An integrated view of an endocrine regulatory system: Direct targets of

insulin signaling and regulation of energy metabolism and glucose

Brain (hypothalamus)
suppression of appetite Liver
lipogenesis,
gluconeogenesis,
Pancreas glycogen synthesis
-cell growth and survival fatty acid secretion

Insulin
Adipocytes glucose
uptake lipogenesis
Differentiation of cells

Kidney
glomerular filtration and
glucose reabsorption
Skeletal muscle
glucose uptake and
glycogen synthesis
 Overview of energy metabolism

Proteins Carbohydrates Fats and lipids

Amino acids Glucose, fructose, galactose Fatty acids, glycerol

Glycogen Glucose-6-phosphate
Nitrogen
Glycolysis
pool Gluco-
neogenesis ATP Lipogenesis
Fatty acid
Tissue Lactate Pyruvate β-oxidation
proteins + H+

Acetyl-CoA
NADH Ketones if glucose is low (oxaloacetate
NH3 + H+ depletion caused by gluconeogenesis)

ADP ADP ADP

Citric
Urea
Acid 2H+ O2
Cycle Electron Transport Chain
Cycle
2e-
H2O
ATP ATP ATP
Urea
CO2
 • The total amount of energy stored as triacylglycerol in adipose tissue
(≈560 MJ) is >60 times the amount stored as glycogen in muscles (≈9
MJ).

• Muscles metabolize their own glycogen at the onset of exercise.

Muscles can run out of glycogen relatively easily.

• The use of fatty acids as a fuel requires hydrolysis of triacylglycerols

(i.e. lipolysis) in adipose tissue and the delivery of the released fatty
acids to skeletal muscle mitochondria for oxidation.

• Therefore muscles do not burn fatty acids immediately at the onset of

exercise
 Benefits of sustained aerobic exercise training
Increased efficiency of use of fatty acids as energy supply skeletal muscle, since
fatty acids are burned earlier after the start of exercise after training.

Muscle burns lipids instead of glycogen, markedly enhancing endurance*. The

store of lipids is inexhaustible.

Fatty acids are released from adipose tissue and transported to skeletal muscle
where they are taken up and burned

Sugar is required for muscle to metabolize fat.

Muscle metabolizes glucose in brief high intensity exercise (to lactate)

There is an optimum intensity of sustained exercise that increases metabolism

of fatty acids

* The total amount of energy stored as triacylglycerol (≈560 MJ) is >60 times the amount
stored as glycogen (≈9 MJ).
Fatty acids and glucose are highly mobile (via circulation)
 Cell types of the pancreas
Pancreatic Islet of Langerhans
duct Pancreas α-cell -cell

Small Exocrine
intestine Pancreas (acini)

Pancreatic Islet
of Langerhans

α-cell secretes glucagon

-cell secretes insulin
 Glucagon opposes many of the actions of insulin
Higher blood glucose, tissues
glucose stores mobilized High blood glucose

Catabolic effects
of glucagon

Anabolic effects
of insulin
Low blood glucose

Lower blood glucose, glucose

stored in tissues
Regulation of insulin secretion: The
glucose sensor in pancreatic -cells

Glucose
uptake ATP-sensitive
K+ channel

↑ ATP Closing K+ channels causes

ADP cell to move away from EK
and therefore depolarize
Functional KATP channels are a complex between a channel protein (Kir6.2)
and a modulatory subunit called the sulfonylurea receptor (SUR1)

It is the ATP/ADP ratio

that is important
Pancreatic -cells are excitable and fire action
potentials in response to glucose

secretion
Insulin

Misaki et al. (2007) Journal of Pharmacology and Experimental Therapeutics 322: 871-878
 Incretin peptides: A second mechanism to increase insulin secretion

Glucose from
digested food 1. Specialized endocrine cells in small
Islets intestine respond to glucose in lumen by
secreting incretin peptides into circulation.
↑ Insulin
secretion 2. Incretin peptides increase glucose-induced
insulin secretion from pancreatic -cells.

Pancreas 3. Incretin peptides exert several effects on -

Incretin
peptides
cells, including stimulation of Ca2+ channels
and making KATP channels more sensitive to
Small inhibition by ATP.
intestine
4. Incretins affect many other cells as well,
generally synergistically with insulin.

5. Glucagon-like peptide-1 (GLP-1) is example

of an incretin. In spite of its name, its
actions oppose those of glucagon.
 Insulin stimulates glucose uptake in skeletal
muscle and fat cells (2/3 of body by weight)
Insulin stimulates the movement of the GLUT4 glucose
uniporter into the plasma membrane Glucose

Metabolic pathways
(lipogenesis, glycogen
synthesis)

Therefore, insulin causes a fall in plasma glucose concentrations

 Other insulin effects in fat cells (adipocytes)
1. Inhibits lipid breakdown (lipolysis) and fatty acid oxidation in adipocytes.

2. Stimulates conversion of glucose to glycerol. Glycerol, together with fatty

acids delivered from liver, is used to synthesize triglycerides and other lipids,
which are stored in adipocytes.

3. Insulin stimulates differentiation of adult precursor cells (pre-adipocytes) into

mature adipocytes (a program requiring major changes in gene expression).
 Insulin effects in the liver
1. Causes the liver to convert glucose to glycogen (a branched
polysaccharide that serves as a short-term energy store). Activates
several enzymes in the glycogen biosynthesis pathway.

2. Once the maximum glycogen storage capacity is reached, insulin

stimulates conversion of glucose to fatty acids.

3. Insulin promotes secretion of fatty acids into the blood (in the form of
VLDL) which are taken up by adipocytes. In other words, insulin
promotes transfer of lipids to a storage compartment.

4. Suppresses liver gluconeogenesis (synthesis of glucose from smaller

substrates).

VLDL = very low density lipoprotein

 Type 1 Diabetes mellitus
• Caused by loss or dysfunction of the  cells of the pancreas. Insufficient or
no insulin secretion.
• Usually childhood onset.
• Can occur from autoimmune attack, possibly a virus, or mutations of genes
encoding key -cell proteins.
• Treated by insulin administration. Experimental islet cell transplantation
under investigation.
• High blood sugar, poor glycemic control, high circulating levels of glycated
proteins, and low circulating insulin (insulin C-peptide is measured clinically).
• Polyuria (frequent urination), increased thirst, increased fatigue, and
spontaneous weight loss.
• Complications effect nearly every other tissue.
 Type 2 Diabetes mellitus
• Reduced response of target tissues to insulin (receptor desensitization).
• Classically occurs with adult onset, especially associated with obesity.
• Often associated with hypertension and hyperlipidemia (metabolic
syndrome)
• High blood sugar, poor glycemic control, high circulating levels of glycated
proteins, and high circulating insulin in early stages of the disease.
• As disease progresses, there is loss of -cells and then a fall in insulin levels.
• Many complications lead to morbidity and mortality
 The relentless progression of type II diabetes

Genetics
Obesity Impaired glucose
tolerance/
Prediabetes Type II
Diabetes
-cell
failure Vascular
complications
Nephropathy
Retinopathy
Regulation of insulin signal transduction-relationship to obesity
Chronically high levels of circulating nutrients reduce insulin responses in target cells

IR

+ High glucose, FFAs

High
glucose P-Ser IRS Tyr-P PTP1B

High FFAs
+
↓Insulin
↑PI3K
+
actions
↑Akt
+
GLUT-4

Gene expression
Adipose derived hormones – contributors to type II diabetes
Adiponectin
Secreted from fat cells into blood, modulate
Leptin
energy metabolism, responses to insulin.
Resistin
Tumor necrosis factor-α

• Adiponectin: Synergistic effects on insulin responses, reduces serine

phosphorylation of IRS. Secretion inversely related to body fat content.

• Leptin: Acts in brain to reduce appetite, also affects peripheral tissues

• Resistin: Acts in opposition to insulin, but not well understood.

• TNF-α: Acts in opposition, secretion increased with adiposity, induces

inflammatory responses in some tissues (pro-inflammatory).
Pharmacological treatment strategies for type II diabetes

1. Increase -cell responses to insulin (incretin mimetics): liraglutide,

exanatide, semaglutide, etc. Also drugs that inhibit GLP-1
degradation (DPP-4 inhibitors also known as gliptins)

2. Sufonylureas (increase insulin secretion)

3. Prevent insulin receptor down-regulation in target tissues

4. Alter diet and weight loss and adapt body to exercise

5. Inhibit liver glucose biosynthesis (metformin)

6. Inhibit glucose reabsorption by the kidney (SGLT2 inhibitors)

Final message from me to you