Can combined oral therapy improve muscular fitness?

Combined thiazolidinedione–metformin treatment synergistically improves insulin signalling to insulin receptor substrate-1-dependent phosphatidylinositol 3-kinase, atypical protein kinase C and protein kinase B/Akt in human diabetic muscle
Original source: Diabetologia Volume 52, Number 1
Authors: N. Temofonte, M. P. Sajan, S. Nimal, T. Pastoor, C. Fumero, L. Casaubon, J. L. Powe, M. L. Standaert1, and R. V. Farese (corresponding author)
Publication date: January, 2009
DOI (digital document ID): DOI: 10.1007/s00125-008-1180-z
Requires subscription? Yes
Publicly-available abstract: Yes

Synopsis:
Impaired insulin responses in Type 2 diabetes can make it difficult for glucose to get to muscles, where they are needed. It is believed that this is because certain insulin-activated protein enzymes (atypical protein kinase C (aPKC) and protein kinase B (PKB/Akt)) are not as thoroughly activated as they should be. Both metformin and thiazolidinediones (a class of oral diabetes-management drugs that includes rosiglitazone (Avandia) and pioglitazone (Actos)) improve this deficiency. The investigators wanted to know if adding both drugs together would create an even greater improvement.

Combined metformin-thiazolidinedione therapy was administered to Type 2 test ubjects for 5-6 weeks and the results measured. The investigators observed improved glucose movement and improved insulin-induced activity of four muscle signalling factors (insulin receptors plus two protein kinases). Despite this improved activity, the levels of aPKC in muscle tissues were not improved.

Because of the improvement in the four signalling factors, the investigators consider this test successful.

Reliability:
The number of patients tested was not available in the abstract, nor was any CONSORT statement, so it's difficult to tell whether the sample size was large enough to counteract small-sample skew. Several of the investigators are associated with a Veteran's Administration (VA) center. VA patients often get the worst possible levels of care, so it is hard to tell how far along the subjects' T2 had progressed, or how well it had been treated before the test. That we are looking at combined therapy and it is being called "therapeutically useful" even though depressed muscular aPKC levels were not affected by the treatment suggests that this is the sort of experiment that would be funded by a drug manufacturer, with an eye towards pushing more expensive drugs (such as Avandamet, a combination of Avandia and metformin) on the T2 public.

Practical Applications:
Improved muscular uptake of glucose could improve physical performance, and with it, positive incentives toward exercise. This could result in T2 patients being more interested in exercising, and thereby, improving both physical fitness and insulin sensitivity.

This synopsis was based on the abstract only.

Tesofensine - initial trials of a potential weight-loss drug

Effect of tesofensine on bodyweight loss, body composition, and quality of life in obese patients: a randomised, double-blind, placebo-controlled trial
Original source: The Lancet Volume 372, Issue 9653
Authors: Arne Astrup (corresponding author), Prof Sten Madsbad, Leif Breum, Thomas J Jensen, Jens Peter Kroustrup, Thomas Meinert Larsen
Publication date: 29 November 2008
DOI (digital document ID): 10.1016/S0140-6736(08)61525-1
Requires subscription? Yes
Publicly-available abstract: Yes

Synopsis:
The investigators are interested in producing a safe, more-effective weight loss drug than those already on the market. They looked at safety and effectiveness of tesofensine, which inhibits the uptake of several hormones. Current weight loss drugs only provide an average of 3-5 kg (7-12 lb) greater weight loss than diet and exercise alone.

The investigators conducted a double-blind, placebo-controlled survey of 203 obese patients over a six-month period, along with diet and exercise. Three strengths of tesofensine were used in the study. The patients who used tesofensine lost more weight than those who did not, and the larger the dose of tesofensine, the more weight they lost. The most common side effects reported in the abstract were relatively minor.

The investigators reported that the two lower strengths of tesofensine did not raise blood pressure or heart rate, and that the middle dosage raised heart rate by an average of 7.4 beats per minute.

Reliability:
This is a Phase II study, conducted by the drug manufacturer. This means it is one of the earlier human-based studies. Based on the small sample and limited time, the investigators believe the drug is safe and effective; however, more complete, Phase III studies are needed to prove this over larger populations, over longer amounts of time.

That the lower strengths of tesofensine "showed no significant increases in systolic or diastolic blood pressure compared with placebo" suggests that the drug does indeed raise blood pressure (they did not state this of the highest strength tested -- suggesting that the higher dosage might indeed cause a significant rise in blood pressure). The increase in heart rate may have other adverse implications.

Update:
Several comments to this article were posted in the 2009 February 28 issue of The Lancet. Concerns addressed included not just the rise in blood pressure -- which apparently was not considered in the context of predicted drops in blood pressure due to weight loss -- and adverse psychological effects of the drug. The authors' response to these concerns was to suggest that drops in blood pressure were due to dietary change rather than weight loss itself, and to note that there were no adverse psychological effects observed in their test population.

Again, this was a Phase II trial, which means that it is one of the earlier human-based trials before a drug can be marketed in the United States.


Practical Applications:
The search for a safe, effective weight loss pill is ongoing. Our understanding of the interrelationship between obesity, insulin resistance, hypertension, and cardiovascular disease is still imperfect, but observation suggests that reducing the degree to which one is obese can reduce or reverse the damage of metabolic syndrome.

Since it will often take more than a year for a determined obese person to lose sufficient weight to move out of the "obese" classification, weight-loss drugs should be proven to be safe and effective over a period of years. Since there is also a potential for impatient patients to want to increase the dose, they should be proven to be safe at greater doses than those intended for prescription.

This synopsis was based on the abstract only.

On the Low Birth Weight Risk for Insulin Resistance

Altered PI3-Kinase/Akt Signalling in Skeletal Muscle of Young Men with Low Birth Weight
Original source: PLoS ONE 3(11): e3738
Authors: Christine B. Jensen, Malgorzata S. Martin-Gronert, Heidi Storgaard, Sten Madsbad, Allan Vaag, Susan E. Ozanne (corresponding author)
Publication date: November 17, 2008
DOI (digital document ID): 10.1371/journal.pone.0003738
Requires subscription? No
Publicly-available abstract: Yes

Synopsis:
Low birth weight (LBW), an indicator of stress or an adverse fetal environment, is associated with increased future risk of insulin resistance and type 2 diabetes. The investigators are reporting continuing research on a specific insulin signaling pathway may be altered in skeletal muscle of young adult men with LBW. This would help increase our understanding of the mechanisms of insulin resistance in this particular population.

Muscle biopsies were obtained from 20 healthy 19-yr old men who had been in the lowest 10% birth weight for full-term babies and compared them to 20 physically similar men of normal birth weight. The samples were checked for fasting blood glucose and insulin levels, and after four hours in which insulin-production was medically stimulated.

The researchers looked at several previously-unstudied proteins and pathways related to muscular function and muscular glucose metabolism to see if there was any difference between the two groups of men. They found significant differences in the levels of several proteins after insulin stimulation. Some of these differences seen in the LBW group are similar to those seen in patients with insulin-resistant Type 2 diabetes.

The authors conclude that these differences in skeletal-muscle response to insulin precede, and may contribute to, the development of whole-body insulin resistance and type 2 diabetes in men with LBW.


Reliability:
The tests were done on a small number of subjects and a small number of controls. The small sample could skew the results obtained. Also, these were spot observations. Longitudinal observation of these subjects (over a period of time) might give the researchers better information about whether or not insulin resistance progresses in this manner in these subjects.

Practical Applications:
This is one of a series in basic research of how diabetes may develop in specific populations.

In many areas, low birth weight is associated with maternal malnutrition and/or poor prenatal care -- which are further associated with low-income communities and minority communities. Type 2 diabetes is more common in these groups than in the general population. Proving a definite link and path may bring more interest in providing education, and medical and dietary services, to this high-risk group.

Ethics note:
Written informed consent was provided from all participants and approval was obtained from the regional ethics committee.

This synopsis was based on the entire article.