Impact of Sex and Gender on Clinical Management of Patients with Advanced Chronic Liver Disease and Type 2 Diabetes

Gender differences in the epidemiology, pathophysiological mechanisms and clinical features in chronic liver diseases that may be associated with type 2 diabetes (T2D) have been increasingly reported in recent years. This sexual dimorphism is due to a complex interaction between sex- and gender-related factors, including biological, hormonal, psychological and socio-cultural variables. However, the impact of sex and gender on the management of T2D subjects with liver disease is still unclear. In this regard, sex-related differences deserve careful consideration in pharmacology, aimed at improving drug safety and optimising medical therapy, both in men and women with T2D; moreover, low adherence to and persistence of long-term drug treatment is more common among women. A better understanding of sex- and gender-related differences in this field would provide an opportunity for a tailored diagnostic and therapeutic approach to the management of T2D subjects with chronic liver disease. In this narrative review, we summarized available data on sex- and gender-related differences in chronic liver disease, including metabolic, autoimmune, alcoholic and virus-related forms and their potential evolution towards cirrhosis and/or hepatocarcinoma in T2D subjects, to support their appropriate and personalized clinical management

Antihypertensive Treatment in Diabetic Kidney Disease: The Need for a Patient-Centered Approach

Diabetic kidney disease affects up to forty percent of patients with diabetes during their lifespan. Prevention and treatment of diabetic kidney disease is currently based on optimal glucose and blood pressure control. Renin-angiotensin aldosterone inhibitors are considered the mainstay treatment for hypertension in diabetic patients, especially in the presence of albuminuria. Whether strict blood pressure reduction entails a favorable renal outcome also in non-albuminuric patients is at present unclear. Results of several clinical trials suggest that an overly aggressive blood pressure reduction, especially in the context of profound pharmacologic inhibition of the renin-angiotensin-aldosterone system may result in a paradoxical worsening of renal function. On the basis of this evidence, it is proposed that blood pressure reduction should be tailored in each individual patient according to renal phenotype

Fracture Risk in Type 2 Diabetes: Current Perspectives and Gender Differences

Type 2 diabetes mellitus (T2DM) is associated with an increased risk of osteoporotic fractures, resulting in disabilities and increased mortality. The pathophysiological mechanisms linking diabetes to osteoporosis have not been fully explained, but alterations in bone structure and quality are well described in diabetic subjects, likely due to a combination of different factors. Insulin deficiency and dysfunction, obesity and hyperinsulinemia, altered level of oestrogen, leptin, and adiponectin as well as diabetes-related complications, especially peripheral neuropathy, orthostatic hypotension, or reduced vision due to retinopathy may all be associated with an impairment in bone metabolism and with the increased risk of fractures. Finally, medications commonly used in the treatment of T2DM may have an impact on bone metabolism and on fracture risk, particularly in postmenopausal women. When considering the impact of hypoglycaemic drugs on bone, it is important to balance their potential direct effects on bone quality with the risk of falling-related fractures due to the associated hypoglycaemic risk. In this review, experimental and clinical evidence connecting bone metabolism and fracture risk to T2DM is discussed, with particular emphasis on hypoglycaemic treatments and gender-specific implications

High Prevalence of Arcobacter Carriage in Older Subjects with Type 2 Diabetes

Arcobacters are potential pathogens related to diarrheic infections and, rarely, septicaemia. This study evaluated the prevalence of arcobacters in stool samples of subjects with (n = 38) and without (n = 61) type 2 diabetes by using cultural and molecular techniques. Three Arcobacter positive cultures were found, all among diabetic subjects, whereas molecular analysis showed a carriage rate of 79% and 26.2% in subjects with and without type 2 diabetes (P < .001), respectively. The multivariate analysis showed that type 2 diabetes (β = 1.913; 95%CI: 2.378–19.285; P < .0001) and age (β = 1.744; 95%CI: 2.077–15.766; P = .001) were the only factors independently associated with arcobacters colonization in this population. Our study demonstrated a high prevalence of arcobacters colonization in type 2 diabetic and older subjects. The clinical significance and the potential health risk associated with these emerging species remain to be determined

Methotrexate Increases Skeletal Muscle GLUT4 Expression and Improves Metabolic Control in Experimental Diabetes

Long-term administration of 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) mimics the effects of endurance exercise by activating AMP kinase and by increasing skeletal muscle expression of GLUT4 glucose transporter. AICAR is an intermediate in the purine de novo synthesis, and its tissue concentrations can be increased, in vivo, by low doses of methotrexate (MTX) through the inhibition of the enzyme AICAR transformylase. We report here the first evidence that, in experimental type 2 diabetes, chronic treatment with low doses of MTX increases skeletal muscle GLUT4 expression and improves metabolic control. MTX (0.5 mg/kg body weight) or vehicle was administered intraperitoneally, once a week for 4 weeks, to genetically diabetic female C57BL/KsJ-m+/+Leptdb mice (db+/db+) and their normoglycemic littermates (db+/+m). In the db+/db+ mice, MTX treatment was associated with a ∼2-fold increase in skeletal muscle GLUT4 protein concentration and a >4-fold increase in GLUT4 mRNA expression (P<0.01, all), as compared to vehicle-treated mice; no significant differences were noted in controls. MTX treatment was also associated with a significant reduction of glucose and insulin serum concentrations in diabetic mice (P<0.001), and glucose levels only (P<0.05) in controls. These data indicate a different route to increase skeletal muscle GLUT4 expression, through the potential inhibition of the enzyme AICAR transformylase

Long-Term Influence of Locus of Control and Quality of Life on Metabolic Profile in Elderly Subjects with Type 2 Diabetes

Background: The Locus of Control (LOC) is a mental disposition indicating the individuals&rsquo; belief that disease-related outcomes are under their own control (Internal), dependent on others (External), or dependent on chance (Chance). Quality of Life (QoL) and LOC may have complex effects on self-care activities and diabetes management in subjects with type 2 diabetes (T2D). The aim of the present study was to evaluate the predictive role of LOC and QoL scores on metabolic control in elderly T2D outpatients, secondly evaluating potential gender differences. Methods: An extensive set of questionnaires was administered to a group of consecutive elderly T2D outpatients on oral glucose-lowering drugs attending a single diabetes center. Personal and clinical variables were analyzed at baseline (between 1 February and 31 March 2015) and after 6 years of follow-up. Results: At baseline, study participants showed an overall good metabolic control. Diabetes Specific Quality of Life (DSQoL) scores indicated an overall good QoL in both genders, with a higher DSQoL satisfaction score in women. Both genders presented higher scores in the LOC-Internal domain, with men reaching higher scores in the LOC-External domain than women. At the 6-years follow-up, subjects with baseline higher LOC-External score presented better metabolic outcome. In the regression analysis, LOC-External score was an independent predictor of good metabolic control maintenance, but this result was only statistically significant in men. Conclusions: LOC scores may influence long-term glycemic control in elderly T2D patients on oral glucose-lowering drugs

GLP-1 Receptor Agonists and Kidney Protection

Type 2 diabetes mellitus (T2DM) is the leading cause of chronic kidney disease (CKD). Diabetic nephropathy (DN) is determined by specific pathological structural and functional alterations of the kidneys in patients with diabetes, and its clinical manifestations are albuminuria and decline of glomerular filtration rate (GFR). Apart from renin–angiotensin–aldosterone system (RAAS) inhibitors, no other drugs are currently available as therapy for diabetic kidney disease (DKD). Glucagon-like peptide-1 receptor (GLP-1R) agonists are a new class of anti-hyperglycemic drugs which have been demonstrated to prevent the onset of macroalbuminuria and reduce the decline of GFR in diabetic patients. These drugs may exert their beneficial actions on the kidneys through blood glucose- and blood pressure (BP)-lowering effects, reduction of insulin levels and weight loss. Clinical benefits of GLP-1R agonists were acknowledged due to data from large randomized phase III clinical trials conducted to assess their cardiovascular(CV) safety. These drugs improved renal biomarkers in placebo-controlled clinical studies, with effects supposed to be independent of the actions on glycemic control. In this review, we will focus on the actions of GLP-1R agonists on glucose metabolism and kidney physiology, and evaluate direct and indirect mechanisms through which these drugs may confer renal protection

Atherogenic dyslipidemia and diabetic nephropathy

Chronic kidney disease is associated with altered lipid metabolism and lipid accumulation. Although it is though that hyperlipemia is a consequence of kidney dysfunction, several lines of evidence support that hyperlipidemia may contribute to the onset and progression of kidney disease, also in diabetes. This review describes the results of recent observational studies supporting the concept that glucose is only partly responsible for kidney damage onset, while a cluster of factors, including hypertriglyceridemia and low HDL-cholesterol, could play a relevant role in inducing onset and progression of DKD. We also report the results of randomized clinical trials investigating in type 2 diabetic patients the role of drug improvement of hypertriglyceridemia on renal outcomes. Finally, we discuss putative mechanisms linking hyperlipidemia (i.e. hypertriglyceridemia or low HDL cholesterol) with kidney disease

Gender Differences in Diabetic Kidney Disease: Focus on Hormonal, Genetic and Clinical Factors

Diabetic kidney disease (DKD) is one of the most serious complications of both type 1 (T1DM) and type 2 diabetes mellitus (T2DM). Current guidelines recommend a personalized approach in order to reduce the burden of DM and its complications. Recognizing sex and gender- differences in medicine is considered one of the first steps toward personalized medicine, but the gender issue in DM has been scarcely explored so far. Gender differences have been reported in the incidence and the prevalence of DKD, in its phenotypes and clinical manifestations, as well as in several risk factors, with a different impact in the two genders. Hormonal factors, especially estrogen loss, play a significant role in explaining these differences. Additionally, the impact of sex chromosomes as well as the influence of gene–sex interactions with several susceptibility genes for DKD have been investigated. In spite of the increasing evidence that sex and gender should be included in the evaluation of DKD, several open issues remain uncovered, including the potentially different effects of newly recommended drugs, such as SGLT2i and GLP1Ras. This narrative review explored current evidence on sex/gender differences in DKD, taking into account hormonal, genetic and clinical factors