with acarbose after titration period respect to baseline and after full treatment respect to the end of titration period. FPI and Homa index decreased after titration period with pioglitazone compared to baseline and to acarbose, and after full treatment with pioglitazone respect to the end of titration period and to acarbose. ADP increased after titration period with pioglitazone compared to baseline and to acarbose, and after full treatment with pioglitazone compared to the end of titration period and to acarbose. Resistin decreased after titration period with pioglitazone compared to baseline and to acarbose, and after full treatment with pioglitazone respect to acarbose. Pioglitazone improves glucose metabolism and insulin-resistance compared to acarbose in type 2 diabetic patients already treated with metformin and sulphonilureas.
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http://dx.doi.org/10.1016/j.biopha.2009.04.044DOI Listing
December 2009

Fenofibrate, simvastatin and their combination in the management of dyslipidaemia in type 2 diabetic patients.

Curr Med Res Opin 2009 Aug;25(8):1973-83

Department of Internal Medicine and Therapeutics, University of Pavia, Fondazione IRCCS Policlinico S. Matteo, 2 - 27100 Pavia, Italy.

Objective: To evaluate the efficacy of fenofibrate, simvastatin or their combination in type 2 diabetic patients with combined dyslipidaemia.

Research Design And Methods: 241 patients, who had never previously taken lipid-lowering medications, received fenofibrate 145 mg/day, or simvastatin 40 mg/day, or fenofibrate 145 mg/day + simvastatin 40 mg/day combination for 12 months. We evaluated lipids, glycaemic, haemostatic, and inflammatory variables at baseline, and after 6 and 12 months.

Results: After 12 months total cholesterol (TC), LDL cholesterol (LDL-C) and triglycerides (Tg) decreased while HDL cholesterol (HDL-C) increased in all groups, even if the values obtained with fenofibrate + simvastatin were the best. At the end of the study apolipoprotein A-1 (Apo A-1) increased with fenofibrate + simvastatin, while apolipoprotein B (Apo B) decreased in all groups compared to baseline. Plasminogen activator inhibitor-1 (PAI-1) and high-sensitivity C reactive protein (hs-CRP) decreased after 12 months compared to baseline with simvastatin, and with fenofibrate + simvastatin even if the value obtained with fenofibrate-simvastatin was the lowest. After 12 months, fibrinogen (Fg) decreased compared to baseline with fenofibrate + simvastatin.

Limitations: This study has some limitations. The first one is the relatively small sample of studied patients. The second one is the lack of an advanced lipid proteins evaluation, such as lipoprotein subfraction changes in the different treatment regimen. Finally, we have not selected patients that could show the best response to fibrate (i.e.: hypertriglyceridemics) or statins (i.e.: hypercholesterolemics) monotherapy, so the effect of these drugs administered alone may have been partly attenuated.

Conclusions: Fenofibrate + simvastatin association improved lipid parameters, prothrombotic and inflammatory factors, and appeared to have a good tolerability profile over 12 months of therapy.
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http://dx.doi.org/10.1185/03007990903073159DOI Listing
August 2009

Oral fat load effects on inflammation and endothelial stress markers in healthy subjects.

Heart Vessels 2009 May 24;24(3):204-10. Epub 2009 May 24.

Department of Internal Medicine and Therapeutics, University of Pavia, Fondazione IRCCS, Policlinico San Matteo, P. C. Golgi 2, 27100 Pavia, Italy.

The aim was to study the effect of a standardized oral fat load (OFL) on different inflammatory parameters in a large sample of adult healthy subjects (n = 286) of both sexes. The fat load was given between 08:00 and 09:00 h after a 12-h fast. Blood samples were drawn before and 3, 6, 9, and 12 h after the OFL. All patients underwent a measurement of body mass index (BMI), blood glucose (BG), systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (Tg), soluble intercellular adhesion molecule-1 (sICAM-1), interleukin-6 (IL-6), high-sensitivity C-reactive protein (hsCRP), soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble E-selectin (sE-selectin), and tumor necrosis factor-alpha (TNF-alpha). Fasting plasma glucose (FPG) increase was +3.26% at 3 h, +4.35% at 6 h, +1.09% at 9 h while FPG decrease was -1.09% at 12 h. High-density lipoprotein cholesterol increase was +2.08% at 3 h, and at 12 h during OFL study; a significant HDL-C decrease was present in subjects after 6 h (-4.17%; P < 0.05 vs 0). A significant Tg change was observed after 6 h (+70.37%; P < 0.01 vs 0) and 9 h (+58.33%; P < 0.05 vs 0) respectively, and the increase was +22.22% at 3 h and +18.52% at 12 h. Total cholesterol increase was +0.52% after 3 h, +1.04% after 6 h, while after 12 h the decrease was -0.52%. Low-density lipoprotein cholesterol increase was +1.64% after 6 h with a decrease of -0.82% at 9 and 12 h. A significant sICAM-1, hsCRP, and sE-selectin variation was observed after 6 and 9 h, while a significant sVCAM-1 change occurred after 3, 6, and 9 h. Soluble ICAM-1 increase was +20.58% at 3 h, +34.10% at 6 h (P < 0.05 vs 0) +25.94% at 9 h (P < 0.01 vs 0), and +19.14% at 12 h; sVCAM-1 increase was +13.97% (P < 0.05 vs 0) at 3 h, +18.55% at 6 h (P < 0.01 vs 0), +12.02% at 9 h (P < 0.05 vs 0), and +8.70% at 12 h. High-sensitivity CRP increase was +36.36% at 3 h, +90.91% at 6 h (P < 0.01 vs 0), +63.64% at 9 h (P < 0.05 vs 0), and +36.36% at 12 h. Soluble E-selectin increase was +27.11% at 3 h, +51.90% at 6 h (P < 0.05 vs 0), +45.19% at 9 h (P < 0.01 vs 0), and +20.12% at 12 h. Interleukin-6 increase was +61.11% at 3 h (P < 0.05 vs 0), +83.33% at 6 h (P < 0.001 vs 0), +55.56% at 9 h (P < 0.01 vs 0), and +22.22% at 12 h. Tumor necrosis factor-alpha increase was +42.86% at 3 h (P < 0.05 vs 0), +71.43% at 6 h (P < 0.01 vs 0), (+50.00% at 9 h (P < 0.05 vs 0), and +28.57% at 12 h. We observed that the OFL induces a complex and massive systemic inflammatory response that includes IL-6, TNF-alpha, hsCRP, and cell adhesion molecules, even before Tg significantly rises.
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http://dx.doi.org/10.1007/s00380-008-1109-yDOI Listing
May 2009

Direct comparison among oral hypoglycemic agents and their association with insulin resistance evaluated by euglycemic hyperinsulinemic clamp: the 60's study.

Metabolism 2009 Aug 18;58(8):1059-66. Epub 2009 Jun 18.

Department of Internal Medicine and Therapeutics, University of Pavia, Fondazione IRCCS Policlinico S Matteo, 2-27100 Pavia, Italy.

The aim of the study was to compare the long-term effect of 4 antidiabetic treatment protocols on insulin resistance evaluated by euglycemic hyperinsulinemic clamp in type 2 diabetes mellitus patients. Two hundred seventy-one type 2 diabetes mellitus patients with poor glycemic control and who were overweight were enrolled in this study. Patients were randomized and titrated to take pioglitazone, metformin, pioglitazone + metformin, or glimepiride + metformin for 15 months. They underwent a euglycemic hyperinsulinemic clamp at baseline, after 3 months, and after 15 months. Anthropometric and metabolic measurements were assessed at baseline, after 3 months, and after 15 months. There was a decrease in glycated hemoglobin in all groups, but glycated hemoglobin value was lower in the group treated with pioglitazone + metformin compared with the groups treated with metformin alone and with pioglitazone alone. There was a decrease in fasting plasma glucose and postprandial plasma glucose values in all groups, but values obtained with pioglitazone + metformin were lower compared with values in the groups treated with metformin alone and with pioglitazone alone. Fasting plasma insulin and postprandial plasma insulin values were higher in the group treated with glimepiride + metformin compared with the other groups. After 15 months, glucose infusion rate and total glucose requirement values observed in the groups treated with pioglitazone alone and with pioglitazone + metformin were higher compared with the values in the group treated with metformin alone and with glimepiride + metformin; furthermore, values obtained in the group treated with pioglitazone + metformin were higher than the value obtained with pioglitazone alone. Pioglitazone-metformin-based therapeutic control is associated with the most quantitatively relevant improvement in insulin resistance-related parameters, whereas the sulfonylurea-metformin-including protocol has less relevant effects.
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http://dx.doi.org/10.1016/j.metabol.2009.03.007DOI Listing
August 2009

Effects of insulin therapy with continuous subcutaneous insulin infusion (CSII) in diabetic patients: comparison with multi-daily insulin injections therapy (MDI).

Endocr J 2009 7;56(4):571-8. Epub 2009 Apr 7.

Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy.

We compared the effects of continuous subcutaneous insulin infusion (CSII) and multi-daily insulin injections therapy (MDI) on glicemic control and on lipid profile in type 1 and type 2 diabetic patients. We divided the patients in two groups: in the first one (n=32) CSII was administered, in the second one (n=32) MDI was administered. HbA(1C) value was lower after 3, 6, 9, and 12 months with CSII compared to MDI. Fasting plasma glucose (FPG) value was lower with CSII after 3, 6, and 12 months compared to MDI. Post-prandial glucose (PPG) value was lower in the group with CSII after 3, 6, 9, and 12 months compared to MDI. A significant TC decrease was observed in the group treated with CSII at 9, and 12 months while a significant TC increase was observed with MDI at 6, and 12 months. A significant LDL-C decrease was obtained with CSII after 9, and 12 months while no significant changes were observed with MDI. A significant HDL-C increase was observed with CSII after 12 months. A significant Tg decrease was observed with CSII after 12 months while a significant Tg increase was observed with MDI at 6, and at 12 months. CSII therapy allows a faster and better achievement of the therapeutic target and also gives an improvement of the lipid profile.
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http://dx.doi.org/10.1507/endocrj.k08e-330DOI Listing
October 2009

Evaluation of metalloproteinase 2 and 9 levels and their inhibitors in combined dyslipidemia.

Clin Invest Med 2009 Apr 1;32(2):E124-32. Epub 2009 Apr 1.

Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy.

Purpose: To evaluate the distribution of matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), and their specific inhibitors in a sample of patients affected by mild dyslipidemia but not yet treated with antihyperlipidemic drugs.

Methods: One hundred and sixty-eight Caucasian patients aged >or=18 yr of either sex with combined dyslipidemia and who had never previously taken lipid-lowering medications were evaluated. As a control population, we enrolled 179 Caucasian healthy subjects, aged >or=18 yr of either sex. We evaluated body mass index (BMI), fasting plasma glucose (FPG), fasting plasma insulin (FPI), homeostasis model assessment (HOMA index), systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C), high density lipoprotein-cholesterol (HDL-C), triglycerides (Tg), lipoprotein(a) Lp(a), plasminogen activator inhibitor-1 (PAI-1), homocysteine (Hct), fibrinogen (Fg), high sensitivity C-reactive protein (Hs-CRP), adiponectin (ADP), MMP-2, MMP-9, tissue inhibitors of metalloproteinase-1 (TIMP-1), and tissue inhibitors of metalloproteinase-2 (TIMP-2).

Results: TC, Tg, and LDL-C were higher (P < < 0.05, P < < 0.01 and P < < 0.05, respectively) in the dyslipidemic group, while HDL-C levels were lower (P < < 0.01) compared with the control group. Increases of PAI-1, Hct, Fg, and Hs-CRP (P < < 0.01, P < < 0.05, P < < 0.05, and P < < 0.05, respectively) were present in the dyslipidemic group, while ADP level was lower (P < < 0.01) in the dyslipidemic patients compared with controls. MMP-2, MMP-9, TIMP-1, and TIMP-2 levels were higher (P < < 0.0001) in the dyslipidemic group.

Conclusions: Combined hyperlipidemic patients have increased levels of prothrombotic and microinflammatory parameters and higher levels of MMP-2, MMP-9, TIMP-1, and TIMP-2 than control subjects. The prognostic importance of this observation has to be evaluated in adequately designed prospective studies.
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http://dx.doi.org/10.25011/cim.v32i2.6030DOI Listing
April 2009

Continuous glucose monitoring system in free-living healthy subjects: results from a pilot study.

Diabetes Technol Ther 2009 Mar;11(3):159-69

Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy.

Background And Aim: The Continuous Glucose Monitoring System (CGMS) (Medtronic Minimed, Northridge, CA) provides an opportunity to better understand abnormalities in glucose metabolism in both healthy subjects and those with diabetes. The aims of our study were to assess the reliability of CGMS compared to self-monitoring of blood glucose (BG) and to analyze the graphs obtained in a sample of healthy free-living subjects in order to establish the suitability of CGMS in physiological studies.

Methods: Eighteen healthy adults, 12 women and six men, were enrolled in this study. Each subject performed 24-h CGMS and inserted 24 glycemic values, measured through a glucose meter, during their common daily activities. Three subjects were excluded from the analysis since they did not meet accuracy criteria. None of the participants received any advice as regard diet and physical activity. Means and standard deviations were used to summarize quantitative data. Normal distribution of data was tested with the Shapiro-Wilk W test. Differences over time and association between glucose levels with other variables were evaluated with linear regression models for repeated measures.

Results: We did not find statistically significant differences between CGMS measures and meter readings. In the subjects studied the mean glucose levels increase according to age, and we found a mean increase in glucose concentration of 0.50 mg/dL for every year of age. As regards gender, men presented a 4.63% higher mean glucose concentration than women. A 1.16% higher glucose concentration for every unit (kg/m(2)) of body mass index (BMI) was observed in both groups. All subjects presented glucose concentrations within the established range of normal glucose levels for 91% of the total duration of CGMS.

Conclusions: Our results suggest that long-term studies on larger groups of healthy subjects performing CGMS would be useful in order to better understand if BMI, daily stressors due to work or psychological stress, or other factors can influence daily BG variability and if these nonpathological alterations are related to development of glucose metabolism disorders.
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http://dx.doi.org/10.1089/dia.2008.0101DOI Listing
March 2009

Pioglitazone metabolic effect in metformin-intolerant obese patients treated with sibutramine.

Intern Med 2009 2;48(5):265-71. Epub 2009 Mar 2.

Department of Internal Medicine and Therapeutics, University of Pavia, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy.

Objective: Metformin is the drug of choice to treat obese type 2 diabetes patients because it reduces either insulin-resistance and body weight. We aimed to comparatively test the efficacy and tolerability of pioglitazone and sibutramine in metformin-intolerant obese type 2 diabetic patients treated with sibutramine.

Materials And Methods: Five hundred and seventy-six consecutive Caucasian obese type 2 diabetic patients were evaluated during a 12-months period and fifty-two patients were resulted intolerant to metformin at maximum dosage (3,000 mg/day). All intolerant patients to metformin received a treatment with pioglitazone (45 mg/day) and sibutramine (10 mg/day) and they were compared with fifty-three patients treated with metformin (3,000 mg/day) and sibutramine (10 mg/day) for 6 months in a single-blind controlled trial. We assessed body mass index, waist circumference, glycated hemoglobin, Fasting Plasma glucose, postprandial plasma glucose, fasting plasma insulin, postprandial plasma insulin, lipid profile, systolic blood pressure, diastolic blood pressure and heart rate at baseline and after 3, and 6 months.

Results: No body mass index change was observed at 3, and 6 months in pioglitazone + sibutramine group, while a significant reduction of body mass index and waist circumference was observed after 6 months in metformin + sibutramine group (p<0.05). A significant decrease of glycated hemoglobin, Fasting Plasma glucose, postprandial plasma glucose, fasting plasma insulin, postprandial plasma insulin and HOMA index was observed after 3, and 6 months in both groups (p<0.05, and p<0.01, respectively). A significant Tg reduction was present after 6 months (p<0.05) in both groups respect to the baseline values. No systolic blood pressure, diastolic blood pressure and heart rate change was obtained after 3, and 6 months in both groups.

Conclusion: Pioglitazone and sibutramine combination appears to be a short-term equally efficacious and well-tolerated therapeutic alternative respect to metformin-intolerant obese type 2 diabetic patients treated with sibutramine.
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http://dx.doi.org/10.2169/internalmedicine.48.1670DOI Listing
June 2009

Sibutramine effect on metabolic control of obese patients with type 2 diabetes mellitus treated with pioglitazone.

Metabolism 2008 Nov;57(11):1552-7

Department of Internal Medicine and Therapeutics, University of Pavia, 19-27100 Pavia, Italy.

Thiazolidinediones are supposed to be the pharmacologic agents that more physiologically fight the insulin resistance, but a possible adverse effect may be a weight increase. The aim of the study was to test the efficacy and tolerability of sibutramine on the metabolic effect of pioglitazone in obese patients with type 2 diabetes mellitus. All enrolled patients were required to have been diagnosed as being diabetic for at least 6 months and did not have glycemic control with diet and oral hypoglycemic agents such as sulfonylureas or metformin, both to the maximum tolerated dose. After a run-in period in which the eligible patients took a fixed dose of pioglitazone (30 mg/d), the patients were randomized to receive also sibutramine (10 mg/d) or placebo for 6 months. We assessed body mass index, hemoglobin A(1c) (HbA(1c)), fasting plasma glucose (FPG), postprandial plasma glucose (PPG), fasting plasma insulin (FPI), postprandial plasma insulin (PPI), lipid profile, lipoprotein parameters, and lipoprotein (a) at baseline and after 3 and 6 months. No body mass index change was observed after 3 and 6 months in the pioglitazone + placebo (pp) group. Significant decrease was present in the pioglitazone + sibutramine (ps) group after 3 (P < .05) and 6 months (P < .01) compared with the baseline values, and this variation was significant (P < .05) between groups. A significant HbA(1c) decrease was observed after 3 (P < .05) and 6 months (P < .01) in both groups with respect to the baseline values. There was no difference in HbA(1c) value between the 2 groups. No FPG, PPG, FPI, PPI, and homeostasis model assessment index change was observed at 3 months, whereas a significant decrease was present after 6 months (P < .05), in both groups with respect to the baseline values. There was no difference in FPG, PPG, FPI, PPI, and homeostasis model assessment index value between the pp and ps groups. No significant low-density lipoprotein cholesterol change was observed at 3 months, whereas a significant decrease was present after 6 months (P < .05), in both groups with respect to the baseline values. There was no difference in low-density lipoprotein cholesterol value between the pp and ps groups. No triglyceride variation was present at 3 and 6 months in the pp group and at 3 months in the ps group, whereas a significant decrease was observed at 6 months (P < .05) in the ps group with respect to the baseline values. There was no difference in triglyceride value between both groups. No high-density lipoprotein cholesterol, apolipoprotein A-I, apolipoprotein B, and lipoprotein (a) changes were present in both groups with respect to the baseline values. Sibutramine appears to be a tolerable and efficacious drug when added to pioglitazone for the global management of obese diabetic patients.
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http://dx.doi.org/10.1016/j.metabol.2008.06.010DOI Listing
November 2008

Rosiglitazone therapy improves insulin resistance parameters in overweight and obese diabetic patients intolerant to metformin.

Arch Med Res 2008 May 10;39(4):412-9. Epub 2008 Mar 10.

Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy.

Background: Few studies have directly compared rosiglitazone and metformin effects on adipocytokines. The aim was to observe the possible effects of rosiglitazone and metformin on glycemic control, insulin sensitivity, plasma leptin (pL), adiponectin (ADN), tumor necrosis factor-alpha (TNF-alpha), and resistin (R) in overweight and obese diabetic patients intolerant to metformin.

Methods: Six hundred and ninety-four consecutive overweight and obese type 2 diabetic patients were evaluated and 56 patients were intolerant to metformin at maximum dosage. We added rosiglitazone to metformin in these intolerant patients (RM) and we compared them with 61 patients treated with metformin (M) in a single-blind placebo-controlled trial. We evaluated body mass index (BMI), glycated hemoglobin (HbA(1c)), fasting plasma glucose (FPG), fasting plasma insulin (FPI), pL, ADN, TNF-alpha, and R at baseline and after 3 and 6 months. Furthermore, we calculated insulin resistance index (HOMA-index) using FPG and FPI.

Results: Glycated hemoglobin, FPG, FPI, and HOMA-index results were lower than baseline values in RM and M groups. Glycated hemoglobin and HOMA-index values were significantly lower in RM group compared to M group at 6 months. Plasma leptin, ADN, TNF-alpha, and R were significantly improved in RM group compared to M group at 6 months.

Conclusions: No BMI change was observed, probably because rosiglitazone was added to metformin, that could mitigate the body increase of rosiglitazone. Rosiglitazone improved glycemic control and insulin resistance-correlated parameters when added to intolerant metformin patients. These data suggest that rosiglitazone may be the drug of choice for the treatment of overweight and obese type 2 diabetic patients.
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http://dx.doi.org/10.1016/j.arcmed.2007.12.009DOI Listing
May 2008

Effects of nateglinide and glibenclamide on prothrombotic factors in naïve type 2 diabetic patients treated with metformin: a 1-year, double-blind, randomized clinical trial.

Intern Med 2007 16;46(22):1837-46. Epub 2007 Nov 16.

Department of Internal Medicine and Therapeutics, University of Pavia, Italy.

Objective: To evaluate the effect on coagulation and fibrinolysis parameters and on non-conventional cardiovascular risk factors of metformin plus nateglinide or glibenclamide in naïve type 2 diabetes patients.

Patients And Methods: A total of 248 type 2 diabetic patients were enrolled and randomly assigned to receive nateglinide or glibenclamide, and metformin for 12 months. We assessed body mass index (BMI), glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), postprandial plasma glucose (PPG), fasting plasma insulin (FPI), postprandial plasma insulin (PPI), homeostasis model assessment index (HOMA index), lipid profile with lipoprotein (a) [Lp(a)], fibrinogen (Fg), plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (t-PA), homocysteine (Hcy), systolic blood pressure (SBP), diastolic blood pressure (DBP).

Results: After 9 months of treatment, both tested drug combinations were similarly associated with a significant reduction in FPG (nateglinide, -17.2%; glibenclamide, -16.9%, both p<0.05) compared to the baseline, while HbA1c (-17.3%, p<0.05) and PPG (-15.2%, p<0.05) significantly decreased only in the nateglinide group. After one year of treatment, compared to the baseline the nateglinide group showed a significant reduction in HbA1c (-21%, p<0.01), FPG (-20.7%), p<0.01, PPG (-21.5%, p<0.05), HOMA index (-25.4%, p<0.05); the glibenclamide group, showed a significant reduction in HbA1c (-11%, p<0.05), FPG (-23.2%, p<0.05), PPG (-11.2%, p<0.05), and HOMA index (-23.9%, p<0.05) but to a minor extent. Moreover, the HbA1c difference value from baseline observed in the nateglinide-treated group was significantly higher than that observed in the glibenclamide group. Therefore the nateglinide-treated patients showed a significant reduction in some prothrombotic parameters (PAI-1=-19%, Lp(a)=-31%, and Hcy=-32.3%, all p<0.05), whereas the glibenclamide-treated patients did not.

Conclusion: Nateglinide appears to improve glycemic control as well as the levels of some prothrombotic parameters compared to glibenclamide when administered in combination with metformin.
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http://dx.doi.org/10.2169/internalmedicine.46.0320DOI Listing
December 2007

Metabolic and antihypertensive effects of moxonidine and moxonidine plus irbesartan in patients with type 2 diabetes mellitus and mild hypertension: a sequential, randomized, double-blind clinical trial.

Clin Ther 2007 Apr;29(4):602-10

Department o f Internal Medicine and Therapeutics, University of Pavia, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy.

Background: The autonomic nervous system plays an important part in the homeostasis of blood pressure (BP), and sympathetic overactivity may contribute to metabolic conditions such as glycemic intolerance or insulin resistance.

Objective: This study evaluated the anti-hypertensive and metabolic effects of moxonidine, a selective imidazoline II-receptor agonist that lowers BP by central inhibition of the sympathetic nervous system, and moxonidine plus the angiotensin II-receptor blocker irbesartan in patients with type 2 diabetes mellitus and mild hypertension.

Methods: This was a study in patients with type 2 diabetes previously untreated with medication and untreated mild hypertension (diastolic blood pressure [DBP] >90 and <105 mm Hg). For the first 3 months of the study, all patients were treated for hypertension with moxonidine 0.2 mg once daily (M0.2) to establish a moxonidine baseline. After this single-arm period, patients were randomized to receive double-blind treatment with moxonidine 0.2 mg BID (M0.4) or moxonidine 0.2 mg plus irbesartan 150 mg (M0.2+1) once daily for 3 months. Changes in DBP, systolic blood pressure (SBP), body mass index (BMI), fasting and postprandial plasma glucose (FPG and PPG), fasting and postprandial plasma insulin (FPI and PPI), glycosylated hemoglobin (HbA(1c)), Homeostasis Model Assessment of insulin sensitivity (HOMA-S), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) were evaluated at baseline, 3 months (end of single arm period), and 6 months (end of randomized treatment period).

Results: The study enrolled 99 patients (50 men, 49 women; mean [SD] age, 55 [7] years; mean BMI, 26.8 [0.9]). No significant changes in BMI, PPG, PPI, TC, or LDL-C were observed over the entire study period. At 3 months, treatment with M0.2 was associated with significant improvements from baseline in SBP and DBP (P < 0.05), whereas there were no significant changes in HbA(1c), FPG, FPI, HOMA-S, HDL-C, or TG. At 6 months, significant decreases from baseline in HbA(1c), FPG, FPI, HOMA-S, and TG were observed in the M0.4 group (all, P < 0.05), but not in the M0.2+1 group. The M0.4 group also had a significant increase from baseline in HDL-C (P < 0.05) that was not seen in the M0.2+1 group. The changes in FPI and HOMA-S were significantly greater in the M0.4 group compared with the M0.2+1 group (P < 0.05). Significant decreases from baseline in SBP and DBP were observed in both the M0.4 and M0.2+1 groups (P < 0.02 and P < 0.01, respectively). No patient withdrew from the study because of a drug-related adverse event, and there were no clinically significant drug-related changes in laboratory values during the study.

Conclusion: In these patients with type 2 diabetes and mild hypertension, the M0.4 group had greater improvements in measures of glucose metabolism and the plasma lipid profile compared with those treated with M0.2+1.
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http://dx.doi.org/10.1016/j.clinthera.2007.03.015DOI Listing
April 2007

Blood pressure control and inflammatory markers in type 2 diabetic patients treated with pioglitazone or rosiglitazone and metformin.

Hypertens Res 2007 May;30(5):387-94

Department of Internal Medicine and Therapeutics, University of Pavia, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy.

The aim of the study was to assess the effects of the combination of metformin plus pioglitazone or rosiglitazone on glucose and blood pressure in type 2 diabetic patients with metabolic syndrome, as well as its tolerability in those patients. In this 12-month, multicentric, double-blind, randomized, controlled, parallel-group trial, all patients began with metformin. Patients were randomized for self-administration of either pioglitazone or rosiglitazone for 12 months. We assessed body mass index (BMI), glycemic control (glycosylated hemoglobin [HbA(1c)], fasting and postprandial plasma glucose and insulin levels [FPG, PPG, FPI and PPI, respectively] and homeostasis model assessment [HOMA] index) and systolic and diastolic blood pressure (SBP and DBP, respectively), at baseline and at 3, 6, 9 and 12 months of treatment, as well as high-sensitivity C-reactive protein (hs-CRP), nitrites/nitrates and adiponectin (ADN) at baseline and at 12 months of treatment. Significant HbA(1c) decreases were obtained after 9 (p<0.05) and 12 (p<0.01) months in both groups. After 9 and 12 months, mean FPG and PPG levels were decreased in both groups (p<0.05 and p<0.01, respectively). We observed decreases in FPI and PPI at 9 and 12 months (p<0.05 and p<0.01, respectively) compared to the baseline values in both groups. Furthermore, HOMA index improvement over the baseline value was obtained only at 12 months (p<0.05) in both groups. SBP and DBP improved significantly (p<0.05, for each) in both groups after 12 months. hs-CRP decreased significantly (p<0.05) in both groups after 12 months; nitrites/nitrates and ADN increased significantly (p<0.05, for each) in both groups after 12 months. The combination of thiazolinediones and metformin is associated with a slight but significant improvement in the long-term blood pressure control of these patients, and with an improvement in the anti-inflammatory state, both of which are related to a similar reduction in insulin-resistance.
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http://dx.doi.org/10.1291/hypres.30.387DOI Listing
May 2007

Telmisartan and irbesartan therapy in type 2 diabetic patients treated with rosiglitazone: effects on insulin-resistance, leptin and tumor necrosis factor-alpha.

Hypertens Res 2006 Nov;29(11):849-56

Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy.

The aim of our study was to investigate the metabolic effect of telmisartan and irbesartan in subjects treated with rosiglitazone, a well-known insulin-sensitizing drug, in order to clarify the direct metabolic effects of the two former drugs. Patients were enrolled, evaluated, and followed at 3 Italian centers. We evaluated 188 type 2 diabetic patients with metabolic syndrome (94 males and 94 females in total; 49 males and 46 females, aged 56+/-5, treated with telmisartan; and 45 males and 48 females, aged 55+/-4, treated with irbesartan). All had been diabetic for at least 6 months, and glycemic control by the maximum tolerated dietary changes and maximum tolerated dose of oral hypoglycemic agents had been attempted and failed in all cases. All patients took a fixed dose of rosiglitazone, 4 mg/day. We administered telmisartan (40 mg/day) or irbesartan (150 mg/day) in a randomized, controlled, double-blind clinical manner. We evaluated body mass index (BMI), glycemic control (HbA1c fasting plasma glucose and insulin levels [FPG, and FPI, respectively], and homeostasis model assessment [HOMA] index), lipid profile (total cholesterol [TC], low density lipoprotein-cholesterol [LDL-C], high density lipoprotein-cholesterol [HDL-C], and triglycerides [TG]), systolic and diastolic blood pressure (SBP and DBP), tumor necrosis factor-alpha (TNF-alpha), and leptin during the 12 months of this treatment. No BMI change was observed after 6 or 12 months in either group. Significant decreases in HbAlc and FPG were observed after 6 months in the telmisartan group, and after 12 months in both groups. The decrease in HbA1c and FPG at 12 months was statistically significant only in the telmisartan group. A significant decrease in FPI was observed at 12 months in both groups, and this decrease was significantly greater in the telmisartan group. Significant decreases in the HOMA index were observed at 6 and 12 months in both groups, and the decrease in the HOMA index after 12 months was significantly greater in the telmisartan group than in the irbesartan group. Significant changes in SBP, DBP, TC, and LDL-C were observed after 6 and 12 months in both groups. Significant decreases in TNF-alpha and leptin levels were observed after 6 months in the telmisartan group, and after 12 months in both groups. In conclusion, in this study of patients with type 2 diabetes mellitus and metabolic syndrome, telmisartan seemed to result in a greater improvement in glycemic and lipid control and metabolic parameters related to metabolic syndrome compared to irbesartan. These observed metabolic effects of different angiotensin type 1 receptor blockers could be relevant when choosing a therapy to correct metabolic derangement of patients affected by metabolic syndrome and diabetes.
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http://dx.doi.org/10.1291/hypres.29.849DOI Listing
November 2006

Synergistic effect of doxazosin and acarbose in improving metabolic control in patients with impaired glucose tolerance.

Clin Drug Investig 2006 ;26(9):529-39

Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy.

Objective: The aim of this study was to evaluate if the expected improvement in glucose and lipid metabolism obtainable with doxazosin is or is not synergistic with standard antihyperglycaemic treatment using the alpha-glucosidase inhibitor acarbose.

Methods: Patients in this randomised, controlled, double-blind clinical trial were enrolled, evaluated and followed up at three Italian centres. We evaluated 107 patients (53 males and 54 females) with impaired glucose tolerance (IGT) as determined by oral glucose tolerance tests (OGTTs). All patients took a fixed dose of acarbose 150 mg/day for 3 months, after which they were titrated up to 300 mg/day for the next 3 months. In addition, patients were randomised to either placebo (53 patients: 27 males and 26 females, aged 50 +/- 4 [mean +/- SD] years) or doxazosin 4 mg/day (54 patients: 26 males and 28 females, aged 51 +/- 5 years) for the entire 6-month treatment period. Parameters evaluated during the 6-month treatment period included body mass index (BMI), glycaemic control (glycosylated haemoglobin [HbA(1c)], fasting plasma [FPG] and post-prandial plasma [PPG] glucose, fasting plasma [FPI] and post-prandial plasma [PPI] insulin levels, homeostasis model assessment [HOMA]-index [insulin resistance]), lipid profile (total cholesterol [TC], low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], and triglycerides [TG]), and systolic (SBP) and diastolic (DBP) blood pressure.

Results: Significant reductions in BMI, HbA(1c), FPG and PPG compared with baseline were observed after 6 months in both groups (p < 0.05). A significant decrease in FPI was obtained after 6 months (p < 0.05) in the doxazosin group compared with baseline, and this difference was also significant (p < 0.05) compared with the placebo group. Similarly, a significant decrease in HOMA-index was observed at 6 months (p < 0.05) compared with baseline in the doxazosin group, and this difference was also significant (p < 0.05) compared with the placebo group. Significant decreases in TC, LDL-C, HDL-C and TG (p < 0.05) were observed in the doxazosin group after 6 months compared with baseline values. Significant decreases in SBP and DBP were also observed at 3 months in the doxazosin group compared with baseline (p < 0.05), and these differences were significant (p < 0.05) compared with placebo. Furthermore, significant decreases in SBP and DBP were observed at 6 months (p < 0.01) in the doxazosin group compared with baseline, and these differences were also significant (p < 0.01) compared with placebo. All patients who completed an OGTT at 6 months (96 patients) were restored to normal glucose tolerance status.

Conclusion: In patients with IGT, doxazosin given in combination with acarbose seemed to improve glycaemic and lipid control compared with placebo, with the benefits observed appearing to extend beyond those expected from improvements in blood pressure. Patients in this study also benefited from acarbose therapy, which restored all patients from IGT to normal glucose tolerance status.
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http://dx.doi.org/10.2165/00044011-200626090-00006DOI Listing
January 2007

Effects of 1 year of treatment with pioglitazone or rosiglitazone added to glimepiride on lipoprotein (a) and homocysteine concentrations in patients with type 2 diabetes mellitus and metabolic syndrome: a multicenter, randomized, double-blind, controlled clinical trial.

Clin Ther 2006 May;28(5):679-88

Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy.

Background: Although the metabolic effects of the thiazolidinediones have been well studied, there is a lack of comparative data on their effects on certain cardiovascular risk factors, such as elevated plasma levels of lipoprotein (a) (Lp[a]) and homocysteine (Hcy).

Objective: This study compared the effects of pioglitazone or rosiglitazone added to glimepiride on a range of lipid parameters, focusing on Lp(a) and Hcy, in patients with type 2 diabetes mellitus and the metabolic syndrome.

Methods: This was a multicenter, randomized, controlled, double-blind study in patients with type 2 diabetes and the metabolic syndrome (hypertension [>or=130/85 mm Hg]) and triglyceridemia (>or=150 mg/dL). In addition to glimepiride 4 mg/d, patients received pioglitazone 15 mg QD or rosiglitazone 4 mg QD for 1 year. The primary efficacy variables were change from baseline in body mass index (BMI), glycosylated hemoglobin (HbA(1c)), Lp(a), and Hey. Secondary efficacy measures were changes in fasting plasma glucose (FPG) and postprandial plasma glucose (PPG) concentrations, fasting and postprandial insulin concentrations (FPI and PPI, respectively), the Homeostasis Model Assessment index, and the lipid profile (total cholesterol [TC], low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], and triglycerides). All these parameters were measured after a 12-hour fast every 3 months for 1 year. Tolerability was assessed based on reported adverse events and laboratory abnormalities at each study visit.

Results: Ninety-one white patients with type 2 diabetes and the metabolic syndrome were enrolled, and 87 completed the study (43 men, 44 women; mean [SD] age, 53 [6] years; mean weight, 68.4 [3.3] kg). Mean baseline values for BMI and HbA(1c) were 24.3 (0.8) kg/m(2) and 8.1 % (0.8 %), respectively. At the end of 1 year, both treatment groups had significant increases from baseline in BMI (4.9% glimepiride + pio glitazone, 6.2% glimepiride + rosiglitazone; P < 0.05). Glimepiride + pioglitazone was associated with the following percent improvements from baseline in measures of glycemic control: -17.1% in HbA(1c), -19.3% in FPG, -17.8% in PPG, -40.1% in FPI, and -22.6% in PPI (all, P < 0.01). The corresponding percent improvements from baseline with glimepiride + rosiglitazone were -16.3%, -19.9%, -15.0%, -44.8%, and -22.1% (all, P < 0.01). There were no significant differences between treatment groups in any of these parameters. The pioglitazone group had significant improvements from baseline in TC (-11.1%), LDL-C (-12.0%), HDL-C (15.0%), and triglycerides (-22.4%) [corrected] (all, P < 0.05), whereas the rosiglitazone group had significant increases in TC (14.9%), LDL-C (16.5%), and triglycerides (17.9%) (all, P < 0.05); the difference between pioglitazone and rosiglitazone was statistically significant (P < 0.05). The change from baseline in Lp(a) was significant in the pioglitazone group, both relative to baseline and compared with the rosiglitazone group (-19.7% vs 0.5%, respectively; P < 0.05 vs baseline and vs rosiglitazone). Changes from baseline in Hey were significant in both the pioglitazone and rosiglitazone groups (-20.2% and -25.0%, respectively; P < 0.05), with no significant difference between groups. Both treatments were well tolerated, and no patients had significant changes in transaminases.

Conclusions: In these patients with type 2 diabetes and the metabolic syndrome, the combinations of glimepiride with pioglitazone and glimepiride with rosiglitazone produced significant improvements in measures of glycemic control, plasma lipids, and homocysteinemia. One year of treatment with the pioglitazone combination was associated with significantly reduced plasma Lp(a) levels compared with the rosiglitazone combination.
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http://dx.doi.org/10.1016/j.clinthera.2006.05.012DOI Listing
May 2006
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