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Endocrine > Biochemistry: Insulin > Flashcards

Biochemistry: Insulin Flashcards

1
Q

What type of hormone is insulin

A

Peptide

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2
Q

Cells of pancreatic islets (4) and secretions

A

Beta- cells
- Secrete insulin

alpha-cells
- secrete glucagon

Delta-cells
- Secrete somatostatin

PP cells
- Secrete pancreatic polypeptide

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3
Q

Insulin Prehormone

A

Synthesized in RER of beta-cells as a larger single chain preprohormone: preproinsulin
Cleaved to form insulin and connecting ( C ) peptide (byproduct of cleavage with no known physiological function

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4
Q

Insulin structure

A

Two peptide chains ( A and B chains) linked together by two disulphide bonds

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5
Q

Synthetic insulin preparations

A

Prepared by changing amino acids

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6
Q

Ultrafast/ ultra-short acting insulin

A 
--> Insulin lispro 
Monomeric
Not antigenic 
Most rapidly acting insulin 
Injected with 15 mins of meal
Must be used in combo with longer acting preparation for T1DM
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7
Q

Ultra-long acting Insulin

A

–> Insulin glargine
Recombinant insulin analog that precipitates in neutral environment of subcutaneous tissue.
Prolonged action
Administered as single bedtime dose

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8
Q

Biological Effects of Insulin

9

A

Turns on

  • Amino acid uptake in muscle
  • DNA synthesis
  • Protein synthesis
  • Growth responses
  • Glucose uptake in muscle and adipose tissue
  • Lipogenesis in adipose tissue and liver
  • Glycogen synthesis in liver and muscle

Turns off

  • lipolysis
  • gluconeoogenesis in liver
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9
Q

Action of glucokinase

A

Glucokinase= Glucose sensor

Glucose enters beta-cells through GLUT-2 glucose transporter and is phosphorylated by glucokinase

Glucokinase Km for glucose lies in physiological range of concentrations

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10
Q

Mechanism of Glucose Secretion (5)

A

Beta-cells secrete insulin in response to blood glucose rising >5mM

  1. Increased metabolism of glucose leads to an increase in intracellular ATP metabolism
  2. ATP inhibits ATP sensitive K+ channel (Katp)
  3. Inhibition of Katp leads to depolarisation of cell membrane
  4. Depolarisation of cell membrane results in opening of voltage-gated Ca2+ channels
  5. Increase in internal Ca2+ concentration leads to fusion of secretory vesicles with cell membrane

–> Insulin released

Amount released is directly related to amount of glucose.

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11
Q

Time of Insulin Secretion

A

Biphasic

First Phase
- Prevents sharp increase in blood glucose

Second Phase
- Related to glucose intake (amount and duration)

Involves presence of 2 different pools of insulin granules

  1. Readily releasable pool (RRP)
  2. Reserve. pool - must undergo preparatory reactions
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12
Q

Diseases caused by defects in insulin secretion/action (5)

A 
T1DM
T2DM 
Gestational Diabetes (GDM) 
Maturity Onset Diabetes of the Round (MODY)
Neonatal Diabetes
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13
Q

Diseases caused by severe insulin resistance

A

Rabson Mendenhall Syndrome

Leprechaunism ( Donohue Syndrome)

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14
Q

Type 1 Diabetes

A

Autoimmune destruction of pancreatic beta cells.

Presence of autoantibodies, combined with declining C-peptide production

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15
Q

Type 2 Diabetes Mellitus

A

Primary problem is reduced insulin sensitivity in tissues

Usually present with hyperinsulinaemia as beta cells try to compensate for hyperglycaemia caused by insulin resistance

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16
Q

Gestational Diabetes

  • Diagnostic Criteria
  • Identifies
  • Association
  • Treatment
A

Different diagnostic criteria = FG > 5.5mM

Identifies women with declining beta-cell function

Associated with high risk of future T2DM

Treatment: Lifestyle advice and sometimes metformin

17
Q

Maturity Onset Diabetes of the Young (MODY)

What it is + Detection + Treatment

A

Defective glucose sensing in pancreas and/or loss of insulin secretion

Monogenic disease

Beta-cell dysfunction but NOT autoimmune destruction

Mutations in at lease 6 different genes (150 mutations) can cause MODY

  • GLucokinase (GCK/ MODY 2)
  • several transcription factors (–> HNF 1 & 3)

Robust genetic screening to differentiate MODY from T1DM allows treatment with sulphonylurea rather than insulin.

18
Q

HNF 1 & 3

A

Transcription Factors

Key role in pancreas foetal development and neogenesis

Regulate beta-cell differentiation and function .

Mutation can result in MODY

19
Q

Neonatal Diabetes

A

Rare form of. monogenic diabetes

mainly caused by mutation in glucose sensing mechanisms (ATP sensitive K channels)

20
Q

Katp Channels Structure

A

Consist of 2 proteins

Inward rectifier proteins (Kir)
- pore subunit = Kir6

Sulphonylurea Receptor
- regulatory subunit= SUR1

Both required to form a functional channel. Channel exists as an octomeric structure ( 4xKir6 = 4xSUR1)

21
Q

Kir6.2 Mutations

  • Disease
  • mechanism
  • treatment
A

Lead to neonatal diabetes

Constituitively activated Katp channels or increase in Katp numbers

In most patients, beta cells are still responsive to SURs, such as tolbutamide

22
Q

Kir6.2 or SUR1 mutations

  • Disease
  • Mechanism
  • treatment
A

Lead to congenital hyperinsulinism

Tafficking or inhibiting mutations

Diazoxide can help inhibit insulin secretion is channels are still getting to membrane

23
Q

Regulation of Katp

  • Drugs to inhibit
  • Drugs to stimulate
A

Intracellular ATP inhibits Katp to elicit depolarisation

Katp is directly inhibited by sulphonylurea class of drugs

  • tolbutamide
  • glibenclamide

Katp is stimulated by diazoxide which inhibits insulin secretion

24
Q

Severe Insulin Resistance

- Monogenic and Polygenic Examples

A

Reduced ability to respond to physiological insulin levels

Monogenic can occur due to mutation in key signalling pathways

  • Leprechaunism (Donohue Syndrome)
  • Rabson Mendenhall Syndrome

Polygenic
- T2DM (large input from environmental influence)

25
Q

Leprechaunism (Donohue Syndrome)

  • Type of. genetic trait
  • Mutation
  • Developmental abnormalities (4)
A

Rare autosomal recessive genetic trait

Mutation in the gene for the insulin receptor
Severe insulin resistance

Developmental Abnormalities

  • elfin facial appearance
  • growth retardation
  • absence of subcutaneous fat
  • decreased muscle mass
26
Q

Rabson Mendenhall Syndrome

  • Type of genetic trait
  • Mechanism
  • Developmental Abnormalities (3)
A

Rare autosomal recessive genetic trait

Severe insulin resistance, hyperglycaemia and compensatory hyperinsulinaemia

Developmental Abnormalities

  • hyperpigmentation
  • fasting hypoglycaemia
  • diabetic ketoacidosis
27
Q

Diabetic ketoacidosis

A

Medical Emergency

Inability to inhibit glucose production from the liver results in hyperglycaemia
- can be extreme and lead to dehydration

Concurrent failure to suppress fatty-acid production from adipose tissue results in excess conversion of fatty acids to ketones in the liver (ketosis) and development of metabolic acidosis

28
Q

Ketone Bodies

A

Formed in liver mitochondria

Diffuse into blood stream and to peripheral tissues

Important molecules of energy metabolism for heart muscle and renal cortex

insulin normal inhibits lipolysis reducing risk of ketone body overload

29
Q

DKA and T1DM/ T2Dm

A

T1DM
- DKA is a risk if insulin supplementation is missed and hyperglycaemia ensues

T2DM

  • lower risk of DKA than T1DM
  • Can occur as insulin resistance and deficiency increases
30
Q

Ketone Body formation

A

Fatty acid oxidation yields acetly-CooA which enters TCA cycle if fat and card degradation are balanced

IF supply of pyruvate/ oxaloacetate is limited, acetyl-CoA is converted to ketones

Having no insulin reduces amount of glucose being taken up by tissues from the blood and reduces glycolysis, making body switch to fatty acid oxidation.

31
Q

DKA Symptoms

A

Vomiting
Dehydration
Increased heart rate
Distinctive smell on breath

32
Q

ketosis in glucose limiting conditions (starvation and diabetes)

A

in starvation, oxaloactetate is consumed in gluconeogenesis- excess acetyl-CoA is converted to ketone bodies

Excessive accumulation of ketone bodies can lead to acidosis

High glucose excretion causes dehydration (exacerbates acidosis)

33
Q

DKA Diagnosis

A

High ketone
Very high glucose
low/absent insulin
Low pH in blood

34
Q

DKA Treatment

A

Insulin

Rehydration

Endocrine (25 decks)

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