Nesidioblastosis Nesidioblastosis After Gastric-Bypass SurgeryAfter Gastric-Bypass Surgery

Heidi Chamberlain Shea, MDHeidi Chamberlain Shea, MD

Endocrine Associates of DallasEndocrine Associates of Dallas

CaseCase

47 year old male presents with recent 47 year old male presents with recent onset of confusiononset of confusion

Occurs 1-3 hours after mealsOccurs 1-3 hours after meals Worse with high carbohydrate intakeWorse with high carbohydrate intake

Resolves when eats or drinks Resolves when eats or drinks carbohydratescarbohydrates

Blood sugar 53 mg/dl with confusionBlood sugar 53 mg/dl with confusion

CaseCase

History of obesityHistory of obesity Roux-en-Y-gastric Roux-en-Y-gastric

bypass 2 years agobypass 2 years ago BMI 45 to current 23BMI 45 to current 23

Glucose 53 mg/dlGlucose 53 mg/dl Insulin 16 Insulin 16 µµU/ml (< 3)U/ml (< 3) C-peptide 1.8 ng/ml C-peptide 1.8 ng/ml

(< 0.6)(< 0.6) Negative sulfonylurea Negative sulfonylurea

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Differential DiagnosisDifferential DiagnosisHypoglycemiaHypoglycemia

Non-Beta cell tumorsNon-Beta cell tumors MesechymalMesechymal

Sarcoma and fibromaSarcoma and fibroma

AdrenocorticalAdrenocortical HepatomasHepatomas CarcinoidCarcinoid

Hormonal deficienciesHormonal deficiencies CortisolCortisol Growth hormoneGrowth hormone

Critical illnessCritical illness Hepatic diseaseHepatic disease Cardiac diseaseCardiac disease Renal diseaseRenal disease SepsisSepsis StarvationStarvation

Alimentary (Reactive)Alimentary (Reactive) Post gastric-bypassPost gastric-bypass

Dumping SyndromeDumping Syndrome

IdiopathicIdiopathic

Differential DiagnosisDifferential DiagnosisHypoglycemiaHypoglycemia

DrugsDrugs InsulinInsulin SulfonylureaSulfonylurea AlcoholAlcohol PentamidinePentamidine QuinineQuinine SalicylatesSalicylates SulfonamidesSulfonamides

Differential DiagnosisDifferential DiagnosisHypoglycemiaHypoglycemia

Metabolic disordersMetabolic disorders GalactosemiaGalactosemia Fructose intoleranceFructose intolerance Fatty acid oxidation Fatty acid oxidation

defectsdefects Glycogen storage Glycogen storage

disordersdisorders

Endogenous Endogenous hyperinsulinismhyperinsulinism InsulinomaInsulinoma Auto-antibodies to Auto-antibodies to

insulin or the insulin or the ββ-cell-cell Functional Functional ββ-cell -cell

disorderdisorder

Beta-cell FunctionBeta-cell FunctionSUR 1 (Kir 6.2)

Glutamate

GDH

α-Ketoglutarate

Differential DiagnosisDifferential DiagnosisPost-prandial HypoglycemiaPost-prandial Hypoglycemia

DrugsDrugs Critical illnessCritical illness Hormonal deficienciesHormonal deficiencies Non-Beta cell tumorsNon-Beta cell tumors Endogenous Endogenous

hyperinsulinismhyperinsulinism AutoimmuneAutoimmune MetabolicMetabolic Alimentary (Reactive)Alimentary (Reactive)

CaseCase Does he have an insulinoma?Does he have an insulinoma?

Should have fasting hypoglycemiaShould have fasting hypoglycemia Only occurring after meals is unusualOnly occurring after meals is unusual

ImagingImaging Triple phase spiral CTTriple phase spiral CT Transabdominal ultrasound of the pancreasTransabdominal ultrasound of the pancreas

Arterial calcium-stimulation testingArterial calcium-stimulation testing Increased insulin from the splenic artery distributionIncreased insulin from the splenic artery distribution

Underwent partial pancreatectomyUnderwent partial pancreatectomy

HistologyHistology

Normal islet Hypertrophic islet cells

Insulin cells lining the pancreatic ducts(Nesidioblastosis)

What is Nesidioblastosis?What is Nesidioblastosis?

Pathological description of islet Pathological description of islet cells budding off pancreatic ductscells budding off pancreatic ducts

Hyperinsulinemic hypoglycemiaHyperinsulinemic hypoglycemia Affects the newborn populationAffects the newborn population

Loss of function in Sur 1 (Kir 6.2)Loss of function in Sur 1 (Kir 6.2) Gain of function GDH and GKGain of function GDH and GK Deletion of chromosome 11p150Deletion of chromosome 11p150

TransientTransient DiazoxideDiazoxide OctreotideOctreotide

PersistentPersistent Partial pancreatectomyPartial pancreatectomy

Hyperinsulinemia Hypoglycemia Hyperinsulinemia Hypoglycemia From Gastric-Bypass?From Gastric-Bypass?

Service et. al., NEJM 2005, 353(3):249-54

Hyperinsulinemia Hypoglycemia Hyperinsulinemia Hypoglycemia In Adults?In Adults?

45 cases in the literature45 cases in the literature Earliest report 1975Earliest report 1975 Found due to surgical Found due to surgical

resection for insulinomaresection for insulinoma One case after pancreatic One case after pancreatic

transplanttransplant No mutations in MEN 1, No mutations in MEN 1,

Sur1 or Kir6.2 Sur1 or Kir6.2

Postprandial Postprandial hypoglycemiahypoglycemia

Neuroglycopenic Neuroglycopenic symptoms symptoms

Incidence Incidence Male = FemaleMale = Female

Obese and leanObese and lean AgeAge

11 to 84 years11 to 84 years

QuestionsQuestions

Does altering gastric Does altering gastric anatomy result in anatomy result in hyperinsulinemia hyperinsulinemia hypoglycemia?hypoglycemia?

Is weight loss revealing Is weight loss revealing underlying pathology?underlying pathology?

Points of DiscussionPoints of Discussion Discuss the interaction between hormones Discuss the interaction between hormones

and regulation of appetite and regulation of appetite Review metabolic changes associated Review metabolic changes associated

with gastric by-pass surgery with gastric by-pass surgery Decide if gastric by-pass is a risk factor for Decide if gastric by-pass is a risk factor for

hyperinsulinemia hypoglycemiahyperinsulinemia hypoglycemia

Peptides, Hormones & NeurotransmittersPeptides, Hormones & Neurotransmitters Effect On EatingEffect On Eating

OrexigenicOrexigenic AnorecticAnorectic

Neuropeptide Y (YNeuropeptide Y (Y11)) SerotoninSerotonin

GABA (A)GABA (A) CholecystokininCholecystokinin

Norepinephrine (Norepinephrine (αα22)) Dopamine (DDopamine (D22))

Glucocorticoid (type II)Glucocorticoid (type II) LeptinLeptin

GalaninGalanin InsulinInsulin

OpiodsOpiods TRHTRH

Aldosterone (type I)Aldosterone (type I) CalcitoninCalcitonin

OpiodsOpiods BombesinBombesin

GHRHGHRH VIPVIP

GhrelinGhrelin CRHCRH

NeurotensinNeurotensin

CGRPCGRP

GlucagonGlucagon

IL-1 and 2IL-1 and 2

TNF, ProstaglandinTNF, Prostaglandin

Appetite ControlAppetite Control

Wynne et. al., JCEM 2004, 89(6):2576-2582

Intestinal Regulation of AppetiteIntestinal Regulation of Appetite

GhrelinGhrelin Secreted from oxyntic Secreted from oxyntic

cells of stomachcells of stomach Initiates hungerInitiates hunger

Increases before mealIncreases before meal Decreases afterwardDecreases afterward

Increases calorie Increases calorie intakeintake

True role in True role in decreasing appetite is decreasing appetite is debateddebated

Intestinal Regulation of AppetiteIntestinal Regulation of Appetite Peptide YY (PYY) Peptide YY (PYY)

Satiety and nutrient Satiety and nutrient absorption absorption

Crosses blood brain barrierCrosses blood brain barrier Secreted from entire intestineSecreted from entire intestine

Greater in distalGreater in distal L cellsL cells

Stimulated by food via vagal Stimulated by food via vagal stimulationstimulation

Increased levelsIncreased levels High calorieHigh calorie FatFat

Inactivated by dipeptidyl Inactivated by dipeptidyl peptidase IV (DPPIV)peptidase IV (DPPIV)

Pancreatic polypeptide (PP)Pancreatic polypeptide (PP) Satiety and nutrient absorptionSatiety and nutrient absorption Produced by pancreasProduced by pancreas

Colon and rectumColon and rectum Stimulated by foodStimulated by food More is released with later More is released with later

meals of the daymeals of the day

Increased with anorexiaIncreased with anorexia Variable levels seen with Variable levels seen with

obesityobesity

Intestinal Regulation of AppetiteIntestinal Regulation of Appetite

Wynne et. al., JCEM 2004, 89(6):2576-2582

Intestinal Regulation of AppetiteIntestinal Regulation of Appetite Glucagon-like peptides Glucagon-like peptides

(GLP-1 & 2)(GLP-1 & 2) SatietySatiety Expressed in brain, Expressed in brain,

pancreas and small pancreas and small intestineintestine

L-cellsL-cells Stimulated by foodStimulated by food Acts via the GLP-1 Acts via the GLP-1

receptorreceptor Augments postprandial Augments postprandial

insulin secretioninsulin secretion Decreases gastric motilityDecreases gastric motility Inhibits gastric acid Inhibits gastric acid

secretionsecretion

Oxyntomodulin (OXM)Oxyntomodulin (OXM) SatietySatiety Expressed in brain, and small Expressed in brain, and small

intestineintestine L-cellsL-cells

Stimulated by foodStimulated by food Acts via the GLP-1 receptorActs via the GLP-1 receptor Augments postprandial Augments postprandial

insulin secretioninsulin secretion Decreases gastric motilityDecreases gastric motility Inhibits gastric acid secretionInhibits gastric acid secretion Meal terminationMeal termination

Inhibits GhrelinInhibits Ghrelin

Intestinal Regulation of AppetiteIntestinal Regulation of Appetite

Cholecystokinin Cholecystokinin (CCK)(CCK) Satiety and nutrient Satiety and nutrient

absorptionabsorption Released by Released by

duodenum and duodenum and jejunumjejunum

L cellsL cells

Stimulated by Stimulated by intraluminal foodintraluminal food

Bariatric SurgeryBariatric Surgery

Gastric Banding30-50% weight loss

Roux-en-Y-gastric bypass50-80% weight loss

Bariatric SurgeryBariatric Surgery

Most effective way to Most effective way to achieve weight lossachieve weight loss

Reduces weight by Reduces weight by 35-40%35-40%

Maintained for 15 Maintained for 15 yearsyears

Decreases appetiteDecreases appetite Malabsorption is Malabsorption is

limitedlimited

Bariatric SurgeryBariatric SurgeryComplicationsComplications

Immediate post surgical Immediate post surgical risksrisks

MalabsorptionMalabsorption Limited timeLimited time

Dumping syndromeDumping syndrome NauseaNausea BloatingBloating ColicColic DiarrheaDiarrhea Light headednessLight headedness DiaphoresisDiaphoresis PalpitationsPalpitations

Bariatric SurgeryBariatric SurgeryBenefitsBenefits

Improves obesity-related Improves obesity-related comorbiditiescomorbidities DiabetesDiabetes HypertensionHypertension DyslipidemiaDyslipidemia Nonalcoholic steatosisNonalcoholic steatosis Sleep apneaSleep apnea

Reflux esophagitisReflux esophagitis Venous stasis ulcersVenous stasis ulcers InfertilityInfertility ArthritisArthritis Pseudotumor cerebriPseudotumor cerebri Stress incontinenceStress incontinence

Bariatric SurgeryBariatric SurgeryPhysiologyPhysiology

Dixon et al., JCEM 2005, 90(2):813-19

BandedN=17

ControlN=17

Bariatric SurgeryBariatric SurgeryPhysiologyPhysiology

0700 0900 1000 1100

0700 0900 1000 1100

Dixon et al., JCEM 2005, 90(2):813-19

135

125

115

105

95

85

60

30

40

20

10

50

Glucose mg/dl Insulin uIU/L

□ BMI matched controls N=17●○ Lap band patients N=17

Gastric-bypassGastric-bypassHormonal ChangesHormonal Changes

After bypassAfter bypass Ghrelin variable resultsGhrelin variable results Leptin decreasesLeptin decreases Glucose decreasesGlucose decreases Insulin decreasesInsulin decreases Adiponectin increasesAdiponectin increases CCK, VIP and CCK, VIP and

Serotonin unaffectedSerotonin unaffected

Gastric-bypassGastric-bypassHormonal ChangesHormonal Changes

Future studiesFuture studies Response of other Response of other

intestinal hormonesintestinal hormones Understand the Understand the

complex interactions complex interactions between hormones between hormones and appetiteand appetite

Other unidentified Other unidentified players?players?

Hyperinsulinemia Hypoglycemia Hyperinsulinemia Hypoglycemia From Gastric-Bypass?From Gastric-Bypass?

Service et. al., NEJM 2005, 353(3):249-54

ββ-cell Proliferation-cell Proliferation

Authors postulate that gastric-bypass Authors postulate that gastric-bypass increases incretin like substances increases incretin like substances Increased bolus delivery to distal small Increased bolus delivery to distal small

intestineintestine ββ-cells stimulated to increased insulin -cells stimulated to increased insulin

secretion = hypertrophysecretion = hypertrophy What happens to islet cells with incretin What happens to islet cells with incretin

supplementation?supplementation?

Animal StudiesAnimal StudiesExenatideExenatide

Non diabetic obese Non diabetic obese male Zucker ratsmale Zucker rats

3 groups3 groups Control given salineControl given saline

N=11N=11 Exenatide treated and Exenatide treated and

PO ad lib PO ad lib N=10N=10

Pair fedPair fed N=10N=10

6 week study6 week study

Gedulin, B. R. et al. Endocrinology 2005;146:2069-2076

Animal StudiesAnimal StudiesExenatideExenatide

Gedulin, B. R. et al. Endocrinology 2005;146:2069-2076

Animal StudiesAnimal StudiesExenatideExenatide

Absolute mass Absolute mass unchangedunchanged

No comment about No comment about hypertrophyhypertrophy Absolute Absolute ββ-cell mass-cell mass

Improved sensitivityImproved sensitivity Decrease in Decrease in ββ-cell mass-cell mass No evidence for No evidence for

hypertrophy in presence hypertrophy in presence of incretins of incretins

Gedulin, B. R. et al. Endocrinology 2005;146:2069-2076

● Ex∆ PF○ CL

ConclusionsConclusions Does altering gastric anatomy Does altering gastric anatomy

result in hyperinsulinemia result in hyperinsulinemia hypoglycemia?hypoglycemia? Currently no evidence to support Currently no evidence to support

Is weight loss revealing Is weight loss revealing underlying pathology?underlying pathology? PossiblyPossibly Insulin resistance is protectiveInsulin resistance is protective

Patients that need surgeryPatients that need surgery Unknown defect in Unknown defect in ββ-cell function-cell function

Hypoglycemia TrialsHypoglycemia TrialsAre patients not identified?Are patients not identified?

Multiple studies Multiple studies Patients are rarely hypoglycemic with Patients are rarely hypoglycemic with

symptomssymptoms Normal non-symptomatic patient can be Normal non-symptomatic patient can be

hypoglycemiahypoglycemia Brun JF, et. al., Diabetologia 1995, 38(4)Brun JF, et. al., Diabetologia 1995, 38(4) Palardy J et. al., NEJM 1989, 321(21)Palardy J et. al., NEJM 1989, 321(21) Buss RW et. al., Hormone & Metabolism Research Buss RW et. al., Hormone & Metabolism Research

1982, 14(6)1982, 14(6) Lev-Rau et al, Diabetes 1981, 30(12)Lev-Rau et al, Diabetes 1981, 30(12)