Page 765 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 41 Pancreatic Hormones & Antidiabetic Drugs 751

TABLE 41–3 Endocrine effects of insulin. administered as an intravenous bolus. Because insulin-treated
patients develop circulating anti-insulin antibodies that interfere
Effect on liver: with radioimmunoassays of insulin, measurements of C-peptide
Reversal of catabolic features of insulin deficiency are used to indicate beta-cell secretion.
Inhibits glycogenolysis
Inhibits conversion of fatty acids and amino acids to keto acids C. Beta-Adrenoceptor Blocker Overdose
Inhibits conversion of amino acids to glucose Glucagon is sometimes useful for reversing the cardiac effects of
an overdose of β-blocking agents because of its ability to increase
Anabolic action
cAMP production in the heart independent of β-receptor func-
Promotes glucose storage as glycogen (induces glucokinase and tion. However, it is not clinically useful in the treatment of heart
glycogen synthase, inhibits phosphorylase)
failure.
Increases triglyceride synthesis and very-low-density lipoprotein
formation
Effect on muscle: D. Radiology of the Bowel
Glucagon has been used extensively in radiology as an aid to
Increased protein synthesis
x-ray visualization of the bowel because of its ability to relax the
Increases amino acid transport intestine.
Increases ribosomal protein synthesis
Increased glycogen synthesis Adverse Reactions
Increases glucose transport Transient nausea and occasional vomiting can result from glu-
Induces glycogen synthase and inhibits phosphorylase cagon administration. These are generally mild, and glucagon is
Effect on adipose tissue: relatively free of severe adverse reactions. It should not be used in
Increased triglyceride storage a patient with pheochromocytoma.
Lipoprotein lipase is induced and activated by insulin to hydro-
lyze triglycerides from lipoproteins ■ DIABETES MELLITUS
Glucose transport into cell provides glycerol phosphate to permit
esterification of fatty acids supplied by lipoprotein transport
Diabetes mellitus is defined as an elevated blood glucose associ-
Intracellular lipase is inhibited by insulin
ated with absent or inadequate pancreatic insulin secretion, with or
without concurrent impairment of insulin action. The disease states
B. Cardiac Effects underlying the diagnosis of diabetes mellitus are now classified into
Glucagon has a potent inotropic and chronotropic effect on the four categories: type 1, type 2, other, and gestational diabetes
heart, mediated by the cAMP mechanism described above. Thus, mellitus.
it produces an effect very similar to that of β-adrenoceptor ago-
nists without requiring functioning β receptors. Type 1 Diabetes Mellitus
The hallmark of type 1 diabetes is selective beta cell (B cell)
C. Effects on Smooth Muscle destruction and severe or absolute insulin deficiency. Type 1 dia-
Large doses of glucagon produce profound relaxation of the intes- betes is further subdivided into immune-mediated (type 1a) and
tine. In contrast to the above effects of the peptide, this action idiopathic causes (type 1b). The immune form is the most com-
on the intestine may be due to mechanisms other than adenylyl mon form of type 1 diabetes. Although most patients are younger
cyclase activation. than 30 years of age at the time of diagnosis, the onset can occur
at any age. Type 1 diabetes is found in all ethnic groups, but the
Clinical Uses highest incidence is in people from northern Europe and from
Sardinia. Susceptibility appears to involve a multifactorial genetic
A. Severe Hypoglycemia linkage, but only 10–15% of patients have a positive family his-
The major clinical use of glucagon is for emergency treatment tory. Most patients with type 1 diabetes have one or more circu-
of severe hypoglycemic reactions in patients with type 1 diabetes lating antibodies to glutamic acid decarboxylase 65 (GAD 65),
when unconsciousness precludes oral feedings and intravenous insulin autoantibody, tyrosine phosphatase IA2 (ICA 512), and
glucose treatment is not possible. Recombinant glucagon is cur- zinc transporter 8 (ZnT8) at the time of diagnosis. These anti-
rently available in 1-mg vials for parenteral (IV, IM, or SC) use bodies facilitate the diagnosis of type 1a diabetes and can also be
(Glucagon Emergency Kit). used to screen family members at risk for developing the disease.
Most type 1 patients with acute symptomatic presentation have
B. Endocrine Diagnosis significant beta cell loss and insulin therapy is essential to control
Several tests use glucagon to diagnose endocrine disorders. In glucose levels and to prevent ketosis.
patients with type 1 diabetes mellitus, a classic research test Some patients have a more indolent autoimmune process
of pancreatic beta-cell secretory reserve uses 1 mg of glucagon and initially retain enough beta cell function to avoid ketosis.