bariatric surgery

Hyperinsulinemic Hypoglycemia Following Gastric Bypass

Mary-Elizabeth Patti MDInvestigator and Adult EndocrinologistJoslin Diabetes CenterAssistant Professor of MedicineHarvard Medical School

Thank you to…

Joslin

Clinical Colleagues

CRC Nurses & Staff

Patients!

Allison GoldfineRaquel BernierEmily Devine

Emmy Suhl

Rohit KulkarniSiming Liu

Susan Bonner-WeirGordon WeirMin Ho Jung

Surgery

Edward MunDaniel JonesBen SchneiderDouglas HantoMark CalleryTom Clancy

Pathology

Jeffrey GoldsmithVania Nose

External Research Colleagues

William HancockNortheastern

Jens HolstUniversity of Copenhagen

Funding

http://www.jdrf.org/index.cfm

• 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.

Introduction

Patti et al Diabetologia 2005; Service et al, NEJM 2005

What can we learn from this syndrome?

OVERVIEWOVERVIEW

• 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

• 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, 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

History – Patient 1

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

Investigation and Clinical Course

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

• 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

• 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

• 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

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

Age GenderPre-Op

BMIPost-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 3.3Confusion, blurred

vision1 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

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

* First neuroglycopenic episode

Anti-Glucagon Stain

CONTROL Patient 1 Patient 2 Patient 3

Patti et al Diabetologia, 2005.

Surgical Pathology in Patients with Post-RNY Hyperinsulinemic Hypoglycemia

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

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 ?

OVERVIEWOVERVIEW







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 hormonal responses contribute to postprandial hypoglycemia in affected patients?

What are the metabolic profiles of these patients?

Overnight Fast

IV Placed

Basal Samples

Ensure240 ml

40 g CHO

0 60 120 180 min30-10

Serial Samples

MIXED MEAL TOLERANCE TEST

Time (min)

0 20 40 60 80 100 120

Glucose (mg/dl)

60

80

100

120

140

160

180

200

Postprandial Glucose Patterns Differ in Post-GB Patients

Goldfine & Patti, JCEM 2007

GB+NG

GBOW MOb

Morbid Obesity

Time (min)

0 20 40 60 80 100 120

Glucose (mg/dl)

60

80

100

120

140

160

180

200


GB+NG

GBOW MOb

Overweight


Time (min)

0 20 40 60 80 100 120

Glucose (mg/dl)

60

80

100

120

140

160

180

200


* *

p (ANOVA) = 0.06

GB+NG

GBOW MOb

Asymptomatic Post GB


Time (min)

0 20 40 60 80 100 120

Glucose (mg/dl)

60

80

100

120

140

160

180

200

* *

p (ANOVA) = 0.06

GB+NG

GBOW MOb

NeuroglycopeniaPost GB



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

Time (min)

0 20 40 60 80 100 120

Glucose (mg/dl)

60

80

100

120

140

160

180

200

Glucose Lower and Insulin Higher in Post-GB Patients with Neuroglycopenia

* *

p (ANOVA) = 0.06

0 20 40 60 80 100 120

Insulin (µU/ml)

0

50

100

150

200

250

300

GB+NG

GBOW MOb

GB+NG

GBOW MOb


Insulin Sensitivity is Increased in Post-Bypass Patients, But Does Not Differ in Patients with

Neuroglycopenia

HOMA-IR (Insulin Resistance Measure)

0

2

4

6

8

* Ŧ

** ŦŦ ##

Adiponectin

µg

/ml

0

10

20

30

* Ŧ ** ŦŦ

GB + NG

GB Ov MOb GB + NG

GB Ov MOb

Time (min)

0 20 40 60 80 100 120

0

100

200

300

GLP-1

Incretin Responses to Mixed Meal are Enhanced Post-GB


*

*

*

*

p (ANOVA) = 0.03

pm

ol/

l

GB+NG

GBOW MOb

GB+NGGB

OWMOb

Fasting GLP-1

pmol/L

10

20

30

*

Ŧ

0 20 40 60 80 100 1200

40

80

120

160

200

GIP

* *

*p (ANOVA) =0.0005

Time (min)

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.

SUMMARY - I

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.

SUMMARY - II

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?

Unanswered Questions and Research Efforts

OVERVIEWOVERVIEW







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 Diagnostic 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

http://www.extendbar.com/

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


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!

bariatric surgery

Health & Medicine

frequent small meals

current research efforts

negative sulfonylurea screen

insulin secretion

dumping syndrome

prolonged fast

gastric bypass

potential mechanisms