Chapter 20- Perturbations of Energy Metabolism: Obesity and Diabetes Mellitus Flashcards
What is intermediary metabolism?
all changes that occur in a food substance beginning with absorption and ending with excretion
What are the energy content of carbohydrates, protein, fat, and alcohol?
Carbohydrate 4, protein 4, fat 9, alcohol 7kcal/g
BMR is increased in what diseases?
hyperthyroidism, fever, Cushing’s syndrome, tumors of adrenal gland, anemia, leukemia, polycythmia, cardiac insufficiency, & injury
BMR is decreased in what diseases?
hypothyroidism, starvation, malnutrition, hypopituitarism, hypoadrenalism (Addison’s disease), and anorexia nervosa
Integration of signals for energy storage and dissipation are mediated by what?
Hypothalamus
what is AMPK?
heterotrimeric protein complex and consists of a catalytic alpha-subunit and regulatory beta and gamma subunits
When AMP levels rise during anabolism what happens to AMPK?
AMPK is allosterically activated -> promotes ATP synthesis by activating key regulatory enzymes in the catabolic pathways
Negative allosteric regulators of AMPK are?
phosphocreatine and glycogen
MOA of metformin
activates AMPK -> inhibits the transcription of key regulatory hepatic enzymes required for gluconeogenesis
What is leptin?
Long-term regulator of energy store in adipocytes, functions in the afferent signal pathway of - feedback loop in regulating the size of adipose tissues & energy balance
Where is leptin synthesized?
adipocytes
how is leptin synthesis increased?
insulin, glucocorticoids, & estrogens
What happens when leptin levels are low
starvation, [low leptin] -> production of neuropeptide Y from hypothalamus, transported to paraventricular nucleus (PVN) of hypothalamus -> ↑appetite, & ↓ energy expenditure, Temp, reproductive function, and ↑ parasympathetic activity
What happens when leptin levels are high?
[↑leptin] -> opposite set of reactions ↓NPY -> activates POMC pathway-> mediated by MSH binding to MC4-R -> initiate reactions, ↓appetite, ↑energy expenditure, and sympathetic activity
Leptin levels in obese individuals are?
High leptin levels in obese individuals -> due to resistance or defect in leptin receptors
What transcription factor regulates conversion of preadipocytes to adipocytes?
peroxisome proliferator-activated receptor-γ (PPAR-γ2)
what are thiazolidinadiones?
hypoglycemic agent given to diabetics, synthetic ligands for PPAR-γ2-> activates PPAR-γ2 -> adipogenesis, increase insulin sensitivity
BMI overweight and obese
BMI- 25-29.9 = overweight
>30= obese
Short term regulators of hunger and satiety are
plasma levels of glu & a.a., cholecystokinin & other hormones
only known appetite stimulating peptide hormone secreted by the stomach
Ghrelin, also stimulates GH secretion
early onset obesity can be characterized by
Congenital human leptin deficiency, defective leptin receptor gene-> high plasma leptin d/t defective leptin metabolism or leptin resistance
Prader-Willi syndrome:
the most prevalent form of dysmorphic genetic obesity, PWS is caused by absence of the paternally derived PWS/AS region of chromosome 15
Angelman syndrome:
inherited chromosome 15 deletions from mother
Obesity treatments
behavioral modifications, dietary restrictions, exercise, pharmacotherapy (sibutramine, orlistat), & surgical intervention (bariatric surgery)
what is orlistat?
pancreatic lipase inhibitor that prevents absorption of lipids from the GI tract
what is sibutramine?
serotonin reuptake inhibitor -> appetite suppressant
primary source of energy during exercise generating maximum power
ATP & P-creatine -> glycolysis from glycogen
Source of energy during High-intensity endurance exercise
P-creatine -> glycogenolysis (muscle & liver)-> increasing aerobic oxidation, FA & plasma glu utilization, BCAA oxidation
Source of energy during Low-level non-fatiguing exercise
similar to long endurance exercise but w/o depletion of P-creatine & minimal muscle glycogen utilization; aerobic oxidation of FAs, glu, & BCAA -> main source of Energy
metabolic homeostasis is regulated by
endocrine system
Metabolic role of liver
- 1st organ to meet nutrients delivered from the intestines (except Lipid), the secreted insulin & glucagon
- Deliver bile into the intestine: cholesterol Homeostasis
- The primary site of glycogen deposition & blood glucose maintenance
- Plays central role in lipid, protein, & Nitrogen homeostasis
- In the typical adult, the liver exports daily 180g of glucose, 100g of TG, & 14g albumin
- Metabolic energy supplied by fatty acid oxidation
Metabolic role of adipose tissue
- 13kg, increase -> obesity
- Brown Adipocyte: production of heat
- White Adipocyte: TG for export as FAs
- Synthesize TG from FA &; Glu
- Energy supplied by FA oxidation & TCA cycle
Metabolic role of skeletal muscle
- 35Kg, contain the major portion of the body’s nonlipid fuels
- Contains 4X as much glycogen as the liver
- Lacks G6Pase -> Can’t be a source of Blood Glu,
- During starvation, muscle provides a.a. -> the primary C source for glucose homeostasis
- Cori cycle; anaerobic metabolism Glycogen -> Lac -> Glu in the liver
Metabolic role of brain
- Constant metabolic fuel user
- ~20% total O2 consumed, 2/3 O2 to maintain transmembrane potential
- Glu, below ~50mg/dL -> dizziness & lightheadedness
Metabolic role of heart
- Aerobic, uses FAs (glu), Ketone bodies, lactate, & pyruvate -> “scavenger”
Metabolic role of kidneys
- Uses Glu, FAs, ketone, a.a.
- Important in a.a. homeostasis
- Has the same gluconeogenic capacity /g tissue as liver -> ~80% used for urine formation
Metabolic role of GI
- CHOs, TG, Protein -> use & store
Metabolic role of blood
- Metabolites utilization and release coordinated
- Simple Monosaccharides, a.a. (high in Ala & Gln), Anions (lactate, pyruvate, acetoacetate, β-hydroxybutyrate), TCA intermediates, toxic metabolites (urea, bilirubin, creatinine, creatine), macromolecules (albumin, lipoproteins)
Metabolic role of other body fluids
- Albumin: most abundant plasma protein, osmotic regulation, transport of FAs, drugs, & toxic metabolites, indicator of hepatic function
- Lipoproteins: complex of TG, protein, Cholesterol, & PLs
Metabolic role of endocrine pancreas
Pivotal in metabolic homeostasis & integral component of metabolic regulation
α- & β-cells make up 20% & 75% of the total weight
Insulin, Glucagon, Somatostatin, Pancreatic polypeptide
Structure of insulin
A & B chain + C peptide,
Insulin synthesis
preproinsulin -> proinsulin -> secretary granules -> cleaves into Insulin + C-peptide by Enzyme
C-peptide is a good measurement of
distinguishing endogenous versus exogenous insulin (determine how much insulin secreted by patient)
Insulin secretion stimulants
Glucose, a.a., glucagon-like peptide (GLP), Ach, incretins, β-adrenergic agents stimulate, sulfonourea
insulin secretion inhibitors
Somatostatin, α-adrenergic agents, diazoxides
Familial hyperproinsulinemia
Genetic mutation where c-peptide remains attached to A chain (autosomal dominant trait); usually no symptoms of insulin resistance or hyperglycemia (maybe mild)
What is Lispro?
Lispro insulin (no dimer formation, insulin of choice to treat diabetes)-> 28Pro29Lys on B chain are switched-> same biological activity-> reduced hexameter formation-> biological activity within 15 min of admin
Biological actions of Insulin
Promote fuel storage & protein synthesis (inhibit breakdown)
Glucose uptake into muscle & adipose tissue via GLUT4 translocation
Describe properties of Insulin Receptor
Heterotetramer, tyrosine kinase, P/deP gene regulation
Describe Leprechaunism
receptor gene problem, type A insulin resistance
short acting insulins are
Lisper, aspart, glulisine
long acting insulin are
glargine, detemir
Glucagon stimulates, inhibits, enhances what
Stimulates glycogenolysis, gluconeogenesis & ketogenesis in the liver, inhibit glycogenesis
Enhance lipolysis of TG in adipocytes to provide FFAs
Glucagon secretion MOA
pancreatic alpha-cell membrane Receptor -> Gs protein complex -> AC activation -> increased cAMP -> cAMP dependent kinase (PKA) -> increased Phosphorylation of the controlling enzymes
High ratio of insulin/glucagon induces
glucokinase, citrate cleavage enzyme, acetyl-CoA carboxylase, HMG-CoA reductase, pyruvate kinase, 6PF1K, 6PF2K, & F2,6BPase
Low ratio of insulin/glucagon represses
glucokinase, citrate cleavage enzyme, acetyl-CoA carboxylase, HMG-CoA reductase, pyruvate kinase, 6PF1K, 6PF2K, & F2,6BPase
Low ratio of insulin/glucagon induces
G6Pase, PEP carboxylase, F1,6BPase
High ratio of insulin/glucagon represses
G6Pase, PEP carboxylase, F1,6BPase
Secretion of glucagon triggered by
hypoglycemia, low blood [glucose], elevated [blood a.a.], exercise, inhibited by high blood [glu]
Somatostatin synthesized by
synthesized in the δ cells of islets, gut, hypothalamus, & several other areas of the brain
In the islets somatostatin does what?
blocks insulin & glucagon secretion
Forms of somatostatin
2 forms, S14, S28 exist
In the pituitary gland somatostatin does what?
inhibit GH & TSH release
In the gut somatostatin does what?
blocks gastrin, motilin secretion -> inhibit gastric acid & pepsin secretion, suppresses gallbladder contraction -> lead to decreased delivery of nutrients to the circulation
Pancreatic polypeptide is secreted when?
in response to fuel ingestion and potentially affect pancreatic exocrine secretion of bicarbonate and protein
In islet cell regulation alpha-cell does what?
stimulates beta and delta cells
In islet cell regulation beta cell does what?
inhibits alpha cells
In islet cell regulation delta cell does what?
inhibits alpha and beta cells
RBC’s only use what kind of glycolysis?
anaerobic glycolysis -> lactate
At rest skeletal muscle use what for energy?
fatty acids
In heavy exercise skeletal muscle use what for energy?
glycogen & blood glucose glucose must be available for these tissues
Fructose is metabolized where?
part of fructose metabolized in intestinal cells, the rest enters portal blood, liver & kidney are the other sites of fructose utilization
Fructose is absorbed on apical membrane on intestinal cells via?
GLUT5
Fructose is absorbed on basolateral membrane intestinal cells via?
GLUT5 and GLUT2
If diet consist of only CHO’s then glucagon levels
decrease
If diet consist of high protein then glucagon levels
increase
The liver converts excess glucose to
TG -> VLDL
insulin directly stimulates glucose uptake by most cells except
brain, liver, and blood cells
effects of insulin on glycogen synthase
activates glycogen synthase -> increased glycogen synthesis
glucocorticoids do what
stimulate FA oxidation, gluconeogenesis, glycogenesis, ↑enzymes of glucagon action
rapid stimulators of lipolysis
Epinephrine, glucagon within minutes
slow stimulators of lipolysis
Growth Hormone, glucocorticoids’ action requires hrs
inhibitors of lipolysis
Insulin & prostaglandin E1 suppress lipolysis by depressing cAMP levels
under normal conditions the brain cannot use ketones because?
the enzyme needed is induced after 4 days of starvation
in prolonged starvation what happens to gluconeogenesis?
liver gluconeogenesis↓, kidney gluconeogenesis↑ as the need for NH3 secretion↑
Acarbose MOA
α-glucosidase inhibitor: inhibit breakdown of CHOs into glu by intestinal brush-border α-glucosidase & pancreatic lipase
Metformin MOA
a biguanidine: inhibition of hepatic gluconeogenesis & glycogenolysis; in muscle, ↑insulin R tyr kinase activity & ↑GLUT4 transporter system -> adverse effect, lactic acidosis
Troglitazone (TZD) MOA
↑insulin sensitivity in liver, muscle, & adipose tissue; promote conversion of non-lipid-storing preadipocytes to mature adipocytes with ↑insulin sensitivity; functions as TF targets PPAR-γ -> regulate expression of proteins controlling metabolic pathways, side effects -> hepatic toxicity
SUR analog (repaglinide) MOA
inhibits different K+ channel -> rapid-onset & short-acting effects
How is leptin synthesis decreased?
decreased by β-adrenergic agonists
