OVERVIEW
This disease is an inappropriate increase in insulin levels due to various reasons.
Usually there are no obvious symptoms, but when accompanied by a hypoglycemic reaction, it may be characterized by panic, sweating, and easy hunger.
This disease is related to genetic factors, insulinoma, and insulin resistance.
Depending on the disease, different treatments are available, including general treatment, medication, and surgery.
Definition
Hyperinsulinemia mainly refers to the excessive elevation of insulin levels that are not compatible with blood glucose levels due to various reasons.
Classification
Classification is based on the cause of the disease and can be divided into the following conditions.
Congenital hyperinsulinemia
It is seen in congenital hyperinsulinemic hypoglycemia (CHI), an autosomal dominant or recessive disorder [1].
CHI is a common cause of hypoglycemia in the neonatal period and early infancy and is characterized by insulin overproduction and recurrent episodes of severe hypoglycemia.
Acquired hyperinsulinemia.
Excessive insulin secretion due to insulin resistance due to obesity and type 2 diabetes mellitus, insulinoma, etc.
Pathogenesis
There is no clear information on the incidence of hyperinsulinemia in China.
The incidence of congenital hyperinsulinemic hypoglycemia (CHI) is l/50,000 to 1/30,000. the incidence is as high as 1/2500 in consanguineous marriages [1-2].
Etiology
Causes of the disease
Congenital hyperinsulinemia is mainly due to genetic factors and acquired hyperinsulinemia is mostly associated with islet pathology and insulin resistance.
Genetic factors
The onset of CHI is closely related to heredity, and it is an autosomal dominant or recessive hereditary disease, mostly starting in the neonatal period.
Pancreatic islet lesions
Insulinoma can lead to dysregulation of the physiological feedback mechanism of insulin secretion, causing tumor cells to continuously secrete insulin, resulting in the occurrence of hyperinsulinemia.
Islet cell hyperplasia, which can lead to increased insulin secretion, is non-insulinoma pancreatic hyperinsulinemia.
Insulin resistance
Obesity, type 2 diabetes mellitus, metabolic syndrome and other patients, most of the existence of insulin resistance, at this time the need to secrete more insulin to meet the needs of the body, resulting in hyperinsulinemia.
Others
Inappropriate use of sulfonylureas, such as glimepiride and glibenclamide, or exogenous insulin can also cause hyperinsulinemia.
Symptoms
Main Symptoms
Patients usually have no obvious symptoms of hyperinsulinemia, except when hypoglycemia occurs, when hypoglycemia-related symptoms are manifested; in the presence of insulin resistance, manifestations such as acanthosis nigricans may also be manifested [3-9].
Hypoglycemia.
In children with hypoglycemia due to CHI, it may manifest as lethargy, hypotonia (flaccidity of muscles due to loss of normal toughness), and even apnea, seizures, and coma.
In hypoglycemia due to other causes, it may be manifested as panic, sweating, weakness, hunger, transient blackouts, pallor, cold clammy skin, nausea, vomiting, etc., and in severe cases, agitation and coma may occur.
Acanthosis nigricans
Usually associated with insulin resistance, acanthosis nigricans and dyskeratosis are skin lesions characterized by brown, velvety, hyperkeratotic plaques.
The lesions usually appear on the back of the neck, armpits, groin, and elbows.
Other
In combination with type 2 diabetes mellitus, there may be typical symptoms of diabetes mellitus such as dry mouth, excessive drinking, polyphagia, and polyuria.
In combination with hyperlipidemia, there may be physical examination findings of elevated free fatty acid levels, elevated triglyceride levels, elevated low-density lipoprotein levels, and decreased high-density lipoprotein levels.
In combination with hypertension, there may be headache and dizziness.
Consultation
Department of Medicine
Endocrinology
If you experience symptoms such as overeating, rapid hunger, palpitations, excessive sweating, dizziness, weakness and drowsiness, you should consult the Department of Endocrinology.
Pediatrics
Pediatricians should consult the Department of Pediatrics for symptoms such as oversized head, pallor, sweating, drowsiness and hypotonia.
Emergency Department
If there is apnea, irritability, drowsiness or even coma, etc., you should go to the Emergency Department immediately.
Preparation
Preparing for a visit: registration, preparation of documents, common problems
Tips
Bring some sugar cubes or food with high sugar content in case of sudden hypoglycemia.
Preparation Checklist
Symptom list
Pay particular attention to the time of onset of symptoms and special signs and symptoms.
Is there pallor, sweating, panic, weakness, hunger?
Is there darkening of the back of the neck, armpits, groin and elbows?
Is there restlessness, coma?
Is there excessive drinking, eating, urinating, weight loss?
Is there dizziness, headache?
Medical History Checklist
Is there a family history of congenital hyperinsulinemia?
Is the mother of the newborn diabetic?
Is there any application of insulin, sulfonylureas?
Is there a history of type 2 diabetes, hypertension, metabolic syndrome, obesity?
Is there any insulinoma?
Checklist
Test results in the last six months, which can be brought to the doctor’s office
Laboratory tests: fasting blood glucose, plasma insulin level, C-peptide measurement, etc.
Imaging tests: pancreatic ultrasound, pancreatic CT, etc.
Medication list
Medication used in the last 3 months, if available in boxes or packages, bring them to the doctor’s office
Insulin, glibenclamide, glimepiride, etc.
Diagnosis
Diagnosis based on
medical history
Patients with this disease may have a history of the following
A family history of congenital hyperinsulinemia.
History of insulinoma.
History of inappropriate use of insulin, pro-insulinotropic drugs.
History of type 2 diabetes, hypertension, metabolic syndrome, and obesity.
Clinical manifestations
Symptoms
Patients usually have no obvious symptoms of hyperinsulinemia, except when hypoglycemia occurs, when hypoglycemia-related symptoms such as panic, sweating, weakness, hunger, and pallor are manifested.
In the presence of insulin resistance, darkening of the skin at the back of the neck, armpits, groin and elbows may also be present.
Laboratory Tests
Blood glucose test
Hyperinsulinemia often causes hypoglycemia, and a blood draw to test blood glucose concentration can assist in the diagnosis.
Hypoglycemia can be considered in non-diabetic adults with blood glucose ≤ 2.8 mmol/L and in diabetic patients ≤ 3.9 mmol/L.
Insulin
Patients with hyperinsulinemia may have elevated blood insulin concentration, and it should be noted that insulin and blood glucose should be tested simultaneously.
Measurement of serum C-peptide concentration
If the C-peptide concentration exceeds the normal range, it can be regarded as excessive insulin secretion, which also needs to be tested simultaneously with blood glucose.
C-peptide and insulin release test
C-peptide and insulin release test helps to understand the function of pancreatic β-cells.
After taking 75g of glucose orally, the insulin and C-peptide secretion is detected at 30 minutes, 1 hour, 2 hours and 3 hours, starting from the first sip.
72-hour fasting test
Measure plasma glucose, serum insulin, and C-peptide after 72 hours of fasting.
Can be used to determine the presence of insulinoma.
Imaging
Transabdominal ultrasound, abdominal CT, abdominal magnetic resonance imaging (MRI)
Abdominal ultrasound is required if the presence of hyperinsulinemia caused by pancreatic pathology such as insulinoma is suspected,
Abdominal CT and Magnetic Resonance Imaging (MRI) are required for further diagnosis, and the following precautions should be taken during the examination.
When undergoing abdominal ultrasound, the skin of the abdomen should be exposed according to the doctor’s requirements and remain relaxed; a gel will be applied during the examination, which is harmless to the body; the gel can be wiped off with paper towels after the examination.
Abdominal MRI should remove items containing metal, as well as electronic products, magnetic cards, etc.; if the body is equipped with steel plates, implantable pacemakers, etc., the doctor should be informed in advance.
Genetic testing
Whole exon testing, through Panel testing (a gene sequencing method) of known causative genes, can clarify the type of mutation in CHI and help in diagnosis.
Differential Diagnosis
There are many causes of hyperinsulinemia, so the main differential point of the disease is to identify the various causes of the disease, such as identifying whether the disease is caused by diabetes, obesity, or CHI, under the guidance of the doctor to clarify the cause of the diagnosis.
Treatment
Aim of treatment: Improve insulin sensitivity, reduce insulin level and decrease the occurrence of hypoglycemia through treatment.
Treatment principle: increase physical exercise and maintain a good lifestyle to increase tissue sensitivity to insulin, and if necessary, medication or surgery.
General treatment
Strengthen physical exercise, physical activity can increase tissue sensitivity to insulin, reduce body weight, improve metabolism and reduce insulin resistance.
Improve dietary structure, excessive calorie intake over consumption, then cause body fat storage triggers obesity, in the diet should be diversified, maintain nutritional balance, avoid overnutrition.
If the mutation of glutamate dehydrogenase causes CHI, patients need to limit the intake of food protein (especially the leucine content of each meal needs to be less than 200 mg), so as to avoid the occurrence of hypoglycemia.
Carry sugary foods such as candy bars with you in case of hypoglycemia.
Medication
For CHI treatment
Diazepam
Diazosine is the drug of choice, often used in conjunction with hydrochlorothiazide.
The effective criterion for treatment is the maintenance of fasting and postprandial blood glucose >3.0 mmol/L after an overnight stay in patients on a normal diet or at least 5 days after stopping intravenous rehydration [1].
Adverse effects of diazoxide include hirsutism, water-sodium retention, and hypotension; hydrochlorothiazide has the ability to reduce diazoxide-induced water-sodium retention.
Growth inhibitor analogs
Octreotide binds to growth inhibitory receptors, thereby inhibiting pancreatic endocrine and exocrine function, and is mostly used in patients who have failed diazepam therapy.
Serious adverse effects include hepatitis, necrotizing small bowel colitis, and long QT syndrome; common adverse effects include vomiting, diarrhea, and cholelithiasis [1].
Glucagon.
It promotes the breakdown of hepatic glycogen, thereby elevating blood glucose, and is currently used as a short-term medication in cases of hypoglycemia.
Others
including carbamazepine, sulfonylureas (e.g., glimepiride), etc., can be used to treat CHI caused by a decrease in the number of ATP-sensitive potassium ion channels.
For insulin resistance
Insulin resistance can be improved by using insulin sensitizers and metformin as prescribed by your doctor.
Insulin sensitizers
Thiazolidinediones are insulin sensitizers that can effectively improve insulin resistance, such as pioglitazone and rosiglitazone.
It is contraindicated for those who are allergic to the ingredients of this product.
Metformin
Metformin belongs to the class of biguanide glucose-lowering drugs, oral metformin can increase the uptake and utilization of glucose by peripheral tissues such as liver, muscle, fat, etc., and inhibit the production of hepatic glycogen, which can improve insulin resistance.
Adverse effects commonly include nausea, vomiting, diarrhea, loss of appetite, and abdominal pain.
It is contraindicated in patients with allergy to metformin, diabetic ketoacidosis, and severe renal failure.
For insulinoma
For patients who are not suitable for surgery, refuse surgery, or have metastatic lesions that cannot be removed by surgery, medication can be administered, with choices such as diazoxide and octreotide.
Others
Blood Sugar Control
For patients who have been diagnosed with type 2 diabetes mellitus, in addition to the application of thiazolidinediones and biguanides glucose-lowering drugs, the application of glucose-lowering drugs such as α-glucosidase inhibitors (e.g., acarbose), SGLT-2 inhibitors (e.g., empagliflozin), DPP-4 inhibitors (e.g., selegiline), and GLP-1 analogues (e.g., liraglutide) is also an option.
Blood pressure control
Many hypertensive patients are often accompanied by insulin resistance and may have hyperinsulinemia. At this time, alpha-blockers (e.g., terazosin), angiotensinase inhibitors (e.g., benazepril, captopril), and angiotensin II receptor blockers (e.g., irbesartan, valsartan), etc., which can lower blood pressure while ameliorating insulin resistance, can be considered.
Diuretics (e.g., hydrochlorothiazide, furosemide) and beta-blockers (e.g., propranolol, metoprolol) may exacerbate insulin resistance, and care needs to be taken to avoid prolonged and massive application.
Lipid control
Lipid metabolism disorder and insulin resistance are closely related, hypertriglyceridemia and high free fatty acidemia can further aggravate insulin resistance, statins (e.g., atorvastatin), fibrates (e.g., fenofibrate), and nicotinic acid (e.g., nicotinic acid) can be used to improve the lipid metabolism disorders and reduce the insulin resistance.
Surgery
There are many causes of hyperinsulinemia and sometimes surgical treatment is required.
For CHI
Surgery is easy to cause pancreatic dysfunction, and can be used for those who are ineffective in drug therapy and have poor compliance with drug therapy, and can choose localized lesion resection and subtotal pancreatectomy.
For most CHI patients, localized focal resection can achieve remission.
For CHI patients with ineffective drug therapy, subtotal pancreatectomy is required. Some studies have reported that about 50% of patients still have hypoglycemic events after surgery or develop postoperative diabetes [1].
Targeting insulinomas
Surgical resection is the treatment of choice for insulinoma.
The surgical approach needs to be determined according to the location of the tumor and its relationship to the pancreatic duct, such as tumor removal, distal pancreatectomy, pancreaticoduodenectomy, etc.
Others
For malignant insulinoma that cannot be completely resected from the metastases and for those who are inoperable, chemotherapy with streptozotocin in combination with drugs such as fluorouracil or doxorubicin may be given.
Prognosis
Cure
Patients with CHI may develop seizures and coma if left untreated, which may lead to death in severe cases.
Patients with insulin resistance can improve insulin sensitivity and reduce insulin levels with active physical exercise and dietary changes, which can normalize plasma insulin levels.
Patients with insulinoma generally have a good prognosis after surgical resection of the tumor.
Hazards
Patients with hyperinsulinemia may have recurrent episodes of hypoglycemia, and may have sudden weakness, panic, fainting, etc., which affects patients’ daily life and work.
Daily
Daily management
Dietary management
Daily diet should be diversified and small and frequent meals are recommended to maintain nutritional balance, control total calorie intake, and try to avoid high-calorie, high-fat and high-cholesterol diets to avoid over-nutrition which may lead to obesity.
Patients with symptoms of hypoglycemia should eat regularly, avoid starvation, and always keep sugar cubes or snacks with high sugar content around in case of hypoglycemia.
Exercise management
Daily physical exercise should be carried out to reduce body weight. Exercise varies according to individual’s physique and focuses on exercise programs that one can tolerate, such as running, playing ball games, hiking and so on.
Psychological support
Maintain optimism in daily life and try to avoid depressing and anxious psychological state, so as to facilitate the improvement of physical fitness.
Disease monitoring
Regularly monitor blood glucose, blood pressure and blood lipids in order to detect low blood glucose, high blood pressure and high blood lipids in time.
Regularly monitor weight, waist circumference to avoid obesity.
Follow-up review
People with diabetes mellitus, hyperlipidemia, hypertension, etc. should undergo regular treatment and follow the doctor’s instructions for regular review of blood glucose, glycosylated hemoglobin, blood lipids, etc.
Prevention
Eat well, exercise regularly, maintain a regular routine, and avoid obesity.
People with diabetes mellitus, hyperlipidemia, hypertension, obesity, etc. should undergo regular treatment and follow the doctor’s instructions for review.
People with a family history of CHI can undergo prenatal genetic counseling before giving birth to assess the corresponding risk.