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Workbook and Casebook for Goodman and Gilman's The Pharmacological Basis of Therapeutics
Hypoglycemia
INTRODUCTION
This chapter will be most useful after having a basic understanding of the material in Chapter 43, Endocrine Pancreas and Pharmacotherapy of
Diabetes Mellitus and Hypoglycemia in Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 12th Edition. In addition to the material
presented here, the 12th Edition includes:
A description of pancreatic islet cell physiology and the synthesis and processing of insulin
A discussion of the signaling pathway that is activated by insulin resulting in its effects on target cells
LEARNING OBJECTIVES
Understand the mechanisms of action of insulin and the oral antidiabetic drugs.
Describe the components for management of the diabetic patient including the goals of therapy.
Describe the pharmacotherapeutic options for the treatment of patients with type 1 or type 2 diabetes.
Learn about the adverse effects of insulin and the oral antidiabetic drugs.
Alogliptin (NESINA)
Bromocriptine (CYCLOSET, not yet available in the United States for treatment of diabetes)
Colesevelam (WELCHOL)
Diazoxide (PROGLYCEM)
Exenatide (BYETTA)
Glimepiride (AMARYL)
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Glipizide
Chapter (GLUCOTROL,
30: others) and Pharmacotherapy of Diabetes Mellitus and Hypoglycemia,
Endocrine Pancreas Page 1 / 12
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Glucagon
Diazoxide (PROGLYCEM)
Exenatide (BYETTA)
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Gliclazide (DIAMICRON, others, unavailable in the United States)
Glimepiride (AMARYL)
Glucagon
Liraglutide (VICTOZA)
Miglitol (GLYSET)
Nateglinide (STARLIX)
Pioglitazone (ACTOS)
Pramlintide (SYMLIN)
Repaglinide (PRANDIN)
Rosiglitazone (AVANDIA)
Saxagliptin (ONGLYZA)
Sitagliptin (JANIVIA)
Insulin Insulin Insulin binds to a plasma membrane receptor that initiates a cascade of signaling events, which results in glucose
utilization and glycogen synthesis (see Figure 301)
Biguanides Metformin Increases the activity of AMPdependent protein kinase (AMPK); activated AMPK stimulates fatty acid oxidation,
glucose uptake, and nonoxidative metabolism, and it reduces lipogenesis and gluconeogenesis; the net result is
increased glycogen storage in skeletal muscle, lower rates of hepatic glucose production, increased insulin
sensitivity, and lower blood glucose concentrations
Insulin Insulin Insulin binds to a plasma membrane receptor that initiates a cascade of signaling events, which results in glucose
utilization and glycogen synthesis (see Figure 301)
Biguanides Metformin Increases the activity of AMPdependent protein kinase (AMPK); activated AMPK stimulates fatty acid oxidation,
glucose uptake, and nonoxidative metabolism, and it reduces lipogenesis and gluconeogenesis; the net result is
increased glycogen storage in skeletal muscle, lower rates of hepatic glucose production, increased insulin
sensitivity, and lower blood glucose concentrations
Insulin Glyburide Stimulate insulin release by binding to a specific site on the β cell KATP channel complex and inhibiting its activity
Secretagogues— Glipizide (see Figure 302)
Sulfonylureas Gliclazide
Glimepiride
Insulin Repaglinide Stimulates insulin release by closing KATP channels in pancreatic β cells (see Figure 302)
Secretagogues— Nateglinide
Nonsulfonylureas
Thiazolidinediones Rosiglitazone Ligands for the peroxisome proliferation activating receptor γ (PPARγ) that are involved in the regulation of genes
Pioglitazone related to glucose and lipid metabolism
GLP1 Agonists Exenatide Glucagonlike peptide 1 (GLP1) agonists that activate the GLP1 receptor, activate the cAMPPKA pathway, and
Liraglutide initiate signals through PKC and P13K (see Figure 302)
Dipeptidyl Sitagliptin Inhibit the DPP4 enzyme that is critical for the inactivation of GLP1 and GIP (glucosedependent insulinotropic
Peptidase4 (DPP Saxagliptin polypeptide); thus the AUC of GLP1 and GIP is increased when their secretion is stimulated by a meal (see Figure
4) Inhibitors Vidagliptin 303)
Alogliptin
αGlucosidase Acarbose Reduces intestinal absorption of carbohydrates from the GI tract and blunts the rate of rise of postprandial glucose
Inhibitors Miglitol by inhibiting αglucosidase in the intestinal brush border
Voglibose
Amylin Agonists Pramlintide Synthetic form of amylin; it acts through the amylin receptor in the brain causing reduction in glucagon release,
delayed gastric emptying, and satiety
Bile Acid Colesevelam Mechanism by which bile acid binding and removal from the enterohepatic circulation lowers blood glucose has
Sequestrants not been established
Agents Used to Glucagon Interacts with GPCR receptor on target cells; the effects of glucagon on the liver are mediated by cAMP
Treat
Hypoglycemia Diazoxide Hyperglycemia results from inhibition of insulin secretion (see Figure 302)
Figure 301
Pathways of insulin signaling. The binding of insulin to its plasma membrane receptor activates a cascade of downstream signaling events. Insulin
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activity of the receptor dimer, resulting in the tyrosine phosphorylation (YP) of the receptor’s β subunits
Chapter 30: Endocrine Pancreas and Pharmacotherapy of Diabetes Mellitus and Hypoglycemia, Page 3 / 12
and a small number of specific substrates (light blue shapes): the insulin receptor substrate (IRS) proteins, Gab1 and SHC; within the membrane, a
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caveolar pool of insulin receptor phosphorylates caveolin (Cav), APS, and Cbl. These tyrosinephosphorylated proteins interact with signaling
cascades via SH2 and SH3 domains to mediate the effects of insulin, with specific effects resulting from each pathway. In target tissues such as skeletal
Hypoglycemia
Pathways of insulin signaling. The binding of insulin to its plasma membrane receptor activates a cascade of downstream signaling events. Insulin
binding activates the intrinsic tyrosine kinase activity of the receptor dimer, resulting in the tyrosine phosphorylation (YP) of the receptor’s β subunits
and a small number of specific substrates (light blue shapes): the insulin receptor substrate (IRS) proteins, Gab1 and SHC; within the membrane, a
caveolar pool of insulin receptor phosphorylates caveolin (Cav), APS, and Cbl. These tyrosinephosphorylated proteins interact with signaling
cascades via SH2 and SH3 domains to mediate the effects of insulin, with specific effects resulting from each pathway. In target tissues such as skeletal
muscle and adipocytes, a key event is the translocation of the Glut4 glucose transporter from intracellular vesicles to the plasma membrane; this
translocation is stimulated by both the caveolar and noncaveolar pathways. In the noncaveolar pathway, the activation of PI3K is crucial, and PKB/Akt
(anchored at the membrane by PIP3) and/or an atypical form of PKC is involved. In the caveolar pathway, caveolar protein flotillin localizes the
signaling complex to the caveola; the signaling pathway involves a series of SH2 domain interactions that add the adaptor protein CrkII, the guanine
nucleotide exchange protein C3G, and small GTPbinding protein, TC10. The pathways are inactivated by specific phosphoprotein phosphatases (eg,
PTB1B). In addition to the actions shown, insulin also stimulates the plasma membrane Na+,K+ATPase by a mechanism that is still being elucidated;
the result is an increase in pump activity and a net accumulation of K+ in the cell. Abbreviations: aPKC, atypical isoform of protein kinase C; APS,
adaptor protein with PH and SH2 domains; CAP, Cbl associated protein; CrkII, chicken tumor virus regulator of kinase II; GLUT4, glucose transporter 4;
Gab1, Grb2 associated binder; MAP kinase, mitogenactivated protein kinase; PDK, phosphoinositidedependent kinase; PI3 kinase,
phosphatidylinositol3kinase; PIP3, phosphatidylinositol trisphosphate; PKB, protein kinase B (also called Akt); Y, tyrosine residue; YP,
phosphorylated tyrosine residue.
FIGURE 302
Regulation of insulin secretion from a pancreatic β cell. The pancreatic β cell in a resting state (fasting blood glucose) is hyperpolarized. Glucose,
entering via GLUT transporters (primarily GLUT1 in humans, GLUT2 in rodents), is metabolized and elevates cellular ATP, which inhibits K+ entry
through the KATP channel; the decreased K+ conductance results in depolarization, leading to Ca2+dependent exocytosis of stored insulin. The KATP
channel, actually a heterooctamer composed of SUR1 and Kir 6.2 subunits, is the site of action of several classes of drugs: ATP binds to and inhibits
Kir6.2; sulfonylureas and meglitinides bind to and inhibit SUR1; all 3 agents thereby promote insulin secretion. Diazoxide and ADPMg2+ (low ATP) bind
to and activate SUR1, thereby inhibiting insulin secretion. Incretins enhance insulin secretion.
FIGURE 303
Pharmacological effects of DDP4 inhibition. DPP4, an ectoenzyme located on the luminal side of capillary endothelial cells metabolizes the incretins,
glucagonlike peptide 1 (GLP1), and glucosedependent insulinotropic polypeptide (GIP), by removing the 2 Nterminal amino acids. The target for
DPP4 cleavage is a proline or alanine residue in the second position of the primary peptide sequence. The truncated metabolites GLP1 [936] and GIP
[342] are the major forms of the incretins in plasma and are inactive as insulin secretagogues. Treatment with a DPP4 inhibitor increases the
concentrations of intact GLP1 and GIP.
CASE 301
A 10yearold girl is diagnosed with type 1 diabetes. She will start on insulin therapy.
The diagnosis of diabetes mellitus is currently based on the correlation of diabetesspecific complications with a particular level of glycemia, that is,
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diabetesspecific complication like retinopathy begins to appear. The criterion for the diagnosis of diabetes is
Chapter 30: Endocrine
shown in Table 301. Pancreas and Pharmacotherapy of Diabetes Mellitus and Hypoglycemia, Page 5 / 12
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b. How should diabetes in this patient be managed? What are the goals of therapy?
CASE 301
A 10yearold girl is diagnosed with type 1 diabetes. She will start on insulin therapy.
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a. How is the diagnosis of type 1 diabetes made?
The diagnosis of diabetes mellitus is currently based on the correlation of diabetesspecific complications with a particular level of glycemia, that is,
the level of glycemia at which a diabetesspecific complication like retinopathy begins to appear. The criterion for the diagnosis of diabetes is
shown in Table 301.
b. How should diabetes in this patient be managed? What are the goals of therapy?
Therapy of diabetes has to be individualized for each patient. Figure 304 shows the components of sound diabetes management. Table 302 lists
the indexes of therapy and the goals for diabetic patients in general.
c. What is hemoglobin A1 c (A1C) and how does it differ from fasting blood glucose?
Exposure of proteins to an elevated glucose concentration produces nonenzymatic glycation of proteins including hemoglobin (Hb). Thus, the level
of HbA1c (A1C) represents the average glucose concentration to which the Hb has been exposed over the past 2 to 3 months.
The pancreatic β cell is a highly specialized cell that quickly senses and responds to the external glucose concentration. The transport of glucose
into the pancreatic β cell via a facilitative transporter (see Figure 302) results in increased intracellular calcium which, in turn, results in exocytotic
release of insulin from storage vesicles.
Once in the circulation, insulin binds, in various tissues, to its plasma membrane receptor (see Figure 301) that activates a cascade of downstream
intracellular signaling events. The tissues that are considered critical for the regulation of blood glucose are liver, skeletal muscle, and fat.
e. What are the options with insulin therapy with this patient?
Insulin preparations are classified according to their duration of action into shortacting and longacting (see Table 453 in Goodman and Gilman’s
The Pharmacological Basis of Therapeutics, 12th Edition). In most patients, insulinreplacement therapy includes longacting insulin (basal) and
shortacting insulin to provide postprandial needs. Most insulin is injected subcutaneously. Shortacting insulins are the only form of the hormone
used in subcutaneous infusion pumps.
Table 301
Criteria for the Diagnosis of Diabetes
Symptoms of diabetes plus random blood glucose concentration ≥11.1 mM (200 mg/dL)a or
Twohour plasma glucose ≥11.1 mM (200 mg/dL) during an oral glucose tolerance testc
HbA1c ≥6.5%
cThe test should be performed using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water; this test is not recommended for
N o t e: In the absence of unequivocal hyperglycemia and acute metabolic decompensation, these criteria should be confirmed by repeat testing on a different day.
Table 302
Goals of Therapy in Diabetes
Glycemic controlb
routine clinical use.
N o t e: In the absence of unequivocal hyperglycemia and acute metabolic decompensation, these criteria should be confirmed by repeat testing on a different day.
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Data adapted from Diabetes Care, 2010; 33:S62–S69.
Table 302
Goals of Therapy in Diabetes
INDEX G O A La
Glycemic controlb
A1C <7.0%c
Lipidse
aAs recommended by the ADA, goals should be individualized for each patient. Goals may be different for certain patient populations.
cWhile the ADA recommends an A1C <7.0% in general, in the individual patient it recommends an appropriate goal for the individual patient be based on age,
duration of diabetes, life expectancy, other medical conditions, and cardiovascular disease.
f In individuals with coronary artery disease, an LDL <1.8 mmol (70 mg/dL) is the goal.
gFor women, some suggest a goal that is 0.25 mmol/L (10 mg/dL) or higher.
Figure 304
CASE 302
A 53yearold man is diagnosed with type 2 diabetes. His doctor follows the treatment algorithm for the management of type 2 diabetes as shown in
Figure 305. The patient’s initial A1C is 8.1%. After attempts at weight reduction, increased physical activity, and metformin pharmacotherapy his A1C is
7.8%.
The diagnosis of type 2 diabetes is made using the same criteria as shown in Table 301.
Therapy of type 2 diabetes has to be individualized for each patient. Figure 304 shows the components of sound diabetes management and is
applicable to type 1 and type 2 diabetes patients. Table 302 lists the indexes of therapy and the goals for diabetic patients in general.
c. What are the options to lower his A1C in addition to lifestyle modifications?
One option that is commonly followed is to add a sulfonylurea drug. Other options include the insulin secretagogues that are nonsulfonylureas or
the thiazolidinediones.
The most severe untoward effect of the sulfonylurea drugs is hypoglycemia. Weight gain is also a common side effect of this class of drugs. Less
common effects include nausea, vomiting, cholestatic jaundice, blood dyscrasias, and dermatological reactions.
FIGURE 305
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 examination, 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 an A1C ≤7% within 34 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 2 oral
agents or metformin plus insulin, if necessary.
CASE 303
The patient in Case 302 has an A1C that is 7.5% after pharmacotherapy with metformin plus a sulfonylurea.
The progressive insulin deficiency in type 2 diabetes often makes it increasingly difficult to achieve tight glycemic control solely with oral
antihyperglycemic agents (see Figure 305). One option would be the addition of a thiazolidinedione drug such as rosiglitazone or pioglitazone. If
this does not achieve the desired goal then the addition of insulin is another option.
The most common side effect of the thiazolidinediones is weight gain and edema. Of greatest concern are the increased incidence of congestive
heart failure and the risk of cardiovascular events (myocardial infarction or stroke). Treatment with thiazolidinediones may increase the risk of
bone fracture in women.
If this patient already has a risk of cardiovascular disease, a better choice might be to add insulin to his diabetic regimen.
The different types of insulin are shown in Table 435 in Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 12th Edition. Patients
with type 2 diabetes are usually best treated with longacting insulin such as glargine. Glargine has a sustained peakless absorption profile and
provides better oncedaily insulin coverage than NPH insulin. Glargine also has a lower risk of hypoglycemia, particularly overnight, compared to
NPH insulin.
If the addition of basal insulin still does not reach the target A1C, the addition of a glucagonlike peptide1 (GLP1) receptor agonist may be
beneficial. A GLP1 agonist such as exenatide or liraglutide stimulates insulin secretion, inhibits glucagon release, delays gastric emptying, reduces
food intake, and normalizes fasting and postprandial insulin secretion. An alternative is a dipeptidyl peptidase4 (DPP4) inhibitor which results in
a rise in the endogenous GLP1 concentration by inhibiting its plasma clearance.
CASE 304
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A 49yearold woman without diabetes is diagnosed with recurring hypoglycemia. This is particularly troublesome because she awakes every morning
with a headache.
If the addition of basal insulin still does not reach the target A1C, the addition of a glucagonlike peptide1 (GLP1) receptor agonist may be
beneficial. A GLP1 agonist such as exenatide or liraglutide stimulates insulin secretion, inhibits glucagon release, delays gastric emptying, reduces
food intake, and normalizes fasting and postprandial insulin secretion. An alternative is a dipeptidyl peptidase4 (DPP4) inhibitor which results in
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a rise in the endogenous GLP1 concentration by inhibiting its plasma clearance.
CASE 304
A 49yearold woman without diabetes is diagnosed with recurring hypoglycemia. This is particularly troublesome because she awakes every morning
with a headache.
Two agents are available for the treatment of hypoglycemia: glucagon and diazoxide.
Glucagon is used to treat severe hypoglycemia, particularly in diabetic patients when the patient cannot safely consume oral glucose and
intravenous glucose is not available. Glucagon interacts with a GPCR on the plasma membrane of target cells.
Diazoxide is an antihypertensive with potent hyperglycemic actions when given orally. The hyperglycemic action of diazoxide is primarily through
the inhibition of insulin secretion (see Figure 302).
KEY CONCEPTS
Insulin is the primary treatment of type 1 diabetes.
There are many different types of insulin (see Table 453 in Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 12th Edition),
including subcutaneous insulin pumps.
Shortacting insulin is the only form of the hormone used in insulin pumps.
Type 2 diabetes is a complex disease that requires multiple forms of treatment (see Figure 305) including diet, exercise, and medications.
The goals of therapy for type 1 and type 2 diabetes are shown in Table 302.
Metformin is the consensus first line of therapy for type 2 diabetes and should be started at the time of diagnosis.
The most common and serious adverse effect of diabetes therapy is hypoglycemia. The more vigorous the attempt to achieve euglycemia, the
more frequent are episodes of hypoglycemia.
Table 303
Some Drugs That May Promote Hyperglycemia or Hypoglycemia
HYPERGLYCEMIA HYPOGLYCEMIA
The most common and serious adverse effect of diabetes therapy is hypoglycemia. The more vigorous the attempt to achieve euglycemia, the
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more frequent are episodes of hypoglycemia.
Table 303
Some Drugs That May Promote Hyperglycemia or Hypoglycemia
HYPERGLYCEMIA HYPOGLYCEMIA
SUMMARY
SUMMARY: DRUGS USED TO TREAT DIABETES MELLITUS AND HYPOGLYCEMIA
TOXICITIES
CLASS AND
NAMES CLINICAL USES COMMON UNIQUE; CLINICALLY IMPORTANT
SUBCLASSES
Biguanides Metformin Firstline treatment of type 2 diabetes Nausea, Lower blood concentrations of vitamin B12
diarrhea, Lactic acidosis
indigestion, and
abdominal pain
Insulin Glyburide Treatment of type 2 diabetes Weight gain Hypoglycemia, cholestatic jaundice,
Secretagogues— Glipizide Nausea and agranulocytosis, aplastic anemia, hemolytic
Sulfonylureas Gliclazide vomiting anemia, generalized hypersensitivity reactions,
Glimepiride and dermatological reactions
Ethanol may enhance the action of
sulfonylureas and cause hypoglycemia
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Chapter 30: Endocrine Pancreas and Pharmacotherapy of Diabetes Mellitus and Hypoglycemia, Page 11 / 12
azole antifungal agents and histamine H2
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antagonists
Insulin Glyburide Treatment of type 2 diabetes Weight gain Hypoglycemia, cholestatic jaundice,
Secretagogues— Glipizide Nausea and agranulocytosis, aplastic anemia, hemolytic
Sulfonylureas Gliclazide vomiting anemia, generalized hypersensitivity reactions,
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Glimepiride and dermatological reactions
Ethanol may enhance the action of
sulfonylureas and cause hypoglycemia
Drug interactions with many drugs including
azole antifungal agents and histamine H2
antagonists
Thiazolidinediones Rosiglitazone Treatment of type 2 diabetes Weight gain and Increased incidence of congestive heart failure
Pioglitazone edema Rosiglitazone, but not pioglitazone may increase
the risk of myocardial infarction and stroke
Thiazolidinediones increase the risk of bone
fracture in women
GLP1 Agonists Exenatide Treatment of type 2 diabetes Nausea and Hypoglycemia is rare
Liraglutide vomiting
Dipeptidyl Sitagliptin Treatment of type 2 diabetes Saxagliptin is metabolized by CYP3A4 and dose
Peptidase4 (DPP Saxagliptin should be adjusted when coadministered with
4) Inhibitors Vidagliptin drugs that inhibit this enzyme
Alogliptin
αGlucosidase Acarbose Adjuncts to diet and exercise in type 2 Malabsorption, Hypoglycemia when added to insulin or an
Inhibitors Miglitol diabetic patients not reaching glycemic flatulence, insulin secretagogue
Voglibose targets diarrhea, and Acarbose can decrease absorption of digoxin
abdominal Miglitol can decrease the absorption of
bloating propranolol and ranitidine
Bile Acid Colesevelam Treatment of hypercholesterolemia (see Constipation, Interferes with the absorption of many
Sequestrants Chapter 20); may be used as an adjunct to dyspepsia, commonly used drugs; most medications
diet and exercise to treat patients with abdominal pain, should be given 4 hours before colesevelam
type 2 diabetes and nausea