Diabetes mellitus Flashcards

1
Q

Which cells are GLUT-4 glucose co-transporter proteins present in?

A

Muscle cells
Adipocytes
Cardiomyocytes

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2
Q

How is GLUT-4 translocated?

A

Insulin binds to the insulin receptor,inducing conformation change of tyrosine kinase. Intracellular phosphorylation stimulates pathway for GLUT-4 synthesis and integration.

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3
Q

What are the inhibitory effects of insulin in muscle cells?

A

Proteolysis is inhibited: Reduces activity of proteases and proteasomes

Indirectly inhibits gluconeogenesis

Inhibits activity of glucose-6-phosphate.

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4
Q

What effect does cortisol have on glucose during hypoglycaemia?

A

Stimulates proteolysis and gluconeogenesis

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5
Q

What effect does IGF-1 and growth hormones have on protein synthesis?

A

Enhances protein synthesis

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6
Q

Overview: What two pathways are down regulated by insulin in carbohydrate metabolism?

A

Glycogenolysis

Gluconeogenesis

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7
Q

Overview: What 3 pathways are up regulated by insulin regarding lipid metabolism?

A

Lipogenesis
Triglyceride synthesis
Cholesterol synthesis

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8
Q

What 2 pathways are inhibited by insulin regarding lipid metabolism?

A

lipids oxidation

Triglyceride breakdown

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9
Q

How is alanine essential in gluconeogenesis?

A

Alanine is converted into pyruvate –> oxaloacetate –> phosphoenolpyruvate (PEP)

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10
Q

What effect does glucagon have on gluconeogenesis?

A

Stimulates pyruvate and lactate uptake into hepatocytes, in addition to AAs.

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11
Q

What effect does insulin have on lipoprotein lipase?

A

Potentiates lipoprotein lipase activity

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12
Q

What is the structure of triglycerides?

A

Triglycerides consist of a glycerol backbone associated with three esterified fatty acid molecules.

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13
Q

Which particles are triglycerides packaged in?

A

Chylomicrons and VLDLs

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14
Q

What is the function of lipoprotein lipase?

A

Circulating triglycerides associated with chylomicrons are hydrolysed by the action lipoprotein lipase, presented on adipocyte cell surface membrane receptors into glycerol and NEFA

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15
Q

Where are lipoprotein lipase located?

A

On the cell surface membrane of adipocytes

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16
Q

What is the fate of glycerol and NEFA, released by the lipoprotein lipase?

A

Enter within the adipocytes cites, to undergo series of condensation and esterification reactions to form triglycerides which are stored in adipose tissue

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17
Q

What effect does insulin exert on intracellular lipase?

A

Inhibits the intracellular lipase (hydrolyses triglycerides to release fatty acid)

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18
Q

Which two hormones stimulate lipolysis?

A

Growth hormone
Cortisol

Enables fatty acid to become available for beta oxidation to generate acetyl-CoA for ketogenesis.

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19
Q

What is ketogenesis?

A

Formation of ketone bodies

20
Q

Where does ketone body formation occur?

A

Within mitochondrial matrix of hepatocytes

21
Q

How does fatty-acyl-CoA enter hepatocytes?

A

Carnitine shuttle

22
Q

What is the fate of acetyl-CoA due to ketone body formation?

A

Undergoes sequences of thiolysis and addition reactions into acetoacetate and ultimately into acetone

23
Q

Why are ketone bodies important during hypoglycaemia?

A

Used as an alternative substrate to satisfy cerebral requirements

24
Q

Which two enzymes does insulin regulate regarding ketone body formation?

A

Hormone sensitive lipases inhibited

Acetyl-CoA activates, reduces fatty acid oxidation and ability to enter into the mitochondria

25
Q

Which hormone stimulates the process of ketone body formation?

A

Glucagon

26
Q

What is glycogenolysis?

A

Glycogenolysis is the degradation of glycogen to glucose. Glycogen branches are catabolised by sequential removal of glucose monomers via phosphorolysis, by glycogen phosphorylase. Phosphorylase activity is regulated by hypoglycaemic signals, under glucagon action.

27
Q

Which enzyme removes phosphorylation groups from glucose-6-phosphate?

A

Glucose-6-phosphatase

28
Q

What effect does insulin have on glycogenolysis?

A

Inhibitory effect, through inhibition of phosphatase enzyme

29
Q

Which concentrations determine hypoglycaemia?

A

Glucose (3-5.5mmol)

Conditions result in low insulin: glucagon ratio

30
Q

Which four processes are unregulated in the fasted state?

A

Lipolysis: Increases NEFA to facilitate b-oxidation, generating acetyl CoA

Proteolysis: Generates glycogenic amino acids as a substrate for gluconeogenesis

Hepatic glucose output: Glycogenolysis and gluconeogenesis
Ketogenesis

31
Q

Which diagnostic tests are performed to identify a patient with diabetes?

A
Fasting glucose
Random glucose
Oral glucose tolerance test
Hb1Ac
C-peptide
Antibodies: GAD
Renal function: Presence of ketone bodies in urine and blood
32
Q

What is fasting glucose test?

A

Fasting glucose: Test to determine the amount of glucose in a blood sample, after a period of fasting. Diagnostic concentration >7.0 mmol/L.

33
Q

What is a random glucose test?

A

Blood sugar test taken from a non-fasting subject. This test, also called the capillary blood glucose (CBG), assumes a recent meal and therefore has higher reference values than the fasting glucose test. Diagnostic concentration >11.1 mmol/L.

34
Q

What is an oral glucose tolerance test?

A

2-hour, 75g oral glucose tolerance test (OGTT), used to test for diabetes. Fasting glucose is measured initial as a baseline comparison. Glucose solution is consumed then glucose concentration is monitored. Patients without diabetes will result in a glucose rise, then decrease due to insulin stimulation.

35
Q

What is HbA1c?

A

Glycosylated haemoglobin is a form of haemoglobin attached to a sugar (glucose, galactose and fructose spontaneously bind with haemoglobin when present in circulation).

36
Q

What is the advantages of HbA1c?

A

Primarily used to determine the three-month average blood-sugar level, can be used as a diagnostic test for diabetes mellitus, and as an assessment test for glycaemic control. 3-month average used due to average erythrocyte lifespan (4-months).

37
Q

What is the pathophysiology of diabetes mellitus?

A

Dysfunctional pancreatic insulin-secreting Beta cell of the islets of Langerhans
B-cell mass decreases declines insulin, level is inadequate to maintain normal blood glucose levels

Autoimmunity: Immunoglobulins complimentary to B cell receptors, stimulate an auto immune response

38
Q

What is the function of glutamic acid decarboxylase?

A

Enzyme present within pancreatic beta cells, catalyses formation of GABA.

GAD antibodies reduces beta cell function.

39
Q

Which type of diabetes is ketoacidosis associated with?

A

Type 1 diabetes

40
Q

What are the three main osmotic symptoms associated with diabetes?

A

Polyuria
Polydipsia
Nocturia

41
Q

Why does glysouria occur?

A

PCT filtrate saturated with so much glucose that not all can be reabsorbed by cotransporter proteins. Osmotic balance is shifted, the glucose decreases water potential, increasing water retention, and more water present in urine

42
Q

What is the pathophysiology of type 2 diabetes?

A

Insulin resistance in myocytes and hepatocytes, and impaired insulin secretion by the pancreatic β-cells are the core characteristics for T2DM.
Β-cell resistance to the incretin ‘glucagon-like peptide 1’ (GLP1) contributes to progressive failure in the function of beta cells, whereas increased glucagon levels and enhanced hepatic sensitivity to glucagon contribute to the excessive glucose production by the liver.

Dysfunctional GLUT-4 expression

Adipocytes: Accelerated lipolysis and increased plasma free fatty acids levels. Elevated levels of NEFAs reduces insulin biosynthesis.
Increased renal glucose reabsorption by SGLT2, and the increased threshold for glucose spillage in the urine contribute to the maintenance of hyperglycaemia.

43
Q

Why does hyperglycaemia cause oxidative stress within pancreatic beta cells?

A

GLUT-2 is insulin independent, therefore there is a continuous influx of glucose by facilitated diffusion within the pancreatic β-cells, subsequently promoting cellular dysfunctionality. Deranged metabolism of glucose, oxidative stress incurs (Increased radicals). This causes decreased insulin secretion, and reduced glucose sensitivity.

44
Q

What effect does metformin induce?

A

Metformin reduces gluconeogenesis and opposes glucagon-mediated signalling within hepatocyte; in addition to increasing glucose uptake in myocytes.

45
Q

How does metformin inhibit liver gluconeogenesis?

A

Metformin inhibits the glucogenic enzymes and stimulates glycolysis by altering activity of multiple enzymes

46
Q

How does metformin increase glucose uptake?

A

Metformin enhances insulin sensitivity and insulin-mediated glucose uptake in skeletal muscle. This is mediated through an increase in tyrosine kinase activity of the insulin receptor and through improved activity and translocation of GLUT-4 glucose cotransporters to the plasma membrane.