A decline in β-cell function is a prerequisite for the development of type 2 diabetes, yet the level of β-cell function in individuals at risk of the condition is rarely measured. This is due, in part, to the fact that current methods for assessing β-cell function are inaccurate, prone to error, labor-intensive, or affected by glucose-lowering therapy. The aim of the current study was to identify novel circulating biomarkers to monitor β-cell function and to identify individuals at high risk of developing β-cell dysfunction. In a nested case-control study from the Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) cohort (n = 1157), proteomics and miRNA profiling were performed on fasting plasma samples from 43 individuals who progressed to impaired glucose tolerance (IGT) and 43 controls who maintained normal glucose tolerance (NGT) over three years. Groups were matched at baseline for age, gender, body mass index (BMI), insulin sensitivity (euglycemic clamp) and β-cell glucose sensitivity (mathematical modeling). Proteomic profiling was performed using the SomaLogic platform (Colorado, USA); miRNA expression was performed using a modified RT-PCR protocol (Regulus Therapeutics, California, USA). Results showed differentially expressed proteins and miRNAs including some with known links to type 2 diabetes, such as adiponectin, but also novel biomarkers and pathways. In cross sectional analysis at year 3, the top differentially expressed biomarkers in people with IGT/ reduced β-cell glucose sensitivity were adiponectin, alpha1-antitrypsin (known to regulate adiponectin levels), endocan, miR-181a, miR-342, and miR-323. At baseline, adiponectin, cathepsin D and NCAM.L1 (proteins expressed by pancreatic β-cells) were significantly lower in those that progressed to IGT. Many of the novel prognostic biomarker candidates were within the epithelial-mesenchymal transition (EMT) pathway: for example, Noggin, DLL4 and miR-181a. Further validation studies are required in additional clinical cohorts and in patients with type 2 diabetes, but these results identify novel pathways and biomarkers that may have utility in monitoring β-cell function and/ or predicting future decline, allowing more targeted efforts to prevent and intercept type 2 diabetes.

/pdf/identification-of-novel-biomarkers-to-monitor-b-cell-5fmfcgo4oz.pdf

Identification of novel biomarkers to monitor β-cell function and enable early detection of type 2 diabetes risk.

Pancreatic β-cells are specialized to properly regulate blood glucose. Maintenance of the mature β-cell phenotype is critical for glucose metabolism, and β-cell failure results in diabetes mellitus. Recent studies provide strong evidence that the mature phenotype of β-cells is maintained by several transcription factors. These factors are also required for β-cell differentiation from endocrine precursors or maturation from immature β-cells during pancreatic development. Because the reduction or loss of these factors leads to β-cell failure and diabetes, inducing the upregulation or inhibiting downregulation of these transcription factors would be beneficial for studies in both diabetes and stem cell biology. Here, we discuss one such factor, i.e., the transcription factor MAFA. MAFA is a basic leucine zipper family transcription factor that can activate the expression of insulin in β-cells with PDX1 and NEUROD1. MAFA is indeed indispensable for the maintenance of not only insulin expression but also function of adult β-cells. With loss of MAFA in type 2 diabetes, β-cells cannot maintain their mature phenotype and are dedifferentiated. In this review, we first briefly summarize the functional roles of MAFA in β-cells and then mainly focus on the molecular mechanism of cell fate conversion regulated by MAFA.

/pdf/role-of-the-transcription-factor-mafa-in-the-maintenance-of-1jbgwrj2.pdf

Role of the Transcription Factor MAFA in the Maintenance of Pancreatic β-Cells

Obesity is a leading cause of cardiovascular diseases and cancer. Body mass is regulated by the balance between energy uptake and energy expenditure. The etiology of obesity is determined by multiple factors including genetics, nutrient absorption, and inflammation. Lymphatic vasculature is starting to be appreciated as a critical modulator of metabolism and obesity. The primary function of lymphatic vasculature is to maintain interstitial fluid homeostasis. Lymphatic vessels absorb fluids that extravasate from blood vessels and return them to blood circulation. In addition, lymphatic vessels absorb digested lipids from the intestine and regulate inflammation. Hence, lymphatic vessels could be an exciting target for treating obesity. In this article, we will review our current understanding regarding the relationship between lymphatic vasculature and obesity, and highlight some open questions.

/pdf/lymphatic-vasculature-in-energy-homeostasis-and-obesity-4dqu0kkx6l.pdf

Lymphatic Vasculature in Energy Homeostasis and Obesity.

Prox1 is involved in muscle fiber conversion, adult-onset obesity, and type 2 diabetes. However, information regarding porcine Prox1 and its relationship with meat quality traits is still unknown. In this study, we characterized the full-length cDNA and proximal promoter of two transcript variants of porcine Prox1. Moreover, Prox1 was expressed abundantly in the skeletal muscle and its expression was higher in the soleus muscle than that in the biceps femoris muscle. Its expression pattern in the high and low meat color (redness) value a* groups was similar to that of myoglobin and MyHC I, but opposed to that of MyHC IIB. Importantly, there was a significant positive correlation between Prox1 expression and meat color (redness) value a* (r = 0.3845, p = 0.0394), and a significant negative correlation between Prox1 expression and drip loss (r = -0.4204, p = 0.0232), as well as the ratio of MyHC IIB to MyHC I expression (r = -0.3871, p = 0.0380). In addition, we found that the polymorphisms of three closely linked SNPs in Prox1 promoter 1 were significantly associated with pH24h in a pig population. Taken together, our data provide valuable insights into the characteristics of porcine Prox1 and indicate that Prox1 is a promising candidate gene affecting meat quality traits.

https://www.mdpi.com/2076-2615/9/10/744/pdf

Comprehensive Analysis of Porcine Prox1 Gene and Its Relationship with Meat Quality Traits.

Gestational diabetes mellitus (GDM) is a metabolic disorder that occurs during pregnancy. HHEX and PROX1 are genetic loci associated with diabetes mellitus type 2. HHEX and PROX1 play significant roles in carbohydrate intolerance and diabetes because these transcription factors may be involved in the regulation of insulin secretion and in glucose and lipid metabolism. The aim of this study was to examine the association between HHEX (rs5015480) and PROX1 (rs340874) gene polymorphisms and GDM. This study included 204 pregnant women with GDM and 207 pregnant women with the normal glucose tolerance (NGT). The diagnosis of GDM was based on a 75-g oral glucose tolerance test at 24–28 weeks’ gestation. There was a statistically significant prevalence of the HHEX rs5015480 CC genotype and C allele among women with GDM (C vs T allele, p = 0.021, odds ratio OR=1.40, 95% CI: 1.05–1.87). Statistically significant higher increase of body mass and BMI during pregnancy was found in women with the HHEX rs5015480 CC genotype. The results of our study suggest an association between the HHEX gene rs5015480 polymorphism and risk of GDM. The HHEX gene rs5015480 C allele may be a risk allele of GDM that is associated with increased BMI during pregnancy.

Hematopoietically expressed homeobox (HHEX) gene polymorphism (rs5015480) is associated with increased risk of gestational diabetes mellitus

Transcription factor expression fluctuates during β-cell ontogeny, and disruptions in this pattern can affect the development or function of those cells. Here we uncovered that murine endocrine pancreatic progenitors express high levels of the homeodomain transcription factor Prox1, whereas both immature and mature β-cells scarcely express this protein. We also investigated if sustained Prox1 expression is incompatible with β-cell development or maintenance using transgenic mouse approaches. We discovered that Prox1 upregulation in mature β-cells has no functional consequences; in contrast, Prox1 overexpression in immature β-cells promotes acute fasting hyperglycemia. Using a combination of immunostaining and quantitative and comparative gene expression analyses, we determined that Prox1 upregulation reduces proliferation, impairs maturation, and enables apoptosis in postnatal β-cells. Also, we uncovered substantial deficiency in β-cells that overexpress Prox1 of the key regulator of β-cell maturation MafA, several MafA downstream targets required for glucose-stimulated insulin secretion, and genes encoding important components of FGF signaling. Moreover, knocking down PROX1 in human EndoC-βH1 β-cells caused increased expression of many of these same gene products. These and other results in our study indicate that reducing the expression of Prox1 is beneficial for the expansion and maturation of postnatal β-cells.

/pdf/lack-of-prox1-downregulation-disrupts-the-expansion-and-2p4di8wkhw.pdf

Lack of Prox1 Downregulation Disrupts the Expansion and Maturation of Postnatal Murine β-Cells

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Lack of Prox1 Downregulation Disrupts the Expansion and Maturation of Postnatal Murine β-Cells