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

Type 2 Diabetes
1267
Assess
A1C
Diabetes Education
Medical Nutrition Therapy
Physical Activity
Metformin
Screen for Complications
• Retinal exam
• Urine microalbuminuria
• Neuropathy exam
• Vascular evaluation
Reassess
A1C
Metformin + Second Agent
Reassess
A1C
Treat Co-morbidities
• Dyslipidemia
• Hypertension
• Obesity
• CV disease
CHAPTER 43
Metformin
+
2 Oral Agents
Figure 43–11. Treatment algorithm for management of type 2 diabetes mellitus. Patients diagnosed with type 2 diabetes, either by
fasting glucose, oral glucose tolerance testing, or A1C, should have diabetes education that includes instruction on medical nutrition
therapy and physical activity. Most patients newly diagnosed with type 2 diabetes have had subclinical or undiagnosed diabetes for
many years previously and should be evaluated for diabetic complications (retinal exam, test for excess protein or albumin excretion
in the urine, and clinical evaluation for peripheral neuropathy and vascular insufficiency); common comorbidities (hypertension and
dyslipidemia) should be treated. Metformin is the consensus first line of therapy and should be started at the time of diagnosis. Failure
to reach the glycemic target, generally a A1C ≤7% within 3-4 months, should prompt the addition of a second oral agent. Reinforce
lifestyle interventions at every visit and check A1C every 3 months. Treatment may escalate to metformin plus two oral agents or metformin
plus insulin, if necessary.
relatively low affinity for glucose, the GK activators have muted
action at fasting glycemia and a low risk for inducing hypoglycemia.
In early phases of clinical trial, GK activators seem to lower blood
glucose in diabetic humans.
The enzyme 11β-hydroxysteroid dehydrogenase 1 (11β-
HSD1) is expressed in the liver, adipose tissue, and skeletal muscle.
11β-HSD1 converts inactive cortisone into the active glucocorticoid
cortisol (Figure 42-6). Cortisol plays an important role in normal
counterregulation of insulin action, but excess activity is
associated with weight gain, visceral adiposity, insulin resistance,
inefficient proinsulin processing, and hyperglycemia. This has led
to the strategy of inhibition of 11β-HSD1 to reduce cortisol levels
in the visceral and splanchnic beds, potentially increasing insulin
sensitivity and glucose metabolism. Potent, orally available, selective
inhibitors of 11β-HSD1 that can inhibit the enzyme in liver
and adipose tissue are under investigation. Inhibition of 11β-HSD1
improves glycemic control, insulin sensitivity, and total cholesterol
in patients with type 2 diabetes.
Several intracellular enzymes serve as nutrient sensors,
including SIRT1, AMPK, DGAT1, and ACC2. Compounds that
Reassess
A1C
Metformin
+
Insulin
stimulate the activities of these enzymes have the potential to
increase glucose utilization, alter fatty acid metabolism, and increase
energy expenditure, potentially resulting in improvements of both
glucose and lipid metabolism as well as a decrease in body weight.
A SIRT1 activator, resveratrol, has been reported to decrease glucose
and insulin levels and improve glucose tolerance in subjects
with type 2 diabetes. Activators of other peripheral nutrient sensors
are in development.
HYPOGLYCEMIA
During prolonged fasting, the blood glucose levels may
drop to 3-4 mM in healthy persons with no symptoms
of hypoglycemia due to gradual shifts in fuel metabolism
to increase the percentage of energy derived from
stored lipids. In the absence of prolonged fasting,
healthy humans almost never have blood glucose levels
<3.5 mM (Cryer, 2008; Cryer et al., 2009). This is due
to a highly adapted neuroendocrine counterregulatory
ENDOCRINE PANCREAS AND PHARMACOTHERAPY OF DIABETES MELLITUS AND HYPOGLYCEMIA