A.6 Hypoglycemic Disorders. Pancreatic Islet Cell Tumors Flashcards
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A.6 Hypoglycemic Disorders. Pancreatic Islet Cell Tumors
List all Hypoglycemic Disorders
EXPLAIN HYPOS”
E: Endocrine (Addison’s, GH def, hypopit) X: Exogenous insulin or sulfonylurea P: Pancreatic tumor (insulinoma) L: Liver failure A: Alcohol I: Inborn errors (GSDs, FAODs) N: Nutrition (starvation, anorexia) H: Hormone deficiencies (GH, cortisol) Y: Your own meds (beta-blockers, ACEi) P: Post-gastrectomy, postprandial O: Organ failure (renal, cardiac) S: Sepsis / severe illness
A.6 Hypoglycemic Disorders. Pancreatic Islet Cell Tumors
How does Adrenal Insufficiency (Addison’s) cause Hypoglycemia
↓ cortisol = ↓ gluconeogenesis
Primary Adrenal Insufficiency
→ Destruction of the adrenal cortex → ↓ production of:
Cortisol
Aldosterone
(Androgens in some cases)
- ↓ Cortisol → ↓ GluconeogenesisCortisol is essential for maintaining blood glucose during fasting and stress
It stimulates hepatic gluconeogenesis and enhances the effect of glucagon
Without cortisol, the liver can’t generate glucose efficiently - ↓ Cortisol → ↑ Insulin Sensitivity
Cortisol normally opposes insulin
In its absence, tissues become more sensitive to insulin, promoting glucose uptake and reducing blood glucose - ↓ Cortisol → Impaired Counter-Regulation
During hypoglycemia, cortisol acts as a counter-regulatory hormone (like glucagon and epinephrine)
Without it, the body can’t correct hypoglycemia effectively
A.6 Hypoglycemic Disorders. Pancreatic Islet Cell Tumors
How does Hypopituitarism cause Hypoglycemia
↓ GH and ACTH → ↓ glucose output
Hypopituitarism = deficiency of one or more anterior pituitary hormones.
Two key hormone deficiencies that lead to hypoglycemia:
1. ↓ ACTH → ↓ Cortisol (Secondary Adrenal Insufficiency)
Cortisol supports gluconeogenesis, lipolysis, and counter-regulation during hypoglycemia
Cortisol deficiency results in:
↓ hepatic glucose output
↑ insulin sensitivity
Impaired response to fasting or stress
- ↓ Growth Hormone (GH)
GH is also a counter-regulatory hormone
GH helps:
Promote lipolysis (to spare glucose)
Stimulate gluconeogenesis
Reduce peripheral glucose uptake
GH deficiency, especially in children, increases risk of fasting hypoglycemia
A.6 Hypoglycemic Disorders. Pancreatic Islet Cell Tumors
How does insulinoma cause hypoglycemia
Pancreatic tumor → ↑ insulin
- Autonomous insulin secretion
Insulin is secreted independently of glucose levels
Even when glucose is low → insulin remains inappropriately high - Excess insulin → ↑ glucose uptake
Promotes glucose uptake into tissues (especially muscle and fat)
Inhibits hepatic glucose production
Inhibits lipolysis and ketogenesis → worsens neuroglycopenia
A.6 Hypoglycemic Disorders. Pancreatic Islet Cell Tumors
How does Liver failure cause Hypoglycemia
↓ glycogen stores & gluconeogenesis
In liver failure (acute or advanced chronic):
1. ↓ Glycogen stores
In chronic liver disease, glycogen is depleted
In acute liver failure, glycogen stores may be present but inaccessible
- ↓ Gluconeogenesis
The failing liver can’t generate new glucose from non-carbohydrates
↓ substrates (like amino acids) due to poor nutrition or catabolism also contribute - ↓ Insulin clearance
The liver normally clears insulin
In liver failure → insulin lingers longer in circulation → hypoglycemia - ↑ Peripheral glucose uptake
Due to prolonged insulin action and inflammatory states - Reduced glucagon response
In advanced liver disease, the counter-regulatory hormone response is also impaired
A.6 Hypoglycemic Disorders. Pancreatic Islet Cell Tumors
How does Alcohol cause Hypoglycemia
Alcohol inhibits gluconeogenesis in the liver by altering the NAD⁺/NADH ratio.
- Ethanol metabolism in the liver:
Ethanol → Acetaldehyde → Acetate
These reactions use NAD⁺, converting it to NADH - High NADH levels inhibit key steps in gluconeogenesis:
Lactate → pyruvate is blocked
Malate → oxaloacetate is blocked
Glycerol → DHAP is impaired
A.6 Hypoglycemic Disorders. Pancreatic Islet Cell Tumors
How does Glycogen storage diseases Cause Hypoglycemia
Glycogen storage diseases are inherited metabolic disorders caused by defects in enzymes involved in glycogen synthesis or breakdown.
Most are autosomal recessive
They result in abnormal glycogen accumulation in liver, muscle, or both
Many present in infancy or childhood
- 🔺 Impaired Glycogenolysis
Normally, during fasting, glycogen in the liver is broken down to release glucose (glycogenolysis)
In many GSDs (e.g., GSD type I, III, VI, IX), this process is blocked
→ Glucose can’t be released into the blood → fasting hypoglycemia - 🔺 Impaired Gluconeogenesis (in some types)
In GSD type I (Von Gierke’s), the enzyme glucose-6-phosphatase is deficient
This blocks both glycogenolysis and gluconeogenesis at the final step
→ Severe fasting hypoglycemia - 🔺 Excess insulin sensitivity in some cases
In some GSDs, insulin regulation may be abnormal or tissues more insulin-sensitive during hypoglycemia
A.6 Hypoglycemic Disorders. Pancreatic Islet Cell Tumors
How Fatty Acid Oxidation Disorders (FAODs) Cause Hypoglycemia
In FAODs:
There is a block in mitochondrial β-oxidation of fatty acids due to enzyme deficiencies (e.g., MCAD, LCHAD, CPT1/2 deficiency)
Resulting Mechanisms of Hypoglycemia:
1. ↓ Ketogenesis → Hypoketotic Hypoglycemia
No ketones generated (classic finding)
Brain is starved of energy during fasting or illness
- ↓ ATP production → Impaired Gluconeogenesis
FA oxidation normally powers gluconeogenesis
No ATP → gluconeogenesis fails → glucose drops - ↑ Glucose utilization (e.g., in fever, illness, exercise)
No backup energy → glucose is rapidly consumed
A.6 Hypoglycemic Disorders. Pancreatic Islet Cell Tumors
How do beta-blockers cause Hypoglycemia
A.6 Hypoglycemic Disorders. Pancreatic Islet Cell Tumors
How does Sulfonylureas / Meglitinides cause hypoglycemia
Both stimulate pancreatic β-cells to increase insulin secretion
They bind to the SUR1 subunit of the ATP-sensitive potassium (K⁺) channels on β-cell membranes → This closes K⁺ channels, depolarizes the cell → Opens voltage-gated Ca²⁺ channels → Calcium influx triggers insulin exocytosis
A.6 Hypoglycemic Disorders. Pancreatic Islet Cell Tumors
β₂‑receptor blockade in the liver
β₂‑adrenergic stimulation → glycogen → glucose (glycogenolysis) + ↑ gluconeogenesis
↓ Hepatic glucose output during fasting, exercise or after insulin → blood glucose falls
β₂‑receptor blockade in the pancreas
β₂ stimulation → glucagon release (a key counter‑regulatory hormone)
Blunted glucagon surge → slower recovery from falling glucose
Masking of adrenergic warning signs
Hypoglycaemia triggers tachycardia, tremor, palpitations (β₁/β₂ mediated)
β‑blockers hide the symptoms → “hypoglycaemia unawareness,” delays self‑treatment
Non‑selective β‑blockers (propranolol, carvedilol, timolol eye drops, etc.) are riskiest because they block β₂ receptors;
cardio‑selective agents (metoprolol, bisoprolol) have much less effect on glucose recovery but still mask symptoms.
A.6 Hypoglycemic Disorders. Pancreatic Islet Cell Tumors
How do ACEi cause Hypoglycemia
The effect is class‑wide but most described with captopril, enalapril, lisinopril.
It is potentiation, not direct insulin release, so isolated ACE i rarely cause hypoglycaemia in non‑diabetics.
ACEi cause:
↓ Angiotensin II (A II) A II antagonises insulin action and promotes hepatic gluconeogenesis
Less A II → ↑ insulin sensitivity in muscle & fat and ↓ hepatic glucose output
↑ Bradykinin / nitric‑oxide signalling
Bradykinin is normally degraded by ACE Higher bradykinin → vasodilation → better skeletal‑muscle blood flow → greater glucose uptake for a given insulin level
Captopril: most commonly assocaited
Enalapril, Lisinopril, and Ramipril:
A.6 Hypoglycemic Disorders. Pancreatic Islet Cell Tumors
how does renal failure cause hypoglycemia
↓ insulin clearance
Insulin lingers far longer than normal.
Healthy kidneys filter and break down a large share of circulating insulin. When glomerular filtration plummets, that degradation slows dramatically, so any endogenous or injected insulin stays active for hours beyond the expected window.
Many glucose‑lowering drugs accumulate.
Sulfonylureas, meglitinides, and a few other oral agents (or their active metabolites) leave the body through the urine. Poor filtration means they build up, driving insulin secretion well past the intended dose.
The kidney normally helps raise glucose during fasting—now it can’t.
After an overnight fast, the renal cortex produces as much as a third of the body’s new glucose via gluconeogenesis. Diseased kidneys lose this ability, so the liver has to carry the whole burden; if hepatic output is already limited by illness or malnutrition, blood sugar falls.
Dialysis itself can drop glucose.
Conventional hemodialysis uses glucose‑free dialysate unless specifically supplemented; circulating glucose can decline rapidly during a run. Peritoneal dialysis adds insulin to the dialysate in some regimens, which can overshoot in sensitive patients.
Uremia often comes with poor oral intake and catabolism.
Anorexia, nausea, and muscle breakdown deplete glycogen and gluconeogenic substrates, so there is little reserve to draw on during overnight fasts or minor illnesses.
Counter‑regulation is blunted.
Kidney failure alters catecholamine and cortisol metabolism; the normal hormonal surge that corrects falling glucose is weaker and slower, letting hypoglycaemia deepen.
A.6 Hypoglycemic Disorders. Pancreatic Islet Cell Tumors
how does Heart Failure cause Hypoglycemia
Hypoperfusion of liver
In advanced heart failure, low cardiac output and venous congestion cut blood flow to the liver and kidneys. The under‑perfused liver cannot perform gluconeogenesis or release glycogen, while the poorly filtered kidneys clear insulin more slowly, so circulating insulin lingers. At the same time, many patients are malnourished (depleted glycogen) and take β‑blockers or ACE inhibitors that blunt adrenergic counter‑regulation and heighten insulin action. The combination of reduced glucose production, prolonged insulin effect, and muted hormonal rescue produces fasting or stress‑related hypoglycaemia.
A.6 Hypoglycemic Disorders. Pancreatic Islet Cell Tumors
How does Sepsis cause Hypoglycemia
↑ glucose use + ↓ hepatic output
In severe sepsis, three things converge:
The liver fails to make new glucose. Endotoxin and poor perfusion shut down hepatic gluconeogenesis and empty glycogen stores. Immune cells and bacteria burn glucose quickly. Cytokine‑driven glycolysis and fever raise whole‑body glucose consumption. Insulin lingers or even rises. Renal/hepatic failure slows insulin clearance, and inflammatory mediators can spur pancreatic insulin release, while adrenal‑cortisol support is often inadequate.
Reduced production + accelerated use + unopposed insulin = septic hypoglycaemia.
A.6 Hypoglycemic Disorders. Pancreatic Islet Cell Tumors
Pancreatic Islet Cell Tumors Definition
Pancreatic neuroendocrine tumors (PNETs) are hormone-secreting tumors of the pancreas that derive from neuroendocrine cells.
They are:
glucagonomas
VIPomas,
somatostatinomas
Insulinomas
gastrinomas
A.6 Hypoglycemic Disorders. Pancreatic Islet Cell Tumors
Glucagonoma defintion
a rare neuroendocrine tumor of the pancreatic α-cells that secretes glucagon. In > 50% of cases, metastasis is present at diagnosis.
affected cell - α-cells - cell responsible for synthesizing and secreting glucagon
A.6 Hypoglycemic Disorders. Pancreatic Islet Cell Tumors
Glucagonoma Clinical
Weight loss
Impaired glucose tolerance or diabetes mellitus (75–95%)
Necrolytic migratory erythema - - characterized by multiple, centrifugally spreading erythematous lesions, especially, on the face, perineum, buttocks, and lower extremities. After 1-2 weeks, these lesions develop into painful, crusty, and pruritic patches
Tend to resolve and reappear in a different location
Skin biopsy shows epidermal necrosis
Chronic diarrhea
Deep vein thrombosis
Depression
increase blood glucose
can cause watery diarrhea
A.6 Hypoglycemic Disorders. Pancreatic Islet Cell Tumors
Glucagonoma DX
Diagnostics: requires a high index of suspicion to make the diagnosis
Laboratory findings: ↑ glucagon > 500 pg/mL, ↑ blood glucose levels, normocytic normochromic anemia
Imaging (CT): to locate the tumor
A.6 Hypoglycemic Disorders. Pancreatic Islet Cell Tumors
Glucagonoma TX
Glycemic control
Tumor resection
Octreotide (if tumor is inoperable)
Octreotide mimics the action of somatostatin, a natural inhibitory hormone that regulates the endocrine system. It binds to somatostatin receptors (primarily SSTR2 and SSTR5) on various cells.
🔹 Mechanism of Action
Inhibits hormone secretion from neuroendocrine tumours: – ↓ Insulin, glucagon, growth hormone – ↓ Gastrin, VIP, serotonin, secretin, motilin Inhibits exocrine secretions: – ↓ Pancreatic enzymes – ↓ Gastric acid and intestinal fluid output Slows GI motility – Delays gastric emptying – Reduces splanchnic blood flow
A.6 Hypoglycemic Disorders. Pancreatic Islet Cell Tumors
Somatostatinoma Definition
a rare neuroendocrine tumor of δ-cell (D-cell) origin that is usually located in the pancreas or gastrointestinal tract and secretes somatostatin.
↑ Somatostatin → ↓ secretion of the following hormones:
Secretin
Cholecystokinin
Glucagon
Insulin
Gastrin
Gastric inhibitory peptide
affects δ-cell - somatostatin-producing cell
A.6 Hypoglycemic Disorders. Pancreatic Islet Cell Tumors
Somatostatinoma Clinical
Abdominal pain
Weight loss
Achlorhydria
Classic triad
Glucose intolerance/diabetes
Cholelithiasis
Steatorrhea
A.6 Hypoglycemic Disorders. Pancreatic Islet Cell Tumors
Somatostatinoma DX
Laboratory findings: ↑ somatostatin, ↑ blood glucose levels
Imaging: locate the tumor
A.6 Hypoglycemic Disorders. Pancreatic Islet Cell Tumors’
Somatostatinoma TX
Tumor resection: curative if no metastases are present
Octreotide (if tumor is inoperable)
Chemothera
