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Week 6 - Obesity and Type-2 Diabetes

Uploaded: 6 years ago
Contributor: DJ
Category: Immunology
Type: Lecture Notes
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Filename:   Week 6 - Obesity and Type-2 Diabetes.ppt (156.5 kB)
Page Count: 22
Credit Cost: 1
Views: 214
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Obesity & Type 2 Diabetes Milly Ryan-Harshman, PhD, RD * * The trouble with food… The increased incidence of obesity, the metabolic syndrome, type 2 diabetes, cardiovascular diseases and many other chronic diseases is caused by overconsumption of calories and certain nutrients Diabesity – a word coined to emphasize the link between obesity and type 2 diabetes The two measures of diabetes are high fasting blood glucose level and delayed metabolic clearing (glucose tolerance test) * * The trouble with food… Obesity is a proinflammatory condition that introduces additional variation in physiology and responsiveness to diet and drugs Metabolic syndrome – dyslipidemia, hypertension, insulin resistance, hyperinsulinemia Simple classification schemes may be necessary for choosing a treatment protocol, but type 2 diabetes is a set of metabolic processes and physiologies that present differently in different patients and change depending upon genetic makeup, environmental influences, age, and the cumulative effects of the disease process itself * * Type 2 Diabetes: Genetic Complexity Type 2 diabetes is a polygenic disease To identify the causative genes relies on genetic association studies in humans, but the mechanisms of action must be determined through cell culture or experimental animal studies Genetic association studies link chromosomal regions with disease sub-phenotypes or incidence * * Type 2 Diabetes: Genetic Complexity A quantitative trait locus (QTL) analysis is a sophisticated type of association study A QTL is a polymorphic locus containing one or more genes that contribute to the phenotypic expression of a continuously variable trait What scientists do is to statistically determine how frequently a region of chromosome is associated with a certain measurable phenotype such as insulin levels or glucose response * * Type 2 Diabetes: Genetic Complexity Mapping can be done in humans, but experiments where mice are inbred are easier to understand Two mice who are susceptible to type 2 diabetes are bred to produce an F1 generation. F1 mice are backcrossed to each of the parental strains producing an F2 generation differing in in disease susceptibility because of independent assortment of chromosomes and chromosomal rearrangements that occur during meiosis. The incidence or severity of sub-phenotypes of the disease is measured in the F2 mice and statistically associated with chromosomal regions from each of the original parental strains. A given pair of mice may have a number of regions that contribute to the complex phenotype in those strains. * * Type 2 Diabetes: Genetic Complexity What actually occurs is that the sum of contributions from alleles of causative genes within different QTLs produces type 2 diabetes. Two hypotheses were proposed to explain gene variants that contribute to quantitative traits – the first is the common disease/common variant hypothesis that suggests that combinations of normally occurring gene variants produce disease – the second is the multilocus/multiallele hypothesis that suggests that combinations of rare allelic variants cause common diseases. Either hypothesis supports the polygenic nature of type 2 diabetes. * * Type 2 Diabetes: Genetic Complexity In humans, there are seven type 2 diabetes QTLs that are thought to be very significant, but there are up to 17 QTLs distributed on chromosomes that could be classed as “near-suggestive linkage”. With just the seven QTLs, there would be a possibility of inheriting a protective allele, a disease causing allele, or a neutral allele. Genetic susceptibility increases with increasing number of alleles that contribute to disease. Risk of type 2 diabetes could range from low probability (all protective alleles) to high probability (all disease causing alleles). * * Type 2 Diabetes: Genetic Complexity Even if two people have the same number of protective, neutral and disease causing alleles, they may not have the same genetic susceptibility. The reasons for this are: Each QTL may contribute differently to a given phenotype Epistatic interactions – gene-gene interactions Epigenetic functions of DNA methylation and chromatin remodeling * * Epistatic Interactions In basic genetics, each individual can only have two alleles of one gene (one allele of a gene per chromosome). So, a person may have two harmless alleles, two disease alleles, or one each - harmless and deleterious. The disease outcome depends upon whether the allele is dominant or recessive. A dominant allele needs only one copy of the allele to show its effects. If two copies are necessary, the disease allele is recessive or masked. Dominant and recessive describes the effect a single gene has on the measurable trait. * * Epistatic Interactions Epistasis refers to at least two genes that are not alleles of each other, interacting to have a measurable effect on a trait. Coat colour in Labrador retrievers is an example of epistasis. Alleles of one gene can be dominant to alleles of a different gene. In other words, the sum of the parts do not equal the whole. The principal of epistasis remains the same for other traits such as body fat which are quantitative and cannot be placed in discrete categories like coat colour. * * Epistatic Interactions Gene-gene interactions means that proteins or enzymes produced by a gene or its variant do not act alone, but are usually part of a pathway, and many pathways are interconnected. Compensation in the activity of parts to maintain the overall balance within the system is called ‘buffering”. * * Epigenetics, again! Both DNA methylation and chromatin remodeling change the accessibility of DNA to regulatory proteins and complexes altering transcriptional regulation. Nutrient intake affects DNA methylation status because interconnected biochemical reactions move methyl groups around the system. Dietary deficiencies of choline, methionine, folate, vitamin B12, vitamin B6, and riboflavin affect one-carbon metabolism and DNA methylation and increase the risk of neural tube defects, cancer and CVD. Chromatin remodeling is regulated in part by energy balance within the cell. Reduction in fat and caloric restriction can both affect chromatin remodeling. * * Epigenetics, again! Long-term exposure to diets that remodel chromatin structure and DNA methylation could induce permanent epigenetic changes. Such changes might explain why some individuals can more easily control symptoms of chronic diseases by changing lifestyle, but other seem to pass an irreversible threshold. Epigenetic changes may also explain “developmental windows” – key times during development where short term environmental influences may produce long-lasting changes in gene expression and metabolic potential. * * Type 2 Diabetes: From Birth Onward Each individual is born with a unique susceptibility to type 2 diabetes and other chronic diseases. Once born, the genotype-environment interactions, including diet, become very significant. Dietary chemicals alter disease incidence and severity. In short, nutrients affect expression of genetic information and genetic makeup affects how nutrients are metabolized. * * Type 2 Diabetes: From Birth Onward A dietary chemical or its metabolite may: Alter expression of a susceptibility gene or its variant that subsequently affects other gene-gene interactions The gene-environment interaction may affect the gene of interest, or the action of that gene on other interacting genes Different functional classes of genes may be more important than others, for example, the expression of a nuclear receptor or signal transduction pathways Interact in various ways because of epistatic interactions or epigenetic regulation and their interconnectedness that is also present * * Type 2 Diabetes: From Birth Onward Defined and controlled experimental systems will be needed to sort out all these interactions. In epidemiological trials, individuals will need to be tested to determine if they have similar genetic makeup before the relationship re: gene-nutrient-disease associations can be worked out. Finally, environment is about more than just diet, and such factors as sleep, medications, exercise, fluid intake (water), stress, exposure to allergens or pollution, seasonal and circadian rhythm changes, and balance between energy intake and expenditure will have an influence as well. * * Dietary Fat in Obesity and Diabetes As mentioned earlier, mouse models are useful in determining gene-diet interactions. These models provide good information about the interconnectedness of organs and pathways that contribute to complex phenotypes associated with type 2 diabetes. In mice, one strain sensitive to diet is a good model of “diabesity”. These mice, when fed a high-fat, high-sucrose diet gain more weight, and have hyperglycemia and hyperinsulinemia whereas the strain resistant to diet is unaffected. * * Dietary Fat in Obesity and Diabetes Caloric restriction within the high-fat diet attenuates but does not prevent the development of obesity and type 2 diabetes. Studies in both rats and humans have shown that fats with differing chain length and saturation have different effects on energy metabolism and/or obesity. * * Dietary Fat in Obesity and Diabetes Detecting gene-diet interactions in humans, however, is difficult because humans have a high degree of heterogeneity (genetic diversity) compared to “lab rats.” One example, though, is that a particular polymorphism interacts with the ratio of polyunsaturated fat to saturated fat in the diet. Carriers of the Ala allele demonstrated a negative association with the P:S ratio and fasting insulin, but only in physically active subjects and not sedentary subjects. What this means is that only in the physically active individuals did a high P:S ratio result in lower fasting insulin levels. * * Obesity and Diabetes: Maternal Effects A mother can influence, either in utero or prior to weaning, the phenotype of the child. Uterine factors, nutrients in mother’s milk, or maternal health status can have a long-lasting effect on the child. Therefore, a mother can influence whether or not her child develops obesity or diabesity. Researchers demonstrated this by transferring mouse embryos who, regardless of genotype, increased postnatal growth and adult body weight when placed in mothers of a certain strain. * * Obesity and Diabetes: Conclusion Genetics has a large influence on obesity, on weight gain in response to diet, on weight loss in response to exercise, and on development and severity of type 2 diabetes, but only a few genes have so far been identified in relatively small numbers of people in some studies. The big picture: Epistasis is common. Diet-genotype interactions are common. Maternal effects are modified by genetics.

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