TABLE 1.
Previous studies that identified the effect of GLP-1 modulation in human or animal or cell-based models are summarized1
| Key findings | Reference | |
|---|---|---|
| Human studies | ||
| Subjects and methods | ||
| Twenty-four men with T2D were randomly assigned to sitagliptin or voglibosetreatment for 6 wk in study 1, and 42 T2D patients were treated with sitagliptin oralogliptin for 6 wk in study 2. Endothelial function was assessed by FMD of thebrachial artery. | Sitagliptin significantly reduced flow-mediated vasodilatation of the brachial artery and improved diabetic status, but voglibose did not affect FMD in study 1. Both sitagliptin and alogliptin improved glycemic control and significantly attenuated FMD in study 2. | (16) |
| For 26 healthy young volunteers, brachial artery diameter and blood flow velocity inthe skeletal and cardiac muscle were determined after the infusion of GLP-1. | Acute GLP-1 infusion in healthy humans resulted in skeletal and cardiac muscle microvascular recruitment as well as an increase in brachial artery diameter and blood flow. | (17) |
| Patients with newly diagnosed and treatment-naive T2D received with liraglutide(n = 30) or metformin (n = 30). Changes in diverse metabolic parameters andvascular markers were measured 6 mo after treatment. | Liraglutide treatment significantly reduced arterial stiffness, oxidative stress burden, and NT-proBNP level, and improved left ventricular longitudinal myocardial strain and strain rate, left ventricular twisting–untwisting, and endothelial function. | (77) |
| Patients with T2D were either treated with sitagliptin (n = 24) or untreated (n = 24).Changes in the parameter related to immune and metabolism were examined usingperipheral blood. | Sitagliptin significantly decreased the level of SAA LDL, C-reactive protein, and TNF-α, but increased IL-10 and GLP-1 in serum. Sitagliptin also decreased TNF-α expression but increased IL-10 expression in peripheral blood monocytes. | (78) |
| Metformin-treated patients with T2D were randomized, and treated with exenatide(n = 30) or insulin glargine (n = 30). On-drug meal test (postprandial glucose, lipidsand lipoproteins, and oxidative stress markers) was performed. | One-year treatment with exenatide significantly reduced prandial glucose, triglycerides, apoB-48, VLDL-C, FFA, and MDA excursions. Insulin glargine predominantly reduced fasting glucose, FFA, and MDA. | (84) |
| Thirty-five subjects with impaired glucose tolerance (n = 20) or recent-onset T2D(n = 15) were administered exenatide or normal saline, and metabolic parameterswere measured from serum or plasma. | Exenatide reduced postprandial elevation of triglycerides, apoB-48, apoC-III, NEFA, and RLP cholesterol and RLP triglyceride. | (85) |
| Twenty-eight patients with overweight and obesity with T2D were treated withliraglutide, and body composition and metabolic markers were measured after24 wk of the treatment. | Liraglutide treatment led to the reduction of fat mass, android fat, trunk fat, and appetite by improving the lipid profile, glucose control, and insulin sensitivity in patients with T2D. | (101) |
| Thirty patients with T2D were treated with exenatide (n = 17) or placebo (n = 13), andserum glucose profiles were measured for 2 wk. | Exenatide was associated with reduced glucose concentrations at multiple time points during 24 h, decreased overall hyperglycemic exposure, decreased postprandial triglyceride excursions in the patients with T2D. | (102) |
| Fifteen healthy male subjects underwent 2 studies each (injection with exenatide vsplacebo), 4 to 6 wk apart in random order, and blood samples were measured atmultiple time points. | Exenatide suppresses plasma concentration of apoB-48 but not apoB-100, independent of changes in body weight, satiety, glucagon, and FFA concentrations. | (103) |
| Fourteen healthy male volunteers were administered either GLP-1(7–36) or placeboover 390 min in random order. Blood samples were measured at multiple timepoints. | GLP-1 administration lowered fasting and postprandial glycemia, abolished the postprandial increase in triglyceride concentrations, delayed gastric emptying, and lowered postprandial plasma concentrations of NEFA. | (104) |
| Animal and cell-based studies | ||
| Experimental model and methods | ||
| Rats were stereotaxically implanted with a bilateral guide cannula directed at the VTAalone or together with a unilateral cannula directed at either the NAc core or shelland injected with exendin-4 or exendin(9–39). | GLP-1R activation in the VTA and NAc decreased food intake and body weight, but blockage of GLP-1R signaling significantly increased food intake. | (71) |
| Spontaneously hypertensive rats were treated with sitagliptin for 2 wk. | Sitagliptin treatment improved endothelial function in renal arteries of spontaneously hypertensive rats via the sequential activation of the PKA/LKB1/AMPKα/eNOS axis. | (79) |
| Male hamsters were administered sitagliptin, exendin-4, or exendin(9–39). | Sitagliptin decreased fasting plasma triacylglycerol, postprandial TRL-triacylglycerol, TRL-cholesterol, and TRL-apoB-48. | (87) |
| Mice received a transvenous injection of exendin-4, after a 60-min focal cerebralischemia. Infarct volume, neurologic deficit score, various physiologic parameters,and immunohistochemical analyses were performed at several time points afterischemia. | Exendin-4 treatment reduced infarct volume, improved functional deficit, and suppressed oxidative stress, inflammatory response, and cell death after reperfusion, showing the neuroprotective effect of exendin-4 against ischemic injury. | (89) |
| For wild-type, global, as well as endothelial and myeloid cell-specific knockout mice ofthe GLP-1R, arterial hypertension was induced by angiotensin II and liraglutide wasadministered. | Liraglutide improved blood pressure, cardiac hypertrophy, endothelial dysfunction, vascular fibrosis, and oxidative stress in angiotensin II–induced arterial hypertension. | (91) |
| High-fat-diet–fed mice were treated with liraglutide for 1 wk. | Liraglutide treatment activated cardioprotective pathways, prevented high-fat-diet–induced insulin resistance and inflammation, reduced monocyte vascular adhesion, and improved cardiac function by activating the AMPK signaling pathway. | (92) |
| ApoE-deficient male mice were treated with liraglutide or exendin(9–39). | Liraglutide treatment improved endothelial function, increased eNOS expression, and reduced ICAM-1 expression in aortic endothelium. | (96) |
| Exendin(9–39) or GLP-1(7–36) was delivered through intracerebroventricular orsubcutaneous infusion on male mice. | GLP-1 system in the central nervous system loses the capacity to modulate adipocyte metabolism in obese states, suggesting an obesity-induced adipocyte resistance to the central nervous system GLP-1. | (106) |
| Platelets obtained from 72 healthy volunteers were incubated with GLP-1(7–36),GLP-1(9–36), or liraglutide. | GLP-1(7–36), GLP-1(9–36), and liraglutide exerted platelet inhibitory effects independently of GLP-1R. | (74) |
| The effects of liraglutide on inflammation were determined in cultured human aorticendothelial cells. | Liraglutide exerted anti-inflammatory effects in endothelial cells through increasing cellular calcium concentration and activating the AMPK-dependent pathway. | (90) |
| Primary cultured mouse cortical astrocytes were treated with exendin-4 orexendin(9–39). | Exendin-4 treatment reduced ischemia-induced inflammation and blood–brain barrier breakdown. | (97) |
1AMPKα, AMP-activated protein kinase α subunit; eNOS, endothelial nitric oxide synthase; FFA, free fatty acid; FMD, flow-mediated dilatation; GLP-1, glucagon-like peptide 1; GLP-1R, GLP-1 receptor; ICAM-1; intercellular adhesion molecule 1;LKB1, liver kinase B1; MDA, malondialdehyde; NAc, nucleus accumbens; NEFA, nonesterified fatty acid; NT-proBNP, N-terminal prohormone of brain natriuretic peptide; PKA, protein kinase A; RLP, remnant lipoprotein; SAA, serum amyloid A; TRL, triacylglycerol-rich lipoprotein; T2D, type 2 diabetes; VLDL-C, VLDL cholesterol; VTA, ventral tegmental area.