Pharmacologic or genetic activation of SIRT1 attenuates the fat-induced decrease in beta-cell function in vivo

Abstract

Background: There is evidence that sirtuin 1 (SIRT1), a key regulator of nutrient metabolism, increases β-cell secretory function. Excess circulating fat, as seen in obesity, has been shown to decrease β-cell function, an effect that may involve decreased SIRT1 activity. Consequently, SIRT1 activation may increase β-cell function in conditions of elevated plasma-free fatty acid levels. Here we attempted to attenuate the lipid-induced decrease in β-cell function in vivo using pharmacological and genetic models of SIRT1 activation.

Methods: Our pharmacologic model involved 48 h intravenous infusion of Wistar rats with either saline or oleate with or without the SIRT1 activator resveratrol. Additionally, we used β-cell-specific SIRT1 overexpressing (BESTO) mice and wild-type littermates infused for 48 h intravenously with either saline or oleate. In both models, the infusion period was followed by assessment of β-cell function using the hyperglycemic clamp method.

Results: Lipid infusion resulted in a significant decrease in β-cell function as expected in both rats (p < 0.05) and mice (p < 0.001). Both models of SIRT1 activation, which did not alter β-cell function in the absence of fat, resulted in partial protection from the fat-induced decrease in β-cell function (NS vs. control).

Conclusion: These results suggest that SIRT1 is a therapeutic target in decreased β-cell function specifically induced by fat.

Fig. 1. Resveratrol partially prevents oleate-induced decrease in glucose infusion rate during a hyperglycemic clamp.

Plasma FFA levels (a), plasma glucose levels (b), and glucose infusion rate (Ginf) (c) during the two-step hyperglycemic clamp. Rats were infused with: (1) Saline (SAL, n = 8), (2) Oleate alone (OLE, n = 7) at 1.4 µmol/min, (3) OLE + Resveratrol at 0.025 mg/kg min (OLE + RSV, n = 6), and (4) RSV alone (RSV, n = 9). Data are means ± SEM. a ^#p < 0.05 OLE vs. SAL and RSV throughout,⁺p < 0.05 OLE + RSV vs. SAL and RSV basal state and 2nd step of clamp. c ***p < 0.001 OLE vs. SAL, ^$$p < 0.01 OLE vs. RSV

Fig. 2. Resveratrol partially prevents oleate-induced decrease in β-cell function.

Plasma insulin levels (a), plasma C-peptide levels (b), sensitivity index (c), and disposition index (d) during the two-step hyperglycemic clamp. Rats were infused with: (1) saline (SAL, n = 8), (2) oleate alone (OLE, n = 7) at 1.4 µmol/min, (3) OLE + resveratrol at 0.025 mg/kg min (OLE + RSV, n = 6), and (4) RSV alone (RSV, n = 9). Significance is indicated during the last 30 min of each clamp step. Data are means ± SEM. a–d ^#p < 0.05 OLE vs. SAL and RSV, *p < 0.05 OLE vs. SAL, **p < 0.01 OLE vs. SAL

Fig. 3. Oleate-induced decrease in glucose infusion rate in wildtype mice is partially prevented in BESTO mice.

Plasma free fatty acid levels (a), plasma glucose levels (b), and glucose infusion rate (Ginf) (c) during the one-step hyperglycemic clamp. BESTO mice (TG) or wildtype (WT) littermates were treated for 48 h with either (1) saline (WTSAL, n = 8; TGSAL, n = 7) or (2) oleate at 3.9 μmol/min (WTOLE, n = 8; TGOLE, n = 8). Data are means ± SEM and refer to the last 30 min of the basal period and clamp. a ^#p < 0.05 WTOLE vs. WTSAL and TGSAL, ⁺⁺p < 0.01 TGOLE vs. TGSAL and WTSAL. b ^#p < 0.05 WTOLE vs. WTSAL and TGSAL, ⁺p < 0.05 TGOLE vs. TGSAL and WTSAL. c Δp < 0.05 vs. all

Fig. 4. Oleate-induced decrease in β-cell function in wildtype mice is partially prevented in BESTO mice.

Plasma insulin levels (a), plasma C-peptide levels (b), sensitivity index (c), and disposition index (d) during the one-step hyperglycemic clamp. BESTO mice (TG) or wildtype (WT) littermates were treated for 48 h with either (1) saline (WTSAL, n = 8; TGSAL, n = 7) or (2) oleate at 3.9 μmol/min (WTOLE, n = 8; TGOLE, n = 8). Data are means ± SEM and refer to the last 30 min of the basal period and clamp. a–d ^##p < 0.01, ^###p < 0.001 WTOLE vs. WTSAL and TGSAL, ⁺⁺⁺p < 0.001 TGOLE vs. TGSAL and WTSAL