Biochemistry of Glucose and Insulin Flashcards by Veronica Haughey

What are the different cell types present in the pancreatic islets?

Beta cells = 60-80%, secrete insulin
Alpha cells = 10=20%, secrete glucagon
Delta cells = about 5%, secrete somatostatin
PP cells = <1%, secrete pancreatic polypeptide

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What is the prehormone form of insulin?

Preproinsulin = cleaved from single large chain to produce insulin

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Where is preproinsulin formed?

In the RER of pancreatic beta cells

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What is the structure of insulin?

Two polypeptide chains linked by disulphide bonds

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What is connecting (C) protein?

Byproduct of cleavage = has no known physiologic function

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What are some insulin preparations?

Short acting = regular insulin
Intermediate acting = NPH
Long acting = ultralente
Ultra fast/ultra short acting = lispro
Ultra-long acting = glargine

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What are some features of lispro?

Lysine (B28) and proline (B29), monomeric, not antigenic, most rapidly acting insulin preparation, injected within 15 mins of beginning a meal

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How is lispro used to treat type 1 diabetics?

Used in combination with longer acting preparations unless being used for continuous infusion

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What is glargine?

Recombinant insulin analogue that precipitates in the neural environment of subcutaneous tissue

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How is glargine used?

Is peakless so has prolonged action

Administered as a single bedtime dose

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How does glucose enter beta cells?

Through GLUT 2 transporters

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What phosphorylates glucose once it is in the cell?

Glucokinase

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What can a change of glucose concentration do to glucokinase?

Causes dramatic change in glucokinase activity

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Where does the Km of glucokinase for glucose lie?

in the physiological range of concentration

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What does the increased metabolism of glucose cause?

An increase in intracellular ATP concentration

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What does ATP inhibit?

The ATP sensitive K+ channel (KATP) = inhibition of KATP leads to depolarisation of the cell membrane

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What does the depolarisation of the cell membrane cause?

Opening of voltage gated Ca2+ channels = rise in internal Ca2+ concentration causes fusion of secretory vesicles within the cell membrane and release of insulin

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Why can insulin be used as a marker for beta cells?

Beta cells are the only cells in the body that make and secrete insulin

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When should beta cells make and secret insulin?

When blood glucose rises above 5mM

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What happens to the beta cells of type 1 diabetics?

They are mostly lost

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Why do beta cells lose the ability to sense changes in glucose in some forms of diabetes?

Due to hyperglycaemia taking glucose concentration outwith the Km of glucokinase

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What kind of process in insulin release?

Biphasic process

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What is the readily releasable pool in relation to insulin release?

5% of insulin granules are immediately available for release

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What must happen to the reserve pool of insulin granules before they can be used?

It must undergo reactions to become mobilised and available for release

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What happens to insulin secretion in poorly controlled type 2 diabetics?

It weakens and flattens = likely due to downregulation of the sensory process

What are the two proteins that make up the KATP channel?

Inward rectifier subunit (KIR) = pore subunit (Kir6) | Sulphonylurea receptor = regulatory subunit (SUR1)

What structure do KATP channels exist as?

Octameric structures

What can inhibit KATP?

Intracellular ATP inhibits KATP to elicit depolarisation | KATP is directly inhibited by sulphonylurea drug class

What can stimulate KATP to inhibit insulin secretion?

Diazoxide

What are SURs used for the therapy of?

Second line therapy for type 2 diabetics

What patients is SURs therapy most effective in?

Patients who have trouble injecting insulin | Patients who have improved their glucose control and lessened the stress on the islet

What can Kir6 mutations cause?

Neonatal diabetes = due to constitutively activated KATP channels or an increase in KATP numbers

What can be used to treat neonatal diabetes?

Some patients may have beta cells responsive to SURs (e.g tolbutamide) = can recover euglycaemia fairly quickly

What can some Kir6 or SUR1 mutations cause?

Congenital hyperinsulinaemia = caused by trafficking or inhibiting mutations

What can be used to treat congenital hyperinsulinaemia?

Diazoxide = can help inhibit secretions if channels are still getting to the membrane

What is maturity-onset diabetes of the young (MODY)?

Monogenic diabetes with genetic defects in beta cell function = familial form of early-onset type 2 diabetes, primary defects in insulin secretion

What type of MODY does mutations in glucokinase cause?

MODY 2 = glucokinase activity is impaired, defect in sensing glucose, blood glucose threshold for insulin secretion is increased

What type of MODY does mutations in HNF transcription factors cause?

MODY 1 and 3

What do HNF transcription factors do?

Play key role in pancreas foetal development and neogenesis, also regulate beta cell differentiation and function

Why is there robust genetic screening to differentiate MODY from type 1 diabetes?

Allows treatment of MODY with sulphonylurea instead of glucose

What causes type 1 diabetes?

Loss of insulin secreting beta cells

What causes type 2 diabetes?

Reduced insulin sensitivity

What does insulin cause in the body when activated?

Amino acid uptake in muscle, DNA/protein synthesis, growth receptors, glucose uptake in muscles/adipose tissue, lipogenesis in adipose tissue/liver, glycogen synthesis in liver/muscle

What does insulin cause in the body when inactivated?

Lipolysis, gluconeogenesis in the liver

How does insulin signalling occur?

Via a cascade

What is the insulin receptor?

Receptor tyrosine kinases

What does binding of insulin to alpha subunits cause?

Causes beta subunits to dimerise and to phosphorylate themselves, thus activating the catalytic activity of the receptor

What is severe insulin resistance associated with?

Obesity (type 2 diabetes) and complete loss of adipose tissues

What causes monogenic severe insulin resistance?

Mutations in key signalling pathways

What is leprechaunism (Donohue syndrome)?

Rare autosomal recessive genetic trait = mutations in gene for insulin receptor cause severe insulin resistance

What are some features of leprechaunism (Donohue syndrome)?

Elfin facial appearance, growth retardation, absence of subcutaneous tissue and decreased muscle mass

What is Robson Mendenhall syndrome?

Rare autosomal recessive genetic trait = severe cases are linked to mutations in the insulin receptor that reduce sensitivity

What are some features of Robson Mendenhall syndrome?

Severe insulin resistance, hyperglycaemia, compensatory hyperinsulinaemia, developmental abnormalities, acanthosis nigricans, fasting hypoglycaemia, diabetic ketoacidosis

What are the symptoms of diabetic ketoacidosis?

Vomiting, dehydration, increased heart rate, smell on breath

Where are ketone bodies formed?

In the liver = derived from acetyl-CoA from the beta oxidation of fats

Where do ketone bodies spread to?

Diffuse into bloodstream and to peripheral tissues = important molecules of energy metabolism for the heart muscle and renal cortex

What do low levels of insulin do in the body?

Inhibit lipolysis and prevent ketone body overload

When can diabetic ketoacidosis occur?

In type 1 = if insulin supplementation is missed | In type 2 = more uncommon, occurs as insulin resistance and deficiency increases

When is acetyl-CoA diverted to ketones?

If the supply of oxaloacetate is limited

When is oxaloacetate consumed for gluconeogenesis?

When ketosis is occurring in glucose limiting states (starvation and diabetes)

What is oxidised when there is no glucose to breakdown to produce energy?

Fatty acids = causes excess acetyl-CoA which is then converted to ketone bodies

What causes dehydration in diabetic ketoacidosis?

High glucose excretion = dehydration exacerbates acidosis and can lead to coma or death

How is diabetic ketoacidosis treated?

Insulin and dehydration