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Hyperinsulinemic Hypoglycemia Following Gastric Bypass

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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Hyperinsulinemic Hypoglycemia Following Gastric Bypass

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  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, 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

  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 recurrenceof seizures requiringtotal 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. 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

  12. 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

  13. 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

  14. 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

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

  21. -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?

  22. 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

  23. 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

  24. 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

  25. 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

  26. Asymptomatic Hypoglycemia is Frequent During MMTT in Post-GB Controls

  27. 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

  28. 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

  29. 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

  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 requiredpartial 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 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.

  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 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?

  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 (<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

  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!

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