The Impact of Substance P on the Pathogenesis of Insulin Resistance Leading to Gestational Diabetes

Abstract

Gestational diabetes mellitus is one of the most often medical conditions during pregnancy affecting 5-6% of all pregnancies. The etiology of gestational diabetes is not clearly understood. In obesity and diabetes mellitus type 2, abnormal insulin signaling is an important agent mediating the increase of insulin resistance. Insulin receptor substrate serine phosphorylation is a time-controlled physiological reaction in insulin signaling that has been disrupted by metabolic and inflammatory stresses to support insulin resistance. Several kinases, including inhibitor of nuclear factor ĸB kinase β (IKK β), c-Jun N-terminal kinase (JNK), mammalian target of rapamycin (mTOR), protein kinase C (PKC) and ribosomal S6 protein kinase (S6K), are activated by these stimulators of insulin resistance and phosphorylate insulin receptor substrate proteins on several serine residues in an uncontrollable method. There are an increasing number of data indicating that substance P, being one of the crucial activators of these kinases, is a potent cytokine that impairs insulin signaling. Here we discuss recent studies that expand our understanding of how substance P may contribute to the development of insulin resistance. In our opinion, there are many interesting data suggesting that substance P may be a new player in the pathogenesis of this unfavorable condition, leading not only to the development of diabetes mellitus type 2, but also gestational diabetes. Since the etiology of gestational diabetes remains unclear, there is a strong need to explore new directions, including those not directly associated with the canonical knowledge regarding this pathology.

Pathogenesis of Type 2 Diabetes Mellitus

“…Gestational diabetes mellitus (GDM) is a heterogeneous pathogenic condition affecting 2-5% of all pregnant women during pregnancy [223,224] in other data is 5-6% [225]. GDM and T2DM share a common pathophysiological background, including β-cell dysfunction and IR [226,227].…”

“…The stimulators or the inducers of IR and phosphorylate insulin receptor substrate (IRS) proteins are activated in uncontrollable method several kinases, including inhibitor of nuclear factor ĸB kinase β (IKK β), c-Jun N-terminal kinase (JNK), mammalian target of rapamycin (mTOR), protein kinase C (PKC) and ribosomal S6 protein kinase (S6K). Substance P is a potent cytokine and is considered one of the crucial activators that contribute in the development of IR by impairment of insulin signaling [225]. The genetic variants in TCF7L2 is the strongest gene associated with GDM risk among other minor alleles of rs7903146 (TCF7L2), rs1225 5372 (TCF7L2), rs1799884 (-30G/A, GCK), rs5219 (E23K, KCNJ11), rs7754840 (CDKAL1), rs4402960 (IGF2BP2), rs10830963 (MTNR1B), rs1387153 (MTNR1B) and rs1801278 (Gly972Arg, IRS1) significantly associated with a higher risk of GDM.…”

Predicting metabolite-disease associations based on KATZ model

“…Gestational diabetes is one kind of common diseases which affects 5 to 6% of pregnant women [24]. There are some predicting associations which shows top 10 predicted metabolites and 9 of top 10 predicted Gestational diabetes-related metabolites have been certified (see Table 5).…”

“…There are some predicting associations which shows top 10 predicted metabolites and 9 of top 10 predicted Gestational diabetes-related metabolites have been certified (see Table 5). More and more details indicated that the Substance might be a new role which lead not only to the development of diabetes gestational diabetes, but also diabetes mellitus type 2 [24]. Although there is no clear evidence to confirm the associations between Guanidoacetic acid and Gestational diabetes, some experimental literatures show that the detection of Guanidoacetic acid is an available indicator for renal tubular dysfunction in the early phase of diabetes mellitus [25].…”

Antiinflammatory effects of aprepitant coadministration with cART regimen containing ritonavir in HIV-infected adults

“…Increased SP levels occur with obesity and diabetes in human SP and in mouse models (for review, see ref. 42). NK1R-KO mice are more resistant to the development of obesity (43); similar effects were observed using NK1R antagonists (44).…”