Lower risk of cancer in patients on metformin in comparison with those on sulfonylurea derivatives: results from a large population-based follow-up study

OBJECTIVE

Numerous studies have suggested a decreased risk of cancer in patients with diabetes on metformin. Because different comparison groups were used, the effect magnitude is difficult to estimate. Therefore, the objective of this study was to further analyze whether, and to what extent, use of metformin is associated with a decreased risk of cancer in a cohort of incident users of metformin compared with users of sulfonylurea derivatives.

RESEARCH DESIGN AND METHODS

Data for this study were obtained from dispensing records from community pharmacies individually linked to hospital discharge records from 2.5 million individuals in the Netherlands. The association between the risk of cancer in those using metformin compared with those using sulfonylurea derivatives was analyzed using Cox proportional hazard models with cumulative duration of drug use as a time-varying determinant.

RESULTS

Use of metformin was associated with a lower risk of cancer in general (hazard ratio 0.90 [95% CI 0.88–0.91]) compared with use of sulfonylurea derivatives. When specific cancers were used as end points, similar estimates were found. Dosage-response relations were identified for users of metformin but not for users of sulfonylurea derivatives.

CONCLUSIONS

In our study, cumulative exposure to metformin was associated with a lower risk of specific cancers and cancer in general, compared with cumulative exposure to sulfonylurea derivatives. However, whether this should indeed be seen as a decreased risk of cancer for the use of metformin or as an increased risk of cancer for the use sulfonylurea derivatives remains to be elucidated.As the drug of first choice in type 2 diabetes, metformin is the most widely prescribed oral glucose-lowering drug (OGLD) (1,2). However, the decision to prescribe metformin also depends on patient characteristics: metformin use is contraindicated in those with renal failure, cardiac, or hepatic failure (2).A statistically nonsignificant relationship between use of metformin and the risk of colon cancer was described in 2004 (3). However, 1 year later, metformin was found to be associated with a decreased risk of cancer in general in a case-control study in a diabetic population (4). Numerous studies followed; among which studies confirming the association between use of metformin and a decreased risk of cancer in general (5–8) or in specific cancers (5,6,9–14). However, for breast cancer (5,6) and prostate cancer (5,14), the decreased risk was not consistently demonstrated; for other cancers, no association with use of metformin was found (6,12). Hence, there is heterogeneity among published studies on cancer in patients with diabetes on metformin (15), partly because different comparison groups were used, such as nonmetformin users, users of other OGLDs, or users of insulin. Higher endogenous insulin levels have been linked to an increased risk of certain cancers (16). Moreover, specifically for insulin glargine, the debate whether this specific insulin increases the risk of cancer is ongoing (17–21).Owing to factors such as different drugs used to attain metabolic control, the duration of diabetes, and the presence of other diseases, the assessment of cancer risk in diabetic patients remains difficult. Therefore, the objective of this study was to analyze whether, and to what extent, use of metformin is associated with a decreased risk of cancer in a cohort of incident users of metformin compared with use of sulfonylurea derivatives.     

Reduced risk of colorectal cancer with metformin therapy in patients with type 2 diabetes: a meta-analysis

OBJECTIVE

Both in vitro and in vivo studies indicate that metformin inhibits cancer cell growth and reduces cancer risk. Recent epidemiological studies suggest that metformin therapy may reduce the risks of cancer and overall cancer mortality among patients with type 2 diabetes. However, data on its effect on colorectal cancer are limited and inconsistent. We therefore pooled data currently available to examine the association between metformin therapy and colorectal cancer among patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS

The PubMed and SciVerse Scopus databases were searched to identify studies that examined the effect of metformin therapy on colorectal cancer among patients with type 2 diabetes. Summary effect estimates were derived using a random-effects meta-analysis model.

RESULTS

The analysis included five studies comprising 108,161 patients with type 2 diabetes. Metformin treatment was associated with a significantly lower risk of colorectal neoplasm (relative risk [RR] 0.63 [95% CI 0.50–0.79]; P < 0.001). After exclusion of one study that investigated colorectal adenoma, the remaining four studies comprised 107,961 diabetic patients and 589 incident colorectal cancer cases during follow-up. Metformin treatment was associated with a significantly lower risk of colorectal cancer (0.63 [0.47–0.84]; P = 0.002). There was no evidence for the presence of significant heterogeneity between the five studies (Q = 4.86, P = 0.30; I² = 18%).

CONCLUSIONS

From observational studies, metformin therapy appears to be associated with a significantly lower risk of colorectal cancer in patients with type 2 diabetes. Further investigation is warranted.Colorectal cancer is one of the most frequent malignant tumors and a leading cause of cancer-related death worldwide (1). The incidence of colorectal cancer continues to increase in economically transitioning countries such as Asia, Eastern Europe, and selected countries in South America (2,3), whereas a declining trend has been noted in several developed countries in recent years (1).Type 2 diabetes is also a common disease, and it is well established that type 2 diabetes is associated with a higher risk of colorectal cancer (4–8). Metformin is a relative of isoamylene guanidine and has been recommended as the initial glucose-lowering therapy for diabetes. Emerging evidence from both in vitro and in vivo studies indicates that metformin may inhibit cancer cell growth and reduce cancer risks. Previous research suggests that metformin may be involved in the tumor suppressor pathway by indirectly activating AMP-activated protein kinase (9)—a key sensor of cellular ATP and AMP balance—and plays a role on activating tumor suppressor genes, e.g., LKB1. Subsequent in vitro studies have shown that metformin inhibits cancer cell proliferation (10,11) and selectively kills cancer stem cells (12). Animal experiments concur with these findings. Rodent models have shown that metformin suppresses colonic epithelial proliferation and colorectal aberrant crypt foci formation (13,14). Similarly, animal models of colon cancer have shown that metformin inhibits colon carcinoma growth (11,15). Given these encouraging findings, interest has arisen that metformin could potentially serve as a new antineoplasm drug to prevent colorectal cancer.Results from preliminary studies conducted in humans are encouraging. In a short-term randomized clinical trial among nondiabetic patients with rectal aberrant crypt foci, a significant decrease in the mean number of aberrant crypt foci was observed after metformin treatment for 1 month as compared with no significant changes in the control group (16). Findings from several epidemiological studies also support an antineoplastic role of metformin on cancer risks (17,18). If metformin therapy ultimately proves effective on reducing the risk of colorectal cancer, it would likely be recommended for the overwhelming majority of diabetes patients for both blood glucose control and cancer prevention. Nonetheless, despite accumulating evidence from population studies that indicate a lower risk of cancer at large with metformin therapy (17,19,20), data on its effect on colorectal cancer are limited and inconsistent. Accordingly, we performed a meta-analysis to pool studies currently available to examine the effect of metformin treatment on colorectal cancer risk among patients with type 2 diabetes.     

Statin use as a moderator of metformin effect on risk for prostate cancer among type 2 diabetic patients

OBJECTIVE

Metformin and statins have shown promise for cancer prevention. This study assessed whether the effect of metformin on prostate cancer (PCa) incidence varied by statin use among type 2 diabetic patients.

RESEARCH DESIGN AND METHODS

The study cohort consisted of 5,042 type 2 diabetic male patients seen in the Veteran Administration Health Care System who were without prior cancer and were prescribed with metformin or sulfonylurea as the exclusive hypoglycemic medication between fiscal years 1999 and 2005. Cox proportional hazards analyses were conducted to assess the differential hazard ratio (HR) of PCa due to metformin by statin use versus sulfonylurea use, where propensity scores of metformin and statin use were adjusted to account for imbalances in baseline covariates across medication groups.

RESULTS

Mean follow-up was ∼5 years, and 7.5% had a PCa diagnosis. Statin use modified the effect of metformin on PCa incidence (P < 0.0001). Metformin was associated with a significantly reduced PCa incidence among patients on statins (HR 0.69 [95% CI 0.50–0.92]; 17 cases/533 metformin users vs. 135 cases/2,404 sulfonylureas users) and an increased PCa incidence among patients not on statins (HR 2.15 [1.83–2.52]; 22 cases/175 metformin users vs. 186 cases/1,930 sulfonylureas users). The HR of PCa incidence for those taking metformin and statins versus those taking neither medication was 0.32 (0.25–0.42).

CONCLUSIONS

Among men with type 2 diabetes, PCa incidence among metformin users varied by their statin use. The potential beneficial influence on PCa by combination use of metformin and statin may be due to synergistic effects.Prostate cancer (PCa) is the most common cancer detected in men in the U.S., accounting for ∼28% of the new cancer burden. Risk for PCa increases significantly with age, and the lifetime risk for a U.S. man is 1 in 6 (1). Although a large proportion of cases will not progress to a life-threatening state, a diagnosis of PCa can have significant daunting effects on the patient and his family, with concomitant lifestyle changes, particularly due to the high risk of voiding and sexual dysfunction resulting from currently available curative treatment options. Therefore, preventive strategies would have substantial benefit. Although risk for PCa has been shown to be lower for men with diabetes (2), preventing PCa is particularly important in men with type 2 diabetes because this population appears to be at higher risk for high-grade PCa compared with men without diabetes (3,4). Metformin and statins, two drug classes with sound safety profiles that are well tolerated, have shown promise for cancer prevention trials, although their efficacy in the prevention or treatment of PCa still remains to be seen (5–11).Metformin is a biguanide drug widely prescribed as a first-line oral antihyperglycemic agent for individuals with type 2 diabetes (12). Its glucose-lowering effects may require activation of AMP-activated protein kinase (AMPK) to inhibit hepatic gluconeogenesis (13), increase peripheral uptake of glucose, and delay gastrointestinal glucose absorption (14). In addition, preclinical and clinical data have suggested antineoplastic effects of metformin, and several potential mechanisms include a reduction of hyperinsulinemia, growth inhibition through activation of the AMPK pathway and downstream inhibition of the mammalian target of rapamycin (mTOR) pathway, blockade of cell cycle progression, and alteration of anti-inflammatory properties (5,15–17).Although the beneficial metabolic effects of metformin make it a good treatment candidate for preventing ensuing metabolic syndrome after androgen-deprivation therapy for PCa (18), there is currently mixed enthusiasm for use of metformin therapy in the prevention of PCa. Observational human studies have examined the effect of metformin on risk or recurrence of PCa. Studies conducted in the general population reported decreased risk for PCa among metformin users (19,20). Given that diabetes has been inversely correlated with PCa risk (2), these early reports may have been subject to this bias. In fact, two studies conducted exclusively among diabetic subjects did not observe a significant reduction in PCa risk by metformin use (21,22); rather, a possible dose-dependent increase in risk was reported (21).Because these results are unexpected and contrast not only with the preclinical data but also with clinical data for other cancers, such as breast cancer, it is important to examine this question in other cohorts using more rigorous approaches to adjust for heterogeneity and potential confounding. For example, because of the high prevalence of dyslipidemia among individuals with type 2 diabetes, a large number will also be treated with a lipid-lowering medication such as a statin drug (23). The combination treatment with metformin and statin has not been explored. Prior studies, such as in Azoulay et al. (21), have adjusted for statin use by including an indicator variable to capture any previous use or no use in their model because statin use has itself been associated with PCa risk. No study has formally examined the interactive and potentially synergistic effects of the combination treatment with both drugs.Supportive evidence for use of statins as a PCa prevention therapy is growing, and two clinical trials are currently being initiated in the U.S. to examine effects of statin use in PCa patients (24). As 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, statins may affect PCa tumorigenesis by blocking the mevalonate pathway and thus reducing cholesterol and/or through multiple pleiotropic effects, as reviewed in Papadopoulos et al. (25). Clinical data have shown cholesterol levels are strongly correlated with PCa risk, so reduction of cholesterol levels is likely a key factor in the anticancer effects of statins (26,27)We conducted a 7-year cohort study to compare the PCa incidence rate associated with metformin monotherapy versus sulfonylurea monotherapy among male patients with type 2 diabetes in the Veteran Health Administration Health Care System (VAHCS). Further, we assessed whether the metformin effect on the PCa incidence rate could be modified by statin use to better examine the heterogeneity of metformin effect.     

Metformin and cancer occurrence in insulin-treated type 2 diabetic patients

OBJECTIVE

Metformin is associated with reduced cancer-related morbidity and mortality. The aim of this study was to assess the effect of metformin on cancer incidence in a consecutive series of insulin-treated patients.

RESEARCH DESIGN AND METHODS

A nested case-control study was performed in a cohort of 1,340 patients by sampling, for each case subject, age-, sex-, and BMI-matched control subjects from the same cohort.

RESULTS

During a median follow-up of 75.9 months, 112 case patients who developed incident cancer and were compared with 370 control subjects. A significantly lower proportion of case subjects were exposed to metformin and sulfonylureas. After adjustment for comorbidity, glargine, and total insulin doses, exposure to metformin, but not to sulfonylureas, was associated with reduced incidence of cancer (odds ratio 0.46 [95% CI 0.25–0.85], P = 0.014 and 0.75 [0.39–1.45], P = 0.40, respectively).

CONCLUSIONS

The reduction of cancer risk could be a further relevant reason for maintaining use of metformin in insulin-treated patients.Several studies have shown that metformin is associated with reduced cancer-related morbidity and mortality (1–4), due to improvement in insulin sensitivity (5) or to the activation of AMP-activated protein kinase (6). In insulin-treated patients, the reduction in insulin doses determined by metformin (7) could theoretically produce a decrease in cancer incidence.     

Long-Term Safety and Efficacy of Empagliflozin,Sitagliptin, and Metformin: An active-controlled,parallel-group,randomized, 78-week open-label extension study in patients with type 2 diabetes

OBJECTIVE

To investigate the long-term safety and efficacy of empagliflozin, a sodium glucose cotransporter 2 inhibitor; sitagliptin; and metformin in patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS

In this randomized, open-label, 78-week extension study of two 12-week, blinded, dose-finding studies of empagliflozin (monotherapy and add-on to metformin) with open-label comparators, 272 patients received 10 mg empagliflozin (166 as add-on to metformin), 275 received 25 mg empagliflozin (166 as add-on to metformin), 56 patients received metformin, and 56 patients received sitagliptin as add-on to metformin.

RESULTS

Changes from baseline in HbA_1c at week 90 were −0.34 to −0.63% (−3.7 to −6.9 mmol/mol) with empagliflozin, −0.56% (−6.1 mmol/mol) with metformin, and −0.40% (−4.4 mmol/mol) with sitagliptin. Changes from baseline in weight at week 90 were −2.2 to −4.0 kg with empagliflozin, −1.3 kg with metformin, and −0.4 kg with sitagliptin. Adverse events (AEs) were reported in 63.2–74.1% of patients on empagliflozin and 69.6% on metformin or sitagliptin; most AEs were mild or moderate in intensity. Hypoglycemic events were rare in all treatment groups, and none required assistance. AEs consistent with genital infections were reported in 3.0–5.5% of patients on empagliflozin, 1.8% on metformin, and none on sitagliptin. AEs consistent with urinary tract infections were reported in 3.8–12.7% of patients on empagliflozin, 3.6% on metformin, and 12.5% on sitagliptin.

CONCLUSIONS

Long-term empagliflozin treatment provided sustained glycemic and weight control and was well tolerated with a low risk of hypoglycemia in patients with type 2 diabetes.Type 2 diabetes is characterized by insulin resistance and progressive deterioration of β-cell function (1). Metformin is the recommended first-line antidiabetes agent for patients with type 2 diabetes (2). However, in order to achieve and maintain glycemic control as the disease progresses, patients often require therapies in addition to metformin (2,3).Despite the availability of a number of antihyperglycemic agents, the side effects associated with existing treatments and their gradual loss of efficacy over time (2,3) mean that many patients with type 2 diabetes do not reach therapeutic goals (3,4). In addition, treatment is often complicated by common comorbidities of type 2 diabetes such as obesity and hypertension, which are not addressed by existing oral antidiabetes agents (5–7).Inhibition of sodium glucose cotransporter 2 (SGLT2), located in the proximal tubule of the kidney, represents an approach for the treatment of type 2 diabetes that is independent of β-cell function and insulin resistance (8,9). SGLT2 mediates most of renal glucose reabsorption, and inhibition of this transporter leads to reduced reabsorption of filtered glucose and increased urinary glucose excretion (8,10), resulting in reduced plasma glucose levels in patients with type 2 diabetes (8–10). In addition, this mechanism leads to weight loss owing to the loss of calories via urinary glucose excretion (8,11).Empagliflozin is a potent and selective inhibitor of SGLT2 (12), which in patients with type 2 diabetes causes urinary glucose excretion of up to 90 g/day (13). In two placebo- and active-controlled, dose-finding trials, treatment with empagliflozin for 12 weeks in patients with type 2 diabetes was generally well tolerated and resulted in placebo-corrected reductions in HbA_1c of up to 0.72% (7.9 mmol/mol) and placebo-corrected reductions in weight of up to 1.7 kg (14,15). In these studies, reductions in HbA_1c were comparable to those of the active comparators metformin and sitagliptin (14,15). The objective of this study was to assess the long-term safety and efficacy of empagliflozin, sitagliptin, and metformin in a 78-week, open-label extension study of two dose-finding trials.     

Association Between Metformin Therapy and Mortality After Breast Cancer: A population-based study

OBJECTIVE

Metformin has been associated with a reduction in breast cancer risk and may improve survival after cancer through direct and indirect tumor-suppressing mechanisms. The purpose of this study was to evaluate the effect of metformin therapy on survival in women with breast cancer using methods that accounted for the duration of treatment with glucose-lowering therapies.

RESEARCH DESIGN AND METHODS

This population-based study, using Ontario health care databases, recruited women aged 66 years or older diagnosed with diabetes and breast cancer between 1 April 1997 and 31 March 2008. Using Cox regression analyses, we explored the association between cumulative duration of past metformin use and all-cause and breast cancer–specific mortality. We modeled cumulative duration of past metformin use as a time-varying exposure.

RESULTS

Of 2,361 breast cancer patients identified, mean (± SD) age at cancer diagnosis was 77.4 ± 6.3 years, and mean follow-up was 4.5 ± 3.0 years. There were 1,101 deaths(46.6%), among which 386 (16.3%) were breast cancer–specific deaths. No significant association was found between cumulative duration of past metformin use and all-cause mortality (adjusted hazard ratio 0.97 [95% CI 0.92–1.02]) or breast cancer–specific mortality (0.91 [0.81–1.03]) per additional year of cumulative use.

CONCLUSIONS

Our findings failed to show an association between improved survival and increased cumulative metformin duration in older breast cancer patients who had recent-onset diabetes. Further research is needed to clarify this association, accounting for effects of cancer stage and BMI in younger populations or those with differing stages of diabetes as well as in nondiabetic populations.Pre-existing diabetes may increase the risk of death by as much as 40% in cancer patients (1). Up to 16% of patients with breast cancer have pre-existing diabetes and are thus at risk for worse outcomes (2,3). Metformin, an insulin sensitizer, is the most commonly prescribed diabetes treatment and is currently recommended as first-line therapy for patients with type 2 diabetes (4,5). If glycemic targets are not met with metformin alone, other glucose-lowering medications are added to or substituted for metformin. Recent evidence suggests that metformin may have antitumor effects (6). Several studies have evaluated the effect of metformin on cancer incidence, and meta-analyses suggest that metformin is associated with a 20–30% reduction in new cancers (6–8). However, of greater interest is the potential therapeutic role of metformin in patients with pre-existing cancer.There is mounting evidence that metformin may affect the prognosis of breast cancer. Metformin use has been associated with higher rates of pathologic complete response after chemotherapy in breast cancer patients with diabetes (9), and clinical trials have shown a reduction in tumor proliferation markers in nondiabetic breast cancer patients treated with metformin (10–12). However, observational studies evaluating the effect of metformin on survival after breast cancer have been inconsistent. One study of women with HER2+ breast cancer found metformin exposure was associated with a 48% reduction in overall mortality compared with other glucose-lowering medications (13). However, another study of women with triple-negative receptor breast cancer did not show a significant association between metformin and cancer mortality (hazard ratio [HR] 1.63 [95% CI 0.87–3.06]) (13,14). Interpretation of these previous studies is hampered by small sample sizes, heterogeneity of disease subtypes, inclusion of diabetic populations with varying disease severity and duration, and inconsistent definitions of metformin exposure. The objective of this study was to evaluate the relationship between cumulative metformin use and mortality in patients with breast cancer and recently diagnosed diabetes.     

Independent and combined effects of exercise training and metformin on insulin sensitivity in individuals with prediabetes

OBJECTIVE

Physical activity or metformin enhances insulin sensitivity and opposes the progression from prediabetes to type 2 diabetes. The combination may be more effective because each treatment stimulates AMP-activated protein kinase activity in skeletal muscle. We evaluated the effects of exercise training plus metformin on insulin sensitivity in men and women with prediabetes, compared with each treatment alone.

RESEARCH DESIGN AND METHODS

For 12 weeks, men and women with prediabetes were assigned to the following groups: placebo (P), 2,000 mg/day metformin (M), exercise training with placebo (EP), or exercise training with metformin (EM) (n = 8 per group). Before and after the intervention, insulin sensitivity was measured by euglycemic hyperinsulinemic (80 mU/m²/min) clamp enriched with [6,6-²H]glucose. Changes due to intervention were compared across groups by repeated-measures ANOVA.

RESULTS

All three interventions increased insulin sensitivity (P < 0.05) relative to the control group. The mean rise was 25–30% higher after EP than after either EM or M, but this difference was not significant.

CONCLUSIONS

Insulin sensitivity was considerably higher after 12 weeks of exercise training and/or metformin in men and women with prediabetes. Subtle differences among condition means suggest that adding metformin blunted the full effect of exercise training.Before developing overt diabetes, most individuals spend years in an intermediate condition called prediabetes. Prediabetes is defined by impaired glucose tolerance (IGT), impaired fasting glucose (IFG), or the combination of IGT plus IFG (1). Approximately 79 million individuals in the U.S. have prediabetes and are at risk to develop type 2 diabetes (2). The progression is not inevitable, however. The U.S. Diabetes Prevention Program (DPP) demonstrated that either lifestyle modification (i.e., low-fat diet and increased physical activity) or the antihyperglycemic medication metformin reduced the transition from prediabetes to type 2 diabetes (3).Habitual exercise and metformin each increase peripheral (mainly skeletal muscle) insulin sensitivity in part by stimulating AMP-activated protein kinase (AMPK) (4–8). Combining exercise plus metformin, compared with either treatment alone, may more effectively activate the key regulatory enzyme AMPK and oppose the transition from prediabetes to type 2 diabetes.The American Diabetes Association strongly recommends exercise as a cornerstone therapy for diabetes prevention and, recently, suggested that some individuals with prediabetes be considered for metformin treatment (9,10). The efficacy of combining lifestyle modification with metformin has been tested only a few times (11–15). Results suggest 2–5 kg more weight loss with the addition of metformin compared with lifestyle modification alone (11,12), but little (11,14) or no further (15,16) improvement to insulin sensitivity. However, the use of self-reports to estimate physical activity and surrogates (via fasting glucose and insulin concentrations or responses to oral carbohydrate) (11,13–15) rather than direct measurement of insulin sensitivity using the glucose clamp limits our understanding of the interaction between exercise and metformin. There is considerable need to better understand the potential for additive effects when physical activity and metformin are used concurrently because the scope of the public health problem is so pressing. Therefore, the purpose of this study was to determine the effect of combining exercise training with metformin (EM) on insulin sensitivity in individuals with prediabetes, compared with either treatment alone.     

Rosiglitazone Decreases C-Reactive Protein to a Greater Extent Relative to Glyburide and Metformin Over 4 Years Despite Greater Weight Gain: Observations from A Diabetes Outcome Progression Trial (ADOPT)

OBJECTIVE

C-reactive protein (CRP) is closely associated with obesity and cardiovascular disease in both diabetic and nondiabetic populations. In the short term, commonly prescribed antidiabetic agents have different effects on CRP; however, the long-term effects of those agents are unknown.

RESEARCH DESIGN AND METHODS

In A Diabetes Outcome Progression Trial (ADOPT), we examined the long-term effects of rosiglitazone, glyburide, and metformin on CRP and the relationship among CRP, weight, and glycemic variables in 904 subjects over 4 years.

RESULTS

Baseline CRP was significantly correlated with homeostasis model assessment of insulin resistance (HOMA-IR), A1C, BMI, waist circumference, and waist-to-hip ratio. CRP reduction was greater in the rosiglitazone group by −47.6% relative to glyburide and by −30.5% relative to metformin at 48 months. Mean weight gain from baseline (at 48 months) was 5.6 kg with rosiglitazone, 1.8 kg with glyburide, and −2.8 kg with metformin. The change in CRP from baseline to 12 months was correlated positively with change in BMI in glyburide (r = 0.18) and metformin (r = 0.20) groups but not in the rosiglitazone (r = −0.05, NS) group. However, there was no longer a significant correlation between change in CRP and change in HOMA-IR, A1C, or waist-to-hip ratio in any of the three treatment groups.

CONCLUSIONS

Rosiglitazone treatment was associated with durable reductions in CRP independent of changes in insulin sensitivity, A1C, and weight gain. CRP in the glyburide and metformin groups was positively associated with changes in weight, but this was not the case with rosiglitazone.C-reactive protein (CRP) has been traditionally viewed as one of the acute-phase reactants and is a sensitive systemic marker of inflammation and tissue damage. This acute-phase inflammatory protein is predominantly secreted in hepatocytes, its release being regulated by interleukin-6 and other inflammatory cytokines (1). Other studies have shown that extrahepatic sources of CRP production from adipocytes could point to a more systemic generation of CRP in the body after stimulation by inflammatory cytokines and more specifically, by the adipokine, resistin (1).Both population-based and prospective studies have demonstrated a clear association between CRP and an increased risk of cardiovascular disease (CVD) and stroke (2). The magnitude of the CRP prediction for future CVD events is similar to that of other traditional CVD risk factors (cholesterol, hypertension, and smoking status) (2). CRP also may be a mediator of atherosclerosis (1,3–6). However, there is no available evidence from clinical trials that a reduction in CRP directly reduces or prevents further CVD events.The production of CRP by adipocytes may partially explain why CRP levels are elevated in patients with the metabolic syndrome (1), in whom CVD risk is increased. The strong association between CRP and body adiposity has been observed in both diabetic (7) and nondiabetic subjects (8–11) and was only moderately attenuated by adjustment of insulin sensitivity. These results suggest that obesity, insulin resistance, and the metabolic syndrome are interconnected in a proinflammatory state that may be mediated by cytokines and subsequently cause elevated levels of CRP. Elevated CRP concentrations have been shown to predict an increased risk of diabetes (9,12,13). Therefore, CRP may play an active role in the causal relationship among obesity, diabetes, and the high risk of future CVD events. Statins (14) and weight loss (15–17), which can reduce CRP levels and improve other CVD risk factors, also show benefits in reducing CVD events.Glucose-lowering agents have different effects on CRP, weight, insulin sensitivity, and glycemic control in the treatment of type 2 diabetes. The thiazolidinediones (TZDs) rosiglitazone and pioglitazone, insulin-sensitizing oral antidiabetic agents, have been shown to be effective in reducing CRP in several short-term (≤6 months) studies (18–21). However, it is not clear whether the weight gain associated with TZDs could attenuate the effect on CRP reduction over larger periods of time. In short-term studies, metformin moderately decreases CRP (16,18), increases insulin sensitivity, and produces weight loss (16). The longer-term relationships among the three commonly used oral antidiabetic agents (TZDs, sulfonylureas, and metformin) with CRP, insulin sensitivity, weight, and glycemic control have not been investigated previously.A Diabetes Outcome Progression Trial (ADOPT) provided the opportunity to evaluate the effects of members of these three classes of oral agents in a randomized, double-blind, controlled trial involving >4,000 patients, treated for a median time of 4 years (22,23). This study compared the efficacy and safety of rosiglitazone, glyburide, and metformin in drug-naive patients with newly diagnosed (≤3 years) type 2 diabetes. We have previously reported the association of CRP, obesity, and insulin resistance in the baseline examination of the ADOPT study (7). We discuss here a subgroup analysis of ADOPT, in which we examined prospectively the long-term effects of rosiglitazone, glyburide, and metformin on CRP reduction and the relationship among CRP, insulin sensitivity, weight, and glycemic variables.     

Diabetes and risk of prostate cancer: a study using the National Health Insurance

OBJECTIVE

The link between diabetes and prostate cancer is rarely studied in Asians.

RESEARCH DESIGN AND METHODS

The trend of age-standardized prostate cancer incidence in 1995–2006 in the Taiwanese general population was calculated. A random sample of 1,000,000 subjects covered by the National Health Insurance in 2005 was recruited. A total of 494,630 men for all ages and 204,741 men ≥40 years old and without prostate cancer at the beginning of 2003 were followed to the end of 2005. Cumulative incidence and risk ratio between diabetic and nondiabetic men were calculated. Logistic regression estimated the adjusted odds ratios for risk factors.

RESULTS

The trend of prostate cancer incidence increased significantly (P < 0.0001). The cumulative incidence markedly increased with age in either the diabetic or nondiabetic men. The respective risk ratio (95% CI) for all ages and age 40–64, 65–74, and ≥75 years was 5.83 (5.10–6.66), 2.09 (1.60–2.74), 1.35 (1.07–1.71), and 1.39 (1.12–1.71). In logistic regression for all ages or for age ≥40 years, age, diabetes, nephropathy, ischemic heart disease, dyslipidemia, living region, and occupation were significantly associated with increased risk, but medications including insulin and oral antidiabetic agents were not.

CONCLUSIONS

Prostate cancer incidence is increasing in Taiwan. A positive link between diabetes and prostate cancer is observed, which is more remarkable in the youngest age of 40–64 years. The association between prostate cancer and comorbidities commonly seen in diabetic patients suggests a more complicated scenario in the link between prostate cancer and diabetes at different disease stages.The association between diabetes and prostate cancer has been inconsistently reported, even though two meta-analyses suggested that diabetic patients have a lower risk of prostate cancer of 9% (1) and 16% (2), respectively.While the two meta-analyses were examined, many studies were case-control and only three focused on the follow-up of cohorts of diabetic patients (3–5). Among the three cohorts, the cases of prostate cancer were 9 (3), 498 (4), and 2,455 (5), respectively; and only the last (5) showed a significant 9% risk reduction in diabetic patients. Except for the first study being conducted in residents with diabetes in Rochester, Minnesota (3), the diabetic patients in the other two were from hospitalized patients in Denmark (4) and Sweden (5), respectively. The meta-analyses have limitations including a mixture of case-control and cohort designs, a mixture of incident and dead cases, a small number of prostate cancer in most studies, and different sources of subjects with potential selection bias. Although the contamination of type 1 diabetes is possibly minimal because >90% of overall patients have type 2 diabetes, residual confounding could not be excluded if the two types of diabetes are not differentiated.Although some recent studies still suggested a lower risk of prostate cancer in diabetic patients including Caucasians (6,7), Iranians (8), Israelis (9), African Americans, Native Hawaiians, and Japanese Americans (6), the lower risk in African Americans and Native Hawaiians (6) was not significant. Two Japanese studies did not find any significant association (10,11). The Ohsaki Cohort Study suggested that diabetes was not predictive for total prostate cancer, but diabetic patients did show a higher risk of advanced cancer (11).Because diabetic patients are prone to develop cancer involving pancreas, liver, breast, colorectum, bladder, and endometrium (12–15) and the protective effect of diabetes on prostate cancer requires confirmation, this study evaluated the possible link between diabetes and prostate cancer, and the potential risk factors, by using the reimbursement database of the National Health Insurance (NHI) in Taiwan.     

Maternal and Neonatal Circulating Markers of Metabolic and Cardiovascular Risk in the Metformin in Gestational Diabetes (MiG) Trial: Responses to maternal metformin versus insulin treatment

OBJECTIVE

This study was designed to compare glucose, lipids, and C-reactive protein (CRP) in women with gestational diabetes mellitus treated with metformin or insulin and in cord plasma of their offspring and to examine how these markers relate to infant size at birth.

RESEARCH DESIGN AND METHODS

Women with gestational diabetes mellitus were randomly assigned to metformin or insulin in the Metformin in Gestational Diabetes trial. Fasting maternal plasma glucose, lipids, and CRP were measured at randomization, 36 weeks’ gestation, and 6–8 weeks postpartum as well as in cord plasma. Women with available cord blood samples (metformin n = 236, insulin n = 242) were included.

RESULTS

Maternal plasma triglycerides increased more from randomization to 36 weeks’ gestation in women treated with metformin (21.93%) versus insulin (9.69%, P < 0.001). Maternal and cord plasma lipids, CRP, and neonatal anthropometry did not differ between treatments. In logistic regression analyses adjusted for confounders, the strongest associations with birth weight >90th centile were maternal triglycerides and measures of glucose control at 36 weeks.

CONCLUSIONS

There were few differences in circulating maternal and neonatal markers of metabolic status and no differences in measures of anthropometry between the offspring of women treated with metformin and the offspring of women treated with insulin. There may be subtle effects of metformin on maternal lipid function, but the findings suggest that treating gestational diabetes mellitus with metformin does not adversely affect lipids or CRP in cord plasma or neonatal anthropometric measures.Gestational diabetes mellitus is carbohydrate intolerance first diagnosed during pregnancy (1) and affects up to 18% of pregnancies. The prevalence varies depending on maternal demographics and diagnostic criteria (2). The prevalence of gestational diabetes mellitus is increasing, which is likely driven by the rising population prevalence of overweight and obesity and increasing maternal age at pregnancy (3). Gestational diabetes mellitus increases maternal and infant morbidity and mortality during pregnancy (4). Women with a history of gestational diabetes mellitus are at risk for metabolic syndrome, type 2 diabetes (5), and cardiovascular disease in later life (6). Children born to women with gestational diabetes mellitus have higher rates of type 2 diabetes and obesity (7).Treating gestational diabetes mellitus improves pregnancy outcomes for both mother and infant (8). Current therapies include modification of diet, increased physical activity, and drug therapy with insulin and oral hypoglycemic agents, including metformin. In addition to improving insulin sensitivity and hyperglycemia, metformin therapy in the setting of type 2 diabetes reduces triglycerides (9), total cholesterol, LDL cholesterol (10), and VLDL cholesterol; increases HDL cholesterol (9); and reduces markers of inflammation and thrombosis (11). Metformin therapy in gestational diabetes mellitus achieves maternal glucose control and pregnancy outcomes similar to insulin therapy (12,13).In contrast to insulin, metformin crosses the placenta (14) and, therefore, could directly influence fetal metabolism. Our recent follow-up studies in 2-year-old offspring of women enrolled in the Metformin in Gestational Diabetes (MiG) trial showed increased subcutaneous fat measurements with no increase in abdominal adiposity or total fat (15). Further assessments are required to determine whether metformin actually reduces visceral/ectopic fat. Therefore, we hypothesized that metformin would be more effective than insulin in improving markers of insulin sensitivity and cardiovascular risk during pregnancy and postpartum in women with gestational diabetes mellitus and in their newborns.     

Long-Term Cardiovascular Risk in Type 2 Diabetic Compared With Nondiabetic First Acute Myocardial Infarction Patients: A population-based cohort study in southern Europe

OBJECTIVE

The aim of this study was to determine whether long-term cardiovascular risk differs in type 2 diabetic patients compared with first acute myocardial infarction patients in a Mediterranean region, considering therapy, diabetes duration, and glycemic control.

RESEARCH DESIGN AND METHODS

A prospective population-based cohort study with 10-year follow-up was performed in 4,410 patients aged 30–74 years: 2,260 with type 2 diabetes without coronary heart disease recruited in 53 primary health care centers and 2,150 with first acute myocardial infarction without diabetes recruited in 10 hospitals. We compared coronary heart disease incidence and cardiovascular mortality rates in myocardial infarction patients and diabetic patients, including subgroups by diabetes treatment, duration, and A1C.

RESULTS

The adjusted hazard ratios (HRs) for 10-year coronary heart disease incidence and for cardiovascular mortality were significantly lower in men and women with diabetes than in myocardial infarction patients: HR 0.54 (95% CI 0.45–0.66) and 0.28 (0.21–0.37) and 0.26 (0.19–0.36) and 0.16 (0.10–0.26), respectively. All diabetic patient subgroups had significantly fewer events than myocardial infarction patients: the HR of cardiovascular mortality ranged from 0.15 (0.09–0.26) to 0.36 (0.24–0.54) and that of coronary heart disease incidence ranged from 0.34 (0.26–0.46) to 0.56 (0.43–0.72).

CONCLUSIONS

Lower long-term cardiovascular risk was found in type 2 diabetic and all subgroups analyzed compared with myocardial infarction patients. These results do not support equivalence in coronary disease risk for diabetic and myocardial infarction patients.The prevalence of diabetes is reaching epidemic proportions in developed countries (1). For example, the U.S. has 18 million diabetic patients, Spain has >2 million diabetic patients, and management of the disease costs >$132 and >$3.3 billion per year, respectively (2).Some studies (3–5), several of them with great influence on important guidelines for cardiovascular prevention (3), suggest that the cardiovascular risk of diabetic patients is similar to that of coronary heart disease secondary prevention patients. Other reports, however, do not confirm these observations (6–10).Part of the discrepancy may stem from differences in the duration of diabetes, type of treatment, and baseline glucose control of diabetic patients included in the studies (3–5). These limit comparability, given the fact that time of evolution and treatment required to attain appropriate glycemic control are key determinants of prognosis (10–16).Among population-based cohort studies that compared the prognosis of diabetic patients with that of myocardial infarction patients without diabetes (3–10), only two analyzed the role of diabetes duration (11,12). Even these studies did not include unstable angina among the end points and risk was not stratified by type of treatment. To our knowledge, the effect of type 2 diabetes on coronary heart disease incidence has barely been studied in southern Europe, a region known for low cardiovascular mortality (17). The aim of this study was to determine whether long-term cardiovascular risk differed between type 2 diabetic patients and first acute myocardial infarction patients and to assess the influence of diabetes duration, type of treatment, and glycemic control at baseline.     

Pleiotropic Action of Short-Term Metformin and Fenofibrate Treatment, Combined With Lifestyle Intervention, in Type 2 Diabetic Patients With Mixed Dyslipidemia

OBJECTIVE

To compare the effect of short-term metformin and fenofibrate treatment, administered alone or in sequence, on glucose and lipid metabolism, cardiovascular risk factors, and monocyte cytokine release in type 2 diabetic patients with mixed dyslipidemia.

RESEARCH DESIGN AND METHODS

We studied 128 type 2 diabetic patients with mixed dyslipidemia complying throughout the study with lifestyle intervention who were randomized twice, initially to either metformin or placebo, and then to micronized fenofibrate or placebo.

RESULTS

Fenofibrate alleviated diabetic dyslipidemia–induced changes in plasma high-sensitivity C-reactive protein, fibrinogen, and plasminogen activator inhibitor (PAI)-1 and in monocyte cytokine release, whereas metformin or lifestyle intervention improved mainly glucose and lipid metabolism. The strongest pleiotropic effect was observed when fenofibrate was added to metformin.

CONCLUSIONS

Fenofibrate, particularly administered together with metformin, is superior to metformin and lifestyle intervention in exhibiting beneficial effects on systemic inflammation, hemostasis, and monocyte secretory function in type 2 diabetic patients with mixed dyslipidemia.Peroxisome proliferator–activated receptor (PPAR)-α activators (fibrates) administered to patients with dyslipidemia (1–4) or early glucose metabolism abnormalities (5) produce many non–lipid-related effects, including anti-inflammatory, antioxidant, and antithrombotic actions and improvement in endothelial function. Apart from normalizing glucose metabolism, metformin, the only oral antidiabetic medication shown to decrease cardiovascular events independent of glycemic control (6), improved dyslipidemia, hemostasis, and systemic inflammation (7). To the best of our knowledge, no previous clinical study has ever compared clinical benefits of metformin and fibrates when it comes to their pleiotropic effects and assessed whether metformin-fibrate combination is superior to treatment with only one of these drugs.     

Sex and Racial/Ethnic Differences in Cardiovascular Disease Risk Factor Treatment and Control Among Individuals With Diabetes in the Multi-Ethnic Study of Atherosclerosis (MESA)

OBJECTIVE

To examine sex and racial/ethnic differences in cardiovascular risk factor treatment and control among individuals with diabetes in the Multi-Ethnic Study of Atherosclerosis (MESA).

RESEARCH DESIGN AND METHODS

This study was an observational study examining mean levels of cardiovascular risk factors and proportion of subjects achieving treatment goals.

RESULTS

The sample included 926 individuals with diabetes. Compared with men, women were 9% less likely to achieve LDL cholesterol <130 mg/dl (adjusted prevalence ratio 0.91 [0.83–0.99]) and systolic blood pressure (SBP) <130 mmHg (adjusted prevalence ratio 0.91 [0.85–0.98]). These differences diminished over time. A lower percentage of women used aspirin (23 vs. 33%; P < 0.001). African American and Hispanic women had higher mean levels of SBP and lower prevalence of aspirin use than non-Hispanic white women.

CONCLUSIONS

Women with diabetes had unfavorable cardiovascular risk factor profiles compared with men. African American and Hispanic women had less favorable profiles than non-Hispanic white women.Population-based health survey data suggest that sex and racial/ethnic disparities are present in diabetes process of care measures and cardiovascular risk factor control (1–9). Available data also indicate that sex-specific race/ethnicity differences are present in cardiovascular risk factor control, but these data are limited to Medicare and Veterans'' Hospital patient populations (5,10–13). We therefore performed analyses of participants with diabetes in the Multi-Ethnic Study of Atherosclerosis (MESA) to examine sex and sex-specific racial/ethnic differences in cardiovascular risk factor treatment and control.     

TRAF-interacting Protein (TRIP): A Novel Component of the Tumor Necrosis Factor Receptor (TNFR)- and CD30-TRAF Signaling Complexes That Inhibits TRAF2-mediated NF-κB Activation

Through their interaction with the TNF receptor–associated factor (TRAF) family, members of the tumor necrosis factor receptor (TNFR) superfamily elicit a wide range of biological effects including differentiation, proliferation, activation, or cell death. We have identified and characterized a novel component of the receptor–TRAF signaling complex, designated TRIP (TRAF-interacting protein), which contains a RING finger motif and an extended coiled-coil domain. TRIP associates with the TNFR2 or CD30 signaling complex through its interaction with TRAF proteins. When associated, TRIP inhibits the TRAF2-mediated NF-κB activation that is required for cell activation and also for protection against apoptosis. Thus, TRIP acts as a receptor–proximal regulator that may influence signals responsible for cell activation/proliferation and cell death induced by members of the TNFR superfamily.Members of the TNF receptor (TNFR)¹ superfamily play important roles in the induction of diverse signals leading to cell growth, activation, and apoptosis (1). Whether the signals induced by a given receptor leads to cell activation or death is, however, highly cell-type specific and tightly regulated during differentiation of cells. For example, the TNFRs can exert costimulatory signals for proliferation of naive lymphocytes but also induce death signals required for deletion of activated T lymphocytes (1). The cytoplasmic domains of these receptors lack intrinsic catalytic activity and also exhibit no significant homology to each other or to other known proteins. Exceptions to this include Fas(CD95) and TNFR1 that share a significant homology within an 80–amino acid region of their cytoplasmic tails (called the “death domain”; 2, 3). Therefore, it is suggested that the TNFR family members can initiate different signal transduction pathways by recruiting different types of intracellular signal transducers to the receptor complex (1).Indeed, several types of intracellular signal transducers have been identified that initiate distinct signal transduction pathways when recruited to the members of TNFR superfamily (4–19). Recent biochemical and molecular studies showed that a class of signal-transducing molecules are recruited to Fas(CD95) or TNFR1 via interaction of the death domains (2, 3, 6, 12, 17, 20). For example, Fas(CD95) and TNFR1 recruit FADD(MORT1)/RIP or TRADD/FADD (MORT1)/RIP through the interactions of their respective death domains (2, 3, 6, 12, 17, 20, 21). Clustering of these signal transducers leads to the recruitment of FLICE/ MACH, and subsequently, to cell death (13, 14).The TNFR family members can also recruit a second class of signal transducers called TRAFs (TNFR-associated factor), some of which are responsible for the activation of NF-κB or JNK (9, 20, 22). TRAF proteins were identified by their biochemical ability to interact with TNFR2, CD40, CD30, or LT-βR (4, 5, 10, 11, 15, 23–27). These receptors interact directly with TRAFs via a short stretch of amino acids within their cytoplasmic tails, but do not interact with the death domain containing proteins (4, 5, 15, 24–27). To date, five members of the TRAF family have been identified as signaling components of the TNFR family members. All TRAF members contain a conserved TRAF domain, ∼230 amino acids in length, that is used for either homo- or heterooligomerization among the TRAF family, for interactions with the cytoplasmic regions of the TNFR superfamily, or for interactions with downstream signal transducers (4, 5, 8, 10, 11, 19, 23–25, 28). In addition to the TRAF domain, most of the TRAF family members contain an NH₂-terminal RING finger and several zinc finger structures, which appear to be important for their effector functions (4, 5, 10, 11, 23–25).Several effector functions of TRAFs were revealed by recent experiments based on a transfection system. TRAF2, first identified by its interaction with TNFR2 (4), was subsequently shown to mediate NF-κB activation induced by two TNF receptors, CD40 and CD30 (9, 28–30). TRAF5 was also implicated in NF-κB activation mediated by LTβR (10), whereas TRAF3 (also known as CRAF1, CD40bp, or LAP1; references 5, 11, 24, and 25) was shown to be involved in the regulation of CD40-mediated CD23 upregulation in B cells (5). The role of other TRAF members in the TNFR family–mediated signal transduction is not clear. They may possess some effector functions as yet to be revealed, or work as adapter proteins to recruit different downstream signal transducers to the receptor complex. For example, TRAF1 is required for the recruitment of members of the cellular inhibitor of apoptosis protein (c-IAP) family to the TNFR2-signaling complex (7). In addition to the signal transduction by the TNFR family members, TRAFs may regulate other receptor-mediated signaling pathways. For example, TRAF6 is a component of IL-1 receptor (IL1R)–signaling complex, in which it mediates the activation of NF-κB by IL-1R (31). Since TRAFs form homo- or heterooligomers, it is suggested that the repertoire of TRAF members in a given cell type may differentially affect the intracellular signals triggered by these receptors. This may be accomplished by the selective interaction of TRAFs with a specific set of downstream signal transducers. Although many aspects of TRAF-mediated effector functions leading to cellular activation have been defined, it needs to be determined whether TRAF proteins will also mediate the apoptotic signals induced by the “death-domain-less” members of the TNFR superfamily (1, 27, 32–36).Here we report the isolation and characterization of a novel component of the TNFR superfamily/TRAFs signaling complex, named TRIP (TRAF-interacting protein). TRIP associates with the receptor/TRAF signaling complex, and inhibits the TRAF2-mediated NF-κB activation. Biochemical studies indicate that TRIP associates with the TNFR2 or CD30 receptor complex via its interaction with TRAF proteins, suggesting a model which can explain why the ligation of these receptors can promote different cell fates: proliferation or death.     

A New Mechanism of NK Cell Cytotoxicity Activation: The CD40–CD40 Ligand Interaction

NK recognition is regulated by a delicate balance between positive signals initiating their effector functions, and inhibitory signals preventing them from proceeding to cytolysis. Knowledge of the molecules responsible for positive signaling in NK cells is currently limited. We demonstrate that IL-2–activated human NK cells can express CD40 ligand (CD40L) and that recognition of CD40 on target cells can provide an activation pathway for such human NK cells. CD40-transfected P815 cells were killed by NK cell lines expressing CD40L, clones and PBLderived NK cells cultured for 18 h in the presence of IL-2, but not by CD40L-negative fresh NK cells. Cross-linking of CD40L on IL-2–activated NK cells induced redirected cytolysis of CD40-negative but Fc receptor-expressing P815 cells. The sensitivity of human TAP-deficient T2 cells could be blocked by anti-CD40 antibodies as well as by reconstitution of TAP/MHC class I expression, indicating that the CD40-dependent pathway for NK activation can be downregulated, at least in part, by MHC class I molecules on the target cells. NK cell recognition of CD40 may be important in immunoregulation as well as in immune responses against B cell malignancies.NK cells represent a distinct lineage of lymphocytes that are able to kill a variety of tumor (1), virus-infected (2), bone marrow transplanted (3), and allogeneic target cells (4). NK cells do not express T cell receptors or immunoglobulins and are apparently normal in mice with defects in the recombinase machinery (5, 6).Our knowledge about NK cell specificity has increased considerably in the last years. NK cells can probably interact with target cells by a variety of different cell surface molecules, some involved in cell adhesion, some activating the NK cytolytic program (7, 8), and other ones able to inhibit this activation by negative signaling (as reviewed in reference 9).A common feature of several inhibitory NK receptors is the capability to bind MHC class I molecules (10, 11), as predicted by the effector inhibition model within the missing self hypothesis of recognition by NK cells (12–14). Interestingly, the MHC class I receptors identified so far belong to different gene families in mouse and man; these are the p58/p70/NKAT or killer cell inhibitory receptors (KIR)¹ of the immunoglobulin superfamily in man and the Ly49 receptors of the C-type lectin family in the mouse. There is also evidence that MHC class I molecules can be recognized as triggering signals in NK cells of humans, rats as well as mice (13). The inhibitory receptors allow NK cells to kill tumor or normal cell targets with deficient MHC class I expression (12, 14). This does not exclude that other activating pathways can override inhibition by MHC class I molecules (15) and, even in their absence, there must be some activating target molecules that initiate the cytolytic program. Several surface molecules are able to mediate positive signals in NK cells. Some of these structures, like NKRP1 (16), CD69 (17), and NKG2 (18) map to the NK complex region (NKC) of chromosome 6 in mice and of chromosome 12 in humans (13). CD2 (19) and CD16 (20) molecules can also play a role in the activation pathway.NK cells resemble T cells in many respects, both may arise from an immediate common progenitor (21, 22), and share the expression of several surface molecules (23). NK cells produce cytokines resembling those secreted by some helper T cell subsets (24) and contain CD3 components in the cytoplasm (21). The expression of some surface structures, involved in TCR-dependent T cell costimulation, like CD28 in human (25), has been described on NK cells, but the functional relevance of these molecules for NK activation processes has not been fully established.Another T cell molecule of interest is CD40L, which interacts with CD40, a 50-kD membrane glycoprotein expressed on B cells (26), dendritic cells (27), and monocytes (28). CD40 is a member of the tumor necrosis factor/nerve growth factor receptor family (29) which includes CD27 (30), CD30 (31), and FAS antigen (32). Murine and human forms of CD40L had been cloned and found to be membrane glycoproteins with a molecular mass of ∼39 kD induced on T cells after activation (33). Also mast cells (34), eosinophils (35), and B cells (36) can be induced to express a functional CD40L. The CD40L–CD40 interaction has been demonstrated to be necessary for T cell–dependent B cell activation (33, 37). Mutations in the CD40L molecule cause a hyper-IgM immunodeficiency condition in man (38, 39, 40). On the other hand, CD40–CD40L interactions also orchestrate the response of regulatory T cells during both their development (41, 42) and their encounter with antigen (43, 44).NK cells have also been suggested to play a role in B cell differentiation and immunoglobulin production (45). Therefore, it was of interest to investigate whether NK cells could use a CD40-dependent pathway in their interactions with other cells. Therefore, we have investigated the ability of target cells expressing CD40 to induce activation of NK cytotoxicity.     

Effect of longitudinal changes in visceral fat area and other anthropometric indices to the changes in metabolic risk factors in Japanese men: the Hitachi Health Study

OBJECTIVE

The effects of longitudinal changes in the visceral fat area (VFA), and other anthropometric indices, on the risk factors of metabolic syndrome were not studied. We calculated the changes in metabolic risk factors in relation to changes in certain anthropometric indices in a large-scale study of Japanese men.

RESEARCH DESIGN AND METHODS

The subjects were 1,106 men participating in the Hitachi Health Study who received a computed tomography examination in both 2004 and 2007. VFA, subcutaneous fat area (SFA), and waist circumference were measured using the computed tomography. We examined how longitudinal changes in each anthropometric index over a 3-year period influenced the value of each metabolic risk factor.

RESULTS

Changes (∆) over a 3-year period in body weight, SFA, and waist circumference strongly correlated, while the changes in body weight and VFA were weakly correlated. Changes in the VFA were associated with changes in metabolic risk factors, especially changes in triglyceride and HDL; we found these changes to be independent of the ∆body weight and ∆waist circumference.

CONCLUSIONS

Change in body weight is not a precise surrogate marker of ∆VFA, and repeated VFA measurements over time are useful. Adopting a lifestyle that does not increase the VFA is important in preventing metabolic syndrome.Cardiovascular disease (CVD) is one of the leading causes of morbidity and mortality in the world (1). Previous reports have shown that obesity plays a significant role in increasing cardiovascular risk (2). Certain indicators of obesity, such as the visceral fat area (VFA), or visceral adipose tissue, are more strongly associated with the risk of CVD than other indicators of obesity, such as waist circumference, BMI (3), or the subcutaneous fat area (SFA) (2). A large VFA is strongly related to a higher prevalence of impaired fasting glucose levels (4,5), diabetes (4,6,7), insulin resistance (4,8–10), hypertension (11,12), abnormality of lipid metabolism (13–16), and metabolic risk factors (14,17,18). Previous studies have examined the relationship between baseline VFA and metabolic risk factors. In a previous intervention study of 54 postmenopausal women, an increase in VFA strongly correlated with changes in triglyceride and HDL cholesterol levels compared with changes in the blood pressure and fasting blood glucose levels (19). In the current study, we examined the relationships between changes in the VFA, SFA, body weight, and waist circumference and changes in CVD risk factors to determine the relative contributions of the longitudinal changes in these anthropometric indices to the changes in metabolic risk factors over a 3-year period. Determining the relationships between the anthropometric indices and metabolic risk factors would be useful for preventing CVD in clinical settings.