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HORMONES: PANCREATIC
In March 2005, the US Food and Drug Administration
(FDA) approved the human hormone amylin analogue pramlintide (Symlin®)
for clinical use in the United States. At the time of
publication, pramlintide was the only amylin supplementation therapy approved
by the FDA for use in the
United States.
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Pramlintide is indicated for the following:
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Type 1 diabetes, as an adjunct treatment for patients who use mealtime
insulin therapy and who have failed to achieve desired glucose control despite
optimal insulin therapy
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Type 2 diabetes, as an adjunct treatment for patients who use mealtime
insulin therapy and who have failed to achieve desired glucose control despite
optimal insulin therapy, with or without a concurrent sulfonylurea agent and/or
metformin
A boxed warning concerning the potential for insulin-induced hypoglycemia is
included in the official prescribing information. Prescribers are encouraged to
read the entire prescribing information, including this warning, before
prescribing pramlintide.
Prescribing
Information
Frequently Asked Questions: Pancreatic Hormones
Amylin
What is amylin, and where is it produced?
What are the physiologic effects and mechanisms of action of amylin?
What are the effects of amylin deficiency?
How can amylin concentrations be measured? Is there an amylin assay
available?
What are the ranges for the fasting and postprandial human plasma
amylin concentrations?
Is there amylin resistance? Does amylin contribute to insulin
resistance?
How is amylin different from leptin?
How is amylin different from somatostatin?
Does amylin work with the enzyme system that acarbose and miglitol
inhibit?
Does amylin cause amyloid deposits?
Does amylin cause Alzheimer's disease?
Where may information or training on amylin be obtained?
What is pramlintide?
How does pramlintide differ from amylin?
What is glucagon?
What is the function of glucagon?
How is glucagon affected by endogenous amylin and by exogenous
pramlintide?
Can pramlintide suppress the inappropriate postprandial rise in
glucagon secretion?
Can long-term suppression of postprandial glucagon secretion improve
long-term glycemic control?
Why is glucagon also a pharmaceutical product?
How is glucagon for injection used?
How is glucagon supplied?
What are the side effects of glucagon?
What happens in case of overdose with glucagon?
What if glucagon does not resolve the hypoglycemic episode?
Does amylin inhibit the secretion of glucagon in response to
hypoglycemia?
Is there an assay for glucagon?
References
What
is amylin, and where is it produced?
Amylin is the 37–amino acid product of a gene located on chromosome 12.1
It is a naturally occurring neuroendocrine hormone that is colocalized and
cosecreted in the same secretory vesicles with insulin from pancreatic β (beta)
cells.2,3 Small amounts of amylin have
also been detected in pancreatic α (alpha) and δ (delta)
cells,4,5 the stomach,6,7
and various neurons of the nervous system. Amylin and insulin are cosecreted in
response to carbohydrate (glucose) and protein-derived amino acids following a
meal stimulus.8,9 Experimental studies
have shown that amylin complements the effects of insulin in postprandial
glucose regulation through several centrally mediated effects.10
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What are the physiologic effects and mechanisms
of action of amylin?
Nearly 60 different effects of amylin have been identified in extensive in
vitro and in vivo studies.10
Recent studies have identified at least 4 physiologic effects of amylin that
complement insulin in regulating postprandial glucose homeostasis. These
effects and their respective mechanisms of
action are as follows:
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Reduction of postprandial glucagon secretion and therefore the reduction of
endogenous glucagon-stimulated hepatic glucose output.11
The mechanism by which amylin suppresses glucagon secretion has not been
directly determined; however, possibilities include a central effect, a direct
effect on the α cell, and a reduced rate of exposure to protein nutrients that
stimulate glucagon secretion because of a reduced rate of gastric emptying.
Results from preclinical studies indicate that this action is mediated
centrally.
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Regulation of gastric emptying and therefore the rate of nutrient delivery
(exogenous glucose)
to the small intestine.12 Amylin-sensitive
neurons in the area postrema, acting via a vagal pathway, are implicated in the
regulation of gastric emptying. Results also support the presence of a
regulatory feedback mechanism via glucose-sensitive amylinergic neurons present
in the area postrema whereby hypoglycemia can override the regulation of
gastric emptying by amylin.
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Reduction in food intake and therefore the reduction of exogenous glucose
entering the circulation.13 As with the
effect of amylin on gastric emptying, the effect on food intake appears
to be mediated via amylin receptors located in the area postrema. However, this
effect does not appear to involve vagal transmission. In one recent trial,
patients with type 2 diabetes who were administered pramlintide had their
nutrient intake reduced by 23% from baseline.14
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Reduction in body weight, which is at least partially due to a reduction in
food intake
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What are the effects of amylin deficiency?
Amylin deficiency has been associated with glucagon excess and relatively
accelerated gastric emptying during the postprandial period and is
characteristic of patients with type 1 diabetes
(β-cell deficiency) and patients with type 2 diabetes who have progressed to
β-cell failure. In these patients, the integrated balance between plasma
glucose inflow and outflow has been disrupted as a result of deficiencies of
insulin, amylin, and other glucoregulatory hormones.
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How can amylin concentrations be measured? Is
there an amylin assay available?
Plasma amylin concentrations may be measured by a commercially available
enzyme-linked immunosorbent assay (ELISA) monoclonal antibody-based sandwich
immunoassay kit.15 This
kit is validated for the measurement of amylin from EDTacontaining plasma
samples and has sensitivity down to 1 pmol/L and a standard range of 1 to 100
pmol/L.15
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What are the ranges for the fasting and
postprandial human plasma amylin concentrations?
In healthy humans, fasting plasma amylin concentrations are in the range of 4
to 8 pmol/L and between 15 to 25 pmol/L in the postprandial state.16
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Is there amylin resistance? Does amylin
contribute to insulin resistance?
Preclinical data from studies using fatty Zucker rats are consistent with
"amylin resistance"
in hyperamylinemic states.17
Current clinical evidence indicates that amylin does not contribute to insulin
resistance. Early in
vitro and in vivo studies in rodents indicated that amylin might oppose the
effect of insulin to promote glycogen storage18
and led to the hypothesis that amylin could be implicated in insulin resistance
in muscle. However, subsequent clinical studies indicated that the initial
preclinical observations were
not due to a direct effect of amylin to oppose insulin action in muscle but
instead due to a direct
insulin-independent activation of glycogen phosphorylase in skeletal muscle.
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How is amylin different from leptin?
Leptin, the product of the obese (ob) gene on chromosome 6,19
is a hormone primarily produced
in adipose cells.19 Amylin, the product
of a distinct gene on chromosome 12,1 is
a neuroendocrine hormone that is primarily produced in the pancreatic β cells.3,20
Leptin is not deficient in people
with diabetes,21 whereas amylin is
deficient in people with diabetes.9
Leptin regulates food intake, energy expenditure, and body weight through
binding to specific receptors in the hypothalamus.19,22
Amylin complements the effects of insulin in postprandial glucose regulation by
reducing postprandial secretion of glucagon by the α cells,11
regulating gastric emptying,12 and
reducing food intake13 and body weight.14
Amylin's effects are primarily vagally mediated through
binding to specific receptors in the brain (primarily in the area postrema,
nucleus accumbens, and dorsal raphe).10
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How is amylin different from somatostatin?
Somatostatin, a hormone primarily produced in the pancreatic δ cells, is
responsible for the inhibition of growth hormone secretion from the pituitary.23
Amylin is a neuroendocrine hormone that is produced in the pancreatic β cells.3
Somatostatin is not deficient in people with diabetes,23
whereas amylin usually becomes deficient as diabetes progresses.9
Somatostatin regulates (inhibits) growth hormone release; pancreatic secretion
of insulin, amylin, and glucagon hormones; and intestinal motility through
binding to specific receptors in the hypothalamus.23
Amylin complements the effects of insulin in postprandial glucose regulation by
reducing postprandial secretion of glucagon by the α cells,11
regulating gastric emptying,12 and
reducing food intake and body weight.13,14
Amylin's effects are primarily vagally mediated through binding to specific
receptors in the brain (primarily in the area postrema, nucleus accumbens, and
dorsal raphe).10
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Does amylin work with the enzyme system that
acarbose and miglitol inhibit?
Amylin, a neuroendocrine hormone, is not known to work with the α-glucosidase
enzyme system that acarbose and miglitol inhibit.
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Does amylin cause amyloid deposits?
It is generally thought that amylin does not cause amyloid deposits in the
pancreatic islets. The naturally occurring human amylin peptide has the
tendency to self-aggregate and form fibrils.
In early-stage type 2 diabetes (a condition of insulin and amylin
hypersecretion), amyloid deposition begins to occur in the pancreatic islets,
and researchers propose that this pathologic process may contribute to β-cell
dysfunction and destruction in type 2 diabetes.
Protein deposits in other tissues and organs are generally referred to as amyloid
deposits. In Alzheimer's plaques, a different protein is involved.
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Does amylin cause Alzheimer's disease?
Current clinical evidence indicates that amylin is unrelated to Alzheimer's
disease.
Amyloid deposits are a principal feature of Alzheimer's-disease pathology and a
major factor in the disease process.24 The
deposits are composed primarily of amyloid-β peptide amyloid deposits, a
completely different protein from amylin.24
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Where may information or training on amylin be
obtained?
An educational Web site,
www.amylin.org, has information on the amylin hormone. This site also
includes an animated video with an overview of the physiology of amylin,
slides, and further background educational materials. This Web site is
sponsored by Amylin Pharmaceuticals, Inc.
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What is pramlintide?
Pramlintide is a synthetic analogue of human amylin recently approved for
treatment of type 1 and
type 2 diabetes. Pramlintide is a 37–amino acid polypeptide, which differs in
amino acid sequence
from human amylin by replacement with proline at positions 25 (alanine), 28
(serine), and 29 (serine)5,6,11 (Pro-h-amylin).
It is the first member of a new class of therapeutic agents known as amylinomimetic
agents, or amylin receptor agonists. Pramlintide was specifically
engineered as a replacement for the naturally occurring neuroendocrine hormone
amylin.25,26 Preclinical and clinical
studies have documented various physiologic actions of pramlintide and its
clinical effect as an adjunct to insulin therapy for diabetes.10
Pramlintide improves glucose control through prevention of the postprandial
rise in plasma
glucagon27 and modulation of gastric
emptying, both of which slow the rate of glucose appearance
into the circulation.28-30
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How does pramlintide differ from amylin?
Pramlintide differs from human amylin in that 3 amino acid residues,
25Alanine, 28Serine, and
29Serine, have been replaced with
prolines. Because of this replacement, pramlintide is a stable, soluble,
nonaggregating, and nonadhesive peptide, whereas amylin is less stable in
solution
and has the propensity to aggregate and adhere to surfaces.31
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What is glucagon?
Glucagon is a peptide hormone consisting of 29 amino acids in a linear
structure. It is produced
within the body as a precursor called proglucagon in the pancreatic
α cells in the Islets of Langerhans. Following proteolytic processing
of proglucagon, glucagon, in the normal state, is secreted in response to low
concentrations of blood glucose. Conversely, in the normal state, glucagon
secretion is inhibited by high concentrations of blood glucose.
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What is the function of glucagon?
Glucagon functions to stimulate an increase in the concentration of blood
glucose. It does so by stimulating breakdown of glycogen stored in the liver to
glucose (glycogenolysis) and activating production of glucose in the liver
(hepatic gluconeogenesis). In either pathway, glucose is released
from the liver. As such, glucagon functions counter to insulin to regulate
blood glucose. Together with insulin, glucagon functions to maintain blood
glucose in a normal range in nondiabetic persons (Fig. 1).
Figure 1.
Control of blood glucose in healthy individuals
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How is glucagon affected by endogenous amylin
and by exogenous pramlintide?
Human amylin is cosecreted with insulin by pancreatic islet β cells as a
response to nutrient intake.32 Amylin
functions to regulate postprandial glucose levels by downregulating the
secretion of glucagon.32 Thus, amylin
plays a central role in glucose homeostasis (Fig. 2). This function of amylin
takes on special significance in diabetes as the secretion of both insulin and
amylin becomes deficient and glucagon secretion is inappropriately upregulated
following a meal. The cumulative effect of the ingestion of glucose and the
inappropriate upregulation of glucagon causes total blood glucose to rapidly
rise and reach a peak within approximately 120 minutes after intake. In light
of these effects, pramlintide, a soluble, nonaggregating, synthetic peptide
analogue of human amylin, was developed as an amylin replacement therapy for
control of postprandial glucose.33
Figure 2.
Possible mechanism of action of amylin in glucose homeostasis
(illustration adapted from Ludvik, et al)
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Can pramlintide suppress the inappropriate
postprandial rise in glucagon secretion?
Yes. In a study of 18 patients with type 1 diabetes, Levetan and colleagues
34 showed that the
mean area under the curve (AUC) for postprandial plasma glucagon concentration
was reduced by
87% following 4 weeks of pramlintide treatment. Similarly, the AUC for
postprandial glucose was reduced by 86%. Further, these effects were associated
with a concurrent reduction of 17% in mealtime insulin dosage requirements.
After discontinuation of pramlintide treatment, postprandial secretion of
glucagon increased and approached baseline values.
In an additional study of patients with type 1 diabetes, Fineman and coworkers35
studied 84 patients
in a 14-day parallel-group design. Patients were randomized to receive 30, 100,
or 300 mcg pramlintide or placebo 3 times daily in addition to insulin. Plasma
glucagon increased in the placebo group in response to nutrient intake but not
in any of the pramlintide-treated groups.
To assess the regulation of glucagon secretion in type 2 disease, Fineman and
coworkers36 compared postprandial
glucagon and glucose levels during 5-hour intravenous infusions of either
pramlintide or placebo in a single-blind, placebo-controlled crossover study of
24 patients with type 2 diabetes. AUCs for both postprandial plasma glucagon
and glucose were significantly reduced during pramlintide infusions compared
with placebo. These effects were equivalent in subgroup analyses of patients
taking insulin or oral sulfonylureas.
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Can long-term suppression of postprandial
glucagon secretion improve long-term
glycemic control?
Evidence indicates that suppression of postprandial glucagon may improve
glycemic control.
Ratner and associates37 studied 538
insulin-treated patients with type 2 disease over a period of
52 months. Patients were randomized to receive 30, 75, or 150 mcg pramlintide
or placebo 3 times daily at major meals. The results showed a mean reduction of
glycosylated hemoglobin (A1C) of
0.9% and 1.0% in the groups receiving 75 and 150 mcg pramlintide, respectively;
this reduction was significant compared with placebo. Because pramlintide
functions by 2 routes—reduction of gastric emptying and downregulation of
postprandial glucagon secretion—it is likely that the regulation of glucagon
had some positive effect on long-term glycemia; however, the magnitude of the
glucagon effect cannot be quantified separately from the gastric emptying
effect.
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Why is glucagon also a pharmaceutical product?
Patients with diabetes who take insulin or oral insulin secretagogues, such as
sulfonylureas, to control their blood glucose may, at times, encounter states
wherein their blood glucose levels are extremely low (severe hypoglycemia) for
any of several reasons, such as too much medication, taking medication without
eating on schedule, or exercising after taking medication. In such a state, the
patient may become unconscious and not able to swallow carbohydrates. The
amount of glucagon within the body may not be enough to stimulate the release
of enough glucose to supply the brain.38-41
For this reason, pharmaceutical companies manufacture glucagon for injection,
usually in the form of a glucagon kit.
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How is glucagon for injection used?
In severe hypoglycemic episodes, glucagon from emergency kits may be injected
intravenously, intramuscularly, or subcutaneously. Intramuscular and
subcutaneous injections are generally
performed outside the hospital setting. For intramuscular and subcutaneous
injections, glucagon reaches maximal plasma concentrations in approximately 15
and 20 minutes, respectively. Maximal glucose concentrations are attained
within 30 minutes by either injection route. (It is important to
note that the patient will likely be unconscious during a severe hypoglycemic
episode. The injection
will therefore be performed by someone other than the patient: preferably, a
family member or friend who can recognize the symptoms of hypoglycemia and
knows how to administer glucagon.) The
person performing the injection should lay the patient on his or her side in
case of vomiting, an infrequent but potential side effect of the injection.
Once the patient regains consciousness, usually within 15 minutes, glucose, in
the form of food, should be provided, and the patient's doctor should
be notified.42
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How is glucagon supplied?
Glucagon is typically supplied as a dry powder in an emergency kit. A diluent
solution is also
provided in the kit. The diluent is added to the glucagon and mixed. The
resulting mixture is then injected immediately. Any unused portion of the mixed
glucagon solution should be discarded
following resolution of the hypoglycemic episode.42
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What are the side effects of glucagon?
Adverse reactions are very rare but may include nausea, vomiting, and headache.
Some people
may have an allergic reaction to animal-derived glucagon, but allergic
reactions to glucagon produced by recombinant DNA techniques are extremely
rare. Allergic reactions typically take the form of itching or development of a
rash.42
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What happens in case of overdose with glucagon?
Overdose of glucagon is extremely rare. Because glucagon is rapidly metabolized
and excreted, treatment of an overdose may be targeted to the symptoms (nausea,
vomiting, diarrhea, and perhaps a transient increase in blood pressure).
However, a local poison-control center should be contacted immediately by
calling 1-800-222-1222. If difficulty in breathing or loss of consciousness
occurs as a result of a glucagon injection, emergency assistance should be
immediately sought.42
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What if glucagon does not resolve the
hypoglycemic episode?
If the patient does not regain consciousness, an additional injection of
glucagon may be performed,
but emergency aid should be sought because it may be necessary to administer
intravenous glucose to the patient.42 Immediate
attention may be very important, as continued severe hypoglycemia may cause
neurologic damage.
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Does amylin inhibit the secretion of glucagon in
response to hypoglycemia?
The suppressive effects of amylin on glucagon are lost in the presence of
hypoglycemia. In a glycemic clamp study, Silvestre and associates43
showed that amylin did not reduce secretion of glucagon compared with placebo
when blood glucose was reduced to 36 mg/dL (2 mmol/L).
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Is there an assay for glucagon?
Yes, a blood test can be performed.44 Plasma
concentrations of glucagon in healthy subjects are generally in the range of 20
to 100 ng/L; however, values in patients with diabetes are generally much
higher (approximately 1500 ng/L). In addition to its use in diabetes, the assay
provides diagnostic information in glucagonoma; chronic renal failure;
hyperlipoproteinemia; severe stress due to infections, trauma, burns, and
surgery; familial hyperglucagonemia; cirrhosis; and various other hepatic and
pancreatic disorders.
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