section 22.8
Abnormalities of Metabolic Homeostasis
Acarbose (an cc-Glucosidase inhibitor)
Glipizide (a sulfonylurea)
Metformin (a biguanidine)
Troglitazone (a thiazolidinedione)
F I G U R E 2 2 - 2 6
Structures of four classes of hypoglycemic agents.
group and belongs to the class meglitinides. This drug
inhibits a different K+ channel than SUR in promoting
secretion and has rapid-onset and short-acting actions.
An example of an a-glucosidase inhibitor is acarbose, a
nitrogen-containing pseudotetrasaccharide. Acarbose in-
hibits the breakdown of carbohydrates into glucose by
inhibiting intestinal brush-border «-glucosidase and pan-
creatic amylase (Chapter 12) and brings about a reduc-
tion in postprandial hyperglycemia. Metformin belongs to
the class of biguanidines and has many effects on carbo-
hydrates and lipid metabolism. Its mechanism of action
may include inhibition of hepatic gluconeogenesis and
glycogenolysis and, in muscle, increased insulin recep-
tor tyrosine kinase activity and enhanced GLUT4 trans-
porter system. An adverse effect of metformin is lactic
Troglitazone is an example of the thiozolidinedione
class of antidiabetic agents. It enhances insulin sensitiv-
ity in liver, muscle, and adipose tissue. Troglitazone pro-
motes the conversion of non-lipid-storing preadipocytes
to mature adipocytes (discussed later) with increased in-
sulin sensitivity. The cellular target for the action of
troglitazone, which functions as a transcription factor, is
the nuclear receptor known as peroxisome proliferation-
activated receptor-y (PPAR-y). PPAR-y upon binding
with troglitazone is activated and forms a heterodimer
with retinoid X receptor (RXR). The PPAR-y/RXR
heterodimer regulates the transcription of genes encod-
ing proteins that control metabolic pathways (e.g., acetyl
CoA-synthetase, lipoprotein lipase, GLUT4, mitochon-
drial uncoupling protein). An adverse effect of trogli-
tazone is hepatic toxicity; periodic monitoring of liver
function by measurement of serum alanine aminotrans-
ferase is recommended. When a diabetic patient becomes
refractory to monotherapy, combination therapy (e.g.,
sulfonylurea and insulin) is used to achieve glycemic
Overweight and obesity are defined based on the body
mass index (BMI), which is calculated as weight in
kilograms divided by the square of height in meters
(BMI = kg/m2). A BMI between 25 and 29.9 is con-
sidered as overweight and >30 is considered obese
). Body weight is determined by a balance be-
tween energy intake and energy expenditure. The energy
expenditure is required to maintain basal metabolic func-
tions, absorption and digestion of foods (thermic effect
of food), physical activity and, in children, linear growth
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