Page 169 - Color Atlas of Biochemistry

160 Metabolism
Diabetes mellitus
Diabetes mellitus is a very common metabolic
disease that is caused by absolute or relative
insulin deficiency. The lack of this peptide
hormone (see p. 76) mainly affects carbohy-
drate and lipid metabolism. Diabetes mellitus
occurs in two forms. In type 1 diabetes (in-
sulin-dependent diabetes mellitus, IDDM),
the insulin-forming cells are destroyed in
young individuals by an autoimmune reac-
tion. The less severe type 2 diabetes (non-
insulin-dependent diabetes mellitus, NIDDM)
usually has its first onset in elderly individu- gluconeogenesisisstimulated, partly due to
als. The causes have not yet been explained in
detail in this type.
A. Insulin biosynthesis
Insulin is produced by the B cells of the islets urine (glucosuria).
of Langerhans in the pancreas. As is usual with
secretory proteins, the hormone’s precursor
(preproinsulin) carries a signal peptide that
directs the peptide chain to the interior of
the endoplasmic reticulum (see p. 210). Proin-
sulin is produced in the ER by cleavage of the
signal peptide and formation of disulfide
bonds. Proinsulin passes to the Golgi appara-
tus, where it is packed into vesicles—the β-
granules. After cleavage of the Cpeptide, ma-
ture insulin is formed in the β-granules and is butyrate see p. 312). As H ions are released
stored in the form of zinc-containing hexam-
ers until secretion.
B. Effects of insulin deficiency
The effects of insulin on carbohydrate
metabolism are discussed on p. 158. In sim-
plified terms, they can be described as stim-
ulation of glucose utilization and inhibition of dary effects. A constantly raised blood sugar
gluconeogenesis. In addition, the transport of
glucose from the blood into most tissues is
also insulin-dependent (exceptions to this in-
clude the liver, CNS, and erythrocytes).
The lipid metabolism of adipose tissue is
also influenced by the hormone. In these cells,
insulin stimulates the reorganization of glu-
cose into fatty acids. This is mainly based on
activation of acetyl CoA carboxylase (see
p. 162) and increased availability of
NADPH+H + due to increased PPP activity
(see p. 152). Onthe other hand, insulinalso
inhibits the degradation of fat by hormone-
Koolman, Color Atlas of Biochemistry, 2nd edition © 2005 Thieme
All rights reserved. Usage subject to terms and conditions of license.
sensitive lipases (see p. 162) and prevents the
breakdown of muscle protein.
The effects of insulin deficiency on metab-
olism are shown by arrows in the illustration.
Particularly noticeable is the increase in the
glucose concentration in the blood, from
–1
5mM to 9 mM (90 mg dL )or more
(hyperglycemia, elevated blood glucose
level). In muscle and adipose tissue –the two
most important glucose consumers—glucose
uptake and glucose utilization are impaired
by insulin deficiency. Glucose utilization in
the liver is also reduced. At the same time,
increased proteolysis in the muscles. This in-
creases the blood sugar level still further.
When the capacity of the kidneys to resorb
glucose is exceeded (at plasma concentrations
of 9 mM or more), glucose is excreted in the
The increased degradation of fat that oc-
curs in insulin deficiency also has serious ef-
fects. Some of the fatty acids that accumulate
in large quantities are taken up by the liver
andusedfor lipoprotein synthesis (hyperlipi-
demia),and therestare broken down into
acetyl CoA. As the tricarboxylic acid cycle is
not capable of taking up such large quantities
of acetyl CoA, the excess is used to form ke-
tone bodies (acetoacetate and E-hydroxy-
+
in this process, diabetics not receiving ad-
equate treatment can suffer severe metabolic
acidosis (diabetic coma). The acetone that is
also formed gives these patients’ breath a
characteristic odor. In addition, large amounts
of ketone body anions appear in the urine
(ketonuria).
Diabetes mellitus can have serious secon-
level can lead in the long term to changes in
the blood vessels (diabetic angiopathy), kid-
ney damage (nephropathy) and damage to
the nervous system (neuropathy), as well as
to cataracts in the eyes.