Metformin and exercise combination less effective for glucose control

It's common enough for researchers to look at the impacts of prescribed drugs on the body. And if you're a diabetes researcher who believes that exercise has great benefits for those with type 2 diabetes, you're hoping your research will show that. But when Normand Boulé looked at the dual impacts of exercise and metformin -- two of the most commonly-prescribed modalities for glucose control -- on that very outcome, the hoped-for double whammy wasn't the result. "The study had three objectives: we wanted to look at the effect of metformin on exercise in people with type 2 diabetes, examine the effect of exercise on metformin concentrations in the body, and finally to look at the effects of metformin and exercise on glucose control, which is essential for people with diabetes," says Boulé, whose study -- a randomized, double-blind, crossover study -- involved a multi-disciplinary team of researchers from five faculties at the U of A.
Ten men and women between 30 and 65 with type 2 diabetes, but not taking glucose-lowering medication or insulin for their condition were recruited into the study. Participants were randomly assigned to take metformin or a placebo for the first 28 days of the study, then crossed over so those taking the placebo received metformin and vice versa for a second 28 day period. On days 27 and 28, participants spent six hours in the exercise physiology lab and performed different tests, including approximately 40 minutes of exercise on day 28.
"Metformin reduces glucose in the blood and many believe it does so by activating exercise-like pathways," explains Boulé. "As expected, in our study metformin lowered the blood glucose concentrations measured during a two-hour period after lunch. But we found that on the non-exercise day metformin led to better glucose control after lunch than on the day our participants took metformin and exercised."
Boulé thinks that because both metformin and exercise act to lower glucose levels, the combination may have triggered a counter regulatory response by the body to prevent glucose levels dipping too much. "During exercise, glucagon concentrations increased in the blood (a hormone secreted by the pancreas that raises glucose levels) but when we combined exercise and metformin the glucagon levels were almost twice as elevated."
He also said that the combination of metformin and exercise is not always worse than metformin alone. The findings of their study was likely impacted by the timing of meals relative to the exercise session participants underwent and that the intensity of exercise may have had an impact as well, including the fact that these levels were measured after a single bout of exercise as opposed to regular daily exercise.
In terms of the other foci of the study Boulé says the data for the impacts of metformin on exercise were consistent with previous studies looking at this: participants showed slightly increased lactate levels, and increased use of fats as an energy source during exercise. However, he believes his study was the first to document a significantly increased heart rate when performing aerobic exercise of various intensities with metformin (six beats per minute on average). "However, all participants were able to complete the exercise portion in both metformin and placebo conditions," he says.
"Also surprising is that throughout the day that they exercised, metformin concentrations were higher than on the day that they didn't," says Boulé. The reasons for this are not well understood.
Boulé says despite these findings, "exercise has hundreds of benefits" and should still be an important part of a healthy approach to glucose control for those with diabetes, including those taking metformin.
"What we've learned is that the relationship between exercise and metformin is complex, and this opens the door for more research to examine how different treatments work together, especially because exercise is widely prescribed for people with diabetes and metformin is often the first line drug of choice for treating type 2 diabetes."
This study was funded by the Alberta Diabetes Institute.

**Source: University of Alberta - Faculty of Physical Education and Recreation

EEUU: Científicos hallan el vínculo común de todas las formas de esclerosis lateral amiotrófica

A veces un pequeño avance en el conocimiento de las bases de una enfermedad basta para cambiar el curso de la investigación y abrir la puerta a nuevos tratamientos. Como si quitando un pequeño nudo, se pudiera desenmarañar toda una madeja de información difícil de comprender. Eso es lo que ha conseguido un grupo de científicos de la Universidad Northwestern de Estados Unidos al identificar por primera vez la causa común para el desarrollo de todas las formas de esclerosis lateral amiotrófica o ELA. Lo que une a estos trastornos es un fallo en el sistema de reciclaje de las células del sistema nervioso que causa una proteína.
El hallazgo se presenta en la revista «Nature» como uno de los avances más importantes en un campo que aún no ha proporcionado grandes alegrías. Con este nuevo paso se cuenta con una diana común sobre la que diseñar terapias eficaces para combatir los distintos tipos de ELA.
Este mal neurológico, también conocido como el mal de Lou Gehrig o de Stephen Hawking, por ser los dos enfermos más conocidos, es una enfermedad cruel. Daña de forma progresiva las neuronas motoras, las células nerviosas que controlan los músculos, hasta perder el control del cuerpo mientras la cabeza conserva sus facultades intactas. No hay ningún tratamiento que frene el deterioro del cuerpo y el desenlace es fatal.
El origen y factores que originan la ELA es un misterio. Existe un tipo familiar de origen genético, aunque los genes no parecen ser los únicos factores involucrados. Ahora el equipo de la Universidad de Northwestern ha descubierto que la enfermedad nace de un fallo en el sistema de reciclaje de proteínas en las neuronas de la médula espinal y el cerebro. El funcionamiento de estas neuronas depende de lo eficiente que sea el reciclaje. Si falla,las proteínas se acumulan, las células nerviosas no pueden autorepararse y acaban sufriendo daños.
Todo esto ocurre cuando una proteína, llamada ubiquilina 2 deja de hacer su trabajo. Este mecanismo se repite en todos los tipos de esclerosis lateral amiotrófica, desde la hereditaria a la esporádica (sin origen familiar) y otro tercer tipo, más raro, que causa demencia.
«Este nuevo conocimiento abre un campo para encontrar un tratamiento eficaz contra la ELA», asegura Teepu Siddique, uno de los autores principales del estudio. Su próximo paso será probar fármacos que mejoren el reciclaje. Siddique apunta que este mecanismo estaría detrás de otras enfermedades neurodegenerativas, como el alzhéimer o el párkinson.

**Publicado en "ABC"

Viajes: Vida rural y tratamientos de spa en el Pirineo catalán

Si quieres disfrutar de unos días en contacto con la naturaleza, practicando deporte y sintiendo todo el encanto de la vida rústica, aunque sin renunciar a un buen masaje o un circuito termal, tu destino está en el Pirineo catalán. Allí se encuentra Berga Resort (tel.: 938.211.250, www.bergaresort.com) un complejo con tres tipos de alojamiento totalmente equipados, facilidades para diversos deportes y un gran Wellness Club con centro deportivo de 12.000 metros cuadrados y Spa con área termal.
Los alojamientos, ideales para una escapada en familia o con un grupo de amigos, consisten en bungalows de madera, mobil-homes y chalets. Todos los alojamientos disponen de cocina, baño completo, habitaciones y comedor-estar. Están totalmente equipados con los utensilios para cocinar, cubertería, sábanas, aire acondicionado, calefacción, tv de plasma, toallas, etc. Su club deportivo y spa es muy completo, con piscina hidrotermal con chorros cervicales y lumbares, camas de agua, fuente de hielo, baño de vapor con aromaterapia, sauna finlandesa, templo de duchas con aromaterapia, hamacas térmicas.
Se sugiere una estancia en plena naturaleza en un bungalow de madera con actividades infantiles cada mañana para niños de 3 a 8 años con monitoras y todas las instalaciones deportivas e infantiles incluidas como las piscinas cubiertas climatizadas, gimnasio, fitness, tenis, padel, y una entrada al circuito de aguas por persona. Los dos primeros fines de semana de septiembre se ofrece alojamiento de dos noches, más masajes relajantes, más circuitos de aguas y disfrute del área relax, desde 357 euros para dos personas.

Curso sobre "Enfoque interdisciplinar de las Enfermedades Raras" en Sevilla

Los días 19 y 20 de septiembre se celebrará en Sevilla, en el marco de los cursos de verano de la UNIA, el curso "Enfoque interdisciplinar de las Enfermedades Raras".

La información relativa al curso (Presentación, dirección y profesorado, calendario y horario, importe y financiación, matricula y becas) se encuentra en el siguiente enlace: http://www.unia.es/component/option,com_hotproperty/task,view/id,644/Itemid,445/

El plazo de matrícula está abierto hasta 72 horas de que comience el curso.

Strengthening fragile immune memories to fight chronic infections

After recovering from the flu or another acute infection, your immune system is ready to react quickly if you run into the same virus again. White blood cells called memory T cells develop during the infection and help the immune system remember the virus and attack it if it comes back. But chronic infections such as those caused by viruses like HIV and hepatitis C are different. If the immune system can't clear the infection out of the body fast enough, the memory T cells that initially developed against the virus upon first encounter are lost. This poses a challenge for vaccine development.
Researchers at the Emory Vaccine Center have identified the conditions that make memory T cells slip away during persistent infections. They have also shown that a molecule called 2B4 on memory cells causes them to slow down during chronic infections. The results are published online this week in the journal Immunity.
The results have implications for vaccine design. The authors emphasize the importance of having vaccines that encourage the immune system to quickly control a potentially chronic infection or prevent it from gaining a foothold -- a task that some experimental vaccines against HIV's cousin SIV have accomplished.
"In a chronic infection, the memory T cells become so tightly regulated that they eventually are ineffective," says first author Erin West, an Emory graduate student in immunology and molecular pathogenesis. "This is why it's so important to have that initial strength at the beginning."
West and most of the co-authors are in the laboratory of Rafi Ahmed, PhD, director of the Emory Vaccine Center and a Georgia Research Alliance Eminent Scholar. Researchers from Harvard Medical School also contributed to the study, including W. Nicholas Haining and Cox Terhorst.
West and her colleagues studied mice infected by a meningitis virus which establishes a chronic infection. A weaker form of the virus can be cleared from the body in a couple weeks. They tracked naïve T cells as well as memory T cells' responses to infections that varied in dose and persistence.
A molecule called 2B4 appears on memory T cells that are activated during chronic infections and slows them down, the Emory team found. This level of regulation probably helps control the immune system and prevents it from developing dangerous over-inflammation, West says.
"Perhaps the body says 'I can't take care of this, so I will shut down,' before too much inflammation and damage occurs," she says.
Emory researchers have identified other molecules that produce "immune exhaustion" on T cells such as PD-1, but 2B4 is different because it seems to specifically regulate memory T cells. If memory T cells are engineered to lack 2B4, they are better able to persist during a chronic infection, although it's not clear whether the cells are then more effective at fighting the infection, West says. Blocking 2B4 might be a way to enhance immune responses against chronic infections, but more information is needed about how it works, she says.
The researchers also found that memory T cells need more "help," in the form of signals from other T cells, in the setting of chronic infection. This is a reversal of the situation in acute infections, where memory T cells are quicker to respond and need less help, she says.
In the paper, the Emory team cites a HIV vaccine tested in Thailand that was shown to have some ability to block initial infection, and an experimental hybrid vaccine against SIV designed by scientists in Oregon that has shown similar effects. They suggest that their results could be used to tune future vaccine design efforts and take advantage of these successes.
The research was supported by the National Institutes of Health.

**Source: Emory University

Single flexible sigmoidoscopy screening associated with reduced colorectal cancer

A single flexible sigmoidoscopy screening between the ages of 55-64 years is associated with a lower level of colorectal cancer (CRC) incidence and mortality, according to a study published online August 18 in the Journal of the National Cancer Institute. Multiple randomized controlled trials have shown that fecal occult blood testing (FOBT) in CRC screening can reduce the mortality rate of patients diagnosed with CRC. Observational studies and a prior, randomized trial from the U.K., known as SCORE have shown a reduction in incidence and mortality for cancer in the rectum and sigmoid colon (distal CRC) among patients who had undergone endoscopy, suggesting that the removal of adenomas at screening can provide long-term protection against the development of distal CRC.
To determine if single flexible sigmoidoscopy is a good preventative measure in CRC screening, the researchers, coordinated by Nereo Segnan, M.D., of the Epidemiology Unit at S. Giovanni University Hospital in Turin, Italy, mailed a questionnaire investigating about subject's interest in FS screening to a random population sample of men and women between the ages of 55-64 years. Eligible interested responders were randomly assigned to either the control group (N= 17148 -- no further contact) or intervention group (N=17144 -- invitation for flexible sigmoidoscopy)
Flexible sigmoidoscopy was performed on 9,911 subjects, and of those, 9,387 (94.71%) were discharged, 55 (0.55%) were referred for surgery, 395 for follow-up surveillance colonoscopy, and the remaining 74 patients did not comply with the recommended total colonoscopy assessment.
The median follow-up period was 10.5 years for CRC incidence and 11.4 years for all-cause and CRC-specific mortality. During this period 557 people (including those detected at initial screening) were diagnosed with a CRC and 148 died of the disease.
The researchers found that in the intent-to-treat analysis, CRC incidence and mortality were reduced by 18% and 22%, respectively. CRC incidence was reduced by 31% among those who were screened (per -protocol analysis), and by 46% for advanced CRC cases.
Furthermore, CRC mortality was statistically significantly reduced by 38% in screened subjects compared to the control group.
The authors write that the reported findings, which are consistent with the observed reduction of CRC incidence and mortality among people screened in the recently published UK Flexible Sigmoidoscopy Screening Trial, support the hypothesis that "Flexible sigmoidoscopy screening offered just once represents a safe and effective method for CRC screening and ensures a long lasting reduction of CRC risk." According to the researchers, "A longer follow-up is needed to fully assess the impact on mortality and to estimate the duration of the protective effect."
In an accompanying editorial, Timothy R. Church, Ph.D., of the University of Minnesota, writes about what the best approach to CRC screenings may be. Underlying the three main CRC tests (flexible sigmoidoscopy, FOBT, and colonoscopy), Church mentions that a cost-effective analysis is an important factor in determining the best available method, stating, "these costs are driven by not only the up-front infrastructure costs for laboratories, equipment, endoscopy facilities, training, and manufacturing but also by the rates of false-positive results."
Church argues that since none of the standard three approaches to CRC screening is more effective than the other, until more substantial evidence is collected, endorsing all three methods is the best way to attack CRC. In the event of conflicting results from the tests, Church writes: "Any concerns about the potential confusion that arises from multiple approaches may be balanced by the advantages of tailoring screening to the preferences of the patient."

**Source: Journal of the National Cancer Institute

SUNY Downstate researchers identify possible new targets for treating pain in women

Women and men experience pain, particularly chronic pain, very differently. The ability of some opioids to relieve pain also differs between women and men. While it has been recognized since the mid-nineties that some narcotic analgesics are more effective in women than men, the reason for this difference was largely unknown. Narcotic analgesics decrease pain by activating opioid receptors, which are located on nerves that transmit painful sensations. Since levels of mu, delta, and kappa opiate receptors -- the three main types of opioid receptor in the brain and spinal cord -- are not thought to differ dramatically in men and women, it was difficult to understand why the effectiveness of some painkillers is dependent on sex.
Now, research supported by the National Institute of Drug Abuse (NIDA) has revealed that the same major types of opioid receptor interact differently, depending on sex. The spinal cord of female laboratory animals was found to contain almost five times more kappa-mu heterodimer -- a complex of mu-opioid and kappa-opioid receptor -- than the spinal cord of male animals. Furthermore, the amount of mu-kappa heterodimer in the spinal cord of the females was about four times higher when their levels of estrogen and progesterone were at their peak. Subsequently, researchers found that both estrogen and progesterone are critical for the formation of mu-kappa opioid receptor heterodimers.
This research was conducted by Alan Gintzler, PhD, professor of biochemistry, Department of Obstetrics and Gynecology, and his senior collaborators Sumita Chakrabarti, PhD, and Nai-Jiang Liu, PhD, at the State University of New York (SUNY) Downstate Medical Center
The discovery of a mu-kappa opioid receptor complex that is more prevalent in the spinal cord of females than males and that is synchronized with the ebb and flow of ovarian hormones could explain why drugs used to treat pain, such as pentazocine, nalbuphine, and butorphanol -- which primarily act on mu-opioid and kappa-opioid receptors -- are more effective in women than men. The activation of the kappa-opioid receptor within the kappa-mu-opioid receptor complex could provide a mechanism for recruiting the pain-relieving functions of spinal kappa-opioid receptors without also activating their pain-promoting functions.
The research by Drs. Gintzler, Liu, and Chakrabarti, which was recently published in the Proceedings of the National Academy of Sciences and the Journal of Neuroscience, suggests that kappa-mu opioid receptor heterodimers could function as a molecular switch that shifts the action of kappa-opioid receptors and endogenous chemicals that act on them from pain-promoting to pain-alleviating. Kappa-mu opioid receptor heterodimers could serve as a novel molecular target for pain management in women.
Dr. Gintzler's research suggests that physicians should take the stage of the menstrual cycle into account before deciding which drugs to prescribe to treat pain in women. While some drugs might be very effective in treating pain at times when estrogen and progesterone levels are high, they could heighten pain when levels are low. "This consideration could become even more critical in managing pain in postmenopausal and elderly women," said Dr. Gintzler. "Further research is needed to flesh out these possibilities."
The Journal of Neuroscience paper appeared in the August 17, 2011 edition.

**Source: SUNY Downstate Medical Center