DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1246 fasting. Beyond the defect in functional properties of the β cell, the
absolute mass of β cells is reduced in type 2 diabetes patients. It is
estimated that persons with early type 2 diabetes have ~50% of the
normal complement of β cells (Butler et al., 2003). This deficit is
compounded by a gradual loss of β cell mass over time, potentially
related to toxic effects of hyperglycemia. Progressive reduction of
β cell mass and function explains the natural history of type 2 diabetes
in most patients who require steadily increasing therapy to
maintain glucose control.
Type 2 diabetic patients frequently have elevated levels of
fasting insulin. This is not a reflection of accentuated β cell function
but a result of their higher fasting glucose levels and insulin
resistance. Another factor contributing to apparently high insulin
levels early in the course of the disease is the presence of increased
amounts of proinsulin. Proinsulin, the precursor to insulin, is inefficiently
processed in the diabetic islet. Whereas healthy subjects have
only 2-4% of total circulating insulin as proinsulin, type 2 diabetic
patients can have 10-20% of the measurable plasma insulin in this
form. Proinsulin has a considerably attenuated effect for lowering
blood glucose compared to insulin.
SECTION V
HORMONES AND HORMONE ANTAGONISTS
Insulin Resistance. Insulin sensitivity is a quantifiable parameter that
is measured as the amount of glucose cleared from the blood in
response to a dose of insulin. The failure of normal amounts of
insulin to elicit the expected response is referred to as insulin
resistance. This is a relative term because there is inherent variability
of insulin sensitivity among cells, tissues, and individuals. Insulin
sensitivity is affected by many factors including age, body weight,
physical activity levels, illness, and medications. Furthermore,
insulin sensitivity varies within individuals over time and across
groups or populations of subjects, even among healthy adults. Thus,
insulin resistance is a relative designation but has considerable
pathological significance because persons with type 2 diabetes or
glucose intolerance have reduced responses to insulin and can easily
be distinguished from groups with normal glucose tolerance.
The major insulin-responsive tissues are skeletal muscle, adipose
tissue, and liver. Insulin resistance in muscle and fat is generally
marked by a decrease in transport of glucose from the circulation.
Hepatic insulin resistance generally refers to a blunted ability of
insulin to suppress glucose production. Insulin resistance in adipocytes
causes increased rates of lipolysis and release of fatty acids into the circulation,
which can contribute to insulin resistance in liver and muscle,
hepatic steatosis, and dyslipidemia. More generally the role of
obesity in the etiology of type 2 diabetes is related to the insulin resistance
in skeletal muscle and liver that comes with increased amounts
of lipid storage, particularly in specific fat depots. The sensitivity of
humans to the effects of insulin administration is inversely related to
the amount of fat stored in the abdominal cavity; more visceral adiposity
leads to more insulin resistance (Kahn, 2003). Similarly, intrahepatocyte
or intramuscular fat, both commonly associated with obesity,
are strongly linked to insulin resistance. Intracellular lipid or its
byproducts may have direct effects to impede insulin signaling
(Savage et al., 2007). Enlarged collections of adipose tissue, visceral
or otherwise, is often infiltrated with macrophages and can become a
site of chronic inflammation. Adipocytokines, secreted from
adipocytes and immune cells, including TNF-α, IL-6, resistin, and
retinol-binding protein 4, can also cause systemic insulin resistance.
Insulin resistance is even more severe in obese persons with type 2
diabetes who have further reductions of insulin-stimulated glucose
uptake into skeletal muscle and relatively low rates of nonoxidative
glucose metabolism (glycogen synthesis), and impaired suppression of
hepatic glucose production and adipocyte lipolysis, despite insulin
concentrations that are often elevated.
Another important variable in determining insulin sensitivity
is activity level. Sedentary persons are more insulin resistant than
active ones, and physical training can improve insulin sensitivity.
Physical activity can decrease the risk of developing diabetes and
improve glycemic control in persons who have diabetes (Crandall
et al., 2008). Insulin resistance is more common in the elderly; within
populations, insulin sensitivity decreases linearly with age. Older
individuals tend to be less physically active, which can contribute to
insulin resistance. In addition, over the normal course of aging there
is a decrease in muscle mass and an increase in fat mass, with an
increased percentage of fat stored in the abdominal cavity.
At the cellular level, insulin resistance involves blunted steps
in the cascade from the insulin receptor tyrosine kinase to translocation
of GLUT4 transporters, but the molecular mechanisms are
incompletely defined. There have been >75 different mutations in
the insulin receptor discovered, most of which cause significant
impairment of insulin action. These mutations affect insulin receptor
number, movement to and from the plasma membrane, binding,
and phosphorylation. Mutations involving the insulin binding
domains of the extracellular α-chain cause the most severe syndromes,
but specific variants in the intracellular portions of the
receptor also cause severe insulin resistance. However, most insulin
resistance associated with obesity and type 2 diabetes is not due to
abnormalities of the insulin receptor. A central feature of the more
common forms of insulin resistance is increased phosphorylation of
serine, rather than tyrosine, in the insulin receptor and IRS proteins,
inhibiting their activation and signaling. This process is mediated by
protein serine/threonine kinases, which respond to an increased
intracellular flux of fatty acids, specific lipid products, particularly
diacylglycerol and ceramide, inflammatory mediators such as TNFα,
and endoplasmic reticulum stress. In addition, chronic hyperinsulinemia,
the typical correlate of insulin resistance, seems to increase
IRS protein catabolism. It is known that insulin sensitivity is under
genetic control, but it is unclear whether insulin-resistant individuals
have mutations in specific components of the insulin signaling
cascade or whether they have a complement of signaling effectors
that operate at the lower range of normal. Regardless, it is apparent
that insulin resistance clusters in families and is a major risk factor
for the development of diabetes.
Dysregulated Hepatic Glucose Metabolism. In type 2 diabetes, hepatic
glucose output is excessive in the fasting state and inadequately suppressed
after meals. These are key components to the abnormal
glycemic profile in diabetic patients, who have elevated glucose levels
in the postabsorptive state and accentuated postprandial rises.
Abnormal secretion of the islet hormones, both insufficient insulin
and excessive glucagon, accounts for a significant portion of dysregulated
hepatic glucose metabolism in type 2 diabetes. Increased
concentrations of glucagon, especially in conjunction with hepatic
insulin resistance, can lead to excessive hepatic gluconeogenesis and
glycogenolysis and abnormally high fasting glucose concentrations.
The liver is also resistant to insulin action in type 2 diabetes.
This contributes to the reduced potency of insulin to suppress hepatic