Humanin and diabetes mellitus: A review of in vitro and in vivo studies

Table 1 In vivo and in vitro studies on humanin and diabetes mellitus

Ref.	Study model	HN dose	Treatment duration	Results
In vitro studies
Rochette et al[51], 2014 (HN)	NIT-1 cells	1-10000 nmol/L	24 h	Reduced apoptosis caused by serum starvation in NIT-1 cells and decreased cytokine-induced apoptosis
Hunter and Jones[19], 2015 (HNGF6A)	Isolated islets and cultured murine β cell line	50 ng/ml	15-120 min	Enhanced glucose-stimulated insulin secretion
Qin et al[57], 2018 (HNG)	HUVECs	1 μΜ	3 h	Inhibited cell death, nucleus pyknosis and deformation. Diminished the expression of cleaved PARP (which reflects the level of apoptosis as well as ROS) Decreased the level of bax (a pro-apoptotic protein). Increased bcl-2 (an anti-apoptotic agent)
Miller et al[11], 2020 (HNG)	HEK293 and SH-SY5Y cells	100 μM	30 min	Is a major GP130 agonist which acts through the GP130/IL6ST receptor complex and activates AKT, ERK1/2, and STAT3
Wang et al[50], 2010 (HN)	Pancreatic MIN6 β-cells	25, 50 and 100 μΜ	24h or48 h	Increased the expression of PGC-1α.Promoted mitochondrial biogenesis. Caused the phosphorylation of AMPK, improved mitochondrial respiration and stimulated ATP generation
Kim et al[60], 2007 (HN)	HUVECs	200 μM	24 h	Promoted the expression of KLF2.Reduced the expression of VCAM-1 and E-selectin; Impeded the secretion of TNF-α and IL-1β
In vivo studies
Animals
Hunter and Jones [19], 2015 (HNGF6A)	Sprague−Dawley rat	0.07 mg/kg/h	2-30 min	Improved insulin sensitivity and help in decreasing blood glucose level
Gong et al[20], 2014 (HN)	Sprague−Dawley rat	0.375 mg/kg/h	360 min	Decreased blood glucose in Sprague−Dawley rats by STAT-3 phosphorylation
Gong et al[20], 2014 (HNGF6A)	Zucker diabetic fatty rat	0.05 mg/kg/h	90-240 min	Decreased blood glucose in Zucker diabetic fatty rats
Rochette et al[51], 2014 (HN)	NOD mice	0.7 mg/kg/day	6 wk20 wk	Decreased lymphocyte infiltration in mice pancreata; Delayed or prevented the onset of diabetes in NOD mice (when the treatment was extended up to 20 wk)
Miller et al[11], 2020 (HNG)	Male C57BL/6 mice	5 mg/kg/day	2 wk	Old mice, but not young mice, showed an increase in phosphorylation in AKT and ERK1/2 in the hippocampus
Humans
Muzumdar et al[61], 2006	Participants attending a diabetes complications screening clinic	-	-	A significant decrease in HN was observed in the IFG group compared to control
Ha[71], 2006	Uncomplicated T1DM patients	-	-	Plasma HN levels were significantly higher in T1D men by comparison with the healthy control men
do Nascimento et al[72], 2013	Pregnant women with and without GDM	-	-	Serum HN levels were significantly lower in women with GDM compared to controls
Hashimoto et al[42], 2003	Normal, prediabetes and diabetes subjects	-	-	Serum HN concentrations are lower in T2DM and correlate with HbA1c

HUVECs: Human umbilical vein endothelial cells; PARP: Poly ADP-ribose polymerase; ROS: Reactive oxygen species; ERK1/2: Extracellular signal-regulated kinase 1/2; STAT3: Signal transducer and activator of transcription 3; PGC-1α: PPAR-γ coactivator-1α; KLF2: Krüppel-like factor 2; VCAM-1: Vascular cell adhesion molecule 1; TNF-α: Tumor necrosis factor-α; IL-1β: Interleukin-1β; IFG: Impaired fasting glucose; T1DM: Type 1 diabetes mellitus; GDM: Gestational diabetes mellitus.