Abstract
Gestational diabetes mellitus (GDM) is a complex condition that involves a variety of pathological mechanisms, including pancreatic β-cell failure, insulin resistance, and inflammation. There is an increasing body of literature suggesting that these interrelated phenomena may arise from the common mechanism of endoplasmic reticulum (ER) stress. Both obesity-associated nutrient excess and hyperglycemia disturb ER function in protein folding and transport. This results in the accumulation of polypeptides in the ER lumen and impairs insulin secretion and signaling. Exercise elicits metabolic adaptive responses, which may help to restore normal chaperone expression in insulin-resistant tissues. Pharmacological induction of chaperones, mimicking the metabolic effect of exercise, is a promising therapeutic tool for preventing GDM by maintaining the body’s natural stress response. Metformin, a commonly used diabetes medication, has recently been identified as a modulator of ER-stress-associated inflammation. The results of recent studies suggest the potential use of chemical ER chaperones and antioxidant vitamins as therapeutic interventions that can prevent glucose-induced ER stress in GDM placentas. In this review, we discuss whether chaperones may significantly contribute to the pathogenesis of GDM, as well as whether they can be a potential therapeutic target in GDM treatment.
Highlights
Gestational diabetes mellitus (GDM) is traditionally defined as any level of hyperglycemia whose onset or first recognition occurs during pregnancy [1]
One of the milestones of the World Health Organization (WHO) guidelines is the strong recommendation that hyperglycemia first detected at any time during pregnancy should be categorized as either “gestational diabetes mellitus” or “diabetes mellitus in pregnancy”
We present the results of recent research, which may clarify the pathogenesis of gestational diabetes mellitus and identifying chaperone-related target mechanisms for its treatment
Summary
Gestational diabetes mellitus (GDM) is traditionally defined as any level of hyperglycemia whose onset or first recognition occurs during pregnancy [1]. It has been demonstrated that elevated maternal BMI is associated with increased maternal cytokines and with induction of the placental p38-MAPK and signal transducer-activated transcription factor-3 (STAT3) pro-inflammatory pathways [12]. The UPR mechanism is induced via three potent mediators: Double-stranded RNA-activated protein kinase (PKR)-like ER kinase (PERK)—eukaryotic initiation factor 2 subunit α (eIF2 α), which attenuates non-essential protein synthesis, and ATF6 (activating transcription factor 6) and inositol-requiring enzyme 1 (IRE1)–X-box binding protein 1 (XBP-1), which promote the synthesis of ER-resident chaperones to increase folding capacity [20]. More than a decade ago, Nakatani et al documented that endoplasmic reticulum stress, which is provoked under diabetic conditions, plays a key role in insulin resistance by modifying the expression of oxygen-regulated protein 150 (ORP150), a molecular chaperone that protects cells from ER stress [22]. Treatment with chemical chaperones, TUDCA or 4-phenylbutyrate (PBA), and GRP78 or protein disulfite isomerase (PDI)—the enzyme catalyzing protein folding [32], has been shown to ameliorate ER stress and improve insulin secretion in a rat pancreatic β-cell line expressing human IAPP [31]
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