Podcast
Questions and Answers
A molecular diagnosis of cystic fibrosis can be made from a venous blood sample that yields a ______ test result.
A molecular diagnosis of cystic fibrosis can be made from a venous blood sample that yields a ______ test result.
positive
A fetal ultrasound revealing an intestinal obstruction can be used for prenatal diagnosis by examining cells from the ______.
A fetal ultrasound revealing an intestinal obstruction can be used for prenatal diagnosis by examining cells from the ______.
chorionic villi
Preimplantation diagnosis of cystic fibrosis can be done by analyzing embryonic cells to identify a ______.
Preimplantation diagnosis of cystic fibrosis can be done by analyzing embryonic cells to identify a ______.
high genetic risk
Molecular diagnosis of cystic fibrosis is challenging due to the ______ size of the gene and the number of mutations.
Molecular diagnosis of cystic fibrosis is challenging due to the ______ size of the gene and the number of mutations.
In diagnosing cystic fibrosis, the most common mutation is ______, which is often the first target in testing.
In diagnosing cystic fibrosis, the most common mutation is ______, which is often the first target in testing.
When diagnosing cystic fibrosis, if only the F508del mutation is checked, only about 50% of couples with an affected child can benefit from a direct ______.
When diagnosing cystic fibrosis, if only the F508del mutation is checked, only about 50% of couples with an affected child can benefit from a direct ______.
Gene therapy for cystic fibrosis aims to introduce the functional ______ gene into the respiratory epithelium using a vector.
Gene therapy for cystic fibrosis aims to introduce the functional ______ gene into the respiratory epithelium using a vector.
In gene therapy for cystic fibrosis, the epithelial cells of the lungs have a limited lifespan, so the transfer of the functional gene is not ______.
In gene therapy for cystic fibrosis, the epithelial cells of the lungs have a limited lifespan, so the transfer of the functional gene is not ______.
The rapid evolution of microorganisms presents challenges in terms of ______ and treatments.
The rapid evolution of microorganisms presents challenges in terms of ______ and treatments.
Variations in genetics, arising from mutations and preserved over generations, imply that not all individuals are equally susceptible to ______.
Variations in genetics, arising from mutations and preserved over generations, imply that not all individuals are equally susceptible to ______.
In individuals with mucoviscidose, the accumulation of mucus in the bronches leads to frequent ______ due to trapped infectious agents.
In individuals with mucoviscidose, the accumulation of mucus in the bronches leads to frequent ______ due to trapped infectious agents.
Mucoviscidose affects the pancreas by blocking enzymes, which then impairs the digestion of food, leading to abdominal pain, diarrhea, or ______.
Mucoviscidose affects the pancreas by blocking enzymes, which then impairs the digestion of food, leading to abdominal pain, diarrhea, or ______.
Mucoviscidose is characterized by the production of mucus that is both thick and ______, leading to various complications.
Mucoviscidose is characterized by the production of mucus that is both thick and ______, leading to various complications.
The primary cause of mortality in mucoviscidose patients is often respiratory ______ due to progressive lung degradation.
The primary cause of mortality in mucoviscidose patients is often respiratory ______ due to progressive lung degradation.
Mucus typically functions to line and moisturize the canals of certain organs, providing ______ to their surface.
Mucus typically functions to line and moisturize the canals of certain organs, providing ______ to their surface.
Gene therapy offers a potential ______ for mucoviscidose by correcting the underlying genetic defect.
Gene therapy offers a potential ______ for mucoviscidose by correcting the underlying genetic defect.
_________, a pancreatic hormone, facilitates the movement of glucose from the blood into cells for use or storage.
_________, a pancreatic hormone, facilitates the movement of glucose from the blood into cells for use or storage.
Chronic hyperglycemia is diagnosed when blood glucose levels are consistently higher than _________ g/L.
Chronic hyperglycemia is diagnosed when blood glucose levels are consistently higher than _________ g/L.
Frequent urination in diabetes is linked to urinary loss of _________.
Frequent urination in diabetes is linked to urinary loss of _________.
In type 2 diabetes development, an excess of muscle and visceral fat leads to increased circulating _________.
In type 2 diabetes development, an excess of muscle and visceral fat leads to increased circulating _________.
During insulin resistance, liver cells transform excess fatty acids into _________, further increasing blood glucose levels.
During insulin resistance, liver cells transform excess fatty acids into _________, further increasing blood glucose levels.
In response to elevated blood glucose, the pancreas increases _________ production, initially compensating for insulin resistance.
In response to elevated blood glucose, the pancreas increases _________ production, initially compensating for insulin resistance.
After prolonged hyperinsulinemia, pancreatic cells can become exhausted, leading to _________, and the onset of type 2 diabetes.
After prolonged hyperinsulinemia, pancreatic cells can become exhausted, leading to _________, and the onset of type 2 diabetes.
Type 2 diabetes is often associated with _________ of the pancreas, resulting in insufficient insulin production.
Type 2 diabetes is often associated with _________ of the pancreas, resulting in insufficient insulin production.
Genetic predisposition in type 2 diabetes involves genes that increase the _________ of developing the disease.
Genetic predisposition in type 2 diabetes involves genes that increase the _________ of developing the disease.
The rising prevalence of type 2 diabetes is correlated with _________ lifestyles, high-calorie diets, and obesity.
The rising prevalence of type 2 diabetes is correlated with _________ lifestyles, high-calorie diets, and obesity.
The majority of known mutations of the CFTR gene are ______ mutations, affecting protein production, cellular maturation, chloride channel function, or protein stability.
The majority of known mutations of the CFTR gene are ______ mutations, affecting protein production, cellular maturation, chloride channel function, or protein stability.
Mucoviscidose is a monogenic genetic disease with ______ recessive transmission.
Mucoviscidose is a monogenic genetic disease with ______ recessive transmission.
For a child to be affected by mucoviscidose, both parents must be ______, each carrying one wild-type allele and one defective allele.
For a child to be affected by mucoviscidose, both parents must be ______, each carrying one wild-type allele and one defective allele.
If both parents are heterozygous carriers of mucoviscidose, the probability of transmitting the disease to their child is ______.
If both parents are heterozygous carriers of mucoviscidose, the probability of transmitting the disease to their child is ______.
Treatments for mucoviscidose aim to compensate for the altered function or to control the conditions of the environment, such as through respiratory ______ or specific diets.
Treatments for mucoviscidose aim to compensate for the altered function or to control the conditions of the environment, such as through respiratory ______ or specific diets.
A systematic neonatal screening for mucoviscidose was implemented, involving a dried blood sample taken three days after birth, alongside screenings for other diseases like ______.
A systematic neonatal screening for mucoviscidose was implemented, involving a dried blood sample taken three days after birth, alongside screenings for other diseases like ______.
The sweat test for mucoviscidose involves stimulating the sweat glands and measuring the ______ concentration in the collected sweat.
The sweat test for mucoviscidose involves stimulating the sweat glands and measuring the ______ concentration in the collected sweat.
A sweat test is considered positive if the concentration of chlorine in the sweat collected is greater than ______ mmol/L.
A sweat test is considered positive if the concentration of chlorine in the sweat collected is greater than ______ mmol/L.
Molecular diagnosis involves directly searching for mutations of the ______ gene in cells obtained from blood samples, chorionic villi, or embryonic cells during IVF.
Molecular diagnosis involves directly searching for mutations of the ______ gene in cells obtained from blood samples, chorionic villi, or embryonic cells during IVF.
The mutation ______ is the most frequent, and is often searched for first in molecular diagnostics.
The mutation ______ is the most frequent, and is often searched for first in molecular diagnostics.
In gene therapy, a functional human gene in the form of ______ is inserted into the viral genome.
In gene therapy, a functional human gene in the form of ______ is inserted into the viral genome.
In type II diabetes, chronic ______ occurs when fasting blood sugar is greater than $1.26 g/L$.
In type II diabetes, chronic ______ occurs when fasting blood sugar is greater than $1.26 g/L$.
Type II diabetes can lead to complications affecting the eyes, feet, and ______.
Type II diabetes can lead to complications affecting the eyes, feet, and ______.
During the insulin resistance phase of type II diabetes, an excess of muscle and ______ fat leads to an increase in circulating fatty acids.
During the insulin resistance phase of type II diabetes, an excess of muscle and ______ fat leads to an increase in circulating fatty acids.
The cells of the pancreas become exhausted after 10 to 20 years of ______, leading to insulin deficiency in type II diabetes.
The cells of the pancreas become exhausted after 10 to 20 years of ______, leading to insulin deficiency in type II diabetes.
Insulin enables the passage of glucose from the blood into the cells that use and/or ______ it.
Insulin enables the passage of glucose from the blood into the cells that use and/or ______ it.
The regulating mechanism involving insulin maintains a constant concentration of glucose in the blood, known as ______, around $1 g/L$.
The regulating mechanism involving insulin maintains a constant concentration of glucose in the blood, known as ______, around $1 g/L$.
In response to excess blood glucose, the pancreas strongly increases its production of ______.
In response to excess blood glucose, the pancreas strongly increases its production of ______.
In cystic fibrosis, blocked enzymes in the ______ hinder food digestion, leading to symptoms like abdominal pain and vitamin deficiencies.
In cystic fibrosis, blocked enzymes in the ______ hinder food digestion, leading to symptoms like abdominal pain and vitamin deficiencies.
The CFTR protein normally resides in the cytoplasm and on the membrane of ______ cells, but in individuals with cystic fibrosis, it may not be produced or properly located.
The CFTR protein normally resides in the cytoplasm and on the membrane of ______ cells, but in individuals with cystic fibrosis, it may not be produced or properly located.
The CFTR protein acts as a ______ channel in healthy cells, facilitating water transport to maintain the fluidity of mucus.
The CFTR protein acts as a ______ channel in healthy cells, facilitating water transport to maintain the fluidity of mucus.
In individuals with cystic fibrosis, the absence of chloride ion secretion leads to increased water reabsorption, causing mucus to ______ and accumulate.
In individuals with cystic fibrosis, the absence of chloride ion secretion leads to increased water reabsorption, causing mucus to ______ and accumulate.
The CFTR gene, responsible for cystic fibrosis, is located on chromosome ______, an autosome.
The CFTR gene, responsible for cystic fibrosis, is located on chromosome ______, an autosome.
The deletion mutation ΔF508, representing 70% of CFTR alleles, eliminates a ______ that encodes phenylalanine, leading to abnormal CFTR maturation.
The deletion mutation ΔF508, representing 70% of CFTR alleles, eliminates a ______ that encodes phenylalanine, leading to abnormal CFTR maturation.
Mutations in the CFTR gene can affect the production, maturation, functioning, or ______ of the CFTR protein, resulting in diverse phenotypic consequences.
Mutations in the CFTR gene can affect the production, maturation, functioning, or ______ of the CFTR protein, resulting in diverse phenotypic consequences.
Cystic fibrosis is a monogenic genetic disease with ______ recessive transmission, requiring both parents to be carriers for a child to be affected.
Cystic fibrosis is a monogenic genetic disease with ______ recessive transmission, requiring both parents to be carriers for a child to be affected.
In a healthy individual, the bronchial epithelium shows a high ______ ion concentration and fluid muscus.
In a healthy individual, the bronchial epithelium shows a high ______ ion concentration and fluid muscus.
For two heterozygous parents, each carrying a wild and a defective allele, the probability of transmitting cystic fibrosis to their child is ______.
For two heterozygous parents, each carrying a wild and a defective allele, the probability of transmitting cystic fibrosis to their child is ______.
Flashcards
Gene Therapy
Gene Therapy
Introducing functional genes into a patient's cells using a modified virus.
Glycemia
Glycemia
The concentration of glucose in the blood, maintained around 1 g/L.
Insulin
Insulin
A pancreatic hormone that helps glucose move from the blood into cells.
Hyperglycemia
Hyperglycemia
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Diabetes Symptoms
Diabetes Symptoms
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Insulin Resistance
Insulin Resistance
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Hyperinsulinemia
Hyperinsulinemia
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Insulin Deficiency
Insulin Deficiency
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Genetic Variability Implications
Genetic Variability Implications
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Mucoviscidose Prevalence
Mucoviscidose Prevalence
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Mucus Function
Mucus Function
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Mucoviscidose Mucus
Mucoviscidose Mucus
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Mucoviscidose Consequences
Mucoviscidose Consequences
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Mucoviscidose Variability
Mucoviscidose Variability
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Mucoviscidose Bronchial Effects
Mucoviscidose Bronchial Effects
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Mucoviscidose Pancreatic Effects
Mucoviscidose Pancreatic Effects
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Molecular Diagnosis
Molecular Diagnosis
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Challenge in CF Molecular Diagnosis
Challenge in CF Molecular Diagnosis
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F508del Mutation
F508del Mutation
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Electrophoresis
Electrophoresis
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Preimplantation Genetic Diagnosis (PGD)
Preimplantation Genetic Diagnosis (PGD)
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Viral Vector
Viral Vector
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Gene Therapy for CF (Limitations)
Gene Therapy for CF (Limitations)
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Mucoviscidose Inheritance
Mucoviscidose Inheritance
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Mucoviscidose Transmission Risk
Mucoviscidose Transmission Risk
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Mucoviscidose Treatments
Mucoviscidose Treatments
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Neonatal Screening
Neonatal Screening
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Sweat Test
Sweat Test
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Molecular Diagnosis Difficulty
Molecular Diagnosis Difficulty
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F508del Mutation Screening
F508del Mutation Screening
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F508del Fragment Size
F508del Fragment Size
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Targeted Prenatal Diagnosis
Targeted Prenatal Diagnosis
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Insulin's Role
Insulin's Role
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Diabetes Clinical Signs
Diabetes Clinical Signs
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Type 2 Diabetes Cause
Type 2 Diabetes Cause
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Susceptibility Genes
Susceptibility Genes
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Diabetes Environmental Factors
Diabetes Environmental Factors
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Prevalence
Prevalence
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Cystic Fibrosis
Cystic Fibrosis
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CFTR Protein Location
CFTR Protein Location
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CFTR Dysfunction
CFTR Dysfunction
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CFTR Gene Location
CFTR Gene Location
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ΔF508 Mutation
ΔF508 Mutation
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CFTR Mutation Types
CFTR Mutation Types
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Monogenic Disease
Monogenic Disease
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Autosomal Recessive
Autosomal Recessive
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Heterozygous
Heterozygous
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Symptoms caused by Cystic Fibrosis
Symptoms caused by Cystic Fibrosis
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Study Notes
Infections
- Enzymes become blocked in the pancreas, hindering food digestion.
- Abdominal pain, diarrhea, or constipation may occur.
- Difficulties in gaining weight and vitamin deficiencies arise due to fat malabsorption.
- Bile ducts in the liver can become obstructed.
- Intestines can also become obstructed.
CFTR Protein Failure and Disease Origin
- CFTR protein is normally in the cytoplasm of epithelial cells lining internal surfaces, such as genital, digestive, and respiratory tracts.
- In individuals with cystic fibrosis, CFTR protein is absent, degraded in the cytoplasm or doesn't appear on the epithelial cell membrane.
- CFTR protein forms a chloride channel across the cell membranes of epithelial cells, facilitating water transport for mucus fluidity.
- Dysfunctional CFTR protein in diseased cells leads to impaired chloride ion secretion and increased water reabsorption, causing mucus dehydration.
- Dehydrated mucus cannot be effectively cleared, accumulates, and disrupts normal function.
Chromosomal Location of the CFTR Gene
- CFTR gene is located on chromosome 7 (autosome).
- It comprises 4443 nucleotides that encode 1480 amino acids, forming the CFTR protein.
- In the general population, approximately 1 in 35 individuals is a carrier of a defective allele.
- Approximately 1 in 5000 births results in cystic fibrosis.
Distribution and Frequency of CFTR Gene Mutations
- Over 1700 CFTR gene mutations have been identified, but only 6 have a frequency exceeding 1% of observed mutations.
- The most frequent mutation is the deletion (ΔF508) eliminating triplet 508 coding for phenylalanine. This results in abnormal maturation of the CFTR protein, preventing it from reaching the apical membrane of the cell.
- The ΔF508 mutation accounts for 70% of mutated alleles.
Mutation Types and Consequences
- The majority of known CFTR gene mutations are point mutations.
- Mutation type affects CFTR protein production, chloride channel function, and protein stability.
- Phenotypic consequences vary based on mutations, resulting in different clinical presentations of cystic fibrosis with variable severity.
Transmission of Cystic Fibrosis Alleles
- Cystic fibrosis is a monogenic recessive genetic disease caused by a single gene.
- A child must inherit two defective alleles (autosomal recessive transmission) to develop the disease.
- Both parents must be heterozygous carriers of one normal and one defective allele.
- The probability of a child inheriting the disease from two heterozygous parents is 1/4.
- The probability of being a heterozygous carrier is 1/2, instead of 1/35 in the general population.
- Family history and genetic counseling can assess the risk of disease transmission.
Treatments and Hope for a Cure
- Treatments focus on managing the altered function or controlling the environment with medication, respiratory physiotherapy, specific dietary regimens.
- Treatments alleviate symptoms and are more effective when started early, requiring early detection.
Neonatal Screening Test
- France implemented a systematic neonatal screening for cystic fibrosis in 2002.
- It involves testing a dried blood spot taken 3 days after birth.
- This screening also detects other genetic conditions, such as phenylketonuria.
- Early management, especially nutritional, improves prognosis.
Sweat Test
- The sweat test is performed on individuals presenting suspect clinical signs.
- The test can be done at any age after 5 weeks of age.
- This requires stimulating sweat glands on the inner arm with a mild electric current.
- The test is positive if the chloride concentration in the collected sweat exceeds 60 mmol/L.
Molecular Diagnosis
- The procedure consists of direct mutation screening of the CFTR gene in cells.
- It's usually performed in cases of positive test results, using venous blood samples.
- It is possible through fetal ultrasound to reveal an intestinal obstruction on chorionic villus sampling (prenatal diagnosis).
- Can also be done in the event of particularly high genetic risk, from IVF cells (preimplantation diagnosis).
- Molecular diagnosis is challenging due to the gene size and mutation number, so exon fragments are used to identify mutations.
Molecular Diagnosis of Cystic Fibrosis
- The F508del mutation is the most common and is tested first.
- Exon fragments of 10 to 50 base pairs (bp) around triplet 508 are analyzed.
- Fragments of F508del mutation are only 47 bp long due to the deletion of three nucleotides; fragments are separated by electrophoresis based on size.
- When diagnosis cannot be based on F508del alone, 50% of affected children benefit from direct genotyping prenatal diagnosis.
- Targeted examination of 8 common mutations using commercial kits covers 65% of cases. In research labs, analyzing 30 mutations covers 87% of cases.
Improved Life Expectancy and Gene Therapy
- Treatments have improved patient life expectancy, with patient life expectancy increasing from 7 years in 1965 to 47 years in 2005.
- Gene therapy aims to correct the disease in affected lung cells by introducing functional CFTR genes via a vector into respiratory epithelial cells.
- Current gene therapy strategies cannot permanently transfer the functional gene, as lung epithelial cells have limited lifespans, preventing permanent cure.
Genetic Variation and Health
- Humans, like infectious microorganisms, have genetic variability due to mutations.
- These variations can affect outcomes to disease.
- Variations can also raise problems in the prevention and treatment of diseases and rapid evolution of microorganisms.
Grand Oral Presentation Topics
- Cystic Fibrosis: Origins, symptoms at different scales, risk assessment within affected families, screening, treatment, and curative hope through gene therapy.
- Type 2 Diabetes: Genetic and environmental components of this multifactorial disease.
Genetic Heritage and Disease
- Cystic Fibrosis is an example of a genetic disease.
Cystic Fibrosis Phenotype
- Cystic fibrosis is the most common genetic disease in European populations.
Macroscopic Phenotype of Cystic Fibrosis
- Mucus is a fluid substance lining and moistening body conduits, protecting their surfaces.
- Cystic fibrosis causes thick, viscous mucus, resulting digestive and respiration difficulties. This leads to malnutrition, lung damage and respiratory failure, the primary cause of mortality.
- In cystic fibrosis, mucus adheres to the walls of the bronchi.
- The bronchi are obstructed, causing coughing and expectoration.
- Infectious agents (viruses and bacteria) are retained, causing infections.
Type II Diabetes
- Diabetes is considered the foremost non-infectious pandemic in humanity.
- Glucose, or blood sugar, is the body's primary metabolic energy source, maintained around 1 g/L.
- Regulation involves insulin, a pancreatic hormone that facilitates transfers glucose from blood to cells and stores.
- Diabetes occurs with chronic hyperglycemia, or fasting blood glucose levels exceeding 1.26 g/L.
Clinical Signs of Diabetes
- Clinical indications of diabetes only appear at advanced stages.
- Frequent urination (due to glucose loss), excessive thirst, extreme hunger, fatigue, drowsiness, blurred vision, numbness/tingling in feet/hands, weight loss, and slow healing of skin.
Development of Type 2 Diabetes - 3 Steps
- Insulin Resistance: Excess visceral fat results in elevated circulating fatty acids. This causes preferential use by muscle cells. The result is increased production of insulin to absorb blood glucose and transform it into glucose by hepatic cells (liver). Both mechanisms increase blood glucose levels.
- Hyperinsulinemia involves pancreas produces insulin in response to high blood glucose, temporarily reducing insulin resistance and normalizing blood glucose levels.
- Insulinodeficiency comes after 10-20 years of hyperinsulinism, pancreatic cells become exhausted and can't secrete enough insulin to maintain normal glucose levels. Type 2 diabetes develops.
- Type 2 Diabetes results from exhaustion of pancreas because of a failure to produce sufficient insulin, leading to complications affecting eyes, kidneys, and feet.
Epidemiology of Type 2 Diabetes - Two Inseparable Components
- Genetic Component: Specific alleles are linked to diabetes development, but their presence isn't necessary or sufficient, indicating predisposition rather than direct cause.
- Environmental Component: Prevalence increases parallel with sedentary lifestyles, hypercaloric diets (rich in sugars and fats), obesity, and aging because obesity doesn't automatically bring on diabetes.
Conclusion
- Most genetic pathologies arise through interaction of multiple genes. Certain alleles increase the likelihood, but individual genetic background plays a role in health.
- Lifestyle and environmental factors can also interact to affect the likelihood of pathology.
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Description
This lesson covers the diagnosis of cystic fibrosis through venous blood samples, fetal ultrasounds, and preimplantation genetic testing. It addresses the challenges in molecular diagnosis due to the gene's large size and numerous mutations, as well as the limitations of screening for only the most common mutation. It also explores gene therapy as a means of introducing the functional CFTR gene into respiratory epithelium.
