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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! Allison Goldfine

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slide1

Hyperinsulinemic Hypoglycemia

Following Gastric Bypass

Mary-Elizabeth Patti MD

Investigator and Adult Endocrinologist

Joslin Diabetes Center

Assistant Professor of Medicine

Harvard Medical School

slide2

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

introduction
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
introduction4
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

slide6

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
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 18
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, β-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
investigation and clinical course
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 recurrenceof seizures requiringtotal pancreatectomy

slide10

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
slide11
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 - II

slide12
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 - III

slide13
Arteriography negative for insulinoma

↑ Calcium-stimulated insulin secretion in distribution of splenic and gastroduodenal arteries

Representative Case - IV

Splenic: Body, Tail

Gastroduodenal:

Head, Uncinate Process

Superior Mesenteric:

Uncinate Process, Head

slide14
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

Representative Case - V

slide15

Characteristics of Patients with Severe Post-Bypass Hypoglycemia (Neuroglycopenia)

* First neuroglycopenic episode

slide16

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.

slide17

Clusters of Islets

  • May be adjacent to ducts
  • Both isolated and in clusters
slide18

Is This Islet Histology Abnormal or Not?

What does human pancreas look like after rapid weight loss of 20 kg/m2 ?

slide19

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
slide20

controls

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
slide21

-10

0

30

60

120

180 min

Serial Samples

Overnight Fast

IV Placed

Basal Samples

Ensure

240 ml

40 g CHO

MIXED MEAL TOLERANCE TEST

What are the metabolic profiles of these patients?

slide22

GB+NG

GB

OW

MOb

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

slide23

Postprandial Glucose Patterns Differ in Post-GB Patients

GB+NG

GB

200

OW

MOb

180

160

140

120

100

80

60

Glucose (mg/dl)

Overweight

0

20

40

60

80

100

120

Time (min)

Goldfine & Patti, JCEM 2007

slide24

GB+NG

GB

200

OW

MOb

180

160

140

120

100

80

60

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

slide25

GB+NG

GB

200

OW

MOb

180

160

140

120

100

80

60

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

slide27

GB+NG

GB+NG

GB

GB

200

300

OW

OW

MOb

MOb

180

250

160

200

140

150

120

100

100

50

80

0

60

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

slide28

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

* Ŧ

* Ŧ

** ŦŦ

20

µg/ml

4

10

2

0

0

GB + NG

GB

Ov

MOb

GB + NG

GB

Ov

MOb

slide29

GIP

200

*

*

GB+NG

*

160

GB

p (ANOVA) =0.0005

OW

120

MOb

80

40

0

0

20

40

60

80

100

120

Time (min)

Fasting GLP-1

Ŧ

30

*

20

pmol/L

10

GB+NG

OW

MOb

GB

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

summary i
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 requiredpartial and/or total pancreatectomy for control of life-threatening neuroglycopenia. In one patient, reversal of gastric bypass was ineffective.

summary ii
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.

slide32

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?
slide33

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
slide34

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?
slide35

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)
slide36

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
slide37

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
slide38

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