Hyperglucagonemia is excess of glucagon in the blood.

It is a common occurrence in
diabetics. However, various tumors especially of the pancreas may also increase
glucagon concentration in the blood. Glucagon raises the blood glucose levels, therefore
an excess of this hormone can cause very high blood glucose levels if it is not
counteracted by insulin. Overall this is a rare condition and more frequently seen in the
chronic stage as a result of pancreatic tumor (glucagonoma). It tens to affect older people
over the age of 55 years of age. Hyperglucagonemia can be life threatening due to it
effects on blood clotting or the spread of malignant tumors of the glucagon-producing
cells of the pancreas (glucagonoma).

Hyperglucagonemia Pathophysiology
Glucose breakdown provides the major source of energy for cells. The blood glucose
level is regulated by the relative activities of insulin and glucagon. Insulin helps in
utilization of glucose and removes it from blood. On the contrary, glucagon breaks down
stored proteins into glucose and increases its level in blood (gluconeogenesis). In a way
insulin and glucagon function with a mutual feedback. Various factors lead to increased
glucagon secretion. A reduced glucose concentration in blood serves as the most
important trigger for glucagon secretion.

Glucagon in diabetes
Blood glucose concentration may be affected by hormones but it is regulated by specific
areas in the brain. This entire system is jointly referred as neuroendocrine system. Upon
sensing reduced glucose level (hypoglycemia), the feeding center in the hypothalamus of
the brain of the brain evokes a hunger response to induce food intake. Reduced glucose
amounts depress activation of brain satiety center. Unopposed functioning of appetite
area of the brain leads to overeating (hyperphagia) and thereby increases blood glucose
level.

In diabetic conditions, energy requirements are met by utilizing protein and fat reserves.
Glucagon increases breakdown of proteins and fats (lipolysis). Increased mobilization of
stored proteins and fats causes significant loss of body weight, a common sign of
diabetes mellitus. Accelerated protein breakdown and reduced synthesis, causes protein
depletion. Depletion of proteins is often associated with impaired functioning (wasting) of
any organ and poor resistance to infections.

The manifestations of disordered fat metabolism are so prominent that diabetes appears
more of a lipid disease than of carbohydrate metabolism. Fat metabolism causes
formation of ketone bodies. During fasting, ketone bodies are used as energy source.
However, the presence of abundant ketone bodies causes extensive loss of electrolytes
(salts) and water from the body. The resulting dehydration could lead to unconsciousness
or coma, referred to as diabetic ketoacidotic coma.

Glucagon from pancreatic tumors

In cases of a pancreatic tumor that affects the glucagon-secreting cells (glucagonoma)
the excessively secreted glucagon becomes free from the feedback mechanism of
insulin. However, it does not amount to an increase in blood glucose level unless glucose
metabolism by liver is impaired. Under normal conditions, glucagon is degraded in the
liver. Glucagon is released first in the portal veins and carried to liver, before being
released in peripheral circulation. It explains the spread of the pancreatic tumor towards
liver. Disruption of liver functioning also increases peripheral glucagon levels (glucose
intolerance), owing to its reduced degradation.

Hyperglucagonemia Causes
 Tumors associated with glucagonoma are usually malignant and can spread all over the
body. Excessive secretion from these tumorous pancreatic alpha cells could cause
hyperglaucogonemia.
 Genetic pre-disposition for tumors of endocrine glands (multiple endocrine neoplasia –
MEN) have an increased risk of presenting glucagonoma.
 Diabetes mellitus and more frequently as a complication of acute diabetic emergencies.
 Diseases of the pancreas like pancreatitis.
 Sudden or severe stress to the body as is seen with trauma, burns, septicemia (“blood
poisoning”) and a myocardial infarction (heart attack).
 Raised cortisol in conditions like Cushing syndrome.
 Kidney failure.
 Liver cirrhosis.

Hyperglucagonemia Symptoms
Hyperglucagonemia show four prominent symptoms, known as the 4 D’s – dermatosis,
diabetes, deep vein thromboisis (DVT) and depression.

Dermatosis
Characterstic rashes appear around oral and genital areas and may spread across
fingers and legs. It is known as necrolytic migratory erythrema (NME). The skin lesions
often present as dark pigmented, fragile blisters or skin crusting.

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High glucagon levels alone could not increase glucose concentration in blood. Spread of
pancreatic tumor to liver, impairs glucagon degradation. Reduced glucose utilization
signals appetite center of the brain causing overeating (hyperphagia). Collectively, the
raised glucose levels and overeating increases the blood glucose level.

Deep vein thrombosis (DVT)

Blood clots form in a deep veins of the leg and usually manifests as swelling with pain. It
often resolves spontaneously but sometime the clot travels to other body parts
(embolism) along the venous flow. The presence of such clots in the lungs interferes with
the normal breathing process and usually proves fatal (pulmonary embolism).

Depression
Large amounts of water and electrolytes escape from the body, owing to abnormally high
levels of glucagon. Severe forms of dehydration affects normal brain functioning.
Depression and irritability are among the most common indicators of deranged mental
status in a patients with hyperglucagonemia.
Other signs and symptoms
 Excessive thirst
 Frequent urination
 Increased appetite
 Inflamed mouth and tongue
 Significant weight loss

Hyperglucagonemia Diagnosis
Common signs such as the typical skin lesions described above along with high blood
glucose levels or impaired glucose tolerance may raise the suspicion of
hyperglucagonemia. This may warrant further testing.

Diagnostic tests include:

 Blood glucagon level over 1000 pg/ml (normal range is 50-200 pg/ml) positively suggests
glucagonoma.
 Fasting blood glucose level and glucose tolerance test to establish diabetes mellitus.
 Studying cells (biopsy) of skin lesions (NME lesions) to differentiate it from normal skin
lesions arising from nutritional deficiencies.
 CT scan of the abdomen to detect blood clots.

Hyperglucagonemia Complications
Usually the malignant pancreatic tumors spread to liver and disrupt its functions. Once
glucose metabolism is affected, it leads to an increase in blood glucose concentration
and its associated symptoms. At the time of diagnosis, almost 60% of these tumors retain
the property to spread (metastasis) to other body parts. Once spread to other organs,
both successful removal of the tumor and its treatment becomes complicated. Due to the
likelihood of blood clot formation, there is the risk of pulmonary embolism which can be
fatal.

Hyperglucagonemia Treatment
 Glucagon release is inhibited by somatostatin, a pancreatic hormone having
complementary functions. Biopsy reports of the pancreatic tumors show presence of
somatostatin receptors on the cell surface. Presently, octreotide, an analogue of
somatostatin is being used for hyperglucagonemia.
 Malignant pancreatic tumors are slow growing and do not respond to chemotherapy.
Therefore, surgical removal of the pancreas is warranted. In cases of pancreatic tumors
metastasized to liver, surgical intervention does not help. Chemotherapy may therefore be
necessary.
 Severe skin rashes may be treated with antibiotics, steroids and aminoacid and zinc
supplementation.
 Low doses of the anticoagulant heparin may be administered as a prophylactic measure to
prevent venous blood clotting and other related fatal effects.