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Year 2 semester 2 > Diabetes > Flashcards

Diabetes Flashcards

1
Q

What cells are there in the pancreas and what do they produce?

A

Beta: insulin, alpha: glucagon and delta: somatostatin also PP cell: pancreatic polypeptide

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2
Q

How is insulin created?

A

Preproinsulin (single chain 86aa) is synthesized in ribosomes and enters endoplasmic reticulum of beta cells where it is cleaved to form proinsulin (amino terminal signal peptide removed). This is transported to the Golgi apparatus where it is packaged into secretary vesicles. While in the secretory vesicle it is cleaved at two sites to form insulin and C peptide fragment

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3
Q

What is the job of C peptide

A

C peptide links the alpha and beta chains allowing proper folding of the molecule and formation of disulfide bonds between the two chains

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4
Q

What do beta cells co-secrete with insulin

A

Islet amyloid polypeptide (IAPP) which is amylin, a 37 aa peptide (role unclear)

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5
Q

What BGL stimulates release of insulin and what receptor stimulates this?

A

3.9mmol/L (70mg/dL) with GLUT2 and it is the metabolism of glucose (rather than the glucose itself) and stimulates secretion

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6
Q

What happens when the glucose enters the beta cells? Steps in glucose release

A
  1. Phosphorylation to form glucose-6-phosphate
  2. Further metabolism via glycolysis generates ATP which inhibits the activity of an ATP sensitive K+ channel
  3. This induces cell membrane depolarization which opens voltage-dependent calcium channels
  4. Influx of calcium triggers exocytosis of insulin-containing granules
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7
Q

Where is GLUT1 found?

A

In most cells, including kidney, colon, RBC and brain microvessels (high affinity, high capacity)

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8
Q

Where is GLUT 2 found?

A

Liver, pancreatic beta cells, basolateral membrane of SI, kidney (low affinity, high capacity, “glucose sensor, carrier for fructose)

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9
Q

Where is GLUT3 found?

A

Neurons (high affinity, high capacity)

Note: when in starvation mode this is the only one still working really

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10
Q

Where is GLUT4 found?

A

Fat, skeletal and cardiac muscle (activated by insulin, high affinity, mediates insulin-stimulated glucose uptake in adipose and muscle tissue)

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11
Q

Where is GLUT5 found?

A

Intestines, testes and kidney (primarily fructose carrier in intestine)

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12
Q

What kind of rhythm is insulin released in and why is this important?

A

Biphasic (5-10 mins and 60-120 mins). It is critical in the suppression of liver glucose production and insulin-mediated glucose disposal by adipose tissue

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13
Q

What factors increase insulin secretion?

A

Increased BG, increased blood free fatty acids, increased blood amino acids, gastrointestingal hormones (gastrin, cholecystokinin, secretin, gastric inhibitory peptide), glucagon/GH/cortisol, parasympthaetic stimulation (ACh), beta adrenergic stimulation, insulin resistance (obesity), sulfonylurea drugs (glyburide, tolbutamide)

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14
Q

What factors decrease insulin secretion?

A

Decreased blood glucose, fasting, somatostatin, alpha adrenergic activty, leptin

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15
Q

How long is the circulatory half life of insulin?

A

3-5 minutes (unextracted- 50% is removed and catabolised by the liver as first pass metabolism and C peptide/proinsulin are catabolized by the kidney and therefore have half lives 3/4x longer)

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16
Q

Draw the insulin receptor and describe how insulin causes it’s effects

A

See notes

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17
Q

What are the short term effects of insulin?

A

Mostly on muscle utilization of glucose: promotes fuel storage (anabolism) and prevents the breakdown and release of fuel that has already been stored (catabolism)

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18
Q

Describe the synthesis of insulin

A

Prepro to pro to insulin (see notes)

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19
Q

What are the overall effects of insulin?

A

The primary role of insulin is in glucose homeostasis, which is accomplished through the stimulation of glucose uptake into insulin-sensitive tissues such as fat and skeletal muscle.
In these tissues, insulin promotes fuel storage (anabolism) and prevents the breakdown and release of fuel that has already been stored (catabolism).

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20
Q

What is the effect of insulin in the liver?

A

Insulin promotes fuel storage by stimulation of glycogen synthesis and storage.
Insulin inhibits hepatic glucose output by inhibiting gluconeogenesis and glycogenolysis (glycogen breakdown):
 Inhibits the gene expression of enzymes involved in glucose production.
 Stimulates the gene expression of enzymes involved in glucose utilization.
 Stimulates glucogen synthesis by increasing phosphatase activity, leading to dephosphorylation (thereby increasing the activity) of glycogen phosphorylase and glycogen synthase.
 Increases the activity of glucokinase, which phosphorylates glucose.
 Inactivates liver phosphorylase (the main enzyme that splits glycogen into glucose) and glucose phosphatase.

Also stimulates glycolysis (metabolism of glucose to pyruvate), promoting the formation of precursors for fatty acid synthesis.

Promotes the conversion of excess glucose into fatty acids:
 Insulin stimulates lipogenesis, leading to the increased synthesis of VLDLs.
 Inhibits fatty acid oxidation and production of ketone bodies.

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21
Q

What effect does insulin have on muscle?

A

Insulin promotes the storage of glucose by stimulating glycogen synthesis and inhibiting glycogen synthesis and inhibiting glycogen catabolism.
Also stimulates protein synthesis.
Stimulates glucose uptake and favours protein synthesis through phosphorylation of a serine/threonine protein kinase known as mammalian target of rapamycin.

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22
Q

What effect does insulin have on adipose tissue?

A

o Stimulates fat storage by stimulating lipoprotein lipase, the enzyme that hydrolyses the triglycerides carried in VLDLs and other triglyceride-rich lipoproteins to fatty acids, which can then be taken up by fat cells.
o Increased glucose uptake caused by upregulation of the GLUT-4 transporter also aids in fat storage because this increases the levels of glycerol phosphate, a substrate in the esterification of free fatty acids, which are then stored as triglycerides.
o Inhibits lipolysis, preventing the release of fatty acids, a potential substrate for hepatic ketone body synthesis. Insulin exerts this effect by decreasing the activity of hormone-sensitive lipase, the enzyme that hydrolyses stored triglycerides to releasable fatty acids.
o Insulin triggers dephosphorylation of hormone-sensitive lipase, and activates acetyl-CoA carboxylase.
o Antagonizes catecholamine-indiced lipolysis through the phosphorylation and activation of phosphodiesterase, leading to a decrease in intracellular cAMP levels and a concomitant decrease in protein kinase A activity.

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23
Q

What other hormones play a role in blood glucose maintenance? What is their basic effect?

A

Insulin (lowers), Somatostatin (lowers), glucagon (raises), epinephrine (raises), cortisol (raises), ACTH (raises), Growth hormone (raises) and thyroxine (raises)

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24
Q

What does glucagon do?

A

A large polypeptide secreted by the alpha cells of the Islets of Langerhans when blood glucose is lowered it raises BGL. The main effects are:
Glycogenolysis (break down of liver glycogen)
Increased gluconeogensis
Minor effects are: increase rate of AA, activates adipose cell lipase making increase in fA for the body and decreasing storage of triglycerides

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25
Q

What does somatostatin do?

A

A polypeptide produced in the delta cells of the islets the principal role is theorised to extend the period of time over which the food nutrients are assimilated into the blood. At the same time, by depressing insulin and gucagon secretion decreased utilization prevents rapid exhaustion of the food.
Inhibitory effects: actly locally on insulin and glucagon, motility of the stomach/duodenum/gall bladder, both secretion and absorption in GIT

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26
Q

What stimulates somatostatin release?

A

Amost all factors related to ingestion: increased BG/AA/FA or increased concentration of the gastrointestinal hormones released from upper GIT in response to food.

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27
Q

What does Epinephrine do with regards to BGL?

A

Produced in the adrenal medulla it enhances the release of glucose from glycogen and enhances the release of fatty acids from adipose tissue

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28
Q

What does cortisol do with regards to BGL?

A

Produced in the adrenal cortex it enhances gluconeogensis and antagonizes insulin

29
Q

What does ACTH do with regards to BGL?

A

Produced in the anterior pituitary it enhances the release of cortisol and enhances the release of fatty acids from adipose tissue

30
Q

What does Growth hormone do with regards to BGL?

A

Produced in the anterior pituitary it antagonizes insulin

31
Q

What does thyroxine do with regards to BGL?

A

Produced in the thyroid it enhances release of glucose from glycogen and enhances absorption of sugars from intestine

32
Q

What is the normal level of insulin in the fasting individual (ie before breakfast)?

A

3.6-5.8mmol/L of blood in fasting person each morning before breakfast

33
Q

What methods does the body have to correct severe hypoglycaemia?

A

A direct effect of low blood glucose on the hypothalamus is to stimulate the sympathetic nervous system, in severe hypoglucaemia. Adrenaline secreted by the adrenal glands causes further release of glucose from the liver.

Over a period of hours to days, both growth hormone and cortisol are secreted in response to prolonged hypoglycaemia. This causes decreased rate of glucose utilization by most cells, converting instead to greater amounts of fat utilization.

34
Q

What are the signs of hyperglycemia?

A

polyphagia, polydipsia, polyuria

Plus: burred vision, tiredness/fatigue, weight loss, poor wound healing, dry or itchy skin, nocturia

35
Q

What are the effects of BGL being too high?

A

Glucose (and amino acids) would be at such high concentrations that the hyperosmolar effect wouldcause progressively severe neurological deficits & even coma
o The concentration of glucose (and amino acids) would be above the renal tubular threshold ofreabsorption in convoluted tubules & these compounds would spill over into the urine ->
glycosuria
o Glycosuria -> osmotic diuresis -> polyuria, nocturia -> dehydration -> polydipsia

36
Q

What are the common causes of hyperglycaemia?

A

Diabetes (low insulin or resistance to insulin)
Drugs (corticosteriods, beta blockers, adrenaline, thiazide diuretics, niacin and some antipsychotics)
Critical illness
Physiological stress

37
Q

What are the common causes of hypoglycaemia?

A

Drugs used to treat diabetes (insulin, oral hypoglycaemic drugs) and other drugs eg alcohol
Critical illnesses (organ failure)
Hormone deficiency (cotisol, insulin deficient diabetes)
Non-islet cell tumor
Exercise or fasting

38
Q

What is Whipple’s triad?

A

Symptoms known or likely to be caused by hyoglycaemia.
Low glucose at the time the symptoms occur.
Reversal or improvement of symptoms or problems when the glucose is restored to normal

39
Q

What are the signs of hypoglycaemia?

A

Adrenergic: shakiness, tremor, anxiety, nervousness, palpitations
Glucagon manifestations: Hunger, borborygmi, nausea, vomiting, headache
Neuroglycopaenia: abnormal cognition, impaired judgement, irritability

40
Q

What is the mechanism of polyuria and polydipsia?

A

Insulin deficiency/resistance- cells do not take up glucose - increased BGL- kidneys unable to reabsorbthe excess glucose (exceed renal threshold for reabsorption in convoluted tubules) -glucose stays in lumen, glycosuria -> increasing osmolarity of urine -increased water excreted (drawn into lumen) due to increased osmotic pressure of urine (osmotic diuresis)- polyuria, increasing water loss & electrolytes - decreased blood volume, dehydration, hyperglycaemia -hyperosmolarity of blood -depletes ICF
water levels due to increasing blood colloid osmotic pressure -> thirst center osmoreceptors in hypothalamus stimulated- polydipsia.

41
Q

What are some of the things targeted by the immune system in type 1 diabetes>

A

Pancreatic isletmolecules targeted by the autoimmune process include insulin, glutamic acid decarboxylase (GAD).

42
Q

What are some abnormalities that have been detected in the humoral and cellular arms of the immune system in type 1 diabetes?

A

Islet cell autoantibodies.
Activated lymphocytes in the islets, peripancreatic lymph nodes and systemiccirculation.
T lymphocytes that proliferate when stimulated with islet proteins.
Release of cytokines within the insulitis (infiltrates islet)
Beta cells seem to be particularly susceptible to the toxic effect of some cytokines (TNF-α), interferon γ and IL-1].

The precise mechanisms of beta cell death are unknown but may involve formation of nitric
oxide metabolites, apoptosis and direct CD8+ T cell cytotoxicity.
Islet destruction is mediated by T lymphocytes rather than islet autoantibodies, as these
antibodies do not generally react with the cell surface of islet cells.

43
Q

What is the major susceptable gene involved in type 1 diabetes?

A

HLA on chromosome 6p21 (encodes MHC class 2 molecules which present antigens to T helper cells)

44
Q

What are some features of diabetes type 1?

A

Loss of blood glucose in the urine, dehydration (increased osmolality of the blood), tissue injury (hypertension, renal injury, atherosclerosis, heart attack, stroke, retinopathy, blindness and ischameia/gangrene of the limbs), metabolic acidosis, depletion of fat and proteins

45
Q

Draw a diagram of the progression on type 2 diabetes (including plasma glucose, and insulin)

A

See notes

46
Q

What are the two metabolic defects that characterise type 2 diabetes?

A

Decreased response of peripheral tissue to insulin and beta cell dysfunction that is manifested as inadequate insulin secretion in the face of insulin resistance and hyperglcaemia

47
Q

What happens to the beta cells in type 2 diabetes?

A

In type II diabetes, beta cells exhaust their capacity to adapt to long term demands of
peripheral insulin resistance.
In insulin resistance, insulin secretion is initially higher than usual. This is an adaptive
mechanism.
Eventually, beta cell compensation becomes inadequate and there is progression to
hyperglycaemia.
Not all obese individuals with insulin resistance develop overt type II diabetes, so there
must also be an intrinsic predisposition to beta cell failure.

48
Q

What is the mechanism of ketoacidosis?

A

Mechanism: body utilizes fats for energy  increase in lipolysis  a lot of Acetyl CoA is produced in theliver  the acetyl CoA produced then condenses into ketone bodies  these ketone bodies travel aroundthe blood to cells needing energy  as there is so much fat breakdown, there is a lot of ketone bodies 
the body can’t utilise all the ketones hence there are a lot of ketones in the blood  ketones are acidic, hence the term ketoacidosis.

49
Q

In ketoacidosis explain how acetone breath is produced?

A

Absence of insulin, presence of excess of fatty acids in liver cells -> carnitine transport
mechanism for transporting fatty acids into mitochondria is increasingly activated ->
mitochondria β-oxidation of fatty acids proceeds rapidly -> releasing extreme amounts
of acetyl-CoA -> large part of acetyl-CoA is condensed to form acetoacetic acid ->
release into blood -> peripheral cells -> converted into acetyl-CoA -> energy

Absence of insulin also depresses utilization of acetocetic acid in peripheral tissues –
release from liver, cannot metabolize by tissue

Some acetoacetic acid is converted into β-hydroxybutyric acid & acetone

Acetoacetic acid & β-hydroxybutyric acid can be converted back to acetyl-CoA in
right conditions – acetone CAN’T (release in breathe & urine)

50
Q

What is the pathogenesis of ketoacidosis?

A

Both insulin deficiency and glucagon excess are necessary for DKA to develop.
The decreased ratio of insulin to glucagon promotes gluconeogenesis, glycogenolysis and
ketone body formation in the liver, as well as increases in substrate delivery from fat and muscle(free fatty acids, amino acids) to the liver.
Glucagon excess decreased the activity of pyruvate kinase (involved in glycolysis), whereas
insulin deficiency increases the activity of phosphoenolypyruvate carboxykinase, involved in
gluconeogenesis. These changes shift the handling of pyruvate toward glucose synthesis and away from glycolysis.
The increased levels of glucagon and catecholamines in the face of low insulin levels promote glycogenolysis.
Ketosis results from a marked increase in free fatty acid release from adipocytes, with a
resulting shift towards ketone body synthesis in the liver.

51
Q

What is the biochemical parameters of ketoacidosis?

A

Increase in the serum concentrations of ketones > 5mEq/L
Blood glucose levels > 14mmol/L
Blood pH < 7.2
HCO3- < 18mEq/L

52
Q

What is the treatment of diabetic ketoacidosis?

A

Emergency – correct hyperosmolality, ketoacidaemia
Confirm diagnosis – increased plasma glucose, positive serum ketones, metabolic acidosis.
Admit to hospital.
Assess serum electrolytes, acid-base status, renal function.
Replace fluids
-Usually fluid deficit is 4-5L so 0.9% saline solution helps re-expand the vascular volume
-Should be ASAP after diagnosis

Administer short acting insulin IV. NOTE: do not administer insulin if the serum potassium is
<3.3mmol/L, wait until this is corrected (insulin can cause K to be redistributed into cells therefore worsens hypokalaemia)

53
Q

What does this patient have?
Hyperglycaemia >250mg/dL
Acidosis pH <15mEq/L
Serum positive for ketones.

A

Ketoacidosis

54
Q

If a patient is in a coma and presents the following results what do they have?
Urine: Glucose 0, Acetone 0
Plasma: G Low, Bi Normal and Acetone 0

A

Hypoglycaemia coma

55
Q

If a patient is in a coma and presents the following results what do they have?
Urine: Glucose high, Acetone high
Plasma: G high, Bi low and Acetone high

A

Diabetic ketoacidosis

56
Q

If a patient is in a coma and presents the following results what do they have?
Urine: Glucose high, Acetone 0
Plasma: G high, Bi Normal/low and Acetone 0

A

Hyperglycemic hyperosmolar state coma

57
Q

If a patient is in a coma and presents the following results what do they have?
Urine: Glucose 0/+, Acetone 0/+
Plasma: G normal/low/high, Bi low and Acetone 0/+

A

Lactic acidosis

58
Q 
What does this patient have? 
Hyperglycaemia >600mg/dL
Serum osmolality >310mosm/kg
 No acidosis
Serum bicarbonate >15mEq/L
Normal anion gap
A

Hyperglycaemic hyperosmolar state/nonketoic coma

59
Q

What is the pathophysiology of hyperglycaemic hyperosmolar coma?

A

Presence of small amounts of insulin inhibits ketosis by inhibiting lipolysis in the
adipose stores
Induces hyperglucagonaemia and increasing hepatic glucose output - glycosuria -
water loss- severe hyperosmolarity develops- unable to maintain adequate fluid
intake -> dehydration -> As plasma volume decreases, chronic kidney disease
develop and the resulting limitation of renal glucose clearance leads to increasingly
higher blood glucose concentrations -> severe hyperosmolality -> mental confusion/coma

As serum osmolality exceeds a certain limit, water is drawn out of the cerebral neurons and coma results.
Hypercortisolaemia increases proteolysis -increased amino acid precursors for
gluconeogenesis -increased glucose.
The reason why ketosis does not occur under insulin insufficiency is unclear but can
be attributed to low growth hormone levels.

60
Q

How do you diagnose diabetes?

A

Random BSL above or equal to 11.1mmol/L.
•Fasting BSL greater than or equal to 7.0 mmol/L. (or 6.9mmol/L)

Diagnostic criteria:
o One of the above plus diabetic symptoms.
o Both of the above without diabetic symptoms.
o Either of the above on two separate occasions without diabetic symptoms.

OGTT 2 hour BSL above or equal to 11.1 mmol/L (200mg/dL) – used for diagnosing
borderline cases and gestational diabetes.

61
Q

What are the Ix for diagnosis/monitoring of diabetes?

A
  1. BSL (drop of blood). Normal 4-8- casual >11.1 or fasting >7
  2. Oral glucose tolerance (ability to metabolise glucose). Fast, check BSL and drink 75 g glucose solution and BSL measured 2hrs later. Normal < 7.8mmol/L, impaired glucose tolerance 7.8– 11.1
  3. HBA1c (glycoslated/glycated Hb) >6.5%
  4. Urinalysis- glucose, ketones, protein, microalbuminuria
62
Q

What is the nonpharmacological management of diabetics?

A

Self monitoring, health eating, exercise, foot care, sexual health help, postural hypotension, avoiding toxins

63
Q

What is the pharmacological management of diabetes?

A

Type 1: subcutaneous insulin (short/ultra after food, long during day and basal intermediate or long before bed)
Type 2: lifestyle stuff then: insulin secretagogues and sensitisers

64
Q

What is Metformin?

A

1st Line T2 DM, part of Bignanide and insulin sensitizers
Acts through AMP activated protein kinase to increase cAMP levels and decrease hepatic glucose output. Also increases insulin mediated glucose utilization in peripheral tissues

65
Q

What is rosiglitazone?

A

Glitazone which is added to Metformin 3rd line
Binds to peroxisome proliferator activated receptor alpha (found in muslce, fat, liver). Modulates gene related to lipid/glucose metabolism and so increases lipogenesis and increases uptake of FA and glucose
SE: fluid retention (weight gain), heart failure, loss of bone density

66
Q

What are Sulfonylureas?

A

Add to Metformin 2nd line to increase insulin secretion
Bind to ATP sensitive K+ channels and therefore can only be used in patients with some function
SE: hypoglycaemia

67
Q

What is Repaglinide?

A

Meglitinide
Regulates K+ efflux through same channels as sulfonyureas
SE: weight gain and hypoglycaemia

68
Q

What are some other drugs that can be used in diabetes management?

A

alpha glucoxidase inhibitors (acarbose- defers digestion of carbs to SI), Incretin enhancers (inhibit GLP-1 or GIP which stimulates insulin release), amylin analogues (pramlintide, suppresses glucagon release)

Year 2 semester 2 (10 decks)

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