Publications by authors named "Lucia Frittitta"

49 Publications

Roles and competencies in the nutritional domain for the management of the metabolic diseases and in the hospital setting: A position paper of the Italian College of Academic Nutritionists, MED-49 (ICAN-49).

Nutr Metab Cardiovasc Dis 2021 Jul 24. Epub 2021 Jul 24.

Biomedicine and Prevention, University of Tor Vergata, Via Montpellier, 1, 00133, Roma, Italy. Electronic address:

Epidemiological evidence has confirmed the potential causal relationship between specific dietary factors and non-communicable diseases. However, currently nutrition was shown to be insufficiently integrated into medical education, regardless of the country. Without an adequate nutrition education, it is reasonable to assume that future physicians, as well as other health care professionals, will be not able to provide the highest quality care to patients in preventing and treating non-communicable diseases. Furthermore, the insufficient availability of physicians with specializations in nutrition has posed the basis for the development of non-medical careers in the field of nutrition. The present document was drafting by the Italian College of Academic Nutritionists, MED-49 (ICAN-49), with the aim to provide an overview on the nutritional competency standards covered by several health care professionals (Physicians Clinical Nutrition Specialists, Clinical Dietitians, Professional Clinical Nutrition Specialists, etc) for the prevention of diseases and/or support of pharmacological therapies. The aim of the ICAN 49 is to suggest a major shift in practice opportunities and roles for many nutritionists, especially for the management of the metabolic diseases, and promote a paradigm change: a clinical and educational leadership role for Physician Clinical Nutrition Specialists in the hospital setting.
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http://dx.doi.org/10.1016/j.numecd.2021.07.017DOI Listing
July 2021

Pharmacological treatment of nonresponders following bariatric surgery: a narrative review of the current evidence.

Minerva Endocrinol (Torino) 2021 Apr 1. Epub 2021 Apr 1.

Diabetes, Obesity and Dietetic Center, Garibaldi Hospital, Catania, Italy.

Introduction: Obesity is a complex chronic disease and requires a long-term multidisciplinary management. Even patients undergoing bariatric surgery, one the most effective treatments for obesity, can have insufficient weight loss (IWL) than expected (primary non responder) or weight regain (WR) after a successful primary procedure (secondary non responder). A poor response represents a challenge of bariatric surgery that can induce persistence or recurrence of obesity-related comorbidities, prejudicing benefits of surgery. Increasing evidence suggests that weight loss medications represent a useful strategy in obesity care also after bariatric surgery procedures.

Evidence Acquisition: This narrative review summarizes the evidence concerning anti-obesity therapy in the management of no-responders to primary bariatric surgery. Available data on liraglutide (one randomized double-blind placebo-controlled trial, three prospective and three retrospective studies), naltrexone/bupropion (three retrospective studies), orlistat (one case control prospective and one retrospective studies) and topiramate and phentermine (5 retrospective studies) have been considered.

Evidence Synthesis: Available data suggest that weight loss medications could offer a significant adjunctive benefit to lifestyle and behavioral modifications in the life-long management of obesity.

Conclusions: Newer treatment modalities including the use of anti-obesity drugs provide patients and healthcare providers with more options in the management of poor response after bariatric surgery.
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http://dx.doi.org/10.23736/S2724-6507.21.03311-3DOI Listing
April 2021

Risk for Coexistent Autoimmune Diseases in Familial and Sporadic Type 1 Diabetes is Related to Age at Diabetes Onset.

Endocr Pract 2021 Feb 13;27(2):110-117. Epub 2020 Dec 13.

Department of Clinical and Experimental Medicine, Endocrinology Section, University of Catania Medical School, Catania, Italy. Electronic address:

Objective: Type 1 diabetes (T1D) is frequently associated with other autoimmune diseases (AIDs). Although most of T1D patients are sporadic cases (S-T1D), 10% to 15% have a familial form (F-T1D) involving 2 or more first-degree relatives. This study evaluated the effect of T1D family aggregation and age onset on AIDs occurrence.

Methods: In this observational, cross-sectional, case-control, single center study, we enrolled 115 F-T1D and 115 S-T1D patients matched for gender, age, T1D age onset, and duration. With respect to T1D age onset (before or after 18 years), both groups were further subdivided into young- or adult-onset F-T1D and young- or adult-onset S-T1D. The presence of organ-specific antibodies and/or overt AIDs was evaluated.

Results: The F-T1D group had a higher percentage of AIDs (29.8% vs 18.4%, P = .04) and a significant earlier onset of AIDs at Cox regression analysis (P = .04) than the S-T1D group. Based on multivariate analysis, the adult-onset F-T1D subgroup had the highest prevalence of both additional organ-specific antibodies (60.5%) and overt AIDs (34.9%), whereas the adult S-T1D subgroup was the least frequently involved (29.1% and 12.7%, respectively). In F-T1D patients, offsprings develop T1D and AIDs earlier than their parents do.

Conclusions: In T1D patients, familial aggregation and adult-onset of T1D increase the risk for coexistent AIDs. These clinical predictors could guide clinicians to address T1D patients for the screening of T1D-related AIDs.
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http://dx.doi.org/10.1016/j.eprac.2020.09.012DOI Listing
February 2021

A Call to Action: Now Is the Time to Screen Elderly and Treat Osteosarcopenia, a Position Paper of the Italian College of Academic Nutritionists MED/49 (ICAN-49).

Nutrients 2020 Aug 31;12(9). Epub 2020 Aug 31.

Biomedicine and Prevention, University of Tor Vergata, Via Montpellier, 1, 00133 Roma, Italy.

Aging is a risk factor for the development of multiple chronic diseases, including cardiovascular disease, cancer and dementia. Life expectancy has increased in certain countries but this phenomenon is associated with a reduction of years of healthy life. Aging is associated with a number of physical and functional changes, especially sarcopenia. Sarcopenia is a clinical condition associated with a decrease in skeletal muscle and muscle strength, however, sarcopenia is a reversible condition. On the basis of the current scientific literature, sarcopenia could more appropriately capture an individual's vulnerability to negative health-related outcomes since it represents an early form of the chronic diseases. Recognition of this clinical condition can improve the management of older individuals in many different clinical settings. Despite the limitations of the indirect methods used to study body composition, the Italian College of the Academic Nutritionists ME/49 recommends that health authorities and health professionals around the world should make a greater effort to diagnose sarcopenia earlier and to manage it more effectively. In line with the development of cancer screening, the use of two diagnostic tools for sarcopenia (BIA and DXA) should be implemented.
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http://dx.doi.org/10.3390/nu12092662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7550989PMC
August 2020

Prevalence and Clinical Characteristics of Children and Adolescents with Metabolically Healthy Obesity: Role of Insulin Sensitivity.

Life (Basel) 2020 Jul 28;10(8). Epub 2020 Jul 28.

Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, 95122 Catania, Italy.

Obesity represents a major risk factor for metabolic disorders, but some individuals, "metabolically healthy" (MHO), show less clinical evidence of these complications, in contrast to "metabolically unhealthy" (MUO) individuals. The aim of this cross-sectional study is to assess the prevalence of the MHO phenotype in a cohort of 246 overweight/obese Italian children and adolescents, and to evaluate their characteristics and the role of insulin resistance. Homeostasis model assessment-insulin resistance (HOMA-IR), insulin sensitivity index (ISI), insulinogenic index (IGI) and disposition index (DI) were all calculated from the Oral Glucose Tolerance Test (OGTT). MHO was defined by either: (1) HOMA-IR < 2.5 (MHO-IRes), or (2) absence of the criteria for metabolic syndrome (MHO-MetS). The MHO prevalence, according to MHO-MetS or MHO-IRes criteria, was 37.4% and 15.8%, respectively. ISI was the strongest predictor of the MHO phenotype, independently associated with both MHO-IRes and MHO-MetS. The MHO-MetS group was further subdivided into insulin sensitive or insulin resistant on the basis of HOMA-IR (either < or ≥ 2.5). Insulin sensitive MHO-MetS patients had a better metabolic profile compared to both insulin resistant MHO-MetS and MUO-MetS individuals. These data underscore the relevance of insulin sensitivity to identifying, among young individuals with overweight/obesity, the ones who have a more favorable metabolic phenotype.
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http://dx.doi.org/10.3390/life10080127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7459932PMC
July 2020

The prevalence of chronic kidney disease and screening of renal function in type 2 diabetic patients in Finnish primary healthcare.

Prim Care Diabetes 2020 12 8;14(6):639-644. Epub 2020 Jun 8.

Rovaniemi Health Center, Rovaniemi, Finland.

Aims: To estimate the prevalence of chronic kidney disease (CKD) in patients with type 2 diabetes (T2D) in Finnish primary healthcare, and to evaluate the screening for CKD and the proportions of patients receiving antihyperglycemic and cardiovascular preventive medication.

Material And Methods: T2D patients treated at the Rovaniemi Health Center, Finland during the years 2015-2019. Data included patient characteristics, blood pressure, HbA1c, lipid levels, kidney function and albuminuria, and medications prescribed. CKD was defined as estimated glomerular filtration rate (eGFR) <60 ml/min/1.72 m and/or albuminuria.

Results: The study population comprised of 5112 T2D patients with a mean (SD) age of 66.7 (13.0) years. Of these, 60.2% were screened for CKD with both eGFR and albuminuria, and 30.1% of these patients had CKD. The prevalence of moderately increased and severely increased albuminuria was 19.6% and 3.2%, respectively. A total of 57.0% of the study population received angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB).

Conclusions: Screening for CKD with both recommended measures (eGFR and albuminuria) was insufficiently performed among this T2D population. Additionally, just over half of the study population had been prescribed ACE inhibitors or ARB. These results suggest an incongruity between the gold standard of diabetes care and real-world clinical practice.
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http://dx.doi.org/10.1016/j.pcd.2020.05.005DOI Listing
December 2020

Implementation of a Personalized Care Plan for Patients With Type 2 Diabetes Is Associated With Improvements in Clinical Outcomes: An Observational Real-World Study.

J Prim Care Community Health 2020 Jan-Dec;11:2150132720921700

University of Oulu, Oulu, Finland.

To analyze the clinical outcomes of patients with type 2 diabetes (T2D) before and after implementation of a personalized care plan in the primary health care setting. Observational, retrospective, real-world study. All T2D patients with a care plan in Rovaniemi Health Center, Rovaniemi, Finland, for whom data were available from a baseline visit (in 2013-2015 during which the care plan was written) and from a follow-up visit, including an updated care plan by the year 2017. In total, 447 patients were included. Mean age was 66.9 (SD 10.1) years, 58.8% were male, 15.4% were smokers, 33.1% had vascular disease, and 17.0% were receiving insulin treatment. The mean follow-up time was 14.4 months. Glycosylated hemoglobin A1 (HbA1c), low-density lipoprotein (LDL), blood pressure (BP), and body mass index (BMI). Clinical values were taken at both baseline and follow-up. LDL decreased by 0.2 mmol/L, systolic blood pressure by 2.2 mm Hg, diastolic blood pressure by 1.5 mm Hg, and BMI by 0.5 kg/m ( < .05 for each). The decrease in HbA1c was 0.8 mmol/mol ( = .07). We observed statistically significant decreases in LDL, BP, and BMI. Our results indicate that, over 14 months of follow-up, implementation of a written care plan was associated with small improvements in the clinical outcomes of T2D patients in a primary health care study population in a real-world setting.
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http://dx.doi.org/10.1177/2150132720921700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7252372PMC
June 2021

Influence of the Mediterranean and Ketogenic Diets on Cognitive Status and Decline: A Narrative Review.

Nutrients 2020 Apr 8;12(4). Epub 2020 Apr 8.

Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi Medical Center, Via Palermo 636, 95122 Catania, Italy.

Alzheimer's disease (AD) is the most common form of senile dementia, accounting for up to 70% of dementia cases. AD is a slowly progressive disease, which causes global mental deterioration by affecting various cognitive areas. A growing body of evidence has demonstrated that lifestyle habits and nutritional patterns could delay the natural course of the neurodegeneration process. There is no single dietary pattern unequivocally proven to prevent AD. Nevertheless, epidemiological data suggest that by adopting several dietary habits, especially if accompanied with a healthy lifestyle, the negative consequences of AD could potentially be delayed. Alongside with others, two specific eating patterns have been well investigated concerning their potential beneficial effect on cognitive status: the Mediterranean diet (MedDi) and the Ketogenic Diet (KD). Despite the different underlying mechanisms, both of them have demonstrated a fairly profitable role in reducing or delaying cognitive impairment. The aim of the present narrative review is to overview the existing research on the efficacy of MedDi and KD against AD-related cognitive decline, focusing on the proposed protective mechanisms of action. Although the current knowledge on this complex topic does not allow us, at this point, to make exhaustive conclusions, this information could be of help in order to better characterize the possible role of MedDi and KD as nonpharmacological therapies in the treatment of AD and, more generically, of neurodegenerative disorders.
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http://dx.doi.org/10.3390/nu12041019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7231139PMC
April 2020

"Adiponectin Paradox" and Cancer Risk: Is It Time for a Reevaluation of the Beneficial Effect of this Adipokine?

J Clin Endocrinol Metab 2020 07;105(7)

Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.

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http://dx.doi.org/10.1210/clinem/dgaa181DOI Listing
July 2020

Effects of polyphenols on cardio-metabolic risk factors and risk of type 2 diabetes. A joint position statement of the Diabetes and Nutrition Study Group of the Italian Society of Diabetology (SID), the Italian Association of Dietetics and Clinical Nutrition (ADI) and the Italian Association of Medical Diabetologists (AMD).

Nutr Metab Cardiovasc Dis 2020 03 5;30(3):355-367. Epub 2019 Dec 5.

Italian Society of Diabetology (SID), Roma, Italy; Dep. of Clinical Medicine and Surgery, Federico II University, Naples, Italy.

Aim: A large body of evidence supports a role of polyphenols in the prevention of chronic diseases, i.e. type 2 diabetes (DMT2), cardiovascular diseases and some types of cancer. In the present manuscript, the effect of polyphenol/phenolic compounds on the main cardio-metabolic risk factors (body weight, blood pressure, blood glucose concentrations, plasma lipids, inflammation and oxidative stress) in humans will be discussed.

Data Synthesis: Epidemiological evidence supports the beneficial effects of polyphenol-rich diets in the prevention of T2D risk. However, the available evidence from randomized controlled clinical trials did not allow the identification of specific phenolic compounds or polyphenol-rich foods that effectively improve cardio-metabolic risk factors. The most promising results in terms of the management of cardio-metabolic risk factors derive from RCTs based on a long-term intake of polyphenol-rich foods and beverages. Therefore, future studies should focus on a diet containing different classes of polyphenols rather than a specific food or phenolic compound. The hypothesis is that a polyphenol-rich diet may have a pleiotropic effect on cardiometabolic risk factors thanks to the specific action of different polyphenol subclasses.

Conclusion: The lack of conclusive evidence on the effectiveness of polyphenols in the management of cardio-metabolic risk factors does not allow recommendation of their use as supplements to reduce T2D and CVD risk. However, the daily consumption of naturally polyphenol-rich foods and beverages might be advised according to the current nutritional dietary recommendation.
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http://dx.doi.org/10.1016/j.numecd.2019.11.015DOI Listing
March 2020

The novel loss of function Ile354Val mutation in PPARG causes familial partial lipodystrophy.

Acta Diabetol 2020 May 20;57(5):589-596. Epub 2019 Dec 20.

Endocrinology Unit, Garibaldi Hospital, Catania, Italy.

Aims: Familial partial lipodystrophy (FPLD) is a rare autosomal dominant disorder, mostly due to mutations in lamin A (LMNA) or in peroxisome proliferator-activated receptor gamma (PPARG) genes. In the present study, we aimed to identify and functionally characterize the genetic defect underlying FPLD in an Italian family presenting with several affected individuals in three consecutive generations.

Methods: Mutational screening by direct Sanger sequencing has been carried out on both LMNA and PPARG genes. In silico analyses and functional in vitro studies on transfected cell lines have been also performed to evaluate the biological impact of the identified mutation.

Results: We identified a novel PPARG missense mutation (i.e., PPARγ2 Ile354Val) segregating with FPLD in the study family. In silico analyses and in vitro experiments showed that probably altering the PPARγ2 ligand binding domain conformation, the Ile354Val aminoacid change leads to a significant reduction (i.e., ~ 30-35%) of transcriptional activity in the mutant receptor, with no evidences of a dominant negative effect on the wild-type receptor.

Conclusions: Our present data extend the spectrum of PPARG mutations responsible for FPLD3 and reinforce the notion that even loss of function mutations affecting transcriptional activity to an extent lower than that observed in the case of haploinsufficiency are able to cause a severe FPLD3 phenotype.
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http://dx.doi.org/10.1007/s00592-019-01462-yDOI Listing
May 2020

Impact of unhealthy childhood and unfavorable parents' characteristics on adiposity in schoolchildren.

Diabetes Metab Res Rev 2019 11 18;35(8):e3199. Epub 2019 Jul 18.

Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.

Background: Childhood obesity is encouraged by low physical activity (PA), time spent using screens (screen time, ST), and by sugar-sweetened beverage consumption (SSBc). It is also influenced by unfavorable parents' characteristics, such as a high body mass index (BMI) and low education level (EL). Our aim was to evaluate the overall and specific influence of these factors on childhood adiposity.

Material And Methods: Anthropometric parameters including BMI z-score, waist circumference (WC), waist to height ratio (WtHR), and fat mass were measured in a cohort of 1702 schoolchildren (6.0-14.5 years, mean 10.7 ± 1.8) and questionnaires concerning children's PA, ST, and SSBc, and parent's BMI and EL were administered to parents.

Results: Overweight/obesity prevalence was higher (P < .0001) in males (57%) than in females (43%). Less physically active children (28.9%) had a higher prevalence of overweight/obesity and higher BMI z-score, WC, WtHR, and fat mass relative to more physically active children (P < .05). PA was negatively associated with the BMI z-score (r = 0.18, P < .0001) and fat mass percentage (r = 0.18, P < .0001). Children with more ST had higher WC and WtHR than non-ST viewers (P < .05) but not BMI. Moreover, SSBc did not influence the anthropometric parameters. At multivariate analysis, male gender, less PA, and parental risk factors (parent's overweight/obesity and low/medium EL) were independently associated with overweight and obesity among childhood with a progressively increasing odds ratio (1.65, 1.40, and 1.80, respectively).

Conclusions: Male gender, behavioral risk factors (particularly low PA), and parent's characteristics are important correlates of obesity in children.
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http://dx.doi.org/10.1002/dmrr.3199DOI Listing
November 2019

Adipose Tissue, Obesity and Adiponectin: Role in Endocrine Cancer Risk.

Int J Mol Sci 2019 Jun 12;20(12). Epub 2019 Jun 12.

Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi Hospital, Via Palermo 636, 95122 Catania, Italy.

Adipose tissue has been recognized as a complex organ with endocrine and metabolic roles. The excess of fat mass, as occurs during overweight and obesity states, alters the regulation of adipose tissue, contributing to the development of obesity-related disorders. In this regard, many epidemiological studies shown an association between obesity and numerous types of malignancies, comprising those linked to the endocrine system (e.g., breast, endometrial, ovarian, thyroid and prostate cancers). Multiple factors may contribute to this phenomenon, such as hyperinsulinemia, dyslipidemia, oxidative stress, inflammation, abnormal adipokines secretion and metabolism. Among adipokines, growing interest has been placed in recent years on adiponectin (APN) and on its role in carcinogenesis. APN is secreted by adipose tissue and exerts both anti-inflammatory and anti-proliferative actions. It has been demonstrated that APN is drastically decreased in obese individuals and that it can play a crucial role in tumor growth. Although literature data on the impact of APN on carcinogenesis are sometimes conflicting, the most accredited hypothesis is that it has a protective action, preventing cancer development and progression. The aim of the present review is to summarize the currently available evidence on the involvement of APN and its signaling in the etiology of cancer, focusing on endocrine malignancies.
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http://dx.doi.org/10.3390/ijms20122863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6628240PMC
June 2019

Short-term adverse effects of anticancer drugs in patients with type 2 diabetes.

J Chemother 2019 May 10;31(3):150-159. Epub 2019 Feb 10.

a Department of Clinical and Experimental Medicine , Endocrinology Section, University of Catania Medical School , Garibaldi-Nesima Hospital , Catania , Italy.

The short-term adverse effects of anticancer drugs (AD) in patients with type 2 diabetes (T2D) are poorly studied and their management still represents an important challenge for clinicians. We carried out a retrospective single-center study in 168 patients with T2D and cancer, evaluating both the short-term effects of first-line AD on glycemic control and chronic diabetes complications. Average glycated hemoglobin significantly increased after AD compared to values before treatment (7.5 vs. 7.1%, p < 0.005). In 46.4% of patients, diabetes therapy had to be potentiated, in most cases (82.1%) by shifting to insulin. The use of alkylating agents and high-dose glucocorticoids predicted the need to potentiate diabetes therapy. After AD transaminase values significantly increased, whereas the estimated glomerular filtration rate decreased (in 12.5% <60 mL/min). Kinase inhibitors significantly increased the risk of microalbuminuria onset or progression. The present study provides a real-life information on the effects of different AD on the management of patients with T2D affected by several types of cancer.
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http://dx.doi.org/10.1080/1120009X.2019.1572297DOI Listing
May 2019

Type 2 Diabetes Mellitus and Alzheimer's Disease: Role of Insulin Signalling and Therapeutic Implications.

Int J Mol Sci 2018 Oct 24;19(11). Epub 2018 Oct 24.

Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Diabetes, Obesity and Dietetic Center, Garibaldi Hospital, Via Palermo n° 636, 95122 Catania, Italy.

In the last two decades, numerous in vitro studies demonstrated that insulin receptors and theirs downstream pathways are widely distributed throughout the brain. This evidence has proven that; at variance with previous believes; insulin/insulin-like-growth-factor (IGF) signalling plays a crucial role in the regulation of different central nervous system (CNS) tasks. The most important of these functions include: synaptic formation; neuronal plasticity; learning; memory; neuronal stem cell activation; neurite growth and repair. Therefore; dysfunction at different levels of insulin signalling and metabolism can contribute to the development of a number of brain disorders. Growing evidences demonstrate a close relationship between Type 2 Diabetes Mellitus (T2DM) and neurodegenerative disorders such as Alzheimer's disease. They, in fact, share many pathophysiological characteristics comprising impaired insulin sensitivity, amyloid β accumulation, tau hyper-phosphorylation, brain vasculopathy, inflammation and oxidative stress. In this article, we will review the clinical and experimental evidences linking insulin resistance, T2DM and neurodegeneration, with the objective to specifically focus on insulin signalling-related mechanisms. We will also evaluate the pharmacological strategies targeting T2DM as potential therapeutic tools in patients with cognitive impairment.
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http://dx.doi.org/10.3390/ijms19113306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6275025PMC
October 2018

Efficacy of Botulinum Toxin A for Treating Cramps in Diabetic Neuropathy.

Ann Neurol 2018 11 16;84(5):674-682. Epub 2018 Oct 16.

Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Medical Center, Catania, Italy.

Objective: Muscle cramps occur in >50% of diabetic patients and reduce the quality of life. No effective treatment is available. We evaluated the clinical effectiveness of botulinum toxin A (BTX-A) injections for treating cramps in diabetic patients with neuropathy.

Methods: This single-center, double-blind, placebo-controlled perspective study investigated the efficacy and safety of BTX-A intramuscular injection for treating calf or foot cramps refractory to common pharmacological drugs. Fifty diabetic patients with peripheral neuropathy and cramps were randomly assigned to 2 matched groups. BTX-A (100 or 30 units) or saline was injected on each side into the gastrocnemius or the small flexor foot muscles. Changes in pain intensity (primary outcome) and cramp frequency were evaluated over the course of 20 weeks after BTX-A administration. Cramp interference in daily life and the electrophysiological cramp threshold frequency were also measured. The treatment was repeated 5 months after first injection in 19 responders.

Results: All outcome measures improved significantly after BTX-A compared with placebo. The changes with respect to baseline were already significant after 1 week and persisted up to week 14. Only 5 of 25 (20%) patients were nonresponders (<50% decrease of the primary outcome). The responses to a second BTX-A injection provided results similar to the first administration. Mild pain at the injection site (4/25 cases) was the only adverse event, and it disappeared within 2 to 3 days.

Interpretation: Local BTX-A infiltration is an efficacious and safe procedure for obtaining a sustained amelioration of muscle cramps associated with diabetic neuropathy. Ann Neurol 2018;84:682-690.
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http://dx.doi.org/10.1002/ana.25340DOI Listing
November 2018

Insulin receptor signaling and glucagon-like peptide 1 effects on pancreatic beta cells.

PLoS One 2017 2;12(8):e0181190. Epub 2017 Aug 2.

Endocrine Unit, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy.

Glucagon-like peptide-1 (GLP-1) is a potent gluco-incretin hormone, which plays a central role on pancreatic beta cell proliferation, survival and insulin secreting activity and whose analogs are used for treating hyperglycemia in type 2 diabetes mellitus. Notably, abnormal insulin signaling affects all the above-mentioned aspects on pancreatic beta cells. The aim of our study was to investigate whether the protective effects of GLP1-1 on beta cells are affected by altered insulin receptor signaling. To this end, several effects of GLP-1 were studied in INS-1E rat beta cells transfected either with an inhibitor of insulin receptor function (i.e., the Ectonucleotide Pyrophosphatase Phosphodiesterase 1, ENPP1), or with insulin receptor small interfering RNA, as well as in control cells. Crucial experiments were carried out also in a second cell line, namely the βTC-1 mouse beta cells. Our data indicate that in insulin secreting beta cells in which either ENPP1 was up-regulated or insulin receptor was down-regulated, GLP-1 positive effects on several pancreatic beta cell activities, including glucose-induced insulin secretion, cell proliferation and cell survival, were strongly reduced. Further studies are needed to understand whether such a scenario occurs also in humans and, if so, if it plays a role of clinical relevance in diabetic patients with poor responsiveness to GLP-1 related treatments.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0181190PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5540605PMC
October 2017

Insulin degludec in the first trimester of pregnancy: Report of two cases.

J Diabetes Investig 2017 Aug 2. Epub 2017 Aug 2.

Endocrinology Section, Department of Clinical and Experimental Medicine, Garibaldi-Nesima Medical Center, University of Catania, Catania, Italy.

Insulin degludec is an extra-long-acting insulin analog that allows for enhanced efficacy and flexibility in the injection time. However, it is not approved for use during pregnancy. We report the pregnancy outcome and newborn conditions in two women with type 1 diabetes who continued preconception degludec treatment during embryogenesis. No pregnancy complication or congenital neonatal malformation was observed. Both babies presented with hypoglycemia and required neonatal intensive care unit admission. Degludec treatment did not cause adverse effects in the mothers or malformations in the newborns. The observed neonatal complications were probably independent of early pregnancy degludec treatment.
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http://dx.doi.org/10.1111/jdi.12721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5934254PMC
August 2017

Cytosolic and Calcium-Independent Phospholipases A2 Activation and Prostaglandins E2 Are Associated with Escherichia coli-Induced Reduction of Insulin Secretion in INS-1E Cells.

PLoS One 2016 15;11(9):e0159874. Epub 2016 Sep 15.

Dept. of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy.

It is suspected that microbial infections take part in the pathogenesis of diabetes mellitus type 1 (T1DM). Glucose-induced insulin secretion is accompanied by the release of free arachidonic acid (AA) mainly by cytosolic- and calcium independent phospholipases A2 (cPLA2 and iPLA2). Insulinoma cell line (INS-1E) was infected with E. coli isolated from the blood culture of a patient with sepsis. Invasion assay, Scanning Electron Microscopy and Transmission Electron Microscopy demonstrated the capacity of E. coli to enter cells, which was reduced by PLA2 inhibitors. Glucose-induced insulin secretion was significantly increased after acute infection (8h) but significantly decreased after chronic infection (72h). PLA2 activities, cPLA2, iPLA2, phospho-cPLA2, and COX-2 expressions were increased after acute and, even more, after chronic E. coli infection. The silencing of the two isoforms of PLA2s, with specific cPLA2- or iPLA2-siRNAs, reduced insulin secretion after acute infection and determined a rise in insulin release after chronic infection. Prostaglandins E2 (PGE2) production was significantly elevated in INS-1E after long-term E. coli infection and the restored insulin secretion in presence of L798106, a specific EP3 antagonist, and NS-398, a COX-2 inhibitor, and the reduction of insulin secretion in presence of sulprostone, a specific EP3 agonist, revealed their involvement in the effects triggered by bacterial infection. The results obtained demonstrated that cPLA2 and iPLA2 play a key role in insulin secretion process after E. coli infection. The high concentration of AA released is transformed into PGE2, which could be responsible for the reduced insulin secretion.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0159874PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5024995PMC
August 2017

Integrated insulin pump therapy with continuous glucose monitoring for improved adherence: technology update.

Patient Prefer Adherence 2015 7;9:1263-70. Epub 2015 Sep 7.

Endocrinology, Garibaldi-Nesima Hospital, Catania, Italy.

Insulin pump therapy combined with real-time continuous glucose monitoring, known as sensor-augmented pump (SAP) therapy, has been shown to improve metabolic control and to reduce the rate of hypoglycemia in adults with type 1 diabetes compared to multiple daily injections or standard continuous subcutaneous insulin infusion. Glycemic variability is also reduced in patients on SAP therapy. This approach allows patients to monitor their glucose levels being informed of glycemic concentration and trend. Trained diabetic patients, therefore, can appropriately modify insulin infusion and/or carbohydrate intake in order to prevent hypo- or hyperglycemia. For these reasons, SAP therapy is now considered the gold standard for type 1 diabetes treatment. To be clinically effective, however, devices and techniques using advanced technology should not only have the potential to theoretically ameliorate metabolic control, but also be well accepted by patients in terms of satisfaction and health-related quality of life, because these factors will improve treatment adherence and consequently overall outcome. SAP therapy is generally well tolerated by patients; however, many clinical trials have identified significant noncompliance in the use of this device, most notably in the pediatric and adolescent populations. In this review we aim to analyze the main reasons for good or poor adherence to SAP therapy and to provide useful tips in order to fully benefit from this kind of novel therapeutic approach.
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http://dx.doi.org/10.2147/PPA.S69482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4567238PMC
September 2015

Strong evidence of sexual dimorphic effect of adiposity excess on insulin sensitivity.

Acta Diabetol 2015 Oct 25;52(5):991-8. Epub 2015 Aug 25.

Research Unit of Diabetes and Endocrine Diseases, Poliambulatorio Giovanni Paolo II, IRCCS "Casa Sollievo della Sofferenza", Viale Padre Pio, 71013, San Giovanni Rotondo, Italy.

Aims: Our aims were to investigate in several large samples, with a wide range of adiposity, whether: (1) the effect of BMI on insulin sensitivity is different between sexes; (2) also waist circumference plays a sex-specific role on insulin sensitivity; and (3) serum adiponectin and resistin are mediators of such sex-dimorphic effect.

Methods: Samples used were: Gargano study 1 (GS1), GS2 and Catania study (CS) comprising 3274 individuals. Adiponectin and resistin were measured by ELISA. Associations between variables were tested by linear models.

Results: In all samples, relationship between BMI and HOMAIR was steeper in males than in females (BMI-by-sex interaction p = 0.04-0.0007). No interaction was observed on serum adiponectin and resistin (p = 0.40-059), which are therefore unlikely to mediate the sex-dimorphic effect of BMI on insulin resistance. Relationship between waist circumference and HOMAIR was similar between sexes in GS1 and GS2 but not in CS (waist-by-sex interaction p = 0.01), comprising much heavier individuals. This suggests that a sex-dimorphic effect of abdominal adiposity on insulin resistance is observable only in the context of high BMI.

Conclusions: Our findings represent a proof of concept that BMI and insulin sensitivity are associated in a sex-specific manner. This may explain why females are protected from diabetes and cardiovascular disease, compared to males of similar BMI.
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http://dx.doi.org/10.1007/s00592-015-0804-2DOI Listing
October 2015

Association between resistin levels and all-cause and cardiovascular mortality: a new study and a systematic review and meta-analysis.

PLoS One 2015 20;10(3):e0120419. Epub 2015 Mar 20.

Research Unit of Diabetes and Endocrine Diseases, IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Italy.

Context: Studies concerning the association between circulating resistin and mortality risk have reported, so far, conflicting results.

Objective: To investigate the association between resistin and both all-cause and cardiovascular (CV) mortality risk by 1) analyzing data from the Gargano Heart Study (GHS) prospective design (n=359 patients; 81 and 58 all-cause and CV deaths, respectively); 2) performing meta-analyses of all published studies addressing the above mentioned associations.

Data Source And Study Selection: MEDLINE and Web of Science search of studies reporting hazard ratios (HR) of circulating resistin for all-cause or CV mortality.

Data Extraction: Performed independently by two investigators, using a standardized data extraction sheet.

Data Synthesis: In GHS, adjusted HRs per one standard deviation (SD) increment in resistin concentration were 1.28 (95% CI: 1.07-1.54) and 1.32 (95% CI: 1.06-1.64) for all-cause and CV mortality, respectively. The meta-analyses included 7 studies (n=4016; 961 events) for all-cause mortality and 6 studies (n=4,187: 412 events) for CV mortality. Pooled HRs per one SD increment in resistin levels were 1.21 (95% CI: 1.03-1.42, Q-test p for heterogeneity<0.001) and 1.05 (95% CI: 1.01-1.10, Q-test p for heterogeneity=0.199) for all-cause and CV mortality, respectively. At meta-regression analyses, study mean age explained 9.9% of all-cause mortality studies heterogeneity. After adjusting for age, HR for all-cause mortality was 1.24 (95% CI: 1.06-1.45).

Conclusions: Our results provide evidence for an association between circulating resistin and mortality risk among high-risk patients as are those with diabetes and coronary artery disease.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0120419PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4368155PMC
February 2016

Efficacy of real-time continuous glucose monitoring on glycaemic control and glucose variability in type 1 diabetic patients treated with either insulin pumps or multiple insulin injection therapy: a randomized controlled crossover trial.

Diabetes Metab Res Rev 2015 Jan;31(1):61-8

Endocrinology, Department of Clinical and Molecular Biomedicine, University of Catania, Garibaldi-Nesima Hospital, Catania, Italy.

Background: The aim of this study was to determine the efficacy of real-time continuous glucose monitoring in T1D patients treated with insulin pump therapy or multiple daily insulin therapy.

Methods: Twenty adult patients (ten insulin pump therapy and ten multiple daily insulin) with poor glycaemic control (HbA1c  > 8.0%) were randomized into two groups for 6 months: the continuous glucose monitoring arm (using real-time continuous glucose monitoring) and the SMBG arm. After 2 months of wash-out, the participants crossed over. The primary outcome was HbA1c reduction. The secondary outcomes were hypoglycaemia and hyperglycaemia risk assessment (area under the curve < 70 mg/dL/day and AUC > 200 mg/dL/day, respectively) and glucose variability.

Results: Fourteen patients (eight multiple daily insulin, six insulin pump therapy) used continuous glucose monitoring appropriately (at least 40% of the time). In these patients, the improvement in glycaemic control was more evident during the real-time continuous glucose monitoring period (7.76% ± 0.4 vs 8.54% ± 0.4, p < 0.05) than during the self-monitoring of blood glucose period (8.42% ± 0.4 vs 8.56% ± 0.5, p = 0.2). Better results with continuous glucose monitoring were observed in patients using multiple daily insulin with greater improvement in both glycaemic control (7.71% ± 0.2 vs 8.58% ± 0.2, p < 0.05) and glucose variability and with a marked reduction in the risk of both hypoglycaemia and hyperglycaemia.

Conclusions: Appropriate use of real-time continuous glucose monitoring improved glycometabolic control in T1D patients. The effects of continuous glucose monitoring were more evident in patients under multiple daily insulin treatment, compared with insulin pump therapy. Glucose variability, in addition to glycaemic control, was improved in compliant diabetic patients.
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http://dx.doi.org/10.1002/dmrr.2557DOI Listing
January 2015

Joint effect of insulin signaling genes on insulin secretion and glucose homeostasis.

J Clin Endocrinol Metab 2013 Jun 30;98(6):E1143-7. Epub 2013 Apr 30.

Casa Sollievo della Sofferenza-Mendel Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico, Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy.

Context: Reduced insulin signaling in insulin secreting β-cells causes defective insulin secretion and hyperglycemia in mice.

Objective: We investigated whether functional polymorphisms affecting insulin signaling (ie, ENPP1 K121Q, rs1044498; IRS1 G972R, rs1801278; and TRIB3 Q84R, rs2295490) exert a joint effect on insulin secretion and abnormal glucose homeostasis (AGH).

Design: Insulin secretion was evaluated by 1) the disposition index (DI) from an oral glucose tolerance test (OGTT) in 829 individuals; 2) insulin secretion stimulation index (SI) in islets from nondiabetic donors after glucose (n = 92) or glibenclamide (n = 89) stimulation. AGH (including impaired fasting glucose and/or impaired glucose tolerance or type 2 diabetes; T2D) was evaluated in case-control studies from the GENetics of Type 2 Diabetes in Italy and the United States (GENIUS T2D) Consortium (n = 6607).

Results: Genotype risk score, obtained by totaling individual weighted risk allele effects, was associated with the following: 1) DI (P = .005); 2) glucose and glibenclamide SI (P = .046 and P = .009); or 3) AGH (odds ratio 1.08, 95% confidence interval 1.03-1.13; P = .001). We observed an inverse relationship between genetic effect and age at AGH onset, as indicated by a linear correlation between AGH-genotype risk score odds ratios and age-at-diagnosis cutoffs (R(2) = 0.80, P < .001).

Conclusions: Functional polymorphisms affecting insulin signaling exert a joint effect on both in vivo and in vitro insulin secretion as well as on early-onset AGH. Our data provide further evidence that abnormal insulin signaling reduces β-cell function and impairs glucose homeostasis.
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http://dx.doi.org/10.1210/jc.2012-4282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6618023PMC
June 2013

Very severely obese patients have a high prevalence of type 2 diabetes mellitus and cardiovascular disease.

Acta Diabetol 2013 Jun 28;50(3):443-9. Epub 2013 Feb 28.

Endocrinology Unit, Department of Clinical and Molecular Bio-Medicine, University of Catania Medical School, Garibaldi Hospital, Via Palermo 636, 95122, Catania, Italy.

The prevalence of very severe obesity has increased progressively and faster than other classes of obesity over the last years. It is unclear whether the prevalence of obesity-related complications and health risks increases progressively or reaches a plateau above a certain degree of obesity. The aim of our study was to investigate whether the severity of obesity was correlated with the prevalence of type 2 diabetes mellitus (T2DM), impaired fasting glucose, impaired glucose tolerance (IGT), metabolic syndrome (MS), and cardiovascular diseases (CVDs) in a large cohort of patients with different degrees of obesity. A cross-sectional study was conducted in 938 obese patients without a previous diagnosis of diabetes. Patients were assigned to different categories of obesity: mild-moderate obesity (BMI 30-39.9 kg/m(2)), morbid obesity (BMI 40-49.9 kg/m(2)), and super-obesity (SO, BMI ≥50 kg/m(2)). The prevalence of IGF, IGT, screen-detected T2DM, MS, and CVD was higher in SO patients than in the other groups. Interestingly, the association between SO and either MS or CVD was independent of glucose tolerance status, indicating that factors other than glucose metabolism also favor cardio-metabolic complications in obese patients. In patients without screen-detected T2DM (n = 807), insulin sensitivity and secretion OGTT-derived indexes indicated that SO patients had the worst glucose homeostasis relative to the other categories of obesity, which was indicated by the most reduced disposition index in these patients, a predictor of future T2DM. In conclusion, SO patients have an extremely high prevalence of glucose metabolism deterioration, and cardio-metabolic complications are more prevalent in these patients compared to less obese patients.
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http://dx.doi.org/10.1007/s00592-013-0460-3DOI Listing
June 2013

Basal insulin and cardiovascular and other outcomes.

N Engl J Med 2012 11;367(18):1761-2; author reply 1763-4

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http://dx.doi.org/10.1056/NEJMc1210553DOI Listing
November 2012

Joint effect of insulin signaling genes on cardiovascular events and on whole body and endothelial insulin resistance.

Atherosclerosis 2013 Jan 16;226(1):140-5. Epub 2012 Oct 16.

Clinical Unit of Endocrinology, IRCCS Casa Sollievo della Sofferenza San Giovanni Rotondo, Italy.

Objective: Insulin resistance (IR) and cardiovascular disease (CVD) share a common soil. We investigated the combined role of single nucleotide polymorphisms (SNPs) affecting insulin signaling (ENPP1 K121Q, rs1044498; IRS1 G972R, rs1801278; TRIB3 Q84R, rs2295490) on CVD, age at myocardial infarction (MI), in vivo insulin sensitivity and in vitro insulin-stimulated nitric oxide synthase (NOS) activity.

Design And Setting: 1. We first studied, incident cardiovascular events (a composite endpoint comprising myocardial infarction-MI, stroke and cardiovascular death) in 733 patients (2186 person-years, 175 events). 2. In a replication attempt, age at MI was tested in 331 individuals. 3. OGTT-derived insulin sensitivity index (ISI) was assessed in 829 individuals with fasting glucose <126 mg/dl. 4. NOS activity was measured in 40 strains of human vein endothelial cells (HUVECs).

Results: 1. Risk variants jointly predicted cardiovascular events (HR = 1.181; p = 0.0009) and, when added to clinical risk factors, significantly improved survival C-statistics; they also allowed a significantly correct reclassification (by net reclassification index) in the whole sample (135/733 individuals) and, even more, in obese patients (116/204 individuals). 2. Risk variants were jointly associated with age at MI (p = 0.006). 3. A significant association was also observed with ISI (p = 0.02). 4. Finally, risk variants were jointly associated with insulin-stimulated NOS activity in HUVECs (p = 0.009).

Conclusions: Insulin signaling genes variants jointly affect cardiovascular disease, very likely by promoting whole body and endothelium-specific insulin resistance. Further studies are needed to address whether their genotyping help identify very high-risk patients who need specific and/or more aggressive preventive strategies.
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http://dx.doi.org/10.1016/j.atherosclerosis.2012.10.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3529747PMC
January 2013

Secular trends in the prevalence of overweight and obesity in Sicilian schoolchildren aged 11-13 years during the last decade.

PLoS One 2012 10;7(4):e34551. Epub 2012 Apr 10.

Endocrinology Unit, Department of Clinical and Molecular Biomedicine, University of Catania Medical School, Garibaldi Hospital, Catania, Italy.

The present study evaluates trends in the prevalence of overweight and obesity in relation to gender and area of residence between two cohorts of students aged 11-13 years in Sicily. The analysis was performed on 1,839 schoolchildren, with 924 and 915 children being studied in 1999-2001 and 2009-2010, respectively. The children who were enrolled during 2009-2010 had significantly higher body mass indexes (BMI), BMI z-scores, and waist circumferences than the children who were studied during 1999-2001 (p<0.0001 for all); these differences was also observed when the cohort was subdivided according to gender or residence area The prevalence of obesity increased significantly from 7.9% in 1999-2001 to 13.7% in 2009-2010 (p<0.0001), whereas thinness decreased significantly from 10.1% to 2.3% (p<0.0001) in the same periods. The increase of trends in the prevalence of obesity was significantly higher in males (9.7% vs. 17.6%, p = 0.0006) than in females (6.3% vs. 9.8%, p = 0.04) and was slightly higher in urban areas (8.8% vs. 14.3%, p = 0.002) than in rural areas (7.8% vs. 13.0%, p = 0.012). The male gender was associated with a higher risk of being overweight or obese (odds ratio: 1.63; 95% confidence intervals: 1.24-2.15; p = 0.0005) in 2009-2010 than in 1999-2001, after adjusting for age and the residence area. In conclusion, this study showed an increasing trend in the prevalence of overweight and obesity in Sicilian schoolchildren during the last decade and that this trend was related to gender, age and the area of residence. More specifically, our data indicated that the prevalence of obesity increased by 5.8%, the prevalence of thinness decreased by 7.8% and the prevalence of normal-weight children did not change over the course of a decade. These results suggest a shift in the body weights of Sicilian children toward the upper percentiles.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0034551PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3323536PMC
October 2012

The SH2B1 obesity locus is associated with myocardial infarction in diabetic patients and with NO synthase activity in endothelial cells.

Atherosclerosis 2011 Dec 19;219(2):667-72. Epub 2011 Aug 19.

IRCSS Casa Sollievo della Sofferenza-Mendel Laboratory, San Giovanni Rotondo, Italy.

Objective: Obesity and cardiovascular disease recognize a common metabolic soil and may therefore share part of their genetic background. Genome-wide association studies have identified variability at the SH2B1 locus as a predictor of obesity. We investigated whether SNP rs4788102, which captures the entire SH2B1 variability, is associated with coronary artery disease (CAD) and/or myocardial infarction (MI) in patients with type 2 diabetes mellitus (T2DM).

Design And Setting: SNP rs4788102 was typed in 2015 White subjects with T2DM from three CAD case-control studies [n=740 from the Gargano Hearth Study (GHS, Italy); n=818 from the Joslin Hearth Study (JHS, Boston); n=457 from the University of Catanzaro (CZ, Italy)].

Results: SNP rs4788102 (G/A) was not associated with CAD (overall allelic OR=1.06, 95% CI=0.93-1.21; p=0.37). On the contrary, it was associated with MI in GHS (1.42, 1.12-1.81; p=0.004) and in the three samples analyzed together (1.21, 1.04-1.41; p=0.016). Insulin stimulated nitric oxide synthase (NOS) activity in human vein endothelial cells from G/G (n=4, p=0.03) but not the G/A (n=5, p=0.83) genotype. Of the SNPs in perfect LD with rs4788102, one (rs7498665) affects amino acid polarity (Ala484Thr) and falls into a highly conserved protein segment of SH2B1 containing a class II SH3 domain binding site.

Conclusions: Variability at the SH2B1 obesity locus is associated with MI in diabetic patients and with reduced insulin-stimulated NOS activity in human endothelial cells. Further studies are needed to replicate this association and dissect the biology underlying this finding.
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http://dx.doi.org/10.1016/j.atherosclerosis.2011.08.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3728428PMC
December 2011
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