The circulating level of the inflammatory cytokine interleukin (IL)-6 is elevated in various insulin-resistant states including type 2 diabetes, obesity, cancer, and HIV-associated lipodystrophy. To determine the role of IL-6 in the development of insulin resistance, we examined the effects of IL-6 treatment on whole-body insulin action and glucose metabolism in vivo during hyperinsulinemic-euglycemic clamps in awake mice. Pretreatment of IL-6 blunted insulin's ability to suppress hepatic glucose production and insulin-stimulated insulin receptor substrate (IRS)-2-associated phosphatidylinositol (PI) 3-kinase activity in liver. Acute IL-6 treatment also reduced insulin-stimulated glucose uptake in skeletal muscle, and this was associated with defects in insulin-stimulated IRS-1-associated PI 3-kinase activity and increases in fatty acyl-CoA levels in skeletal muscle. In contrast, we found that co-treatment of IL-10, a predominantly anti-inflammatory cytokine, prevented IL-6 -induced defects in hepatic insulin action and signaling activity. Additionally, IL-10 co-treatment protected skeletal muscle from IL-6 and lipidinduced defects in insulin action and signaling activity, and these effects were associated with decreases in intramuscular fatty acyl-CoA levels. This is the first study to demonstrate that inflammatory cytokines IL-6 and IL-10 alter hepatic and skeletal muscle insulin action in vivo, and the mechanism may involve cytokineinduced alteration in intracellular fat contents. These findings implicate an important role of inflammatory cytokines in the pathogenesis of insulin resistance.

Direct evidence that hyperglycemia, rather than concomitant increases in known risk factors, induces atherosclerosis is lacking. Most diabetic mice do not exhibit a higher degree of atherosclerosis unless the development of diabetes is associated with more severe hyperlipidemia. We hypothesized that normal mice were deficient in a gene that accelerated atherosclerosis with diabetes. The gene encoding aldose reductase (AR), an enzyme that mediates the generation of toxic products from glucose, is expressed at low levels in murine compared with human tissues. Mice in which diabetes was induced through streptozotocin (STZ) treatment, but not nondiabetic mice, expressing human AR (hAR) crossed with LDL receptor-deficient (Ldlr -/-) C57BL/6 male mice had increased aortic atherosclerosis. Diabetic hAR-expressing heterozygous LDL receptor-knockout mice (Ldlr +/-) fed a cholesterol/cholic acid-containing diet also had increased aortic lesion size. Lesion area at the aortic root was increased by STZ treatment alone but was further increased by hAR expression. Macrophages from hARtransgenic mice expressed more scavenger receptors and had greater accumulation of modified lipoproteins than macrophages from nontransgenic mice. Expression of genes that regulate regeneration of glutathione was reduced in the hAR-expressing aortas. Thus, hAR increases atherosclerosis in diabetic mice. Inhibitors of AR or other enzymes that mediate glucose toxicity could be useful in the treatment of diabetic atherosclerosis. IntroductionAlthough people with both type 1 and type 2 diabetes develop increased atherosclerosis, which leads to more heart attacks and strokes, direct evidence that this is mediated by hyperglycemia is lacking. In part, this is because additional atherogenic factors such as lipid abnormalities and hypertension accompany the diabetes (1, 2). Efforts to demonstrate the presumed toxic effects of hyperglycemia in experimental animals have been similarly hindered (3). Diabetes has been superimposed onto wild-type and atherosclerosis-prone mice in an attempt to reproduce the relationship between diabetes and macrovascular disease. However, a clear model of diabetes-induced accelerated atherosclerosis is lacking. In several situations, genetic insulin resistance and streptozotocin-mediated (STZ-mediated) destruction of islet cells produced greater hyperlipidemia and, not surprisingly, more atherosclerosis (4). This was noted in both LDL receptorknockout (Ldlr -/-) (5, 6) and apoE-knockout mice (7). In a recent study, chow-fed Ldlr -/-diabetic mice had more atherosclerosis at the aortic root, but when these mice were fed cholesterol-containing diet, the atherosclerosis correlated with plasma cholesterol and not glucose (8). Thus, as in many previous reports, the more advanced vascular lesions in these mice were attributable to greater hyperlipidemia and not hyperglycemia or defective insulin actions.

Pancreatic β-cell failure in type 2 diabetes is associated with functional abnormalities of insulin secretion and deficits of β-cell mass. It’s unclear how one begets the other. We have shown that loss of β-cell mass can be ascribed to impaired FoxO1 function in different models of diabetes. Here we show that ablation of the three FoxO genes (1, 3a, and 4) in mature β-cells results in early-onset, maturity onset diabetes of the young (MODY)-like diabetes, with abnormalities of the MODY networks of Hnf4α, Hnf1α, and Pdx1. FoxO-deficient β-cells are metabolically inflexible, i.e., they preferentially utilize lipids rather than carbohydrates as an energy source. This results in impaired ATP generation, and reduced Ca2+-dependent insulin secretion. The present findings demonstrate a secretory defect caused by impaired FoxO activity that antedates dedifferentiation. We propose that defects in both pancreatic β–cell function and mass arise through FoxO-dependent mechanisms during diabetes progression.

Objective There are several pathways that mediate the aberrant metabolism of glucose and that might induce greater vascular damage in the setting of diabetes. The polyol pathway mediated by aldose reductase (AR) has been postulated to be one such pathway. However, it has been reported that AR reduces toxic lipid aldehydes and, under some circumstances, might be anti-atherogenic. Methods and Results Atherosclerosis development was quantified in two lines of transgenic mice expressing human AR (hAR) crossed on the apoE knockout (apoE−/−) background. The transgenes were used to increase the normally low levels of this enzyme in wild type mice. Both generalized hAR overexpression and hAR expression via the Tie 2 promoter increased lesion size in streptozotocin (STZ) diabetic mice. In addition, pharmacologic inhibition of AR reduced lesion size. Conclusion Although in some settings AR expression might reduce levels of toxic aldehydes, transgenic expression of this enzyme within the artery wall leads to greater atherosclerosis.