• Credits
  • Section Writer: Dr. Om J Lakhani
  • Section Editor: Dr. Om J Lakhani

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• Video lecture

Connected notes:
- Hypoglycemia in patients with diabetes mellitus
- Insulin autoimmune syndrome
- NICTH (Non Islet cell Tumor hypoglycemia) & IGF-2 related hypoglycemia

• Q. Summarize the approach to hypoglycemia in patients not having diabetes.
  • 
    • 
• Q. What are the various classifications for Hypoglycemia in non-diabetics?
  • Fasting vs postprandial
  • Insulin mediated vs non-insulin mediated
  • Hypoglycemia in ill patient vs seemingly well patient

• Q. Enlist the causes of hypoglycemia in a non-diabetic individual.

  -
  • Hypoglycemia in seemingly well individual
    • Exogenous use of Insulin/sulphonylurea
    • Insulinoma
    • Insulin autoimmune syndrome
    • NIPHS - non-insulinoma pancreatogogus hyperinsulinemia syndrome
    • Post-bariatric hypoglycemia
  • Hypoglycemia in ill or seemingly unwell individual
    • Medications- insulin, alcohol, etc
    • Critical illness
    • Liver failure
    • Renal failure
    • NICTH- Non-islet cell tumor
    • Adrenal insufficiency
    • Panhypopituitarism
• Q. Which drugs other than antidiabetics cause hypoglycemia?
  • Alcohol
  • IGF1 (Increlex)
  • Quinolone
  • Quinine
  • Pentamidine
  • ACEI
  • Beta-blockers
• Q. How does alcohol produce hypoglycemia?
  • Alcohol inhibits gluconeogenesis
• Q. What is the cause of hypoglycemia in NICTH (Non-islet cell tumor hypoglycemia)?
  • It is due to IGF-II
  • They are mainly mesenchymal tumors
• Q. What is pseudo hypoglycemia?
  • When a fluoride bulb is not used for the transport of blood sample
  • BG is utilized by the cells @ 10-20 mg/dl per hour
• Q. is hypoglycemia common in patients with liver disease?
  • No. Not all individuals
  • It occurs only when there is rapid and fulminant liver damage like toxic hepatitis
• Diagnostic approach to hypoglycemia in non-diabetic individuals
• Q. What test is done for patients having fasting hypoglycemia and what is done for post-prandial hypoglycemia?
  • 
  • Fasting hypoglycemia – 72-hour fast test
  • Postprandial hypoglycemia- Mixed meal diagnostic test
• Q. What are mixed meal diagnostic tests and mixed meal tolerance tests?
  • Mixed meal diagnostic test- for postprandial hypoglycemia
  • Mixed meal tolerance test- due to seeing C peptide response to meal to different type 1 and type 2 diabetes or evaluated endogenous glucose production in diabetes
• Q. When is hypoglycemia considered fasting and when is it postprandial?
  • <5 hours after a meal – postprandial
  • More than 5 hours after meal- fasting
• Q. At what glucose cutoff are tests for C-peptide etc performed on the sample?
  • When BG concentration <60 mg/dl –samples are analyzed
  • BG <55 mg/dl for interpretation of reports
• Q. What tests are done once hypoglycemia is achieved?
  • Plasma glucose
  • C peptide
  • Insulin
  • Proinsulin
  • Beta-hydroxybutyrate
  • Sulphonylurea / Meglitinide screen
  • Insulin autoantibody (no need for fasting)
• Q. Describe the protocol for the Mixed meal diagnostic test.
  • Baseline sample as described above
  • Take a regular meal or the meal that causes hypoglycemia
  • Blood was collected every 30 min for 5 hours and check PG
  • Once PH <60 mg/dl- do the additional tests
  • If symptoms of hypoglycemia develop midway – then take additional samples at that time
• Q. Describe the 72-hour fast test.
  • Discontinue all nonessential meds
  • Patient can take liquids during the test – must not have calorie or caffeine
  • Collect samples every 6 hrly till BG <60 mg/dl  then every 1-2 hourly
  • Analyze samples that have BG <60 mg/dl only
• Q. When is fast ended?
  • Symptoms of hypoglycemia develop
  • BG <55 mg/dl with Whipple’s trial established
  • BG<45 mg/dl – with or without Whipple’s triad
  • 72 hours have passed
• Q. What is done at the end of the fast?
  • Give 1 mg of glucagon IV
  • Then take samples for glucose at 10,20 and 30 min
• **Interpretation of the data **

• Q. Give the summary for interpretation of the results.

  -
• Q. What is a normal response?
  • When Glucose <55 mg/dl
    • C peptide <0.6 ng/ml
    • Insulin  <3 uU/ml
    • Proinsulin - <5 pmol/l
    • BOHB - >2.7 mmol/l (since insulin is suppressed, ketones are formed)
    • Glucose increase to glucagon - <25 mg/dl (glycogen stores are depleted, hence there is no immediate response to glucagon )
• Q. What happens in case of Hyperinsulinemic hypoglycemia?
  • When Glucose <55 mg/dl
    • C peptide >0.6 ng/ml
    • Insulin  >3 uU/ml
    • Proinsulin - >5 pmol/l
    • BOHB - <2.7 mmol/l (since insulin is not suppressed, ketones are not formed)
    • Glucose increase to glucagon - >25 mg/dl (glycogen stores are not depleted because of insulin, hence there is no quick response to glucagon )
• Q. What happens in case of Exogenous insulin use?
  • When Glucose <55 mg/dl
    • C peptide <0.6 ng/ml
    • Insulin  >3 uU/ml
    • Proinsulin - <5 pmol/l
    • BOHB - <2.7 mmol/l (since insulin is not suppressed, ketones are not formed)
    • Glucose increase to glucagon - >25 mg/dl (glycogen stores are not depleted because of insulin, hence there is no quick response to glucagon )
• Q. What happens in the case of NICTH? (Due to IGF-II)
  • When Glucose <55 mg/dl
    • C peptide <0.6 ng/ml
    • Insulin  <3 uU/ml
    • Proinsulin - <5 pmol/l
    • BOHB - <2.7 mmol/l (IGF-2 acts like insulin)
    • Glucose increase to glucagon - >25 mg/dl
• Q. Summarize the response in all conditions.
  • 
• **Localization of Insulinoma **
• Q. What are the tests for localization in case of a suspected insulinoma?
  • 1. CT pancreatic protocol
  • 2. Endoscopic ultrasound
  • 3. PET scan- Gallium DOTANOC PET or Exendin scan
  • 4. Selective arterial calcium stimulation test
• Q. Give the interpretation of the Selective arterial calcium stimulation test.
  • More than 2 fold increase in insulin in any artery territory is a positive response
  • If there is an increase in response in all arteries- suggestive of a Diffuse process of NIPHS
  • If there is increased uptake in one artery alone- s/o of  Insulinoma
• Q. Response in which artery suggests what location of an insulinoma?
  • Gastroduodenal – Head of the pancreas
  • Superior mesenteric artery- Body of pancreas
  • Splenic artery- tail of the pancreas
  • 
• Postprandial Hypoglycemia
• Q. What is the definition of Postprandial hypoglycemia?
  • Hypoglycemia within 4-5 hrs of meal
• Q. What are the causes of Postprandial hypoglycemia?
  • NIPHS (Noninsulinoma pancreatogenous hypoglycemia syndrome)
  • Insulin autoimmune syndrome
  • Post gastric bypass
  • Post-bariatric surgery
  • Insulinoma
  • Hereditary fructose intolerance
  • Factitious hypoglycemia
  • Mild early type 2 diabetes
  • Early Post pancreatic transplant
  • Large amount of alcohol with simple carbs- Gin and Tonic syndrome
• Q. What is post prandial syndrome ?
  • Post-prandial syndrome was previously called reactive hypoglycemia
  • It is anxiety, perspiration, or palpitation after a meal
  • It is blood glucose <50 mg/dl on extended OGTT but symptoms not correlating with the drop in blood sugar
  • Only those patients with PPS fulfilling Whipple’s triad may be subjected to further evaluation
• Q. How is post-prandial syndrome treated?
  • With reassurance
  • Small frequent meals with high fiber content
  • Acarbose may help
• Q. What is the investigation of choice for Postprandial hypoglycemia?
  • It is a mixed meal diagnostic test
• Q. Give the protocol for the mixed meal diagnostic test
  • Draw blood before giving a meal
  • Then give the normal meal which the patient takes every day or the meal that specifically causes hypoglycemia (avoid using glucose or liquid meals- conflicting results)
    • Collect blood samples every 30 min for 5 hrs
    • If a patient develops symptoms then collect additional blood samples before giving carbohydrate
    • All samples labeled and sent to the lab
    • First check glucose in the lab- further tests are to be done only if glucose in the sample is <55 mg/dl
      • Additional tests are :
        • Insulin
        • C peptide
  • If Whipple’s triad is established then also test for
    • Insulin antibodies
    • SU/ Meglitinide
• Q. What is alimentary hypoglycemia?
  • It is a form of a post-prandial syndrome rather than true post-prandial hypoglycemia in patients who have undergone upper GI surgery
• Q. What is dumping syndrome?
  • This also occurs in patients who have undergone GI surgery
  • It is the feeling of fainting after a meal
  • Because of undigested food in the intestine- there is an increase osmotic shift of fluid into the GI tract
  • This leads to a reduction of circulating volume
  • This occurs 15-30 min after a meal and is not associated with hypoglycemia

- Insulin autoimmune syndrome- See separate notes - click on the link

• NIPHS (NON-INSULINOMA PANCREATOGENOUS HYPOGLYCEMIA SYNDROME)

• Q. What type of hypoglycemia is seen with NIPHS?

  • Mainly postprandial hypoglycemia

• Q. What are the histological changes seen in NIPHS?

  • The histological changes are called NESIDOBLASTOSIS
  • The beta cell hypertrophies and has enlarged hyperchromatic nuclei

• Q. What are the biochemical changes in NIPHS?

  • They are similar to Insulinoma ie when BG <55 mg/dl there is
    • Insulin > 3 mIU/ml
    • C peptide > 0.6 ng/dl
    • Beta-hydroxybutyrate < 2.7 mmol/l
    • Glucose increases by >25 mg/dl after glucagon

• Q. What are the DD of Nesidoblatosis ?

  • NIPHS
  • Nesdioblastosis in neonates and infants
  • Prolonged use of Sulphonylureas
  • Non-tumor cells in insulinoma
  • Post roux en  Y gastric bypass

• Q. How is NIPHS localized?

  • NIPHS is a diffuse process so not localized
    • However, you need to rule out insulinoma hence localization studies may be required
    • Absence of insulinoma may SUGGEST NIPHS, however it is difficult to distinguish in such  a scenario
    • The best approach would be to do selective arterial calcium stimulation
    • In Insulinoma- there would be a response to a single artery, in NIPHS there would response in multiple arteries

• Q. What is the treatment of NIPHS?

  • In mild to moderate cases
    • Small frequent meals
    • Acarbose / Octreotide
  • In severe cases
    • Partial or subtotal pancreatectomy
    • Region for resection dictated by Selective arterial calcium stimulation

- NICTH (Non Islet cell Tumor hypoglycemia) & IGF-2 related hypoglycemia - See separate notes. Click on the link

- Insulinoma

• Q. Insulinoma is commonly malignant, True or false?
  • False
  • It is mainly benign
  • Malignancy is rare
• Q. What is the demographic of a patient having an insulinoma
  • Mean age- 48 years
  • M > F
• Q. Is the Octerotide scan or DOTA scan a good idea for Insulinoma?
  • No
  • Often does not pick up insulinoma since they often lack SSTR2 receptor
• Q. What is the new functional scan for localization of Insulinoma?
  • GLP-1 scintigraphy
  • ⁶⁸Ga-DOTA-Exendin-4 PET/CT is often used for this purpose
• Q. What will you suspect if there is recurrence or persistence of symptoms post-op in case of an insulinoma?
  • MEN1 syndrome
• Q. What is the surgery done for Insulinoma in MEN1 syndrome?
  • Resection of any visible tumor in the head of the pancreas + distal subtotal pancreatectomy
• Q. Summarize the management of insulinoma in Non-MEN1 cases.
  • 
  • 
• Q. What is the principle of hepatic artery embolization?
  • Liver has a dual blood supply
  • Normal liver tissue  blood supply from the portal vein
  • Metastasis → blood supply from hepatic artery
  • Hence embolization of hepatic artery – cuts off supply to mets but maintains supply to hepatocytes
• #Updates Date April 10th, 2021
  • Q. Which antiviral drug has been known to produce Hypoglycemia in patients not having diabetes?
    • Oseltamivir has been known to produce Hypoglycemia in people not having diabetes, especially in the elderly
    • This has been reported in the article by Kimberlin et al
      • Ref: Kimberlin DW, Escude J, Gantner J, Ott J, Dronet M, Stewart TA, Jester P, Redden DT, Chapman W, Hammond R. Targeted antiviral prophylaxis with oseltamivir in a summer camp setting. Archives of pediatrics & adolescent medicine. 2010 Apr 5;164(4):323-7.
• Exendin scan
• Q. What is the Exendin scan ?
  • This is the PET scan done using Gallium-68 DOTA-Exendin-4 Positron Emission Tomography-Computed Tomography
• Q. What is the sensitivity of the current conventional imaging techniques for preop localization of Insulinoma?
  • CT- 65-70%
  • MRI- 55-65%
  • Endoscopic ultrasound- 75-80%
• Q. What is the gold standard for preop localization of Insulinoma?
  • Selective arterial calcium stimulation test
• Q. What is the basis for the Exendin scan?
  • Insulinoma tends to have a high density of GLP-1 receptor
  • This is detected with an Exendin scan
• Q. What is the correlation between the Exendin scan can Gallium DOTANOC scan?
  • GLP1 receptors have high density in 95% of insulinoma
  • Gallium DOTANOC picks up the SSTR2 receptor which is present in 70% of insulinoma
  • Hence Exendin is more sensitive than DOTANOC for insulinoma
  • However, in cases of Exendin negative- DOTANOC can be positive
• Q. Can Exendin scan have a false positive?
  • This is very rare
• Q. What about the false negative?
  • This is possible
  • 1. Insulinoma may have have no GLP1 receptor
    • In this case, sometimes they may have SSTR2
    • Hence Gallium DOTANOC can make a diagnosis
  • 2. Renal uptake can cause false negative
    • Intense physiological renal uptake can cause reconstruction artifact which can cause false negative in the adjacent insulinoma in the tail of the pancreas
• Q. What is the common side effect during an Exendin scan?
  • Exendin scan cause produce Hypoglycemia - some patients may have nausea and vomiting because of the same
• Q. If an insulinoma has already been detected by another imaging technique- what PET scan would you do to confirm the same?
  • In this case, DOTANOC is preferred over Exendin because of the following reasons:
  • 1. If there is distant mets or poorly differentiated lesion- DOTANOC is more likely to pick up the diagnosis than exendin
  • 2. If required this can be used as a therapeutic agent (theranostic therapy) compared to Exendin which is not suitable as a theranostic agent