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.

A possible reason for increased risk of infection of obese people and those with Type 2 diabetes

Interleukin-18 resistance in patients with obesity and type 2 diabetes mellitus
Original source: International Journal of Obesity (2008) Vol. 32, pp. 1407–1414
Authors: G R C Zilverschoon, C J Tack, L A B Joosten, B J Kullberg, J W M van der Meer and M G Netea (corresponding author)
Publication date: published online 22 July 2008
DOI (digital document ID): doi:10.1038/ijo.2008.109
Requires subscription? Not for this article
Publicly-available abstract: Yes

Synopsis:
Interleukin-18 (IL-18) is a signalling chemical (similar to hormones) that has a strong effect on stimulating interferon (IFN) release. It is produced by a number of different white blood cells and central nervous system cells. Interferon is an important chemical in fighting infections.

Higher levels of IL-18 have been shown to decrease abnormally large appetite and to improve insulin sensitivity. Interestingly, several studies have shown high levels of IL-18 in obese people with insulin resistance, and a recent study has demonstrated that a common version of the genes producing IL-18 is associated with a higher body mass index (weight) in people with type 2 diabetes or coronary heart disease. In addition, weight loss after bariatric surgery (such as gastric bypass or lapband) results in lowered blood concentrations of IL-18.

The investigators suspect that the cells of obese people and those with insulin resistant diabetes may have high levels of IL-18 because they do not respond as well to IL-18 as those of people of normal weight and who are not diabetic. To test this theory, they tested white blood cells of obese and Type 2 diabetes patients and compared them to those of lean, non-diabetic people, and measured their IFN production in relation to their IL-18 levels. They found that in the obese and the diabetic subjects, these cells respond poorly to IL-18 and produce less interferon. They also show impaired release of IFN after exposure to disease-carrying bacteria and fungi.

They conclude that the reduced response to IL-18 may be responsible for the increased susceptibility to infection among those who are obese or who have Type 2 diabetes.

Reliability:
The study was conducted with a small number of subjects: seventeen control subjects, eleven obese non-diabetic subjects, and fourteen subjects with Type 2/insulin-resistant diabetes. (The possibility of LADA or other autoimmune diseases was ruled out at the start of the study.) The smaller the number of subjects, the greater the possibility for skewed or atypical results. The research was published in a peer-reviewed journal, and the investigators are all associated with the a University Medical Center in the Netherlands. Based on the small number of subjects, the results should be considered to point in the direction of larger studies to confirm the investigators' results, as well as further research into why these cells have an impaired reaction to IL-18.

Practical Applications:
A confirmed pathway and reason for increased risk of infection among obese people and people with Type 2 diabetes could lead to therapy to reduce that risk and to better fight those infections that do occur. If insulin resistance and excessive appetite are also directly related to impaired IL-18 response, then improving that response could conceivably result in weight loss and improved insulin sensitivity as well.


This synopsis was based on the entire article.

Investigating Insulin Resistance in the Liver

Inhibition of cytohesins by SecinH3 leads to hepatic insulin resistance
Authors: Markus Hafner, Anton Schmitz, Imke Grüne, Seergazhi G. Srivatsan, Bianca Paul, Waldemar Kolanus, Thomas Quast, Elisabeth Kremmer, Inga Bauer and Michael Famulok
Original source: Nature Volume 444, pp. 941-944
Publication date: 14 December 2006
DOI (digital document ID): doi:10.1038/nature05415
Requires subscription? For complete article
Publicly-available abstract: Yes

Synopsis:
G proteins regulate biochemical "switches" in all living systems. They are switched on and off by chemicals called "guanine nucleotide exchange factors" or GEFs. Finding chemicals which increase or inhibit GEFs may be useful both to find out how GEFs work and to treat diseases in which the G proteins are affected.

A specific class of GEFs called "cytohesins" includes some GEFs that are associated with insulin production and signalling. The investigators found that in humans, a chemical called "SecinH3" might inhibit the cytohesins associated with insulin signalling. To test this theory, mice were treated with SecinH3 and observed to determine whether or not they showed increased signs of insulin resistance.

The mice exhibited increased glucose production, reduced glycogen storage and glycogen-to-glucose conversion, a reduced ability to metabolize fatty acids and ketones, and increased plasma insulin. These are all symptoms of insulin resistance, suggesting that increased levels of SecinH3, and/or decreased activity of cytohesins, may be responsible for insulin resistance.

The importance of this finding is that insulin resistance is one of the first signs of Type 2 diabetes.

Reliability:
The initial hypothesis was based on the isolation of SecinH3 and its effects in isolated human liver tissue, so even though this experiment took place in mice, it has a good probability of being directly transferrable to people. The article was published in a peer-reviewed journal, and the authors are professional researchers in biochemistry and immunology.
This leads to high confidence in the results.

Practical applications:
This research is still very early on in the process of developing new treatments for insulin resistance and Type 2 Diabetes.

This synopsis was based on the abstract only.