Type 2 Diabetes: Genetic, Physiological, and Nutritional Risk Factors

Amy R. Bestick and Saloni S. Parikh Intro Type 2 diabetes is one of the most serious burgeoning health crises currently facing the United States and developed nations around the world. It is estimated that if present trends continue, one in three US adults will have diabetes in the near future. This alarming increase in the disease coincides with the obesity epidemic already underway in the US where one third of adults are obese. Clearly, uncovering the causes of these conditions and effective treatments is paramount in the medical and scientific communities. Type 2 diabetes is a metabolic disease characterized by insulin resistance, inadequate insulin production, and subsequent hyperglycemia. Complications associated with diabetes are caused by prolonged hyperglycemia and usually consist of damage to vascular tissue potentially resulting in blindness, loss of limbs, or renal failure. These facts seem grim, but type 2 diabetes is actually highly treatable or even preventable. Information pertaining to diabetes treatment and prevention is the primary concern of this paper. We asked the following questions to guide our research: What do we know about genes that predispose people to developing this disease? If we know more about genetic causes, we can better identify and treat at-risk individuals. What is the correlation between obesity and type 2 diabetes? Obesity is a known risk factor for diabetes, but understanding the mechanisms that link these conditions could help us to formulate treatments. What is the effect of nutrition on glycemic control and type 2 diabetes? Nutrition plays an interesting role in current treatments and could contribute greatly to future

preventative measures. Together, these questions provide a framework for us to build our understanding of this complicated disease. Genetics We know diabetes is heritable to some extent due to its tendency to run in families. It is currently a top priority to find what genes cause diabetes because if people know they are genetically predisposed to getting the disease they can potentially tailor their diet and lifestyle in the hopes of prevention.10 This is a better approach than waiting until they are pre-diabetic to begin undoing years of damage. Unfortunately, finding the genes that cause diabetes is proving to be more difficult than scientists had originally hoped it would be. The problem lies in the fact that the disease we call diabetes is really a cluster of symptoms (insulin resistance and insufficient insulin production resulting in elevated blood-glucose levels) that can appear with varying degrees of severity and have multiple possible causes. In this paper, our primary concern is type 2 diabetes, the most prevalent form, but there also exists type 1 diabetes (usually diagnosed in childhood or adolescence) and MODY (maturity onset diabetes of the young) a relatively rare, monogenic form of the disease with several variants.9 Type 2 diabetes the least understood of these three due to its many risk factors and potential causes. Type 2 diabetes presents the largest problem to the general public but also shows great potential for prevention. Although there is no single type 2 diabetes gene, several observational studies of large populations performed recently have yielded information linking alleles at several specific loci containing SNPs (single-nucleotide polymorphisms) to the presence of diabetes.16,17,20 Each of these genes increases ones chances of having

the disease by a small percentage. At this time little is known about the gene products and target tissues of these loci, but many are potentially associated with various aspects of insulin secretion by the -cells of the pancreas. Our current level of knowledge allows us to appreciate the complexity of this disease but we still are trying to understand the genetic mechanisms causing insulin resistance and insufficient insulin production. For the time being we can only continue to hypothesize. Future research will likely focus on positively identifying more genes responsible for increasing an individuals risk of developing diabetes, learning more about the gene products and their mechanisms of action, and discovering what regulates the expression of these genes.9 Knowledge of the regulation of gene expression is critical because it will aid us in formulating therapies for prevention. Obesity As the obesity rate in the United States skyrockets, the number of people with diabetes is also increasing rapidly. There has long been an observed correlation between obesity and diabetes, along with other conditions such as high blood pressure and heart disease, collectively referred to as Metabolic Syndrome.9 Only recently have we begun to understand the mechanisms underlying this correlation. An important step in in the advancement of this understanding was the scientific paradigm shift that occurred with respect to adipose tissue. In the past, adipose tissue was viewed solely as a repository for excess energy, but recent discoveries have revealed that it is actually a complex endocrine organ responsible for the secretion of regulatory proteins called adipokines.15 The expression of these proteins varies with respect to the amount of adipose tissue present. As the

amount of adipose tissue increases, the production of some adipokines increases while that of others decreases. This is important for diabetes research because certain adipokines are thought to have a part in the regulation of glucose homeostasis or the inflammatory state associated with obesity and causally linked to type 2 diabetes. For example, high levels of adiponectin have an insulinsensitizing, anti-inflammatory effect, and the production of this adipocyte decreases as adipose tissue mass increases.14 Other adipokines have the opposite effect and have been shown to increase in concentration with increasing adipose tissue.13 Our current knowledge of the mechanisms by which these proteins act is relatively limited, but this topic is currently being researched heavily because it presents great potential for future therapies to increase insulin sensitivity by either reducing the production of harmful adipokines or increasing the production of helpful ones. See the Table 1 and Figure 1 for more detailed information.

Table 1- Diabetes-related Proteins Produced in Adipose Tissue2,5,11-14

Protein Associated effects

adiponectin insulin sensitivity, decreased inflammation TNF- resistin IL-6 RBP4 Sfrp5 insulin resistance, increased inflammation hepatic insulin resistance hepatic insulin resistance whole-body insulin resistance insulin sensitivity, decreased inflammation

Figure 1-Changes in adipokine production with increases in adipose tissue2,5,11-14

There exists a well-documented correlation specifically between the amount of visceral fat and the incidence of type 2 diabetes, and other conditions such as heart disease. Conversely, large amounts of subcutaneous fat do not seem to have comparable deleterious effects. The difference between these two types of fat has been the subject of much controversy. It has been postulated that visceral fat is responsible for secreting greater concentrations of disease-causing adipokines, or perhaps that it is more dangerous simply because it is so close to our internal organs. To date, no conclusions have been reached with regard to the mechanism that makes visceral fat a greater risk factor for disease.2 It also remains unknown why some individuals tend to store more fat viscerally or subcutaneously. These questions continue to be studied vigorously and the answers, when reached, could prove to be very informative and beneficial. Nutrition

Dietary guidelines can offer a more effective approach to controlling and preventing type 2 diabetes. Nutritional goals for patients with type 2 diabetes include maintaining near-normal blood glucose levels by balancing food intake with activity and medication or insulin, achieving optimal blood pressure and lipid levels, and increasing awareness of caloric intake and body weight. However, the dietary modifications needed to achieve these goals must be tailored to the individual patient. Medical nutrition therapy (MNT) creates specific dietary guidelines for a patient based on medical, lifestyle, and personal factors.6 Although MNT is a customized treatment approach, there are certain key nutritional components that can be applied to a wide range of type 2 diabetes patients. Fat We have previously discussed the causal relationship between body fatness and diabetes. Body fatness can be altered and managed by monitoring intake of macronutrients, namely dietary fats. Studies of blood glucose and insulin concentrations as measured outcomes highlight the role of the specific type of fatty acids in the development of type 2 diabetes. The detrimental effect of saturated fat was observed by examining the correlation between fatty acid composition of cholesterol esters and risk of type 2 diabetes. Subjects who developed type 2 diabetes had a higher proportion of saturated fatty acids and a lower proportion linoleic acid (unsaturated omega-6 fatty acid) in the cholesterol esters than participants who did not develop diabetes.4 These results suggest that a diet lower in saturated fat and higher in polyunsaturated fat may reduce the risk for type 2 diabetes.

Carbohydrate Certain carbohydrate sources are largely responsible for raising blood glucose levels after meals. Thus, to reduce the glucose content of a diet, the type of carbohydrate in addition to the total carbohydrate content should be considered. Readily digestible starches, which are 100% glucose, increase blood glucose and insulin concentrations. Sucrose and lactose are 50% glucose thus resulting in smaller increase in glucose levels relative to starch.4 Foods that have a high glycemic index cause a rapid rise in blood sugar levels and are also linked to increased diabetes risk.18 Glycemic index measures the effect of a specific carbohydrate containing food on blood sugar levels. However, a more accurate indicator of the relative glycemic response to dietary carbohydrates is glycemic load, which is based on glycemic index and a standardized portion size of 100g.1 After a high glycemic load meal, blood glucose levels rise rapidly and insulin demand is greater.18 However, there is insufficient and inconsistent information to claim that low glycemic load and index diets reduce the risk for diabetes. Nevertheless, foods low in glycemic index tend to be fiber rich.3 Fiber Fiber is the indigestible part of plant foods consisting of soluble and insoluble fibers. Soluble fibers such as vegetable gums slow the rate of nutrient absorption in the small intestine and help reduce glucose levels after meals.18 Both soluble and insoluble fiber binds to cholesterol and slows the rate of glucose absorption. Examples of high fiber foods are vegetables, whole grains, bran, and legumes.1 Protein

Amino acids derived from dietary protein are converted to glucose by the process of gluconeogenesis. To study the effect of protein on glucose and insulin levels, mixed meals experiments were conducted on untreated type 2 diabetes patients. The control diet consisted of a protein: carbohydrate: fat ratio of 15:55:30. In the test diet, the macronutrient ratio was altered to 30:40:30. Results showed that a fiveweek high-protein diet improves glycemic control and lipid profiles.4 Evolutionary Approach Discoveries in nutritional science are often affected by confounding variables. An evolutionary approach has been examined to understand the relationship between nutrition and treatment of type 2 diabetes. Diabetes has been referred to as the disease of civilization.8 When aboriginal populations first started consuming a high-glucose, high fat Western diet, obesity and diabetes began to appear.19 The traditional plant-rich, high-fiber diet was replaced with a diet consisting of processed carbohydrates, sugar, and saturated fat. Understanding the evolution of human diet could perhaps allow for a breakthrough in medical nutrition therapy for type 2 diabetes.6 Foods eaten during the Paleolithic era (the Old Stone Age) are examined with regards to prevention and treatment of type 2 diabetes. A Paleolithic diet includes lean meat, fish, shellfish, fruits, vegetables, roots, eggs, and nuts. This diet excludes grains, dairy products, salt and refined fats and sugar. In a randomized crossover study, the effects of a Paleolithic diet were compared with effects of a conventional diabetes diet. The study involved type 2 diabetes patients without insulin treatment who consumed a Paleolithic diet and diabetes diet during two consecutive 3-month periods. The diabetes diet involved evenly distributed meals

with increased intake of vegetables, fiber, whole-grain products, and fruits, in addition to a decreased intake of total fat with more unsaturated fat. Compared to the diabetes diet, the Paleolithic diet resulted in lower mean values of glycated hemoglobin, triacylglycerol, diastolic blood pressure, weight, BMI, and waist circumference. Furthermore, the Paleolithic diet was lower in total energy, energy density, carbohydrates, dietary glycemic load, and saturated fatty acids, and higher in unsaturated fatty acids, and dietary cholesterol. The Paleolithic diet had a relatively a lower carbohydrate intake and a higher intake of protein and fat.7 The Paleolithic diet offers a dietary means to control glucose levels and potentially prevent the development of type 2 diabetes. Diabetes Food Plate By compiling all these results regarding macronutrients and blood glucose response, we can create a model for the dietary management of type 2 diabetes. Overall goals are to decrease total carbohydrate content, decrease metabolically available glucose content by eating foods with lower glycemic index and load, and increasing protein content. The food plate presented below is a dietary model for type 2 diabetes patients. It incorporates a modern version of the Paleolithic diet and other nutritional components in order to manage blood glucose levels.

Figure 2-Diabetes food plate

Table 2- Recommended foods for type 2 diabetes management

Conclusion Type 2 diabetes is characterized by strong interactions of genetics and environment over time. Although the gene products and target tissues of the specific gene loci are poorly understood, management of type 2 diabetes can still be developed primarily through modifications in diet and lifestyle. Genes are critical for determining function and mechanisms; however, nutrition can modify the extent to which different genes are expressed. Thus gene by environment interactions can answer questions about prevention and treatment of type 2 diabetes. Dietary factors can control obesity and act to stabilize the genome once genetic abnormalities have occurred. The future of type 2 diabetes research continues to yield greater understanding of disease processes and innovations in treatment.

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