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Z MD1 metabolism block > diabetes > Flashcards

diabetes Flashcards

0
Q

what is the use of measuring C peptide when monitoring diabetes

A

it is a measure of at least some insulin being made - some functional beta cells left when C peptide is present
(C peptide:insulin is 1:1)

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1
Q

why is T1 diabetes not an acute illness

A

because you start to make autoantibodies many years prior to diagnosis (long preclinical period)

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2
Q

which type of antibodies for diabetes has autoantibodies but looks like T2DM

A

autoantibodies against GAD

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3
Q

is T1 diabetes B cell or T cell mediated

A

T cell - CD8

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4
Q

what are the mechanisms by which CD8 T cells destroy beta cells of the pancreas

A

via perforin and granzyme B

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5
Q

what is wrong with the current treatment for T1DM

A
  • incapable of mimicking physiological glucose control and therefore cannot prevent complications such as hypoglycaemia very well
  • have to inject multiple times per day
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6
Q

which group of diabetics are suitable for autologous haematopoietic stem cell transplantation

A

newly diagnosed diabetes with no ketoacidosis

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7
Q

who is suitable for islet transplantation

A

people with severe hypoglyacemia

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8
Q

problems with islet transplantation

A
  • availability of organ donors (quantity and quality)
  • viability and function of islets
  • immunosuppression
  • longevity of the graft
  • cost
  • allosensitization
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9
Q

explain the mechanism for the release of insulin

A

glucose enters beta cell via GLUT2 –> glucose undergoes glycolysis –> ATP –> increased ATP/ADP ratio leads to inhibition and closure of ATP-sensitive K+ channels –> depolarisation –> opening of voltage dependent Ca channels –> Ca influx –> fusion of insulin containing secretory granules with plasma membrane

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10
Q

action of the SNS on insulin release

A

NA inhibits insulin release

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11
Q

what are the effects of insulin of carbohydrate metabolism

A
  • glucose transport into adipose and muscle (GLUT 4)
  • increases rate of glycolysis in muscle and adipose tissue
  • glycogen synthesis in adipose tissue, muscle and liver
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12
Q

what are the effects of insulin on lipid metabolism

A
  • FA and TAG synthesis in adipose tissue
  • uptake of TG from the blood into adipose tissue and muscle
  • increase rate of cholesterol synthesis in the liver
  • increases the production of malonylcoenzyme A - reduces the amount of FA entering hepatic mitochondria
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13
Q

explain the effects of insulin on protein metabolism

A
  • amino acid transport into tissues

- protein synthesis in muscle

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14
Q

finish this sentence…

the excess carbohydrates that cannot be stored as glycogen are converted under the stimulus of insulin into

A

fats - stored in adipose tissue

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15
Q

where are GLUT 1, 2, 3 and 4 found

A

1 - all the cells of the body
2 - pancreatic beta cells, liver, intestine and kidney
3 - neurons
4 - striated muscle and adipose tissue

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16
Q

function of GLUT 2

A

ensures that glucose uptake by pancreatic beta cells and hepatocytes occurs only when circulating glucose is high

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17
Q

function of GLUT 3

A

crucial for allowing glucose to cross the BBB and enter neurons

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18
Q

insulin deficiency leads to what

A

hyperglycaemia, ketoacidosis, dehyradtion, polyuria, polydispsia, glucosuria, hypotension

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19
Q

what things push towards ketogenesis in diabetes

A
  • increased oxaloacetate
  • decreased malonylCoA –> increases carnitine action
  • increased FFA (due to TAG hydrolysis)
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20
Q

what are the ketoacids

A

acetone
acetoacetate
beta-hydroxybutyrate

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21
Q

what are the drug names of the genetically modified long acting insulin?

A 
glargine insulin (lantis)
detemir insulin (levemir)
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22
Q

why is detemir insulin also linked to weight loss in diabetics

A

because the genetic modification of adding a FA to the end of the B chain means that it is able to pass the BBB and act on the brain to suppress appetitie

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23
Q

what are the drug names of the genetically modified short acting insulin?

A 
insulin glulisine (apidra)
insulin Lispro (humalog)
insulin aspart (novorapid)
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24
Q

what is the typical insulin regime for a T1 diabetic

A

basal bolus

  • one injection of long acting insulin at bed time
  • one inject of short acting insulin immediately prior to each meal
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25
Q

what is the advantage of an artificial pancreas

A

has a continuous glucose sensor to determine the flow of insulin from the pump

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26
Q

what are the three main chronic complications of diabetes

A
  • retinopathy
  • nephropathy
  • neuropathy
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27
Q

three ways you can measure the level of diabetes control

A
  • measuring blood glucose
  • HbA1C
  • fructosamine
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28
Q

how is HbA1C formed

A

when glucose is high it non-enzymatically binds to proteins on Hb via an irreversible covalent bond

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29
Q

what is the advantage of measuring HbA1C over blood glucose

A

HbA1C gives you an indication of the average level of blood glucose for the preceding 3 months

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30
Q

what is the target HbA1C

A

7%

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31
Q

why is a target of less than 7% of HbA1C not a good thing

A

due to the risk of mortality due to increased incidence of hypoglycaemia

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32
Q

what does the fructosamine level indicate and when would you measure it

A

the level of red cell turnover

measure when a patient has high blood glucose but low HbA1C –> its low because of the high number of reticulocytes

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33
Q

how do you monitor the development of nephropathy in diabetics

A

measure the urinary microalbumin

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34
Q

what is the classification of hypoglycaemia

A

blood glucose <4mmol/L

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35
Q

how do you have 2 types of symptoms for hypoglycaemia in diabetics and what are the symptoms

A

acute fall - sympathetic nerve drive –> tachycardia, anxiety, dry mouth an tremor
chronic low levels - brain malfunction, paralysis, coma and death

36
Q

treatment of hypoglyacemia

A
  • if conscious - give glucose orally followed by a meal containing carbs
  • if diminished consciouness - give bolus of glucagon
37
Q

precipitating causes of ketoacidosis

A
  • infection
  • cessation of insulin
  • new onset diabetes
  • AMI or pancreatitis or other illness
  • unknown
38
Q

what is the treatment for ketoacidosis

A
  • admission to hospital
  • IV saline
  • administration of insulin
  • replacement of potassium
39
Q

why do you replace potassium when treating for ketoacidosis

A

because insulin pushes K into cells and therefore you will have low potassium in the blood
- need to prevent this as this can cause arrhythmia and death

40
Q

how many cells does an islet of Langerhans contain

A

50-300

41
Q

4 types of cells in the islet of langerhans and what do they produce

A

alpha - glucagon
beta - insulin and amylin
gamma - pancreatic polypeptide
delta cells - somatostatin

42
Q

what forms the majority of the islet of Langerhans

A

beta cells

43
Q

what enzymes cleave preproinsulin

A

prohormone convertase 1 (pre) and 2 (pro)

44
Q

explain phases of insulin secretion

A
  • initial sharp rise in secretion that lasts for 2-5 minutes in response to increased blood glucose
  • prolonged secretion phase if the glucose lasts for a long time
45
Q

how do amino acids cause insulin release

A

transported into the beta cell via specific transporters, and is then used in the TCA cycle like glucose

46
Q

how do FAs cause insulin release

A

increased FA causes an increased malonyl CoA which inhibits CPT-1 causing insulin secretion

47
Q

why is more insulin secreted if glucose is given orally compared to intravenously

A

due to the incretin effect - the glucose in the gut triggers the release of incretin hormones which increases the release of insulin

48
Q

two main incretin hormones

A

glucagon-like peptide-1 (GLP-1) - (more potent)

glucose-induced insulinotropic polypeptide (GIP)

49
Q

which cells of the gut secrete GLP-1

A

L cells of small intestine

50
Q

when is GLP-1 released

A

in response to glucose and FAs

51
Q

action of GLP-1

A
  • both stimulates secretion of insulin and the synthesis of insulin
  • inhibits gastric emptying
  • inhibits glucagon secretion
  • promotes beta-cell proliferation, differentation and maturation
52
Q

what are the 2 groups of drugs that are mimicing the effects of GLP-1

A

GLP-1 agonists

DPP-4 inhibitors

53
Q

how do DPP-4 inhibitors work

A

they inhibit the enzyme that degrades GLP-1 –> enhances endogenous GLP-1 effects

54
Q

which cells produce GIP

A

K cells of the duodenum

55
Q

what stimulates GIP secretion

A

glucose and FAs

56
Q

action of GIP

A

activates lipoprotein lipase to enhance fat clearance from the blood

57
Q

explain the regulation of GIP

A

its effect is dependent on the plasma glucose concentration

58
Q

action of amylin

A
  • inhibits glucagon secretion
  • delays gastric emptying
  • inhibits food intake
59
Q

what is the drug that is an analogue of amylin

A

pramlintide

60
Q

action of pancreatic polypeptide

A
  • inhibits food intake
  • increases energy expenditure
  • inhibits secretion of enzymes from the pancreas
  • blocks the contraction of the gall bladder
61
Q

what is the function of somatostatin on the pancreas

A
  • inhibits insulin and glucoagon secretion
  • inhibits pancreatic exocrine function
    (appears to be to prevent exaggerated responses to a meal)
62
Q

definition of diabetes

A

a disorder of the metabolism causing excessive thirst and the production of large amounts of urine

63
Q

what is the difference between diabetes mellitus and diabetes insepidus

A

mellitus - polyuria is secondary to glycosuria, in turn due to hyperglycaemia
insipidus - pituitary problem causing increased ADP –> polyuria

64
Q

what are the two intracellular pathways that insulin activates

A

MAP kinase

PI-3K pathway (this one causes GLUT4 expression on cell surface)

65
Q

the consequences of diabetes relates to what 3 things

A
  • macrovascular changes
  • microvascular changes
  • cellular changes
66
Q

what are the macrovascular changes that occur with chronic poorly controlled diabetes

A
  • accelerated and more severe atheroma

- this leads to sequelae such as MI, stroke, angina

67
Q

what causes accelerated atheroma in diabetics

A
  • increased hepatic production of atherogenic lipoproteins
  • suppression of lipid uptake in peripheral tissues
  • abnormal endothelial function with pro-coagulant results
    (lead to hyperlipiaemia and hypertension)
68
Q

what 3 organs/system are particularly affected by the macrovascular changes associated with diabetes

A

kidney
retina
would healing

69
Q

The microvascular changes that occur with chronic poorly controlled diabetes relate to

A

glycosylation of proteins

70
Q

what are advanced glycation end products

A

stable and irreverisble glycosylated proteins due to hyperglyceamia

71
Q

why does diabetes predispose to nephropathy

A
  • diabetic glomerulosclerosis/arteriolosclerosis
  • impaired neutrophil function –> pyelonephritis
  • papillary necrosis
  • accelerated atherosclerosis in larger arteries
72
Q

what are the two histological signs of diabetic nephropathy

A
  • Kimmelsteil Wilson nodules in the mesangium of the glomerulus –> eventually become balls of collagen
  • arteriolar wall thickening by acellular proteinaceous material (hyaline arteriolosclerosis)
    (result in very thick BM and poor perfusion to the glomerulus)
73
Q

what is the primary process underlying diabetic retinopathy

A

vascular proliferation in response to ischaemia due to microvascular injury (hyaline arteriolosclerosis) and reduced perfusion

74
Q

why is there poor wound healing in diabetics

A

related to impaired perfusion due to microvascular injury

75
Q

3 pathways for chronic hyperglycaemia that cause damage to tissues

A
  • AGEs
  • activation of protein kinase C
  • intracellular hyperglycaemia and abnormal polyol pathways
76
Q

how do AGEs elicit their effects

A

they bind to RAGE (specific receptor) on inflammatory cells (T cells and macrophages), endothelial cells and vascular smooth muscle

77
Q

what are the receptor mediated effects of AGEs

A
  • release of pro-inflammatory cytokines and GFs from macrophages causing growth and proliferation abnormalities
  • generation of ROS in endothelial cells –> damage
  • increased pro-coagulant activity by endothelial cells
  • proliferation and matrix production by vascular smooth muscle –> hyaline arteriolosclerosis
78
Q

what are the extracellular effects of AGEs

A
  • cross linking of Type 1 collagen in vessel walls altering their dynamics (can lead to vessel injury)
  • AGE-induced cross linking of collagen IV in BM –> alters attachment of endothelium, permeability and causes thickening
  • can trap other proteins including LDL
79
Q

how does hyperglycaemia cause activation of protein kinase C

A

intracellular hyperglycaemia stimulates DAG overproduction –> PKC activation

80
Q

actions of PKC in diabetes

A
  • pro-angiogenic GFs
  • elevated endothelin-1 and reduced NO –> small vessel constriction
  • pro-fibrogenic GFs like TGF-beta –> increases production of BM and matrix
  • pro-inflammatory cytokines from endothelium
81
Q

overall function of PKC in diabetes

A

causes structural and functional abnormalities in the capillary bed including wall thickening, constriction and abnormal responses to attempts to modulate calibre, abnormal endothelial function and pro-inflammatory cytokines

82
Q

how are polyols made during diabetes

A

excessive IC glucose is metabolized through intermediates called polyols to fructose

83
Q

how do polyols cause damage in diabetes

A

metabolism to fructose uses up glutathione (need this to protect the cell against oxidative stress)

84
Q

what causes neuropathy in diabetics

A
  • AGE-related damage leading to loss of axons
  • possibly polyol-related damage
  • microvascular injury leading to neuronal ischaemia
85
Q

which liver problem is associated with diabetes

A

non-alcoholic steatohepatitis/non-alcoholic fatty liver disease

86
Q

histology of NASH

A
  • fat accumulation
  • infiltrate of neutrophils and lymphocytes
  • fibrosis
87
Q

commonest cause of death in a diabetic is

A

MI/stroke/renal failure due to macrovascular changes

Z MD1 metabolism block (9 decks)

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