Drugs Used in the Treatment of Diabetes Mellitus and Errors of Glucose Metabolism

Chapter 24 Drugs Used in the Treatment of Diabetes Mellitus and Errors of Glucose Metabolism

I. General Considerations (Table 24-1)

A. Types of diabetes mellitus (DM) (see Rapid Review Pathology)

TABLE 24-1 Characteristics of Type 1 and Type 2 Diabetes Mellitus

Characteristic	Type 1	Type 2
Age of onset	Usually <25 yr	Usually >40 yr
Acuteness of onset	Usually sudden	Usually gradual
Presenting features	Polyuria, polydipsia, polyphagia, acidosis	Often asymptomatic
Body habitus	Often thin	Usually overweight
Control of diabetes	Difficult	Easy
Ketoacidosis	Frequent	Seldom, unless under stress
Insulin requirement	Always	Often unnecessary
Control by oral agents	Never	Frequent
Control by diet alone	Never	Frequent
Complications	Frequent	Frequent

Type 1 DM: autoimmune destruction of β-islet cells in pancreas; absolute insulin deficiency.

a. Autoimmune disease associated with destruction of pancreatic β-islet cells

b. Absolute insulin deficiency

a. Decreased number of insulin receptors

• Down-regulation of receptor synthesis related to increased adipose

b. Postreceptor dysfunction

• Examples: dysfunction of tyrosine kinase; glucose transport unit dysfunction

c. Relative insulin deficiency

Type 2 DM: insulin resistance due to ↓ insulin receptor synthesis and postreceptor abnormalities; relative insulin deficiency.

3. Secondary causes

(1) Glucocorticoids

(2) Thiazide diuretics

(3) Interferon-α

(4) Pentamidine

b. Some endocrine diseases

• Examples: Cushing’s syndrome; glucagonoma; acromegaly

c. Some genetic diseases

• Examples: hemochromatosis; metabolic syndrome; maturity onset DM

d. Insulin-receptor deficiency

• Acanthosis nigricans is a phenotypic marker

Acanthosis nigricans is a phenotypic marker of insulin-receptor deficiency.

e. Some infections

• Examples: mumps; cytomegalovirus in acquired immune deficiency syndrome (AIDS)

4. Impaired glucose tolerance

5. Gestational diabetes

B. Regulation of insulin secretion and physiological actions

1. Endocrine pancreas

a. α Cells secrete

b. β cells secrete

c. δ cells secrete

• Somatostatin

Pancreatic cells; α cells secrete glucagon; β cells secrete insulin; δ cells secrete somatostatin

2. Insulin structure and storage

a. Proinsulin is hydrolyzed to:

(1) Insulin (51 amino acids)

• Insulin molecule stored in secretory cells

(2) C-peptide (endogenous marker of insulin synthesis)

Use C peptide levels to differentiate between exogenous insulin (overdose) and endogenous insulin (overproduction/insulinoma).

3. Insulin release (Fig. 24-1)

a. Glucose partially depolarizes β cells

(1) Glucose enters via GLUT-2 transporter

(2) Metabolism of glucose yields adenosine triphosphate (ATP)

(3) Increased ATP/ADP (adenosine diphosphate) ratio closes the SUR1 (K_IR6.2) K⁺ channel

• SUR = Sulfonylurea receptor

(4) Decreased K⁺ permeability, which leads to partial depolarization of β cells

(5) Open voltage gated Ca²⁺ channels

(6) Increased Ca²⁺ stimulates exocytosis of insulin

b. Secretagogues, also, depolarize β cells

(1) They bind to and close SUR1 (K_IR6.2) K⁺ channel

(2) This causes insulin release by mechanism above

c. Effect of serum K⁺

(1) Hypokalemia inhibits insulin secretion

(2) Hyperkalemia stimulates insulin secretion

4. Insulin actions (Fig. 24-2)

24-1 Mechanism of insulin secretion from pancreatic β cells by glucose or secretagogues. ADP, adenosine diphosphate; ATP, adenosine triphosphate; FADH, flavin adenine dinucleotide; Glc, glucose; GLUT-2, glucose transporter; G6P, glucose 6-phosphate; NADH, nicotinamide-adenine dinucleotide; SUR1r (K_IR6.2), K⁺ channel; TCA, tricarboxylic acid cycle.

(From Wecker L, et al.: Brody’s Human Pharmacology, 5th ed. Philadelphia, Mosby, 2010, Figure 43-3.)

24-2 Regulation of insulin secretion and physiologic actions of insulin. GH, growth hormone; GI, gastrointestinal; GLUT, glucose transporter; TAG, triacylglycerides; VLDL, very low density lipoprotein.

(From Brown TA: Rapid Review Physiology. Philadelphia, Mosby, 2007, Figure 3-18.)

Most important actions of insulin are in liver, skeletal muscle, and adipose tissue.

a. Translocation of GLUT-4 transporter to the cell surface

b. Promotion of glucose uptake by

Insulin promotes uptake of glucose in muscle and adipose via GLUT-4.

c. Major role of insulin is to maintain plasma glucose levels and, to a lesser extent, serum K⁺ levels

C. Complications

1. Chronic hyperglycemia

a. Glucose combines with amino groups in proteins.

b. Produces advanced glycosylation end (AGE) products

• Assessed by measuring glycosylated HbA_1c

2. Protein glycosylation and osmotic changes contributes to many diseases

a. Neuropathy (osmotic damage of Schwann cells from sorbitol)

b. Retinopathy (osmotic damage to pericytes by sorbitol)

d. Peripheral vascular disease

e. Coronary artery disease

f. Lacunar strokes

Diabetes causes neuropathy, retinopathy, nephropathy, peripheral vascular disease, strokes, coronary artery disease.

3. Diabetic ketoacidosis (type 1 diabetes)

a. Produces severe volume depletion and coma

b. Multiple metabolic changes (Fig. 24-3)

II. Antidiabetic Agents (Box 24-1)

A. Insulins

1. Different insulin preparations (Table 24-2)

a. Rapid-acting insulin

(1) Insulin aspart

(2) Insulin glulisine

(3) Insulin inhalation (limited availability)

(4) Insulin lispro

b. Short-acting insulin

• Regular insulin

24-3 Mechanisms of metabolic changes in untreated type 1 diabetes mellitus (DM). VLDL, very low-density lipoprotein.

(From Pelley JW and Goljan EF: Rapid Review Biochemistry, 2nd ed. Philadelphia, Mosby, 2007, Figure 9-5.)

BOX 24-1 Drugs Used in the Treatment of Diabetes Mellitus

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Tags: Rapid Review Pharmacology

Apr 8, 2017 | Posted by admin in PHARMACY | Comments Off

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