Featured research

Featured research

Alterations of the circadian clock in the heart by streptozotocin-induced diabetes
Young ME, Wilson CR, Razeghi P, Guthrie PH, Taegtmeyer H. J Mol Cell Cardiol. 2002;34:223–231.

The heart possesses a fully functional internal clock [1]. This clock provides the selective advantage of anticipation, enabling the organ to prepare for a given stimulus, thereby optimizing the appropriate response. As many of the potential timekeepers (zeitgebers) are altered in diabetes, and given that the morphology, gene expression, metabolism, and contractile performance of the heart are also altered in diabetes, the authors investigated whether the clock of the heart is also affected within this environment.
The circadian patterns of gene expression of several components of the mammalian clock were compared in hearts isolated from control and insulin-dependent diabetic (induced by streptozotocin b-cell destruction) rats. All components of the clock investigated, possessed circadian rhythms of gene expression. In the hearts isolated from diabetic rats, the phases of these circadian rhythms were altered (approximately 3 hours early) in comparison with those of control rats. The clock in the heart has therefore lost normal synchronization with its environment during diabetes.

Commentary
It is likely that insulin, or an additional humoral factor which is influenced by insulin (either directly or indirectly), acts as a zeitgeber in the heart. These results are consistent with a recently published study showing that restriction of caloric intake causes phase shifting of peripheral clocks, including the clock of the heart [2]. Streptozotocin is commonly used for the induction of diabetes in rodent models. Despite this, it is possible that the streptozotocin-induced alterations of the circadian clock in the heart are independent of diabetes development. Additional models of diabetes might provide useful information to clarify this issue. It is also possible that during prolonged periods of uncontrolled diabetes, alterations of the circadian clock in the heart are amplified. Long-term studies are therefore required to investigate this possibility. If diabetes is impairing the normal rhythms of neurohumoral zeitgebers, it is likely that the central clock is relatively unaltered. Future studies will be required to answer these important questions, as well to identify the major zeitgebers affecting the circadian clock of the heart.
Alterations of the clock in the heart could result in a loss of the synchronization between the stimulus and responsiveness of the system, eg, responsiveness to increased sympathetic activity in the early hours of the morning for humans, or increased fatty acid availability (due to lipolysis) during an overnight fast. Whether such loss of synchronization plays a role in the development of contractile dysfunction associated with the heart during diabetes requires elucidation.

REFERENCES

 
Restricted feeding uncouples circadian oscillators in peripheral tissues from the central pacemaker in the suprachiasmatic nucleus.

Damiola F, Le Minh N, Preitner N, Kornmann B, Fleury-Olela F, Schibler U.

Departement de Biologie Moleculaire, Sciences II, Universite de Geneve, CH-1211 Geneva, Switzerland.

In mammals, circadian oscillators exist not only in the suprachiasmatic nucleus, which harbors the central pacemaker, but also in most peripheral tissues. It is believed that the SCN clock entrains the phase of peripheral clocks via chemical cues, such as rhythmically secreted hormones. Here we show that temporal feeding restriction under light-dark or dark-dark conditions can change the phase of circadian gene expression in peripheral cell types by up to 12 h while leaving the phase of cyclic gene expression in the SCN unaffected. Hence, changes in metabolism can lead to an uncoupling of peripheral oscillators from the central pacemaker. Sudden large changes in feeding time, similar to abrupt changes in the photoperiod, reset the phase of rhythmic gene expression gradually and are thus likely to act through a clock-dependent mechanism. Food-induced phase resetting proceeds faster in liver than in kidney, heart, or pancreas, but after 1 wk of daytime feeding, the phases of circadian gene expression are similar in all examined peripheral tissues.

PMID: 11114885 [PubMed - indexed for MEDLINE]

Danielle Feuvray

Adiponectin, metabolic risk factors, and cardiovascular events among patients with end-stage renal disease
Zoccali C, Mallamaci F, Tripepi G, et al. J Am Soc Nephrol. 2002;13:14–41.

Adiponectin, which is a secretory protein of adipose tissue, attenuates endothelial inflammatory responses in vitro. In human subjects, plasma adiponectin concentrations are reduced among patients with atherosclerotic complications but are substantially increased among patients with advanced renal failure. The clinical and biochemical correlates of plasma adiponectin levels were investigated and the predictive power of adiponectin levels with respect to survival rates and cardiovascular events was prospectively tested in a cohort of 227 hemodialysis patients, who were monitored for 31 ± 13 months. Plasma adiponectin levels were 2.5 times higher (P < 0.0001) among dialysis patients (15.0 ± 7.7 mg/mL) than among healthy subjects (6.3 ± 2.0 mg/mL), were independent of age, and were higher (P = 0.03) among women (15.2 ± 7.9 mg/mL) than among men (14.0 ± 7.4 mg/mL). For both genders, plasma adiponectin levels were inversely related to body mass index, plasma leptin, insulin, and serum triglyceride levels, and homeostatic model assessment index values.
Furthermore, plasma adiponectin levels were directly related to high-density lipoprotein cholesterol and inversely related to von Willebrand factor levels. Plasma adiponectin levels were lower (P < 0.05) among patients who experienced new cardiovascular events (13.7 ± 7.3 mg/mL) than among event-free patients (15.8 ± 7.8 mg/mL).
There was a 3% risk reduction for each 1 mg/mL increase in plasma adiponectin levels, and the relative risk of adverse cardiovascular events was 1.56 times (95% CI, 1.12–1.99 times) higher among patients in the first adiponectin tertile, compared with those in the third tertile. Plasma adiponectin levels are an inverse predictor of cardiovascular outcomes among patients with endstage renal disease.
Furthermore, adiponectin is related to several metabolic risk factors in a manner consistent with the hypothesis that this protein acts as a protective factor for the cardiovascular system.

Predictive value of the adipocyte-derived plasma protein adiponectin for restenosis after elective coronary stenting
Shimada K, Miyauchi K, Mokuno H, et al. Jpn Heart J. 2002;43:85–91.
The purpose of this study was to test the hypothesis that plasma levels of adiponectin can predict angiographic in-stent restenosis after coronary stenting. We prospectively examined adiponectin levels in 127 consecutive patients undergoing elective coronary stenting. Restenosis was defined as more than 50% stenosis at follow-up study by quantitative coronary angiography. There were no significant differences in clinical characteristics or angiographic findings between the groups with restenosis and no restenosis. The levels of adiponectin did not differ between the restenosis group and the no-restenosis group (5.7 ± 2.8 vs 5.9 ± 3.6mg/mL, P = 0.72). The plasma levels of adiponectin were not related to the late loss index after coronary stenting
(r = 0.01, P = 0.89). The levels of adiponectin were significantly lower in men than in women (5.5 ± 3.2 vs 8.8 ± 3.7 mg/mL, P < 0.001), and were negatively correlated with body mass index (r = –0.21, P = 0.01). We analyzed adiponectin levels in male, female, obese, nonobese, diabetic, and nondiabetic patients; however, there were no significant differences between the restenosis group and the no-restenosis group. This study demonstrated that the measurement of adiponectin could not predict angiographic restenosis after elective coronary stenting, whereas the plasma levels of adiponectin were associated with some coronary risk factors in patients with coronary artery disease.

Commentary
Adiponectin is a novel, adipocyte-derived hormone that has recently generated considerable interest in the research community. Adiponectin has an important role in the regulation of energy homeostasis and insulin sensitivity, and also appears to have antiatherogenic properties due to an attenuation of endothelial inflammation. Levels of circulating adiponectin are decreased in type 1 diabetic patients, insulin-resistant patients, as well as in obese individuals. Weight reduction in diabetics subjects also results in a significant increase in adiponectin levels. Emerging evidence suggests that adiponectin plays a protective role against insulin resistance and atherosclerosis. Because of the beneficial actions of adiponectin on energy homeostasis, a number of clinical studies have suggested that plasma adiponectin levels negatively correlate with the severity of insulin resistance and obesity. These recent articles also suggest that low plasma adiponectin levels are predictive for restenosis after elective coronary stenting, as well as adverse cardiovascular outcomes among patients with endstage renal disease. Due to the potential adverse metabolic implications of decreasing plasma adiponectin levels, a large research effort is presently underway to understand the molecular basis of the beneficial actions of adiponectin. The exciting developments in adiponectin research in the last few years suggest that increasing adiponectin levels may be a therapeutic approach to treating obesity, insulin resistance, and atherosclerosis.

Gary D. Lopaschuk

Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin
Knowler WC, Barrett-Connor E, Fowler SE, et al, for the Diabetes Prevention Program Research Group. N Engl J Med. 2002;346:393–403.
Type 2 diabetes affects approximately 8% of adults in the United States. Some risk factors — elevated plasma glucose concentrations in the fasting state and after an oral glucose load, overweight, and a sedentary lifestyle — are potentially reversible. We hypothesized that modifying these factors with a lifestyle intervention program or the administration of metformin would prevent or delay the development of diabetes. We randomly assigned 3234 nondiabetic persons with elevated fasting and postload plasma glucose concentrations to placebo, metformin (850 mg twice daily), or a lifestyle modification program with the goals of at least a 7% weight loss and at least 150 min of physical activity per week. The mean age of the participants was 51 years, and the mean body mass index was 34.0 kg/m2; 68% were women and 45% were members of minority groups. The average follow-up was 2.8 years. The incidence of diabetes was 11.0, 7.8, and 4.8 cases per 100 person-years in the placebo, metformin, and lifestyle groups, respectively. Lifestyle intervention reduced the incidence by 58% (95% CI, 48%–66%) and metformin by 31% (95% CI, 17%–43%), compared with placebo; lifestyle intervention was significantly more effective than metformin. To prevent one case of diabetes during a period of 3 years, 6.9 persons would have to participate in the lifestyle intervention program, and 13.9 would have to receive metformin. Lifestyle changes and treatment with metformin both reduced the incidence of diabetes in persons at high risk. Lifestyle intervention was more effective than metformin.

Commentary
Lifestyles. Individuals in the study with a body mass index >24 kg/m2, a plasma glucose of 5.3 to 6.9 mM/L in the fasting state and 7.8 to 11 mM/L after a 2-hour post-75-g oral glucose load were randomized to three interventions. The lifestyle intervention was systematic, intensive, and individualized. Its purpose was to achieve and maintain a weight reduction of 7% of initial body weight through a low-calorie, low-fat diet and moderate exercise of at least 150 min/week. This was attempted through a curriculum of 16 lessons, taught on a one-to-one basis during the first 24 weeks after randomization. The study participants were recruited from within the USA and over 40% were from minority ethnic groups, predominantly African American and Hispanic. The delivery of the lifestyle curriculum was sensitive to cultural issues. In addition to the 16 sessions, monthly individual and group sessions were held to reinforce the lifestyle advice.
The average weight of individuals in the lifestyle group was 94 kg. Six months after randomization this group had lost an average of 7 kg, with some weight gain over the ensuing years; however, even after 4 years, the cohort was 4 kg lighter than at randomization.
Lifestyle intervention and metformin similarly reduced fasting glucose levels but lifestyle intervention had a greater effect on glycosylated hemoglobin and postload glucose.
The authors estimate that 10 million individuals in the USA meet the entry criteria for this study. It is reassuring to know that there is hope for this huge and growing population. All it needs is time and motivation.

Michael Marber