1. Diabetes and the pancreas
Phil Copeman and Alex Hammant

2. Glucose Transport How do they work?
GLUT family:
How do they work?
Allow facilitated diffusion
GLUT 1,3 and 4 allow movement at basal glucose levels
Which GLUT is responsible for insulin dependent response in fat and muscle?
GLUT 4
Which GLUT is present on Beta-islet cells?
GLUT 2
SGLT (sodium dependent glucose transporter) family:
Use sodium to move glucose against concentration gradient.
SGLT1 –in intestines
SGLT2 –in kidney
GLUT 4
predominantly stored in intracellular vesicles
Insulin promotes their insertion into cell walls
Thus facilitates glucose transport into cells

3. Glucose Balance Substrates are: Where does it happen?
Gluconeogenesis:
Substrates are:
Lactate (from non-oxidative metabolism – Cori cycle)
Glycerol (from fats)
Glutamine and alanine (from protein)
Where does it happen?
both liver and kidneys
Glycogen & glycogenolysis
Energy storage molecule in humans
Where are the 2 main storage sites?
liver and muscle cells

4. Hormonal Control of Glucose Homeostasis
Glucose Production
Glucose Utilisation
Lipolysis
Insulin ↓ ↑
Glucagon
Adrenaline
Cortisol
Growth Hormone
FFA -

5. Insulin Produced by β-cells of Islets of Langerhans
Provide pancreatic endocrine function
Contain 3 major cell types
α-cells : produce glucagon
β-cells : produce insulin
δ-cells : produce somatostatin
Strong inhibitor of insulin and glucagon. Exact role is unclear.

6. Insulin Release
Extracellular glucose is transported into the β -cell via GLUT-2.
Glucose is metabolised which increases adenosine triphosphate to diphosphate (ATP:ADP) ratio within the cell.
This leads to closure of ATP-dependent K+ channels
Closure of K+ channels leads to cell membrane depolarisation
Membrane depolarisation leads to opening of voltage dependent Ca2+ channels and Ca2+ influx
Ca2+ influx leads to exocytosis of stored insulin vesicles
Glucose
GLUT 2
Glucose
Metabolism
↑ ATP
Ca2+ K+ K+
ins
ins
ins
Depolarisation
insulin
insulin
insulin

7. Insulin Release
Release of pre-docked and primed vesicles  First phase response
Release of insulin from granules is complex
Transport  Docking  Priming  Fusion
Second phase
Time
Insulin secretion
Basal
1st phase
2nd phase
High glucose levels 5
min

8. Roles of insulin
Glycogen synthesis (via activation of glycogen synthase)
Promotes protein synthesis and inhibits protein breakdown
Promotes lipogenesis and inhibits lipolysis
Also promotes mitogenesis (induces cell division)

9. Glucagon Produced by pancreatic islet α-cells Suppressed by: Actions:
insulin secretion
Hypoglycaemia results in loss of insulin secretion and suppression
Actions:
Stimulates gluconeogenesis and glycogenolysis
Increases hepatic fatty acid oxidation and ketone formation
Stimulates lipolysis in adipose cells, increasing circulating free fatty acids, and reduces adipocyte glucose uptake.

10. Entero-insular axis Fed state: L-cells produce… GLPs and GIPs
These act to increase insulin secretion in response to oral glucose load
Degraded by DPP4

11. Diabetes Mellitus Type I = problem with insulin secretion
Autoimmune destruction of β-cells
Type 2 = problem with insulin resistance
Loss of first phase insulin response
4 stages:
Normal
Impaired fasting glycaemia
Impaired glucose tolerance
Diabetes

12. Cases Barry is a 18 year old student who has the following symptoms:
Tiredness for around 6 weeks
Unquenchable thirst
Weight loss of 2 stone in the last month
Has to get up >4 times per night to urinate
What is your likely diagnosis?
Type 1 Diabetes

13. Cases
Simone is a 63 year old Greggs store manager with a BMI of 38. She presents with:
Tiredness
Polyuria
Oral thrush
What is the likely diagnosis?
Type 2 Diabetes

14. Diabetes Symptoms Broadly the same for both types:
Polyuria
Polydipsia
Lethargy
Type 1 more likely in younger, more lean people and may have:
Weight loss
Dehydration
Ketonuria
Hyperventilation
Type 2:
Longer duration of symptoms, subacute presentation

15. Diabetes II Risk factors
Modifiable
Non-modifiable
BMI >25
Age >40
Central obesity
Family History
Lack of physical activity
Ethnicity
Smoking
Gestational diabetes or baby >4.5 kg at birth
Poor diet
Previous Hx of mental health conditions
Low socioeconomic status
Cardiovascular, hypertension, stroke history
Low birth weight
PCOS

16. Type 2 Diabetes - Management
Diet/exercise/lifestyle
Oral Hyperglycaemics
Biguanides (e.g. metformin): decreases hepatic gluconeogenesis
Sulfonyureas (e.g. gliclazide): increase insulin secretion
Thiazolidinediones (e.g. ? ): reduce insulin resistance
Injectable agents
Insulin
GLP-1 analogue

17. Complications of DM Hypoglycaemia Microvascular Macrovascular
Nephropathy
Retinopathy
Neuropathy
Macrovascular
Ischaemic heart disease
Cerebrovascular
Peripheral Vascular disease

18. Other functions of the pancreas
Alkali – from Duct Cells
An isotonic solution rich in HCO3-.
Neutralizes duodenal contents.
Digestive Enzymes – from Acinar Cells
Trypsin (endopeptidase)
Chymotrypsin (endopeptidase)
Carboxypeptidase (ectopeptidase)
Pancreatic amylase (breaks down starches)
Lipases (break down fats) – remember you need these to break down fat soluble vitamins!
Other enzymes (phospholipase, cholesterol esterase, ribonuclease etc)
These are all exocrine functions

19. Control of pancreatic secretion
Enzyme secretion
Controlled by: CCK and ACh
Alkali secretion
Controlled by: Secretin and potentiated by CCK and ACh
pancreas
bile production
HCO3-
secretion
enzyme secretion
gall bladder
contraction