Akt/mTOR Role in Human Foetoplacental Vascular Insulin Resistance in Diseases of Pregnancy

Table 1

Effect of pathologies of pregnancy on insulin signalling in the human foetoplacental vasculature.

Cell or tissue	Molecule or activity	Effect of the pathology	Effect of insulin	References
Preeclampsia
Placenta (EOPE)	p44/42^mapk	Increase	na	[57]
Placenta (EOPE)	ET-1, ETA, and ETB (mRNA)	Increase	na	[108]
Placenta	Akt-Ser^473	Decrease	na	[61]
Placenta	eNOS	Increase	na	[109]
Placenta (LOPE)	β-IR, IRS-1-Tyr^465, IRS-1-Ser^312, and IRS-2-Ser^731	No effect	Increase	[65]
Placenta (LOPE)	Akt-Ser^473	No effect	Increase	[110]
HUVECs (LOPE)	eNOS-Thr^495, eNOS-Ser^1177	Increase	Restored	[20]
HUVECs (LOPE)	eNOS-Ser^1177	Increase	na	[111]
HUVECs (EOPE)	eNOS	Decrease	na	[111]
HUVECs	eNOS	Decrease	na	[112]
HUVECs (LOPE)	L-Arginine transport	Increase	Restored	[20]
HUVECs (LOPE)	hCAT-1	Increase	Increase	[20]
Gestational diabetes mellitus
Placenta	IRs	Increase	na	[113]
Placenta (insulin therapy)	β-IR	Increase	Restored	[90]
Placenta	IRS-1	Increase	na	[113]
Placenta (insulin therapy)	IRS-1	Increase	Restored	[90]
Placenta (insulin therapy)	IRS-2	Increase	Increase	[90]
Placenta	PI3K p85α	Increase	Restored	[90]
Placenta	PI3K p85α	Increase	na	[113]
Placenta (insulin therapy)	PI3K p110	Increase	No effect	[90]
Placenta	mTOR-Ser^2448, S6K1-Thr^421/Ser^424	Increase	na	[83]
Placenta	S6 K1-Thr^389, 4EBP1-Thr^37/46	Increase	na	[114]
Placenta	4EBP1-Thr^37/46	Increase	na	[83]
Placenta	AMPK (mRNA)	Decrease	na	[88]
Placenta	Adiponectin	Decrease	na	[115]
Placenta	TNF-α	Increase	na	[85, 116]
Placenta (insulin therapy)	TNF-α	Unaltered	na	[86]
Placenta	IL-1β	Increase	na	[116]
Placenta	Leptin receptor	Increase	na	[88]
Trophoblast	Leptin receptor	Increase	na	[87]
HUVECs	IR-A (mRNA)	Increase	Restored	[21]
HUVECs	Akt-Ser^473	No effect	Increase	[80]
HUVECs	eNOS, eNOS-Ser^1177	Increase	Restored	[80]
HUVECs	p44/42^mapk-Thr^202/204	Increase	Restored	[80]
HUVECs (insulin therapy)	eNOS, eNOS-Ser^1177	Increase	Restored	[117]
HUVECs	hENT1, adenosine transport	Decrease	Increase	[21, 80]
HUVECs	L-Arginine transport	Increase	Restored	[82]
HUVECs (insulin therapy)	L-Arginine transport	Increase	Restored	[117]
hPMECs	p44/42^mapk-Thr^202/204, Akt-Ser^473	Decrease	Restored	[118]
hPMECs	IR-A (mRNA)	Decrease	Restored	[118]
hPMECs	IR-B (mRNA)	Increase	Restored	[118]
hPMECs	hENT1	Decrease	No effect	[118]
hPMECs	hENT2	Decrease	Restored	[118]
hPMECs	hENT1 transport activity	Decrease	No effect	[118]
hPMECs	hENT2 transport activity	Decrease	Restored	[118]
Umbilical cord plasma	Leptin	Increase	na	[88]
Umbilical cord plasma	Adiponectin	Decrease	na	[89]
Pregestational maternal obesity
Placenta	AMPK-Thr^172	Decrease	na	[102, 103]
Placenta	AMPK	Decrease	na	[103]
Placenta	S6 K1-Thr^389	Increase	na	[88, 119]
Placenta	JNK-Thr^183/Tyr^185	Increase	na	[119]
Placenta	mTOR (mRNA)	Decrease	na	[102, 103]
Placenta	IRS-1 (mRNA)	Decrease	na	[103]

AMPK: adenosine monophosphate protein kinase; AMPK-Thr¹⁷²: AMPK phosphorylated at threonine 172; S6K1: S6 kinase 1; S6K1-Thr⁴²¹/Ser⁴²⁴: S6K1 phosphorylated at threonine 421 and serine 424; S6K1-Thr³⁸⁹: S6K1 phosphorylated at threonine 389; JNK: c-Jun N-terminal kinases; JNK-Thr¹⁸³/Tyr¹⁸⁵: JNK phosphorylated at threonine 183 and tyrosine 185; mTOR: mammalian target of rapamycin; IRS-1: insulin receptor substrate 1; IRS-1-Tyr⁴⁶⁵: IRS-1 phosphorylated at tyrosine 465; IRS-1-Ser³¹²: IRS-1 phosphorylated at serine 312; IRS-2: insulin receptor substrate 2; IRS-2-Ser⁷³¹: IRS-2 phosphorylated at serine 731; EOPE: early-onset preeclampsia; LOPE: late-onset preeclampsia; p44/42^mapk: 44 and 42 kDa mitogen-activated protein kinases; p44/42^mapk-Thr^202/204: p44^mapk phosphorylated at threonine 202 and p42^mapk phosphorylated at threonine 204; Akt: protein kinase B/Akt; Akt-Ser⁴⁷³: Akt phosphorylated at serine 473; eNOS: endothelial nitric oxide synthase; eNOS-Thr⁴⁹⁵: eNOS phosphorylated at threonine 495; eNOS-Ser¹¹⁷⁷: eNOS phosphorylated at serine 1177; IRs: insulin receptors; IR-A: insulin receptor A; IR-B: insulin receptor B; β-IR: insulin receptor β-subunit; PI3K: phosphatidylinositol 3 kinase; PI3K p85α: p85α regulatory subunit of PI3K; PI3K p110: p110 catalytic subunit of PI3K; EGFR: epidermal growth factor receptor; mTOR-Ser²⁴⁴⁸: mTOR phosphorylated at serine 2448; S6K1-Tyr³⁸⁹: S6K1 phosphorylated at threonine 389; 4EBP1: eukaryotic translation initiation factor 4E binding protein 1; 4EBP1-Thr^37/46: 4EBP1 phosphorylated at threonine 37 and 46; TNF-α: tumour necrosis factor α; AP1: activator protein 1; NF-κB: nuclear factor-kappa B; ET-1: endothelin 1; ET_A: endothelin receptor type A; ET_B: endothelin receptor type B; IL-1β: interleukin 1β; hCAT-1: human cationic amino acid transporter 1; hENT1: human equilibrative nucleoside transporters 1; hENT2: human equilibrative nucleoside transporters 2; HUVECs: human umbilical vein endothelial cells; hPMECs: human placental microvascular endothelial cells. Cells incubated with insulin in the presence of ZM-241385 (A_2AAR antagonist). GDM mothers were obese. Results include GDM mother under diet and insulin therapy. GDM mother on oral insulin-sensitizing antidiabetic undefined medication. na: not assayed.