Patients with comorbidities of obesity and diabetes are recognized to be at high risk of breast cancer development and face worse breast cancer outcomes. Though several reports showed the reinforced link between obesity, diabetes, and prediabetes with breast cancer, the underlying molecular mechanisms are still unknown. The present study aimed to investigate the underlying molecular link between increased risks of breast cancer due to coincident diabetes or obesity using a spontaneous obese rat model with impaired glucose tolerance (WNIN/GR-Ob rat). A single dose of solubilized DMBA suspension (40 mg/kg body weight) was orally administered to the animals at the age of 60 days to induce breast tumors. The tumor incidence, latency period, tumor frequency, and tumor volume were measured. Histology, immunohistochemistry, and immunoblotting were performed to evaluate the tumor morphology and expression levels of signal molecules. The development of mammary tumors in GR-Ob rats was characterized by early onset and shorter latency periods compared to control lean rats. While 62% of obese rats developed breast tumors, tumor development in lean rats was only 21%. Overexpression of ER, PR, Ki67, and p53 markers was observed in tumor tissues of obese rats in comparison with lean rats. The levels of the hallmarks of cell proliferation and angiogenesis involved in IGF-1/PI3K/Akt/GSK3β/β-catenin signaling pathway molecules were upregulated in obese rat breast tumors compared to lean rats. Furthermore, obesity with prediabetes is associated with changes in IGF-1 signaling and acts on PI3K/Akt/GSK3β/β-catenin signaling, which results in rapid cell proliferation and development of breast tumors in obese rats than the lean rats. These results indicate that tumor onset and development were faster in spontaneous obese rat models with impaired glucose tolerance than in their lean counterparts.

Biliverdin reductase-A (BVRA) is involved in the regulation of insulin signaling and the maintenance of glucose homeostasis. Previous research showed that BVRA alterations are associated with the aberrant activation of insulin signaling in dysmetabolic conditions. However, whether BVRA protein levels change dynamically within the cells in response to insulin and/or glucose remains an open question. To this aim, we evaluated changes of intracellular BVRA levels in peripheral blood mononuclear cells (PBMC) collected during the oral glucose tolerance test (OGTT) in a group of subjects with different levels of insulin sensitivity. Furthermore, we looked for significant correlations with clinical measures. Our data show that BVRA levels change dynamically during the OGTT in response to insulin, and greater BVRA variations occur in those subjects with lower insulin sensitivity. Changes of BVRA significantly correlate with indexes of increased insulin resistance and insulin secretion (HOMA-IR, HOMA-β, and insulinogenic index). At the multivariate regression analysis, the insulinogenic index independently predicted increased BVRA area under curve (AUC) during the OGTT. This pilot study showed, for the first time, that intracellular BVRA protein levels change in response to insulin during OGTT and are greater in subjects with lower insulin sensitivity, supporting the role of BVR-A in the dynamic regulation of the insulin signaling pathway.

Type 2 diabetes mellitus (T2DM) is linked with several neurodegenerative and psychiatric disorders, either as a comorbid condition or as a risk factor. We aimed to expand the evidence by examining associations with a broad range of brain disorders (psychiatric and neurological disorders, excluding late-onset neurodegenerative disorders), while also accounting for the temporal order of T2DM and these brain disorders.
In a population-based cohort-study of 1,883,198 Danish citizens, born 1955-1984 and followed until end of 2016, we estimated associations between T2DM and 16 brain disorders first diagnosed between childhood and mid-adulthood. We calculated odds ratios (OR) and hazard ratios (HR) with 95% confidence intervals (CI) in temporally ordered analyses (brain disorder diagnosis after T2DM and vice versa), adjusted for sex, age, follow-up, birth year, and parental factors.
A total of 67,660 (3.6%) of the study population were identified as T2DM cases after age 30 and by a mean age of 45 years (SD of 8 years). T2DM was associated with most psychiatric disorders. Strongest associations were seen with other (i.e. non-anorectic) eating disorders (OR [95% CI]: 2.64 [2.36-2.94]) and schizophrenia spectrum disorder (2.73 [2.63-2.84]). Among neurological disorders especially inflammatory brain diseases (1.73 [1.57-1.91]) and epilepsy (1.67 [1.60-1.75]) were associated with T2DM. Most associations remained in both directions in the temporally ordered analyses. For most psychiatric disorders, associations were strongest in females.
T2DM was associated with several psychiatric and neurological disorders, and most associations were consistently found for both temporal order of disorders. This suggests a shared etiology of T2DM and those brain disorders. This study can form the starting point for studies directed at further elucidating potential causal links between disorders and shared biological mechanisms.

Type 2 diabetes mellitus (DM) is a complex chronic disorder and a major global health problem. Insulin resistance is the primary detectable abnormality and the main characteristic feature in individuals with type 2 DM. Protein tyrosine phosphatase 1B (PTP1B) is a key negative regulator of the insulin signaling pathway, which dephosphorylates insulin receptor and insulin receptor substrates, suppressing the insulin signaling cascade. Therefore, the inhibition of PTP1B has become a potential strategy in the management of type 2 DM. In this study, a library of 22 pyrazoles was evaluated here for the first time against human PTP1B activity, using a microanalysis screening system. The results showed that 5-(2-hydroxyphenyl)-3-{2-[3-(4-nitrophenyl)-1,2,3,4-tetrahydronaphthyl]}-1-phenylpyrazole 20 and 3-(2-hydroxyphenyl)-5-{2-[3-(4-methoxyphenyl)]naphthyl}pyrazole 22 excelled as the most potent inhibitors of PTP1B, through noncompetitive inhibition mechanism. These findings suggest that the presence of additional benzene rings as functional groups in the pyrazole moiety increases the ability of pyrazoles to inhibit PTP1B. The most active compounds showed selectivity over the homologous T-cell protein tyrosine phosphatase (TCPTP). Molecular docking analyses were performed and revealed a particular contact signature involving residues like TYR46, ASP48, PHE182, TYR46, ALA217 and ILE219. This study represents a significant beginning for the design of novel PTP1B inhibitors.

The physiological regulation and contribution of the multiple phosphorylation sites of insulin receptor substrate 1 (IRS1) to the pathogenesis of insulin resistance is unknown. Our aims were to map the phosphorylated motifs of IRS1 in skeletal muscle from people with normal glucose tolerance (NGT; n = 11) or type 2 diabetes mellitus (T2DM; n = 11).
Skeletal muscle biopsies were obtained under fasted conditions or during a euglycemic clamp and IRS1 phosphorylation sites were identified by mass spectrometry.
We identified 33 phosphorylation sites in biopsies from fasted individuals, including 2 previously unreported sites ([Ser393] and [Thr1017]). In men with NGT and T2DM, insulin increased phosphorylation of 5 peptides covering 10 serine or threonine sites and decreased phosphorylation of 6 peptides covering 9 serine, threonine or tyrosine sites. Insulin-stimulation increased phosphorylation of 2 peptides, and decreased phosphorylation of 2 peptides only in men with NGT. Insulin increased phosphorylation of 2 peptides only in men with T2DM.
Despite severe skeletal muscle insulin resistance, the pattern of IRS1 phosphorylation was not uniformly altered in T2DM. Our results contribute to the evolving understanding of the physiological regulation of insulin signaling and complement the comprehensive map of IRS1 phosphorylation in T2DM.

Aging is a complex phenomenon caused by the time-dependent loss of cellular homeodynamics and consequently of physiological organismal functions. This process is affected by both genetic and environmental (e.g., diet) factors, as well as by their constant interaction. Consistently, deregulation of nutrient sensing and signaling pathways is considered a hallmark of aging. Nutrigenomics is an emerging scientific discipline that studies changes induced by diet on the genome and thus it considers the intersection of three topics, namely health, diet, and genomics. Model organisms, such as the fruit fly Drosophila melanogaster, have been successfully used for in vivo modeling of higher metazoans aging and for nutrigenomic studies. Drosophila is a well-studied organism with sophisticated genetics and a fully annotated sequenced genome, in which ~ 75% of human disease-related genes have functional orthologs. Also, flies have organs/tissues that perform the equivalent functions of most mammalian organs, while discrete clusters of cells maintain insect carbohydrate homeostasis in a way similar to pancreatic cells. Herein, we discuss the mechanistic connections between nutrition and aging in Drosophila, and how this model organism can be used to study the effect of different diets (including natural products and/or their derivatives) on higher metazoans longevity.

Insulin resistance (IR) is one of the significant aberrations in polycystic ovarian syndrome (PCOS), however is only observed in 70%-80% of obese PCOS and 20%-25% of lean PCOS. Hyperinsulinemia accompanies PCOS-IR along with hyperandrogenemia against normal insulin and androgen levels in PCOS-non insulin resistance (NIR). This could possibly be due to defects in the downstream signaling pathways. The study thus aims to unravel insulin and steroidogenic signaling pathways in luteinized granulosa cells isolated from PCOS-IR and NIR vs matched controls. Luteinized granulosa cells from 30 controls and 39 PCOS were classified for IR based on a novel method of down regulation of protein expression of insulin receptor-β (INSR- β) as shown in our previous paper. We evaluated expression of molecules involved in insulin, steroidogenic signaling and lipid metabolism in luteinized granulosa cells followed by analysis of estradiol, progesterone and testosterone in follicular fluid. Protein expression of INSR- β, pIRS (ser 307), PI(3)K, PKC-ζ, pAkt, ERK1/2, pP38MAPK and gene expression of IGF showed differential expression in the two groups. Increased protein expression of PPAR-γ was accompanied by up regulation in SREBP1c, FAS, CPT-1 and ACC-1 genes in PCOS-IR group. Expression of StAR, CYP19A1, 17 β- HSD and 3 β- HSD demonstrated significant decrease along with increase in CYP11A1, FSH-R and LH-R in both the groups. Follicular fluid testosterone increased and progesterone decreased in PCOS-IR group. This study shows how candidate molecules that were differentially expressed, aid in designing targeted therapy against the two phenotypes of PCOS.

The aim of present study was to evaluate the significance of estradiol (E2) in testicular activities and to find out the mechanism by which E2 regulates spermatogenesis in mice. To achieve this, both in vivo and in vitro effect of Letrozole on testis of adult mice was investigated. Letrozole-induced changes in testicular histology, cell proliferation (proliferating cell nuclear antigen; PCNA), cell survival (B cell lymphoma factor-2; Bcl2), apoptotic (cysteine-aspartic proteases; caspase-3), steroidogenic (side chain cleavage; SCC, 3β-hydroxy steroid dehydrogenase enzyme; 3β HSD, steroidogenic acute regulatory protein; StAR, aromatase and luteinizing hormone receptor; LH-R) markers, glucose level, and rate of expression of glucose transporter (GLUT) 8 and insulin receptor (IR) proteins in the testis along with changes in serum E2 and testosterone (T) levels were evaluated. Letrozole acts on testis and caused significant decrease in E2 synthesis, but increase in testosterone level and showed regressive changes in the spermatogenesis. Letrozole-induced changes in various testicular markers were compared with the changes in serum E2 level. The correlation study showed that decreased circulating E2 level may be responsible for decreased insulin receptor (IR) level in the testis. The decreased effects of insulin inhibited the glucose transport in the testis by suppressing GLUT8. The decreased level of testicular glucose may produce less lactate as energy support to developing germ cells consequently resulting in decreased cell proliferation and cell survival, but increased apoptosis. Thus, Letrozole suppresses spermatogenesis by reducing insulin sensitivity and glucose transport in the testis, but significantly increased testosterone level by promoting gonadotrophin release by decreased E2.