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

Table 43–4
Goals of Therapy in Diabetes
INDEX
GOAL a
Glycemic control b
A1C
<7.0% c
Preprandial capillary plasma glucose 3.9-7.2 mmol/L (70-130 mg/dL)
Peak Postprandial capillary plasma glucose 10.0 mmol/L (<180 mg/dL) d
Blood pressure <130/80
Lipids e
Low-density lipoprotein
<2.6 mmol/L (<100 mg/dL) f
High-density lipoprotein
>1.1 mmol/L (>40 mg/dL) g
Triglycerides
<1.7 mmol/L (<150 mg/dL)
a
As recommended by the ADA goals should be individualized for each patient. Goals may be different for
certain patient populations.
b
A1C is primary goal.
c
While the ADA recommends an A1C <7.0% in general, in the individual patient it recommends that an approprprate
goal for the individual patient based on age, duration of diabetes, life expectancy, other medical conditions,
cardiovascular disease).
d
One to two hours after beginning of a meal.
e
In decreasing order of priority
f
In individuals with conronary artery disease, an LDL <1.8 mmol (70 mg/dL) is the goal.
g
For women, some suggest a goal that is 0.25 mmol/L (10 mg/dL) higher.
Adapted from Diabetes Care 33:S11, 2010.
physiologist Nicolas Paulesco found that injections of pancreatic
extracts reduced urinary sugar and ketones in diabetic dogs and published
results clearly indicating isolation of a glucose-lowering compound.
The significance of these findings was recognized only years
later.
Unaware of much of this work, Frederick Banting, a young
Canadian surgeon, convinced J.J.R. Macleod, a professor of physiology
in Toronto, to allow him access to a laboratory to search for the
antidiabetic principle of the pancreas. Banting began work on the
assumption that the islets secreted a glucose-lowering hormone that
was destroyed by proteolytic digestion prior to or during extraction.
Together with Charles Best, a fourth-year medical student, he
attempted to overcome the problem by ligating the pancreatic ducts
so that the acinar tissue degenerated, leaving the islets undisturbed.
Using an ethanol and acid extraction procedure, Banting and Best
obtained a pancreatic isolate that decreased the concentration of
blood glucose in diabetic dogs. Under the guidance of Macleod,
Banting and Best received help from J.B. Collip, a chemist with
expertise in extraction and purification of epinephrine. The first
patient to receive the active extracts was Leonard Thompson, age
14. He presented at the Toronto General Hospital with a blood glucose
level of 500 mg/dL (28 mM). Despite rigid control of his diet
(450 kcal/day), he continued to excrete large quantities of glucose,
and, without insulin, would likely have died within a few months.
The administration of the pancreatic extracts reduced the
plasma concentration and urinary excretion of glucose, and the
patient demonstrated marked clinical improvement. Replacement
therapy with the newly discovered hormone, insulin, had interrupted
what was clearly an otherwise fatal metabolic disorder. Stable
extracts eventually were obtained, and patients in many parts of
North America soon were being treated with insulin from porcine
and bovine sources. The first of several Nobel Prizes associated with
insulin was awarded to Banting and Macleod in 1923. A furor over
credit followed immediately, and Banting announced that he would
share his prize with Best; Macleod did the same with Collip (Bliss,
2005). Frederick Sanger established the amino acid sequence of
insulin and received the Nobel Prize in 1958. Dorothy Hodgkin
(Nobel prize for chemistry, 1964) and coworkers elucidated insulin’s
three-dimensional structure. Insulin was the hormone for which
Yalow and Berson first developed the radioimmunoassay, which was
recognized with the Nobel Prize in 1977.
Insulin Preparation and Chemistry. Human insulin, produced by
recombinant DNA technology, is soluble in aqueous solution. Most
preparations are supplied at neutral pH, which improves stability and
permits short-term storage at room temperature. Beginning shortly
after its discovery in 1921, patients were treated with insulin
preparations prepared from porcine or bovine pancreatic extracts for
>70 years. With the advent of human insulin, beef and pork insulin
are no longer produced. A number of other insulin preparations that
once were widely used such as lente, ultralente, and protamine zinc
insulin are no longer available.
Doses and concentration of clinically used insulin preparations
are expressed in international units. This tradition dates to a
time when preparations of hormones were impure and the concentration
of the hormone was standardized by bioassay. One unit of
insulin is defined as the amount required to reduce the blood glucose
concentration in a fasting rabbit to 45 mg/dL (2.5 mM).
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CHAPTER 43
ENDOCRINE PANCREAS AND PHARMACOTHERAPY OF DIABETES MELLITUS AND HYPOGLYCEMIA