Long-term Effects of Pioglitazone vs Glimepiride on Lipoproteins and Glyco-oxidation in Patients with Type 2 Diabetes

Background and aim Cardiovascular complications are the first cause of mortality and morbidity in type 2 diabetic patients. Among antidiabetic drugs, those who have shown cardiovascular benefits have ancillary activities that simultaneously control several risk factors. In the PROACTIVE trial, pioglitazone determined a 16% reduction of death for all causes, non-fatal myocardial infarction, non-fatal stroke, compared to placebo. The aim of the study is to investigate the effects of 5 years treatment with pioglitazone/metformin compared to 5 years treatment with glimepiride/metformin on diabetic dyslipidemia, both quantitatively and qualitatively, and on glyco-oxidation processes. Methods 96 diabetic patients, treated with metformin (2g/day) for at least 2 months, were randomized to treatment with pioglitazone or glimepiride. Patients were followed for 5 years: body mass index (BMI), waist circumference (CV), blood pressure, HbA1c; total cholesterol (CT), high density lipoproteins (HDL), low density lipoproteins (LDL), triglycerides (TG), advanced glycation end products (AGE), oxidized LDL (oxLDL) were determined at baseline and after 5 years of treatment. Results Treatment with pioglitazone resulted in significant increase in HDL (47.1±11.7 vs 51.3±15.7 mg/dl; p=0.02), non-significant reduction in CT, LDL and TG. Glimepiride treatment resulted in a significant reduction in HDL (48.6±14.1 vs 45.8±12.7 mg/dl; p=0.03), a non-significant reduction in CT, LDL and TG. Only the variation of HDL and oxLDL were significantly different between the two groups (ΔHDLPioglitazone= +4.2±10.5 mg/dl vs ΔHDLGlimepride= -2.9±7.7 mg/dl; p=0.002); (ΔoxLDLPioglitazone= -2.1±9.8 U/l vs ΔoxLDLGlimepride= +3.6±11.4 U/l; p=0.01). AGEs reduction, significant for both treatments, is not significantly different between the two groups. HbA1c reduction was significant only in patients treated with glimepiride (7.7±0.4 vs 7.1±0.8 %; p <0001) and was not correlated with AGEs variation (r=1.22; p=0.59). Conclusions Long-term treatment with pioglitazone significantly improves lipid profile of type 2 diabetic patients, increasing HDL levels and reducing oxLDL levels. In addition, it reduces AGEs formations. The inhibition of glyco-oxidative processes is one of the mechanisms that may explain the drug ability to prevent cardiovascular events

Anti-diabetic combination therapy with pioglitazone or glimepiride added to metformin on the AGE-RAGE axis: a randomized prospective study

Introduction: The ratio between advanced glycation end products (AGEs) and soluble form of receptor (s-RAGE) has been proposed as a risk marker for renal and cardiovascular diseases. The aim of this study was to evaluate in the diabetes condition the influence of two different oral anti-diabetic treatments on the AGE/ s-RAGE ratio, during a 5-year observation period. Methods: Seventy-three patients with type 2 diabetes mellitus were randomly assigned to a drug therapy with pioglitazone or glimepiride, combined to metformin. Each subject was evaluated at baseline and after 5 years of treatment. Results: In both groups s-RAGE levels did not significantly vary, while the levels of AGE and AGE/s-RAGE were both significantly reduced, basal compared to 5-year values. Within pioglitazone group, as well within glimepiride group, significant variations (D, as difference between 5 years of treatment minus basal) were observed for AGE (D= ˗21.1±13.4 μg/ml, P<0.001 for pioglitazone; D= ˗14.4±11.4 μg/ml, P<0.001 for glimepiride) and in AGE/s-RAGE (D= -0.037±0.022 μg/pg, P<0.001 for pioglitazone; D= -0.024±0.020μg/pg, P<0.001 for glimepiride), suggesting an average decrease of the parameters by more than 50% in both treatments. Pioglitazone was more effective than glimepiride in reducing AGE/s- RAGE ratio after 5 years of therapy. Conclusion: These data can help to explain the benefits of oral anti-diabetic therapy in relation to the reduction of cardiovascular risk, as suggested by variations in AGE/s-RAGE ratio as biochemical marker of endothelial function; in particular, treatment with pioglitazone seems to offer greater long-term benefit on AGE-RAGE axis

Mediterranean Diet and Red Yeast Rice Supplementation for the Management of Hyperlipidemia in Statin-Intolerant Patients with or without Type 2 Diabetes

Lipid profile could be modified by Mediterranean diet (MD) and by red yeast rice (RYR). We assessed the lipid-lowering effects of MD alone or in combination with RYR on dyslipidemic statin-intolerant subjects, with or without type 2 diabetes, for 24 weeks. We evaluated the low-density lipoprotein (LDL) cholesterol level, total cholesterol (TC), high-density lipoprotein (HDL) cholesterol, triglyceride, liver enzyme, and creatinine phosphokinase (CPK) levels. We studied 171 patients: 46 type 2 diabetic patients treated with MD alone (Group 1), 44 type 2 diabetic patients treated with MD associated with RYR (Group 2), 38 dyslipidemic patients treated with MD alone (Group 3), and 43 dyslipidemic patients treated with MD plus RYR (Group 4). The mean percentage changes in LDL cholesterol from the baseline were -7.34±3.14% (P0.05). No significant increase in AST, ALT, and CPK levels was observed in all groups. Our results indicate that MD alone is effective in reducing LDL cholesterol levels in statin-intolerant patients with a presumably low cardiovascular risk, but associating MD with the administration of RYR improves patients’ LDL cholesterol levels more, and in patients with type 2 diabetes

Opinion, knowledge, and clinical experience with functional neurological disorders among Italian neurologists: results from an online survey

Background: Functional neurological disorders (FND) are disabling medical conditions commonly seen in neurological practice. Neurologists play an essential role in managing FND, from establishing a diagnosis to coordination of multidisciplinary team-based treatment for patients. With this study, we investigated the knowledge and the clinical experience of Italian neurologists in managing patients with FND. Methods: Members of the Italian Society of Neurology were invited via e-mail to participate in this ad hoc online survey; 492 questionnaires were returned completed. Results: The term "Functional neurological disorders" in reference to FND was used more frequently than other psychological (e.g., psychogenic or conversion), or descriptive terms (e.g., non-organic or stress-related). When speaking with patients, the respondents stated that they preferred explaining symptoms based on abnormal functioning of the nervous system than discussing mental illness and that they would refer their patient to a psychologist rather than to a psychiatrist. Few considered that physiotherapy and psychiatric interventions are useful approaches to treating FND. Some believed that patients simulate their symptoms. Conclusions: Overall, the responses suggest that knowledge about scientific advances in FND is somewhat sparse. A psychiatric-centered view of FND opens the way to an approach in which neurobiological and psychological aspects constitute essential factors of the condition. In this context, professional education could improve understanding of FND and optimize patient management

Long-term Effects of Pioglitazone vs Glimepiride on Lipoproteins and Glyco-oxidation in Patients with Type 2 Diabetes

Background and aim Cardiovascular complications are the first cause of mortality and morbidity in type 2 diabetic patients. Among antidiabetic drugs, those who have shown cardiovascular benefits have ancillary activities that simultaneously control several risk factors. In the PROACTIVE trial, pioglitazone determined a 16% reduction of death for all causes, non-fatal myocardial infarction, non-fatal stroke, compared to placebo. The aim of the study is to investigate the effects of 5 years treatment with pioglitazone/metformin compared to 5 years treatment with glimepiride/metformin on diabetic dyslipidemia, both quantitatively and qualitatively, and on glyco-oxidation processes. Methods 96 diabetic patients, treated with metformin (2g/day) for at least 2 months, were randomized to treatment with pioglitazone or glimepiride. Patients were followed for 5 years: body mass index (BMI), waist circumference (CV), blood pressure, HbA1c; total cholesterol (CT), high density lipoproteins (HDL), low density lipoproteins (LDL), triglycerides (TG), advanced glycation end products (AGE), oxidized LDL (oxLDL) were determined at baseline and after 5 years of treatment. Results Treatment with pioglitazone resulted in significant increase in HDL (47.1±11.7 vs 51.3±15.7 mg/dl; p=0.02), non-significant reduction in CT, LDL and TG. Glimepiride treatment resulted in a significant reduction in HDL (48.6±14.1 vs 45.8±12.7 mg/dl; p=0.03), a non-significant reduction in CT, LDL and TG. Only the variation of HDL and oxLDL were significantly different between the two groups (ΔHDLPioglitazone= +4.2±10.5 mg/dl vs ΔHDLGlimepride= -2.9±7.7 mg/dl; p=0.002); (ΔoxLDLPioglitazone= -2.1±9.8 U/l vs ΔoxLDLGlimepride= +3.6±11.4 U/l; p=0.01). AGEs reduction, significant for both treatments, is not significantly different between the two groups. HbA1c reduction was significant only in patients treated with glimepiride (7.7±0.4 vs 7.1±0.8 %; p <0001) and was not correlated with AGEs variation (r=1.22; p=0.59). Conclusions Long-term treatment with pioglitazone significantly improves lipid profile of type 2 diabetic patients, increasing HDL levels and reducing oxLDL levels. In addition, it reduces AGEs formations. The inhibition of glyco-oxidative processes is one of the mechanisms that may explain the drug ability to prevent cardiovascular events

Pregnancy after Bariatric Surgery: Nutrition Recommendations and Glucose Homeostasis: A Point of View on Unresolved Questions

: Obesity is increasing in all age groups and, consequently, its incidence has also risen in women of childbearing age. In Europe, the prevalence of maternal obesity varies from 7 to 25%. Maternal obesity is associated with short- and long-term adverse outcomes for both mother and child, and it is necessary to reduce weight before gestation to improve maternal and fetal outcomes. Bariatric surgery is an important treatment option for people with severe obesity. The number of surgeries performed is increasing worldwide, even in women of reproductive age, because improving fertility is a motivating factor. Nutritional intake after bariatric surgery is dependent on type of surgery, presence of symptoms, such as pain and nausea, and complications. There is also a risk of malnutrition after bariatric surgery. In particular, during pregnancy following bariatric surgery, there is a risk of protein and calorie malnutrition and micronutrient deficiencies due to increased maternal and fetal demand and possibly due to reduction of food intake (nausea, vomiting). As such, it is necessary to monitor and manage nutrition in pregnancy following bariatric surgery with a multidisciplinary team to avoid any deficiencies in each trimester and to ensure the well-being of the mother and fetus

Weight gain during pregnancy: A narrative review on the recent evidences

Gestational weight gain is necessary for the normal fetus development, in fact a series of studies have evidenced that both low and excessive gestational weight gain is associated with negative fetal-neonatal outcomes. So, evidences on the optimal gestational weight gain across the ranges of the pre-pregnancy maternal body mass index are necessary. In this context, while for normal weight and underweight the recommendations of IOM are clearly stated and supported by well designed and conducted clinical studies, those for the obese pregnant women are even today debated. Pre-pregnancy obesity is associated with high risk to develop hypertension, gestational diabetes, cesarean section and high birth weight. The Institute of Medicine guidelines, in 2009, recommended that women with obesity gain 11-20 lb at a rate of 0.5 lb/week during the second and third trimesters of pregnancy. Successively, taking into account a series of meta-analysis, the American College of Obstetricians and Gynecologists emphasized that the IOM weight gain targets for obese pregnant women are too high. However the high risk to have babies small for gestational age, related to a low weight gain or a losing of weight during pregnancy, has also been demonstrated. More recent studies have taken into consideration the maternal and fetal outcomes of obese pregnant women with different obesity class (I,II,III) and different weight gain during pregnancy. The analysis of these studies, discussed in this narrative review, show that the appropriate gestational weight gain should be personalized considering the three obesity class; furthermore both an upper and lower limit of gestational weight gain should be reconsidered in order to prevent the negative maternal and fetal outcomes in these women

Pregnancy and Type 2 Diabetes: Unmet Goals

The increased frequency of type 2 diabetes worldwide has led to a concomitant increase in pregnancies complicated by type 2 diabetes for the past 20 years. This is mainly due to two factors: the earlier age of diabetes onset and the advanced age of pregnancy occurrence. Patients with type 2 diabetes in pregnancy show a high frequency of maternal and fetal complications, posing a series of problems in the follow-up of these women. In this narrative review, changes in epidemiology, maternal and fetal complications, and evidence of critical unmet needs before and during pregnancy complicated by type 2 diabetes are reported and discussed to review the possible approaches

AGEs, rather than hyperglycemia, are responsible for microvascular complications in diabetes: a "glycoxidation-centric" point of view.

AIMS: Advanced glycation end products (AGE) excess is one of the most important mechanisms involved in the pathophysiology of chronic diabetic complications. This review first summarizes the role of these compounds in microvascular pathogenesis, particularly in the light of recently proposed biochemical mechanisms for diabetic retinopathy, nephropathy and neuropathy. Then we focus on the relationship between AGE and metabolic memory, trying to clarify the former's role in the missing link between micro- and macrovascular complications. DATA SYNTHESIS: An excessive AGE formation has been demonstrated in the newly disclosed biochemical pathways involved in the microvascular pathobiology of type 2 diabetes, confirming the central role of AGE in the progression of diabetic neuropathy, retinopathy and nephropathy. As shown by recent studies, AGE seem to be not "actors", but "directors" of processes conducting to these complications, for at least two main reasons: first, AGE have several intra- and extracellular targets, so they can be seen as a "bridge" between intracellular and extracellular damage; secondly, whatever the level of hyperglycemia, AGE-related intracellular glycation of the mitochondrial respiratory chain proteins has been found to produce more reactive oxygen species, triggering a vicious cycle that amplifies AGE formation. This may help to explain the clinical link between micro- and macrovascular disease in diabetes, contributing to clarify the mechanisms behind metabolic memory. CONCLUSIONS: The pathophysiological cascades triggered by AGE have a dominant, hyperglycemia-independent role in the onset of the microvascular complications of diabetes. An effective approach to prevention and treatment must therefore focus not only on early glycemic control, but also on reducing factors related to oxidative stress, and the dietary intake of exogenous AGE in particular

Epigenetic: New Insight in Gestational Diabetes Mellitus

Gestational diabetes mellitus (GDM) is the more frequent metabolic complication of pregnancy with a prevalence that is significantly increased in the last decade accounting for 12–18% of all pregnancies. Recent evidences strongly suggests that epigenetic profile changes could be involved in the onset of GDM and its related maternal and fetal complications. In particular, the unfavorable intrauterine environment related to hyperglycemia, a feature of GDM, has been evidenced to exert a negative impact on the establishment of the epigenome of the offspring. Furthermore the adverse in utero environment could be one of the mechanisms engaged in the development of adult chronic diseases. The purpose of this article is to review a number of published studies to fill the gap in our understanding of how maternal lifestyle and intrauterine environment influence molecular modifications in the offspring, with an emphasis on epigenetic alterations