Elisabetta L. Romeo

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.

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 +/+ Lept db 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.

Markers of Systemic Inflammation and Apo-AI Containing HDL Subpopulations in Women with and without Diabetes

Background. Besides their role in reverse cholesterol transport, HDL particles may affect the atherosclerotic process through the modulation of subclinical inflammation. HDL particles differ in size, composition, and, probably, anti-inflammatory properties. This hypothesis has never been explored in diabetic women, frequently having dysfunctional HDL. The potential relationship between lipid profile, Apo-AI containing HDL subclasses distribution, and common inflammatory markers (hsCRP, IL-6) was examined in 160 coronary heart disease- (CHD-) free women with and without type 2 diabetes. Results. Compared to controls, diabetic women showed lower levels of the atheroprotective large α-1, α-2, and pre-α-1 and higher concentration of the small, lipid-poor α-3 HDL particles (P < 0.05 all); diabetic women also had higher hsCRP and IL-6 serum levels (age- and BMI-adjusted P < 0.001). Overall, HDL subclasses significantly correlated with inflammatory markers: hsCRP inversely correlated with α-1 (P = 0.01) and pre-α-1 (P = 0.003); IL-6 inversely correlated with α-1 (P = 0.003), α-2 (P = 0.004), and pre-α-1 (P = 0.002) and positively with α-3 HDL (P = 0.03). Similar correlations were confirmed at univariate regression analysis. Conclusions. More atheroprotective HDL subclasses are associated with lower levels of inflammatory markers, especially in diabetic women. These data suggest that different HDL subclasses may influence CHD risk also through the modulation of inflammation.

Clinical correlates of persistently elevated liver enzymes in type 2 diabetic outpatients.

AIMS To evaluate the prevalence and the clinical implication of persistently elevated liver enzymes in diabetic subjects, with no evidence of viral hepatitis infection or alcohol abuse. METHODS Clinical, lifestyle, anthropometric data and laboratory test values were collected in 916 type 2 diabetic subjects, examined for alanine aminotransferase (ALT), aspartate aminotransferase (AST) and γ-glutamyltranspeptidase (γ-GT) levels at two different time points. RESULTS Five hundred forty four patients (59.4%) showed normal (NLT group) and 182 (19.9%) persistently elevated (ELT group) liver tests in both determinations. ELT patients were prevalently men (P=0.016), younger (P<0.0001) and with a lower duration of diabetes (P=0.008). Adjusting for age and sex, ELT subjects had significantly higher BMI (P<0.001), waist circumference (P=0.010), systolic (P=0.017) and diastolic blood pressure (P<0.001), and higher levels of fasting blood glucose (P=0.023), and triglycerides (P<0.0001). Current hypoglycemic and/or hypolipidemic drugs were comparable between the two groups. At multivariate analysis, male gender (OR=3.017, P=0.012), worse metabolic control (HbA1c, OR=1.408, P=0.017), and a younger age (OR=1.054, P=0.007) predicted the presence of persistently elevated liver enzymes. CONCLUSIONS Persistently elevated liver enzymes are a common finding in outpatient type 2 diabetic subjects, particularly in young men with suboptimal metabolic control and with the features of metabolic syndrome. The persistence of abnormal liver tests may be of potential utilization in clinical practice for the screening of patients at high risk of NAFLD.

HDL subclasses and the common CETP TaqIB variant predict the incidence of microangiopatic complications in type 2 diabetic women: A 9 years follow-up study

AIMS Diabetic kidney disease (DKD) and retinopathy (DR) develop in a considerable number of subjects with Type 2 Diabetes (T2D) despite the achievement of the recommended targets for glycaemia and blood pressure. Atherogenic dyslipidemia may play a relevant role, especially in T2DM women. METHODS We report our findings on the effect of diabetic dyslipidaemia, the HDL subclasses distribution and the common cholesteryl ester transfer protein (CETP)TaqIB variant on the incidence or the progression of DKD and DR in 97 T2D women, after a ∼9years of follow-up. RESULTS At baseline, T2D women presented with low HDL-C levels and higher levels of large lipid rich α-1 (16.34mg/dl), α-2 (33.39mg/dl) and pre- α1 (4.81mg/dl) HDL subparticles. The CETP TaqIB polymorphism and baseline HbA1c, triglycerides, and HDL-C levels as well as specific HDL subpopulations were associated to the occurrence of RD after ∼9years of follow-up. At stepwise regression analysis, HbA1c, triglycerides and the less atheroprotective α-3 HDL particles were the only factors independently associated to the incidence of RD. These same variables were also associated with the progression from background to proliferative RD. BMI, LDL/HDL ratio and low levels of α-1 HDL particles were associated to the occurrence of DKD at univariate analysis, although BMI was the only significant predictor at stepwise multivariate regression analysis. CONCLUSIONS In T2D women, atherogenic dyslipidemia as well as subtle modifications in lipoprotein particles profile are associated with incidence and progression of microvascular disease.

Thionamides-Related Vasculitis in Autoimmune Thyroid Disorders: Review of Current Literature and Case Reports

Graves’ disease is the most common cause of hyperthyroidism. It is an autoimmune disorder, caused by the presence of autoantibodies directed against the thyroid-stimulating hormone (TSH) receptor (TRAb), chronically stimulating thyroid hormone synthesis and secretion, and resulting in an excessive amount of triiodothyronine (T3) and thyroxine (T4) and gland growth. In iodine sufficient areas, this prototypical autoimmune disease is the most common cause of thyrotoxicosis in young women as well as in children and adolescents, and it is characterized by thyrotoxicosis, goitre and typical manifestations such as ophthalmopathy and pretibial myxedema. According to the American Association of Clinical Endocrinologists guidelines (AACE, 2002), the diagnosis of hyperthyroidism relates on TSH values. Thus, with the exception of the excess of TSH secretion, hyperthyroidism of any cases results in a lower-than-normal or

Influence of peroxisome proliferator-activated receptor-γ exon 2 and exon 6 and insulin receptor substrate (IRS)-1 Gly972Arg polymorphisms on insulin resistance and beta-cell function in southern mediterranean women with polycystic ovary syndrome

Background and objective The Pro12Ala (exon 2) and His447His (exon 6) polymorphisms of PPAR-γ, and Gly972Arg polymorphism of IRS-1 have been implicated in insulin resistance (IR) and adiposity. Our aim was to investigate the influence of these polymorphisms on metabolic features of polycystic ovary syndrome (PCOS). Methods Fifty-three PCOS women and 26 control women underwent a clinical and biochemical evaluation, including a 75-g oral glucose tolerance test. Insulin secretion and insulin sensitivity indices were calculated. Results Frequencies of PPAR-γ polymorphisms did not differ from those predicted by the Hardy-Weinberg equilibrium. Instead, the IRS-1 Gly972Arg allele was significantly more frequent in the PCOS group compared to controls. The most frequent allelic combinations were IRS1+/exon2-/exon6- (which prevailed in PCOS) and IRS-1-/exon2-/exon6- (which prevailed in controls). Among PCOS women, compared with the wild type patients, carriers of the Gly972Arg IRS-1 allele had lower E2 levels, while carriers of the Pro12Ala PPAR-γ (exon 2) allele had lower free testosterone levels. No other significant relationships were noted. When compared with the wild type, in PCOS group IR and beta-cell function were: (i) trendwise greater in carriers of the variant IRS-1 allele; (ii) trendwise lower in carriers of the variant PPAR-γ exon 6 allele; (iii) significantly lower in carriers of the variant PPAR-γ exon 2 allele. Conclusions Our data support the protective influence of PPAR-γ-exon 2 and exon 6 variants on IR and beta cell function, whereas IRS-1 polymorphism is associated with an unfavorable metabolic profile. However, these associations do not fully explain the high metabolic risk associated with PCOS.

Corrigendum to “Fracture Risk in Type 2 Diabetes: Current Perspectives and Gender Differences”

[This corrects the article DOI: 10.1155/2016/1615735.].