Hyperinsulinemic Hypoglycemia

1
Hyperinsulinemic Hypoglycemia Following Gastric
Bypass
Mary-Elizabeth Patti MD Investigator and Adult
Endocrinologist Joslin Diabetes Center Assistant
Professor of Medicine Harvard Medical School
2
Thank you to
Joslin Clinical Colleagues CRC
Nurses Staff Patients! Allison
Goldfine Raquel Bernier Emily Devine Emmy
Suhl Rohit Kulkarni Siming Liu Susan
Bonner-Weir Gordon Weir Min Ho Jung
Surgery Edward Mun Daniel Jones Ben
Schneider Douglas Hanto Mark Callery Tom Clancy
External Research Colleagues William
Hancock Northeastern Jens Holst University of
Copenhagen
Pathology Jeffrey Goldsmith Vania Nose
Funding
3
Introduction

• Postprandial hypoglycemia is increasingly
  recognized in patients following gastric bypass.
  
• Often considered a component of the dumping
  syndrome and managed with dietary modification
• frequent small meals
• controlled portions of low glycemic index
  carbohydrates
• Medical therapy with acarbose may be helpful
  adjunct

4
Introduction

• Some patients have very severe hypoglycemia with
  neuroglycopenia
• Loss of consciousness, confusion, motor vehicle
  accidents, and seizures
• Documented hypoglycemia, with inappropriately
  high insulin levels
• Typically unresponsive to nutritional management
• Many of these patients require medical therapy to
  reduce insulin secretion e.g. acarbose,
  octreotide, diazoxide
• A small subset of patients with severe
  life-threatening hypoglycemia unresponsive to
  nutrition and medical management require partial
  pancreatectomy to achieve safety.

Patti et al Diabetologia 2005 Service et al,
NEJM 2005
5
What can we learn from this syndrome?
6
OVERVIEW

• Clinical presentation of post-bypass
  hyperinsulinemic hypoglycemia syndrome
• Pancreas pathology
• What are the metabolic profiles in affected
  patients?
• Potential mechanisms?
• Current research efforts
• Practical diagnostic and management strategies

7
History Patient 1

• 27 year old female with obesity dating to
  childhood underwent vertical banded gastroplasty
  (VBG) for severe obesity (BMI 39 kg/m2)
• No personal or family history of diabetes or
  hypoglycemia
• Family history of severe obesity in mother and
  sister, both treated with bariatric surgery
• Weight loss of 100 pounds in first year
• VBG converted to gastric bypass (RYGB) due to
  mesh erosion
• Continued weight loss, which stabilized at BMI 24
  kg/m2

8
History Patient 1

• Presented with progressive postprandial
  hypoglycemia 1 year after RYGB
• Initially episodes 2-3 hours postprandial, but
  later some not clearly linked to food intake
• No response to dietary intervention, phenytoin,
  ß-blockers, acarbose, diazoxide or somatostatin
  analogue
• No response to reversal of RYGB and regain of 100
  pounds
• Episodic hypoglycemia increased in frequency and
  severity
• minimum glucose 20 mg/dl
• loss of consciousness, motor vehicle accident

9
Investigation and Clinical Course

• Symptomatic episode
• Glucose 40 mg/dl, Insulin 10 µU/ml, C-peptide
  2.6 ng/ml
• Negative sulfonylurea screen
• Negative anti-insulin antibodies
• Abdominal CT, MRI, octreotide scan negative
• Selective arteriography and arterial injection of
  calcium no insulinoma, diffuse insulin response
• 80 pancreatectomy performed 7 yrs after initial
  VBG (6 years post GB) due to increasing frequency
  of hypoglycemia
• Pathology diffuse islet hyperplasia, no
  insulinoma
• Initial improvement, then recurrence of seizures
  requiring total pancreatectomy

10
Representative Case - I

• 66 year old female with obesity since
  adolescence (BMI 48 kg/m2)
• No personal or family history of DM or
  hypoglycemia
• Roux-en-Y gastric bypass without complications
• Symptoms of dumping syndrome immediately
  postoperatively, resolved with dietary
  modification
• Presented at 24 months postop (BMI 35 kg/m2,
  stable) with palpitations, sweating, and
  confusion
• Capillary glucose as low as 25 mg/dl, typically
  2-3 hours postprandial and in association with
  symptoms
• No fasting hypoglycemia

11
Representative Case - II

• Despite avoidance of simple CHO and acarbose,
  symptoms increased in frequency and severity (3
  per day), with falls, loss of consciousness, and
  witnessed seizures
• Unprovoked symptomatic episode
• glucose 58 mg/dl, insulin 11 µU/ml, C-peptide
  2.9 ng/ml
• Negative sulfonylurea screen
• Negative anti-insulin antibodies
• No hypoglycemia and normal suppression of insulin
  secretion with 72 hr fast

12
Representative Case - III

• Increasing symptoms (confusion, syncope, falls)
  despite efforts to reduce stimulus for insulin
  secretion
• dietary modification low glycemic index
• cornstarch (Extend bars)
• acarbose
• octreotide (both SQ and IM long-acting LAR)
• diazoxide
• calcium channel blockade
• CT, MRI negative for pancreatic mass
• Genetic analysis negative for mutations
  associated with hyperinsulinism (SUR1, Kir 6.2,
  GK, MEN1)

13
Representative Case - IV

• Arteriography negative for insulinoma
• ? Calcium-stimulated insulin secretion in
  distribution of splenic and gastroduodenal
  arteries

14
Representative Case - V

• Subtotal pancreatectomy performed (3 years post
  RYGB) due to increasing frequency of hypoglycemia
  with seizures and falls despite dietary and
  medical therapy
• No insulinoma identified by intraoperative
  ultrasound or detailed gross pathological
  examination
• No postoperative hypoglycemia for 3 months, but
  then developed mild hypoglycemia controlled with
  long-acting octreotide
• 3 years post-pancreatectomy octreotide weaned
  due to modest fasting hyperglycemia

15
Characteristics of Patients with Severe
Post-Bypass Hypoglycemia (Neuroglycopenia)
Age Gender Pre-Op BMI Post-Op BMI Time Postop (yr) Clinical Description Timing (hour) Glucose (mg/dL)
46 M 40.6 23.1 1.6 Motor vehicle accident 1-1.5 hr 29
69 F 48.4 35.2 1.8 Loss of consciousness 1 hr 50
62 F 49.7 24.5 2.4 Presyncope, confusion 3 hr low
37 F 49.7 26.8 2.8 Unresponsive 2 hr 58
42 F 65.1 37.1 0.8 Syncope, blurred vision 1 hr 24
41 F 42.0 27.7 3.3 Confusion, blurred vision 1 hr 47
52 F 54.0 28.7 1.7 Confusion 1-1.5 hr 25
56 F 65.3 37.6 1.3 Confusion 1.5 hr 39
36 F 44.8 28.1 2.7 Confusion 1 hr 23
31 F 42.8 31.1 2.0 Presyncope, confusion 3-4 hr 40s
51 M 37.0 32.4 1.3 Syncope 2-3 hr low
56 F 73.6 35.4 3.8 Grand mal seizure 1.5 48
First neuroglycopenic episode
16
Surgical Pathology in Patients with Post-RNY
Hyperinsulinemic Hypoglycemia
Anti-Glucagon Stain
CONTROL
Patient 1
Patient 2
Patient 3

• No insulinoma
• Diffuse increase in islet number
• Islets of varying size shape

Patti et al Diabetologia, 2005.
17
Clusters of Islets

• May be adjacent to ducts
• Both isolated and in clusters

18
Is This Islet Histology Abnormal or Not?
What does human pancreas look like after rapid
weight loss of 20 kg/m2 ?
19
OVERVIEW

• Clinical presentation of post-bypass
  hyperinsulinemic hypoglycemia syndrome
• Pancreas pathology
• What are the metabolic profiles in affected
  patients?
• Potential mechanisms?
• Current research efforts
• Practical diagnostic and management strategies

20
What hormonal responses contribute to
postprandial hypoglycemia in affected patients?

• 4 experimental groups
• GB NG Post-bypass hypoglycemia patients
  with neuroglycopenia
• GB Post-bypass, NO symptoms of hypoglycemia
• OW Obese, matched to patients current BMI
• MOb Morbidly obese, matched to patients
  preop BMI

21
What are the metabolic profiles of these patients?
22
Postprandial Glucose Patterns Differ in Post-GB
Patients
Glucose (mg/dl)
200
180
160
140
120
100
Morbid Obesity
80
60
0
20
40
60
80
100
120
Time (min)
Goldfine Patti, JCEM 2007
23
Postprandial Glucose Patterns Differ in Post-GB
Patients
Glucose (mg/dl)
Overweight
0
20
40
60
80
100
120
Time (min)
Goldfine Patti, JCEM 2007
24
Postprandial Glucose Patterns Differ in Post-GB
Patients
Glucose (mg/dl)


Asymptomatic Post GB
0
20
40
60
80
100
120
Time (min)
p (ANOVA) 0.06
Goldfine Patti, JCEM 2007
25
Postprandial Glucose Patterns Differ in Post-GB
Patients
Glucose (mg/dl)


NeuroglycopeniaPost GB

0
20
40
60
80
100
120
Time (min)
p (ANOVA) 0.06
Goldfine Patti, JCEM 2007
26
Asymptomatic Hypoglycemia is Frequent During MMTT
in Post-GB Controls
Subject Fasting 30 min 60 min 120 min
1 79 114 39 69
2 91 179 91 70
3 83 167 110 82
4 93 155 97 68
5 72 109 47 66
6 79 226 119 76
7 87 179 83 57
8 90 196 104 83
9 79 135 74 62
27
Glucose Lower and Insulin Higher in Post-GB
Patients with Neuroglycopenia
Glucose (mg/dl)
Insulin (µU/ml)


p (ANOVA) 0.06
0
20
40
60
80
100
120
0
20
40
60
80
100
120
Time (min)
Goldfine Patti, JCEM 2007
28
Insulin Sensitivity is Increased in Post-Bypass
Patients, But Does Not Differ in Patients with
Neuroglycopenia
HOMA-IR (Insulin Resistance Measure)
Adiponectin
TT
8
30
6
T
T
TT
20
µg/ml
4
10
2
0
0
GB NG
GB
Ov
MOb
GB NG
GB
Ov
MOb
29
Incretin Responses to Mixed Meal are Enhanced
Post-GB
GLP-1
300

200

pmol/l
100


0
p (ANOVA) 0.03
0
20
40
60
80
100
120
Time (min)
Goldfine Patti, JCEM 2007
30
SUMMARY - I

• Post-bypass hypoglycemia syndrome is
  characterized by severe postprandial hypoglycemia
  hyperinsulinemia.
• 2 - 4 years after gastric bypass surgery
• often unresponsive to diet acarbose
• most commonly responsive to octreotide,
  diazoxide
• Accurate estimate of incidence not possible
• To date, no genetic causes have been identified
• Rare case reports in patients with T2D predating
  surgery
• Some patients with severe hypoglycemia required
  partial and/or total pancreatectomy for control
  of life-threatening neuroglycopenia. In one
  patient, reversal of gastric bypass was
  ineffective.

31
SUMMARY - II

• Post-bypass hypoglycemia syndrome patients have a
  functional abnormality in insulin secretion
  resulting in hypoglycemia.
• Potential mechanisms include
• Improved insulin sensitivity post weight loss,
  unmasking familial hyperinsulinemia
• Enhanced insulin secretion related to the
  post-bypass hormonal milieu, including excess
  incretins (GLP1)
• ? inappropriately ? islet mass in affected
  patients - will require further studies of
  ß-cell mass in humans with obesity and major
  weight loss
• Lack of regression of increased ß-cell mass with
  prior obesity
• Active expansion of ß-cell mass, perhaps
  mediated by GLP-1?
• Additional factors may contribute to disease
  severity in symptomatic vs. asymptomatic
  patients.

32
Unanswered Questions and Research Efforts

• 1. What are the genetic risk factors for
  post-bypass hypoglycemia?
• DNA analysis of candidate genes
• 2. Is this syndrome caused by incretin
  hypersecretion?
• Is there hyperresponsiveness to IV glucose as
  well?
• Can we therapeutically block GLP1 action to
  improve hypoglycemia?
• 3. Can we identify other systemic factors
  contributing to hypoglycemia?
• Novel hormones or peptides known candidates,
  proteomic analysis
• Alterations in enterohepatic recirculation?
• Role of macro- and micronutrient deficiencies?
• Alterations in energy expenditure or systemic
  metabolism?
• 4. What is the role of ß-cell
  hyperresponsiveness vs. increased mass?
• Noninvasive imaging
• How is islet gene expression altered in post-GB
  patients?
• laser capture microdissection (LCM) of islet
  samples
• Do islets hyperrespond ex vivo?

33
OVERVIEW

• Clinical presentation of post-bypass
  hyperinsulinemic hypoglycemia syndrome
• Pancreas pathology
• What are the metabolic profiles in affected
  patients?
• Potential mechanisms?
• Current research efforts
• Practical diagnostic and management strategies

34
Clinical Diagnostic Strategies

• History
• Has hypoglycemia been documented by venous sample
  at the time of symptoms?
• If not, consider other potential causes of
  postprandial symptoms - e.g. dumping syndrome.
• Asymptomatic hypoglycemia is not infrequent
  post-bypass.
• Is hypoglycemia always postprandial?
• Any fasting patterns? Nocturnal hypoglycemia? If
  so, need to exclude fasting hyperinsulinemia
  (e.g. insulinoma) with outpatient overnight fast
  and/or prolonged fast in hospital
• Fasting pattern may also suggest nutritional
  deficiency (inadequate glycogen stores or
  impaired gluconeogenesis)
• Personal or family history of hypoglycemia? MEN?
• Any symptoms to suggest adrenal insufficiency,
  other causes of hypoglycemia?
• Alcohol, excess caffeine, other medications?

35
Clinical Diagnostic Strategies

• Clinical and laboratory evaluation
• What is insulin secretion at time of documented
  episode of symptomatic hypoglcyemia?
• Assess insulin C-peptide levels in context of
  glucose. With hypoglycemia, insulin should be
  fully suppressed.
• Sulfonylurea screen
• Anti-insulin antibodies
• Consider evaluation of adrenal function.
• Assess general health status, wt stability,
  renal/hepatic tests, CBC.
• Is hypoglycemia always postprandial?
• If not, need to assess fasting insulin secretion
  overnight fasting for glucose/insulin, or
  prolonged fast in hospital
• Consider anatomic evaluation CT, MRI
  (endoscopic US technically limited)

36
Clinical Management Strategies

• Dietary interventions to reduce stimulus for
  insulin secretion frequent small meals,
  moderate intake of low glycemic index
  carbohydrates (lt30 g/meal) RD assessment
• Extend bars (cornstarch) www.extendbar.com
• Avoid EtOH, caffeine.
• Safety Test glucose before driving, before bed,
  in situations where hypoglycemia likely
• After meals
• After exercise
• Nocturnal, especially if AM headaches, vivid
  dreams, sweating
• Consider CGMS evaluation and/or purchase to
  detect trends early.
• Family instruction in glucagon use, medical ID
  bracelet.
• Correct nutrient deficiencies Fe, B12, vitamin
  D, Ca, B-complex, minerals

37
Clinical Management Strategies

• Stepped pharmacology
• Acarbose to block CHO absorption
• usually limited by abdominal gas
• Octreotide to reduce insulin secretion
• options preprandial SQ and monthly IM
• 50 µg pre-meal to start (1 mg/ml multidose vials,
  dose using insulin syringe)
• Usually limited by diarrhea
• Occasional worsening of hypoglycemia immediately
  after injection, presumably due to inhibition of
  glucagon secretion
• Diazoxide to reduce insulin secretion
• Pramlintide (Symlin) efficacy in several
  patients
• No response to calcium channel blockade,
  anticholinergics, ?-blockade in our experience

38
Clinical Management Strategies

• If pt not responsive to conservative dietary and
  pharmacological therapy
• AND
• Continues to have severe life-threatening
  documented hypoglycemia
• Arteriography with calcium-stimulated insulin
  secretion testing
• 1. Rule out insulinoma
• 2. Confirm typical pattern of abnormal response
• 3. Guide decision-making for potential
  surgical management
• Only then --- consider partial pancreatectomy

39
Thank you!