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chapter 22
Metabolic Homeostasis
increase in urine albumin excretion rate between
2 0
and
200 /xg/min (or 30-300 mg/d). This degree of albumin loss
in the urine is called microalbuminuria and is a harbinger
of renal failure and other complications of diabetes. It
is important to identify individuals with microalbumin-
uria because with appropriate therapeutic intervention at-
tenuation of loss of renal function can be accomplished.
Therapeutic interventions include blood glucose control,
treatment for high blood pressure if present, and the inhibi-
tion of formation of angiotensin II by use of angiotensin-
converting enzyme (ACE) inhibitors. The formation of
angiotensin II involves the following steps: release of the
protease renin by justaglomerular cells in response to de-
creased renal perfusion pressure, release of angiotensin
I from angiotensinogen by the action of renin, and con-
version of angiotensin I to angiotensin II by ACE. Phys-
iologic functions of angiotensin II in the kidney include
restoration of normal renal blood flow and glomerular fil-
tration and stimulation of aldosterone secretion, which af-
fects Na+ reabsorption (Chapter 32). In diabetes mellitus,
renal hemodynamics are altered due to glomerular hyper-
filtration. Angiotensin II has been postulated to contribute
to the progression of renal disease. Some of the deleterious
effects of angiotensin II may involve its action on vaso-
motor functions and induction of cytokines (e.g., TGF-/5,
see Chapter 35) that lead to hypertrophy of mesangial
cells. Thus, ACE inhibitors as well as angiotensin II re-
ceptor antagonists can prevent or slow the rate of progres-
sion of renal disease in diabetes mellitus. Clinical studies
have shown that even in normotensive diabetic patients,
ACE inhibitors are beneficial in the management of renal
disease.
Chronic Complications of Diabetes Mellitus
These
stem from elevated plasma glucose levels
per se
and
involve tissues that do not require insulin (e.g., lens,
retina, peripheral nerve) for the uptake and metabolism
of glucose. In these tissues, the intracellular level of glu-
cose parallels that in plasma. The chronic complications,
which cause considerable morbidity and mortality, are
atherosclerosis, microangiopathy, retinopathy, nephropa-
thy, neuropathy, and cataract. The biochemical basis of
these abnormalities may be attributed to increased tis-
sue ambient glucose concentration and may involve the
following mechanisms: nonenzymatic protein glycation
(Chapter 2), increased production of sorbitol, and de-
creased levels of myo-inositol. The ramifications of gly-
cation of proteins are not clear. Sorbitol is produced from
glucose by NADPH-dependent reduction catalyzed by al-
dose reductase. Sorbitol may also be converted to fructose
by NAD+-dependent oxidation. Sorbitol (and fructose)
diffuses poorly across cell membranes and accumulates
inside the cell causing osmosis-induced disturbances (e.g.,
cataract formation). The myoinositol depletion may be
due in part to the competition of glucose with myoinositol
for its intracellular transport; glucose and myoinositol are
strikingly similar in structure (Chapter 9). Myoinositol
can also be synthesized from glucose-
6
-phosphate. De-
creased myoinositol may lead to decreased phospho-
inositide turnover. The latter yields at least two active
catabolites (inositol polyphosphates and diacylglycerol)
that function as second messengers (Chapter 30). The di-
minished activity of Na+,K+-ATPase found in nerve fibers
is thought to be related to the altered phosphoinositide
turnover. Potential therapeutic use of myoinositol supple-
mentation and aldose reductase inhibitor administration is
being explored.
Management of Diabetes Mellitus
The primary
goal in the management of all types of diabetes mel-
litus (type 1, type 2, and GDM) is to maintain near-
normal plasma glucose levels in order to relieve symp-
toms (polydipsia, polyuria, polyphagia) and to prevent
both acute and chronic complications. The glycemic con-
trol is assessed by monitoring of glucose (by self and
in clinical settings), hemoglobin Aic, fructosamine, and
microalbuminuria. In type 1
diabetes mellitus due to
/
6
-cell
destruction,
administration
of
insulin
is
re-
quired throughout the person’s lifetime. There are many
insulin preparations that differ in duration of action
(ultrashort, short, intermediate, and long acting) and
in their origin (human, porcine, and bovine). Human
insulin analogues
lispro
and
aspart
(B28) do not undergo
polymerization and are rapid acting insulins. The side ef-
fects of insulin therapy include hypoglycemia and weight
gain.
The management of type 2 diabetes mellitus is based on
both behavioral changes with lifestyle modifications and
pharmacological measures. Diet, exercise, and weight loss
(in the obese) are the cornerstone of treatment in main-
taining euglycemia. Physical activity stimulates insulin
sensitivity, whereas physical inactivity leads to insulin
resistance. In the absence or failure of lifestyle and be-
havioral measures in the management of type
2
diabetes
mellitus, pharmacological therapy is employed. Pharma-
cological agents used in the treatment of type
2
diabetes
mellitus include insulins, sulfonylureas, a-glucosidase
inhibitors, biguanidines, and thiazolidinediones (Figure
22-26). Sulfonylureas bind to specific /1-cell plasma mem-
brane receptors and cause closure of the ATP-dependent
K+ channel with accompanying depolarization. The de-
polarization leads to influx of Ca2+ followed by in-
sulin secretion. A benzoic acid derivative (repaglinide)
is structurally similar to sulfonylurea without the sulfur
