Obesity-induced excess of 17-hydroxyprogesterone promotes hyperglycemia through activation of glucocorticoid receptor

Lu, Yan; Wang, E; Chen, Ying; Zhou, Bing; Zhao, Jiejie; Xiang, Liping; Qian, Yiling; Jiang, Jingjing; Zhao, Lin; Xiong, Xuelian; Lu, Zhiqiang; Wu, Duojiao; Liu, Bin; Yan, Jun; Zhang, Rong; Zhang, Huijie; Hu, Cheng; Li, Xiaoying

doi:10.1172/jci134485

Cited by 33 publications

(25 citation statements)

References 72 publications

(79 reference statements)

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“…The slightly diverging observations could be due to differences in ethnicity, lifestyle factors, socioeconomic status, and sample size between the populations. A recent study in men and women by Lu et al 9 reported positive correlations between 17-OHP and fasting glucose, 2hG, and HbA 1c . This was consistent with our observations of a positive association between fasting glucose and 17-OHP among women.…”

Section: Discussionmentioning

confidence: 92%

“…This was consistent with our observations of a positive association between fasting glucose and 17-OHP among women. However, the study by Lu et al 9 performed correlation analyses without appropriate confounder adjustments, therefore limiting its interpretability. A Swedish longitudinal study (n=240) conducted among opposite-sex twins found no association between progesterone and diabetes risk.…”

Section: Discussionmentioning

confidence: 99%

“…Elevated 17-OHP can induce hyperglycemia in female mice, and CYP17A1 is suggested to play a role in modulating this effect. 9 CYP17A1 converts progesterone to 17-OHP, 28 and Lu et al 9 proposed that increased 17-OHP levels due to aberrant expression of CYP17A1 in obese mice increase blood glucose via the glucocorticoid (GC) receptor. GCs can confer hyperglycemia and gluconeogenesis 29 and could explain the positive association between 17-OHP and fasting glucose in women.…”

Section: Discussionmentioning

confidence: 99%

“… 8 The product of progesterone hydrolysis, 17α-hydroxyprogesterone (17-OHP), has been observed to be elevated in patients with T2D. 9 A study conducted in pregnant women showed that administration of 17-OHP caproate, a progestin-only contraceptive used to prevent preterm delivery, was associated with increased postchallenge glucose levels and increased risk of gestational diabetes (GD). 10 Notably, women who develop GD are at higher risk of developing T2D later in life.…”

Section: Introductionmentioning

confidence: 99%

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Cross-sectional and prospective relationships of endogenous progestogens and estrogens with glucose metabolism in men and women: a KORA F4/FF4 Study

Lau

Nano

Cecil

et al. 2021

BMJ Open Diab Res Care

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IntroductionRelationships between endogenous female sex hormones and glycemic traits remain understudied, especially in men. We examined whether endogenous 17α-hydroxyprogesterone (17-OHP), progesterone, estradiol (E2), and free estradiol (fE2) were associated with glycemic traits and glycemic deterioration.Research design and methods921 mainly middle-aged and elderly men and 390 perimenopausal/postmenopausal women from the German population-based Cooperative Health Research in the Region of Augsburg (KORA) F4/FF4 cohort study were followed up for a median of 6.4 years. Sex hormones were measured at baseline using mass spectrometry. We calculated regression coefficients (β) and ORs with 95% CIs using multivariable-adjusted linear and logistic regression models for Z-standardized hormones and glycemic traits or glycemic deterioration (ie, worsening of categorized glucose tolerance status), respectively.ResultsIn the cross-sectional analysis (n=1222 men and n=594 women), in men, 17-OHP was inversely associated with 2h-glucose (2hG) (β=−0.067, 95% CI −0.120 to −0.013) and fasting insulin (β=−0.074, 95% CI −0.118 to −0.030), and positively associated with Quantitative Insulin Sensitivity Check Index (QUICKI) (β=0.061, 95% CI 0.018 to 0.105). Progesterone was inversely associated with fasting insulin (β=−0.047, 95% CI −0.088 to −0.006) and positively associated with QUICKI (β=0.041, 95% CI 0.001 to 0.082). E2 was inversely associated with fasting insulin (β=−0.068, 95% CI −0.116 to −0.020) and positively associated with QUICKI (β=0.059, 95% CI 0.012 to 0.107). fE2 was positively associated with glycated hemoglobin (HbA1c) (β=0.079, 95% CI 0.027 to 0.132). In women, 17-OHP was positively associated with fasting glucose (FG) (β=0.068, 95% CI 0.014 to 0.123). fE2 was positively associated with FG (β=0.080, 95% CI 0.020 to 0.141) and HbA1c (β=0.121, 95% CI 0.062 to 0.180). In the sensitivity analyses restricted to postmenopausal women, we observed a positive association between 17-OHP and glycemic deterioration (OR=1.518, 95% CI 1.033 to 2.264).ConclusionsInter-relations exist between female sex hormones and glucose-related traits among perimenopausal/postmenopausal women and insulin-related traits among men. Endogenous progestogens and estrogens appear to be involved in glucose homeostasis not only in women but in men as well. Further well-powered studies assessing causal associations between endogenous female sex hormones and glycemic traits are warranted.

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cross-sectional and prospective relationships of endogenous progestogens and estrogens with glucose metabolism in men and women: a KORA F4/FF4 Study

Lau

Nano

Cecil

et al. 2021

BMJ Open Diab Res Care

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“…Glucocorticoid receptor (GR) of hepatocyte is found critical for both direct and indirect transcriptional regulations of IR, hyperglycemia, gluconeogenesis and fatty liver [ 19 ]. A recent study targeting 17-hydroxyprogesterone (17-OHP), an intermediate product of steroid synthesis, pointed out the involvement of hepatic Cyp17A1/17-OHP/GR pathway in the development of IR [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

Multiple organs involved in the pathogenesis of non-alcoholic fatty liver disease

Wang

2020

Cell Biosci

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Non-alcoholic fatty liver disease (NAFLD) represents the leading cause of chronic liver disease worldwide and the anticipated health burden is huge. There are limited therapeutic approaches for NAFLD now. It’s imperative to get a better understanding of the disease pathogenesis if new treatments are to be discovered. As the hepatic manifestation of metabolic syndrome, this disease involves complex interactions between different organs and regulatory pathways. It’s increasingly clear that brain, gut and adipose tissue all contribute to NAFLD pathogenesis and development, in view of their roles in energy homeostasis. In the present review, we try to summarize currently available data regarding NAFLD pathogenesis and to lay a particular emphasis on the inter-organ crosstalk evidence.

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GMFB/AKT/TGF‐β3 in Müller cells mediated early retinal degeneration in a streptozotocin‐induced rat diabetes model

Zhu,

Li,

Zhu

et al. 2023

Glia

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Retinal degeneration, characterized by Müller cell gliosis and photoreceptor apoptosis, is considered an early event in diabetic retinopathy (DR). Our previous study proposed that GMFB may mediate diabetic retinal degeneration. This study identified GMFB as a sensitive and functional gliosis marker for DR. Compared to the wild type (WT) group, Gmfb knockout (KO) significantly improved visual function, attenuated gliosis, reduced the apoptosis of neurons, and decreased the mRNA levels of tumor necrosis factor α (Tnf‐α) and interleukin‐1β (Il‐1β) in diabetic retinas. Tgf‐β3 was enriched by hub genes using RNA sequencing in primary WT and KO Müller cells. Gmfb KO significantly upregulated the transforming growth factor (TGF)‐β3 protein level via the AKT pathway. The protective effect of TGF‐β3 in the vitreous resulted in significantly improved visual function and decreased the number of apoptotic cells in the diabetic retina. The protection of Gmfb KO in primary Müller cells against high glucose (HG)‐induced photoreceptor apoptosis was partially counteracted by TGF‐β3 antibody and administration of TGFBR1/2 inhibitors. Nuclear receptor subfamily 3 group C member 1 (NR3C1) binds to the promoter region of Gmfb and regulates Gmfb mRNA at the transcriptional level. NR3C1 was increased in the retinas of early diabetic rats but decreased in the retinas of late diabetic rats. N′‐[(1E)‐(3‐Methoxyphenyl)Methylene]‐3‐Methyl‐1H‐Pyrazole‐5‐Carbohydrazide (DS‐5) was identified as an inhibitor of GMFB, having a protective role in DR. We demonstrated that GMFB/AKT/TGF‐β3 mediated early diabetic retinal degeneration in diabetic rats. This study provides a novel therapeutic strategy for treating retinal degeneration in patients with DR.

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Obesity-induced excess of 17-hydroxyprogesterone promotes hyperglycemia through activation of glucocorticoid receptor

Abstract: dent-Newman-Keuls test was used to compare more than 2 groups. P values of less than 0.05 were considered statistically significant. Study approval. The human study was approved by the Human

Cited by 33 publications

References 72 publications

Cross-sectional and prospective relationships of endogenous progestogens and estrogens with glucose metabolism in men and women: a KORA F4/FF4 Study

Cross-sectional and prospective relationships of endogenous progestogens and estrogens with glucose metabolism in men and women: a KORA F4/FF4 Study

Multiple organs involved in the pathogenesis of non-alcoholic fatty liver disease

GMFB/AKT/TGF‐β3 in Müller cells mediated early retinal degeneration in a streptozotocin‐induced rat diabetes model

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