Aims/hypothesis: Inflammation is implicated in the development of type 2 diabetes and CHD, but the trigger of inflammation is unclear. Although in vitro and animal studies support a role of elevated levels of atherosclerotic lipoproteins in the activation of inflammation, plasma cholesterol cannot predict inflammatory markers in humans. Moreover, the association between inflammatory markers and other traditional risk factors of diabetes and CHD is unclear. To increase our knowledge of in vivo regulation of inflammation, we examined the association between several traditional risk factors and inflammatory markers. We hypothesised that because apolipoprotein B (ApoB) reflects atherogenic particle number, it is the primary predictor of inflammatory status. Subjects, materials and methods: We examined the association between several traditional risk factors and plasma high-sensitivity (hs) C-reactive protein (CRP), hsTNF-α, soluble TNF receptor 1, IL-6, orosomucoid, haptoglobin and α 1 -antitrypsin in 77 non-diabetic overweight and obese postmenopausal women. Results: The inflammatory markers correlated positively with total and abdominal adiposity, blood pressure, 2-h OGTT glucose, insulin resistance, triglyceride, total/HDL cholesterol, ApoB, ApoB:apolipoprotein A1 (ApoA1) ratio and Framingham CHD risk points. They correlated negatively with ApoA1, and total, LDL and HDL cholesterol. ApoB was an independent predictor of the interindividual variation in IL-6, hsCRP, orosomucoid, haptoglobin and α 1 -antitrypsin (R 2 range 8-40%); other risk factors were less predictive. Compared with BMI-matched control subjects, women with hyperapobetalipoproteinaemia (hyperapoB) had higher hsTNF-α, IL-6, hsCRP and orosomucoid (increase 17-104%). Conclusions/interpretation: ApoB is the primary predictor of inflammatory markers in postmenopausal overweight and obese women. Given elevated levels of inflammatory markers in hyperapoB women, we hypothesise that hyperapoB women may have an increased risk of developing both CHD and diabetes.

This article is available online at http://www.jlr.org among the most common is reduced triglyceride-rich lipoprotein (TRL) clearance by peripheral tissue. White adipose tissue (WAT) is a major regulator of TRL clearance, particularly in the postprandial state ( 2-6 ). Following a meal, dietary fat enters the circulation in the form of chylomicrons, TRL with apoB48. Effi cient clearance of chylomicrons by WAT requires three sequential steps: i ) the hydrolysis of chylomicrons by endothelial lipoprotein lipase (LPL); ii ) the uptake of LPL-generated nonesterifi ed fatty acid (NEFA) by underlying adipocytes; and iii ) the utilization or storage of NEFA ( 3, 5 ). Dietary TRL remnants and NEFA that are not cleared by peripheral tissue are then taken up by the liver for utilization and resecretion as VLDL (TRL with apoB100).Healthy WAT is able to respond promptly to postprandial signals, such as insulin increasing the hydrolysis of dietary TRL and the uptake and storage of generated NEFA, thus reestablishing the homeostasis in plasma lipids. The storage versus the release of TRL-generated NEFA in human subcutaneous WAT was reported to be almost absent in the fasting state, to increase to 100% 1 h after the ingestion of a meal, and to decrease to 10-30% 6 h after the meal ( 5 ). Accordingly, delayed plasma clearance of postprandial TRL by WAT is believed to increase the infl ux of dietary TRL remnants and NEFA into nonadipose peripheral tissues, including muscle, pancreas, and liver, inducing lipotoxicity and insulin resistance ( 6-8 ). In the liver, this also leads to increased synthesis and secretion of VLDL, which further reduces chylomicron clearance due to competitive binding to LPL ( 9-14 ). Altogether, this increases the plasma concentrations of apoB-lipoproteins, which is measured as plasma apoB and represents mostly LDL particles (>90%) ( 14-16 ). Dysfunctional WAT is thus Postprandial hypertriglyceridemia is an independent risk factor for cardiometabolic disease ( 1 ). Many factors have been implicated in the etiology of hyperlipidemia;

Type 1 and type 2 diabetic patients often show elevated plasma ketone body concentrations. Because ketone bodies compete with other energetic substrates and reduce their utilization, they could participate in the development of insulin resistance in the heart. We have examined the effect of elevated levels of ketone bodies on insulin action in primary cultures of adult cardiomyocytes. Cardiomyocytes were cultured with the ketone body beta-hydroxybutyrate (beta-OHB) for 4 or 16 h, and insulin-stimulated glucose uptake was evaluated. Although short-term exposure to ketone bodies was not associated with any change in insulin action, our data demonstrated that preincubation with beta-OHB for 16 h markedly reduced insulin-stimulated glucose uptake in cardiomyocytes. This effect is concentration dependent and persists for at least 6 h after the removal of beta-OHB from the media. Ketone bodies also decreased the stimulatory effect of phorbol 12-myristate 13-acetate and pervanadate on glucose uptake. This diminution could not be explained by a change in either GLUT-1 or GLUT-4 protein content in cardiomyocytes. Chronic exposure to beta-OHB was associated with impaired protein kinase B activation in response to insulin and pervanadate. These results indicate that prolonged exposure to ketone bodies altered insulin action in cardiomyocytes and suggest that this substrate could play a role in the development of insulin resistance in the heart.

There is a strong positive correlation between insulin resistance and cardiac diseases. We have already shown that chronic exposure to the ketone body beta-hydroxybutyrate (OHB) decreases insulin-mediated activation of protein kinase B (PKB) and glucose uptake in cardiomyocytes. To gain further insights into the mechanism underlying ketone body-induced insulin resistance, we examined whether OHB alters activation of the insulin-signaling cascade and whether the insulinomimetic agent vanadate could bypass insulin resistance and stimulate glucose uptake in these cells. Cardiomyocytes were incubated with 5 mM OHB, 50 microM vanadate or both for 16 h before the measurement of glucose uptake or the activation of insulin-signaling molecules. While chronic exposure to OHB did not alter insulin- or vanadate-mediated activation of the insulin receptor, it suppressed insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation in response to both agonists. Furthermore, this treatment decreased by 54 and 36% the phosphorylation of the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3-K) and PKB in response to insulin, whereas it did not alter vanadate-mediated activation of these enzymes. Although insulin did not significantly stimulate p38MAPK phosphorylation, vanadate increased it by 3.8-fold. Furthermore, chronic exposure to OHB potentiated vanadate's action, resulting in a 250% increase in enzyme activation compared to control cells. Though OHB induced a 2.1-fold increase of basal ERK1/2 phosphorylation, inhibition of this enzyme with the MEK inhibitor PD98059 demonstrated that ERK1/2 did not participate in OHB-induced insulin resistance. In conclusion, ketone bodies promote insulin resistance probably through decreased activation of the PI3-K/PKB signaling cascade. Furthermore, vanadate can bypass insulin resistance and stimulate glucose uptake in OHB-treated cardiomyocytes.

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Since the OGTT is required on a regular basis in CF patients to screen for CFRD, OGTT-derived indices appear to be suitable for evaluating insulin secretion.

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Coderre. Stimulation of glucose uptake by chronic vanadate pretreatment in cardiomyocytes requires PI 3-kinase and p38 MAPK activation. Am J Physiol Endocrinol Metab 284: E1055-E1064, 2003. First published December 10, 2002 10.1152 10. /ajpendo.00134.2002 inhibitor of tyrosine phosphatases, has insulin-mimetic properties. It has been shown that acute vanadate administration enhances glucose uptake independently of phosphatidylinositol (PI) 3-kinase and p38 MAPK. However, therapeutic vanadate use requires chronic administration, and this could potentially involve a different signaling pathway(s). Thus, we examined the mechanisms by which chronic vanadate exposure (16 h) stimulates glucose uptake in primary cultures of adult cardiomyocytes. The effect of vanadate on the activation of insulin-signaling molecules was evaluated 60 min after its withdrawal and in the absence of insulin. We therefore evaluated the persistent effect of vanadate on the insulin-signaling cascade. Our results demonstrate that preincubation with low vanadate concentrations (25-75 M) induces a dose-dependent increase in glucose uptake. The augmentation of this process was not due to alterations in GLUT1 or GLUT4 protein levels, transcription, or de novo protein synthesis. Chronic vanadate exposure was associated with activation of the insulin receptor, insulin receptor substrate-1 (IRS-1), PKB/Akt, and p38 MAPK. Furthermore, inhibition of PI 3-kinase or p38 MAPK by wortmannin and PD-169316, respectively, significantly inhibited vanadate-mediated glucose uptake in cardiomyocytes. Thus, over time, different (albeit overlapping) signaling cascades may be activated by vanadate. insulin signaling; protein kinase B/Akt; diabetes; vanadium; heart; phosphatidylinositol 3-kinase DESPITE THE ABILITY OF THE HEART to use multiple substrates to meet its energy requirements, this organ has one of the highest rates of glucose utilization in vivo (18,45). Decreased glucose uptake has been observed in both type 1 and type 2 diabetic subjects (25,29,45), and it has been proposed that abnormal regulation of this process has a role in the development of cardiac dysfunction (13). In db/db mice, a model of type 2 diabetes characterized by a reduction in glucose utilization and myocardial dysfunction, selective overexpression of the major glucose transporter GLUT4 expressed in the heart normalized these abnormalities (4). Interestingly, vanadate administration to streptozotocin-induced diabetic rats improved both insulin action and myocardial function in these animals (49). Furthermore, it has been shown that chronic vanadate exposure augments glucose uptake and improves ischemic tolerance in the hypertrophied heart (41). Together, these data suggest that glucose is an important cardiac substrate and that vanadate, by stimulating glucose uptake, could have a beneficial effect on the diabetic heart.Vanadium is a trace element found in most cells in concentrations ranging from 0.1 to 1 M (31). Vanadium compounds, such as vanadate, are inhibitors of protein tyrosine...