Transcript Document

Hyperinsulinemic Hypoglycemia
Following Gastric Bypass
Mary-Elizabeth Patti MD
Investigator and Adult Endocrinologist
Joslin Diabetes Center
Assistant Professor of Medicine
Harvard Medical School
Thank you to…
Joslin
Clinical Colleagues
CRC Nurses & Staff
Patients!
Surgery
Edward Mun
Daniel Jones
Ben Schneider
Douglas Hanto
Mark Callery
Tom Clancy
Allison Goldfine
Raquel Bernier
Emily Devine
Pathology
Emmy Suhl
Jeffrey Goldsmith
Vania Nose
Rohit Kulkarni
Siming Liu
Susan Bonner-Weir
Gordon Weir
Min Ho Jung
External Research
Colleagues
William Hancock
Northeastern
Jens Holst
University of Copenhagen
Funding
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
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
What can we learn from this syndrome?
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
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
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, βblockers, 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
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
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
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
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)
Representative Case - IV
• Arteriography negative
for insulinoma
Splenic:
Body, Tail
Gastroduodenal:
Head, Uncinate
Process
Superior Mesenteric:
Uncinate Process, Head
• ↑ Calcium-stimulated
insulin secretion in
distribution of splenic
and gastroduodenal
arteries
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 longacting octreotide
3 years post-pancreatectomy: octreotide weaned due to
modest fasting hyperglycemia
Characteristics of Patients with Severe Post-Bypass
Hypoglycemia (Neuroglycopenia)
Post-Op
BMI
Time
Postop
(yr)*
Clinical Description
Timing
(hour)
Glucose
(mg/dL)
Age
Gender
Pre-Op
BMI
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
40’s
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
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.
Clusters of Islets
• May be adjacent to ducts
• Both isolated and in clusters
Is This Islet Histology Abnormal or Not?
What does human pancreas look like after
rapid weight loss of 20 kg/m2 ?
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
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
controls
What are the metabolic profiles of these patients?
MIXED MEAL TOLERANCE TEST
-10
Overnight
Fast
IV Placed
0
Basal Ensure
Samples 240 ml
40 g CHO
30
60
120
Serial
Samples
180 min
Postprandial Glucose Patterns Differ in Post-GB
Patients
Glucose (mg/dl)
200
GB+NG
180
GB
OW
MOb
160
140
120
100
Morbid Obesity
80
60
0
20
40
60
80
100
120
Time (min)
Goldfine & Patti, JCEM 2007
Postprandial Glucose Patterns Differ in Post-GB
Patients
Glucose (mg/dl)
200
GB+NG
180
GB
OW
MOb
160
140
120
100
Overweight
80
60
0
20
40
60
80
100
120
Time (min)
Goldfine & Patti, JCEM 2007
Postprandial Glucose Patterns Differ in
Post-GB Patients
Glucose (mg/dl)
200
**
180
GB+NG
GB
OW
MOb
Asymptomatic
Post GB
160
140
120
100
80
60
0
20
40
60
80
100
120
Time (min)
p (ANOVA) = 0.06
Goldfine & Patti, JCEM 2007
Postprandial Glucose Patterns Differ in
Post-GB Patients
Glucose (mg/dl)
200
**
180
GB+NG
Neuroglycopenia
Post GB
160
GB
OW
MOb
140
120
100
80
60
0
20
40
60
80
100
120
Time (min)
p (ANOVA) = 0.06
Goldfine & Patti, JCEM 2007
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
Glucose Lower and Insulin Higher in Post-GB
Patients with Neuroglycopenia
Glucose (mg/dl)
Insulin (µU/ml)
300
200
**
180
GB+NG
GB
OW
MOb
160
GB+NG
250
GB
OW
MOb
200
140
150
120
100
100
50
80
0
p (ANOVA) = 0.06
60
0
20
40
60
80
100
0
120
20
40
60
80
100
120
Time (min)
Goldfine & Patti, JCEM 2007
Insulin Sensitivity is Increased in Post-Bypass
Patients, But Does Not Differ in Patients with
Neuroglycopenia
HOMA-IR (Insulin
Resistance Measure)
Adiponectin
** ŦŦ ##
8
30
6
µg/ml
*Ŧ
4
* Ŧ ** ŦŦ
20
10
2
0
0
GB +
NG
GB
Ov
MOb
GB +
NG
GB
Ov
MOb
Incretin Responses to Mixed Meal are
Enhanced Post-GB
GLP-1
GIP
300
200
*
GB
OW
MOb
200
*
100
*
*
160
*
p (ANOVA) =0.0005
120
80
40
0
p (ANOVA) = 0.03
0
20
40
60
80
Time (min)
100
120
0
0
20
40
60
80
100
120
Time (min)
Fasting GLP-1
Ŧ
pmol/L
pmol/l
* *
GB+NG
30
20
10
*
GB+NG
GB
OW
MOb
Goldfine & Patti, JCEM 2007
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 lifethreatening neuroglycopenia. In one patient, reversal
of gastric bypass was ineffective.
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 β-cell mass in humans with obesity and major
weight loss
–
Lack of regression of increased β-cell mass with prior obesity
–
Active expansion of β-cell mass, perhaps mediated by GLP-1?
Additional factors may contribute to disease severity in symptomatic
vs. asymptomatic patients.
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 β-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?
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
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?
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)
Clinical Management Strategies
• Dietary interventions to reduce stimulus for insulin secretion:
frequent small meals, moderate intake of low glycemic index
carbohydrates (<30 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
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
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
Thank you!