Effect of free fatty acids on insulin secretion, insulin sensitivity and incretin effect - a narrative review

ABSTRACT Deleterious effects of free fatty acids, FFAs, on insulin sensitivity are observed in vivo studies in humans. Mechanisms include impaired insulin signaling, oxidative stress, inflammation, and mitochondrial dysfunction, but the effects on insulin secretion are less well known. Our aim was to review the relationship of increased FFAs with insulin resistance, secretion and mainly with the incretin effect in humans. Narrative review. Increased endogenous or administered FFAs induce insulin resistance. FFAs effects on insulin secretion are debatable; inhibition and stimulation have been reported, depending on the type and duration of lipids exposition and the study subjects. Chronically elevated FFAs seem to decrease insulin biosynthesis, glucose-stimulated insulin secretion and β-cell glucose sensitivity. Lipids infusion decreases the response to incretins with unchanged incretin levels in volunteers with normal glucose tolerance. In contrast, FFAs reduction by acipimox did not restore the incretin effect in type-2 diabetes, probably due to the dysfunctional β-cell. Possible mechanisms of FFAs excess on incretin effect include reduction of the expression and levels of GLP-1 (glucagon like peptide-1) receptor, reduction of connexin-36 expression thus the coordinated secretory activity in response to GLP-1, and GIP (glucose-dependent insulinotropic polypeptide) receptors downregulation in islets cells. Increased circulating FFAs impair insulin sensitivity. Effects on insulin secretion are complex and controversial. Deleterious effects on the incretin-induced potentiation of insulin secretion were reported. More investigation is needed to better understand the extent and mechanisms of β-cell impairment and insulin resistance induced by increased FFAs and how to prevent them.

Single-cell RNA Sequencing Reveals Sexually Dimorphic Transcriptome and Type 2 Diabetes Genes in Mouse Islet β Cells / 基因组蛋白质组与生物信息学报·英文版

Type 2 diabetes (T2D) is characterized by the malfunction of pancreatic β cells. Susceptibility and pathogenesis of T2D can be affected by multiple factors, including sex differences. However, the mechanisms underlying sex differences in T2D susceptibility and pathogenesis remain unclear. Using single-cell RNA sequencing (scRNA-seq), we demonstrate the presence of sexually dimorphic transcriptomes in mouse β cells. Using a high-fat diet-induced T2D mouse model, we identified sex-dependent T2D altered genes, suggesting sex-based differences in the pathological mechanisms of T2D. Furthermore, based on islet transplantation experiments, we found that compared to mice with sex-matched islet transplants, sex-mismatched islet transplants in healthy mice showed down-regulation of genes involved in the longevity regulating pathway of β cells. Moreover, the diabetic mice with sex-mismatched islet transplants showed impaired glucose tolerance. These data suggest sexual dimorphism in T2D pathogenicity, indicating that sex should be considered when treating T2D. We hope that our findings could provide new insights for the development of precision medicine in T2D.

ACP1 y la asociación entre obesidad y diabetes tipo 2. Un estudio confirmatorio / ACP1 AND THE ASSOCIATION BETWEEN OBESITY AND TYPE 2 DIABETES . A CONFIRMATION STUDY

En un estudio previo sobre sujetos con enfermedades cardiovasculares (ECV) hemos observado que en los pacientes obesos con genotipo *B/*B en el gen ACP1, la proporción de pacientes con diabetes mellitus tipo 2 (DM2) es significativamente menor en comparación con pacientes con otros genotipos en el gen ACP1. En este trabajo hemos llevado a cabo un nuevo estudio en sujetos con DM2 sin ECV y en sujetos no diabéticos sin ECV. Hemos estudiado 277 sujetos con DM2 sin ECV y 137 sujetos sanos sin DM2 y sin ECV. Se obtuvo el consentimiento informado de estos sujetos para participar en el estudio que fue aprobado por el Departamento institucional respectivo. El genotipo presente en el gen ACP1 se determinó por análisis de ADN. Las pruebas estadísticas fueron realizadas con el programa SPSS. El genotipo *B/*B que está asociado con la mayor concentración de isoforma F ejerce un efecto protector sobre la susceptibilidad a la DM2 en sujetos obesos. Se observa una correlación negativa entre la concentración de la isoforma F y el índice de probabilidades para la susceptibilidad a la DT2 en sujetos obesos. La presente observación confirma la asociación previamente observada en sujetos con ECV haciendo improbable la posibilidad de un mero artefacto casual de muestreo. La expresión de las isoformas de ACP1 en el tejido adiposo a través de una acción sobre la proteína de unión a los lípidos de los adipocitos y el metabolismo de los lípidos puede ejercer un papel importante en la susceptibilidad a la DM2 en sujetos obesos.

In a previous study on subjects with cardiovascular diseases (CVD) we have observed that in obese patients with ACP1*B/*B genotype the proportion of those with type 2 diabetes (T2D) is significantly lower as compared to other ACP1 genotypes. We have now carried a new study in subjects with T2D without CVD and in non diabetic subjects without CVD. We have studied 277 subjects with T2D without CVD and 137 healthy subjects without T2D and without CVD. Iinformed consent was obtained from these subjects to participate to the study that was approved by the Council of Department. ACP1 genotype was determined by DNA analysis. Statistical tests were carried out by SPSS programs. ACP1*B/*B genotype which is associated with the highest concentration of F isoform exerts a protective effect on susceptibility to T2D in obese subjects. A negative correlation is observed between F isoform concentration and odds ratio for susceptibility to T2D in obese subjects The present observation confirms the association previously observed in subjects with CVD making unlikely the possibility of a mere sampling chance artifact. The expression of ACP1 isoforms in adipose tissue trough an action on adipocytes lipid binding protein and lipid metabolism may exert an important role in the susceptibility to T2D in obese subjects

Type 2 diabetes associated variants of KCNQ1 strongly confer the risk of cardiovascular disease among the Saudi Arabian population

Abstract Genome-wide association studies have identified several loci associated with an increased risk for cardiovascular disease (CVD) and type 2 diabetes (T2D). Polymorphisms within the KCNQ1 (potassium voltage-gated channel, KQT-like subfamily, member 1) gene are consistently associated with T2D in a number of populations. The current study was undertaken to evaluate the association of 3 polymorphisms of KCNQ1 (rs2237892, rs151290 and rs2237895) with T2D and/or CVD. Patients diagnosed with either T2D (320 patients), CVD (250 patients) or both (60 patients) and 516 healthy controls were genotyped by TaqMan assay run on a real time PCR thermocycler. A statistically significant association was found for SNPs rs151290 (OR = 1.76; 95%CI = 1.02-3.05; p = 0.0435) and rs2237895 (OR = 2.49; 95%CI = 1.72-3.61; p < 0.0001) with CVD. SNP rs151290 (OR = 7.43; 95%CI = 1.00-55.22; p = 0.0499) showed a strong association in patients with both T2D and CVD. None of the SNPs showed any significant association with T2D. Haploview analysis showed that the ACC (rs151290, rs2237892 and rs2237895) haplotype is the most significant risk allele combination for CVD, while CCA is the most significant risk haplotype for co-morbidity with T2D. KCNQ1 polymorphism at SNPs rs151290 and rs2237895 is strongly associated with CVD in this population, but presented no association with T2D.

Prognostic Significance of ACE and PAI-1 Genes Polymorphisms with Diabetic Retinopathy and Diabetic Non-Retinopathy in Type 2 Diabetes.

Background: ACE a renin-angiotensin system that regulates blood pressure, balance of fluids and salts in body and PAI-1 is a serine protease inhibitor, which inhibits tissue plasminogen activator andurokinase.They are thought to play an important role in pathophysiology of kidney disease in diabetes. Aim: In our present study, we studied the association of altered ACE-gene and PAI-1 gene with diabetic retinopathy (DR) and NDR in 592 samples consisted of (cohort I; 196 DR patients, cohort II; 200 diabetic nonretinopathy (DNR) and cohort III, 196 respective controls. Methods: For genotyping of ACE-gene and PAI-1 gene, genomic DNA was isolated and purified which was then amplified by PCR, and thePCR products analyzedwere by Agarose gel electrophoresis. Results: In first part, the ACE genotype and allele frequency distribution was studied. For ACE gene polymorphism, the genotype and allele frequency distribution were analyzed in DR subjects and respective controls. The results indicated that there is no statistically significant difference between DR males and females compared to respective controls. The results were significantly high between genotype frequencies of DR and DNR in males. The recessive model was found to be significantly associated with the DR male subjects (OR=0.45 [95% CI=0.20-0.99], p<0.05), whereas in females these are non-significant as compared to respective controls individuals. In second part of study, the disease status analysis of ACE gene on basis of DR stages (NPDR and PDR) was observed. The χ2 analysis indicated that results are significantly different between NPDR and respective controls (χ2=8.75, p=0.01) .And in third part of present study, disease status analysis for PAI-1 gene on the basis of DR stages (NPDR and PDR) was studied, which indicated statistically nonsignificance. The χ2 analysis values for DNR and NPDR and for DNR and PDR was (χ2=0.48, p>0.05)(χ2 =2.00, p>0.05) respectively, Conclusion: Our present study suggests that changes in genetic polymorphisms of ACE-gene and PAI-1 gene in DR, DNR and T2D Patients are risk factors, which may serve as useful prognostic markers.

Identification of Causal and/or Rare Genetic Variants for Complex Traits by Targeted Resequencing in Population-based Cohorts

Genome-wide association studies (GWASs) have greatly contributed to the identification of common variants responsible for numerous complex traits. There are, however, unavoidable limitations in detecting causal and/or rare variants for traits in this approach, which depends on an LD-based tagging SNP microarray chip. In an effort to detect potential casual and/or rare variants for complex traits, such as type 2 diabetes (T2D) and triglycerides (TGs), we conducted a targeted resequencing of loci identified by the Korea Association REsource (KARE) GWAS. The target regions for resequencing comprised whole exons, exon-intron boundaries, and regulatory regions of genes that appeared within 1 Mb of the GWA signal boundary. From 124 individuals selected in population-based cohorts, a total of 0.7 Mb target regions were captured by the NimbleGen sequence capture 385K array. Subsequent sequencing, carried out by the Roche 454 Genome Sequencer FLX, generated about 110,000 sequence reads per individual. Mapping of sequence reads to the human reference genome was performed using the SSAHA2 program. An average of 62.2% of total reads was mapped to targets with an average 22X-fold coverage. A total of 5,983 SNPs (average 846 SNPs per individual) were called and annotated by GATK software, with 96.5% accuracy that was estimated by comparison with Affymetrix 5.0 genotyped data in identical individuals. About 51% of total SNPs were singletons that can be considered possible rare variants in the population. Among SNPs that appeared in exons, which occupies about 20% of total SNPs, 304 nonsynonymous singletons were tested with Polyphen to predict the protein damage caused by mutation. In total, we were able to detect 9 and 6 potentially functional rare SNPs for T2D and triglycerides, respectively, evoking a further step of replication genotyping in independent populations to prove their bona fide relevance to traits.