Nesidioblastosis After Gastric-Bypass Surgery Heidi Chamberlain Shea, MD Endocrine Associates of Dallas

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

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 (< 3) C-peptide 1.8 ng/ml (< 0.6) Negative sulfonylurea screen

Differential Diagnosis Hypoglycemia 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

Differential Diagnosis Hypoglycemia Drugs Insulin Sulfonylurea Alcohol Pentamidine Quinine Salicylates Sulfonamides

Differential Diagnosis Hypoglycemia Metabolic disorders Galactosemia Fructose intolerance Fatty acid oxidation defects Glycogen storage disorders Endogenous hyperinsulinism Insulinoma Auto-antibodies to insulin or the β-cell Functional β-cell disorder

Beta-cell Function SUR 1 (Kir 6.2) α-Ketoglutarate GDH Glutamate

Differential Diagnosis Post-prandial Hypoglycemia Drugs Critical illness Hormonal deficiencies Non-Beta cell tumors Endogenous hyperinsulinism Autoimmune Metabolic Alimentary (Reactive)

Case Does he have an insulinoma? Imaging 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

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

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

Hyperinsulinemia Hypoglycemia From Gastric-Bypass? Service et. al., NEJM 2005, 353(3):249-54

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

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

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

Peptides, Hormones & Neurotransmitters Effect On Eating Orexigenic Anorectic Neuropeptide Y (Y1) Serotonin GABA (A) Cholecystokinin Norepinephrine (α2) Dopamine (D2) Glucocorticoid (type II) Leptin Galanin Insulin Opiods TRH Aldosterone (type I) Calcitonin Bombesin GHRH VIP Ghrelin CRH Neurotensin CGRP Glucagon IL-1 and 2 TNF, Prostaglandin

Appetite Control Wynne et. al., JCEM 2004, 89(6):2576-2582 Intestinal peptides have local effects with secretion of digestion enzymes and affecting gastric emptying, also have neural affects Wynne et. al., JCEM 2004, 89(6):2576-2582

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

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

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

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

Intestinal Regulation of Appetite Cholecystokinin (CCK) Satiety and nutrient absorption Released by duodenum and jejunum L cells Stimulated by intraluminal food Satiety affected by decreased gastric emptying,

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

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

Bariatric Surgery Complications Immediate post surgical risks Malabsorption Limited time Dumping syndrome Nausea Bloating Colic Diarrhea Light headedness Diaphoresis Palpitations

Bariatric Surgery Benefits Improves obesity-related comorbidities Diabetes Hypertension Dyslipidemia Nonalcoholic steatosis Sleep apnea Reflux esophagitis Venous stasis ulcers Infertility Arthritis Pseudotumor cerebri Stress incontinence

Bariatric Surgery Physiology Banded N=17 Banded versus non banded controls satiety with breakfast. Ghrelin levels were Control N=17 Dixon et al., JCEM 2005, 90(2):813-19

Bariatric Surgery Physiology 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 N=17 ●○ Lap band patients N=17 Dixon et al., JCEM 2005, 90(2):813-19

Gastric-bypass Hormonal Changes After bypass Ghrelin variable results Leptin decreases Glucose decreases Insulin decreases Adiponectin increases CCK, VIP and Serotonin unaffected Adiponectin from adipose tissues responsible for increasing fatty acid oxidation and increasing insulin sensitivity without changing appetite

Gastric-bypass Hormonal Changes Future studies Response of other intestinal hormones Understand the complex interactions between hormones and appetite Other unidentified players? Adiponectin from adipose tissues responsible for increasing fatty acid oxidation and increasing insulin sensitivity without changing appetite

Hyperinsulinemia Hypoglycemia From Gastric-Bypass? Service et. al., NEJM 2005, 353(3):249-54

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

Animal Studies Exenatide Non diabetic obese male Zucker rats 3 groups Control given saline N=11 Exenatide treated and PO ad lib N=10 Pair fed 6 week study Gedulin, B. R. et al. Endocrinology 2005;146:2069-2076

Animal Studies Exenatide Insulin sensitivity increased as beta cell mass increased. When compared to insulin sensitivity, beta cell mass increased. When gross pancreas and Beta cells evaluated no change. Gedulin, B. R. et al. Endocrinology 2005;146:2069-2076

Animal Studies Exenatide ∆ PF ○ CL Absolute mass unchanged No comment about hypertrophy Absolute β-cell mass Improved sensitivity Decrease in β-cell mass No evidence for hypertrophy in presence of incretins Gedulin, B. R. et al. Endocrinology 2005;146:2069-2076

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 β-cell function When you consider all of the gastric procedures that have been done in the last 5 years alone, the incidence is rare. Also our authors are from Mayo clinic , so there may be referral bias.

Hypoglycemia Trials Are 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)