EAST 501 Lecture 14: 3- R. Sladek
21 Jun 2018
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3- R. Sladek
6- The Genetics of Type 2 Diabetes
●Complex diseases
○Example of diabetes. Has a strong genetic component, but extremely hard to find it.
■Often find familial forms of diabetes, but extremely hard to start learning what
was causing the more common forms of the disease.
■If want to treat this disease well, it would help to know what's causing it.
●Symptoms of diabetes
○Polyuria, polyphagia, polydipsia.
○High blood sugar gets lost in the urine. Need to eat to make up for lost sugar. If you
don’t, you lose weight.
○May also have other problems in term of immune function, heart disease, or neurologic
function.
●Diabetes Mellitus- Diagnostic Criteria
○The diagnosis of the disease is quite strict.
■Normal people have fasting blood sugars of less than 5.5
●Most young people in the 3-4 range.
■Once the fasting blood sugar goes above 7 mmol/l, after several tests, you have
diabetes.
■An alternate diagnosis of the disease is two hours following a meal, if your sugar
is over 11.1, you have diabetes.
●Diabetes Mellitus- Major Complications
○The problem with the disease is not so much the high blood sugar. What is going to be
problematic is microvascular and macrovascular diseases.
■Worried about: strokes, coronary artery disease, retinopathy, and renal disease.
●Most common cause of blindness in Canada.
○Potential number of years lost is 10-15 years for an individual.
○Goal is to find a drug that you can give at start of illness that will prevent these diseases
from developing to reverse those lost years of life.
○Want to find gene targets + overlap of these genes that cause heart disease, for instance.
●Diabetes Mellitus- Retinal Disease
○See hemorrhages, exudates (fluid is pushed out into the retinal layer).
■Needs treatment. If bleeding and fluid extends into the fovea, lose vision.
●Diabetes Mellitus- Foot Ulcers
○Full thickness ulcers go to the connective tissue underneath.
○Ulcers form because of poor circulation and due to damaged nervous systems → can’t
tell that they’re putting too much force on their feet.
■May have impaired position of pain sense.
●Comparison of Type 1 and Type 2 Diabetes Mellitus
○There are two common types of diabetes:
■Type 1 → occurs in childhood or adolescence.
■Type 2 → one that people get through adulthood.
●Environmental and genetic component.
●Causes about 90% of diabetes in Canada.
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3- R. Sladek
●Timeline
○Two processes going on: people are obese and overweight, which causes them to become
insulin resistant.
■Turns out that insulin resistance is a genetic trait → can find genes in the muscles
that alter insulin sensitivity in the muscles.
○In the beta cells of the pancreas, initially, the beta cell mass is going to increase to
compensate for the overweight condition.
■High levels of insulin act as growth factors on coronary arteries.
■Eventually, in a third of obese people, pancreatic compensation will fail, glucose
levels go up, and they develop diabetes.
●Type 2 diabetes is a multifactorial disorders
○Genetic factors:
■Frequently compare DZ (fraternal twins) and MZ (identical) twins.
■MZ twins often have a high concordance for the disease than siblings or DZ
twins.
■For diabetes, we think about 70% of risk comes from genetics.
■If you have one parent with diabetes, your chances of having it is about 40%. If
have two parents with diabetes, 70% chance of getting it.
■Increased risk if Aboriginal, African, Arabic, Hispanic, or Asian ancestry.
■But we didn’t use to have this problem → environmental lifestyle comes into
play.
○Environmental, lifestyle, and medical factors: urban experience, lack of exercise, food,
etc. → contribute to diabetes risk.
■If you’re overweight, over 45 years, poor diet and non physically active →
increases your risk significantly.
○Non-modifiable risk factors:
■Include age, family history, race.
○Modifiable risk factors:
■Diet, exercise, etc.
●Millions of cases of diabetes in 2000 and projections for 2030
○Expecting in all areas of the world that diabetes will increase.
■China had already doubled in 2008.
■Also quite concerned about the Middle East.
■Economies that won’t be able to sustain the complications that will come with
diabetes/ healthcare.
●Putative contributors to the secular increase in obesity: exploring the roads less traveled
○There are many things about our lifestyle that make us more prone to develop obesity.
○From 1960-2000: lots of trends got worse.
■Dietary intake, amount of air condition people are using, escalators…
■Number of hours we’re sleeping has decreased.
■In this paper, they were able to identify several dozen changes in the environment
that could be promoting bad metabolic fitness.
●Direct, predimed
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3- R. Sladek
○Could one prevent diabetes by fixing the weight?
■But generally, see rapid weight loss, but need to look at 2-5 years follow up.
■From month 12 to 24, weight starts coming back.
■Very hard to use programs of diet and exercise to fix the problem.
○Looking at heart disease risk: even a modest weight loss will benefit in terms of CV
disease.
●Disease-related genetic variation
○On the one hand, Mendelian diseases, and on the other common diseases.
■Mendelian variants: a single damaged gene stops the protein from being made,
or an amino acid change makes the protein non functional.
●These things tend to be rare, the mutant allele frequency is very small.
●Most common Mendelian disease is cystic fibrosis in Caucasians.
●These genes tend to be recent → impair the individual to reproduce.
Problem with fitness. Tend to run in families, be rare, and have big
effects.
■Common variants: tend to have small effects. Slightly change your metabolic
efficiency → often quite ancient mutations, that spread through the population.
●Arose in Africa, and followed to Europe.
●Not uncommon that these variants affect 30-40% of a population.
●Disease-related genetic variation
○Linkage = family studies, and association = population studies.
■Linkage: pedigrees.
■Association: want a lot of people.
●Family (linkage) study- rare monogenic diabetes
○Looked at four-generation family.
○Identified a mutation in a gene called glucokinase-1→ called it maturity onset diabetes.
(MODY)
■This type of disease is a monogenic form of diabetes. Represents only 1-2% of
cases but made it clear a gene was causing the disease.
●Many monogenic diabetes genes alter beta-cells
○MODY1= a TF called Hnf4alpha → affected insulin synthesis and secretion by
beta-cells.
○What was interesting with this set of genes was that they had a very tight link to the
pathogenesis of the disease.
■Could explain their function in term of development and physiology quite
clearly.
●Variant of TF 7-like gene confers risk of type 2 diabetes
○Came in with a gene that didn’t cause MODY, but caused type II diabetes.
○Stirred a lot of interest because this gene (TCFL2) is part of the Wnt-beta-catenin
pathway, and everyone had thought of this gene as cancer-causing.
●Genetics of type 2 diabetes
○For each of these monogenic forms, could find genes where the coding sequence was
disrupting in genes that made sense in terms of beta cell physiology.
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Document Summary
Has a strong genetic component, but extremely hard to find it. Often find familial forms of diabetes, but extremely hard to start learning what was causing the more common forms of the disease. If want to treat this disease well, it would help to know what"s causing it. High blood sugar gets lost in the urine. Need to eat to make up for lost sugar. May also have other problems in term of immune function, heart disease, or neurologic function. The diagnosis of the disease is quite strict. Normal people have fasting blood sugars of less than 5. 5. Most young people in the 3-4 range. Once the fasting blood sugar goes above 7 mmol/l, after several tests, you have diabetes. An alternate diagnosis of the disease is two hours following a meal, if your sugar is over 11. 1, you have diabetes. The problem with the disease is not so much the high blood sugar.
