In my opinion the nutritional factor and lifestyle are very important, since individuals with a genetic predisposition may develop TDM2 or not depending on their nutritional status

I agree with Magna. Obesity is the very high risk factor for diabetes and obesity is associated with life style and nutrition. Diabetes is very complex diseases and i think that it is the result of many factors at the same time.

Life style and nutritional status, mainly waist circumference status are more important risk factors, genes related to obesity or T2D have not changed for many years, so, which have been come from observed changes to our lifestyle and environment

Both are extremely important factors. This disease is a combination of both genetic and environmental factors.

There is a very complex interrelationship between them. However, I believe genetics play a major role. T2DM does not develop in all the persons with a sedentary life style or even obesity. It is seen in those with genetic susceptibilities, although obesity or other environmental risk factors worsen the situation.

Both factors are important but which is more important depends on what you think is the heritability. Reported heritability is between 22%–73% from twin and family studies. So take your pick :-)

Both factors are important role but Genetic is a predisposing factor for T2DM and genetic modification is an expensive approach in T2DM treatment and prevention. Lifestyle modifications, diet therapy and exercise are reasonable goals , cost-benefit approaches and more socially acceptable changes in T2DM prevention and prevention of complications specially.

More information is available via this link

http://www.ncbi.nlm.nih.gov/pubmed/22079683

While lifestyle can be involved, there are genetic factors, more and more being discovered with type 2. There is immunologic evidence that obesity establishes an inflammatory environment. An important consideration though is that during diabetogenesis the body thinks it is starving. No matter how much someone eats the body is not sated. It is also extremely important to consider that clinical diagnosis cannot occur (hyperglycemia) until the disease has been occurring for perhaps several years. Therefore T2D begins, hyperglycemia does not occur for some time, the body is not utilizing nutrients, hunger signals go to the hypothalmus, more food is requested, the person gains weight, obesity occurs and then hyperglycemia occurs.

A different aspect is that obesity occurs, fat cells produce insulin shut off signals, hyperglycemia occurs. In the latter case simple weight reduction should solve the problem. However, what if the disease has multiple components? No all diabetics get to diabetes through the same pathway. Complicated. No?

Dear Dr David Wagner thanks for your contribution in our discussion. as you mentioned there are different scenario for T2DM. most of the time diabetic challenge is very vast and there are lots of biologic compensations in molecular level (i.e nucleus) but there is not any clinical sign (a silent response occurs). as you mentioned genetic is not a CAUSAL FACTOR but only a predisposition, a matrix.

none of those peoples with a genetic predisposition takes diabetes. epi-genetic factors lead to diabetes. of course genetic predisposition can speed-up or worsen the situation. isn't it?

Really the same is somewhat true for type 1...there certainly are genetic factors, more perhaps than for T2D, BUT having the right set of genes does not guarantee disease. Dr Rezapour you are right on the money by saying that genetics is NOT a causal factor

Heritability does not always mean genes. We also inherit our initial infection of gut flora from our mothers. Family and twin studies will not separate the two. David Wagner has commented on aberrant signaling in the development of T2DM. The principle organ involved appears to be the duodenum since surgical isolation of the duodenum causes remission of T2DM with reversal when the surgery is reversed. Since the production of most of the hunger hormones and insulin is mediated by the hexamine signalling pathway, an organism capable of interfering with this pathway is suspected. C. noyii Type A alpha toxin is uniquely an O-linked N-acetylglucosamine transferase so interferes with the hexamine signalling pathway. This may be the environmental factor since it is in the food chain of the western diet via intensively farmed animals. The absence of suitable phages in the gut flora may be the predisposing factor. In my own case antibiotic treatment has caused remission of my T2DM and all the complications. Unfortunately C. novyii has riddled my body with its resistant spores resulting in periodic reinfection. Long term serum glucose is negatively correlated with frequency of antibiotic use.

The genes vs environment debate is sterile. What we should be doing is investigating what is really going on with these signalling pathways.

gender also have affected the DM type 2 after aged 50 years because of estrogen declining in menopausal women.

At least currently including genetic risk factors do not improve the risk scores for prediction of T2DM in a significant way (see for instance [2]). On the other hand lifestyle changes showed a large improvment in T2DM (DPP study and follow ups [1]).

In my opinion lifestyle and the nutritional status are the mayor factors. A strong indicator is for me the high correlation between the increase in T2DM and changes in western nutrition towards high sugar, high fructose-corn sirup in the last 20 years, which is not explainable by changes in the prevalance of genetic risk factors.

The idea of genetic risk factors is mainly due to the current genome techniques at hand and the multitude of studies reported with them (people look in the areas where they can shine with their flashlights). Sequencing is cheap, mRNA chips are cheap, and everybody is reporting genome-scale analysis.

Of course some clear genetic defects are known, for instance related to the secretion of insulin, or Glucokinase mutations in the case of the MODY diabetes. But there are no clear genetic risk factors which can explain the T2DM epidemics.

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[1] Reduction in the Incidence of Type 2 Diabetes with Lifestyle Intervention or Metformin; Diabetes Prevention Program Research Group

N Engl J Med 2002; 346:393-403February 7, 2002DOI: 10.1056/NEJMoa012512

[2] J Clin Endocrinol Metab. 2012 Jul;97(7):E1338-41. Epub 2012 Apr 24.

Current genetic data do not improve the prediction of type 2 diabetes mellitus: the CoLaus study.

Schmid R, Vollenweider P, Bastardot F, Vaucher J, Waeber G, Marques-Vidal P.

"Two hundred seven participants (7.3%) developed T2DM during follow-up. On bivariate analysis, no differences were found for all but one genetic score between nondiabetic and diabetic participants. After adjusting for the validated clinic + biological risk score, none of the genetic scores improved discrimination, as assessed by changes in the area under the receiver-operating characteristic curve (range -0.4 to -0.1%), sensitivity (-2.9 to -1.0%), specificity (0.0-0.1%), and positive (-6.6 to +0.7%) and negative (-0.2 to 0.0%) predictive values. Similarly, no improvement in T2DM risk prediction was found: net reclassification index ranging from -5.3 to -1.6% and nonsignificant (P ≥ 0.49) integrated discrimination improvement."

That is a great question and Ali is right to ask about whether strictly genetic models of T2DM could ever successfully encompass all the facets of the disease progression in the clinic. One key aspect missing in this discussion thus far is the role aging plays in the etiology of diabetes. I would then argue that no genetic model comes close unless the animals are aged or aging.

someone has aged more than 35 years getting increase of risk for DM type 2 in young executive community. Majority of people in that age become enjoy with good salary, married, full facilities at home, sedentary lifestyle, indulge their self

It is Goto-Kakizaki rats whihc is known to have insulin degrdaing enzyme gene deficiecny

Now a days diabetes 2 appears as epidemic and has less or no genetic relation. This may be due to some environmental effects such as poluted environment, adulterated food, social and environmental stress etc. Theses stresses are obvious in some underdevelopped and politically unstable countries. People even with lean thin body is suffering from T2DM.

I agree with Matthias Konig about the influence of life style and high correlation between the increase in T2DM and changes in western nutrition. We can cited as example the Pima Indian study, which is well know.

Well done,Dr. Md. Rezaul Karim for throwing up a counter example to the simplistic "truths" about lifestyle/self-indulgence causes. What we have is a correlation between lifestyle and T2DM. Correlations do not imply causality. The famous example is the strong correlation between storks and babies in Sweden implying the truth of the lies told to children about storks bringing the babies. The moralising, blame the victim, approach has little to recommend it. Without a plausible mechanism at the molecular level for the destabilisation of signalling pathways we remain in the realm of folklore not scientific medicine.

Moon Song also raises a valid counter example to the lack of insulin folklore. The Goto-Kakizaki rats used as an animal model of T2DM suffer from hyperinsulineamia. For years they told me my Beta-cells were incapable of producing enough insulin. When tested they could reduce serum glucose at 19mM/l/hour compared to the healthy young man on the glucose tolerance test at 2.3nM/l/hour. Needless to say, neither insulin nor insulin stimulating drugs worked but I was labelled uncooperative and lectured on my lifestyle.

We need to start from where we are at, which is the causes and mechanisms of T2DM are unknown and the word multifactoral means I don't know but want to sound clever.

Dear Ali,

I have read all the comments on your question and I am very happy that so many researchers responded on your question. I invite all of them to read the recent paper entitled "Lipid composition of cell membranes and its relevance in type 2 diabetes mellitus", Current Diabetes Reviews 2012;8:390-400. [open access].

I hope that this paper may be the start of a fruiful discussion.

Enjoy the read and remember that you can always contact me with specific questions.

One typing error: fruiful = fruitful (sorry)

We can learn from India Population. India leads the world with largest number of diabetic subjects earning the dubious distinction of being termed the ‘‘diabetes capital of the world’’. I think the condition is affected by changing of lifestyle in certain age groups with specific genetic background

I agree with others that lifestyle changes are mainly responsible for the increased prevalence of T2DM. These lifestyle changes have led to obesity. In fact the epidemic of diabetes is parallel to an epidemic of obesity. DPP showed that for every 1 kg reduction in body weight there was a 13% reduction in the risk of developing diabetes.

a point came to my mind about Rezaul statement "Nowadays diabetes 2 appears as epidemic" : so diabetes is not related to an especial ethnic or group of people in somewhere of world.

genetic controlers overwhelmed with epi-genetic factors. so future protocols of diabetes management should be lifestyle-based recommendations.

in last years genetic is not changed but lifestyle is changeing and this change is correlated to diabetes increment.

I think the researchers are preoccupied with the genetic factors and lifestyle alone but other possible factors such as insecticides, use of formalin as preservatives and some nonfood grade coloring agents in food perhaps silently causing destruction of the beta cells or inhibiting the receptor molecules are not yet given attention. Hope these issues should not go untouched.

I fully agree with Dr. Md. Rezaul Karim. Until we understand how the complex signalling pathways in the gut work in healthy individuals we are in no position to make grand pronouncements about causes. Linda Jaber is certain that it is lifestyle changes on the basis of correlation between obesity and lifestyle. This faulty logic precludes the consideration of a common cause which the effects of bariatic surgery seems to support. What we need is a human "gutome" project to find out what all these hormones and neurotransmitters are doing in there. Until we know that we have no way to understand how they go wrong.

We are treating patients in India for diabetes using plants and plant products. People with blood sugar levels upto 450-500, on insulin for almost 2-3 years and multiple organ degeneration are finding our treatment very effective. Within 2-3 months their sugar levels are almost normal and the medication is reduced to very low levels. In our observation the main cause of sudden growth of the number of patients is the life style and the processed food that is being increasingly consumed, besides the pesticides and polluted atmosphere. There is no genetic factor at all. The genetic factor is to a large extent is the inherited food habits and the life style. Please check and you will find that in the same family, the children who follow the same life style are likely to inherit the disease. The children who do not follow the life style of the diabetic parents do not necessarily become diabetic. Similarly poeple without a diabetic back ground may become diabetic with a defective life style.

Dear Ali,

This is in my opinion simply the wrong question (or better: the wrong way to ask this question). T2DM is a multi-factorial or multi-causal condition and hence it is not getting us much further asking whether it is either OR between different factors. It is AND. We need to choose then the right research approaches rather than hunting down THE cause of T2DM - there is no single cause.

Atul Jain appears to be asking the right question, how can we reverse T2DM? Perhaps Atul would like to tell us what protocols are used. Pants and plant products may contain substances with systemic effects of they may simply modify the gut flora. My own experience indicates that modification of gut flora is the most likely explanation.

in Jakarta the capital city of Indonesia we made comparison between rural area and urban area on prevalence of diabetes type 2. In rural area the prevalence is 4 % and in urban area is 12%. This is the fact of difference lifestyle in both area.

The report of Jakarta by Syaefudin Akhmad supports what we feel is a cause of increase in the diabetic cases. More money should be spent on educating people so that the number stops growing. But it does not suit the industry- perhaps.

I have a question for Syaefudin Akhmad. What are they eating in the urban areas that they are not eating in the rural areas? I suspect meat from intensive agriculture.

I want to stick to my opinion that not only lifestyle, urban people have to face most challenges in life and have to bear more stresses and tension compared to the rural ppeople.

Dr. Md. Rezaul Karim is right when it comes to stresses in urban life. However the rural people also have stress of different nature. While the urbal people stress themselves with unnecessary competiontion, the rural people have stress because of lack of basic amminities. No doubt stress is an important factor.

eating fast food, high lipid in all kind of fried food such as fried tofu, fried rice, fried tempeh (soybean), fried chicken, fried fish, and so on. Also special food in Indonesia is mixed with coconut milk to make savory.

I agree with Dr. Md. Rezaul Karim, stress is a likely factor but by what mechanism?

I am shocked and appalled to see so many scientists ascribe T2DM to lifestyle alone. The fact is that among identical twins, there is a 95% concordance for T2DM. Most obese persons do not develop T2DM and many with T2DM are not obese. Typically obesity is present early in T2DM and weight loss occurs as the disease progresses.

Eliminating fast food from the diet is not a cure for T2DM and it is dangerous to suggest that this is valid treatment.

I am disheartened but not shocked by scientists on both sides of this debate mistaking correlation for a causative mechanism. Identical twins share a genome and their mother's gut flora plus whatever happened to their mother's biochemistry during the gestation. 95% concordance can not tell us which is the more important of these 100% shared factors. I agree with Paul Ernsberger's comments on lifestyle but there does seem to be a correlation. It is those lifestyles of which we disapprove for moral reasons that we are likely to find causative for T2DM and many other diseases of which we are ignorant of the cause.

One thing we know for sure is that T2DM involves an interaction between the duodenum and whatever is passing through it because bariatic procedures that isolate the duodenum also cure T2DM and reversal of procedures causes it to return. The literature has little to say on these interactions. An obvious question for the practicing doctors among you is "What proportion of your T2DM patients are suffering from or report repeated episodes of duodenal edema and how does this compare to the rest of your patients?" It is easy to spot, even through clothes when you know what to look for. It is the pointy lump just below the sternum. There is a paper in this for someone.

I remember that early twin studies for diabetes reporting phenomenal high rates turned out to have purposefully recruited twins with diabetes. When looking at population based registries of twins and the occurrence of diabetes then a different picture emerges: the concurrence is between 20 - 30% in Finland http://tinyurl.com/buurkfo and Denmark http://tinyurl.com/bqvhlro.

And there is certainly more inherited than only genes.

So the conclusion re genes versus environment is: it is an AND, genes and environment or more eloquently paraphrasing from the Danish study: "We therefore propose that genetic predisposition is important for the development of [diabetes]. Non-genetic factors, however, might play a predominant role in controlling whether a genetically predisposed individual progresses to overt Type 2 diabetes.

i found a novel answer in: Holt R.I.G. et al., 2010. Textbook of diabetes. 4th edition. Weily Blackwell. Chapter 8. p 126 : "genes load the gun and a permissive or toxic environment pulls the trigger"

Dr. Andy, stress affects the homonal secretion and one hormone has a counter effect on the others synthesis and secretion. Long term stress may prolong such counter effects and in turn may lead to a permanent hormonal imbalance.

Dr. Md. Rezaul Karim , that is what I thought you meant but without plausible mechanisms, preferably backed by hard data this debate will just be the airing of opinions justified by small data sets which may be, as Maximilian de Courten points out, of dubious quality and only selected to support preconceived ideas. Getting hard data on perceived stress may not be straightforward. If I am correct in my hypothesis that T2DM and all its complications is caused by C. novyi type A alpha-toxin then we have the complicating factor of its inhibition of the alpha-1 GABA receptor. In the pancreas this leads to runaway serum glucose, in the brain this causes increased anxiety and risk aversion behaviours which are perceived as increased stress. Another factor may be the well documented adverse affects of stress on the immune system. I certainly agree that stress may be an important piece of the jigsaw puzzle. What does the literature have to say on any links between stress and T2DM?

Developing theories to prove that stress is a causative factor in the development of T2DM are problematic given that mental stress is relative to the individual's perception and may be difficult to quantify. The overarching theory was T2DM prevalence was greater in minority groups who experience more stress due to less ability to procure societal rewards = good jobs, good schools.

Life style and food habits, definitely.

Good levels of exercise has been shown to be beneficial for skeletal muscle muscle glucose uptake. Consumption of high fat or high fructose results in cellular insulin resistance, a main abnormality associated with type II.

Does the etiology really matter that much? Lifestyle changes are still guideline-recommended 1st line approaches to control the condition, although few are able to adhere to this. Most end up receiving oral agents. Metformin is the 1st line agent per ADA and Endocinology-based guidelines, where outcomes measures are the driving factors.

There is definite animal and human studies to show that there is a definite intra-uterine environment and infant feeding correlation with the development of childhood obesity and the subsequent development of T2DM. These factors include both underfeeding [Barker's hypothesis of foetal origins of adult-onset disease] and overfeeding [Pedersen's relationship]. The mechanisms for this correlation is through epigenetic modulation. These settings may be further determined by genetic factors.

for T2DM, at early stages (before pre-DM and pre-DM), life styles are important.

T2DM is a complex metabolic disorder determined by both genetic and enviornmental factors like life style, diet and enviornmental exposure. but genetic factors are trigeered by environmental factors and i think T@DM can be completly controled by physical activity and dietary regulation

The simple answer is that type 2 diabetes mellitus is caused by an excessive consumption of sugars (sucrose mainly so glucose and fructose as specific sugars) No other cause explains the pandemic nature of this disease with its very close relationship to obesity and as one of the definitional aspects of metabolic syndrome. The management is simple in concept, reduce sugars intakes and complex in practice.

Your question touches on the issue of genetics (single gene differences) and genomics (the environment and interactions of multiple genes). To conclude that it is a continuing overdose of simple carbohydrates does not invalidate the genomic approach, but taking action for individuals or populations must focus on the external cause, excess simple carbohydrates in the diet.

This article will help you get started

Nature: international weekly journal of science 492:7428 World View Article

Treat obesity as physiology, not physics 12 Dec 2012

http://www.nature.com/news/treat-obesity-as-physiology-not-physics-1.12014

Fei and Zhao have looked at obesity and found a bacterial cause for the epidemic http://jmm.sgmjournals.org/content/60/3/281.full

Their organism is now called Klebsiella mobilis. Its toxins are not yet well characterised but at least one may be an O-linked-N-acetylglucoseamine transferase similar to the C. novyi alpha-toxin which is capable of causing T2DM and all its complications. K. mobilis toxins certainly cause the rounding and shrinkage of cells which is the result of C. novyi alpha-toxin's action on the actin cytoskeleton. The fact that it interferes with hunger hormones also suggests interference with hexamine pathways. A Klebsiella with this capability and its ability to readily become multi-drug resistant is really bad news but Fei and Zhao have shown it is possible to control by traditional medicines.

Life style and food habits, definitely. T2DM can be prevented and regulated with good physical activity and a proper diet.

@Mario Roska. Easy to say but if it was that easy we would all be doing it. My personal data shows no correlation between diet and exercise and serum glucose. 8 hours of heavy digging on my allotment with healthy diet 20+ mM, sitting in front of TV all day eating jam doughnuts 6-6.2mM. At other times the these figures would be reversed. The symptoms of T2DM are often idiopathic. Until this is recognised we have only simplistic answers to complex problems. This presents the illusion of understanding thus preventing the difficult questions from being asked.

I agree, but... Soon I will post my colleagues research about how exercise and proper diet effects on T2DM . Good levels of exercise has been shown to be beneficial for muscle glucose uptake.

sedentary lifestyle cannot be ignored as a causal factor in type 2 diabetes. Incidence increases as calories become more abundant and people make their living by sedentary type work.

Its complex problem needs full evaluation for proper type of diabetes than we go for mangement no doult the sedentry life style have effect on blood sugar level but it was said that even slight increase sugar level means prediabtic have same long term complication as high level of sugar do.So its wise to evaluate early through glucose tolarance test in borderline high normal sugar to prevent irreversible changes that made to different organs.

Type 2 Diabetes is certainly a complex disorder and thus a main area of focus. It has a genetic and environmental component that may explain the heritability of this disorder. Although there have been a lot of Genome wide association studies and family linkage studies to identify the causative genetic loci, it appears that a lot of heritability is still missing and the answer may be lying in the gene x environment interactions which comprises diet and physical activity as vital components. So if I were you I would explore both these factors : genes and diet (at least) to begin with. Other mechanisms that may be important for the pathophysiology include epigenetic modifications and regulatory elements in non-coding regions.

There are large body of evidence for third factor; organic pollutants, either persistent or short lived. They act on several targets, among which is mitochondrion. One can explain genetic, epigenetic and other "inherited" components by quality and quantity of mitochondrial status of a person. Nutritional state (and protective phytochemicals) also affect mitochondrial function. Please see our paper just published in J Diab Invest 2013.

In the underlying pathophysiology of the type 2 diabetes genetic factors are of the highest level of importance. Multiple studies have shown 70% hazard of future diabetes for those with a positive family history of diabetes that means that those with positive family history of diabetes have 70% more chance to get diabetes in their life compared to those with a negative family history. This (70%) figure has been confirmed various studies in different communities. Although changing in dietary pattern to more use of fast foods has increased the incidence of type 2 diabetes, we could not neglect the strong predominance of genetic predisposition. On the other hand, the environmental factors themselves could change the genetic characteristics through epigenetic mechanisms.

In this issue you can see the article "lamarckism revisited" by Dr. Karsten Schmidt (2007).

How much is attributable to genetic factor is answered by twin studies. GWAS results might help. I believe Scandinavian (i.e. Danish) studies, as mentioned above, which showed only about 30% concordance. This number might come from also from environmental factors shared by twins. Earlier reported number of 90% is somewhat of overestimation.

Another strong evidence against genetic effect is rapid rise of diabetes prevalence or incidence in recent years, around the globe. How you could explain this "epidemic" with genetic factor(s). Genes do not change over decades.

Furthermore, 'a cause' should be useful or modifiable, to be truly be 'a cause'. One gene one disease hypothesis is fine, because that gene is useful. You can change that gene and cure disease. Polygenic disease(s) is sham. Only exception is mitochondrial genome. Again, please see my review paper on this issue.

Type 2 Diabetes is due to diet and sedentary lifestyle on the background of genetic susceptiblity. In different ethnic groups genetic susceptibility is distributed unevenly. I presume Europe's caucasian population has a prevalence of genetic susceptibility of 10% to 20%. Historically social factors that meant physical labour for the greater part of the population and nutrition just adequate to survive prevented obesity and thus developement of type 2 diabetes for most of those genetically susceptible. The social changes of the last 60 years lead to the diabetes epidemy.

A model of the interaction of genes and environment are the Pima in the USA and Mexico.

The Pima are an ethnic group of Native Americans with a high genetic susceptibility for type 2 Diabetes. Part of the Pima Nation live in Arizona and another part in Mexico. Those in Arizona have a mean BMI of 33 kg/sqm and a Diabetes prevalence of 50 - 60%, much higher than in other ethnic groups in the US. The Pima in Mexico have a mean BMI of 24 kg/sqm due to much harsher living conditions. In this population type 2 Diabetes is rare in spite of the same genetic background.

My idea is published and taken up by MDLinx today as a featured article;

My article 'Extension of the mitochondria dysfunction hypothesis of metabolic syndrome to atherosclerosis with emphasis on the endocrine-disrupting chemicals and biophysical laws' in Journal of Diabetes Investigation was featured on www.MDLinx.com site today.

MDLinx is the world's most current index of articles that matter in the daily lives of physicians and other healthcare professionals. We send millions of free briefings across 35 specialty areas daily. Your article was assigned to the following specialties: Cardiology, Internal Medicine, Family Medicine, Endocrinology. You can see my article by clicking here: http://www.mdlinx.com/cardiology/news-article.cfm/4435393.

The article was summarized by our physician editor as:

Lee HK et al. – Metabolic syndrome and its component phenotypes, hyperglycemia, hypertension, (abdominal) obesity and hypertriglyceridemia, are major risk factors for atherosclerosis. Murray's law and fractal geometry of the vascular branching system, the authors propose that atherosclerosis could be explained as an ill–adaptive change occurring in nutrient–supplying arteries in response to the decreasing tissue energy demand caused by tissue mitochondrial dysfunction. Various aspects of this new hypothesis are discussed.

Again, congratulations on your publication and we hope the article is widely read!

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