Increased insulin sensitivity and reduced micro and macro vascular disease induced by 2-deoxy-D-glucose during metabolic syndrome in obese JCR: LA-cp rats

Abstract

Background and purpose: The metabolic syndrome, characterized by obesity, insulin resistance and dyslipidemia, is a major cause of cardiovascular disease. The origins of the syndrome have been hypothesized to lie in continuous availability of energy dense foods in modern societies. In contrast, human physiology has evolved in an environment of sporadic food supply and frequent food deprivation. Intermittent food restriction in rats has previously been shown to lead to reduction of cardiovascular risk and a greater life span. The non-metabolizable glucose analogue, 2-deoxy-D-glucose (2-DG) is taken up by cells and induces pharmacological inhibition of metabolism of glucose. We hypothesized that intermittent inhibition of glucose metabolism, a metabolic deprivation, may mimic intermittent food deprivation and ameliorate metabolic and pathophysiological aspects of the metabolic syndrome.

Experimental approach: Insulin resistant, atherosclerosis-prone JCR:LA-cp rats were treated with 2-DG (0.3% w/w in chow) on an intermittent schedule (2 days treated, one day non-treated, two days treated and two days non-treated) or continuously at a dose to give an equivalent averaged intake.

Key results: Intermittent 2-DG-treatment improved insulin sensitivity, which correlated with increased adiponectin concentrations. Further, intermittent treatment (but not continuous treatment) reduced plasma levels of leptin and the inflammatory cytokine IL-1 beta. Both 2-DG treatments reduced micro-vascular glomerular sclerosis, but only the intermittent schedule improved macro-vascular dysfunction.

Conclusions and implications: Our findings are consistent with reduction in severity of the metabolic syndrome and protection against end stage micro- and macro-vascular disease through intermittent metabolic deprivation at a cellular level by inhibition of glucose oxidation with 2-DG.

Figure 1

Body weight (a) and food intake (b) of 2-DG-treated and control JCR:LA-cp rats. Data are mean±s.e.m., 10 rats in each group. The continuously treated group had significantly greater body weight than the cp/cp control rats at the end of the experiment (P<0.001). In (b), rats treated with 2-DG intermittently consumed more food on the days when they were given dietary 2-DG (P<0.001).

Figure 2

Effects of 2-DG treatment on plasma insulin (a) and glucose (b) levels in JCR:LA-cp rats, fasted and in response to a meal challenge. Data are mean±s.e.m., 10 rats in each group. ^*P<0.05; ^**P<0.01 vs cp/cp control.

Figure 3

Fasting plasma lipid concentrations in JCR:LA-cp rats treated with 2-DG. ^*P<0.05; ^***P<0.001 vs cp/cp control.

Figure 4

Regression analysis of plasma concentrations of adiponectin and 30 min insulin response to test meal of cp/cp rats. The slope of the regression line is significant (P<0.025).

Figure 5

Plasma concentrations of IL-1β of JCR:LA-cp rats, treated with 2-DG. ^**P<0.005 vs cp/cp control.

Figure 6

Urine albumin/creatinine ratio (a) and fraction of glomeruli exhibiting sclerosis (b) in 2-DG–treated rats. ^*P<0.02; ^**P<0.01; ^***P<0.005; P<0.0001 vs cp/cp control animals.

Figure 7

Contractile dose response to PE of aortic rings from cp/cp and +/? rats. (a), in the absence of L-NAME; (b), in the presence of L-NAME. Data are mean±s.e.m., 10 rats in each group. There are significant differences in maximum contractile response to PE between cp/cp control and 2-DG-treated rats (P<0.0001), as detailed in the text.

Figure 8

Relaxant dose response to ACh (a) and SNP (b), of aortic rings, precontracted with PE, from cp/cp and +/? rats. Data are mean±s.e.m., 10 rats in each group. The 2-DG-treated aortae showed significantly improved ACh-mediated relaxation compared with cp/cp controls (P<0.0001 and P<0.001 for intermittently and continuously treated, respectively). There was no significant difference between groups in the response to SNP.