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Endocrine System > Hormonal Regulation of Metabolism > Flashcards

Hormonal Regulation of Metabolism Flashcards

1
Q

What commonly causes obesity and how is obesity related to diabetes?

A

Disruption of caloric homeostasis results in obesity, it causes the overproduction of glucose by the liver and the inability of other tissues to use glucose, which then manifests as diabetes mellitus

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2
Q

Who is more likely to develop DM if the BMI is high, women or men?

A

Women

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3
Q

What is the fate of intracellular glucose?

A

Glucose 6 phosphates can be reversibly converted into Glycogen, Glucose, and Fructose - 1,6 phosphate

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4
Q

What can fructose -1,6 phosphate be then reversibly converted into?

A

Pyruvate which can then be reversible converted into Lactate or irreversibly converted into Acetyl-CoA

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5
Q

What does Glucose-6-phosphate irreversibly get converted into?

A

Glycoproteins, peptidoglycans and glycolipids

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6
Q

Which enzymes are responsible for reversible conversion of glucose-6-phosphate to glycogen?

A

Glycogen synthase converts into glycogen, and glycogen phosphorylase converts into glucose-6-phosphate

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7
Q

Which enzymes are responsible for reversible conversion of glucose-6-phosphate to glucose?

A

Glucose-6-phosphatase converts glucose 6 phosphate into glucose and hexokinase/glucokinase converts glucose back into glucose-6-phosphate

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8
Q

Which enzymes are responsible for reversible conversion of glucose-6-phosphate to fructose-6-phosphate?

A

Phosphofructokinase

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9
Q

Which enzymes are responsible for reversible conversion of glucose-6-phosphate to glycogen?

A
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10
Q

Which enzymes are responsible for irreversible conversion of glucose-6-phosphate to glycoproteins, peptidoglycans and glycolipids?

A

Glutamine - Fructose 6- phosphate amidotransferase (GFAT)

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10
Q

Which enzyme converts pyruvate into acetyl-CoA?

A

Pyruvate dehydrogenase (PDH)

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11
Q

Why is glucose phosphorylated by hexokinase?

A

In order to trap glucose within cells (since all the GLUTs are potentially bidirectional)

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11
Q

What is the dephosphorylation of glucose process?

A

The reserve reaction is catalyzed by glucose-6-phosphatase, which is a necessary step for the export of glucose from hepatic cells and renal cells

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11
Q

What is the rate-limiting step in glucose metabolism?

A

Glucokinase

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11
Q

What is Glucokinase currently considered as?

A

A strong candidate target for antihyperglycemic drugs for type 2 diabetes

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11
Q

What is the role of glucokinase (hexokinase IV)?

A

Has a major role in the control of blood glucose homeostasis because it is the predominantly hexokinase expressed in the liver, it plays a role in hepatic glucose disposal

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11
Q

What does overactivity of the glucose-6-phosphatase mean?

A

A feature of the increased hepatic glucose production –> typical of type 2 diabetes and is often associated with reduced responsiveness to insulin

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11
Q

What is glucokinase?

A

It is the glucose sensor for insulin secretion in beta cells, thus determining the rate of insulin secretion

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11
Q

What does a deficiency of the glucose-6-phosphatase enzyme result in?

A

Glycogen storage disease type 1 –> von Gierke disease

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11
Q

Which agents appear to reduce the activity of glucose-6-phosphatase?

A

Insulin-sensitising agents such as metformin and thiazolidinediones

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11
Q

What are the four distinct metabolic fates of glucose after it has entered the cell and undergone phosphorylation?

A
  1. Storage as Glycogen
  2. Used to synthesize other molecules such as glycerol, 6-phosphoglutarate, glycoproteins, peptidoglycans, and glycolipids
  3. Metabolized anaerobically to yield energy –> lactate
  4. Metabolized aerobically to yield energy –> ATP, H2O, CO2
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11
Q

In vivo, what is the primary signal for insulin secretion?

A

It is not glucose itself but neurotransmitters such as acetylcholine and norepinephrine

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11
Q

What releases acetylcholine and norepinephrine?

A

Released in response to sensory cues like the sight or smell of food during the cephalic phase of release

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11
Q

What is the purpose of acetylcholine and norepinephrine?

A

Early insulin secretion in anticipation of nutrient intake prepares the body to regulate blood glucose levels even before food is consumed

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11
Q

How do gut-derived factors contribute to postprandial insulin secretion?

A

Glucose crossing the apical membrane of enteroendocrine K cells or L cells via SGLT1 triggers the secretion of the glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1), respectively

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11
Q

What are the receptors for GIP and GLP-1 on beta cells coupled to?

A

Increased levels of cAMP via G proteins, and when activated at the same time as rising glucose concentration –> result in amplified insulin secretion –> enabling the body to respond appropriately to ingested glucose enetring the bloodstream

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11
Q

What is the contribution of gut-derived factors to postprandial insulin secretion?

A
  1. Following ingestion of 75 g glucose orally
  2. With or without incretin receptor antagonist infusions in healthy individuals
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12
Q

What is the incretin effect?

A

It describes the phenomenon whereby oral glucose elicits higher insulin secretory responses than intravenous glucose

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13
Q

What % does the incretin effect account for when it comes to postprandial insulin secretion?

A

As much as 70% of postprandial insulin secretion

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14
Q

Because of the incretin effect, we can ingest increasing amounts of glucose…

A
  1. Without increasing postprandial glucose excursions, which otherwise might have severe consequences
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15
Q

What is the mechanism behind the incretin effect?

A

Incretin-stimulated insulin secretion

16
Q

What do defects in the incretin axis contribute in?

A

Contribute to the impaired insulin secretion in type 2 diabetes

17
Q

What initiates the metabolism of glucose? Which enzyme is involved?

A

The phosphorylation of glucose, a reaction catalyzed by the enzyme glucokinase (GCK)

18
Q

What is the rate-limiting step in insulin secretion?

A

Phosphorylation of glucose and loss of function mutations in GCK also impair glucose-induced insulin secretion

19
Q

What are the different clinical impact of mutations in GCK?

A

Heterozygous mutations lead to maturity-onset-diabetes-of-the-young (MODY), while homozygous mutations result in neonatal diabetes

20
Q

What is insulin?

A

A 51-amino acid peptide hormone that is synthesized and secreted by pancreatic beta cells

21
Q

What is the role of insulin?

A

Plays a crucial role in regulating blood sugar (glucose) levels in the body

22
Q

What is the active insulin composed of?

A

Two polypeptide chains (A-chain and B-chain) linked by two interchain disulfide bonds

23
Q

What is a characteristic of the A chain?

A

It has an addituonal intrachain disulfide bind

24
Q

What is connecting-C peptide?

A

Polypeptide originating from insulin proinsulin after its cleavage in the beta cells in the pancreas

25
Q

How is C-peptide secreted?

A

Equimolarly with the other cleavage product, insulin, into the circulation

26
Q

Where is C-peptide removed from?

A

A minimal fraction is removed from the liver, mainly removed from the kidney

27
Q

Does C-peptide have any biological activity?

A

It is devoid of biological activity

28
Q

What are the clinical applications of C-peptide?

A

Differentiating between endogenous and exogenous hyperinsulinism and establishing the need for insulin therapy in diabetic patients already treated with insulin

29
Q

What is insulin?

A

It is the most potent anabolic hormone

30
Q

What is the purpose of insulin?

A
  1. Promotes the synthesis and storage of carbohydrates, lipids, and proteins while inhibiting their degradation and release into the circulation
  2. Stimulates the uptake of glucose, amino acids, and fatty acids into cells and increases the expression of enzymes that catalyze glycogen, lipid, and protein synthesis while inhibiting the activity or expression of those that catalyze degredation
31
Q

What is the purpose of the insulin signaling pathway and what is it divided into?

A

It controls metabolism and can be divided into proximal and distal segments

32
Q

What does the proximal segment consist of?

A

The canonical elements:
1. Insulin receptor
2. Insulin receptor substrate (IRS) proteins,
3. Phosphoinositide 3-kinase (PI3K)
4. Activated kinase (Akt)

33
Q

What does the distal segment of the insulin signalling pathway refer to?

A

Substrates of Akt substrates are intimately linked to the various physiological functions of insulin and are often specific to a particular cell type

34
Q

What is the key node in the insulin signaling pathway?

A

Activated kinase (Akt), it has more than 100 substrates that have been implicated in a multitude of biological functions

35
Q

What happens upon activation of Akt?

A

It can diffuse throughout the cell and mediates most if not all, physiological, metabolic actions of insulin

36
Q

What does the pathway diversification of insulin signaling do?

A

Downstream targets of Akt activation, which leads to different distal signaling in target tissues in response to insulin

37
Q

What does insulin increase? How?

A

Glucose transport in fat and muscle cells by stimulating the translocation of the transporter GLUT4 from intracellular sites to the plasma membrane

38
Q

Where is GLUT4 found within the cell?

A

In vesicles that continuously cycle from intracellular stores (cytoplasm) to plasma membrane

39
Q

How does insulin increase the glucose transport?

A

Increasing the rate of GLUT-4 vesicle exocytosis, and by slightly decreasing the rate of internalisation

40
Q

What happens if the muscle and fat cells are insulin resistant?

A

A primary disruption occurs in insulin’s ability to stimulate glucose transport effectively

41
Q

How does insulin resistance in muscle contribute to pancreatic falure?

A
  1. The beta cells respond to insulin resistance by making and secreting more insulin in an attempt to overcome the initial insulin resistance,
  2. The machinery becomes overwhelmed, and unfolded/misfolded proteins accumulate, activating the unfolded protein response (UPR)
  3. If the UPR continues, apoptosis is triggered, beta cells die, and insulin secretion ceases
42
Q

What is Glucagon?

A

A 29 amino acid peptide hormone processed from proglucagon

43
Q

Where is proglucagon expressed?

A

In various tissues like the brain, pancreas, and intestines

44
Q

What is proglucagon processed into?

A

Multiple peptide hormones in a tissue-specific fashion, for example:
1. Proglucagon is processed into functional GLP-1 by PC1-3 in intestinal L cells,
2. Processed into functional glucagon by PC2 in the pancreatic cells

45
Q

In the context of glucose metabolism, what does GCGR signaling stimulate?

A
  1. Hepatic glycogenolysis
  2. Gluconeogenesis with concomitant inhibition of glycogen synthesis
  3. Promotion of amino acid uptake and catabolism pathways
46
Q

What is the function of GCGR signaling?

A

It rapidly increases hepatic glycogenolysis via a signaling cascade involving the canonical cAMP-PKA pathway

47
Q

What does the GCGR signaling activate?

A

Activates glycogen phosphorylase kinase and subsequent activation of glycogen phosphorylase

48
Q

What is the net effect of the GCGR signaling pathway?

A

Breakdown of glycogen into glucose-1- phosphate, which can then be used to produce energy

49
Q

When is glucose-1-phosphate used as a source of energy?

A

During periods when immediate glucose is needed by the body

50
Q

What does GCGR signaling ihibit?

A

Inhibits glycogen synthase, preventing hepatic glycogen synthesis

51
Q

WHat is the net effect of GCGR signaling via PKA inhibiting glycogen synthase?

A

A decrease in hepatic glycogen storage, resulting in more glucose being available in the bloodstream

52
Q

How does the GCGR signaling mechanism help?

A

It helps maintain blood glucose levels,ring fas particularly duting or times of low glucose intake

53
Q

What kind of metabolism is insulin associated with?

A

Well-fed, absorptive metabolism

54
Q

What kind of metabolism is Glucagon associated with?

A

Fasting and postabsorptive metabolism

55
Q

What is the relationship between insulin and glucagon?

A

Usually oppose each other with respect to pathways of energy metabolism

56
Q

How does Glucagon work?

A

Through the cAMP system to activate protein kinase A

57
Q

What does the activation of Glucagon favour?

A

The phosphorylation of rate-limiting enzymes, like glycogen phosphorylase and glycogen synthase

58
Q

What is the result of the activation of Glucagon?

A
  1. Glycogen degradation increases
  2. Glycogen synthesis slows

–> Release of glucose from the liver during hypoglycemia

59
Q

In which other metabolic pathways is the opposing relationship between glucagon and insulin manifested?

A

Triglyceride synthesis and degradation

60
Q
A

Endocrine System (10 decks)

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