INSULIN-SENSITIVE - in MUSCLE and ADIPOSE TISSUE (only if insulin is available and working)

5. DIABETES TYPE 1 & 2 (and normal regulation of glucose) Flashcards by Ibby Khan

Blood Glucose is regulated within very tight limits:

4.0-7.0 mmol/L

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Insulin is produced in response to..

eating

high insulin levels after a meal to bring down blood glucose levels

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Glycolysis makes ATP.
3 stages of Glycolysis:

Stage 1: Trap glucose in the cell
(Glucose-6-phosphate cannot leave
the cell)

Stage 2: Cleave fructose 1,6-
bisphosphate into two three-carbon
fragments. These resulting three-
carbon units are readily
interconvertible

Stage 3: Generate ATP from the
phosphorylated three-carbon
metabolites of glucose.

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Glycolysis makes ATP.
3 stages of Glycolysis:

Stage 1: Trap glucose in the cell
(Glucose-6-phosphate cannot leave
the cell)

Stage 2: Cleave fructose 1,6-
bisphosphate into two three-carbon
fragments. These resulting three-
carbon units are readily
interconvertible

Stage 3: Generate ATP from the
phosphorylated three-carbon
metabolites of glucose.

Glucose converted to Pyruvate

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Krebs/Tricarboxylic acid (TCA)/citric
in mitochondrial matrix

a series of chemical reactions used by all aerobic organisms to GENERATE ENERGY through the OXIDATION of ACETATE derived from carbohydrates, fats and proteins into carbon dioxide and chemical energy in the form of adenosine triphosphate (ATP).

oxidises organic fuel derived from pyruvate,
generating
1 ATP, 3NADH
and 1 FADH2 per turn

NADH and FADH2, produced by
the cycle, relay electrons
extracted from food to the
electron transport chain

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THE ELECTRON TRANSPORT CHAIN
- In the cristae of the mitochondrion

*Most of the chain’s components are proteins, which exist in multiprotein complexes
*The carriers alternate reduced and oxidised states as they accept and or donate electrons
*Electrons drop in free energy as they go down the chain and are finally passed to O2, forming H2O.

*each of the reactions is EXERGONIC and
thus RELEASES FREE ENERGY.
- This free energy is used to TRANSLOCATE PROTONS across the inner mitochondrial membrane, this will GENERATE ATP
*the electrons that finally end up in water
are of low energy.
*during the coupled oxidation reduction
reactions, iron ions that are complexed
with the proteins become oxidized and
reduced. That is, the Fe ions participate in
catalysis.

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There are > 10 different glucose transporters, which ones are most studied

GLUT1
GLUT2
GLUT3
GLUT4

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How is GLUT1 in terms of
Affinity?
Km?
Which tissues?

HIGH AFFINITY
therefore LOW Km (approx 1mM)

-BRAIN
- ERYTHROCYTES (have no mitochondria)
- placenta
- fetal tissue

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How is GLUT2 in terms of
Affinity?
Km?
Which tissues?

LOWER AFFINITY (but still high)
therefore HIGH Km (15-20Km)

PANCREATIC B CELL
-liver, kidney, intestine

Allows intracellular and extracellular glucose to equilibrate across membrane

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How is GLUT3 in terms of
Affinity?
Km?
Which tissues?

HIGHER AFFINITY (higher than GLUT1 and GLUT2)
so LOW Km (<1 mM)

BRAIN
(needs lots of glucose)

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GLUT4

INSULIN-SENSITIVE

in MUSCLE and ADIPOSE TISSUE (only if insulin is available and working)

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GLUCOSE UPTAKE from the GUT
(and also from the GLOMERULAR FILTRATE in the KIDNEY) is achieved by which transporters?

SODIUM DEPENDENT GLUCOSE TRANSPORTERS
- SGLT1 & SGLT2

therefore REQUIRE SODIUM GRADIENT from the lumen to the cell

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GLUCOSE UPTAKE from the GUT transport is SATURABLE, so if GLUCOSE in the LUMEN RISES above a certain level..

Not all the glucose is absorbed

(cause of glycosuria in diabetes - glucose in urine)

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2 MAJOR HORMONES secreted by PANCREAS

INSULIN
GLUCAGON

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2 MINOR HORMONES secreted by PANCREAS

SOMATOSTATIN
PANCREATIC POLYPEPTIDE

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SOMATOSTATIN
where is it found and what does it do?

primarily NERVOUS and DIGESTIVE SYSTEM
INHIBITS SECRETION of PANCREATIC HORMONES (including insulin and glucagon)

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PANCREATIC POLYPEPTIDE
where is it produced and what does it do?

-produced and secreted by PP CELLS (originally termed F cells) of the PANCREAS

DECREASES FOOD INTAKE
INCREASES ENERGY EXPENDITURE

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INSULIN
-how many amino acids

51 AMINO ACIDS

(synthesised as pro-insulin with 84 amino acids, cleaved to 51)

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What is INSULIN PRODUCED BY

BETA CELLS

in islets of Langerhans of pancreas

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when is INSULIN release stimulated by

HIGH BLOOD GLUCOSE LEVELS

and the PARASYMPATHETIC nervous system (PNS)

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how does INSULIN LOWER BLOOD GLUCOSE LEVELS

INCREASES
UPTAKE & STORAGE OF GLUCOSE,

also increases uptake and storage of fatty acids and amino acids in cells/tissues

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what 2 hormones stimulate insulin secretion

Gastric inhibitory polypeptide (GIP)
and
glucagon-like peptide-1 (GLP-1)

(primary incretin hormones secreted from the intestine upon ingestion of glucose or
nutrients)

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state of PANCREATIC BETA CELLS at REST

ATP SENSITIVE K+ CHANNELS OPEN
K+ ions diffuse OUT
VOLTAGE-GATED Ca2+ ION CHANNELS CLOSED

INSIDE NEGATIVE

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After EATING (increase in blood glucose) what takes place in BETA CELLS to release INSULIN (6 steps)

GLUT2 transporters transport GLUCOSE INTO cell
GLYCOLYIS takes place in the cell which GENERATES ATP
this causes ATP-SENSITIVE K+ channels to CLOSE
K+ can no longer diffuse out of cell, so potential difference across the cell becomes POSITIVE
this causes voltage-gated calcium ION CHANNELS to OPEN, INFLUX of Ca 2+
VESICLES containing INSULIN MOVE to cell surface and RELEASE insulin

insulin release stimulated by GLP-1 (incretin)

Insulin signals the FED state, it stimulates...

Storage of fuels & Synthesis of proteins in various ways

How does INSULIN lead to GLUCOSE UPTAKE in MUSCLE cells?

1. INSULIN binds to RECEPTOR 2. Vesicles containing GLUT4 move and GLUT4 proteins are integrated into cell membrane 3. GLUCOSE can be transported INTO muscle cells via GLUT4

Where is GLUCOSE STORED

in the LIVER as GLYCOGEN The liver helps to limit the amount of glucose in the blood during times of plenty by storing it as glycogen - release glucose in times of scarcity.

the action of the LIVER after a meal (FED state)

1. INSULIN ACCELERATES UPTAKE of GLUCOSE from blood into the LIVER by GLUT2 2. The CATALYTIC SITES of GLUCOKINASE (a hexokinase) become filled with glucose 3. glucose is converted into GLUCOSE-6-PHOSPHATE (trapped in cell) so RISE in levels of G-6-P 4. leads to a BUILD UP of GLYCOGEN STORES

which GLUCOSE TRANSPORTER is used in the liver

GLUT2

which GLUCOSE TRANSPORTER is used in MUSCLE

GLUT4

many actions of INSULIN: (5)

*Increases glucose uptake into fat and muscle *Stimulates glycogen synthesis * Stimulates storage of triglyceride (end product of digesting and breaking down fats in food) in adipose tissue *Increases protein synthesis *Decreases hepatic gluconeogenesis

If you are deriving ENERGY FROM FAT (as not enough glucose for energy conversion) what is produced

KETONES (increase ketones in blood)

when blood GLUCOSE levels begin to FALL (FASTING state), what increases

RISE in GLUCAGON - INCREASE BLOOD GLUCOSE LEVELS mobilizes glucose, fatty acids and amino acids from stores into the blood. (decrease in insulin)

where is GLUCAGON produced

ALPHA CELLS of islets of Langerhans of pancreatic cells

what is the MAIN TARGET ORGAN of GLUCAGON

LIVER

EFFECTS of GLUCAGON

*stimulates GLYCOGEN BREAK DOWN *inhibits glycogen synthesis *stimulates GLUCONEOGENESIS in the liver * blocks glycolysis. *inhibits fatty acid synthesis by diminishing the production of pyruvate

upon INGESTION of food what does the GI TRACT RELEASE and what does this cause

release of INCRETIN GUT HORMONES - INCREASE INSULIN release from Beta cell (GLP-1 and GIP) - DECREASE GLUCAGON release from Alpha cells (GLP-1)

what does the BRAIN switch to when blood glucose levels are LOW

use of KETONE BODIES

what is DIABETES (raised blood glucose) due to

either - DEFICIENCY of INSULIN and/or - RESISTANCE to INSULIN ACTION

DIABETES treatment can lead to...

HYPOGLYCAEMIA (excess insulin)

TYPE 1 DIABETES cause

usually AUTOIMMUNE TOTAL LACK of INSULIN

TYPE 1 develops most commonly in....

children and young adults

TYPE 2 cause

usually obesity-related - insulin resistance & deficiency

TYPE 2 occurs most commonly in...

older adults

what is TYPE 3C

diabetes secondary to pancreatic disease (cancer) usually diagnosed as type 2

what happens in TYPE 1 to cause lack of production of insulin

- ISLETS OF LANGERHANS in pancreas are DESTROYED *1:300 of UK population *Doubled in last 25 years *Common in Europe, rare in Japan

result of having TYPE 1

* Uncontrolled GLUCONEOGENESIS * FAILURE of GLUCOSE UPTAKE into muscle and fat * Use of alternative fuels (FATTY ACIDS - increases ketones in blood)

what do you develop from TYPE 1

HYPERGLYCAEMIA KETOACIDOSIS eventual coma and death if untreated

TYPE 1: fall in insulin results in...

increase of GLUCAGON (increases gluconeogenesis)

TYPE 1 blood contents

HIGH GLUCOSE, HIGH KETONES HIGH FATTY ACIDS (lipolysis)

HYPOGLYCAEMIA causes and effects

- excess of insulin or - rare insulin secreting pancreatic tumour *Sympathetic response (sweating, tachycardia, hunger) *Confusion and coma as brain starved of glucose

2 obesity related problems in TYPE 2: INSULIN-RESISTANCE

PERIPHERAL TISSUES are NOT RESPONSIVE to insulin; higher levels of insulin are required in order to keep blood glucose within the normal range. * Genetic component * Exacerbated by obesity and physical inactivity

2 obesity related problems in TYPE 2: PROGRESSIVE INSULIN DEFICIENCY

* pancreas does not make ENOUGH INSULIN * Amyloid and fat deposits in pancreas * Defective incretin response

How does being overweight lead to diabetes and heart disease?

FAT CELLS: - Reduced response to insulin - High cholesterol and blood fats - High blood pressure - Inflamed arteries - Increased blood clotting

what also increase risk of diabetes (type 1 & 2)

GENES

how do pancreatic BETA CELLS INITIALLY COMPENSATE for insulin RESISTANCE

by INCREASING PRODUCTION (HYPERINSULINAEMIA), thereby maintaining normal blood glucose levels. However, in most patients with type 2 diabetes, the PANCREATIC BETA-CELL FUNCTION PROGRESSIVELY DECLINES, leading to hyperglycaemia and clinical diabetes.

Type 2 diabetes usually appears in people over the age of

40 South Asian people, who are at greater risk, it often appears from the age of 25. increasingly becoming more common in children, adolescents and young people

Complete absence of insulin results in

ketoacidosis