Glucose Homeostasis & Diabetes

Dr Harprit Singh

Learning Outcomes• Understand normal range of blood glucose level• Explore the mechanism of how glucose homeostasis is

maintainedMechanism of insulin release from isletsAction of insulinAction of glucagon

• Explore the two types of Diabetes Signs and symptomsAetiologyComplications

Blood glucose is tightly regulated

• Normal range between 4-7.8 mmol/L

• This range is tightly controlled by the two endocrine pancreatic hormones

• Excess glucose must be used or stored– Insulin

• Glucose needs to be released from stores during fasting– Glucagon

The islets of Langerhans perform the endocrine function of the pancreas

• ~ 1 million islets• Clusters of well vascularised cells• 4 cell types: α, β, δ, pp • 4 hormones:

1. Insulin2. Glucagon3. Somatostatin4. Pancreatic polypeptide

Pancreas, H&E., BIOM2003 2010.

Islet of Langerhans

IHC showing glucagon and insulin

Glucose homeostasis

Creative commons

Insulin Secretion and Action

After a meal, blood glucose exceeds metabolic demand

Glucose

Glucose(Glucokinase)

Glucose-6-phosphate

PyruvateGlycogen

Interstitial fluid

StorageAcetyl CoA*

Krebs cycle

(Glycogen synthase)

ATP

ADP

ATP

Glycolysis

Glyc

ogen

esis

*mitochondria

Glucose enters cells via Glucose Transporters

Glucose

cell membrane• GLUT1 – ubiquitous (i.e. RBC)• GLUT2 - pancreas, liver, small intestine, kidney• GLUT3 - ubiquitous• GLUT4 - skeletal muscle, adipocytes, heart• GLUT5 - kidney tubules, jejunum, intestine

• Cells can express a variety of transporters: e.g. Liver normally expresses GLUT 2, but GLUT 1 and 3 during starvation

Insulin is a β-cell polypeptide hormone

S SS S

SS

SS

SS

S

S

Pro-insulin 9 kDa

Insulin 6 kDa

C-peptide3 kDa

α-chain

β-chain*

*Human - pig: Thr30-Ala

NH+ NH+

-COOH -COOH

C-peptide is used as an indicator of beta cell function

• C-peptide is cleaved from pro-insulin• Equimolar secretion to insulin• Much lower hepatic clearance• More accurate indicator of beta cell function

Glut 2

Glucose 5mM

K+(open)

Ca2+=closed)

Ca2+

Ca2+

Ca2+

Ca2+

Ca2+Ca2+

Blood

Low ATP:ADP ratio

Resting potential = -70 mV

How is Insulin secreted from beta cells?

Insulin secretion is stimulated by β-cell depolarisation

Glucose (> 10 mM)

Glucose

Glucose-6-phosphate

Pyruvate

ATPADP

K+(ATP=Close)

Ca2+(increase voltage =open)

Ca2+

Ca2+

Ca2+

Ca2+

Ca2+Ca2+

Blood

Glycogen

(Glucokinase)

Insulin secretion is stimulated by β-cell depolarisation• Transporters facilitate glucose diffusion into cells• Glucokinase acts as a glucose sensor• During glucose oxidation, [ATP] ↑• KATP channels close, K+ efflux is suppressed• Depolarisation• Ca2+ influx activates secretory granule movement• Exocytosis of insulin

•Glucose induced•Hormonal-Incretin (GLP-1) response to nutrients in digestive tract

Incretins

Insulin

Pancreas

Glucagon

Digestive tract

Blood sugar

Nutrients

In which individual will insulin be secreted more?

A) In a person given glucose intravenously

B) In a person given the same amount of glucose orally

- Glucose- Fatty acids- Amino acids- GIT hormones (GLP-1, )

- Oral glucose leads to a greater insulin response than i.v. infusion

Four stimulants of insulin release

Action of insulin on liver, muscle and adipose• Entry into cells (Glut transporters) • Glycogen storage & synthesis (Glycogenesis)• Glycolysis• Glycogenolysis• Gluconeogenesis• Lipogenesis• Lipolysis • Amino acid uptake• Protein synthesis

Insulin signalling

Insulin Receptor Substrate

Degraded, stored or recycled

GLUT4 re-localisation

Glut4 transporters are located deep within the cytoplasm contained in vesicles

Glut4 transporters are incorporated into the cell membrane

Insulin

Immunoflourescent labelling of GLUT4

Action of Glucagon

During fasting, glucose is mobilised and alternative energy sources may be required

Glucose

Glucose

(Glucokinase)

Glucose-6-phosphate

PyruvateGlycogen

Interstitial fluid

Storage

FFA Amino acids

KetonesCitrate

Glyc

ogen

olys

is

Gluconeogenesis

Acetyl CoA*

Krebs cycle

• 29 amino acids, 3 kDa • Mobilises glucose, triglycerides and amino acids.

In almost all respects, the actions of glucagon are opposite to insulin.

Glucagon

Glycogenolysis Gluconeogenesis

Glucose made available = ↑ blood glucose

The primary target of glucagon is the liver, where it promotes:

Liver

Glucagon

PKAGlycogenolysis;Gluconeogenesis

GsAC

cAMP

ATP

Glucose

Glucagon Mode of Action

Lipolysis

Glycolysis

Diabetes

Diabetes:

• Type 1 diabetes can develop quickly• Type 2 diabetes can go undetected for years

Two Classifications of Diabetes• Type 1: Insulin dependent

• Auto-immune disorder• Islet β-cell destruction

• Type 2: Non-insulin dependent• Life style related• Insulin resistance• Leading to a progressive loss of insulin • Many eventually require insulin treatment

Two very different aetiologies with the same clinical consequences!

synonym IDDM NIDDMYoung onset Mature onset

prevalence 10-20% 80-90%Prevalence ↑

onset childhood, puberty >35yrs

defect cell destroyed insulin resist. cell

dysfunc.nutrition undernourished obese

genetics moderate strong

ketosis common rare

Type 1 Type 2

Onset rapid gradual

lipids normal TG high

plasma insulin low/absentnormal/high

C-peptide absentnormal/high

Auto-antibodies present rare

Type 1 Type 2

Diabetic Complications

QUESTIONS