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Phase 2a - Endocrinology > Diabetes > Flashcards

Diabetes Flashcards

1
Q

Where does all glucose come from in the fasted state in a non-diabetic human?

A

From the liver, but some also from the kidneys.

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2
Q

What are the ways of glucose production in the fasted state?

A

Breakdown of glycogen and gluconeogensis (3C precursors to synthesise glucose).

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3
Q

Give some examples of 3C precursors utilised in gluconeogenesis?

A

Lactate
Alanine
Glycerol

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4
Q

Give an example of a glucose dependent tissue.

A

Brain + RBC

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5
Q

Describe insulin levels in the fasted state.

A

Low.

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6
Q

What do muscles use for fuel in the fasted state?

A

FFAs

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7
Q

Low levels of insulin can prevent what?

A

Unrestrained breakdown of fat.

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8
Q

What happens after feeding (post prandial)?

A

Physiological need to dispose of a nutrient load.

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9
Q

What starts to rise 5-10 mins after eating?

A

Glucose starts to rise which induces the secretion of insulin and suppress glucagon secretion at the same time.

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10
Q

What ratio of ingested glucose goes to the liver?

A

40%

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11
Q

What ratio of ingested glucose goes to the periphery (muscles)?

A

60%

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12
Q

Ingested glucose helps replenish what?

A

Glycogen stores both in liver and muscle.

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13
Q

What happens in the body due to high insulin and glucose levels?

A

Suppression of lipolysis and levels of non-esterified fatty acids fall.

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14
Q

Insulin is secreted by?

A

Beta cells of islets of Langerhans.

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15
Q

Glucagon is secreted by?

A

Alpha cells of islets of Langerhans.

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16
Q

Describe the crosstalk between alpha and beta cells.

A

Paracrine: local insulin release inhibits glucagon.

This effect is lost in diabetes.

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17
Q

Describe insulin secretion by the beta cells.

A

Glucose enters the beta-cell via GLUT2 transporter.

Glucokinase cleaves glucose and we are left with ADP/ATP.

ADP/ATP binds to SUR1 (regulatory subunit) and Kir 6.2 (inward rectifying channel) which causes the potassium channels (ATP dependent) to close.

This leads to depolarisation of the cell membrane.

As a result calcium channels open and influx of Ca2+

This prompts the insulin secretory granules to migrate to the plasma membrane and secrete insulin into the circulation.

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18
Q

Describe the action of insulin in muscle and fat cells.

A

Insulin binds to insulin receptor on the cell membrane.

Triggers an intracellular signalling cascade.

This mobilises intracellular GLUT4 vesicles to insert into the cell’s plasma membrane.

This allows glucose to enter the cells.

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19
Q

What are the actions of insulin?

A

Suppresses hepatic glucose output:
- decrease glycogenolysis
- decrease gluconeogenesis

Increases glucose uptake into insulin sensitive cells.

Suppresses:
- lipolysis
- breakdown of muscle

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20
Q

What are the actions of glucagon?

A

Increases hepatic glucose output:
- increases glycogenolysis
- increases gluconeogenesis

Reduces peripheral glucose uptake.

Stimulates peripheral release of gluconeogenic precursors (glycerol, AAs):
- lipolysis
- muscle glycogenolysis and breakdown

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21
Q

List other counterregulatory hormones to insulin?

A

Adrenaline
Cortisol
Growth hormone

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22
Q

What is DM?

A

Disorder of CHO metabolism - characterised by hyperglycaemia.

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23
Q

How does DM cause morbidity and mortality?

A

Acute hyperglycaemia = if untreated, DKA, hyperosmolar hyperglycaemic state.

Chronic hyperglycaemia = tissue complications (micro- and macrovascular).

Side-effects of treatment leading to hypoglycaemia.

24
Q

What are some of the serious complications DM is associated with?

A

Diabetic retinopathy
Diabetic nephropathy
Stroke
CVD
Diabetic neuropathy

25
Q

What are the types of diabetes?

A

T1
T2 (includes gestational and medication induced)
MODY = monogenic diabetes
Pancreatic diabetes
Endocrine diabetes (Acromegaly/Cushing’s)
Malnutrition related diabetes

26
Q

Definition of DM:

A

Symptoms are present and plasma glucose is >11mmol/L.

Fasting plasma glucose > 7 mmol/L

27
Q

If there are no symptoms, what is the criteria for DM Dx?

A

GTT (75g glucose)
Fasting > 7 mmol/L or 2h value >11mol/L (repeated on two occasions).

28
Q

What is a third way of defining DM?

A

HbA1c is > 48mmol/mol (6.5%).

29
Q

What is the pathogenesis of T1DM?

A

Insulin deficiency due to loss of beta cells.

Autoimmune cause - Beta cells express AGs of HLA - perhaps due a viral infection?

Activates a chronic cell mediated immune process = chronic insulitis.

30
Q

Failure of insulin secretion leads to what?

A

Continued breakdown of liver glycogen.

Unrestrained lipolysis and skeletal muscle breakdown = gluconeogenic precursors.

Inappropriate increase in hepatic glucose output and suppression of peripheral glucose uptake.

31
Q

Rising glucose concentration leads to…

A

Increased urinary glucose losses, as renal threshold (10mM) is exceeded.

32
Q

In the absence of treatment (T1) it increases

A
  • Circulating glucagon (as the inhibition from insulin on alpha cells is lost) further increasing glucose.
  • Stress = increased cortisol and adrenaline
  • Progressive catabolic state = increasing levels of ketones
33
Q

T2DM

A

Impaired insulin secretion and insulin resistance.

34
Q

Aetiology of T2DM

A

Genes and the environment lead to impaired insulin secretion and or insulin resistance.

This leads to impaired glucose tolerance = T2DM

T2DM leads to progressive hyperglycaemia and high FFAs (which further exacerbate impaired secretion and resistance).

35
Q

What does the UKPDS suggest about the progressive nature of diabetes?

A

Decline of beta-cell function starts years prior to diagnosis.

Impaired Glucose Tolerance leading to first undiagnosed then diagnosed diabetes.

36
Q

T2DM

A

A consequence of insulin resistance and progressive failure of insulin secretion (BUT INSULIN LEVELS ARE ALWAYS DETECTABLE!)

37
Q

What does impaired insulin action lead to?

A
  • Reduced muscle and fat uptake after eating.
  • Failure to suppress lipolysis and high circulating FFAs.
  • Abnormally high glucose output after a meal.
38
Q

Low levels of insulin is capable to do what?

A

Prevent muscle catabolism and ketogenesis.

Therefore, profound muscle breakdown and gluconeogenesis are restrained and ketone production is rarely excessive.

39
Q

Pathogenesis of T1DM

A

One defect.

Absent insulin secretion has no hepatic insulin effect and no muscle/fat insulin effect.

They lead to unrestrained glucose + ketone production and impaired glucose clearance + muscle/fat breakdown, respectively.

More glucose enters the blood and less glucose enters the peripheral tissues.

Ultimately, leading to hyperglycaemia and raised plasma ketones = glycosuria and ketonuria.

40
Q

Pathogenesis of T2DM

A

Two defects.

Impaired insulin secretion.
+
Hepatic insulin resistance (= excessive glucose production)

Muscle/fat insulin resistance (= impaired glucose clearance)

More glucose enters the blood and less glucose enters the peripheral tissues.

HYPERGLYCAEMIA and Glycosuria

41
Q

Lipid deposition in the liver and pancreas lead to what?

A

Insulin resistance and impaired insulin secretion.

42
Q

Principle treatment of diabetes

A
  • Control of symptoms.
  • Prevention of acute emergencies (DKA, HHS)
  • Identification and prevention of long-term microvascular complications
  • Glucose control reduces CV events (limited evidence)
  • Tight glucose control = modest reduction in IHD
  • HbA1c 50mmol/mol - (as low as possible in those not on insulin or sulphonylureas)
43
Q

Treatment of T2DM

A

Ideally weight loss + exercise (if substantial will reverse hyperglycaemia).

Lifestyle changes.

Medication to control BP, blood glucose and lipids.

44
Q

Sulphonylureas (gliclazide, glibenclamide)

A

Stimulates insulin release by binding to B-cell receptor.

Improve glycaemic control but significant weight gain

Do not prevent the gradual failure of insulin secretion

Can cause hypoglycaemia (in elderly and when renal function is impaired)

Gliclazide in most people.

45
Q

Thiazolidinediones (pioglitazone)

A

Bind to the nuclear receptor PPAR-gamma (peroxisome proliferator-activated receptor).

Activate genes concerned with glucose uptake and utilisation and lipid metabolism.

Improve insulin sensitivity.

Need insulin for a therapeutic effect

(Glitazones relatively rarely used;
useful in some groups.
- increase weight
- increase the risk of HF
- increase risk of Fx).

46
Q

What would an ideal drug for T2 look like?

A
  • Reduce appetite and induce weight loss.
  • Preserve B-cells and insulin secretion.
  • Increase insulin secretion at meal times.
  • Inhibit counterregulatory hormones which increase blood glucose such as glucagon.
  • Not increase the risk of hypoglycaemia during treatment.
47
Q

Effects of glucagon-like-peptide 1

A

GLP-1 is secreted from the L cells in the intestine (upon ingestion of food).

Stimulates insulin secretion.

Suppresses glucagon secretion.

Slows gastric emptying.

Reduces food intake.

Increases B-cell mass and maintains their function.

Improves insulin sensitivity.

Enhances glucose disposal.

48
Q

What is the problem with native GLP-1?

A

Rapidly degraded by DPP-IV.

Due to enzymatic cleavage and high renal clearance; its half life is 1-2 minutes.

49
Q

Extending the duration of action of GLP-1 by

A

Using incretin mimetics or DPP-IV inhibitors.

50
Q

Incretin mimetics MOA

A

Lower glucose
Reduce weight and CVD independent of glucose lowering.

51
Q

DPP-IV inhibitors MOA

A

Oral agents but modest glucose lowering effect.

No effect on CVD or weight.

52
Q

Examples of incretins

A

Exenatide(BYETTTA) twice daily
Once weekly exenatide (BYDUREON)
Liraglutide (VICTOZA) once daily
Lixisenatide (LYXUMIA) once daily
Dulaglutide (TRULICITY) once weekly
Semaglatide (OZEMPIC) once weekly
Oral semaglutide (RYBELSUS) daily

53
Q

Examples of DPP-IV inhibitors

A

Vildagliptin (GALVUS)
Sitagliptin (JANUVIA)

54
Q

SGLT2 inhibitors

A

Sodium-glucose cotransporter.

SGLT2 inhibitors block the reabsorption of glucose in the kidney, increase glucose excretion, and lower blood glucose levels.

Agents include empagliflozin, canagliflozin, dapagliflozin.

May have specific benefit in reducing CV mortality.

Side effects, genital thrush, increased risk of euglycaemic ketoacidosis including in type 2 diabetes.

55
Q

First line agents to treat T2DM?

A

Metformin

56
Q

Second line treatment of T2DM?

A

No longer sulphonylureas; replaced by DPP-IV inhibitors, GLP1 analogues and SGLT-2 inhibitors.

57
Q

Glitazones are

A

Rarely used.

Phase 2a - Endocrinology (11 decks)

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