A possible genetic component of Type 2 diabetes

Variance of the SGK1 Gene Is Associated with Insulin Secretion in Different European Populations: Results from the TUEF, EUGENE2, and METSIM Studies
Original source: PLoS ONE 3(11): e3506.
Authors: Björn Friedrich, Peter Weyrich, Alena Stančáková, Jianjung Wang, Johanna Kuusisto, Markku Laakso, Giorgio Sesti, Elena Succurro, Ulf Smith, Torben Hansen, Oluf Pedersen, Fausto Machicao, Silke Schäfer, Florian Lang, Teut Risler, Susanne Ullrich, Norbert Stefan, Andreas Fritsche (corresponding author), Hans-Ulrich Häring
Publication date: 5 November 2008
DOI (digital document ID): 10.1371/journal.pone.0003506
Requires subscription? No
Publicly-available abstract: Yes

Synopsis:
The authors used a "classical candidate-gene approach" to examine genes that play a role in insulin secretion and their potential roles in the development of insulin-resistant diabetes. The gene they focused on is serum and glucocorticoid inducible kinase SGK1, which is encoded by the gene SGK on chromosome 6q23. The action of this gene is increased in the presence of corticoids and insulin, among other things, and seems to provide a molecular link between electrolyte activation and glucose stability. It also appears to play a role in both insulin signalling and insulin secretion and blood pressure.

The investigators looked at genetic variance in SGK, and potential associations with insulin secretory function, in two specific groups of people (the 725-person TUEF cohort and the 634-person EUGENE2 participants) whose diabetes risks had been examined for insulin secretion traits among those who were prediabetic. These were compared with the results of a study on an older, genetically-similar population (the 4457-person METSIM cohort) to determine whether their hypothesis was correct.

Insulin sensitivity and insulin production were measured using oral glucose tolerance tests (OGTT), measuring c-peptide levels or plasma insulin levels to determine insulin secretion, along with blood glucose levels to determine insulin sensitivity. BMI and waist-hip ratio were also measured in these populations. The patients were correlated to specific variations of one of four tagged alleles (rs9402571) of the SGK-1 gene.

There was no association of the specific tagged alleles with insulin sensitivity in either the TUEF screening population or in the EUGENE2 study, but the authors suggest that this expression of the gene's expression is based on BMI. They mention that the spot in which the SGK1 gene sits has been "associated with BMI progression in participants of the Framingham Heart Study."

On the other hand, the TUEF and EUGENE2 studies did report an increase in insulin secretion in lean patients with one specific variation of the rs9402571 allele. METSIM participants with this variation had a lower incidence of Type 2 diabetes. The authors suggest that this variation may protect against Type 2 diabetes, but that its effect may become blocked or blurred in overweight or obese individuals.

Their analysis suggests that the rs9402571 allele of the SGK1 gene is associated with altered insulin secretion and with Type 2 diabetes.


Reliability:
The authors are associated with accredited medical institutions and the results were published in a peer-reviewed journal. The subsets of the TUEF and EUGENE2 participants' data analyzed in the paper are relatively small. The correlation with an older population of similar genome poses a good initial check on the original hypothesis; the ongoing nature of the TUEF study (Tübingen Family Study) suggests that a more definitive correlation will be possible at some time in the future.

Practical Applications:
The developing discipline of genomics suggests that we might one day be able to base our healthcare on how our own particular genes work.

This synopsis was based on the entire article.

Can fish oil counteract sleep deprivation?

Dietary fish oil did not prevent sleep deprived rats from a reduction in adipose tissue adiponectin gene expression
Original source: Lipids in Health and Disease 2008, 7:43
Authors: Ana BM Mattos, Monica JS Pinto, Cristiane Oliveira, Carolina Biz, Eliane B Ribeiro, Claudia M Oller do Nascimento, Monica L Andersen, Sergio Tufik, and Lila M Oyama (corresponding author)
Publication date: 5 November 2008
DOI (digital document ID): 10.1186/1476-511X-7-43
Requires subscription? No
Publicly-available abstract: Yes

Synopsis:
Sleep deprivation has been one of the hallmarks of modern society. Where it was once limited to the elderly, now even youth are chronically sleep deprived. Sleep deprivation is linked to adverse metabolic effects, including insulin resistance. Omega-3 fatty acids found in fish oil have been seen to improve insulin sensitivity -- decrease insulin resistance. We don't yet know how this works, but researchers believe that adiponectin has a role.

The aim of this study is to assess the effects of diets high in fish oil on sleep-deprived subjects. The authors note that while in humans, sleep deprivation is associated with weight gain, sleep-deprived rats tend to lose weight. This suggests to them a method of measuring insulin resistance in such a way that it is not related to weight gain. Glucose tolerance, serum insulin, and adiponectin levels are examined in both sleep-deprived and non-sleep-deprived rats.

The rats were kept awake for 96 hours, which is when the most dramatic alterations in lipid and hormone concentrations occur. At that time, the rats were subjected to a glucose tolerance test, starting with blood drawn after a 12-hour fast, and then after the glucose was given, at time intervals of 4, 12, 20, 24, 28 and 32 minutes. The blood sampled was tested for glucose concentration, insulin, and adiponectin levels. The animals were then killed, weighed, and the fat and protein contents of their bodies separated and measured. Adiponectin and transfer-RNA were measured from the animals' adipose tissues.

Sleep deprivation caused the rats to lose weight whether or not they were on fish-oil-rich diets (this is normal for rats). Non-sleep-deprived rats did not lose weight. Sleep-deprived rats fed a normal diet lost fat; those fed a fish-oil-rich diet did not. No change was observed in protein content of any of the groups.

Following the glucose tolerance tests, glucose concentration was significantly higher in the rats allowed to sleep than those who were sleep-deprived -- and in the last measurement, the glucose level in the rats who were both sleep-deprived and fed a fish-oil-rich diet dropped even further relative to the other groups.

Serum insulin and adiponectin was similar across all groups; however, the gene expression of adiponectin in abdominal tissue was lower in the sleep-deprived rats than the non-sleep-deprived rats. Insulin levels were lower in sleep-deprived male rats, so there may have been unaccounted-for factors in the test.

The authors examine the findings of previous studies on lipid consumption, fish oil, sleep deprivation, and adiponectin expression in rats to put their study into context. They conclude that sleep deprivation does cause a stress-related drop in adiponectin gene expression, which negatively effects insulin sensitivity.


Reliability:
There were only 5-9 rats per group studied. This is a very small sample, in which results can be skewed. Rats may not be a good model for humans in this environment, as humans tend to gain weight when sleep-deprived and there are perceived correlations between weight gain and insulin sensitivity. The readings for the rats were taken at the point of peak change of a single episode of sleep deprivation, rather than after a long period of chronic sleep deprivation (e.g., 1 month at 2 hrs less sleep than normal mice get). This is the difference between students spending a couple of all-nighters cramming for an exam versus a young professional working sixteen-hour days for several years to establish himself in a competitive field.

Practical Applications:
If it could be proven that fish oil supplements (or a diet rich in fish) could protect humans against some of the adverse metabolic effects of sleep deprivation, then this could be an effective and inexpensive treatment against those medical risks.

This synopsis was based on the entire article.

Can metformin help Type 1 diabetics?

Effect of Adjunct Metformin Treatment in Patients with Type-1 Diabetes and Persistent Inadequate Glycaemic Control. A Randomized Study
Original source: PLoS ONE 3(10): e3363
Authors: Søren Søgaard Lund (corresponding author), Lise Tarnow, Anne Sofie Astrup, Peter Hovind, Peter Karl Jacobsen, Amra Ciric Alibegovic, Ida Parving, Lotte Pietraszek, Merete Frandsen, Peter Rossing, Hans-Henrik Parving, Allan Arthur Vaag
Publication date: October 9, 2008
DOI (digital document ID): 10.1371/journal.pone.0003363
Requires subscription? No
Publicly-available abstract: Yes

Synopsis:
Despite intensive insulin use, many people who have had Type 1 (autoimmune) diabetes for a long period of time have trouble maintaining adequate glucose control and achieving an HbA1c of under 7%, which is considered a threshold beneath which the risk of developing complications of diabetes is reduced. There are a number of reasons -- physiological (medical), environmental, and psychological -- for poor control. One of the physiological reasons may be the development of insulin resistance over time. This study looks at the potential for adding the use of metformin -- an initial drug of choice in treating Type 2 (metabolic) diabetes (which often includes insulin resistance) -- to the use of insulin to improve blood glucose control in Type 1 diabetes.

The study included 100 Type 1 diabetes patients with poorly-controlled blood glucose levels (defined as HbA1c over 8%). A one-month period in which all of them received identical placebo pills was followed by a three-week period in which the pills of half of the patients was gradually changed to include 1000 mg metformin, twice daily. The other patients continued to receive placebo pills. The patients were followed at one- to three-month intervals, for a period of a year after maximum/target dose was achieved.

The study was conducted as a double-blind study, which means that neither the investigators nor the patients knew who was taking metformin and who was not.

At each clinic visit before and during the study, patients were tested for HbA1c, c-peptide levels (a protein used as an indicator of remaining beta-cell function), and blood glucose level. Their body mass index (BMI -- a comparison of weight to height) was also measured. They were asked to estimate the average of the blood glucose measurements they took themselves at home. They were also requested to report serious adverse effects (including life-threatening events requiring hospitalization, or which resulted in persistent or significant loss of physical abilities, or which caused an adverse reaction due to a birth defect, and hypoglycemic events which resulted in unconsciousness or which required the intervention of a third party) and minor adverse effects (including hypoglycemia mild enough for the patient to be able to treat himself). They were also asked to report any changes to their insulin prescriptions and treatments (change of type of insulin, number of injections per day, sites used, and dosage).

In addition to analyzing the HbA1c measurements of the entire groups (metformin and placebo), researchers counter-checked changes in HbA1c with changes in patient weight and insulin dosage. They also analyzed the measurements from overweight and obese patients separately from those of normal weight, and the results from those taking higher amounts of insulin daily from those taking smaller amounts, since insulin resistance is often treated with higher doses of insulin; it is also associated with overweight and obesity.

The results of the analysis showed no significant changes in HbA1c level for either group. However, the metformin users lost, on average, a little more than a kilogram of body weight and were able to reduce their daily insulin usage by, on average, 0.03 units per kilogram of body weight. By comparison, those patients on placebo did not lose weight and, on average, needed to increase their insulin usage by 0.03 units per kilogram of body weight. (This corresponds to average total daily insulin use of 3 units less per day for the metformin group, and about 2.5 units more per day for the placebo group.)

The results of this study were compared to the results of previous studies, and the strengths and limitations of both this study and those were examined.

Reliability:
The authors are professionals in the fields of endocrinology and diabetes care, associated with accredited institutions. The results were published in a peer-reviewed journal.

The study size was small, so there is some potential for skew.

The use of double-blinding and placebos removed the variables of being able to attribute all good effects to the use of the drug, as well as that of all positive effects being due to the suggestion of the pills being effective.

The duration of the study was long enough to determine whether metformin would have any effect on HbA1c; however, the reduction in insulin use among the metformin patients may have counteracted the drug's effects on lowering HbA1c. The authors note that had they specified that the patients not drop their insulin dosages, there may have been a greater risk of serious hypoglycemic events.

Practical Applications:
The authors suggest that the mild weight reduction and apparent improved insulin sensitivity among the patients treated with metformin may lower these patients' diabetes-related cardiovascular risks; however, metformin does not appear to be a useful tool for improving glycemic control in patients with long-duration Type 1 diabetes.


This synopsis was based on the entire article.

Are moderate-protein diets better than low-protein diets for people with metabolic syndrome?

Moderate carbohydrate, moderate protein weight loss diet reduces cardiovascular disease risk compared to high carbohydrate, low protein diet in obese adults: A randomized clinical trial

Original source: Nutrition & Metabolism 2008, 5:30
Authors: Denise A Walker Lasker (corresponding author), Ellen M Evans, and Donald K Layman
Publication date: 7 November 2008
DOI (digital document ID): 10.1186/1743-7075-5-30
Requires subscription? No
Publicly-available abstract: Yes

Synopsis:
This study compares the effectiveness of the standard USDA Food Pyramid diet with a higher-protein, lower-carbohydrate diet for weight loss in general, for fat loss in particular, and for lowering the blood-based indicators of cardiovascular risk and insulin resistance. A total of 50 people completed the testing, split between the two dietary approaches.

Both diets under test had the same amount of calories, with about 30% of total calories coming from fats. Carbohydrates supplied about 55% of the Food Pyramid diet group's caloric intake, and protein, the remaining 15%. The people assigned to this group were instructed to eat whole grains for their bread products. About 30% of the high-protein group's calories came from protein, with the remaining 40% coming from carbohydrates. (This is the same protein-carbohydrate-fat distribution advocated by the Zone Diet.) This group was instructed to eat primarily "high quality protein", including lean meats, dairy, and eggs. Both groups had similar amounts of fruits and vegetables in their daily diets. All subjects were instructed on portion sizes, dietary substitutions, how to weigh foods, and how to keep a food diary. There was no difference in exercise between the two groups.

Baseline measurements (weight, body fat percentage, cholesterol, and postprandial insulin) were taken at the start of the experiment. The subjects followed their assigned diet plans for four months, at which time the same measurements were repeated.

• The moderate-protein group lost about 5 pounds more per person than the USDA group, and more of their weight loss was from fatty tissues.
• Fasting glucose levels were unchanged, but fasting insulin levels decreased in the moderate protein group, while it increased in the USDA group. In addition, postprandial insulin levels dropped 85% for the protein group, but only 50% for the Food Pyramid group. (High plasma insulin levels are indicative of insulin resistance, which is often a predecessor to Type 2 diabetes.)
  
• There was a greater drop in total cholesterol in the USDA group than in the protein group. LDL ("bad") cholesterol dropped in the USDA group but rose in the protein group; on the other hand, HDL ("good") cholesterol dropped in the USDA group but rose in the protein group. The protein group also showed greater improvement in triglyceride levels than the USDA group. (High triglyceride levels are associated with increased risk of heart attack.)
  

Reliability:
The study was small scale, with only 50 people completing the four-month study. While the two groups of subjects were selected to be closely-matched, there is still opportunity for the results to be skewed. An initial run-in period put all subjects on as close to an even footing as possible before the trial started.
The authors are associated with an accredited university; the paper was published in a peer-reviewed journal.
Longer-term studies of larger groups may be needed to determine the long-term safety and effectiveness of high-protein diets.

The principal investigator (Denise A Walker Lasker) received funding from the National Cattleman’s Beef Association, The Beef Board and Kraft Foods. Both Beef associations have a vested interest in increasing protein consumption (in the form of beef).
The investigators have made no comparison between a higher-fat restricted-carbohydrate diet and a higher-protein restricted-carbohydrate diet.

Practical Applications:
The 30/40/30 protein/carb/fat (PCF) ratio is the basis of the Zone Diet. While this diet is higher in protein than traditionally advised for people with diabetes, recent publications suggest that this is not as high a risk as formerly perceived.

For further reading:
WebMD evaluates the Zone Diet
Wikipedia entry on the Zone Diet

This synopsis was based on the entire article.

Prenatal diet may affect insulin resistance for multiple generations

Insulin sensitivity is normalized in the third generation (F3) offspring of developmentally programmed insulin resistant
(F2) rats fed an energy-restricted diet
Original source: Nutrition and Metabolism 2008, 5:26
Authors: Daniel C Benyshek (corresponding author), Carol S Johnston, John F Martin and William D Ross
Publication date: 17 October 2008
DOI (digital document ID): 10.1186/1743-7075-5-26
Requires subscription? No
Publicly-available abstract: Yes

Synopsis:
A number of studies have shown that the way animals develop before birth can affect the birth weights, blood pressure, and glucose metabolisms of their children, grandchildren, and so on. Most research to date has only gone two generations beyond the original parents. This study takes observation to the third generation (great-grandchildren) and focuses on impairments to the animals' glucose metabolisms. A parent generation of female rats were fed protein-deficient diets while pregnant and nursing, and both they and three generations of their offspring were fed low-calorie diets, to see how this affected the insulin sensitivity of multiple generations of their offspring. A group of control rats was fed normal-calorie diets over the same number of generations.

The first generation of offspring (children) tended to be of low birth weight, while the second and third generations (grandchildren and great-grandchildren) were of normal birth weight. All generations were of lower than normal weight as adults, due to the caloric restriction. The first=generation offspring had normal insulin metabolism, While the second generation, as adults, had reduced insulin sensitivity and reduced insulin production -- a set of symptoms consistent with impaired glucose tolerance. The third generation did not show insulin resistance -- indeed, the males were even more insulin-sensitive than the control animals, whether they were fed calorie-restricted diets or allowed to eat at will.

Previous studies of this type showed insulin resistance in the first-generation offspring, which was not found in this particular study; however, the second-generation female offspring in this study were insulin-resistant.

The investigators are unsure why the third-generation offspring did not show impaired glucose tolerance or insulin resistance, even though both of those traits are considered to be adaptive traits that show up in "nutrient poor environments" (reduced protein, reduced calories). They suggest that one reason for this may be that the second-generation mother's insulin resistance left more energy in the bloodstream to be used by the fetus. On the other hand, the relative insulin sensitivity of previous-generation mothers (who had not been fed sufficient calories after weaning) made fewer nutrients available for the developing fetus, resulting in insulin resistance in the offspring.

The investigators suggest that more research is required to determine how pregnancy and nursing diets, and maternal insulin sensitivity, affects the insulin sensitivity of her offspring.

Reliability:
The authors are from accredited institutions, across a number of medical and social disciplines. The research was published in a peer-reviewed online journal. References are all from peer-reviewed journals. Therefore the experiment design is reliable. Since only four female rats from each child generation were bred, the study was small in size and therefore subject to skew. The authors did note that further research was warranted to find out why they got the results they did.

Practical Applications:
The normal birth weight and increased insulin sensitivity of child generations born to insulin-resistant mothers suggests a parallel mechanism for the large baby size common for human mothers with diabetes. While this study was conducted on rats, the rats are intended to be a shorter-lived and expendable model for human childbirth and development. A closer understanding of which maternal nutrients affect insulin resistance may lead to improved recommendations for pregnancy and nursing diets and supplements, and will ideally prevent insulin resistance in future generations of human adults.

This synopsis was based on the entire article.