GDF11 Attenuates Development of Type 2 Diabetes via Improvement of Islet β-Cell Function and Survival

Li, Huan; Li, Yixiang; Xiang, Lingwei; Zhang, Jiajia; Zhu, Biao; Xiang, Lin; Dong, Jing; Liu, Min; Xiang, Guangda

doi:10.2337/db17-0086

Cited by 67 publications

(62 citation statements)

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“…Garcia-Ocana et al reported a complex role for hepatocyte growth factor (HGF) signaling in β-cell apoptosis 54,55 . A recent study reported the role of growth differentiation factor 11 (GDF11) in β-cell apoptosis via actions on TGF-β/Smad2 signaling 56 . Activin receptor-like 7 (ALK7) has also been linked to apoptosis via Smad2 and Caspase-3 30,57 .…”

Section: Discussionmentioning

confidence: 99%

Protection from β-cell apoptosis by inhibition of TGF-β/Smad3 signaling

et al. 2020

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Prevailing insulin resistance and the resultant hyperglycemia elicits a compensatory response from pancreatic islet beta cells (β-cells) that involves increases in β-cell function and β-cell mass. However, the sustained metabolic stress eventually leads to β-cell failure characterized by severe β-cell dysfunction and progressive loss of β-cell mass. Whereas, β-cell dysfunction is relatively well understood at the mechanistic level, the avenues leading to loss of β-cell mass are less clear with reduced proliferation, dedifferentiation, and apoptosis all potential mechanisms. Butler and colleagues documented increased β-cell apoptosis in pancreas from lean and obese human Type 2 diabetes (T2D) subjects, with no changes in rates of β-cell replication or neogenesis, strongly suggesting a role for apoptosis in β-cell failure. Here, we describe a permissive role for TGF-β/Smad3 in β-cell apoptosis. Human islets undergoing β-cell apoptosis release increased levels of TGF-β1 ligand and phosphorylation levels of TGF-β's chief transcription factor, Smad3, are increased in human T2D islets suggestive of an autocrine role for TGF-β/Smad3 signaling in β-cell apoptosis. Smad3 phosphorylation is similarly increased in diabetic mouse islets undergoing β-cell apoptosis. In mice, β-cell-specific activation of Smad3 promotes apoptosis and loss of β-cell mass in association with β-cell dysfunction, glucose intolerance, and diabetes. In contrast, inactive Smad3 protects from apoptosis and preserves β-cell mass while improving β-cell function and glucose tolerance. At the molecular level, Smad3 associates with Foxo1 to propagate TGF-β-dependent β-cell apoptosis. Indeed, genetic or pharmacologic inhibition of TGF-β/Smad3 signals or knocking down Foxo1 protects from β-cell apoptosis. These findings reveal the importance of TGF-β/Smad3 in promoting β-cell apoptosis and demonstrate the therapeutic potential of TGF-β/Smad3 antagonism to restore β-cell mass lost in diabetes.

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Section: Discussionmentioning

confidence: 99%

Protection from β-cell apoptosis by inhibition of TGF-β/Smad3 signaling

et al. 2020

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“…Afamin has been associated with both prevalent and incident T2DM in a large-scale pooled study of eight prospective cohorts 33 and we here obtain support from both two-and one-sample MR analyses for it to play a causal role in the disease. Less is known about the function of the other two proteins; inhibin β C is one of the inhibin/activin hormones and is highly expressed in liver whereas WFIKKN2 is known to bind GDF8/11 proteins with high affinity 34 , both of which have been implicated in diabetes 35,36 . We and others have shown that genetic variants in the WFIKKN2 region regulate serum GDF8/11 levels in trans via WFIKKN2 protein levels 14,19 and previously noted a correlation between WFIKKN2 and GDF8/11 serum levels 14 , however in the current study we did not find a significant association between GDF8/11 and T2DM so additional studies are required to understand the mechanisms by which WFIKKN2 may affect risk of T2DM.…”

Section: Discussionmentioning

confidence: 99%

“…Prior to the analysis of the protein measurements, we applied a Yeo-Johnson transformation on the protein data to improve normality, symmetry and to maintain all protein variables on a similar scale 40 35 . Logistic regression was run for all 4,782 SOMAmers targeting 4,137 human proteins for incident or prevalent T2DM as outcome, with age and sex included as covariates, and an additional model including BMI.…”

Section: Methodsmentioning

confidence: 99%

Deep serum proteomics reveal biomarkers and causal candidates for type 2 diabetes

Guðmundsdóttir

Emilsson

Aspelund

et al. 2019

Preprint

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18The prevalence of type 2 diabetes mellitus (T2DM) is expected to increase rapidly in the next 19 decades, posing a major challenge to societies worldwide. The emerging era of precision 20 medicine calls for the discovery of biomarkers of clinical value for prediction of disease 21 onset, where causal biomarkers can furthermore provide actionable targets. Blood-based 22 factors like serum proteins are in contact with every organ in the body to mediate global 23 homeostasis and may thus directly regulate complex processes such as aging and the 24 development of common chronic diseases. We applied a data-driven proteomics approach 25 measuring serum levels of 4,137 proteins in 5,438 Icelanders to discover novel biomarkers for 26 incident T2DM and describe the serum protein profile of prevalent T2DM. We identified 536 27 proteins associated with incident or prevalent T2DM. Through LASSO penalized logistic 28 regression analysis combined with bootstrap resampling, a panel of 20 protein biomarkers that 29 accurately predicted incident T2DM was identified with a significant incremental 30 improvement over traditional risk factors. Finally, a Mendelian randomization analysis 31 provided support for a causal role of 48 proteins in the development of T2DM, which could 32 be of particular interest as novel therapeutic targets. 33 34 for age and sex, we identified 520 unique proteins that were significantly associated with 84 prevalent T2DM after Bonferroni correction for multiple hypothesis testing (P adj < 0.05), with 85 the strongest associations observed for ARFIP2, MXRA8 and CPM ( Fig. 1a, Table S2). In a 86 second model including adjustment for body mass index (BMI), 322 proteins remained 87 statistically significant ( Table S2). Many of the proteins were inter-correlated, with pairwise 88 Pearson's r ranging from -0.60 to 0.97 ( Fig. S2a). A pathway and gene ontology (GO) 89 enrichment analysis of all 520 proteins associated with prevalent T2DM revealed an 90 enrichment of proteins involved in extracellular matrix (ECM)-receptor interaction, 91 complement and coagulation cascades, metabolic processes and extracellular region (Fig. 92 S3a, Table S3). We furthermore found the genes encoding the 520 prevalent T2DM-93 associated proteins to be enriched for high expression in liver, followed by other tissues that 94 included kidney, gastrointestinal tract and pancreas ( Fig. S4a). Thus, the diabetic state is 95 reflected in a major shift in the serum proteome that is involved in metabolic, inflammatory 96 and ECM processes. 97 98 Serum protein profile of incident T2DM 99The serum protein profiles of T2DM patients observed in the cross-sectional analysis 100 described above may represent shifts that occurred either before or after the onset of the 101 disease. To identify serum protein signatures that preceded the onset of T2DM, we next 102 focused our analysis on the 2,940 non-diabetic AGES participants who participated in a 103 second study visit (AGESII) 5-years after the baseline visit, of which 112 develop...

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“…Tissues were fixed in 4% formaldehyde, then sectioned and stained with H&E or van Gieson (VG). The immunofluorescence staining of pancreatic tissues was performed as previously reported (Li et al, ). Livers were frozen at −80°C and stained with oil red O or ROS fluorescent probe‐dihydroethidium.…”

Section: Methodsmentioning

confidence: 99%

Alogliptin improves survival and health of mice on a high‐fat diet

Zhu

Xiang³

et al. 2019

Aging Cell

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Alogliptin is a commonly prescribed drug treating patients with type 2 diabetes. Here, we show that long‐term intervention with alogliptin (0.03% w/w in diet) improves survival and health of mice on a high‐fat diet. Alogliptin intervention takes beneficial effects associated with longevity, including increased insulin sensitivity, attenuated functionality decline, decreased organ pathology, preserved mitochondrial function, and reduced oxidative stress. Autophagy activation is proposed as an underlying mechanism of these beneficial effects. We conclude that alogliptin intervention could be considered as a potential strategy for extending lifespan and healthspan in obesity and overweight.

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GDF11 Attenuates Development of Type 2 Diabetes via Improvement of Islet β-Cell Function and Survival

Cited by 67 publications

References 50 publications

Protection from β-cell apoptosis by inhibition of TGF-β/Smad3 signaling

Protection from β-cell apoptosis by inhibition of TGF-β/Smad3 signaling

Deep serum proteomics reveal biomarkers and causal candidates for type 2 diabetes

Alogliptin improves survival and health of mice on a high‐fat diet

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