Plasma Progranulin Concentrations Are Increased in Patients with Type 2 Diabetes and Obesity and Correlated with Insulin Resistance

Qu, Hua; Deng, Hongkui; Hu, Zhen-ping

doi:10.1155/2013/360190

Cited by 79 publications

(106 citation statements)

References 20 publications

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“…3 Proteolytic cleavage of this precursor protein by extracellular proteases gives rise to smaller peptide fragments termed granulins (GRNs) or epithelins. 5,6,34 Consistent with previous evidences implicating the aggressive inflammation and insulin resistance, 9,11,14 we demonstrated that PGRN treatment led to the attenuated insulin signaling and ER stress, which, in turn, contributes to insulin resistance and relates with inflammation. 35,36 However, the normal function of PGRN is complex, with intact PGRN having anti-inflammatory properties, whereas GRNs have been shown to promote inflammation.…”

Section: Discussionsupporting

confidence: 90%

“…7 Moreover, circulating PGRN is significantly higher in clinical subjects with type 2 diabetes and positively correlated with macrophage infiltration in omental adipose tissue. 9,11,12 In particular, PGRN is more highly expressed in visceral adipose tissue of the insulin-resistant patients with morbid obesity than in their age-, sex-and BMI-matched insulin-sensitive counterparts. [13][14][15] Thus, PGRN may be an important modulator in a variety of glucose and energy regulation with specific effect on target tissues.…”

Section: Introductionmentioning

confidence: 99%

“…[1][2][3][4] Recently, PGRN has emerges as a novel regulator associated with proinflammatory properties and insulin resistance. [5][6][7][8][9][10] Specifically, PGRN-deficient mice exhibited resistant to diet-induced obesity and insulin insensitivity through the modulation of inflammation, whereas adipocytes exposed to PGRN have increased susceptibility to be insulin-resistant. 7 Moreover, circulating PGRN is significantly higher in clinical subjects with type 2 diabetes and positively correlated with macrophage infiltration in omental adipose tissue.…”

Section: Introductionmentioning

confidence: 99%

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Administration of progranulin (PGRN) triggers ER stress and impairs insulin sensitivity via PERK-eIF2α-dependent manner

Zhou

Liu

et al. 2015

Cell Cycle

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Progranulin (PGRN) has recently emerged as an important regulator for glucose metabolism and insulin sensitivity. However, the direct effects of PGRN in vivo and the underlying mechanisms between PGRN and impaired insulin sensitivity are not fully understood. In this study, mice treated with PGRN for 21 d exhibited the impaired glucose tolerance and insulin sensitivity, remarkable ER stress as well as attenuated insulin signaling in liver and adipose tissue but not in skeletal muscle. Furthermore, treatment of mice with phenyl butyric acid (PBA), a chemical chaperone alleviating ER stress, resulted in a significant restoration of systemic insulin sensitivity and recovery of insulin signaling induced by PGRN. Consistent with these findings in vivo, we also observed that PGRN treatment induced ER stress, impaired insulin signaling in cultured hepatocytes and adipocytes, with such effects being partially nullified by blockade of PERK. Whereas PGRN-deficient hepatocytes and adipocytes were more refractory to palmitate-induced insulin resistance, indicating the causative role of the PERK-eIF2a axis of the ER stress response in action of PGRN. Collectively, our findings supported the notion that PGRN is a key regulator of insulin resistance and that PGRN may mediate its effects, at least in part, by inducing ER stress via the PERK-eIF2a dependent pathway.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Administration of progranulin (PGRN) triggers ER stress and impairs insulin sensitivity via PERK-eIF2α-dependent manner

Zhou

Liu

et al. 2015

Cell Cycle

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“…Deficiency of the secreted protein progranulin in the central nervous system (CNS) causes neurodegeneration: the neurodegenerative disease frontotemporal dementia (FTD, see glossary) with partial progranulin deficiency and neuronal ceroid lipofuscinoisis with total deficiency [1] . In peripheral tissues, progranulin excess is linked to obesity and insulin resistance [2, 3] (Figure 1). It is unclear how alterations in progranulin levels result in such diverse disease mechanisms.…”

Section: A Progranulin Primermentioning

confidence: 99%

Progranulin: at the interface of neurodegenerative and metabolic diseases

Nguyen

Martens

et al. 2013

Trends in Endocrinology & Metabolism

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Progranulin is a widely expressed, cysteine-rich, secreted glycoprotein originally discovered for its growth factor–like properties. Its subsequent identification as a causative gene for frontotemporal dementia (FTD), a devastating early-onset neurodegenerative disease, has catalyzed a surge of new discoveries about progranulin’s function in the brain. More recently, progranulin was recognized as an adipokine involved in diet-induced obesity and insulin resistance, revealing its metabolic function. Here, we review progranulin biology in both neurodegenerative and metabolic diseases. In particular, we highlight progranulin’s growth factor–like, trophic, and anti-inflammatory properties as potential unifying themes in these seemingly divergent conditions. We also discuss potential therapeutic options for raising progranulin levels to treat progranulin-deficient FTD, as well as the possible consequences of such treatment.

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“…Progranulin levels were reported to be higher in subjects with obesity [9,10,15], type 2 diabetes [10,15] or insulin resistance [16]. In addition, progranulin levels decline during long-term weight loss intervention [17].…”

mentioning

confidence: 99%

Serum Progranulin Concentrations are not Responsive During Oral Lipid Tolerance Test and Oral Glucose Tolerance Test

et al. 2015

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The postprandial regulation of progranulin by oral uptake of lipids and carbohydrates in healthy individuals has not yet been investigated. The regulation of progranulin in 2 large cohorts of healthy volunteers during oral lipid tolerance test (OLTT; n=100) and oral glucose tolerance test (OGTT; n=100) was analyzed. One hundred healthy volunteers underwent OLTT and OGTT in an outpatient setting. Venous blood was drawn at 0 hours (h) (fasting) and at 2, 4, and 6 h in OLTT or 1 and 2 h in OGTT. A novel OLTT solution completely free of carbohydrates and protein was applied. Subjects were characterized by anthropometric and laboratory parameters. Serum concentrations of progranulin were measured by enzyme-linked immunosorbent assay (ELISA). Circulating progranulin levels remained unchanged during OLTT and OGTT. Fasting progranulin levels ranged between 31.3±8.7 and 40.6±7.7 ng/ml and were not different in subgroups addressing BMI, gender, family history, smoking habits, and hormonal contraception. There was a reciprocal correlation of progranulin with HDL (negative) and LDL cholesterol levels (positive). In healthy adults, fasting and postprandial circulating progranulin levels are not different in BMI subgroups. Oral uptake of carbohydrates and lipids does not influence circulating progranulin levels in a short-term manner. A postprandial and short-term regulation of this adipokine is absent, at least in healthy subjects. There is a negative correlation of progranulin with HDL cholesterol, but a positive correlation with LDL cholesterol. This reciprocal association might be of physiological importance for an individual's atherosclerotic risk.

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Plasma Progranulin Concentrations Are Increased in Patients with Type 2 Diabetes and Obesity and Correlated with Insulin Resistance

Cited by 79 publications

References 20 publications

Administration of progranulin (PGRN) triggers ER stress and impairs insulin sensitivity via PERK-eIF2α-dependent manner

Administration of progranulin (PGRN) triggers ER stress and impairs insulin sensitivity via PERK-eIF2α-dependent manner

Progranulin: at the interface of neurodegenerative and metabolic diseases

Serum Progranulin Concentrations are not Responsive During Oral Lipid Tolerance Test and Oral Glucose Tolerance Test

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