Dataset Information

Follistatins in glucose regulation in healthy and obese individuals.

ABSTRACT: AIMS:It has been suggested recently that follistatin (FST) and its homologous protein, follistatin-like 3 (FSTL3), may be a therapeutic target in the treatment of type 2 diabetes because of their glucose-regulatory effects in rodents. MATERIALS AND METHODS:We investigated this hypothesis in humans by studying the physiology of a possible glycaemia-follistatin feedback loop, that is, whether glucose, but not lipid intake (oral or intravenous), can regulate circulating FST and FSTL3 in healthy humans (n = 32), whether the levels of follistatins change in response to various types of bariatric operation in morbidly obese individuals, with or without type 2 diabetes (n = 41), and whether such changes are associated prospectively with improvement of glucose homeostasis/insulin sensitivity. RESULTS:In healthy individuals, circulating FST decreases after intravenous or oral glucose intake compared to controls, indicating the presence of a negative feedback mechanism. In morbid obesity, insulin resistance, glycaemia, circulating FST and FSTL3 are all reduced (by 22%-33%) after Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy. Importantly, the changes in circulating FST 3 months after bariatric surgery are associated prospectively with the changes in glucose, insulin, HOMA-IR and HbA1c observed 6 months postoperatively in individuals with and without type 2 diabetes. CONCLUSIONS:Our findings provide evidence of an important role of FST in glucose homeostasis in healthy individuals as well as in severely obese individuals with insulin resistance and type 2 diabetes. Our data extend recent results from animal studies to humans and support the need for further evaluation of FST inactivation strategies for targeting hyperglycaemia and insulin resistance.

SUBMITTER: Perakakis N

PROVIDER: S-EPMC6368471 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Follistatins in glucose regulation in healthy and obese individuals.

Perakakis Nikolaos N Kokkinos Alexander A Peradze Natia N Tentolouris Nicholas N Ghaly Wael W Tsilingiris Dimitrios D Alexandrou Andreas A Mantzoros Christos S CS

Diabetes, obesity & metabolism 20181203 3

<h4>Aims</h4>It has been suggested recently that follistatin (FST) and its homologous protein, follistatin-like 3 (FSTL3), may be a therapeutic target in the treatment of type 2 diabetes because of their glucose-regulatory effects in rodents.<h4>Materials and methods</h4>We investigated this hypothesis in humans by studying the physiology of a possible glycaemia-follistatin feedback loop, that is, whether glucose, but not lipid intake (oral or intravenous), can regulate circulating FST and FSTL3 ...[more]

PMID: 30393997

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Project description:PurposeObesity is characterized by chronic inflammation that may contribute to insulin resistance and promote type 2 diabetes. We have investigated whether inflammatory responses to glycemic and insulinemic variations are altered in obese individuals.MethodsEight obese and eight lean individuals without diabetes had undergone hyperinsulinemic-euglycemic-hypoglycemic and hyperglycemic clamps in a previous study. Using Proximity Extension Assay, 92 inflammatory markers were analyzed from plasma samples at fasting, hyperinsulinemia-euglycemia, hypoglycemia and hyperglycemia.ResultsIn all participants, hyperinsulinemia, hypoglycemia and hyperglycemia led to reductions of 11, 19 and 62 out of the 70 fully evaluable biomarkers, respectively. FGF-21 increased during both hypoglycemia and hyperglycemia while IL-6 and IL-10 increased during hypoglycemia. In obese vs lean participants, Oncostatin-M, Caspase-8 and 4E-BP1 were more markedly suppressed during hypoglycemia, whereas VEGF-A was more markedly suppressed during hyperglycemia. BMI correlated inversely with changes of PD-L1 and CD40 during hyperinsulinemia, Oncostatin-M, TNFSF14, FGF-21 and 4EBP-1 during hypoglycemia and CCL23, VEGF-A and CDCP1 during hyperglycemia (Rho ≤ -0.50). HbA1c correlated positively with changes of MCP-2 and IL-15-RA during hyperinsulinemia (Rho ≥ 0.51) and inversely with changes of CXCL1, MMP-1 and Axin-1 during hypoglycemia (Rho ≤ -0.55). M-value correlated positively with changes of IL-12B and VEGF-A during hyperglycemia (Rho ≥ 0.51). Results above were significant (p < 0.05).ConclusionOverall, hyperinsulinemia, hypo- and hyperglycemia led to suppression of several inflammatory markers and this tended to be more marked in individuals with obesity, insulin resistance and dysglycemia. Thus, acute glycemic or insulinemic variations do not seem to potentiate possible inflammatory pathways in the development of insulin resistance and disturbed glucose metabolism.

Project description:BackgroundObesity is associated with severe co-morbidities such as type 2 diabetes and nonalcoholic steatohepatitis. However, studies have shown that 10-25 percent of the severely obese individuals are metabolically healthy. To date, the identification of genetic factors underlying the metabolically healthy obese (MHO) state is limited. Systems genetics approaches have led to the identification of genes and pathways in complex diseases. Here, we have used such approaches across tissues to detect genes and pathways involved in obesity-induced disease development.MethodsExpression data of 60 severely obese individuals was accessible, of which 28 individuals were MHO and 32 were metabolically unhealthy obese (MUO). A whole genome expression profile of four tissues was available: liver, muscle, subcutaneous adipose tissue and visceral adipose tissue. Using insulin-related genes, we used the weighted gene co-expression network analysis (WGCNA) method to build within- and inter-tissue gene networks. We identified genes that were differentially connected between MHO and MUO individuals, which were further investigated by homing in on the modules they were active in. To identify potentially causal genes, we integrated genomic and transcriptomic data using an eQTL mapping approach.ResultsBoth IL-6 and IL1B were identified as highly differentially co-expressed genes across tissues between MHO and MUO individuals, showing their potential role in obesity-induced disease development. WGCNA showed that those genes were clustering together within tissues, and further analysis showed different co-expression patterns between MHO and MUO subnetworks. A potential causal role for metabolic differences under similar obesity state was detected for PTPRE, IL-6R and SLC6A5.ConclusionsWe used a novel integrative approach by integration of co-expression networks across tissues to elucidate genetic factors related to obesity-induced metabolic disease development. The identified genes and their interactions give more insight into the genetic architecture of obesity and the association with co-morbidities.

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Follistatins in glucose regulation in healthy and obese individuals.

Publications

Follistatins in glucose regulation in healthy and obese individuals.

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