Table 2.

Interventional studies with arginase inhibitors in DM and DM complications.

Arginase inhibitors	Chemical class	Dose range	Models	Effects	Refs.
Chemical arginase inhibitors
NOHA	Nω-OH-based arginine analog	10 μmol/L, 30 min (ex vivo)	Patients with DM	↑Restoration of endothelium-dependent agonist-induced dilation in coronary arterioles of patients with DM	[15]
nor-NOHA		25 mg/kg/day 4 weeks (Ip)	Zucker rats with obese	↓Prevention in the development of hypertension ↓Reduction in body weight and insulin resistance	[12]
		1 and 3 mmol/L, 20 min (ex vivo)	RBCs from diabetes mice	↑Improvement in postischemic-myocardial function	[153]
		30 mg/kg, 24 days (Ip)	Female mouse with T1DM	↓Reduction in the incidence of autoimmune diabetes	[154]
		0.1 mg/min, 20 min (Ia)	Male patients with CAD or CAD+T2DM	↑Improvement in endothelial function following ischemia-reperfusion	[17]
		0.1 mmol/L, 90 minutes intraluminal	Pigs with DM	↑Improvement in endothelial function of retinal arterioles	[149]
		100 mg/kg, 15 min (Iv)	Rat with T2DM	↑Improvement in myocardial microvascular function	[111]
		1 mL/min, 2 h (Ia)	Patients with type 2 diabetes+CAD	↑Improvement in endothelial function irrespective of glucose-lowering regimen	[16]
		0.1 mg/min, 2 h (Ia)	Patients with T2DM and microvascular dysfunction	↑Improvement in endothelium-dependent microvascular dilatation	[104]
ABH	Boronic acid-based arginine analog	8 mg/kg, 5 days (Sc)	Mouse with T1DM	↑ Improvement in retinal endothelial function	[124]
		10 mg/kg/day, 1 month (Po)	Mice with obesity and T2DM	↓Prevention in diabetic bone complications	[156]
BEC		50 μmol/L, 30 minutes (ex vivo)	Mouse with T1DM	↑Improvement in endothelial function	[139]
		2.3 mg/kg/day， 6 weeks~12 weeks (Sc)	Mice with T1DM	↑Protection of kidney tissue by eNOS-dependent ↑Recruitment in kidney macrophage by eNOS-independent	[120, 121]
		100 μmol/L, 45 min (ex vivo)	Mouse and rat with DM	↑Improvement in retinal vascular endothelial function	[124]
		10−4 mol/L (ex vivo)	Mice with DM	↑Improvement in cavernosal relaxation	[158]
DFMO	L-ornithine analog	50 μmol/L, 1 h (ex vivo)	Rat with T1DM	↑Improvement in endothelial function	[52]
Natural arginase inhibitors
L-citrulline	—	250 μmol/L, 1 h (ex vivo), 2 g/kg/day, 8 weeks (Po)	H4IIE cell and SHRSP.Z-Leprfa/IzmDmcr rats	↑Improvement in insulin sensitivity	[49]
		2000 mg/day day, 1 month (Po)	Patients with T2DM	↑Improvement in H1Ac levels	[162]
		1 mmol/L (ex vivo)	Rat with T1DM	↑Improvement in endothelial function	[52]
		1 mmol/L， 1 h (ex vivo)	Rats with T1DM	↓Reduction in hypertension	[113]
L-norvaline	L-valine analog	20 mg/kg/day, continuing every third day for five weeks (Ip)	Mice with HFD/DM	↓Reduction in blood glucose levels	[166]
		10 mg/kg, 30 days (Ip)	Adult male rats with DM	↑Improvement in the diabetic sexual impairment	[168]
Quercetin	Polyphenolic compounds	5 and 10 mg/kg, 21 days (Ip)	Zebrafish with type 1 DR	↑Remission in diabetic retinopathy	[173]
Moringa oleifera		5% of Moringa concentrate (MC), 12 weeks	Mice with VHFD	↑Improvement in glucose tolerance and insulin sensitivity	[175]
		4% of Moringa oleifera, 14 days	Male rats with DM	↑Improvement in diabetic-induced ED	[176]
Semen cuscutae	Traditional Chinese medicine	0.5~10 μg/mL (ex vivo)	Rats with HFD	↓Reduction in hepatic lipid metabolism and systemic adiposity	[182]
HGWWD		60 g/kg/d, 2 weeks (gavage)	Mice with T1DM	↑Improvement in vascular dysfunction	[183]
XSF		3 g/kg/d， 6 weeks (gavage)	Mice with T1DM	↓Prevention in diabetic kidney damage	[184]

Ia: intra-arterial; Ic: Intracoronar; Iv: intravenous; Ip: intraperitoneal; Sc: subcutaneous; Po: peros.