Nesidioblastosis After Gastric-Bypass Surgery

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Nesidioblastosis After Gastric-Bypass Surgery

• Heidi Chamberlain Shea, MD
• Endocrine Associates of Dallas

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Case

• 47 year old male presents with recent onset of
  confusion
• Occurs 1-3 hours after meals
• Worse with high carbohydrate intake
• Resolves when eats or drinks carbohydrates
• Blood sugar 53 mg/dl with confusion

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Case

• History of obesity
• Roux-en-Y-gastric bypass 2 years ago
• BMI 45 to current 23
• Glucose 53 mg/dl
• Insulin 16 µU/ml (lt 3)
• C-peptide 1.8 ng/ml (lt 0.6)
• Negative sulfonylurea screen

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Differential DiagnosisHypoglycemia

• Critical illness
• Hepatic disease
• Cardiac disease
• Renal disease
• Sepsis
• Starvation
• Alimentary (Reactive)
• Post gastric-bypass
• Dumping Syndrome
• Idiopathic

• Non-Beta cell tumors
• Mesechymal
• Sarcoma and fibroma
• Adrenocortical
• Hepatomas
• Carcinoid
• Hormonal deficiencies
• Cortisol
• Growth hormone

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Differential DiagnosisHypoglycemia

• Drugs
• Insulin
• Sulfonylurea
• Alcohol
• Pentamidine
• Quinine
• Salicylates
• Sulfonamides

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Differential DiagnosisHypoglycemia

• Metabolic disorders
• Galactosemia
• Fructose intolerance
• Fatty acid oxidation defects
• Glycogen storage disorders

• Endogenous hyperinsulinism
• Insulinoma
• Auto-antibodies to insulin or the ß-cell
• Functional ß-cell disorder

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Beta-cell Function
SUR 1 (Kir 6.2)
a-Ketoglutarate
GDH
Glutamate
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Differential DiagnosisPost-prandial Hypoglycemia

• Drugs
• Critical illness
• Hormonal deficiencies
• Non-Beta cell tumors
• Endogenous hyperinsulinism
• Autoimmune
• Metabolic
• Alimentary (Reactive)

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Case

• Does he have an insulinoma?
• Should have fasting hypoglycemia
• Only occurring after meals is unusual
• Imaging
• Triple phase spiral CT
• Transabdominal ultrasound of the pancreas
• Arterial calcium-stimulation testing
• Increased insulin from the splenic artery
  distribution
• Underwent partial pancreatectomy

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Histology
Normal islet
Hypertrophic islet cells
Insulin cells lining the pancreatic
ducts (Nesidioblastosis)
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What is Nesidioblastosis?

• Pathological description of islet cells budding
  off pancreatic ducts
• Hyperinsulinemic hypoglycemia
• Affects the newborn population
• Loss of function in Sur 1 (Kir 6.2)
• Gain of function GDH and GK
• Deletion of chromosome 11p150
• Transient
• Diazoxide
• Octreotide
• Persistent
• Partial pancreatectomy

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Hyperinsulinemia Hypoglycemia From Gastric-Bypass?

Service et. al., NEJM 2005, 353(3)249-54
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Hyperinsulinemia Hypoglycemia In Adults?

• Postprandial hypoglycemia
• Neuroglycopenic symptoms
• Incidence
• Male Female
• Obese and lean
• Age
• 11 to 84 years

• 45 cases in the literature
• Earliest report 1975
• Found due to surgical resection for insulinoma
• One case after pancreatic transplant
• No mutations in MEN 1, Sur1 or Kir6.2

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Questions

• Does altering gastric anatomy result in
  hyperinsulinemia hypoglycemia?
• Is weight loss revealing underlying pathology?

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Points of Discussion

• Discuss the interaction between hormones and
  regulation of appetite
• Review metabolic changes associated with gastric
  by-pass surgery
• Decide if gastric by-pass is a risk factor for
  hyperinsulinemia hypoglycemia

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Peptides, Hormones Neurotransmitters Effect
On Eating
Orexigenic Anorectic
Neuropeptide Y (Y1) Serotonin
GABA (A) Cholecystokinin
Norepinephrine (a2) Dopamine (D2)
Glucocorticoid (type II) Leptin
Galanin Insulin
Opiods TRH
Aldosterone (type I) Calcitonin
Opiods Bombesin
GHRH VIP
Ghrelin CRH
Neurotensin
CGRP
Glucagon
IL-1 and 2
TNF, Prostaglandin
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Appetite Control
Wynne et. al., JCEM 2004, 89(6)2576-2582
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Intestinal Regulation of Appetite

• Ghrelin
• Secreted from oxyntic cells of stomach
• Initiates hunger
• Increases before meal
• Decreases afterward
• Increases calorie intake
• True role in decreasing appetite is debated

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Intestinal Regulation of Appetite

• Peptide YY (PYY)
• Satiety and nutrient absorption
• Crosses blood brain barrier
• Secreted from entire intestine
• Greater in distal
• L cells
• Stimulated by food via vagal stimulation
• Increased levels
• High calorie
• Fat
• Inactivated by dipeptidyl peptidase IV (DPPIV)

• Pancreatic polypeptide (PP)
• Satiety and nutrient absorption
• Produced by pancreas
• Colon and rectum
• Stimulated by food
• More is released with later meals of the day
• Increased with anorexia
• Variable levels seen with obesity

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Intestinal Regulation of Appetite
Wynne et. al., JCEM 2004, 89(6)2576-2582
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Intestinal Regulation of Appetite

• Glucagon-like peptides (GLP-1 2)
• Satiety
• Expressed in brain, pancreas and small intestine
• L-cells
• Stimulated by food
• Acts via the GLP-1 receptor
• Augments postprandial insulin secretion
• Decreases gastric motility
• Inhibits gastric acid secretion

• Oxyntomodulin (OXM)
• Satiety
• Expressed in brain, and small intestine
• L-cells
• Stimulated by food
• Acts via the GLP-1 receptor
• Augments postprandial insulin secretion
• Decreases gastric motility
• Inhibits gastric acid secretion
• Meal termination
• Inhibits Ghrelin

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Intestinal Regulation of Appetite

• Cholecystokinin (CCK)
• Satiety and nutrient absorption
• Released by duodenum and jejunum
• L cells
• Stimulated by intraluminal food

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Bariatric Surgery


Gastric Banding 30-50 weight loss
Roux-en-Y-gastric bypass 50-80 weight loss
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Bariatric Surgery

• Most effective way to achieve weight loss
• Reduces weight by 35-40
• Maintained for 15 years
• Decreases appetite
• Malabsorption is limited

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Bariatric SurgeryComplications

• Immediate post surgical risks
• Malabsorption
• Limited time

• Dumping syndrome
• Nausea
• Bloating
• Colic
• Diarrhea
• Light headedness
• Diaphoresis
• Palpitations

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Bariatric SurgeryBenefits

• Improves obesity-related comorbidities
• Diabetes
• Hypertension
• Dyslipidemia
• Nonalcoholic steatosis
• Sleep apnea

• Reflux esophagitis
• Venous stasis ulcers
• Infertility
• Arthritis
• Pseudotumor cerebri
• Stress incontinence

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Bariatric SurgeryPhysiology
Banded N17
Control N17
Dixon et al., JCEM 2005, 90(2)813-19
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Bariatric SurgeryPhysiology
Glucose mg/dl
Insulin uIU/L
60
135
50
125
40
115
30
105
20
95
10
85
0700 0900 1000 1100
0700 0900 1000 1100
? BMI matched controls N17 ?? Lap band
patients N17
Dixon et al., JCEM 2005, 90(2)813-19
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Gastric-bypassHormonal Changes

• After bypass
• Ghrelin variable results
• Leptin decreases
• Glucose decreases
• Insulin decreases
• Adiponectin increases
• CCK, VIP and Serotonin unaffected

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Gastric-bypassHormonal Changes

• Future studies
• Response of other intestinal hormones
• Understand the complex interactions between
  hormones and appetite
• Other unidentified players?

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Hyperinsulinemia Hypoglycemia From Gastric-Bypass?

Service et. al., NEJM 2005, 353(3)249-54
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ß-cell Proliferation

• Authors postulate that gastric-bypass increases
  incretin like substances
• Increased bolus delivery to distal small
  intestine
• ß-cells stimulated to increased insulin secretion
  hypertrophy
• What happens to islet cells with incretin
  supplementation?

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Animal StudiesExenatide

• Non diabetic obese male Zucker rats
• 3 groups
• Control given saline
• N11
• Exenatide treated and PO ad lib
• N10
• Pair fed
• N10
• 6 week study

Gedulin, B. R. et al. Endocrinology
20051462069-2076
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Animal StudiesExenatide


Gedulin, B. R. et al. Endocrinology
20051462069-2076
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Animal StudiesExenatide

? Ex ? PF ? CL

• Absolute mass unchanged
• No comment about hypertrophy
• Absolute ß-cell mass
• Improved sensitivity
• Decrease in ß-cell mass
• No evidence for hypertrophy in presence of
  incretins

Gedulin, B. R. et al. Endocrinology
20051462069-2076
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Conclusions

• Does altering gastric anatomy result in
  hyperinsulinemia hypoglycemia?
• Currently no evidence to support
• Is weight loss revealing underlying pathology?
• Possibly
• Insulin resistance is protective
• Patients that need surgery
• Unknown defect in ß-cell function

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Hypoglycemia TrialsAre patients not identified?

• Multiple studies
• Patients are rarely hypoglycemic with symptoms
• Normal non-symptomatic patient can be
  hypoglycemia
• Brun JF, et. al., Diabetologia 1995, 38(4)
• Palardy J et. al., NEJM 1989, 321(21)
• Buss RW et. al., Hormone Metabolism Research
  1982, 14(6)
• Lev-Rau et al, Diabetes 1981, 30(12)