Nesidioblastosis in an adult with short gut syndrome and type 2 diabetes

Adult nesidioblastosis is characterized by endogenous hyperinsulinemia typically causing post-prandial hypoglycemia, and most commonly occurs post-Rouxen-Y gastric bypass.

AACE CLINICAL CASE REPORTS Vol 5 No 6 November/December 2019 e375

Copyright © 2019 AACE

NESIDIOBLASTOSIS IN AN ADULT WITH SHORT GUT SYNDROME AND TYPE 2 DIABETES

Mimi Wong, BSc, MBBS(Hons) 1,2 ; Luke Conway, MBBS, FRACP 1 ; Caroline Cooper, MBBS(Hons), FRCPA 2,3 ; Ashim Sinha, MD, FRACP, FACE 1,4 ;

Nirjhar Nandi, FRACP 1

Submitted for publication May 26, 2019

Accepted for publication August 2, 2019

From 1 Department of Diabetes and Endocrinology, Cairns Hospital,

Queensland, Australia, 2 School of Medicine, University of Queensland,

Australia, 3 Pathology Queensland, Princess Alexandra Hospital,

Queensland, Australia, and 4 Department of Medicine, James Cook

University, Queensland, Australia.

Address correspondence to Dr Mimi Wong, Department of Medicine, 165

Esplanade, Cairns City, QLD, 4870 Australia.

E-mail: mimi.wong@uqconnect.edu.au.

DOI: 10.4158/ACCR-2019-0243

To purchase reprints of this article, please visit: www.aace.com/reprints.

Copyright © 2019 AACE.

ABSTRACT

Objective: Adult nesidioblastosis is characterized by

endogenous hyperinsulinemia typically causing

post-pran-dial hypoglycemia, and most commonly occurs

post-Roux-en-Y gastric bypass

Methods: We report a unique case of nesidioblastosis

occurring in a 67-year-old female

Results: A 5-year history of symptomatic

hypoglyce-mia occurred in a patient with short bowel syndrome and

type 2 diabetes mellitus (T2DM) managed previously with

a glucagon-like peptide 1 (GLP-1) agonist, which achieved

significant weight loss Continuous glucose monitoring

captured 42 hypoglycemia episodes in a 2-week period,

and following an oral glucose tolerance test there was the

suggestion of a hyperinsulinemia state She was managed

with an open distal pancreatectomy, and subsequently

required medical therapy to maintain euglycemia

Conclusion: We present the first case of

nesidioblas-tosis occurring in a patient with short bowel syndrome,

pre-existing T2DM managed with a GLP-1 agonist which

achieved significant weight loss, all of which we

specu-late could have predisposed to hypoglycemia and

devel-opment of nesidioblastosis (AACE Clinical Case Rep

2019;5:e375-e379)

Abbreviations:

BSL = blood sugar level; GLP-1 = glucagon-like peptide 1; MMT = mixed meal test; RYGB = Roux-en-Y gastric bypass; T2DM = type 2 diabetes mellitus INTRODUCTION

Adult nesidioblastosis is a rare hyperinsulinemic state, classically associated with post-prandial hypoglycemia (1) Typically, hypoglycemia is provoked with a mixed-meal test (MMT) and localizing studies are invariably negative (2) It is not possible to diagnose nesidioblastosis clinically, with imaging, or biochemically Histopathologic features of adult nesidioblastosis are more variable than the more common newborn setting, and include exclusion of

an insulinoma, the presence of conspicuous islet cells with enlarged, hyperchromatic nuclei, and islet hypertrophy and hyperplasia Formation of ductuloinsular complexes is not

a distinctive feature in adults but is well reported In some cases the histopathologic changes are minimal and distinc-tion from normal pancreas is difficult (3,4)

The pathophysiology of adult nesidioblastosis remains

to be elucidated Genetic factors, trophic factors, and receptor expression on islet cells have been suggested to

be involved Roux-en-Y gastric bypass (RYGB) has been linked to nesidioblastosis, and it is thought that elevated glucagon-like peptide 1 (GLP-1) and gastric inhibitory peptide may unmask a b-cell defect (1,3)

CASE REPORT

A 67-year-old female was referred to our institution in

2018 In 2009, she had a motor vehicle accident which led

to total colectomy, resection of 75% of her small bowel, and formation of an end ileostomy This was complicated

by high-output stoma and malnutrition She was referred

to a dietician, and dietary advice included having small

and frequent meals with high fiber In addition, she had

trailed multiple pharmacologic therapies which had limited

effects, including loperamide and buscopan Enteral

feed-ing had never been used

In 2013, she was diagnosed with type 2 diabetes

mellitus (T2DM) which coincided with weight gain, from

a baseline of 45 to 50 kg (body mass index [BMI] 19),

to 75 kg (BMI 29.7) Hemoglobin A1c (HbA1c) and oral

glucose tolerance test (OGTT) at diagnosis were not

avail-able, though blood sugar levels (BSLs) through

glucom-eter peaked to 23 mmol/L Initially she was managed with

metformin for a month, and subsequently with a GLP-1

agonist (exenatide, 10 mcg twice a day) in 2013 for 18

months, which led to a dramatic weight reduction to 45

kg Lifestyle optimization and malabsorption also likely

contributed to this significant weight loss Following this, exenatide was ceased Her diabetes has since been managed with lifestyle measures with good glycemic control (HbA1c 5.3%, 34 mmol/mol), and her weight has been between 55 to 59 kg in the past few years

Since 2013 she reported having episodes of symp-tomatic hypoglycemia, with BSLs less than 4 mmol/L, which consisted of sweating, tremor, light-headedness and lethargy Initial BSL monitoring revealed fasting and post-prandial hypoglycemia to as low as 2.3 mmol/L These episodes resolved within 5 to 10 minutes of correction Initially hypoglycemia occurred once every 2 months; however, in the last 12 months she had increased episodes, and in 2018, an episode resulted in loss of consciousness which was complicated by a tibial fracture At the time her BSL was 3.6 mmol/L, and occurred 30 minutes following

a meal

A

B

Fig 1 Flash glucose monitor readings Episodes of symptomatic hypoglycemia occurred with BSL less than 4

mmol/L, and each hypoglycemic episode was treated A, Readings prior to subtotal pancreatectomy B, Readings

following subtotal pancreatectomy and commencement of 50 mg octreotide 3 times a day BSL = blood sugar level;

M = Main meals of breakfast, lunch, and dinner

Diagnostic Evaluation

Flash glucose monitoring (FreeStyle Libre, Abbott

Laboratories Ltd.) was used and captured 42 episodes of

symptomatic hypoglycemia in a 2-week period (Fig 1)

Simultaneous BSL recording via a glucometer yielded

similar readings There was no suggestion of a medical

illness or medication contributing to her hypoglycemia,

though there was suspicion of a hyperinsulinemia state

(Table 1) A 24-hour fast did not induce BSLs less than

4.3 mmol/L

Localizing studies including magnetic resonance

imaging, fluorine-18 dihydroxyphenylalanine positron

emission tomography, and endoscopic ultrasound did not

identify a focal pancreatic lesion

Management

The patient was provided with dietary advice which

included avoiding short-acting carbohydrates, and

consum-ing a high protein and fiber diet, and limitconsum-ing complex

carbohydrates and fat Oral therapy to manage

hyperin-sulinemia was deemed to be likely ineffective due to her

short bowel syndrome Prior to her open distal

pancreatec-tomy, she was provided with a trial of octreotide; however,

she preferred to pursue surgical management

Histology of her operative specimen confirmed the

diagnosis of nesidioblastosis Findings included retained

lobular architecture of the exocrine pancreas, normal

pancreatic ducts, an increased number of islets, enlarged

islets, formation of ductuloinsular complexes, and islet

cells with enlarged and hyperchromatic nuclei and

abun-dant clear cytoplasm (Fig 2)

Progress

Following her distal pancreatectomy, she

contin-ued to have episodes of symptomatic hypoglycemia The

frequency, however, was less; she had 17 episodes in a

2-week period Subsequently, acarbose and diazoxide were

commenced; however, due to limited absorption from short

bowel syndrome they were ceased and she was commenced

on octreotide She has responded well to octreotide (Fig 1), and it has been uptitrated to 100 mg 3 times a day subcutaneously

DISCUSSION

Here we present a case of nesidioblastosis occurring in

a patient with short bowel syndrome, pre-existing T2DM managed with a GLP-1 agonist, which we speculate could have predisposed to nesidioblastosis

This is the first report of nesidioblastosis occurring

in the context of short bowel syndrome There have been cases of hyperinsulinemic hypoglycemia in patients with intestinal failure, though these patients were managed with parenteral nutrition and had a high infusion of glucose which may have altered insulin secretion (5)

Short bowel syndrome induced in mouse models is associated with increased pancreatic islet size, number, and proliferation (6,7) The upper intestinal hypothesis where glycemic control improves if ingested contents avoid contact with the proximal small intestine, namely the duodenum, has been suggested to have a role, though its exact mechanism is yet to be defined (6) Additionally, increased secretion of growth factors and cytokines for intestinal adaptation may play a role (8) Perez-Arana et

al (6) postulated that the pancreatic islet cell change could reflect a stage of development of nesidioblastosis However, Barron et al (7) have shown in mouse models following intestinal resection, evidence of metabolic consequences including glucose intolerance, hepatic steatosis, and abnor-mal body composition with less lean mass (7) Though, the underlying pathophysiology of a paradoxical decrease in b-cell function following short bowel syndrome remains to

be defined (7)

Another unique feature is of pre-existing T2DM We identified only 5 prior cases of nesidioblastosis occurring

in patients with T2DM (9-13) Although the association

Table 1 Preoperative Evaluation of Hypoglycemia Fasting sample

Other

75 g oral glucose tolerance test Baseline 2.5 hours post 75 g glucose

with diabetes and nesidioblastosis is unknown, Choi et

al (11) hypothesized that the pancreatic islet cell changes

could reflect a reactive response to the b-cell destruction

or functional insufficiency seen in T2DM (11) Reports

of nesidioblastosis in patients with T2DM have been

with sulphonylurea and insulin use In our case, a GLP-1

agonist was used, the commencement of which coincided

with the same year of onset of symptomatic

hypoglyce-mia Though there are no case reports of GLP-1 agonist

use being associated with nesidioblastosis, elevated GLP-1

levels following bariatric surgery have been linked with

nesidioblastosis (1,3)

Significant weight loss, which likely resolved the

patient’s T2DM, may have also increased her propensity

to hypoglycemia Following RYGB, it has been

specu-lated that the persistent increased size of the b-cell mass

which develops in the setting of obesity, increased insulin

sensitivity and dysregulated counter-regulatory secretion

including that of glucagon, possibly predisposes patients

to hypoglycemia (14) It is possible these mechanisms may have predisposed our patient to hypoglycemia following her significant weight loss

Continuous glucose monitoring use has been described with insulinoma (15), and has been recom-mended as a hypoglycemia screening tool post-RYGB, as

it is more effective in detecting hypoglycemia than MMT (16) A flash glucometer was used for evaluation, along with an OGTT, though it is acknowledged that a MMT is the gold standard test for evaluating nesidioblastosis The limitation of using a flash glucometer is that lower BSLs are often recorded BSLs obtained from Freestyle Libre were compared to HemoCue, and the mean absolute rela-tive difference was 13.2%; with BSLs less than 4 it was 20.3% (17) We acknowledge the issue of Libre monitor-ing for hypoglycemia, though given the frequent hypo-glycemia episodes, it was believed it would be the most practical approach

CONCLUSION

We present a rare case of nesidioblastosis occur-ring in a patient with short bowel syndrome, pre-existing T2DM managed with a GLP-1 agonist, all of which may have been a predisposing factor for islet cell hyperplasia Significant weight loss could have also heightened the risk

of hypoglycemia

DISCLOSURE

The authors have no multiplicity of interest to disclose

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