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what is type II diabetes?
what are the different functions of glucose?
- Converted to glycogen to store energy
- Converted to fat to store energy
- Oxidized for energy: for the brain, RBCs, Mammary glands, fetus, spermatogenesis (notably not the gut)
- Precursor of amino acid C-skeleton
- Prevent ketosis
what organs use glucose for energy?
- Mammary glands
- NOT THE GUT: USES AA METABOLISM FOR ENERGY
can you synthesis glucose from AA?
where do we get get CHO from our diet?
- Plant based foods + milk
what is the AMDR for carbs?
what are monosaccharides?
- Monomers Cn (H2O)n
- Hexoses C6H12O6
what are starches?
what is amylose?
alpha(1-4) chains of glucose
what is amylopectin?
- alpha(1-4) chains of glucose with alpha(1-6) branches
what are the three types of fibre?
what is soluble fiber?
Forms a gel in water, pectins (found in fruits)
what is insoluble fibre?
- Hemicellulose, cellulose
- Have beta bonds, which we cannot digest
what is functional fibre?
psyllium added to foods
what are the features of soluble fibre?
- Viscous gel
- Delays gastric emptying
- Glycemic control
- Binds Cholesterol and bile acids
- Fermended by colonic bacteria
- Low GI
What are the features of insoluble fibre?
- Bulk (laxitive effect)
- Delays gastric emptying
- Some glycemic control
- Binds cations
- Minor fermentation by colonic bacteria
how are CHO digested?
- Mouth: salivary amylase
- Small intestinal lumen: pancreatic amylase, glucoamylase
- Small intestinal brush border: sucrase-isomaltase, lactase
what is lactose intolerance?
- β-galactocidase (gene family) deficiency in adults
- Lactose not digested in small intestine and reaches colon
- It is fermented in the colon by bacteria producing flatulence (methane, hydrogen, CO2)
- Osmotic diarrhea
- Breath hydrogen test to diagnose
- Not immune related
what is primary lactose non-persistance?
- Decreased lactase production after weaning
- 70% of adults worldwide but varies with population
- Mutation for lactase persistance (autosomal dominance- Single-Nucleotide-Polymorphism (SNP) in intron)
- Dairy farming VS malaria hypothesis
what is secondary lactose intolerance?
- Caused by some injury to the small intestine
- Eg. Parasite infection, celiac disease, pathology, malnutrition
what is congenital lactose intolerance?
- Non-functioning protein
- Infants, lactase-free formula (unable to digest breast milk)
- Same as lactose intolerance after infancy
what is a milk allergy?
- Not the same as lactose intolerance
- Protein, or peptides in milk
- IgE antibodies
- Mast cell degranulation
- Massive histamine response
- Involves immune reaction
how is galactose absorbed?
- SGLT-1 (sodium-glucose transport proteins) and GLUT-2
- First pass removal by liver
- Preferential conversion to glycogen
how is fructose absorbed?
- GLUT5 facilitated diffusion agains concentration gradient into cell
- GLUT5 or GLUT2 to exit cell
- First pass removal by liver (GLUT2)
- Rapid oxidation (faster than glucose)
- Preferential conversion to fatty acids, triglycerides
what stimulates glucose synthesis?
- plasma glucose
- rapid response = relaying on activation of enzyme rather than new glucose
how is glycogen broken down ?
explain the degradation of glucose
what is the cori cycle (lactic acid cycle)?
what is the fasting plasma glucose?
- so if the molecular weight of glucose is 180g/L
- then 180g/l x 5 = 90 g/d
what is the brains glucose requirement?
what is the hepatic glucose requirement?
what is gluconeogenesis?
Production of NEW glucose from non-carbohydrate carbon substrates
what are the precursors for gluconeogenesis?
Amino acids, pyruvate, glycerol
what stimulates gluconeogenesis?
Stimulated by glucagon and glucocorticoids when plasma glucose is low
what happens as a result of gluconeogenesis?
Protein breakdown is high ↑
how do glucose levels affect an athletes performance?
- Requirements for glucose ↑ with exercise intensity
- Marathon: glycogen for 1-3 hours
- Carbohydrate loading to maximize glycogen
- More later with protein metabolism
Glucose Homeostasis - Long term fast
what is ketogenesis?
- Fatty acid β-oxidation in the absence of glucose = ↑ rate of generation of Acetyl CoA
- No anaplerosis (building up of TCA cycle, build up of acetyl CoA) of TCA cycle
- Causes acetyl-CoA to accumulate
- β-hydroxybutyrate and acetoacetate are products (ketones)
- Ketone bodies are an alternate fuel for the brain (do have negative impact)
- But: ketoacidosis, impact on brain
- GENERAL CONCEPT
- β-oxidation of FA ---> generates Acetyl CoA
how does ketone synthesis work?
- β-oxidation of FA in absence of glucose
- TCA cycle intermediates depleted for gluconeogenesis during fasting
- Acetyl CoA accumulates ↑
- HMG-CoA lyase increased ↑ in fating (glucagon:insulin ration)
use of ketone bodies in preripheral tissues???adbasjbcjkdskvjacdruaehvkuH
what is ketoacidcosis?
- Ketone bodies are strong acids and they lower blood pH
- Acidification is bad because it impairs the ability of hemoglobin to bind to oxygen
- Eventually resulting in a coma
what is the respiratory quotient (RQ)?
RQ = CO2 produced/O2 consummed
- Substrate utilization:
- if burning CHO --> RQ = 1 (during fed state)
- if burning FAT --> RQ = 0.7 (during fasting)
what are the components of total energy expenditure?
- 67% - Basal Metabolic Rate (BMR)
- 10% - Diet-Induced Thermogenesis
- 23% - Activity
- %- Adaptive Thermogenesis
what is the BMR for males?
- For a 70 kg male:
- 1.0kcal/kg/h --> 1700kcal/day
what is the BMR for females?
- For a 55kg woman:
- 0.9kcal/kg/h --> 1200kcal/d
what happens when there is low blood glucose?
Hypoglycemia, isnulin shock (hypoglycemia coma) due to lack of enough glucose to meet the brains needs
hwhat happens when you have a high blood glucose?
Hyperglycemia, dehydration, ketoacidosis, cerebral edema (diabetic coma)
how much is the glucose levels found in our blood?
what happens when there is high blood glucose?
- Pancreas --> secrete insulin by the beta ells
- Insulin --> stimulates glucose oxidation, storage (in skeletal muscle) and conversion to fat (in the liver)
- Insulin --> also inhibits glucose production
what are major facultative glucose transporters?
- high affinity for glucose
- good at picking all glucose
what is an example of a major facultative
- SLC2A1-5 (solute carrier family 2 members 1-5)
- GLUT1- RBCs, brain (blood brain barrier), fetus (increase at low glucose concentration)
- GLUT2- Liver, B-cell, kidney, smal intestine (high capacity of glucose uptake)
- GLUT3- Brain (neurons), palcenta (high affinity at low concentration)
- GLUT4- Muscle, heart, adipose tissue (insulin mediated / sensitive to insulin)
- GLUT5- Small intestine (fructose transporter)
- Glucose transporter (GLUT2) to exit (facilitative transport)
- SGLT1 in intestine; SGLT2 in kidneys for re-uptake of glucose
- High concentration of glucose found in urine and feces
how does the regulation of insulin secretion by the β cells work?
- 1. Glucose enters the beta cell through GLUT2 (glucose 2 transporter) and ATP production ↑
- 2. ATP blocks the exit of K from the cells through K channels thus ↑ cellular K concentration
- 3. ↑ K concentrations causes the plasma membrane to open Ca channels thus allowing Ca to enter the beta cells
- 4. ↑ Ca in β cells causes insulin containing granules to be released by the β cells
how do insulin receptors interact with GLUT4?
*anabolic effects of insulin that are mediated by the insulin receptors**
- 1. Insulin binds to the α subunit of the insulin receptor
- 2. That ↑ glucose transport and autophosphorylation of the β subunit of the receptor
- 3. That will activate tyrosine kinase activity
- 4. Tyrosine phosphorylation will activate a cascade of intracellular signalling proteins that mediate the effects of insulin on glucose, fat and protein metabolism
what are incredins?ihwdqhdiwh
what is type 1 diabetes (TD)
- Diabetes mellitus: "sweet urine"
- Blood sugar levels above normal levels --> spoiled in urine
- Metabolic disorder - carbs (glcuose), protein and fat
- 10% of total diabetes cases
- Cell mediated autoimmune β cell destruction
- Genetic predisposition + precipitating event
- Autoimmune disease: pancreatic β cells are destroyed by body's immune system
- Lab tests for antibodies to glutamic acid decarboxylase (GAD), a protein found in pancreatic cells
- GAD catalyses the decarboxylation of glutamate to --> γ-aminobutyric acid, a neurotransmitter
- Autoimmune disease could be also caused by viral infection
what are the stages in developing TYPE 1A diabetes?
- 1. Genetic presupposition
- 2. Overt immunologic abnormalities & normal insulin release - Antibodies attacking beta-cells)
- 3. Progressive loss insulin release & glucose normal - Remainder beta-cells secrete more insulin
- 4. Overt diabetes & C-peptide present
- 5. No C-peptide - Due to complete beta-cell destruction / C-peptide is a part of the inactive form of insulin (precursor of insulin)
what happens if no insulin is produced?
how is the metabolism during untreated type 1 DM?
- GLUT4 peripheral tissuesNot getting any insulin
- Have to rely on: Fat Based economy, Low muscle glycogen, Increased muscle proteolysis for gluconeogenic AAs, Cori cycle
- Liver (GLUT2)Gluconeogenesis = ↑ rate due to FA synthesis
- Lipogenesis = ↑
- VLDL - fat metabolism
- NAFLD - fat droplet accumulating in the liver
- Other non GLUT4 peripheral tissuesGlucose/Glycogen excess
How is T1DM diagnosed?
- Glucosuria/Ketonuia- urinalysis
- Fasting plasma glucose concentration >7.00mmol/L (normal 5mmol/L)
- Oral glucose tolerance test- plasma glucose >11mmol/L
- Glycated hemoglobin (hemoglobin A1c) >6.5% (normal range 3.5-5.5%)
what are the consequences of untreated diabetes?
- No glucose in cells Hyperglycemia (↑ blood glucose)
- ↓ ↓
- Ketoacidosis Dehydration
what are 2 types of chronic type 1 diabetes ?
- Microvascular (↑ hexokinase)
- artherosclerosis (more dominant in T2DM)
what is microangiopathy?
- High ↑ glucose in some non-insulin sensitive tssues damages cells
- Accumulation of AGEs (advanced glycation end products)
what is retinopathy?
- Leading cause of blindness
what is nephropathy?
- Thickening of the glomerulus
- Results in microalbuminuria - small levels of protein in the blood
- Dialysis, transplant - can cause kidney failure
what is neuropathy?
Nerve damage in periphery because of impaired blood flow
how do we manage T1DM?
- Insulin injections (pump, nasal, islet transplant)
- Balance intake, activity, insulin
what are the risk factors for T2DM?
- Age of on set: generally over 40 years
- Risk factors heredity - multigenic disorderobesity (visceral)
what is the T2DM prevalence in Canada?
- More than 2 million Canadians have diabetes
- By the end of decade, number expected will be 3 million
- Why? the population is aging, obesity rates are ↑, Canadian lifestyle = sedentary
- Indigenous poeple in Canada are 3 x to 5 times more likely than the general population to develop T2DM
- 30% of American children born in 2000 forcast to develop T2DM
what is type 2 Diabetes mellitus?
- Typically overproduction of insulin
- there is an insulin resistance
- central obesity
- Followed by β cells exhaustion
- need for insulin
what is hyperinsulinemia and hyperglycemia?
Hyperinsulinemia: normal insulin metabolism and normal intracellular glucose
Hyperglycemia: insulin resistance and low ↓ intracellular glcuose
what are symptoms and clinical findings of T2DM?
what is glucosuria?
- Blood glucose 10mml/L --> blood sugar flushed out via kidneys
- Frequent urination and excessive thirst (polyuria and polydipsia)
how does de novo lipogenesis work?
how is T2DM monitored?
- Fasting plasma glucose ≥ 7 mmol/L (FPG)
- Oral glucose tolerance test (OGTT)
- glycemic response to 75 glucose load
- plasma glucose > 11-2 hours after load
- Glycated hemoglobin (HbA1c) ≥ 7%
what are the stages of development of T2DM?
- FPG < 5.6 mmol/l
- high ↑ insulin sensitivity
- moderate plasma insulin
- low plasma glucose
- FPG 5.6-6.9 mmol/Llow insulin sensitivity
- high ↑ plasma insulin - compensatory hyperinsulinemia and progressive β cell failure
- increasing plasma glucose
- FPG > 6.9mmol/Llower insulin sensitivity
- extremely high plasma glucose - hyperglycemia
- very low plasma insulin - failed β cells
what are some T2DM drug treatments?