Surgical treatment of post-menopausal ovarian hyperandrogenism improves glucometabolic profile alongside clinical hirsutism.

Hyperandrogenism during menopause is often underestimated by clinicians and attributed to the natural aging process. Hyperandrogenism can be associated with some metabolic abnormalities linked together in a vicious circle by insulin resistance. We present the case of an elderly woman affected with type 2 diabetes and obesity who reported the occurrence of clinical hirsutism after physiological menopause at the age of 47 years. At presentation, physical examination and Ferriman-Gallwey score revealed a condition of moderate hirsutism, with markedly increased levels of plasma testosterone and delta-4-androstenedione, obesity (body mass index 31.9), and inadequate glycemic control (glycated hemoglobin 65 mmol/mol). The patient underwent a thorough differential diagnosis by a multidisciplinary team approach, including the various causes of hyperandrogenism during menopause. After choosing surgical option as the appropriate treatment, clinical resolution of hirsutism was observed alongside patient satisfaction and marked improvement of the glucometabolic profile.

Diabetic peripheral neuropathic pain is a stronger predictor of depression than other diabetic complications and comorbidities.

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.

Common polymorphisms in MIR146a, MIR128a and MIR27a genes contribute to neuropathy susceptibility in type 2 diabetes.

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, P adj = 0.02), whereas the C allele of rs2910164 SNP in MIR146a was associated with a lower risk to develop DPN (ORadj = 0.49, P adj = 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 (P adj = 0.023 and ORadj = 3.43). The rs2910164 SNP in MIR146a showed a protective effect respect to early CAN (P adj = 0.052, ORadj = 0.32) and to confirmed CAN (P adj = 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.

MicroRNA genetic variations: association with type 2 diabetes.

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.

TCF7L2 gene polymorphisms and type 2 diabetes: association with diabetic retinopathy and cardiovascular autonomic neuropathy.

Type 2 diabetes (T2DM) is a complex disease resulting from the contribution of both environmental and genetic factors. Recently, the list of genes implicated in the susceptibility to T2DM has substantially grown, also as a consequence of the great development of the genome-wide association studies in the last decade. Common polymorphisms in TCF7L2 gene have shown to have a strong effect with respect to many other involved genes. The aims of our study were to confirm the role of TCF7L2 in the susceptibility to T2DM in the Italian population and to investigate whether TCF7L2 genotypes also contribute to the clinical phenotypes variability and to diabetic complications development. Three TCF7L2 polymorphisms (rs7903146, rs7901695 and rs12255372) have been analyzed by allelic discrimination assays in a cohort of 154 Italian patients with T2DM and 171 healthy controls. A case-control association study and a genotype-phenotype correlation study have been carried out. Consistent with previous studies, all three SNPs showed a strong association with susceptibility to T2DM, both at genotypic (P = 0.003, P = 0.004 and P = 0.012) and at allelic level (P = 0.0004, P = 0.0004 and P = 0.003). Moreover, we observed associations between TCF7L2 variants and the following diabetic complications: diabetic retinopathy, cardiovascular disease and coronary artery disease. We also found a strong correlation between the rs7903146 and the presence of cardiovascular autonomic neuropathy (P = 0.02 with a high OR = 8.28). In conclusion, our study, in addition to confirming the involvement of TCF7L2 gene in the T2DM susceptibility, has shown that TCF7L2 genetic variability also contributes to the development of diabetic complications such as retinopathy and cardiovascular autonomic neuropathy.

Clinical correlates of painful diabetic neuropathy and relationship of neuropathic pain with sensorimotor and autonomic nerve function.

BACKGROUND: This study investigated the clinical correlates of painful diabetic polyneuropathy (PDPN) and the relationship of neuropathic pain with sensorimotor and autonomic nerve function. METHODS: Seventy-eight diabetic patients with PDPN (PDPN(+)), 57 with non-painful diabetic polyneuropathy (DPN(+)), and 56 without diabetic polyneuropathy (DPN(-)) were prospectively studied. Autonomic neuropathy, neuropathic symptoms and signs, vibration perception threshold, and neuropathic pain were assessed using 4 cardiovascular tests, scoring systems for symptoms and signs (Michigan Diabetic Neuropathy Score, MDNS), Biothesiometer, and a numerical rating scale. RESULTS: Compared to DPN(+), PDPN(+) patients displayed higher BMI (P=0.0043), waist circumference (P=0.0057), neuropathy symptom score (P<0.0001), MDNS (P<0.0001), and lower Valsalva ratio (P=0.037). In a multiple logistic regression analysis including PDPN as the dependent variable and age, sex, body mass index (BMI), abdominal obesity, diabetes type, diabetes duration, HbA1c, blood pressure, triglycerides, smoking, peripheral arterial disease, Valsalva ratio and MDNS as the independent variables, BMI (OR 1.22, P=0.0012) and MDNS (OR 1.27, P=0.0005) were significantly and independently associated with PDPN. In a multivariate regression analysis including as independent variables also sex, age, diabetes type, diabetes duration and Valsalva ratio, 24-h pain score was significantly related to neuropathy symptom score (P=0.0011), MDNS (P=0.0158), and 10g monofilament (P=0.018). DISCUSSION: BMI and sensorimotor deficits were the main determinants of PDPN and, as a novel finding, neuropathic pain intensity was related to the degree of neuropathy deficits. Thus, some peculiarity exists in metabolic correlates of diabetic neuropathic pain compared to insensate neuropathy but painfulness can still coexist with insensitivity.