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Carla GRECO
CULTORE DELLA MATERIA
Dipartimento di Scienze Biomediche, Metaboliche e Neuroscienze sede ex-Sc. Biomediche
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Pubblicazioni
2023
- Alterations in the Menstrual Cycle as a Peculiar Sign of Type 1 Diabetes Mellitus: A Meta-analytic Approach
[Articolo su rivista]
Greco, Carla; Cacciani, Marta; Corleto, Rossella; Simoni, Manuela; Spaggiari, Giorgia; Santi, Daniele
abstract
Background: Menstrual irregularities are present in >30% of women with type 1 diabetes mellitus (T1DM). These abnormalities will likely lead to reduced fertility and earlier menopause. T1DM management has changed over time, with even more emphasis on stringent levels of glycemic control. Thus, we investigated whether therapeutic T1DM changes have an influence on the proportion of menstrual disorders in women with T1DM. Methods: A meta-analysis was performed that included clinical trials in which menstrual abnormalities in women with T1DM were studied. The literature was checked for studies in which women with T1DM were compared with healthy, age-matched controls. Case-control, cohort, and cross-sectional studies were included. The primary endpoint was rate of menstrual dysfunction. Results: Menstrual dysfunction was higher in women with T1DM compared with controls (odds ratio 2.08, 95% confidence interval [CI] 1.43 to 3.03, p<0.001), even when sensitivity analysis was performed, considering only studies published after 2000. The age at menarche was higher for women with T1DM compared with controls (mean difference 0.53, 95% CI 0.32 to 0.74 year, p<0.001). The proportion of menstrual abnormalities in T1DM was inversely related to diabetes duration, but was unrelated to both body mass index and glycated hemoglobin. Conclusions: The meta-analytic approach used confirmed the correlation between T1DM and menstrual irregularities. T1DM menstrual dysfunction seemed unrelated to change in therapeutic management across years, as well as to glycemic control and body weight. The underlying pathogenetic mechanisms are not fully understood.
2023
- Glycemic control predicts SARS-CoV-2 prognosis in diabetic subjects.
[Articolo su rivista]
Greco, Carla; Pirotti, Tommaso; Brigante, Giulia; Filippini, Tommaso; Pacchioni, Chiara; Trenti, Tommaso; Simoni, Manuela; Santi, Daniele
abstract
Aim The coronavirus disease (COVID)‐19 incidence was higher in diabetes mellitus (DM), although several differences
should be considered on the basis of characteristics of cohorts evaluated. This study was designed to evaluate the prevalence
and potential consequences of COVID-19 in a large diabetic population in Northern Italy.
Design Observational, longitudinal, retrospective, clinical study.
Methods Subjects with both type 1 and type 2 DM living in the Province of Modena and submitted to at least one SARSCoV-
2 swab between March 2020 and March 2021 were included. Data were extracted from the Hospital data warehouse.
Results 9553 diabetic subjects were enrolled (age 68.8 ± 14.1 years, diabetes duration 11.0 ± 6.9 years, glycated hemoglobin
57.2 ± 16.2 mmol/mol). COVID-19 was detected in 2302 patients (24.1%) with a death rate of 8.9%. The mean age and diabetes
duration were significantly lower in infected versus non-infected patients. SARS-CoV-2 infection was more frequent in
youngest people, according to quartile of age and retirement pension age of 65 years. No differences were detected considering
sex. Higher HbA1c was detected in infected compared to non-infected patient. Death was predicted by diabetes duration
and HbA1c. ROC analyses for death risk showed significant threshold for diabetes duration (10.9 years) and age (74.4 years).
Conclusion In our cohort, SARS-CoV-2 infection correlates with age, diabetes duration and disease control. Diabetic patients
2023
- Ketogenic state improves testosterone serum levels-results from a systematic review and meta-analysis
[Articolo su rivista]
Furini, Chiara; Spaggiari, Giorgia; Simoni, Manuela; Greco, Carla; Santi, Daniele
abstract
It is widely demonstrated that obesity and hypogonadism are bi-directionally correlated, since the hypogonadism prevalence is higher in obese population, while weight loss increases testosterone serum levels. Several approaches are available to contrast weight excess, from simple dietary regimens to more complex surgical procedures. Ketogenic diets (KD) fit in this context and their application is growing year after year, aiming to improve the metabolic and weight patterns in obese patients. However, KD influence on testosterone levels is still poorly investigated.
2023
- Long-term trajectories of bone metabolism parameters and bone mineral density (BMD) in obese patients treated with metabolic surgery: a real-world, retrospective study.
[Articolo su rivista]
Greco, Carla; Passerini, Francesca; Coluccia, Silvia; Teglio, Marta; Bondi, Mario; Mecheri, Fouzia; Trapani, Vincenzo; Volpe, Alessandro; Toschi, Patrizia; Madeo, Bruno; Simoni, Manuela; Rochira, Vincenzo; Santi, Daniele
abstract
Purpose Potential negative effects of metabolic surgery on skeletal integrity remain a concern, since long-term data of
different surgical approaches are poor. This study aimed to describe changes in bone metabolism in subjects with obesity
undergoing both Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG).
Methods A single center, retrospective, observational clinical study on real-world data was performed enrolling subjects
undergoing metabolic surgery.
Results 123 subjects were enrolled (males 31: females 92; ages 48.2 ± 7.9 years). All patients were evaluated until
16.9 ± 8.1 months after surgery, while a small group was evaluated up to 4.5 years. All patients were treated after surgery
with calcium and vitamin D integration. Both calcium and phosphate serum levels significantly increased after metabolic
surgery and remained stable during follow-up. These trends did not differ between RYGB and SG (p = 0.245). Ca/P ratio
decreased after surgery compared to baseline (p < 0.001) and this decrease remained among follow-up visits. While 24-h
urinary calcium remained stable across all visits, 24-h urinary phosphate showed lower levels after surgery (p = 0.014), also
according to surgery technique. Parathyroid hormone decreased (p < 0.001) and both vitamin D (p < 0.001) and C-terminal
telopeptide of type I collagen (p = 0.001) increased after surgery.
Conclusion We demonstrated that calcium and phosphorous metabolism shows slight modification even after several years
since metabolic surgery, irrespective of calcium and vitamin D supplementation. This different set point is characterized
by a phosphate serum levels increase, together with a persistent bone loss, suggesting that supplementation alone may not
ensure the maintenance of bone health in these patients.
2023
- Microbiota Composition and Probiotics Supplementations on Sleep Quality—A Systematic Review and Meta-Analysis
[Articolo su rivista]
Santi, D.; Debbi, V.; Costantino, F.; Spaggiari, G.; Simoni, M.; Greco, C.; Casarini, L.
abstract
The gut microbiota (GM) plays a crucial role in human health. The bidirectional interaction between GM and the central nervous system may occur via the microbiota-gut-brain axis, possibly regulating the sleep/wake cycle. Recent reports highlight associations between intestinal dysbiosis and sleep disorders, suggesting that probiotics could ameliorate this condition. However, data are poor and inconsistent. The aim of this quantitative metanalytic study is to assess the GM composition in sleep disturbances and evaluate probiotics' effectiveness for managing sleep disorders. A systematic review was carried out until July 2022 in online databases, limiting the literature research to human studies and English language articles. No significant GM diversity between patients with sleep disturbances versus healthy controls was found, revealed by alpha-diversity, while beta-diversity is missing due to lack of proper reporting. However, probiotics supplementation significantly reduced the self-assessed parameter of sleep quality and disturbances Pittsburgh Sleep Quality Index (PSQI) score compared with the placebo. No difference in the Epworth Sleepiness Scale (ESS) score was found. While available data suggest that GM diversity is not related to sleep disturbances, probiotics administration strongly improves sleep quality as a subjective perception. However, heterogeneity of data reporting in the scientific literature should be considered as a limitation.
2023
- New antidiabetic drugs’ role in the management of testosterone deficiency and of the cardiovascular disease in hypogonadal diabetic men
[Articolo su rivista]
Genchi, V. A.; Zanni, E.; Colzani, M.; Lauriola, C.; Cignarelli, A.; Santi, D.; Greco, C.
abstract
2022
- Clinical scoring systems for the risk of cardiovascular autonomic neuropathy in type 1 and type 2 diabetes: A simple tool.
[Articolo su rivista]
Menduni, Marika; D'Amato, Cinzia; Leoni, Martina; Izzo, Valentina; Staltari, Mariateresa; Greco, Carla; Abbatepassero, Andrea; Seminara, Giuseppe; D'Ippolito, Ilenia; Lauro, Davide; Spallone, Vincenza
abstract
This study was aimed at developing a clinical risk score for cardiovascular autonomic
neuropathy (CAN) for type 1 and type 2 diabetes. In a retrospective cross-sectional
one-centre study in an unselected population, 115 participants with type 1 diabetes
(age 41.1 ± 12.2 years) and 161 with type 2 diabetes (age 63.1 ± 8.9 years), wellcharacterized
for clinical variables, underwent standard cardiovascular reflex tests
(CARTs). Strength of associations of confirmed CAN (based on 2 abnormal CARTs) with
clinical variables was used to build a CAN risk score. CAN risk score was based on resting
heart rate, HbA1c, retinopathy, nephropathy, cardiovascular disease in both type
1 and type 2 diabetes, and on HDL cholesterol, systolic blood pressure, and smoking in
type 1 diabetes or insulin treatment and physical activity in type 2 diabetes (range
0-10). In type 1 diabetes, CAN risk score showed an area under the ROC curve (AUC)
of 0.890 ± 0.034, and at cut-off of 4 sensitivity of 88%, specificity of 74.4%, and negative
predictive value (NPV) of 95.7% for confirmed CAN. In type 2 diabetes, CAN risk
score showed an AUC of 0.830 ± 0.051 and at the cut-off of 4 sensitivity and specificity
of 78.6% and 73.5%, respectively, and NPV of 97.3% for confirmed CAN. These
newly developed CAN risk scores are accessible in clinical practice and, if confirmed in a
validation study, they might identify asymptomatic individuals with diabetes at greater
risk of CAN to be referred to CARTs, thus limiting the burden of a universal screening.
2022
- Diabetic Neuropathic Cachexia: A Clinical Case and Review of Literature
[Articolo su rivista]
Bellelli, A.; Santi, D.; Simoni, M.; Greco, C.
abstract
A 46-year-old man was admitted to the surgical department because of abdominal pain and anemia, with the radiological finding of a perforated duodenal ulcer, and underwent laparoscopic surgical treatment. Type 2 diabetes mellitus (T2DM) had been diagnosed 5 years earlier and treated with diet. At clinical investigation, the patient was depressed and anorexic; moreover, he complained of lower extremity weakness and bilateral feet pain, burning in nature and accompanied by allodynia. This painful sensation had been preceded by an 8-month history of fatigue and anorexia with profound weight loss of 35 kg. After clinical evaluation and a nerve conduction study, diagnosis of diabetic cachectic neuropathy was made based on the rapid onset of severe neuropathic pain in the context of diabetic neuropathy, marked weight loss, and depressed mood. The therapy with pregabalin and duloxetine had scarce effect and was gradually discontinued. The patient, however, obtained progressive relief and amelioration of neuropathic lower-limb pain concomitant with weight gain. This clinical trend also confirmed the diagnosis of this rare form of diabetic neuropathy. A few cases of diabetic neuropathic cachexia have been reported in the literature and are briefly reviewed here.
2022
- Effect of the Glucagon-Like Peptide-1 Receptor Agonists on Autonomic Function in Subjects with Diabetes: A Systematic Review and Meta-Analysis
[Articolo su rivista]
Greco, Carla; Santi, Daniele; Brigante, Giulia; Pacchioni, Chiara; Simoni, Manuela
abstract
Background: In addition to the metabolic effects in diabetes, glucagon-like peptide 1 receptor (GLP-1R) agonists lead to a small but substantial increase in heart rate (HR). However, the GLP-1R actions on the autonomic nervous system (ANS) in diabetes remain debated. Therefore, this meta-analysis evaluates the effect of GLP-1R agonist on measures of ANS function in diabetes. Methods: According to the Cochrane Collaboration and Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement, we conducted a meta-analysis considering clinical trials in which the autonomic function was evaluated in diabetic subjects chronically treated with GLP-1R agonists. The outcomes were the change of ANS function measured by heart rate variability (HRV) and cardiac autonomic reflex tests (CARTs). Results: In the studies enrolled, HR significantly increased after treatment (P<0.001), whereas low frequency/high frequency ratio did not differ (P=0.410); no changes in other measures of HRV were detected. Considering CARTs, only the 30:15 value derived from lying-to-standing test was significantly lower after treatment (P=0.002), but only two studies reported this measurement. No differences in other CARTs outcome were observed. Conclusion: The meta-analysis confirms the HR increase but seems to exclude an alteration of the sympatho-vagal balance due to chronic treatment with GLP-1R agonists in diabetes, considering the available measures of ANS function.
2022
- Effects of bariatric and metabolic surgical procedures on dyslipidemia: a retrospective, observational analysis.
[Articolo su rivista]
Greco, Carla; Passerini, Francesca; Coluccia, Silvia; Bondi, Mario; Mecheri, Fouzia; Trapani, Vincenzo; Volpe, Alessandro; Toschi, PATRIZIA FEDERICA; Carubbi, Francesca; Simoni, Manuela; Santi, Daniele
abstract
Aim: Obesity and co-existing metabolic comorbidities are associated with increased cardiovascular (CV) morbidity and mortality risks, generally clustered to risk factors such as dyslipidemia. The aim of this study was to evaluate the lipid profile changes in subjects with severe obesity undergoing different procedures of bariatric and metabolic surgery (BMS), sleeve gastrectomy (SG), and Roux-en-Y gastric bypass (RYGB) in a real-world, clinical setting.
Methods: A single-center, retrospective, observational clinical study was performed enrolling patients undergoing BMS. The primary outcome was the change in total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL) cholesterol, and triglycerides.
Results: In total, 123 patients were enrolled (males 25.2% and females 74.8%) with a mean age of 48.2 ± 7.9 years and a mean BMI of 47.0 ± 9.1 kg/m2. All patients were evaluated until 16.9 ± 8.1 months after surgery. Total and HDL cholesterol did not change after surgery, while a significant reduction in triglyceride levels was recorded. Moreover, a rapid decline of both LDL and non-HDL cholesterol among follow-up visits was observed. In particular, significant inverse correlations were found between total cholesterol, LDL cholesterol, non-HDL cholesterol, and triglycerides and the number of months elapsed after bariatric surgery. Similarly, a direct correlation was found considering HDL cholesterol. Moreover, total cholesterol, LDL cholesterol, non-HDL cholesterol, and triglycerides significantly changed among visits after RYGB, while no changes were observed in the SG group. Finally, considering lipid-lowering therapies, the improvement in lipid asset was detected only in non-treated patients.
Conclusion: This study corroborates the knowledge of the improvement in lipid profile with BMS in clinical practice. Together with sustained weight loss, the BMS approach efficiently corrects dyslipidemia, contributing to decreasing the CV risk.
2022
- Ketogenic state is able to improve testosterone serum levels - a meta-analytic approach
[Abstract in Atti di Convegno]
Furini, C; Spaggiari, G; Greco, C; Simoni, M; Santi, D
abstract
Background: It is widely demonstrated that obesity and hypogonadism are bi-directionally correlated, since the hypogonadism prevalence is higher in obese population, while weight loss increases testosterone serum levels. Several approaches are available to contrast weight excess, from simple dietary regimens to more complex surgical procedures. Ketogenic diets (KD) fit in this context and their application is growing year after year, aiming to improve the metabolic and weight patterns in obese patients. However, KD influence on testosterone levels is still poorly investigated.
Objectives: To systematically evaluate the potential effect of KD on testosterone levels.
Methods: A literature search was performed until April 2022 including studies investigating testosterone levels before and after KD. Secondary endpoints were body weight, estradiol and sex hormone binding globulin serum levels. Any kind of KD was considered eligible, and no specific criteria for study populations were provided.
Results: Seven studies (including eight trials) were included in the analysis, five using normocaloric KD and three very low calories KD (VLCKD). Only three studies enrolled overweight/obese men. A significant total testosterone increase was recorded after any kind of KD considering 111 patients (2.86 [0.95, 4.77], P = 0.003). This increase was more evident considering VLCKD compared to normocaloric KD (6.75 [3.31, 10.20], P < 0.001, vs 0.98 [0.08, 1.88], P = 0.030). Meta-regression analyses highlighted significant correlations between the post-KD testosterone raise with patients’ age (R-squared 36.4, P < 0.001) and weight loss (R-squared 73.6, P < 0.001).
Conclusions: Comprehensively, KD improved testosterone levels depending on both patients’ age and KD-induced weight loss. However, the lack of information in included studies on hormones of the hypothalamic-pituitary-gonadal axis prevents an exhaustive comprehension about mechanisms connecting ketosis and testosterone homeostasis.
2022
- Menstrual cycle abnormalities as distinctive sign of type 1 diabetes mellitus: results from a meta-analysis
[Abstract in Atti di Convegno]
Corleto, Rossella; Greco, Carla; Cacciani, Marta; Spaggiari, Giorgia; Simoni, Manuela; Santi, Daniele
abstract
Background: Type 1 diabetes mellitus (T1DM) management profoundly changed across years, with increasing emphasis on stringent glycaemic control. While it is well demonstrated that the progressive improvement of glycaemic control allows a tighter command of diabetes-related complications, the positive implications thereof on reproductive functions are still unclear. Indeed, it is well known that oligomenorrhea and amenorrhea are more frequently detected in young women with T1DM compared to healthy age-matched controls. However, whether the menstrual abnormalities incidence changed across years is still matter of debate.
Aim of the study: To evaluate the menstrual cycle abnormalities rate in T1DM young women, compared to healthy subjects, and to search for potential T1DM-related factors influencing female reproductive system. Secondary aim was the evaluation of the possible effects of the change in T1DM management, occurred in the late 90’s, on menstrual cycle dysfunction.
Methods: A meta-analysis was performed considering all clinical trials in which menstrual cycle abnormalities in T1DM young women were reported, compared to healthy age-matched subjects. Primary endpoint was the rate of oligomenorrhea/amenorrhea and secondary objective was age at menarche. Sensitivity analysis was conducted dividing studies into two groups, i.e. before and after 2000, according to the change in T1DM management. Three meta-regression analyses were performed, considering the influence of diabetes duration, body mass index (BMI) and glycated haemoglobin (HbA1c) serum levels on menstrual irregularities.
Results: From 623 papers initially identified, 12 studies were finally included. Menstrual cycle dysfunction rate was significantly higher in T1DM women compared to controls, also considering only studies published after 2000 (OR:2.08; 95%CI: 1.43,3.03, P<0.001). Age at menarche was significantly higher in T1DM women compared to controls (P<0.001) also when studies published after 2000 were evaluated separately (mean difference:0.53; 95%CI: 0.32,0.74 years, P<0.001). In meta-regression analyses, the menstrual abnormalities rate in T1DM women were inversely related to diabetes duration (R2 =0.396,P=0.023), but not to BMI (R2 =0.134,P=0.373) and HbA1c serum levels (R2 =0.083,P=0.409).
Conclusion: The meta-analytic approach confirmed the high incidence of menstrual cycle dysfunction in T1DM young women. The improvement in T1DM management, introduced after 2000, seems not able to influence this rate, leaving menstrual cycle abnormalities one of the distinctive signs of this chronic condition. Indeed, T1DM-related menstrual dysfunction is associated neither to anthropometrical variables, nor glycemic control. Although actual pathogenetic mechanisms are not fully understood, here we demonstrate a potential association with T1DM duration, suggesting that the process of disease acceptance could underlie these irregularities.
2022
- Non-Alcoholic Fatty Liver Disease Is not Related to the Prevalence of Diabetic Polyneuropathy in Diabetes
[Poster]
Greco, Carla; Boni, Stefano; Coluccia, Silvia; Colzani, Massimiliano; Santi, Daniele; Simoni, Manuela
abstract
Aim: Nonalcoholic fatty liver disease (NAFLD) has been suggested as
independent predictor for kidney disease and proliferative retinopathy in
patients with type 2 diabetes (T2D), while the association with diabetic
polyneuropathy (DPN) is debated. The aim of this study is to evaluate the
association between DPN and predictive tools and ultrasonography diagnosis of
NAFLD.
Methods: Forty-two diabetic patients (mean age 57.83 ± 11.47 years, duration
9.44 ± 8.92 years, HbA1c 59.19 ± 13.85 mmol/mol, 27 males, 93% T2DM),
underwent clinical evaluation of DPN by Michigan Neuropathy Screening
Instrument (MNSI), Michigan Diabetic Neuropathy Score (MDNS) and Diabetic
Neuropathy Index (DNI). NAFLD was evaluated by predictive tools Fatty Liver
Index (FLI) and Hepatic Steatosis Index (HIS), and confirmed by liver
ultrasonography.
Results: DPN was present in 22 (52.4%) participants. DPN patients were older
(p=0.04) and characterized by higher prevalence of impaired urinary albumin
excretion (p=0.035), hypertension (p=0.011) and dyslipidemia (p=0.041). High risk FLI and HIS scores were detected in 81% and 64.3% of subjects, while
ultrasonography NAFLD was present in 31 out of 36 (85.7%%) patients (20 with
mild and 11 with moderate-severe grade), resulting more frequent in females
than males (93.3% versus 63.0%, p=0.032).
87
No significant difference was found in DPN prevalence in patients with NAFLD
than those without (54.8 versus 45.2 %, p=0.338), also considering only high grade steatosis. No association was identified between DPN and non-invasive
predictive tools of NAFLD.
Conclusion: Although in a small sample of diabetic subjects, liver steatosis is not
independently associated with clinical diagnosis of DPN.
2022
- Retrospective observational study of Italian patients with diabetes mellitus in Covid-19 era: a big data approach
[Abstract in Atti di Convegno]
Greco, Carla; Pirotti, Tommaso; Brigante, Giulia; Filippini, Tommaso; Pacchioni, Chiara; Trenti, Tommaso; Simoni, Manuela; Santi, Daniele
abstract
Background: Diabetes mellitus (DM) prevalence in patients with severe acute respiratory coronavirus virus (SARS-CoV-2) infection differs among studies, although pre-existing DM seems to double the risk of critical infection and mortality.
Objectives: To evaluate incidence and mortality risk of SARS-CoV-2 infection in a large diabetic population in Northern Italy in pre-vaccine era.
Methods: Retrospective, observational, big data study including non-vaccinated subjects with type 1 and type 2 DM in the Province of Modena, submitted to at least 1 swab for SARS-CoV-2 between March 2020 and March 2021.
Results: SARS-CoV-2 infection was detected in 2302 of 9553 diabetic patients (24.1%) with death in 8.9% of cases. No difference in SARS-CoV-2 prevalence was detected considering sex, whereas youngest people showed highest SARS-CoV-2 infection rate. DM duration was shorter in infected than uninfected patients (P < 0.001), but HbA1c was higher in infected compared to uninfected patients (P < 0.001). Accordingly, SARS-CoV-2 was less frequent in patients treated with anti-diabetic drugs compared to those not treated (P < 0.001). SARS-CoV-2 infection was predicted by age (OR 1.013, 95%CI:1.008-1.017), DM duration (OR 1.007, 95%CI:1.001-1.013), and HbA1c (OR 1.009, 95%CI:1.002-1.016). COVID-19 mortality was predicted by DM duration (OR 1.010, 95%CI: 1.005-1.015) and HbA1c (OR 1.005, 95%CI:1.002-1.009). At ROC analyses with death as test variable, worse prognosis was predicted by DM duration longer than 10.9 years (AUC=0.639, 95%CI:0.601–0.676) and age older than 74.4 years (AUC=0.797, 95%CI:0.767–0.827).
Conclusion: Our study confirms the correlation between SARS-CoV-2 related mortality and DM. Although SARS-CoV-2 infection was more frequent in the younger patients, a poor glycemic control worsens outcomes, especially in older diabetic people with long DM duration. Patients with DM and SARS-CoV-2 should be followed carefully when older than 74 years and with long DM duration.
2022
- Retrospective observational study of italian patients with diabetes mellitus in Covid-19 pre-vaccine ERA: a big data approach
[Abstract in Atti di Convegno]
Colzani, M; Greco, C; Pirotti, T; Brigante, G; Filippini, T; Pacchioni, C; Trenti, T; Simoni, M; Santi, D
abstract
2021
- Association of nonalcoholic fatty liver disease (Nafld) with peripheral diabetic polyneuropathy: A systematic review and meta-analysis
[Articolo su rivista]
Greco, C.; Nascimbeni, F.; Carubbi, F.; Andreone, P.; Simoni, M.; Santi, D.
abstract
Aims. The relationship between nonalcoholic fatty liver disease (NAFLD) and diabetic polyneuropathy (DPN) has been demonstrated in many studies, although results were conflicting. This meta-analysis aims to summarize available data and to estimate the DPN risk among NAFLD patients. Materials and methods. We performed a comprehensive literature review until 4 June 2021. Clinical trials analyzing the association between NAFLD and DPN were included. Results. Thirteen studies (9614 participants) were included. DPN prevalence was significantly higher in patients with NALFD, compared to patients without NAFLD (OR (95%CI) 2.48 (1.42–4.34), p = 0.001; I2 96%). This finding was confirmed in type 2 diabetes (OR (95%CI) 2.51 (1.33–4.74), p = 0.005; I2 97%), but not in type 1 diabetes (OR (95%CI) 2.44 (0.85–6.99), p = 0.100; I2 77%). Also, body mass index and diabetes duration were higher in NAFLD subjects compared to those without NAFLD (p < 0.001), considering both type 2 and type 1 diabetes. Conclusion. Despite a high heterogeneity among studies, a significantly increased DPN prevalence among type 2 diabetes subjects with NAFLD was observed. This result was not found in type 1 diabetes, probably due to the longer duration of disease. Physicians should pay more attention to the early detection of DPN, especially in patients with NAFLD.
2021
- Male hypogonadism and pre-diabetes interplay: association or causal interaction? A systematic review
[Articolo su rivista]
Greco, Carla; Corleto, Rossella; Ebert, Riccardo; Simoni, Manuela; Rochira, Vincenzo; Santi, Daniele
abstract
Aim: The association between type 2 diabetes mellitus (T2DM) and male hypogonadism has been largely
demonstrated. Testosterone (T) serum levels are often lower in men with T2DM compared to the general
population, and, conversely, men with higher T serum levels have shown lower risk of T2DM. On the contrary, the
association between pre-diabetes and male hypogonadism has been less investigated thus far. Pre-diabetes is a
common clinical condition preceding T2DM and has been recognized as a potential risk factor for other metabolic
disorders and cardiovascular diseases. Therefore, the aims of this review are to investigate the association between
pre-diabetes and male hypogonadism and to evaluate the potential effect of T treatment on glucose metabolism
and anti-diabetic therapy on T serum levels.
Methods: We conducted this systematic review developing different literature searches, following the Preferred
Reporting Items for Systematic Reviews and Meta-Analysis protocol.
Results: In our analysis, male hypogonadism has a prevalence of around 24%-35% in pre-diabetic men. Moreover,
we observed improvement of metabolic parameters in pre-diabetes with T treatment. On the contrary, antidiabetic
therapy seems to have no particular effects on T serum levels.
Conclusion: Overall, we demonstrated that, although T administration could be considered in pre-diabetic men,
pre-diabetes-related treatments should be confined to the control glucose metabolism, since no evidence for a
positive effect on total T serum levels is available. Future research should be oriented to study the role of new antidiabetic
drugs in the sex hormonal status in hypogonadal men.
2021
- Manifestazioni cliniche della neuropatia autonomica diabetica: valutazione dei sintomi.
[Articolo su rivista]
Greco, Carla; Pacchioni, Chiara; Simoni, Manuela
abstract
La neuropatia autonomica diabetica (NAD) è
una complicanza frequente del diabete, a insorgenza precoce
e a forte impatto in termini di diagnosi, gestione di malattia
e compromissione della qualità di vita dei soggetti affetti.
Le manifestazioni cliniche della NAD sono numerose e possono
interessare tutti gli organi e apparati; in questo contesto,
la NAD cardiaca è la forma clinicamente più importante
in quanto fattore di rischio per mortalità cardiovascolare.
Il gold standard per la diagnosi di NAD cardiaca è rappresentato
dai test cardiovascolari (cardiovascular autonomic
reflex tests, CARTs), mentre la valutazione dei sintomi in
passato era stata considerata di utilità diagnostica non rilevante
date la bassa specificità dei sintomi e l’indisponibilità
di questionari validati. Pertanto, la seguente rassegna prende
in esame le novità in termini di valutazione e monitoraggio
dei sintomi disautonomici nella NAD.
2021
- The “hitchhiker’s guide to the galaxy” of endothelial dysfunction markers in human fertility
[Articolo su rivista]
Santi, D.; Spaggiari, G.; Greco, C.; Lazzaretti, C.; Paradiso, E.; Casarini, L.; Poti, F.; Brigante, G.; Simoni, M.
abstract
Endothelial dysfunction is an early event in the pathogenesis of atherosclerosis and represents the first step in the pathogenesis of cardiovascular diseases. The evaluation of endothelial health is fundamental in clinical practice and several direct and indirect markers have been suggested so far to identify any alterations in endothelial homeostasis. Alongside the known endothelial role on vascular health, several pieces of evidence have demonstrated that proper endothelial functioning plays a key role in human fertility and reproduction. Therefore, this stateof‐the‐art review updates the endothelial health markers discriminating between those available for clinical practice or for research purposes and their application in human fertility. Moreover, new molecules potentially helpful to clarify the link between endothelial and reproductive health are evaluated herein.
2020
- Early diagnosis of medullary thyroid cancer in case of low serum calcitonin: Role of calcitonin measurement in fine-needle aspiration washout fluid
[Abstract in Atti di Convegno]
Greco, C.; Madeo, B.; Rochira, V.; De Santis, M. C.; Brigante, G.
abstract
Background
Screening serum calcitonin (sCT) measurement in patients with thyroid nod- ules is still debated. Moreover, sCt cutoffs for medullary thyroid carcino- ma (MTC) are not univocally defined. Also, sensitivity of cytology by fine needle aspiration biopsy (FNAb) has been demonstrated to detect approx- imately half of MTCs. Ct measurement in fine-needle aspiration washout fluid (Ct-FNAb) has high sensitivity and specificity and is helpful in case of non-diagnostic cytology1. Recently, a series oflow sCt MTC has been collected2.
Aim
The objectives of this retrospective observational study were to define Ct- FNAb levels in subjects with low sCt (below cutoffs diagnostic for MTC) and to evaluate their clinical, ultrasonographic (US), cytological and histo- logical characteristics.Methods
We selected subjects with sCt above local normal ranges but below one of the diagnostic cutoff proposed for MTC (26 pg/ml in females and 68 pg/ ml in males), subjected to FNAb with Ct-FNAb measurement and then thy- roidectomized.
Results
Surprisingly, 50% (8/16) had MTC at histology, 19% cellular C hyperplasia (CCH) and only 31% neither MTC nor CCH. Ct-FNAb was significantly higher in MTC compared to both no MTC no CCH (2001 vs 25.32±55.72 pg/ml; P = 0.013) and to CCH (2001 vs 195.56 ± 286.09 pg/ml; P = 0.008). Even if below the diagnostic cutoff, also sCt was higher in MTC compared to no CCH and no MTC group (19±7 vs 9±4 pg/ml; P=0.019) but was not able to discriminate MTC from CCH. US failed to identify suspicious nod- ules, since MTC differed only for being solid and not haloed. At cytology nearly 90% of MTC lesions were non-diagnostic or, mainly, indeterminate. At histology, 7/8 were low risk micro MTCs.
Conclusion
HighCt-FNAb despite sCt only slightly elevated suggests: i) early detection of MTC before the onset of high secretion of Ct, ii) a peculiar variant of MTC, able to produce Ct but not to secrete it in bloodstream because of intracellular secretory pathway alteration, iii) possible methodological in- terferences in the dosage of sCt. In conclusion, this study demonstrates the importance of Ct-FNAb to discover early stages of MTC with sCt below diagnostic cutoffs.
2020
- Effect of a standard schema of self-monitoring blood glucose in patients with poorly controlled, non-insulin-treated type 2 diabetes mellitus: A controlled longitudinal study
[Articolo su rivista]
Madeo, B.; Diazzi, C.; Granata, A. R. M.; Ghoch, M. E.; Greco, C.; Romano, S.; Scaltriti, S.; Rochira, V.
abstract
The effect of self-monitoring of blood glucose (SMBG) on glycemic control with regard to non-insulintreated Type 2 diabetes mellitus (NIT-Type 2 DM) is still a controversial topic. Against this backdrop, we sought to compare the effect of a continuous short-term SMBG schema with as-usual treatment, based on changes in oral antidiabetic treatment in patients with poorly controlled Type 2 DM. We reviewed 492 NIT-Type 2 DM record charts, selecting 27 patients, with poor glycemic control, who were thought to self-monitor their blood glucose levels (SMBG group). We then compared them with 27 patients treated with modifying drugs or diets to achieve and maintain the glycemic target (Control Group). Haemoglobin A1c (HbA1c) and fasting plasma glucose (FPG) were evaluated at baseline, after 3 and 6 months. HbA1c values decreased after 3 and 6 months in the SMBG group (P < 0.001 on both occasions) and in the control group (P < 0.05 and P < 0.01, respectively), but without a significant difference between the two groups when compared at the same time. The FPG progressively decreased in both groups, reaching a significant difference in the SMBG group after 3 months and in the control group after 6 months, and without a significant difference between the two groups. The SMBG schema used in our study could be adopted for target groups before proceeding to the next therapeutic enhancement drug step, representing a useful tool that can help diabetic patients in raising awareness of and treating their disease.
2020
- Expression study of candidate miRNAs and evaluation of their potential use as biomarkers of diabetic neuropathy.
[Articolo su rivista]
Ciccacci, Cinzia; Latini, Andrea; Colantuono, Antonella; Politi, Cristina; D'Amato, Cinzia; Greco, Carla; Rinaldi Maria, Elena; Lauro, Davide; Novelli, Giuseppe; Spallone, Vincenza; Borgiani, Paola
abstract
Aim: To evaluate the expression of candidate miRNAs in relation to diabetic polyneuropathy (DPN) and
cardiovascular autonomic neuropathy (CAN). Materials & methods: The expression of six candidate miRNAs
has been evaluated in 49 Type 2 diabetes patients with neurological evaluation. Results: A higher
expression of miR-128a was seen in patients with DPN compared with those without DPN (p = 0.015).
miR-155 and miR-499a seemed to be down-expressed in patients with DPN (p = 0.04 and p = 0.05, respectively).
A lower expression of miR-155 (p = 0.05) was observed even in patients with CAN with respect to
CAN-negative. A higher expression of miR-155 was associated with the rs767649 polymorphism variant
allele compared with the wild-type allele (p = 0.03). Conclusion: miR-128a, miR-155 and miR-499a might
be involved in diabetic neuropathies development.
2020
- Mitochondrial DNA Copy Number in Peripheral Blood Is Reduced in Type 2 Diabetes Patients with Polyneuropathy and Associated with a MIR499A Gene Polymorphism.
[Articolo su rivista]
Latini, Andrea; Borgiani, Paola; De Benedittis, Giada; D'Amato, Cinzia; Greco, Carla; Lauro, Davide; Novelli, Giuseppe; Spallone, Vincenza; Ciccacci, Cinzia
abstract
Our aim was to evaluate in a cohort of 125 Italian patients with type 2 diabetes (T2D), who underwent neurological evaluation, the possible differences in the number of mitochondrial DNA copies (mtDNA) comparing positive and negative patients for cardiovascular autonomic neuropathy (CAN) or diabetic peripheral neuropathy (DPN) and comparing them with healthy controls. We also investigated a possible correlation of the number of mtDNA copies with the polymorphism rs3746444 of the MIR499A. T2D patients show a decrease in the number of mtDNA copies compared to healthy controls (p = 2 × 10-10). Dividing the T2D subjects by neurological evaluation, we found a significant mtDNA decrease in patients with DPN compared with those without (p = 0.02), while no differences were observed between subjects with and without CAN. Furthermore, the homozygous variant genotype for the polymorphism rs3746444 of MIR499A correlates with a decrease in the number of mtDNA copies, particularly in T2D patients (p = 0.009). Our data show a decrease in the number of mtDNA copies in subjects with T2D and suggest that this decrease is more evident in patients who develop DPN. Furthermore, the association of the variant allele of MIR499A with the number of mtDNA copies allows us to hypothesize a possible effect of this polymorphism in oxidative stress.
2020
- Morning blood pressure surge is associated with autonomic neuropathy and peripheral vascular disease in patients with diabetes.
[Articolo su rivista]
Di Gennaro, Federica; D'Amato, Cinzia; Morganti, Roberto; Greco, Carla; Longo, Susanna; Corradini, Diana; Lauro, Davide; Spallone, Vincenza
abstract
Although vascular and autonomic nervous system have been involved in the regulation of morning surge in blood pressure
(MBPS), data on clinical correlates of MBPS in diabetic population are scarce, in particular with regard to diabetic
complications. This study was aimed at investigating predictors and correlates of MBPS in diabetes. In a cross-sectional
study including 167 patients with diabetes (age 58.5 ± 11.1 years, duration 15.9 ± 12.1 years), clinical variables, diabetic and
neuropathic complications, and MBPS (using 24-h ambulatory blood pressure monitoring) were measured. The upper
quartile of MBPS (>30.5 mmHg) was associated with higher values of waist circumference (P = 0.027), triglycerides (P =
0.021), and Michigan Diabetic Neuropathy Score (P = 0.042), with lower HDL cholesterol (P = 0.030), and with the
presence of cardiovascular autonomic neuropathy (CAN) (P = 0.016) and peripheral vascular disease (PVD) (P < 0.0001). In
a logistic regression analysis, PVD (odds ratio: 10.2, P = 0.001), CAN (odds ratio: 6.09, P = 0.016), and diastolic blood
pressure (BP) (odds ratio: 1.06, P = 0.022) predicted MBPS upper quartile (r2 = 0.20, P = 0.0005). In a multiple regression
analysis, PVD (P = 0.002) and diastolic BP (P = 0.003) were the only determinants of MBPS (r2 = 0.20). MBPS upper
quartile was associated with BP dipping (systolic BP day–night reduction > 10%) (P = 0.012), and MBPS was positively
related to systolic (rho = 0.41, P < 0.0001) and diastolic BP day–night reduction. In conclusion, metabolic syndrome
stigmata, diastolic BP, CAN and PVD are the main predictors of MBPS in the diabetic population. Excessive MBPS and
nondipping are not concurrent 24-h BP alterations. Autonomic dysfunction might exert an exacerbating effect on MBPS
phenomenon.
2020
- The diagnostic usefulness of the combined COMPASS 31 questionnaire and electrochemical skin conductance for diabetic cardiovascular autonomic neuropathy and diabetic polyneuropathy.
[Articolo su rivista]
D'Amato, Cinzia; Greco, Carla; Lombardo, Giorgio; Frattina, Valentina; Campo, Mariagrazia; Cefalo, Chiara; Izzo, Valentina; Lauro, Davide; Spallone, Vincenza
abstract
The study investigated the diagnostic performance for diabetic cardiovascular autonomic
neuropathy (CAN) and diabetic polyneuropathy (DPN) of the combined use of
composite autonomic symptom score (COMPASS) 31, validated questionnaire for
autonomic symptoms of CAN, and electrochemical skin conductance (ESC), proposed
for detecting DPN and CAN. One-hundred and two participants with diabetes (age
57 ± 14 years, duration 17 ± 13 years) completed the COMPASS 31 before assessing
cardiovascular reflex tests (CARTs), neuropathic symptoms, signs, vibratory perception
threshold (VPT), thermal thresholds (TT), and ESC using Sudoscan. Two patterns
were evaluated: (a) the combined abnormalities in both tests (COMPASS 31+ESC),
and (b) the abnormality in COMPASS 31 and/or ESC (COMPASS 31 and/or ESC). CAN
(≥1 abnormal CART) and confirmed CAN (≥2 abnormal CARTs) were present in
28.1% and 12.5%, DPN (two abnormalities among symptoms, signs, VPT, and TT) in
52%, abnormal COMPASS 31 (total weighted score >16.44) in 48% and abnormal
ESC (hands ESC <50 μS and/or feet ESC <70 μS) in 47.4%. Both the patterns—COMPASS
31+ESC and COMPASS 31 and/or ESC—were associated with CAN and DPN
(P < .01). COMPASS 31 and ESC reached a sensitivity of 75% and 83% for confirmed
CAN, and a specificity of 65% and 67% for DPN. When combining the tests, the sensitivity
for CAN rose by up to 100% for CAN and the specificity up to 89% for DPN.
The combination of the tests can allow a stepwise screening strategy for CAN, by
suggesting CAN absence with combined normality, and prompting to CARTs with combined abnormality.
2019
- Concomitant medullary thyroid carcinoma with paraganglioma-like pattern and papillary thyroid carcinoma
[Articolo su rivista]
Greco, C.; Brigante, G.; Taliani, E.; Corrado, S.; Simoni, M.; Madeo, B.
abstract
A 74-year-old man was referred to the Endocrinology Unit because of multinodular goiter. The dominant nodule (1.7 × 1.9 × 2.4 cm), at the medium-superior third of the left lobe, was inhomogeneously hypoechoic, with irregular margins, macrocalcifications and intranodular vascularization. Fine-needle aspiration biopsy (FNAB) was performed. The cytological diagnosis was TIR 2, benign, according to the 2013 Italian thyroid cytology classification system. Moderately high serum calcitonin (s-Ct) (61.5 pg/mL, n.r. 0–7.5) and normal CEA were detected. The Ct level in FNAB wash-out fluid (Ct-FNAB) was 1450 pg/mL. Based on s-Ct and Ct-FNAB levels, patient underwent total thyroidectomy. Macroscopically, a dominant circumscribed nodule of 2 ecm was described; the histological and immunohistochemical features identified medullary thyroid carcinoma (MTC) with paraganglioma (PG)-like pattern positive for Ct, CEA and chromogranin and negative for S-100 sustentacular cells (SC). Moreover, papillary carcinoma of 3 mm in the right lobe was also associated. No areas of hyperaccumulation of the tracer were documented at Ga68 PET/CT. No RET-proto-oncogene mutations were found. Post-surgery s-Ct levels were within normal range (4 pg/mL). Two years after thyroidectomy, the patient is still disease-free. We reported a case of sporadic and rare variant of MTC: this is the ninth described case of PG-like MTC. In this case, cytologically benign, the clinical suspicion arose from high Ct values at FNAB wash-out fluid. Even if clinical behavior of this variant seems indolent, additional studies are necessary to understand prognoses and predictive factors.
2018
- Association between a MIR499A polymorphism and diabetic neuropathy in type 2 diabetes.
[Articolo su rivista]
Ciccacci, Cinzia; Latini, Andrea; Greco, Carla; Politi, Cristina; D'Amato, Cinzia; Lauro, Davide; Novelli, Giuseppe; Borgiani, Paola; Spallone, Vincenza
abstract
Aims: Diabetic polyneuropathy (DPN) and cardiovascular autonomic neuropathy (CAN) affect a large percentage of diabetic people and impact severely on quality of life. As it seems that miRNAs and their variations might play a role in these complications, we investigated whether the rs3746444 SNP in the MIR499A gene could be associated with susceptibility to DPN and/or CAN.
Methods: We analyzed 150 participants with type 2 diabetes. DNA was extracted from peripheral blood samples and genotyping was performed by TaqMan genotyping assay. Cardiovascular tests, MNSI-Q and MDNS for neuropathic symptoms and signs, VPT, and thermal thresholds were used for CAN and DPN assessment. We performed a genotype-phenotype correlation analysis.
Results: We observed that the GG genotype was associated with a higher risk of developing CAN (P=0.002 and OR=16.08, P=0.0005 and OR=35.02, for early and confirmed CAN, respectively) and DPN (P=0.037 and OR=6.56), after correction for BMI, sex, age, HbA1c and disease duration. Moreover, the GG genotype was associated with worse values of MDNS (P=0.017), VPT (P=0.01), thermal thresholds (P=0.01), and CAN score (P<0.001). A logistic multivariate analysis confirmed that MIR499A GG genotype, disease duration and HbA1c contributed to early CAN (R2=0.26), while the same variables and age contributed to DPN (R2=0.21). With a multiple linear regression, we observed that GG genotype (P=0.001) and disease duration (P=0.035) were the main variables contributing to the CAN score (R2=0.35).
Conclusions: We described for the first time that the MIR499A genetic variation could be involved in diabetic neuropathies susceptibility. In particular, patients carrying the rs3746444 GG genotype had a higher risk of CAN development, together with a more severe form of CAN.
2018
- Insulin autoimmune syndrome in an Argentine woman taking α-lipoic acid: A case report and review of the literature.
[Articolo su rivista]
Izzo, Valentina; Greco, Carla; Corradini, Diana; Infante, Marco; Staltari, Mariateresa; Romano, Maria; Bellia, Alfonso; Lauro, Davide; Uccioli, Luigi
abstract
Insulin autoimmune syndrome is an unusual cause of spontaneous hypoglycaemia in non-Asian populations. In the majority
of cases, this syndrome appears a few weeks after the administration of drugs containing a sulfhydryl group. A strong
association between this syndrome and HLA-DR4 has been shown. Only seven cases have been described in non-Asian
patients. We report the first case of insulin autoimmune syndrome in an Argentine woman taking alfa-lipoic acid. She
developed hypoglycaemic symptoms approximately 1 month after starting therapy. Blood sampling collected during an episode
of symptomatic hypoglycaemia showed low blood glucose level (2.39 mmol/L), high level of serum insulin (1971.55 pmol/L),
inappropriately high level of C-peptide (2.36 nmol/L) and high levels of insulin antibodies (274.78 IU/mL). HLA-DNA typing
identified DRB1*04:03. Due to the widespread use of alfa-lipoic acid for its antioxidant properties, clinicians should be aware
that it may trigger an autoimmune hypoglycaemia in people with a genetic predisposition.
2017
- Validation of the Composite Autonomic Symptom Score 31 (COMPASS 31) for the assessment of symptoms of autonomic neuropathy in people with diabetes.
[Articolo su rivista]
Greco, Carla; Di Gennaro, Federica; D'Amato, Cinzia; Morganti, Roberto; Corradini, Diana; Sun, Alice; Longo, Susanna; Lauro, Davide; Pierangeli, G; Cortelli, Pietro; Spallone, Vincenza
abstract
Aim: To validate the Composite Autonomic Symptom Score (COMPASS) 31, in its Italian version, for the diagnosis of diabetic cardiovascular autonomic neuropathy in a clinic-based, single-centre study.
Methods: A total of 73 participants with diabetes (age 55 ± 14 years) completed the COMPASS 31 questionnaire before undergoing cardiovascular autonomic neuropathy and diabetic polyneuropathy assessment according to cardiovascular reflex tests, neuropathic symptoms and signs, and vibration and thermal thresholds.
Results: The COMPASS 31 total weighted score differed between participants with and without cardiovascular autonomic neuropathy (29.9 ± 19.5 vs 16.1 ± 14.7; P = 0.003) and with and without diabetic polyneuropathy (28.9 ± 19.1 vs 12.7 ± 11.3; P < 0.0001). It was related to cardiovascular reflex tests score (rho = 0.38, P = 0.0013) as well as diabetic polyneuropathy symptoms (rho=0.61, P < 0.0001) and signs scores (rho = 0.49, P < 0.0001). Receiver-operating curve analysis showed a fair diagnostic accuracy of total score for cardiovascular autonomic neuropathy (area under the curve 0.748 ± 0.068, 95% CI 0.599-0.861) and diabetic polyneuropathy (area under the curve 0.742 ± 0.061, 95% CI 0.611-0.845). The best score thresholds were 16 for early cardiovascular autonomic neuropathy (sensitivity 75.0%, specificity 64.9%, positive predictive value 37.5% and negative predictive value 90.2%), and 17 for both confirmed cardiovascular autonomic neuropathy and diabetic polyneuropathy (sensitivity 70.0% and 65.5%, respectively; specificity 66.7% and 79.5%, respectively; positive predictive value 25.0% and 67.9%, respectively; and negative predictive value 93.0% and 77.8%, respectively). COMPASS 31 had a good internal consistency according to Cronbach's α coefficient of 0.73.
Conclusions: COMPASS 31 can represent a valid, easy-to-use, quantitative assessment tool for autonomic symptoms in diabetic neuropathy, with a fair diagnostic accuracy for both cardiovascular autonomic neuropathy and diabetic polyneuropathy.
2016
- ASSOCIATION BETWEEN MIR499 GENE POLYMORPHISMS AND DIABETIC NEUROPATHY IN TYPE 2 DIABETES
[Poster]
Greco, C; Ciccacci, C; Latini, A; D’Amato, C; Di Gennaro, F; Cacciotti, L; Politi, C; Novelli, G; Sangiuolo, F; Lauro, D; Borgiani, P; Spallone, V
abstract
Background: MicroRNAs (miRNAs) are non-coding RNAs that regulate gene expression. Genetic variants (such as Single-Nucleotide Polymorphisms, SNPs) in miRNA genes may be involved in the deregulation of target gene expression. The miR499 is a novel miRNA, mainly expressed in the muscle, heart, and brain, and implicated in cardiovascular dis¬ease, cancer, rheumatoid arthritis, and metabolic syndrome.
Aim: To investigate whether the miR499 A/G rs3746444 SNP is associated with susceptibility to diabetic polyneuropathy (DPN) and/or cardiovascular autonomic neuropathy (CAN) in type 2 diabetes.
Methods: In 150 type 2 patients (age 63.8±8.1 years, duration 12.7±9.5 years, BMI 30.8±5.2 Kg/m2, 89 males) the rs3746444 was investigated by TaqMan genotyping assay. Cardiovascular tests, MNSI-Q and MDNS for neuropathic symptoms and signs, VPT, and Thermal Thresholds (TT) were used for CAN and DPN assessment.
Results: AA, AG, and GG genotypes were present in 56%, 38%, and 6% of patients, respectively. After ANOVA analysis and adjustment for sex, age, BMI, duration, and HbA1c, GG genotype was associated with higher insulin dose (P=0.030), CAN score (P<0.0001), MDNS (P=0.010), and VPT (P=0.004) in comparison with AA and AG genotypes. Moreover, GG genotype was associated with the presence of early CAN (Chi2=9.75, P=0.006, OR 7.57, 95% C.I. 1.8-32.2), confirmed CAN (Chi2=13.1, P=0.006, OR 9.92, 95% C.I. 1.8-32.2), and abnormal TTs (Chi2=7.65, P=0.01, OR 11.4, 95% C.I. 1.3-98.1). In a logistic regression analysis, including sex, age, BMI, duration, HbA1c, insulin dose, physical activity, LDL cholesterol, systolic BP, eGFR, retinopathy, and GG genotype as independent variables, CAN was predicted by duration (OR 1.1, CI 95% 1.01-1.19, P=0.031) and GG genotype (OR 35.8, CI 95% 2.7-467, P=0.006) (r2=0.36). In a multiple regression analysis with the same variables, GG genotype was the major determinant of CAN score (P=0.001, adjusted r2=0.27). The association with DPN was lost in multivariate analyses.
Conclusions: This novel association of miR499 rs3746444 SNP with CAN susceptibility, albeit requiring replication in larger cohorts, might suggest a role of miR499 in cardiovascular autonomic dysfunction in diabetes.
2016
- Diabetic peripheral neuropathic pain is a stronger predictor of depression than other diabetic complications and comorbidities.
[Articolo su rivista]
D'Amato, Cinzia; Morganti, Roberto; Greco, Carla; Di Gennaro, Federica; Cacciotti, Laura; Longo, Susuanna; Mataluni, Giorgia; Lauro, Davide; Marfia Girolama, Alessandra; Spallone, Vincenza
abstract
Aims: To investigate the independent effect on depression of painless diabetic polyneuropathy, painful diabetic polyneuropathy, and general and diabetes-related comorbidities.
Methods: In 181 patients, the presence of painless diabetic polyneuropathy, painful diabetic polyneuropathy, comorbidities and depression was assessed using the Michigan Neuropathy Screening Instrument Questionnaire, the Michigan Diabetic Neuropathy Score, nerve conduction studies, the Douleur Neuropathique en 4 Questions, the Charlson Comorbidity Index and the Beck Depression Inventory-II.
Results: In all, 46 patients met the criteria of confirmed painless diabetic polyneuropathy and 25 of painful diabetic polyneuropathy. Beck Depression Inventory-II scores indicative of mild-moderate-severe depression were reached in 36 patients (19.7%). In a multiple logistic regression analysis (including age, sex, body mass index, being unemployed, duration, haemoglobin A1c, insulin treatment, systolic blood pressure, nephropathy, retinopathy, Charlson Comorbidity Index and painful diabetic polyneuropathy), female sex (odds ratio: 5.9, p = 0.005) and painful diabetic polyneuropathy (odds ratio: 4.6, p = 0.038) were the only independent predictors of depression. Multiple regression analysis, including Douleur Neuropathique en 4 Questions and Michigan Diabetic Neuropathy Score instead of painful diabetic polyneuropathy, showed that Douleur Neuropathique en 4 Questions, in addition to female sex, was a significant predictor of depressive symptoms severity (p =0.005).
Conclusion: Painful diabetic polyneuropathy is a greater determinant of depression than other diabetes-related complications and comorbidities. Painful symptoms enhance depression severity more than objective insensitivity.
2016
- Obstructive Sleep Apnoea Syndrome and Diabetes. Fortuitous Association or Interaction?
[Articolo su rivista]
Greco, C; Spallone, V.
abstract
Abstract: This review explores the relation between obstructive sleep apnoea syndrome (OSAS) and
diabetes. It aims to address the following issues: 1. the epidemiological evidence of the association between
OSAS and type 2 diabetes; 2. the independence of this association from the comorbidities
shared by the two conditions; 3. the chronological and quantitative characteristics of this association
(Which comes first? Is there severity interdependence? Is treatment of one condition able to modify
the natural history of the other?); 4. the mechanisms that make interaction plausible; 5. the impact of
the OSAS-diabetes relation on micro- and macrovascular diabetic complications.
OSAS is common in type 2 diabetes. Despite the association being affected by the confounding action of type 2 diabetes
comorbidities (also risk factors for OSAS), it does not seem to be fully attributable to them. There is also a relation between
OSAS severity and glucose metabolism alteration. A link between OSAS and insulin resistance appears early, prior
to impaired glucose tolerance and the onset of diabetes. Therefore, a debate is ongoing on the pathogenetic role of OSAS
in type 2 diabetes development and any consequent relevance to diabetes treatment with no conclusive evidence to date.
A multiplicity of hypothetical mechanisms may mediate this relation. Most experimental findings support sympathetic activation
and changes in chemoreflex sensitivity based on the interaction between chemoreflex and baroreflex. Some studies
suggest bidirectional relationship between OSAS and diabetes, additive or synergistic effects for diabetic complications
and a reciprocal enhancement in their impact on hypertension and cardiovascular disease. Clarification of these
items could benefit diabetes management and prevention of diabetic cardiovascular complications.
2014
- A novel association between nondipping and painful diabetic polyneuropathy.
[Articolo su rivista]
D'Amato, Cinzia; Morganti, Roberto; Di Gennaro, Federica; Greco, Carla; Marfia Girolama, Alessandra; Spallone, Vincenza
abstract
OBJECTIVE
We hypothesized themeaningful coexistence of neuropathic pain and nondipping
in painful diabetic polyneuropathy (PDPN).
RESEARCH DESIGN AND METHODS
In 113 patients with PDPN, with painless diabetic polyneuropathy (DPN+) and
without DPN (DPN2), neuropathic pain, sleep, risk for obstructive sleep apnea
(OSA), autonomic function, and blood pressure (BP) circadian pattern were
assessed using the Douleur Neuropathique en 4 Questions (DN4), the Medical
Outcomes Study Sleep Scale, the Berlin Questionnaire, cardiovascular reflex tests,
and ambulatory BP monitoring.
RESULTS
Patients with PDPN showed higher nighttime systolic BP (130.4 6 15.6 mmHg)
than both DPN2 (119.9610.6mmHg; P < 0.0001) and DPN+ patients (124.2612.3
mmHg; P < 0.05), and lower day–night difference (Δ) in systolic BP (5.5 6 6.5 vs.
8.667.7%; P < 0.05) and diastolic BP than DPN2 patients. In a stepwise regression
analysis, orthostatic hypotension, high risk for OSA, and PDPN (DN4 interview)
were independent determinants of Δ in systolic BP (r = 0.46; P = 0.0001), Δ in
diastolic BP, and nighttime systolic BP.
CONCLUSIONS
PDPN is associated with higher nocturnal systolic BP and impaired BP circadian
pattern independent of pain-related comorbidities, suggesting a condition of high cardiovascular risk.
2014
- Common polymorphisms in MIR146a, MIR128a and MIR27a genes contribute to neuropathy susceptibility in type 2 diabetes.
[Articolo su rivista]
Ciccacci, Cinzia; Morganti, Roberto; Di Fusco, Davide; D'Amato, Cinzia; Cacciotti, Laura; Greco, Carla; Rufini, Sara; Novelli, Giuseppe; Sangiuolo, Federica; Marfia Girolama, Alessandra; Borgiani, Paola; Spallone, Vincenza
abstract
Abstract Diabetic polyneuropathy (DPN) and cardiovascular
autonomic neuropathy (CAN) are common type 2
diabetes complications with a large inter-individual variability
in terms of clinical manifestations and severity. Our
aim was to evaluate a possible involvement of genetic
polymorphisms in miRNA regions in the susceptibility to
DPN and CAN. Nine polymorphisms in miRNA genes
were studied in a sample of 132 type 2 diabetes patients
(T2D) analysed for DPN and 128 T2D patients analysed for
CAN. A genotype–phenotype correlation analysis was
performed. The T allele of rs11888095 single nucleotide
polymorphism (SNP) in MIR128a was significantly associated
with a higher risk (ORadj = 4.89, Padj = 0.02),
whereas the C allele of rs2910164 SNP in MIR146a
was associated with a lower risk to develop DPN
(ORadj = 0.49, Padj = 0.09), respectively. A multivariate
logistic regression analysis confirmed that both SNPs
contribute to DPN (p\0.001 and p = 0.01 for MIR128a
and MIR146a, respectively). MIR128a SNP significantly
contributed also to DPN score (p = 0.026). Rs895819 SNP
in MIR27a was significantly associated with a higher risk
to develop early CAN (Padj = 0.023 and ORadj = 3.43).
The rs2910164 SNP in MIR146a showed a protective
effect respect to early CAN (Padj = 0.052, ORadj = 0.32)
and to confirmed CAN (Padj = 0.041, ORadj = 0.13). The
same SNP resulted significantly associated with a lower
CAN score and a higher E/I (p = 0.002 and p = 0.003,
respectively). In conclusion, we described associations of
MIR128a and MIR146a SNPs with DPN susceptibility and
of MIR146a and MIR27a SNPs with CAN susceptibility.
This is the first study showing that genetic variability in
miRNA genes could be involved in diabetic neuropathies
susceptibility.
2013
- MicroRNA genetic variations: association with type 2 diabetes.
[Articolo su rivista]
Ciccacci, Cinzia; Di Fusco, Davide; Cacciotti, Laura; Morganti, Roberto; D'Amato, Cinzia; Greco, Carla; Rufini, Sara; Novelli, Giuseppe; Sangiuolo, Federica; Spallone, Vincenza; Borgiani, Paola
abstract
Abstract MicroRNAs are small single-stranded molecules
that have emerged as important genomic regulators in
different pathways. Different studies have shown that they
are implicated in the metabolism and glucose homeostasis,
and therefore, they could also be involved in the pathogenesis
of metabolic disorders such as type 2 diabetes (T2DM).
The aim of this study was to verify whether genetic variations
in candidate microRNA (miRNA or miR) genes could contribute
to T2DM susceptibility. We have selected 13 miRNAs
as candidate loci according to literature data and to a
computational analysis. MicroRNA genes were analyzed by
direct sequencing in a cohort of 163 Italian T2DM patients
and 185 healthy controls. We identified 6 novel variants
never described before and 9 SNPs already described in
databases. Five newly identified variants were found only in
the cases group. We performed a case/control association
study to test the associations of particular alleles/genotypes
of identified SNPs with the disease. Two polymorphisms
were associated with T2DM susceptibility: in particular, the
G allele of rs895819 in hsa-mir-27a has shown a significantly
protective effect (OR = 0.58 and P = 0.008), while
the G allele of rs531564 in hsa-mir-124a appears to be a risk
allele (OR = 2.15, P = 0.008). This is the first report indicating
that genetic polymorphisms in miRNA regions could
contribute to T2DM susceptibility.
2013
- Painful and painless diabetic neuropathy: one disease or two?
[Articolo su rivista]
Spallone, Vincenza; Greco, Carla
abstract
Abstract Painful diabetic polyneuropathy (PDPN) is generally
considered a variant of diabetic polyneuropathy (DPN)
but the identification of distinctive aspects that characterize
painful compared with painless DPN has however been
addressed in many studies, mainly with the purpose of better
understanding the mechanisms of neuropathic pain in the
scenario of peripheral nerve damage of DPN, of determining
risk markers for pain development, and also of recognizing
who might respond to treatments. This review is aimed at
examining available literature dealing with the issue of similarities
and differences between painful and painless DPN in
an attempt to respond to the question of whether painful and
painless DPN are the same disease or not and to address the
conundrum of why some people develop the insensate variety
of DPN whilst others experience distressing pain. Thus, from
the perspective of comparing painful with painless
forms of DPN, this review considers the clinical correlates
of PDPN, its distinctive framework of symptoms,
signs, and nerve functional and structural abnormalities,
the question of large and small fiber involvement, the
peripheral pain mechanisms, the central processing of
pain and some new insights into the pathogenesis of
pain in peripheral polyneuropathies and PDPN.
2012
- Neuropathic pain impact on sleep and circadian rhythm of blood pressure in painful diabetic polyneuropathy
[Abstract in Atti di Convegno]
D'Amato, C; Morganti, R; Di Gennaro, F; Greco, Carla; Cacciotti, L; Rotella, Sefora; MARFIA GIROLAMA, Alessandra; Spallone, Vincenza
abstract
2012
- Validation of DN4 as a screening tool for neuropathic pain in painful diabetic polyneuropathy.
[Articolo su rivista]
Spallone, Vincenza; Morganti, Roberto; D'Amato, Cinzia; Greco, Carla; Cacciotti, Laura; Marfia Girolama, Alessandra
abstract
Aims DN4(DouleurNeuropathique en 4Questions) is a screening tool for neuropathic pain consisting of interviewquestions
(DN4-interview) and physical tests. It has not formally been validated in diabetes. We evaluated the validity and diagnostic
accuracy of DN4 and DN4-interview in identifying neuropathic pain of painful diabetic polyneuropathy.
Methods In 158 patients with diabetes, the presence of diabetic polyneuropathy and neuropathic pain was assessed using
scoring system for symptoms and signs, quantitative sensory testing, nerve conduction studies, pain history, numerical rating
scale, and Short-Form McGill Pain Questionnaire. Painful diabetic polyneuropathy was defined as the presence of diabetic
polyneuropathy plus chronic neuropathic pain in the same area as neuropathic deficits. Ablinded investigator performed DN4.
Results The DN4 score was significantly related to all the neurological and electrophysiological measurements and to Short-
FormMcGill Pain Questionnaire (q = 0.58, P < 0.0001). DN4 and DN4-interview scores showed a high diagnostic accuracy
for painful diabetic polyneuropathy with areas under the receiver operating characteristic curve of 0.94 and 0.93, respectively.
At the cut-off of 4, DN4 displayed sensitivity of 80%, specificity of 92%, positive predictive value (PPV) of 82%, negative
predictive value (NPV) of 91%, and likelihood ratio for a positive result (LR+)of 9.6.At the cut-offof 3,DN4-interviewshowed
sensitivity and specificity of 84%, PPV of 71%, NPV of 92%, and LR+ of 5.3.
Conclusions This is thefirst validation study ofDN4for painful diabetic polyneuropathy, which supports itsusefulness as both
a screening tool for neuropathic pain in diabetes and a reliable component of the diagnostic work up for painful diabetic
polyneuropathy.
2011
- Sensory profiles of neuropathic pain in painful diabetic polyneuropathy
[Abstract in Atti di Convegno]
Spallone, Vincenza; Morganti, R; Greco, Carla; D'Amato, C; Cacciotti, L; Rotella, S; Marfia, Ga
abstract
2010
- Is DN4 as a screening tool for neuropathic pain suitable for painful diabetic polyneuropathy?
[Abstract in Atti di Convegno]
Morganti, R; Spallone, V; D’Amato, C; Cacciotti, L; Rotella, S; Greco, Carla; Marfia, Ga.
abstract
2010
- Validity of DN4 as a screening tool for neuropathic pain of painful diabetic polyneuropathy
[Abstract in Atti di Convegno]
Spallone, Vincenza; Morganti, Roberto; D'Amato, Cinzia; Greco, Carla; Cacciotti, Laura; Rotella, Sefora; MARFIA GIROLAMA, Alessandra
abstract