Chapter 22
The Pancreas and Diabetes Mellitus
Learning Objectives
• Describe pathogenesis and treatment of acute and
chronic pancreatitis
• Describe pathogenesis, manifestations,
complications, prognosis of cystic fibrosis
• Differentiate type 1 and type 2 diabetes mellitus
Pancreas (1 of 2)
• Two glands in one
– Digestive gland
– Endocrine gland
• Exocrine function: exocrine tissue of the
– Concerned solely with digestion
– Secretes alkaline pancreatic juice rich in digestive
enzymes into the duodenum through the
pancreatic duct to aid digestion
Duct System of pancreas.
Pancreatic Islets
• Pancreatic tissue that functions as an
endocrine gland
• Produce hormones
– Beta cells: insulin production
– Alpha cells: glucagon
– Delta cells: somatostatin
Pancreas (2 of 2)
• Endocrine function: endocrine tissue of the
• Consists of multiple small clusters of cells
scattered throughout the gland as pancreatic
islets or Islets of Langerhans
– Discharge secretions directly into the bloodstream
– Each islet is composed of different types of cells
• Alpha cells: secrete glucagon; raise blood glucose
• Beta cells: secrete insulin; lower blood glucose
• Delta cells: secrete somatostatin; inhibit secretion of
glucagon and insulin
Photomicrograph of pancreatic islet surrounded
by exocrine pancreatic tissue.
Acute Pancreatitis (1 of 3)
• Pathogenesis
– Escape of pancreatic juice from the ducts into the
pancreatic tissue
– Pancreatic digestive enzymes cause destruction
and severe hemorrhage
– Involves active secretion of pancreatic juice
despite an obstructed pancreatic duct at its
entrance into the duodenum
– Resulting build-up of pancreatic juice increases
pressure within the duct system, causing ducts to
Acute Pancreatitis (2 of 3)
• Predisposing factors
– Gallbladder disease/gallbladder stones
• Common bile duct and common pancreatic duct enter
the duodenum via the ampulla of Vater
• Impacted stone in ampulla obstructs pancreatic duct
– Excessive alcohol consumption
• Potent stimulus for pancreatic secretions
• Induces edema, spasm of pancreatic sphincter, in
ampulla of Vater
• Result in high intraductal pressure, duct necrosis, and
escape of pancreatic juice
Acute Pancreatitis (3 of 3)
• Clinical manifestations
– Severe abdominal pain
– Seriously ill
– High mortality rate
Chronic Pancreatitis
• Repeated episodes of mild inflammation of pancreas
• Each bout destroys some pancreatic tissue
• Inflammation subsides and damaged pancreatic
tissue is replaced by scar tissue, leading to
progressive destruction of pancreatic tissue
• Manifestations
– Difficulty digesting and absorbing nutrients
– Not enough surviving pancreatic tissue to produce
adequate enzymes
– Destruction of pancreatic islets may lead to diabetes
Cystic Fibrosis
• Autosomal Recessive Disorder
• Problem with the gene that codes for a protein
known as the Cystic Fibrosis Transmembrane
Conductance Regulator
• Gene Found on Chromosome 7 at the p31.2
• Gene is 230,00 base pairs creating a protein
1,480 AA long
• Most common problem is a deletion of three
nucleotides – thus causing phenylalanine to not
be placed at the 508th position
• The protein created by this gene is anchored to
the outer membrane of cells in the sweat
glands, lungs, pancreas, and other affected
organs. The protein spans this membrane and
acts as a channel connecting the inner part of
the cell (cytoplasm) to the surrounding fluid.
• This channel is primarily responsible for
controlling the movement of halogens from
inside to outside of the cell; however, in the
sweat ducts it facilitates the movement of
chloride from the sweat into the cytoplasm.
• When the CFTR protein does not work,
chloride and thiocyanate ([SCN]−). are
trapped inside the cells in the airway and
outside in the skin. Then hypothiocyanite,
OSCN, cannot be produced by immune
defense system.
• Normally, as primary sweat moves along the
duct most of the NaCl is
reabsorbed. Reabsorption is driven by a large
inward gradient for Na+, which flows into the
cell through epithelial Na+ channels (ENaC) in
the apical membrane. The basolateral sodium
pump then transports Na+ out of the cell and
into the blood. Cl- is electrically attracted to
Na+ and follows it by flowing through CFTR
Cl- channels in the apical membranes of the
duct cells; the exit pathway may also be via
• The duct epithelium has an unusually high
conductance for ions and is thought to have a
low permeability to water, allowing
reabsorption of salt in excess of water. This
results in the production of dilute sweat, so
that we can be cooled by evaporation without
losing an undue amount of salt.
• In CF sweat ducts, the Cl- conductance is
virtually abolished because CFTR is the only
apical pathway for chloride: no other anion
channels appear to be in the duct. The
sodium conductance also seems to be low,
leading to the hypothesis that CFTR activates
ENaC in the sweat duct. When Na+
attempts to flow out of a CF duct through
remaining sodium-selective pathways, it is
unaccompanied by Cl- and so it creates an
excess of negative charge in the duct that
attracts Na+ and prevents its further
• The net result is that very little NaCl is
reabsorbed, resulting in a high salt content in
CF sweat. The salt is so high (>100 mM vs.
typical values of 20 or 30 mM in healthy
individuals, that the sweat chloride
concentration is the most reliable single
physiological marker of CF.
Sweat pore
Dermal connective
Secretory cells
(b) Photomicrograph of a
sectioned eccrine gland (220x)
Figure 5.5b
Cystic Fibrosis (1 of 3)
• Serious hereditary disease, autosomal recessive
• Mutation of a normal gene, CF gene, on long arm
of chromosome 7
• Manifests in infancy and childhood
• Incidence in whites: 1 in 3,000
• Incidence in blacks and other races: rare
• Mortality, more than 50% die before age 32
• Pathogenesis
– Defective transport of chloride, sodium, and H2O across
cell membrane
– Deficient electrolyte and H2O in the mucus secreted by
the pancreas, bile ducts, respiratory tract, and other
secretory cells
Cystic Fibrosis (2 of 3)
• Pathogenesis
– Mucus becomes abnormally thick, precipitates,
and forms dense plugs that obstruct the
pancreatic ducts, bronchi, bronchioles, and bile
– Obstruction of pancreatic ducts: causes atrophy
and fibrosis
– Obstruction of bronchi: causes lung injury
– Obstruction of biliary ducts: causes liver scarring
– Abnormal function of sweat glands: unable to
conserve sodium and chloride with excessively
high salt concentration in sweat; basis of
diagnostic test
Cystic Fibrosis (3 of 3)
• Treatment
– Oral capsules containing pancreatic enzymes to
compensate for lack of pancreatic digestive
– Various treatments to preserve as much
pulmonary function as possible
– Vigorous treatment of pulmonary bacterial
– Lung transplant may eventually be required if
lungs are severely damaged
Low magnification photomicrograph with pancreas
of patient with cystic fibrosis.
Inability to regulate blood glucose levels
Type 1 diabetes
Type 2 diabetes
Gestational diabetes
Uncontrolled diabetes can cause nerve
damage, kidney damage, blindness,
and can be fatal
Diabetes Mellitus
• Very common and important metabolic disease
• Two major groups depending on cause
– Type 1 diabetes
• Insulin deficiency
• Occurs primarily in children and young adults
– Type 2 diabetes
Inadequate response to insulin
Typically an adult-onset diabetes
More common than Type 1
Becoming more common in children
• Manifestation: Increased glucose levels in blood or
Some Skin Problems Linked to Diabetes
• Scleroderma diabeticorum: While rare,
this skin problem affects people with type 2
diabetes, causing a thickening of the skin
on the back of the neck and upper back.
The treatment is to bring your blood sugar
level under control. Lotions and
moisturizers may help soften skin.
• Vitiligo: Vitiligo, a skin problem more
commonly associated with type 1
diabetes than type 2 diabetes, affects
skin coloration. With vitiligo, the special
cells that make pigment (the substance
that controls skin color) are destroyed,
resulting in patches of discolored skin.
Vitiligo often affects the chest and
abdomen, but may be found on the face
around the mouth, nostrils, and eyes.
• Acanthosis nigricans. This is a skin problem that
results in the darkening and thickening of certain
areas of the skin especially in the skin folds. The
skin becomes tan or brown and is sometimes
slightly raised and described as velvety. Most often
the condition, which typically looks like a small
wart, appears on the sides or back of the neck, the
armpits, under the breast, and groin. Occasionally
the top of the knuckles will have a particularly
unusual appearance. Acanthosis nigricans usually
strikes people who are very overweight. While
there is no cure for acanthosis nigricans, losing
weight may improve the skin condition. Acanthosis
nigricans usually precedes diabetes and is
considered to be a marker for the disease.
• Diabetic neuropathies are neuropathic
disorders that are associated with diabetes
mellitus. These conditions are thought to
result from diabetic microvascular injury
involving small blood vessels that supply
nerves (vasa nervorum) in addition to
macrovascular conditions that can culminate
in diabetic neuropathy. Relatively common
conditions which may be associated with
diabetic neuropathy include third nerve palsy;
mononeuropathy; mononeuropathy multiplex;
diabetic amyotrophy; a painful
polyneuropathy; autonomic neuropathy; and
thoracoabdominal neuropathy.
• Influences carbohydrate, protein, and fat
metabolism on liver cells, muscle, and adipose
• Main stimulus for release: high glucose in blood
• Promotes
Entry of glucose into cells
Utilization of glucose as source of energy
Storage of glucose as glycogen
Conversion of glucose into triglycerides
Storage of newly formed triglyceride in fat cells
Entry of amino acids into cells and stimulates protein
Insulin Actions
• Increased glycogen synthesis – insulin
forces storage of glucose in liver (and
muscle) cells in the form of glycogen;
lowered levels of insulin cause liver cells to
convert glycogen to glucose and excrete it
into the blood. This is the clinical action of
insulin, which is directly useful in reducing
high blood glucose levels as in diabetes.
• Increased fatty acid synthesis – insulin
forces fat cells to take in blood lipids, which
are converted to triglycerides; lack of insulin
causes the reverse.
• Increased esterification of fatty acids –
forces adipose tissue to make fats (i.e.,
triglycerides) from fatty acid esters; lack of
insulin causes the reverse.
• Decreased proteolysis – decreasing the
breakdown of protein
• Decreased lipolysis – forces reduction in
conversion of fat cell lipid stores into blood
fatty acids; lack of insulin causes the
• Decreased gluconeogenesis – decreases
production of glucose from nonsugar
substrates, primarily in the liver (the vast
majority of endogenous insulin arriving at
the liver never leaves the liver); lack of
insulin causes glucose production from
assorted substrates in the liver and
• Increased amino acid uptake – forces
cells to absorb circulating amino acids; lack
of insulin inhibits absorption.
• Increased potassium uptake – forces
cells to absorb serum potassium; lack of
insulin inhibits absorption. Insulin's
increase in cellular potassium uptake
lowers potassium levels in blood.
• GLUT1 Is widely distributed in fetal tissues. In
the adult, it is expressed at highest levels in
erythrocytes and also in the endothelial cells
of barrier tissues such as the blood-brain
• GLUT2 Is expressed by renal tubular cells
and small intestinal epithelial cells that
transport glucose, liver cells and pancreatic
β cells. All three monosaccharides are
transported from the intestinal mucosal cell
into the portal circulation by GLUT2 Is a highcapacity and low-affinity isoform
• GLUT3 Expressed mostly in neurons
(where it is believed to be the main glucose
transporter isoform), and in the placenta. Is
a high-affinity isoform
• GLUT4 Found in adipose tissues and
striated muscle (skeletal muscle and
cardiac muscle).
Diabetes—Type 1
Accounts for 10% of all cases
Body does not produce enough insulin
Causes hyperglycemia (high blood glucose)
Requires insulin injections
May be an autoimmune disease
Type 1 Diabetes Mellitus
• Results from damage to pancreatic islets
leading to reduction or absence of insulin
• Often follows a viral infection that destroys the
pancreatic islets
• Abnormal immune response may play part:
production of autoantibodies directed against
islet cells
• With a hereditary predisposition
• Complication
– Diabetic ketosis
• Maturity onset diabetes of the young
(MODY) refers to any of several hereditary
forms of diabetes caused by mutations in an
autosomal dominant gene (sex independent,
i.e. inherited from any of the parents)
disrupting insulin production. MODY is often
referred to as "monogenic diabetes" to
distinguish it from the more common types of
diabetes (especially type 1 and type 2), which
involve more complex combinations of
causes involving multiple genes (i.e.,
"polygenic") and environmental factors.
Diabetes—Type 2
• Insulin insensitivity (insulin resistance):
cells become less responsive to insulin
• Metabolic syndrome: a cluster of risk
factors that increase the risk for type 2
• Once known as adult-onset diabetes
• Increasing in children and adolescents
Metabolic Syndrome
International Diabetes Federation
• Central obesity (defined as waist circumference# with
ethnicity specific values)
• AND any two of the following:
• Raised triglycerides: > 150 mg/dL (1.7 mmol/L), or
specific treatment for this lipid abnormality.
• Reduced HDL cholesterol: < 40 mg/dL
• Raised blood pressure: systolic BP > 130 or diastolic
BP >85 mm Hg, or treatment of previously diagnosed
• Raised fasting plasma glucose :(FPG)>100 mg/dL
Type 2 Diabetes Mellitus (1 of 2)
• Complex metabolic disease
• Occurs in older, overweight, or obese adults
• Increasingly seen among younger people who
are overweight or obese
• Insulin secretion is normal or increased
• Reduced response of tissues to insulin
• Cause is not completely understood but weight
reduction restores insulin responsiveness
• Islet function is not completely normal as
pancreas is not able to increase insulin output
to compensate for the insulin resistance
Type 2 Diabetes Mellitus (2 of 2)
• Hereditary disease
• Children of parents with diabetes are at a
significant risk
• Incidence in some populations as high as 40%
(Pima Indians of Arizona)
• Complication
• Hyperosmolar nonketotic coma due to marked
Insulin Resistance and
Type 2 Diabetes
• 40% of older people are insulin resistant
mostly secondary to obesity and
inactivity (important in prevention and
• 20% of the elderly have type 2 diabetes
• 8.5% of all adults have type 2 diabetes
• 90% of diabetics are managed in
primary care
Major metabolic derangements in type 1 diabetes mellitus.
Complications of Diabetes
Increased susceptibility to infection
Diabetic coma
Hyperosmolar coma
Renal failure
Peripheral neuritis
• Diabetic nephropathy (nephropatia
diabetica), also known as KimmelstielWilson syndrome, or nodular diabetic
glomerulosclerosis and intercapillary
glomerulonephritis, is a progressive
kidney disease caused by angiopathy of
capillaries in the kidney glomeruli. It is
characterized by nephrotic syndrome and
diffuse glomerulosclerosis. It is due to
longstanding diabetes mellitus, and is a
prime indication for dialysis in many
Western countries.
Diabetic Nephropathy
• Diabetic retinopathy is caused by damage to
blood vessels of the retina.
• There are two types, or stages of
retinopathy: Nonproliferative or proliferative
• Nonproliferative diabetic retinopathy
develops first. Blood vessels in the eye
become larger in certain spots (called
microaneurysms). Blood vessels may also
become blocked. There may be small
amounts of bleeding (retinal hemorrhages),
and fluid may leak into the retina. This can
lead to noticeable problems with your
• Proliferative retinopathy is the more
advanced and severe form of the
disease. New blood vessels start to
grow in the eye. These new vessels are
fragile and can bleed (hemorrhage).
Small scars develop, both on the retina
and in other parts of the eye (the
vitreous). The end result is vision loss,
as well as other problems.
Ketone Bodies (1 of 2)
• Glucose is absorbed normally but is not used properly
for energy due to insulin deficiency or insensitivity
• Body turns to fat as a source of energy
• Fat is broken down into a fatty acid and glycerol
• Fatty acid broken down further into 2 carbon
fragments combined with carrier molecule, acetyl
coenzyme A
• Some acetyl-CoA are converted by the liver into
ketone bodies
• More acetyl-CoA molecules are produced than can be
oxidized as a source of energy
• Ketosis: accumulation of ketone bodies in blood and
excreted in the urine together with H2O and
Ketone Bodies (2 of 2)
• Acetoacetic acid: from condensation of 2
acteyl-CoA molecules
• Beta-hydroxybutyric acid: from addition of a
hydrogen atom to an oxygen atom and
converted into a –OH group
• Acetone: from removal of a carboxyl group of
• Type 1 diabetes complication
• Ketoacidosis: overproduction of ketone bodies
– Buffer systems cannot maintain normal pH
– May lead to coma
Structure of ketone bodies.
Hyperosmolar Hyperglycemic
Nonketotic Coma
• Type 2 diabetes complication
• Severe hyperglycemia
– Blood glucose increases 10 to 20 x normal value
• Absence of ketosis
– Less insulin is required to inhibit fat mobilization than is
needed to promote entry of glucose into cells
– Patients have enough insulin to prevent ketosis, not
enough to prevent hyperglycemia
• Results in coma due to extreme hyperosmolarity of
– H2O moves out of the cells into the extracellular fluid
– Cells become dehydrated disturbing functions of neurons
leading to coma
• Elevated blood glucose levels
• Also from other conditions that impair glucose
utilization but are less common than diabetes
– Chronic pancreatic disease: damage or
destruction of pancreatic islets
– Endocrine diseases: overproduction of pituitary or
adrenal hormones that raise blood glucose
– Drugs that impair glucose utilization as a side
– Hereditary diseases characterized by disturbed
carbohydrate metabolism
Hypoglycemia in Diabetes (1 of 2)
• Pancreas regulates the glucose in blood by
adjusting its output of insulin
– Hypoglycemia: low blood sugar
– Adrenal medulla: responds by discharging
epinephrine that raises blood glucose
• Neurologic manifestations appear if blood
glucose continues to fall
• Other causes of hypoglycemia
– Oral hypoglycemic drugs in type 2 diabetics
– Self-administration of oral hypoglycemic drugs
or insulin by emotionally disturbed person
– Islet cell tumor
Hypoglycemia in Diabetes (2 of 2)
• Must adjust dose of insulin to match the amount of
ingested carbohydrate
– Insufficient insulin, glucose levels increase
– Too much insulin, glucose levels decrease
• Conditions predisposing to hypoglycemia in a
diabetic patient taking insulin
– Skipping a meal: carbohydrate intake is insufficient in
relation to amount insulin and blood glucose falls
– Vigorous exercise: with high physical activity there is high
glucose utilization; excess insulin
• Too much insulin causes a precipitous drop in
glucose leading to insulin reaction or insulin shock
• A fasting plasma glucose (FPG) test
measures blood glucose in a person who
has not eaten anything for at least 8 hours.
This test is used to detect diabetes and prediabetes.
• An oral glucose tolerance test (OGTT)
measures blood glucose after a person fasts
at least 8 hours and 2 hours after the person
drinks a glucose-containing beverage. This
test can be used to diagnose diabetes and
• The FPG test is the preferred test for diagnosing
diabetes because of its convenience and low cost.
However, it will miss some diabetes or prediabetes that can be found with the OGTT. The
FPG test is most reliable when done in the
morning. Results and their meaning are shown in
Table 1. People with a fasting glucose level of 100
to 125 milligrams per deciliter (mg/dL) have a form
of pre-diabetes called impaired fasting glucose
(IFG). Having IFG means a person has an
increased risk of developing type 2 diabetes but
does not have it yet. A level of 126 mg/dL or
above, confirmed by repeating the test on another
day, means a person has diabetes.
• Research has shown that the OGTT is more
sensitive than the FPG test for diagnosing prediabetes, but it is less convenient to administer. The
OGTT requires fasting for at least 8 hours before the
test. The plasma glucose level is measured
immediately before and 2 hours after a person
drinks a liquid containing 75 grams of glucose
dissolved in water. If the blood glucose level is
between 140 and 199 mg/dL 2 hours after drinking
the liquid, the person has a form of pre-diabetes
called impaired glucose tolerance (IGT). Having
IGT, like having IFG, means a person has an
increased risk of developing type 2 diabetes but
does not have it yet. A 2-hour glucose level of 200
mg/dL or above, confirmed by repeating the test on
another day, means a person has diabetes.
• Gestational diabetes is also diagnosed based
on plasma glucose values measured during
the OGTT, preferably by using 100 grams of
glucose in liquid for the test. Blood glucose
levels are checked four times during the test.
If blood glucose levels are above normal at
least twice during the test, the woman has
gestational diabetes.
• . Gestational diabetes: Above-normal
results for the OGTT* When Plasma Glucose
Result (mg/dL) Fasting 95 or higher At 1 hour
180 or higher At 2 hours 155 or higher At 3
hours 140 or higher
Treatment of Diabetes
• Diet
• Type 1 diabetes: requires insulin; dosage
adjusted to control level of blood glucose
• Type 2 diabetes
– Management: weight reduction and diet
– Oral hypoglycemic drugs if patient does not
respond adequately to diet and exercise
Types of Insulin
• There are four basis types of insulin based
primarily on the time of onset of action and the
duration of action
• Rapid Acting – onset generally in 10 – 30
minutes – duration 30 – 90 minutes
• Short Acting - onset generally in 30 minutes
to 1 hour – duration 2 – 5 hours
• Intermediate Acting - onset generally in 1 – 2
½ hours – duration 3 – 12 hours
• Long Acting - onset generally in 1 – 3 hours
– duration 6 – 20 hours
Types of Oral Hypoglycemics (1)
• Oral hypoglycemic drugs are used only in
the treatment of type 2 diabetes which is a
disorder involving resistance to secreted
• There are now four classes of hypoglycemic
• Sulfonylureas
• Metformin
• Thiazolidinediones
• Alpha-glucosidase inhibitors.
Classes of Oral Medications
for Type 2 Diabetes
• Drugs that help the body use
insulin (sensitizers)
• Drugs that stimulate the
pancreas to release more insulin
• Drugs that block the breakdown
of starches and sugars
(a-glucosidase inhibitors)
Types of Oral Hypoglycemics (2)
• SULFONYLUREAS – Sulfonylureas are the most
widely used drugs for the treatment of type 2
diabetes and appear to function by stimulating
insulin secretion.
• METFORMIN –It is effective only in the presence of
insulin but, in contrast to sulfonylureas, it does not
directly stimulate insulin secretion. Its major effect
is to increase insulin action. How metformin
increases insulin action is not known but it is known
to affect many tissues. One important effect
appears to be suppression of glucose output from
the liver.
Metformin (Glucophage and Glucophage XR)
• Decreases hepatic glucose output
• Increases insulin sensitivity
• Decreases LDL and triglycerides
• Decreases C-reactive protein
• Causes weight loss or stabilization
• No risk of hypoglycemia
• Causes nausea, cramps and diarrhea
• Lactic acidosis rare (contraindications –
CHF, renal impairment, age greater than 80)
Types of Oral Hypoglycemics (3)
• THIAZOLIDINEDIONES – The thiazolidinediones
such as Avandia (Rosiglitazone) reverse insulin
resistance by acting on muscle, fat and to a lesser
extent liver to increase glucose utilization and
diminish glucose production. The mechanism by
which the thiazolidinediones increase insulin action
is not well understood but they may be acting by
redistributing fat from the visceral compartment to
the subcutaneous compartment. We know that
visceral fat is associated with insulin resistance.
Types of Oral Hypoglycemics (4)
They inhibit the upper gastrointestinal
enzymes that converts dietary starch and
other complex carbohydrates into simple
sugars which can be absorbed. The result
is to slow the absorption of glucose after
Monitoring Control of Diabetes
• Goal: achieve control of blood glucose as
close as possible to normal
– 1. Frequent periodic measurements of blood
– 2. Urine test: detects glucose spilling into the
urine when blood glucose is too high
– 3. Measurement of glycosylated hemoglobin:
serves as an index of long-term control of
Glycosylated Hemoglobin, HgA1c
• Glycosylated hemoglobin monitors how well blood
glucose is being controlled by treatment
– Excess glucose molecules attach permanently to red
blood cells that circulate in body for about 3 months
before they die
– Concentration of glycosylated hemoglobin is directly
proportional to average blood glucose for the preceding
6-12 weeks
• Normal persons: 6% of hemoglobin is glycosylated
• Well-controlled diabetes: 7% or less
• Poorly controlled diabetes: 8% and above
Tumors of the Pancreas
• Carcinoma of the pancreas
– Usually develops in the head of the pancreas
• Blocks common bile duct
• Causes obstructive jaundice
– Tumors elsewhere in pancreas: no specific
symptoms, usually far advanced when first
• Islet cell tumors
– Benign
– Beta cell tumors produce hyperinsulinism and
• Insulin performs all of the following functions
– A. It promotes entry of amino acids into the cells
– B. It promotes storage of glucose in muscle and
liver cells
– C. It promotes entry and absorption of glucose
into cells for use as energy
– D. It promotes the breakdown of fat
– E. It lowers blood glucose
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