ENDOCRINE AND GLUCOSE METABOLISM

Rondang R. Soegianto
2014

Hormone = Regulatory
molecule
Others:

Enzymes
Transporters
Channels

Regulatory system is essential.

Organism (body system)
constantly makes
homeostatic adaptation to
respond to
changing environment (condition)

Hormones interact with receptors

Receptor = protein molecule capable
of
conformational changes
Result of H-R interaction:
Intracellular signal

Signal can have various targets

depending
type of H and its specific receptor.
Specific receptors only present in
function
related cells
Ex: Insulin receptors present in muscle
but not in liver cells.

Intracellular signals are passed on

in
several steps before
accomplishing
its purpose, such as
- enzyme activation thru
phosphorylation
- gene activity for protein
expression (biosynthesis)

Chemical Nature
of Hormones
a. Peptides
b. Amino acid
derivatives
c. Steroids

ad. a. Insulin
Decreases blood glucose after
meals
Glucagon
Releases gluc into blood in fasting
state
ad. b. Catecholamines
- Adrenaline (Epinephrine)
- Noradrenaline (Norepinephrine)

ad. c Steroids ( see cholesterol

structure)
Intact steroid molecule:
- Cortisol
- Androgens
- Oestrogens
Steroid molecule disrupted:
- Calcitriol (H derived from vit D3)

Harper 27 Fig.18-2

Harper 27 Fig 17-2

Harper 27

Fig 17-3

Glucose-stimulated insulin release from pancreas B cell

Diabetes Mellitus and Starvation

Similarity:

Lack of intracellular energy

Difference: What causes the problem

Cause of the problem

DM: Deficient mechanism to obtain energy
from glucose
- Starvation: Lack of nutrients input for the
provision of fuel substances

Alternative to obtain energy in DM and

Starvation
a. Switch from carbohydrate to fat
metabolism
b. Switch from gluconeogenesis to ketone
production
Consequences (what are they?) have to be
monitored.

Diabetes Mellitus type1

-

Less common than type 2

- Autoimmune destruction of pancreatic

B cells
- Severe insulin deficiency
- Diabetic ketoacidosis

Diabetes Mellitus type 2

- Insulin resistance
- Do not require insulin treatment
- Managed with diet alone or
diet plus medications

Purpose of medications:
- Enhance endogenous insulin secretion
(sulfonylureas)
- Decrease insulin resistance
- Decrease intestinal carbohydrate
absorption (-glycosidase inhibitors)

Explain biochemical aspects of:

1. Hyperglycaemia
2. Glucosuria
3. Decreased glycogenesis
4. Decreased fatty acid synthesis
5. Increased lypolysis

6. Increased fatty acids in blood

7. Ketonaemia
8. Ketonuria
9. Metabolic acidosis
10. Negative Nitrogen Balance

Explanation of 1-4

Actions of insulin on target tissues

Hyperglycaemia
- Decreased glucose uptake by insulin
dependent glucose transporter
(Glut 4, muscle, adipose tiss)
- Decreased glycogenesis
Not sufficient insulin to activate
phosphodiesterase, enzyme for
conversion of cAMP to AMP, meaning
to decrease cAMP concentration
cAMP inhibiting factor in glycogenesis

Explanation of 5 6
Due to a switch from utilization of glucose to
fat for source of energy.
Low levels of oxaloacetate (OAA) in liver
Ketone body production increases

Explanation of 7 8
Increased production of ketone bodies
Less utilization in muscle (low OAA)
Develops ketonaemia in type 1 DM and
type 2 DM with insulinopenia.

Type 2 DM: Deficient control of insulin secretion

Glucose is insulin secretagogue for insulin secretion

Explanation 9 - 10
In severe cases of DM,
tissue protein utilized for energy
Cysteine sulphates acid urine
Negative N-balance due to ineffective amino
acid metabolism.

Complications and Therapy

Advanced glycation end products (AGEs)
A serious complication of diabetes
Glycoprotein = covalent linkage of sugar to protein

Can occur nonenzymatically

Glycation causes change to protein function

Circulation, joint and vision problems.
Nonenzymatic glycation of Hb (glycated Hb) is
Used to estimate blood glucose over past several
months

Chronic Complications
Microvascular complications induced by:
1. Polyol pathway
2. AGE formation
3. Protein kinase C (PKC)
4. Hexosamine Pathway

ad 1. Aldose reductase converts glucose to sorbitol

In hyperglycemia: accumulation of sorbitol
osmotic stress in nerves, endothelial cells,
eye lens (cataract)

ad 2. AGEs can cause :

- Microvascular damage
- Formation of glycated HbA (= HbA1c)
Used as index of glycemic control over
preceding 2-3 months

ad 3. Intracellular hyperglycemia in endothelium

increased DAG (diacylglycerol) activates
protein kinase C (PKC) effects on blood
flow and endothelial permeability.

ad 4. Increase of glucose entering hexosamine

pathway produces substrates that
can bind covalently to transcription
factors stimulate protein expression
e.g. transforming growth factor,
enhancing microvascular damage

Gluconeogenesis Inhibitors
Metformin improves sensitivity to insulin in type
2 DM
Stimulates glucose uptake by glucose
transporters in peripheral tissues
Increases binding of insulin to insulin receptors
Stimulates tyrosine kinase activity of insulin
reseptor
Inhibits glukoneogenesis in liver

REFERENCES
1. Medical Biochemistry (MASTER MEDICINE)
Brownie, A.C., Kernohan, J.C. 2nd ed. 2005
2. BIOCHEMISTRY
Garrett, R.H., Grisham, C.M. 3rd ed. 2005
3. Harrpers Illustrated Biochemistry 27th ed. 2006
4. BIOCHEMISTRY
Lippincotts Illustrated Reviews 6th ed. 2014
5. Textbook of BIOCHEMISTRY With Clinical
Correlations, Davlin, Th. M 7th ed. 2011