Glucose Regulation in the Peripheral Tissues Flashcards
EFFECT OF INSULIN IN THE PERIPHERY
primary insulin target tissues are where
skeletal muscle, liver, and adipose tissue
role of the pancreas
what does insulin secrete/produce
digestive enzymes
produces primary messengers (hormones)
EFFECT OF INSULIN IN THE PERIPHERY
primary insulin target tissues are skeletal muscle, liver, and adipose tissue, in which the hormone modulates _______ of intracellular proteins
phosphorylation (within minutes)
EFFECT OF INSULIN IN THE PERIPHERY
primary insulin target tissues are skeletal muscle, liver, and adipose tissue, in which the hormone modulates phosphorylation of intracellular proteins(within minutes) and affects gene transcription and protein synthesis (timeframe?)
hours
PKB is activated following a cascade from what
insulin binding
when insulin activates PKB, what protein is activated
mTOR
insulin activates PKB through a series of _____ events
phosphorylation
PKB promotes glucose uptake by cells through _________ of GLUT4 transporters to the cell membrane
translocation
by enhancing GLUT4 translocation, PKB promotes increased ________ _____ by cells
increased glucose uptake
PKB promotes _____ synthesis in the liver and muscle, contributing to glucose storage
glycogen
what are the effects of insulin on muscle?
insulin promotes uptake of glucose by muscle for immediate use during exercise or storage as glucagon
how does insulin influence the liver
insulin stimulates the uptake of glucose by the liver, ->storage as glycogen
insulin inhibits glycogen phosphorylase, activates glycogen synthase, and prevents glucose synthesis
excess glucose in converted to fatty acids under the influence of insuiln
what role does insulin play in adipose tissue
insulin ______ the uptake of glucose by adipose tissue, facilitating its conversion to _____ for fat production
promotes
glycerol
what role does insulin play in adipose tissue
insulin ______ lipolysis which is the breakdown of ______ in adipose tissue
inhibits
triglycerides
MUSCLE’S ROLE IN GLUCOSE UPTAKE
What percentage of whole-body insulin-stimulated glucose uptake is accounted for by skeletal muscle
skeletal muscle accounts for 60-70% of whole-body insulin-stimulated glucose uptake
SIGNIFICANCE OF MUSCLE IN INSULIN RESISTANCE
why is muscle considered a major site of insulin in obesity and T2DM
muscle is a significant site of insulin resistance, making it a therapeutic target especially in obesity and T2DM
EFFECTS OF MUSCLE SPECIFIC INSULIN RECEPTOR KO
What were the consequence of muscle-specific KO of the insulin receptor (IR) mice
muscle specific knockout of IR led to increased fat mass, elevated serum triglyceride levels, and muscle insulin resistance in mice -> no significant effects on global glucose tolerance
impaired glucose uptake in IRS1 and IRS2 mice
what happens to glucose uptake in mice lacking both IRS1 and IRS2 in skeletal and cardiac muscle
mice lackibg both IRS1 and IRS2 in skeletal and cardiac muscle experience impaired glucose uptake, although without hyperglycaemia and hyperinsulineamia
REGULATION OF HGP BY INSULIN AND GLUCAGON
how does insulin regulate HGP in relation to glucagon
insulin regulates HGP by inhibiting glucagon secretion from pancreatic alpha cells
INSULIN’S EFFECT ON HEPATIC GLUCOSE PRODUCTION
how does insulinsuppress hepatic glucose prodcution
Insulin suppresses HGP by inhibiting gluconeogenic enzymes and activating glycolytic and fatty acid synthetic enzymes, resulting in the switch from fatty acid oxidation to synthesis
ROLE OF INSULIN IN CENTRAL SIGNALLING
What is the role of central insulin i hepatic IL-6-STAT3 signalling
Central insulin activates hepatic IL-6-STAT3 signaling through the brain liver axis
CONSEQUENCES OF LIVER-SPECIFIC IR KNOWCKOUT
what are the metabolic consequences of liver specific insulin receptor KO min mice
LIRKO are hyperglycaemic and hyperinsulinmemic and displayed reduced liver size compared to WT mice
INSULIN RESISTANCE IN LIVER-SPECIFIC IRS1 AND IRS2 KOs
How do liver specific IRS1KO mice and liver specific IRS2 KO mice differ in terms of insulin resistance
LIRS1-KO mice show insulin resistance after re-feeding but not during fasting, while LIRS2 KO mice display insulin resistance during fasting but not after re-feeding
CONSEQUENCES OF DUAL IRS1 AND IRS2 KO IN THE LIVER
What are the consequences of liver-specific KO of both IRS1 and IRS2
Liver specific KO of both IRS1 and IRS2 leads to severe glucose intolerance and impaired lipid metabolism
Role of Adipose Tissue Expansion
what effects does adipose tissue expansion have on preventing ectopic deposition of lipids in other organs
Adipose tissue expansion exerts a buffering effects, preventing lipids from being ectopically deposited in other organs such as the liver , muscle and pancreas
Relationship Between Diet-Induced Obesity and Insulin Resistance
What remains the cause of insulin resistance under conditions of excess nutrition
diet-induced obesity remains the cause of insulin resistance under conditions of excess nutrition
Insulin’s Effect on Glucose Uptake in Adipocytes
How does insulin stimulate glucose uptake in adipocytes, and what is the converted form of glucose
Insulin stimulates glucose uptake in adipocytes, where it converts into lipids as a more efficient energy storage
Insulin’s Role in Lipolysis Inhibition
what is the effect of insulin on lipolysis, and what does lipolysis involve
insulin inhibits lipolysis, which is the breakdown of truglcyerides into glycerol and free fatty acids
Impairments in Adipose Tissue of Type 2 Diabete
what changes are observed in the tyrosine phosphorylation of IRS1 and PI3K activation in the adipose tissue of T2DM
tyrosine phsophorylation of IRS1 and activation of PI3K are decreased in adipose tissue of type 2 diabetes
Consequences of Fat-Specific Deletion of Insulin Receptor (IR)
What are the consequences of fat-specific deletion of IR in terms of fat mass, obesity protection and glucose tolerance
Fat-specific deletion of IR reduces fat mass, protects against obesity and guards against obesity-related glucose tolerance, thereby increasing longevity
Impact of Fat-Specific Deletion of GLUT4
What happens when GLUT4 is specifically deleted in fat tissue concerning insulin-stimulated glucose uptake and insulin-mediated suppression of HGP
fat specific deletion of GLU4 results in decreases in insulin-stimulated glucose uptake in fat and muscle, along with impairment in insulin-mediated suppression of HGP
Carbohydrate (CHO) Regulation of Gene Expression
how does glucose regulate gene expression, and what s the name of the transcription factor involved
Glucose acts via ChoRF (Transcription Factors) which binds to ChoRE on glucose responsive genes
examples may include PDX-1 and C/EBP
Lipid Regulation of Gene Expression
how do polyunsatureted fatty acids (PUFA) contribute to transcriptional regulation and what are the key players in this process
Polyunsatureted fatty acids (PUFA) contribute to normal transcriptional regulation via PPARs (peroxisome proliferator)
Cholesterol’s Role in Gene Expression
how is cholesterol involved in the regulation of gene expression, and which regulatory element is key in this process
Cholesterol is involved in gene expression regulation via SREBP (sterol regulatory element BP)
Amino Acids’ Impact on Gene Expression
WHat are the various effects of amino acods on gene expression, including the aspects they influence
amino acids can impact transcription, ribosomes, signalling, and amino acids transport
Glucose Regulation of Lipogenic Genes
How does glucose regulate lipogenic genes, and what is the role of ChoRE in this process
Glucose can regulate lipogenic genes by having ChoRE ( Carbohydrate Response Element) identified on the promoters of these genes. ChREBP binds to the CHoRE, promoting the transcription of these lipogenic genes
Regulatory Sequences of L-type Pyruvate Kinase and S Genes
what sequences are present in ChoREs (carbohydrate response elements) and why is the correct spacing of these elements crucial fopr the transcriptional response to carbohydrate
ChoREs contain two E-box sequence motifs, and the correct spacing of these elements is critical for the carbohydrate control of gene transcription
ChREBP (ChoRF) Characteristics
WHat are the key charcteristics of ChREBP
ChREBP is a large protein, 864 amino acids long, mainly expressed in the liver, kidney, white adipose tissue and brown adipose tissue, it contains domains suc as NLS, poly-proline doamins, basic helix loop -helic leucine zipper domain and a leucine zipper like domain.
Additionally it has potential phosphorylation sites for PKA (P1, P2 adnd P3) and a putative AMPK phosphorylation site (p4)
ChREBP Localization and Activation
describe the cellular localisation of ChREBP in the presence of low and high glucose
low glucose -> ChREBP is located in the cytosol, when blood glucose increases, it translocates to the nucleus
ChREBP-Mlx Heterodimeric Complex
How does ChREBP function, and what is its interaction with another transcription factor
ChREBP functions in a heterodimeric complex with another transcription factor knows as MAx-like protein X (Mlx)
Phosphorylation State and Nuclear Localization of ChREBP
What is the role of Ser196 phosphorylation in the localisation of ChREBP, and how does its dephosphorylation affect its function
Ser196 phosphorylation retains ChREBP in the cytosol, but dephosphorylation, along with dephosphorylation of Ser626, and Thr666, results in nuclear localisation and binding to DNA
Activation of Protein Phosphatase 2A (PP2A)
How is protein phosphatase 2A (PP2A) activated and what is its role in ChREBP dephosphorylation
PP2A is activated by xylulose 5-phopshate, a metabolote generated by the pentose phopshate pathway under high glucose conditions. It dephosphorylates Ser196, Ser626, and Thr666 of ChREBP
ChREBP Synergy with SREBP-1c
what is the synergy between ChREBP abd Sterol Regulatory Element binding protein - 1c (SREBP-1c)
ChREBP acts in synergy with SREBP-1c a major mediator of insulin action on hepatic glucokinase (GK) and lipogenic genes
Induction of Lipogenic Genes by High Carbohydrate Diet
how does insulin and glucose contribute to the induction of lipogenic genes in the liver during a high carbohydrate diet
(1)Insulin acts on hepatocyte insulin receptors (inc SREBP-1c) which binds to the promoter region of lipogenic enzyme genes to stimulate transcription
(2)Simultaneously, increased glucose elevates glycolysis, activating ChoRF/ ChoRF binds to a distinct site from SREBP-1c on the promoter regions of many lipogenic enzyme genes to activate their expression. ChoRF may function synergestically with SREBP to promote lipogenesis in the liver
ChoRF/GRBP and Glucose Response
What is the role of ChoRF (glucose response binding protein) in response to glucose, and what signalling molecule is associated with it?
ChoRF/GRBP is involved in glucose response, potentially using glucose-6-phosphate as a signalling molecule
Response to Glucose Deprivation
How is the response to glucose deprivation regulated, and what are the nutrient sensing response elements (NSRE) 1 and 2
many genes regulated by glucose, requiring insulin, are involved in the response to glucose deprivation. NSRE 1 and 2 are necessary for gene activation, with C/EBPbeta binding to the NSRE-1 sequence
Role of PGC-1α in Gluconeogenic Enzymes
What is the role of PGC-1α in the transcription of gluconeogenic enzymes, and how is it induced?
PGC-1α, a transcriptional coactivator is induced in the fasted liver and by cAMP (possibly glucagon) and gluccocorticoids. It overexpresses gluconeogenic enzymes and coactivated gluccorticoid receptor and HNF-4alpha
Role of PGC-1 in Gluconeogenesis
what is the key role of PGC-1 in regulating gluconeogensis, and which transcription fcator does it work with
PGC-1 is a key regulator of gluconeorgenesis, working with transcription factors such as N+HNF-4 to induce gluconeogenic genes, for example PEPCK
Regulation of Glucose Production by Glucagon and Insulin
How does glucagon and insulin regulate glucose production in the liver through PGC-1
glucagon activates the cAMP pathway, leading to increased glucose production via PGC-1 expression. INsulin counteracts gluconeogenesis by inhibiting the expression such as PEPCK, potentially by blocking PGC-1 expression
Activation of Gluconeogenic Gene Expression by Glucocorticoids
what is the role of glucocorticoids, along with PGC-1 in the activation of gluconeogenic gene expression
Glucocorticoids, in conjunction with PGC-1 activate the expression of gluconeogenic genes
CREB Co-activators in Gluconeogenesis
Name the co-activators of CREB involved in gluconeogenesis
CREB co-activators include CREB binding protein (CBP) and TORC2 (transducer of regulated CREB activities)
