Obesity & Diabetes Flashcards
what is a complex phenotypeq
the consequence of complex interactions of large number of genetic + non-genetic determining factors
- obesity is a complex phenotype
3 types of obesity
1) monogenic obesity = single gene mutation usually in leptin-metalocortin pathway
- serious but rare
2) syndromic obesity = severe obesity, assoc w other phenotypes (neurodevelopmental abnormalities) or other organ/system malformations
3) polygenic obesity = cumulative contribution of large number of mutations, effect is amplifed by weight gaining environment
example of monogenic cause of obesity
- nonsense/ recessive mutation to leptin ob gene –> stop codon –> non functional leptin = insatiable appetite = mice keep eating
OB PHENOTYPE
what does leptin regulate ?
- leptin is secreted by adipocytes into blood –> moves through blood brain barrier –> binds specific receptor on hypothalamus
- ->regulates NAMRE
1) neuropeptide Y expression
2) appetite
3) metabolic rate
4) reporductive function
5) energy expenditure
congenital leptin deficinecy
- homozygous for frameshift mutation on ob gene
- causes hyperphagia - constant eating, insatiable appetite)
- advanced skeletal maturation
- impaired T cell mediated immunity
- hypogonadotropic hypogonadism (problem w pit gland/ hypo= produce no sex hormones)
MC4R deficiency
- monogenic obesity= most common of all monogenic obesity (1 in 2000)
- MC4R= critical relay centre in hypothalamus = send projections to other strcutres in brain (strucutres involved in reward + satiety)
1) codominant inheritance
2) results in early onset of obesity
3) hyperphagia since 1 st yr
4) increased fat mass + lean mass
5) increase bone mineral density
6) increased linear growth
7) disporportionate hyperinsulinaemia
GWAS studies of obesity
1) 75 obesity susceptibility loci
2) many located in non coding areas
3) large prop of loci r undiscovered (identified loci explain only 2-4% of obesity heritability- large prop of loci remain undiscovered)
4) obesity linked genes highly expressed in brain (regions involving regulating appetite + food intake)
5) neuronal influence on body weight
6) BMI = GWAS found variants related to body fat distribution (waist circumference/ waist:hip ratio)
FTO
- first gene identified by GWAS for obesity susceptibility
- locus has largest effect on BMI + obesity risk = LARGE EFFECT SIZE
- FTO = RNA demethylase (links function to epigenetics)
FTO mediates effect on BMI –>
SNP in FTO gene =assoc. w NON ADIPOSITY TRAITS = cardiometabolic traits, T2D, osteoarthritis
- RISK ALLELE A= variant rs1558902 of FTO gene = interacts w dietary proteins (proteins assoc w changes in body comp + abdominal fat distribution)
- -> HIGH protein diet =
1) weight loss
2) improvement of body composition + fat distribution compared to NON carriers of allele A = LARGE EFFECT SIZE
NUTRTION + LIFESTYLE ADVICE:
1) useful to eat foods that promote satiety = HIGH PROTEIN DIET
2) importance of execise
severe early onset obesity
- treated with leptin administration
- those that are resistant to leptin administration = have rare mutation in leptin receptor
order of hyperphagia (increased eating behaviour)
- leptin deficiency (ob mutation)
- MC4R mutation complete
- MC4R mutation partial
- controls (healthy)
explain T2D cause & background
1) result of excess body weight + physical inactivity + modern day lifestyle/diet
2) caused by:
1. insulin resistance
2. beta cell dysfunction
3) results in microvascular + macrovascular complications
- significant impact on healthcare costs
3) symptoms are similar to T1D but are less marked
4) disease may be diagnosed years after onset, once complications have already begun
5) increasingly seen in chidlren as well (90% of diabetes in the world)
insulin production pathway
translation of insulin –> pre-cursor signal peptide removed –> cleaved into 3 peptides: A, B C –> A + B peptides joined by disulphide bonds –> forms insulin + C peptide –> Insulin binds insulin receptor
T1D rough explain
- autoimmune disease = onset is not affected by lifestyle
- cause not known
- not preventable
- result of no insulin production (beta cell destroyed)
pathology of T2D?
serious & progressive characterised by
1) insulin resistance
2) beta cell dysfunction
causes microvascular + macrovascular compliations
1) insulin receptors on cells down-regulated
2) liver, skeletal + muscle cells progressively less sensitive to insulin
3) insulin overproduction weakens beta cells
(prod so much bc receptor isnt responding to it- causes beta cells to weaken)
4) reduced ability for beta cells to secrete insulin
5) impaired ability for beta cells to compensate for insulin resistance
MODY features
- monogenic/ Mendelian form of diabetes mellitus
- mody genotype determines phenotype = determines TREATMENT
- Mendellian pattern of inheritance
- early age onset + pancreatic beta cell dysfunction
