Hyperinsulinemic Hypoglycemia  Following Gastric Bypass Mary-Elizabeth Patti MD Investigator and Adult Endocrinologist Jos...
Thank you to… Joslin   Clinical Colleagues CRC Nurses & Staff Patients! Allison Goldfine Raquel Bernier Emily Devine Emmy ...
<ul><li>Postprandial hypoglycemia  is increasingly recognized in patients following gastric bypass.  </li></ul><ul><li>Oft...
<ul><li>Some patients have  very severe hypoglycemia with  neuroglycopenia: </li></ul><ul><ul><li>Loss of consciousness, c...
What can we learn from this syndrome?
OVERVIEW <ul><li>Clinical presentation of post-bypass hyperinsulinemic hypoglycemia syndrome </li></ul><ul><li>Pancreas pa...
<ul><li>27 year old female with obesity dating to childhood underwent vertical banded gastroplasty (VBG) for severe obesit...
<ul><li>Presented with progressive postprandial hypoglycemia 1 year after RYGB </li></ul><ul><li>Initially episodes 2-3 ho...
<ul><li>Symptomatic episode: </li></ul><ul><li>Glucose 40 mg/dl, Insulin 10  μ U/ml, C-peptide 2.6 ng/ml </li></ul><ul><li...
Representative Case - I <ul><li>66  year old female with obesity since adolescence  (BMI 48 kg/m2) </li></ul><ul><li>No pe...
<ul><li>Despite avoidance of simple CHO and acarbose, symptoms increased in frequency and severity (3 per day), with falls...
<ul><li>Increasing symptoms (confusion, syncope, falls)  despite efforts to reduce stimulus for insulin  secretion: </li><...
<ul><li>Arteriography negative for insulinoma </li></ul><ul><li>↑  Calcium-stimulated insulin secretion in distribution of...
<ul><li>Subtotal pancreatectomy   performed (3 years post RYGB) due to increasing frequency of hypoglycemia with seizures ...
Characteristics of Patients with Severe Post-Bypass Hypoglycemia (Neuroglycopenia) * First neuroglycopenic episode Age Gen...
Anti-Glucagon Stain CONTROL Patient 1 Patient 2 Patient 3 Patti et al Diabetologia, 2005.  Surgical Pathology in Patients ...
Clusters of Islets <ul><li>May be adjacent to ducts </li></ul><ul><li>Both isolated and in clusters </li></ul>
Is This Islet Histology Abnormal or Not? What does human pancreas look like after rapid weight loss of 20 kg/m 2  ?
OVERVIEW <ul><li>Clinical presentation of post-bypass hyperinsulinemic hypoglycemia syndrome </li></ul><ul><li>Pancreas pa...
<ul><li>4 experimental groups:  </li></ul><ul><li>GB + NG :  Post-bypass hypoglycemia patients with  neuroglycopenia  </li...
What are the metabolic profiles of these patients? Overnight Fast IV Placed Basal Samples Ensure 240 ml 40 g CHO 0 60 120 ...
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 Pos...
Time (min) 0 20 40 60 80 100 120 Glucose (mg/dl) Postprandial Glucose Patterns Differ in Post-GB Patients Overweight Goldf...
Time (min) 0 20 40 60 80 100 120 Glucose (mg/dl) Postprandial Glucose Patterns Differ in Post-GB Patients * * p (ANOVA) = ...
Time (min) 0 20 40 60 80 100 120 Glucose (mg/dl) * * p (ANOVA) = 0.06 NeuroglycopeniaPost GB Postprandial Glucose Patterns...
Asymptomatic  Hypoglycemia is Frequent During MMTT in Post-GB Controls Subject Fasting 30 min 60 min 120 min 1 79 114 39 6...
Time (min) 0 20 40 60 80 100 120 Glucose (mg/dl) Glucose Lower and Insulin Higher in Post-GB Patients with Neuroglycopenia...
Insulin Sensitivity is Increased in Post-Bypass Patients, But Does Not Differ in Patients with Neuroglycopenia HOMA-IR (In...
Time (min) 0 20 40 60 80 100 120 0 100 200 300 GLP-1 Incretin Responses to Mixed Meal are Enhanced Post-GB  Goldfine & Pat...
<ul><li>Post-bypass hypoglycemia syndrome is characterized by  severe postprandial hypoglycemia & hyperinsulinemia. </li><...
<ul><li>Post-bypass hypoglycemia syndrome patients have a  functional abnormality in insulin secretion resulting in hypogl...
<ul><li>1.  What are the genetic risk factors for post-bypass hypoglycemia? </li></ul><ul><ul><li>DNA analysis of candidat...
OVERVIEW <ul><li>Clinical presentation of post-bypass hyperinsulinemic hypoglycemia syndrome </li></ul><ul><li>Pancreas pa...
<ul><li>History: </li></ul><ul><li>Has hypoglycemia been documented by venous sample at the time of symptoms? </li></ul><u...
<ul><li>Clinical and laboratory evaluation: </li></ul><ul><li>What is insulin secretion at time of documented episode of s...
<ul><li>Dietary interventions  to reduce stimulus for insulin secretion:  frequent small meals, moderate intake of low gly...
<ul><li>Stepped pharmacology : </li></ul><ul><ul><li>Acarbose  – to block CHO absorption </li></ul></ul><ul><ul><ul><li>us...
<ul><li>If pt  not responsive  to conservative dietary and pharmacological therapy </li></ul><ul><li>AND  </li></ul><ul><l...
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Bariatric Surgery

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  • Patterns verified by cgms
  • Unable to do endoscopic US due to anatomy
  • Move this to prior to pathology?
  • I’ve told you about one of my patients. Let’s review some of the others to get a sense of the type of patients with this complication. Note age range, gender, postop BMI, time post op, postprandial timing, low glc
  • Several impt points I’d like to callyour attn to Excursion in post-GB pts higher, but less so in pts with neuroglycopenia – lower throughout as compared with GB no Sx Even in patients with gb who have no Sx, pp glc can be low
  • From the previous graphs, we noted that hypoglycemia is also present in post-GB patients who are ocmpletely asymptomatic. We do not yet understand the reasons for such differences,, but possibilities include differences in CNS thresholds for sensing of hyhpoglcyemia, chronic adaptations, etc.
  • The left panel again demonstrates glc levels following mixed meal testing. The right panel demonstrates results of plasma insulin levels following mixed meal. Note that patients with GB have rapid robust increase in insulin secretion following meal ingestion as compared with either OW or MOB subjects. Patients with neuroglycopenia have even higher insulin levels, despite lower glc levels than asymptomatic GB patients.
  • Subject numbers at this time limit our conclusions
  • In 1999, Service presented 5 adults (cared for from 1995-1998) with hyperinsulinemic hypoglycemia and neuroglycopenic episodes within 4 hrs after meals, and negative 72 hr fasts
  • In 1999, Service presented 5 adults (cared for from 1995-1998) with hyperinsulinemic hypoglycemia and neuroglycopenic episodes within 4 hrs after meals, and negative 72 hr fasts
  • In 1999, Service presented 5 adults (cared for from 1995-1998) with hyperinsulinemic hypoglycemia and neuroglycopenic episodes within 4 hrs after meals, and negative 72 hr fasts
  • In 1999, Service presented 5 adults (cared for from 1995-1998) with hyperinsulinemic hypoglycemia and neuroglycopenic episodes within 4 hrs after meals, and negative 72 hr fasts
  • In 1999, Service presented 5 adults (cared for from 1995-1998) with hyperinsulinemic hypoglycemia and neuroglycopenic episodes within 4 hrs after meals, and negative 72 hr fasts
  • Bariatric Surgery

    1. 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. 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 Pathology Jeffrey Goldsmith Vania Nose External Research Colleagues William Hancock Northeastern Jens Holst University of Copenhagen Funding
    3. 3. <ul><li>Postprandial hypoglycemia is increasingly recognized in patients following gastric bypass. </li></ul><ul><li>Often considered a component of the dumping syndrome and managed with dietary modification </li></ul><ul><ul><li>frequent small meals </li></ul></ul><ul><ul><li>controlled portions of low glycemic index carbohydrates </li></ul></ul><ul><li>Medical therapy with acarbose may be helpful adjunct </li></ul>Introduction
    4. 4. <ul><li>Some patients have very severe hypoglycemia with neuroglycopenia: </li></ul><ul><ul><li>Loss of consciousness, confusion, motor vehicle accidents, and seizures </li></ul></ul><ul><ul><li>Documented hypoglycemia, with inappropriately high insulin levels </li></ul></ul><ul><ul><li>Typically unresponsive to nutritional management </li></ul></ul><ul><li>Many of these patients require medical therapy to reduce insulin secretion e.g. acarbose, octreotide, diazoxide </li></ul><ul><li>A small subset of patients with severe life-threatening hypoglycemia unresponsive to nutrition and medical management require partial pancreatectomy to achieve safety. </li></ul>Introduction Patti et al Diabetologia 2005; Service et al, NEJM 2005
    5. 5. What can we learn from this syndrome?
    6. 6. OVERVIEW <ul><li>Clinical presentation of post-bypass hyperinsulinemic hypoglycemia syndrome </li></ul><ul><li>Pancreas pathology </li></ul><ul><li>What are the metabolic profiles in affected patients? </li></ul><ul><li>Potential mechanisms? </li></ul><ul><li>Current research efforts </li></ul><ul><li>Practical diagnostic and management strategies </li></ul>
    7. 7. <ul><li>27 year old female with obesity dating to childhood underwent vertical banded gastroplasty (VBG) for severe obesity (BMI 39 kg/m 2 ) </li></ul><ul><li>No personal or family history of diabetes or hypoglycemia </li></ul><ul><li>Family history of severe obesity in mother and sister, both treated with bariatric surgery </li></ul><ul><li>Weight loss of 100 pounds in first year </li></ul><ul><li>VBG converted to gastric bypass (RYGB) due to mesh erosion </li></ul><ul><li>Continued weight loss, which stabilized at BMI 24 kg/m 2 </li></ul>History – Patient 1
    8. 8. <ul><li>Presented with progressive postprandial hypoglycemia 1 year after RYGB </li></ul><ul><li>Initially episodes 2-3 hours postprandial, but later some not clearly linked to food intake </li></ul><ul><li>No response to dietary intervention, phenytoin, β -blockers, acarbose, diazoxide or somatostatin analogue </li></ul><ul><li>No response to reversal of RYGB and regain of 100 pounds </li></ul><ul><li>Episodic hypoglycemia increased in frequency and severity </li></ul><ul><ul><li>minimum glucose 20 mg/dl </li></ul></ul><ul><ul><li>loss of consciousness, motor vehicle accident </li></ul></ul>History – Patient 1
    9. 9. <ul><li>Symptomatic episode: </li></ul><ul><li>Glucose 40 mg/dl, Insulin 10 μ U/ml, C-peptide 2.6 ng/ml </li></ul><ul><li>Negative sulfonylurea screen </li></ul><ul><li>Negative anti-insulin antibodies </li></ul><ul><li>Abdominal CT, MRI, octreotide scan negative </li></ul><ul><li>Selective arteriography and arterial injection of calcium: no insulinoma, diffuse insulin response </li></ul><ul><li>80% pancreatectomy performed 7 yrs after initial VBG (6 years post GB) due to increasing frequency of hypoglycemia </li></ul><ul><li>Pathology: diffuse islet hyperplasia, no insulinoma </li></ul><ul><li>Initial improvement, then recurrence of seizures requiring total pancreatectomy </li></ul>Investigation and Clinical Course
    10. 10. Representative Case - I <ul><li>66 year old female with obesity since adolescence (BMI 48 kg/m2) </li></ul><ul><li>No personal or family history of DM or hypoglycemia </li></ul><ul><li>Roux-en-Y gastric bypass without complications </li></ul><ul><li>Symptoms of dumping syndrome immediately postoperatively, resolved with dietary modification </li></ul><ul><li>Presented at 24 months postop ( BMI 35 kg/m 2 , stable) with palpitations, sweating, and confusion </li></ul><ul><li>Capillary glucose as low as 25 mg/dl, typically 2-3 hours postprandial and in association with symptoms </li></ul><ul><li>No fasting hypoglycemia </li></ul>
    11. 11. <ul><li>Despite avoidance of simple CHO and acarbose, symptoms increased in frequency and severity (3 per day), with falls, loss of consciousness, and witnessed seizures </li></ul><ul><li>Unprovoked symptomatic episode: </li></ul><ul><li>glucose 58 mg/dl, insulin 11 μ U/ml, C-peptide 2.9 ng/ml </li></ul><ul><li>Negative sulfonylurea screen </li></ul><ul><li>Negative anti-insulin antibodies </li></ul><ul><li>No hypoglycemia and normal suppression of insulin secretion with 72 hr fast </li></ul>Representative Case - II
    12. 12. <ul><li>Increasing symptoms (confusion, syncope, falls) despite efforts to reduce stimulus for insulin secretion: </li></ul><ul><li>dietary modification – low glycemic index </li></ul><ul><li>cornstarch (Extend bars) </li></ul><ul><li>acarbose </li></ul><ul><li>octreotide (both SQ and IM long-acting LAR) </li></ul><ul><li>diazoxide </li></ul><ul><li>calcium channel blockade </li></ul><ul><li>CT, MRI negative for pancreatic mass </li></ul><ul><li>Genetic analysis negative for mutations associated with hyperinsulinism (SUR1, Kir 6.2, GK, MEN1) </li></ul>Representative Case - III
    13. 13. <ul><li>Arteriography negative for insulinoma </li></ul><ul><li>↑ Calcium-stimulated insulin secretion in distribution of splenic and gastroduodenal arteries </li></ul>Representative Case - IV Splenic: Body, Tail Gastroduodenal: Head, Uncinate Process Superior Mesenteric: Uncinate Process, Head
    14. 14. <ul><li>Subtotal pancreatectomy performed (3 years post RYGB) due to increasing frequency of hypoglycemia with seizures and falls despite dietary and medical therapy </li></ul><ul><li>No insulinoma identified by intraoperative ultrasound or detailed gross pathological examination </li></ul><ul><li>No postoperative hypoglycemia for 3 months, but then developed mild hypoglycemia controlled with long-acting octreotide </li></ul><ul><li>3 years post-pancreatectomy: octreotide weaned due to modest fasting hyperglycemia </li></ul>Representative Case - V
    15. 15. Characteristics of Patients with Severe Post-Bypass Hypoglycemia (Neuroglycopenia) * First neuroglycopenic episode 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 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
    16. 16. Anti-Glucagon Stain CONTROL Patient 1 Patient 2 Patient 3 Patti et al Diabetologia, 2005. Surgical Pathology in Patients with Post-RNY Hyperinsulinemic Hypoglycemia <ul><li>No insulinoma </li></ul><ul><li>Diffuse increase in islet number </li></ul><ul><li>Islets of varying size & shape </li></ul>
    17. 17. Clusters of Islets <ul><li>May be adjacent to ducts </li></ul><ul><li>Both isolated and in clusters </li></ul>
    18. 18. Is This Islet Histology Abnormal or Not? What does human pancreas look like after rapid weight loss of 20 kg/m 2 ?
    19. 19. OVERVIEW <ul><li>Clinical presentation of post-bypass hyperinsulinemic hypoglycemia syndrome </li></ul><ul><li>Pancreas pathology </li></ul><ul><li>What are the metabolic profiles in affected patients? </li></ul><ul><li>Potential mechanisms? </li></ul><ul><li>Current research efforts </li></ul><ul><li>Practical diagnostic and management strategies </li></ul>
    20. 20. <ul><li>4 experimental groups: </li></ul><ul><li>GB + NG : Post-bypass hypoglycemia patients with neuroglycopenia </li></ul><ul><li>GB: Post-bypass, NO symptoms of hypoglycemia </li></ul><ul><li>OW: Obese, matched to patients’ current BMI </li></ul><ul><li>MOb: Morbidly obese, matched to patients’ preop BMI </li></ul>What hormonal responses contribute to postprandial hypoglycemia in affected patients? controls
    21. 21. What are the metabolic profiles of these patients? Overnight Fast IV Placed Basal Samples Ensure 240 ml 40 g CHO 0 60 120 180 min 30 -10 Serial Samples MIXED MEAL TOLERANCE TEST
    22. 22. 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 Morbid Obesity GB+NG GB OW MOb
    23. 23. Time (min) 0 20 40 60 80 100 120 Glucose (mg/dl) Postprandial Glucose Patterns Differ in Post-GB Patients Overweight Goldfine & Patti, JCEM 2007 60 80 100 120 140 160 180 200 GB+NG GB OW MOb
    24. 24. Time (min) 0 20 40 60 80 100 120 Glucose (mg/dl) Postprandial Glucose Patterns Differ in Post-GB Patients * * p (ANOVA) = 0.06 Asymptomatic Post GB Goldfine & Patti, JCEM 2007 60 80 100 120 140 160 180 200 GB+NG GB OW MOb
    25. 25. Time (min) 0 20 40 60 80 100 120 Glucose (mg/dl) * * p (ANOVA) = 0.06 NeuroglycopeniaPost GB Postprandial Glucose Patterns Differ in Post-GB Patients Goldfine & Patti, JCEM 2007 60 80 100 120 140 160 180 200 GB+NG GB OW MOb
    26. 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. 27. Time (min) 0 20 40 60 80 100 120 Glucose (mg/dl) 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) Goldfine & Patti, JCEM 2007 60 80 100 120 140 160 180 200 0 50 100 150 200 250 300 GB+NG GB OW MOb GB+NG GB OW MOb
    28. 28. 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 µ g/ml 0 10 20 30 * Ŧ ** ŦŦ GB + NG GB Ov MOb GB + NG GB Ov MOb
    29. 29. Time (min) 0 20 40 60 80 100 120 0 100 200 300 GLP-1 Incretin Responses to Mixed Meal are Enhanced Post-GB Goldfine & Patti, JCEM 2007 * * * * p (ANOVA) = 0.03 pmol/l GB+NG GB OW MOb GB+NG GB OW MOb Fasting GLP-1 pmol/L 10 20 30 * Ŧ 0 20 40 60 80 100 120 0 40 80 120 160 200 GIP * * * p (ANOVA) =0.0005 Time (min)
    30. 30. <ul><li>Post-bypass hypoglycemia syndrome is characterized by severe postprandial hypoglycemia & hyperinsulinemia. </li></ul><ul><ul><li>2 - 4 years after gastric bypass surgery </li></ul></ul><ul><ul><li>often unresponsive to diet & acarbose </li></ul></ul><ul><ul><li>most commonly responsive to octreotide, diazoxide </li></ul></ul><ul><li>Accurate estimate of incidence not possible </li></ul><ul><li>To date, no genetic causes have been identified </li></ul><ul><li>Rare case reports in patients with T2D predating surgery </li></ul><ul><li>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. </li></ul>SUMMARY - I
    31. 31. <ul><li>Post-bypass hypoglycemia syndrome patients have a functional abnormality in insulin secretion resulting in hypoglycemia. </li></ul><ul><li>Potential mechanisms include: </li></ul><ul><li>Improved insulin sensitivity post weight loss, unmasking familial hyperinsulinemia </li></ul><ul><li>Enhanced insulin secretion related to the post-bypass hormonal milieu, including excess incretins (GLP1) </li></ul><ul><li>? inappropriately  islet mass in affected patients - will require further studies of β -cell mass in humans with obesity and major weight loss </li></ul><ul><ul><li>Lack of regression of increased β -cell mass with prior obesity </li></ul></ul><ul><ul><li>Active expansion of β -cell mass, perhaps mediated by GLP-1? </li></ul></ul><ul><li>Additional factors may contribute to disease severity in symptomatic vs. asymptomatic patients. </li></ul>SUMMARY - II
    32. 32. <ul><li>1. What are the genetic risk factors for post-bypass hypoglycemia? </li></ul><ul><ul><li>DNA analysis of candidate genes </li></ul></ul><ul><li>2. Is this syndrome caused by incretin hypersecretion? </li></ul><ul><ul><li>Is there hyperresponsiveness to IV glucose as well? </li></ul></ul><ul><ul><li>Can we therapeutically block GLP1 action to improve hypoglycemia? </li></ul></ul><ul><li>3. Can we identify other systemic factors contributing to hypoglycemia? </li></ul><ul><ul><li>Novel hormones or peptides: known candidates, proteomic analysis </li></ul></ul><ul><ul><li>Alterations in enterohepatic recirculation? </li></ul></ul><ul><ul><li>Role of macro- and micronutrient deficiencies? </li></ul></ul><ul><ul><li>Alterations in energy expenditure or systemic metabolism? </li></ul></ul><ul><li>4. What is the role of β - cell hyperresponsiveness vs. increased mass? </li></ul><ul><ul><li>Noninvasive imaging </li></ul></ul><ul><ul><li>How is islet gene expression altered in post-GB patients? </li></ul></ul><ul><ul><ul><li>laser capture microdissection (LCM) of islet samples </li></ul></ul></ul><ul><ul><li>Do islets hyperrespond ex vivo ? </li></ul></ul>Unanswered Questions and Research Efforts
    33. 33. OVERVIEW <ul><li>Clinical presentation of post-bypass hyperinsulinemic hypoglycemia syndrome </li></ul><ul><li>Pancreas pathology </li></ul><ul><li>What are the metabolic profiles in affected patients? </li></ul><ul><li>Potential mechanisms? </li></ul><ul><li>Current research efforts </li></ul><ul><li>Practical diagnostic and management strategies </li></ul>
    34. 34. <ul><li>History: </li></ul><ul><li>Has hypoglycemia been documented by venous sample at the time of symptoms? </li></ul><ul><ul><li>If not, consider other potential causes of postprandial symptoms - e.g. dumping syndrome. </li></ul></ul><ul><ul><li>Asymptomatic hypoglycemia is not infrequent post-bypass. </li></ul></ul><ul><li>Is hypoglycemia always postprandial? </li></ul><ul><ul><li>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 </li></ul></ul><ul><ul><li>Fasting pattern may also suggest nutritional deficiency (inadequate glycogen stores or impaired gluconeogenesis) </li></ul></ul><ul><li>Personal or family history of hypoglycemia? MEN? </li></ul><ul><li>Any symptoms to suggest adrenal insufficiency, other causes of hypoglycemia? </li></ul><ul><li>Alcohol, excess caffeine, other medications? </li></ul>Clinical Diagnostic Strategies
    35. 35. <ul><li>Clinical and laboratory evaluation: </li></ul><ul><li>What is insulin secretion at time of documented episode of symptomatic hypoglcyemia? </li></ul><ul><ul><li>Assess insulin & C-peptide levels in context of glucose. With hypoglycemia, insulin should be fully suppressed. </li></ul></ul><ul><ul><li>Sulfonylurea screen </li></ul></ul><ul><ul><li>Anti-insulin antibodies </li></ul></ul><ul><ul><li>Consider evaluation of adrenal function. </li></ul></ul><ul><ul><li>Assess general health status, wt stability, renal/hepatic tests, CBC. </li></ul></ul><ul><li>Is hypoglycemia always postprandial? </li></ul><ul><ul><li>If not, need to assess fasting insulin secretion: overnight fasting for glucose/insulin, or prolonged fast in hospital </li></ul></ul><ul><ul><li>Consider anatomic evaluation: CT, MRI (endoscopic US technically limited) </li></ul></ul>Clinical Diagnostic Strategies
    36. 36. <ul><li>Dietary interventions to reduce stimulus for insulin secretion: frequent small meals, moderate intake of low glycemic index carbohydrates (<30 g/meal); RD assessment </li></ul><ul><li>Extend bars (cornstarch): www.extendbar.com </li></ul><ul><li>Avoid EtOH, caffeine. </li></ul><ul><li>Safety: Test glucose before driving, before bed, in situations where hypoglycemia likely: </li></ul><ul><ul><li>After meals </li></ul></ul><ul><ul><li>After exercise </li></ul></ul><ul><ul><li>Nocturnal, especially if AM headaches, vivid dreams, sweating </li></ul></ul><ul><li>Consider CGMS evaluation and/or purchase to detect trends early. </li></ul><ul><li>Family instruction in glucagon use, medical ID bracelet. </li></ul><ul><li>Correct nutrient deficiencies: Fe, B12, vitamin D, Ca, B-complex, minerals </li></ul>Clinical Management Strategies
    37. 37. <ul><li>Stepped pharmacology : </li></ul><ul><ul><li>Acarbose – to block CHO absorption </li></ul></ul><ul><ul><ul><li>usually limited by abdominal gas </li></ul></ul></ul><ul><ul><li>Octreotide – to reduce insulin secretion </li></ul></ul><ul><ul><ul><li>options: preprandial SQ and monthly IM </li></ul></ul></ul><ul><ul><ul><li>50 μ g pre-meal to start (1 mg/ml multidose vials, dose using insulin syringe) </li></ul></ul></ul><ul><ul><ul><li>Usually limited by diarrhea </li></ul></ul></ul><ul><ul><ul><li>Occasional worsening of hypoglycemia immediately after injection, presumably due to inhibition of glucagon secretion </li></ul></ul></ul><ul><ul><li>Diazoxide – to reduce insulin secretion </li></ul></ul><ul><ul><li>Pramlintide (Symlin) – efficacy in several patients </li></ul></ul><ul><ul><li>No response to calcium channel blockade, anticholinergics,  -blockade in our experience </li></ul></ul>Clinical Management Strategies
    38. 38. <ul><li>If pt not responsive to conservative dietary and pharmacological therapy </li></ul><ul><li>AND </li></ul><ul><li>Continues to have severe life-threatening documented hypoglycemia: </li></ul><ul><li>Arteriography with calcium-stimulated insulin secretion testing </li></ul><ul><li>1. Rule out insulinoma </li></ul><ul><li>2. Confirm typical pattern of abnormal response </li></ul><ul><li>3. Guide decision-making for potential surgical management </li></ul><ul><li>Only then --- consider partial pancreatectomy </li></ul>Clinical Management Strategies
    39. 39. Thank you!

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