Virtual and in Vitro Screening Employing a Repurposing Approach Reveal 13-cis-Retinoic Acid is a PTP1B Inhibitor.

Current treatments for type 2 diabetes (T2D) mainly rely on exercise, dietary control, and anti-diabetic drugs to enhance insulin secretion and improve insulin sensitivity. However, there is a need for more therapeutic options, as approved drugs targeting different pharmacological objectives are still unavailable. One potential target that has attracted attention is the protein tyrosine phosphatase 1B (PTP1B), which negatively regulates the insulin signaling pathway. In this work, a comprehensive computational screening was carried out using cheminformatics and molecular docking on PTP1B, employing a rigorous repurposing approach. The screening involved approved drugs and compounds under research as anti-diabetics that bind to targets such as peroxisome proliferator-activated receptor gamma (PPAR-γ) and α-glucosidase. Several computational hits were then meticulously tested in vitro against PTP1B, with 13-cis-retinoic acid (3a) showing an IC50 of 0.044 mM and competitive inhibition. Molecular dynamics studies further confirmed that 3a can bind to the catalytic binding site of PTP1B. Finally, 3a is the first time it has been reported as an inhibitor of PTP1B, making it a potentially valuable candidate for further studies in D2T treatment.

Ancestry effects on type 2 diabetes genetic risk inference in Hispanic/Latino populations.

BACKGROUND: Hispanic/Latino (HL) populations bear a disproportionately high burden of type 2 diabetes (T2D). The ability to predict T2D genetic risk using polygenic risk scores (PRS) offers great promise for improved screening and prevention. However, there are a number of complications related to the accurate inference of genetic risk across HL populations with distinct ancestry profiles. We investigated how ancestry affects the inference of T2D genetic risk using PRS in diverse HL populations from Colombia and the United States (US). In Colombia, we compared T2D genetic risk for the Mestizo population of Antioquia to the Afro-Colombian population of Chocó, and in the US, we compared European-American versus Mexican-American populations. METHODS: Whole genome sequences and genotypes from the 1000 Genomes Project and the ChocoGen Research Project were used for genetic ancestry inference and for T2D polygenic risk score (PRS) calculation. Continental ancestry fractions for HL genomes were inferred via comparison with African, European, and Native American reference genomes, and PRS were calculated using T2D risk variants taken from multiple genome-wide association studies (GWAS) conducted on cohorts with diverse ancestries. A correction for ancestry bias in T2D risk inference based on the frequencies of ancestral versus derived alleles was developed and applied to PRS calculations in the HL populations studied here. RESULTS: T2D genetic risk in Colombian and US HL populations is positively correlated with African and Native American ancestry and negatively correlated with European ancestry. The Afro-Colombian population of Chocó has higher predicted T2D risk than Antioquia, and the Mexican-American population has higher predicted risk than the European-American population. The inferred relative risk of T2D is robust to differences in the ancestry of the GWAS cohorts used for variant discovery. For trans-ethnic GWAS, population-specific variants and variants with same direction effects across populations yield consistent results. Nevertheless, the control for bias in T2D risk prediction confirms that explicit consideration of genetic ancestry can yield more reliable cross-population genetic risk inferences. CONCLUSIONS: T2D associations that replicate across populations provide for more reliable risk inference, and modeling population-specific frequencies of ancestral and derived risk alleles can help control for biases in PRS estimation.

Vortioxetine versus sertraline in metabolic control, distress and depression in Mexican patients with type 2 diabetes.

BACKGROUND: Depression in patients with type 2 diabetes (T2D) is often undiagnosed and remains untreated, leading to poor therapy adherence and ill health-related outcomes. We evaluated the effect of vortioxetine versus sertraline in the treatment of depression, distress and metabolic control in subjects with T2D and depression. METHODS: Participants were selected from the Clinic for Diabetes, diagnosed with depression when the score was ≥14 in the Hamilton Depression Rating Scale, and verified by a psychiatrist in agreement with the DSM-5 instrument (Diagnostic and Statistical Manual of Mental Disorders, fifth edition). The criteria for recruitment also included glycosylated hemoglobin ≥7.5%, 18 to 60 years of age, and written informed consent. Pharmacological treatment for depression was assigned randomly: vortioxetine (10 mg/day) or sertraline (75 mg/day) for 8 weeks. Biochemical parameters, anthropometric measures and depression symptoms were evaluated after antidepressant treatment. This was a randomized singled-blind study. RESULTS: Subjects that met the inclusion criteria were 50, of which only 21 patients with T2D and depression finished the treatment. Vortioxetine and sertraline showed partial remission of depression. Vortioxetine showed a major effect size in glycosylated hemoglobin and a moderate effect size on weight loss, fasting plasma glucose (FPG), cholesterol and triacylglycerol levels. On the other hand, patients treated with sertraline presented a slight increase in body weight, body mass index (BMI), and in all biochemical markers. CONCLUSIONS: Vortioxetine may ameliorate depressive symptoms and metabolic control in patients with T2D and depression. Trial registration number: NCT03978286.

Obesity and increased susceptibility to arsenic-related type 2 diabetes in Northern Chile.

BACKGROUND: The prevalence of type 2 diabetes (T2D) has nearly doubled since 1980. Elevated body mass index (BMI) is the leading risk factor for T2D, mediated by inflammation and oxidative stress. Arsenic shares similar pathogenic processes, and may contribute to hyperglycemia and ß-cell dysfunction. OBJECTIVES: We assessed a unique situation of individuals living in Northern Chile with data on lifetime arsenic exposure to evaluate the relationship between arsenic and T2D, and investigate possible interactions with BMI. METHODS: We analyzed data collected from October 2007-December 2010 from an arsenic-cancer case-control study. Information on self-reported weight, height, smoking, diet, and other factors were obtained. Diabetes was defined by self-reported physician-diagnoses or use of hypoglycemic medication. A total of 1053 individuals, 234 diabetics and 819 without known diabetes were included. RESULTS: The T2D odds ratio (OR) for cumulative arsenic exposures of 610-5279 and ≥ 5280 µg/L-years occurring 40 years or more before interview were 0.97 (95% CI: 0.66-1.43) and 1.53 (95% CI: 1.05-2.23), respectively. Arsenic-associated T2D ORs were greater in subjects with increased BMIs. For example, the ORs for past cumulative exposures ≥ 5280 µg/L-years was 1.45 (95% CI: 0.74-2.84) in participants with BMIs < 25 kg/m2 but 2.64 (95% CI: 1.14-6.11) in those with BMIs ≥ 30 kg/m2 (synergy index = 2.49, 95% CI: 0.87-7.09). Results were similar when people with cancer were excluded. CONCLUSIONS: These findings identify increased odds of T2D with arsenic exposure, which are significantly increased in individuals with excess BMI.