ORIGINAL
ARTICLE
Post-Gastric Bypass Hyperinsulinemic Hypoglycemia: Fructose is a Carbohydrate Which Can Be Safely Consumed Anne E. Bantle, Qi Wang, and John P. Bantle Division of Endocrinology and Diabetes, Department of Medicine (A.E.B., J.P.B.), and Clinical and Translational Science Institute (Q.W.), University of Minnesota, Minneapolis, Minnesota 55455
Context: Postprandial hypoglycemia after gastric bypass surgery is a serious problem. Available treatments are often ineffective. Objective: The objective was to test the hypotheses that injection of rapid-acting insulin before a high-carbohydrate meal or replacement of other carbohydrates with fructose in the meal would prevent hypoglycemia. Design: This was a randomized, crossover trial comparing a high-carbohydrate meal with premeal saline injection (control), a high-carbohydrate meal with premeal insulin injection, and a highfructose meal with total carbohydrate content similar to the control meal. Setting: The setting was an academic medical center. Patients: Ten patients with post-gastric bypass hyperinsulinemic hypoglycemia participated. Interventions: Interventions included lispro insulin injected before test meals and replacement of other carbohydrates with fructose in test meals. Main Outcome Measure: The main outcome measure was plasma glucose ⬍ 60 mg/dL after test meals. Results: After the control meal, mean peak glucose and insulin were 173 ⫾ 47 mg/dL and 134 ⫾ 55 mU/L, respectively; mean glucose nadir was 44 ⫾ 15 mg/dL; and eight of 10 subjects demonstrated glucose ⬍ 60 mg/dL. Five subjects demonstrated a glucose nadir ⬍ 40 mg/dL. There were no significant differences in the corresponding values after premeal insulin treatment, except that the mean glucose nadir of 34 ⫾ 10 mg/dL was lower (P ⬍ .05). After the fructose meal, mean peak postprandial glucose and insulin were 117 ⫾ 20 mg/dL and 45 ⫾ 31 mU/L, respectively (both P ⬍ .001 for comparison with control), mean glucose nadir was 67 ⫾ 10 mg/dL (P ⬍ .001), and two of 10 subjects demonstrated glucose ⬍ 60 mg/dL (P ⬍ .05). Conclusions: People with post-gastric bypass hypoglycemia can consume a meal sweetened with fructose with little risk of hypoglycemia. Treatment with rapid-acting insulin before a carbohydrate-containing meal did not prevent hypoglycemia. (J Clin Endocrinol Metab 100: 3097–3102, 2015)
n 2005, Service et al (1) first described postprandial hypoglycemia causing neuroglycopenia after Roux-en-Y gastric bypass surgery. Several of their patients experi-
I
enced confusion and loss of consciousness during episodes. Subsequently, additional patients with this disorder have been described in small series and case reports (2– 8).
ISSN Print 0021-972X ISSN Online 1945-7197 Printed in USA Copyright © 2015 by the Endocrine Society Received February 1, 2015. Accepted May 28, 2015. First Published Online June 2, 2015
Abbreviations: BMI, body mass index; GLP-1, glucagon-like peptide 1.
doi: 10.1210/jc.2015-1283
J Clin Endocrinol Metab, August 2015, 100(8):3097–3102
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The prevalence of post-gastric bypass hyperinsulinemic hypoglycemia is unknown but is at least 0.36% of those patients having gastric bypass surgery (6). This is almost certainly an underestimate because it is likely that all patients with the syndrome were not identified. The syndrome appears to be specific for gastric bypass and does not occur after purely restrictive procedures such as adjustable gastric banding (9). The pathogenesis of post-gastric bypass hyperinsulinemic hypoglycemia has not been established. In the original report, Service et al (1) suggested that patients with this disorder developed hyperinsulinemia as a result of islet cell hyperplasia, perhaps due to an increase in glucagon-like peptide 1 (GLP-1) secretion. Postprandial serum insulin and GLP-1 responses are known to increase after gastric bypass surgery (10 –12), and GLP-1 has been shown to increase -cell mass in rodent models (13, 14). Several investigators, in addition to Service, have suggested that -cell mass is increased after gastric bypass (2– 4). However, this has not been a universal finding (7). Moreover, Meier et al (15) reexamined the pancreatic tissues of the patients in Service’s original report and found no evidence of increased -cell mass. They suggested that postprandial hypoglycemia after gastric bypass was due to the combination of gastric dumping and increased insulin secretion. Consistent with this, McLaughlin et al (16) described a unique patient with this disorder. The patient had a gastrostomy tube inserted into her remnant stomach. When she was given a standardized liquid test meal orally, she developed postprandial hyperglycemia and hyperinsulinemia, followed by hypoglycemia. However, when the standardized test meal was given through the gastrostomy tube into her remnant stomach, no postprandial hyperinsulinemia or hypoglycemia developed. Thus, it is not clear whether post-gastric bypass hypoglycemia results from rapid digestion and absorption of ingested nutrients or, alternatively, an increase in functional insulin secretion with or without an increase in -cell mass, perhaps induced by an increase in GLP-1 or other -cell trophic peptides. A variety of treatments for post-gastric bypass hyperinsulinemic hypoglycemia have been attempted. Service et al (1) employed an arterial calcium stimulation test to localize excessive pancreatic insulin secretion and subsequent subtotal pancreatic resection, with improvement in symptoms in some patients. However, total pancreatectomy has been required to eliminate hypoglycemia in other patients (3), resulting in iatrogenic, insulin-deficient diabetes mellitus. Gastric restriction by laparoscopic placement of a Silastic ring around the gastric pouch has been reported to be an effective treatment (7). Noninvasive treatments include low-carbohydrate diets (5, 6), coinges-
J Clin Endocrinol Metab, August 2015, 100(8):3097–3102
tion of the medication acarbose with meals containing carbohydrate to retard carbohydrate digestion (17, 18), treatment in a single patient with the somatostatin analog pasireotide (19), and continuous infusion of the GLP-1 receptor antagonist exendin 9 –39 (20). However, these approaches have not been consistently effective or are not generally available. Patients with post-gastric bypass hyperinsulinemic hypoglycemia demonstrated a greater than normal rise in plasma glucose after eating carbohydrate-containing meals (5, 6, 8). This led to a robust insulin response, hyperinsulinemia, and subsequent hypoglycemia although insulin levels declined rapidly as plasma glucose fell. Thus, it is plausible that treatment that reduces the postprandial rise in plasma glucose after a carbohydrate-containing meal would also reduce the insulin response and, thereby, the risk of hypoglycemia. With this in mind, we studied two interventions intended to prevent postprandial hyperglycemia and subsequent hypoglycemia. The first was a rapid-acting insulin analog given before a high-carbohydrate meal. The second was replacement of glucose with fructose in a high-carbohydrate meal. In healthy subjects, ingestion of fructose has been shown to produce a more modest rise in plasma glucose than ingestion of a comparable amount of glucose or glucose-containing polysaccharides and, thereby, to stimulate insulin secretion to a lesser degree (21, 22).
Subjects and Methods Three treatments were compared in random order using a crossover design. The treatments were a high-carbohydrate test meal (control condition), a high-carbohydrate test meal after pretreatment with rapid-acting lispro insulin (insulin condition), and a high-fructose test meal that was low in glucose and glucosecontaining carbohydrates but with total carbohydrate and caloric content similar to the control meal (fructose condition). The hypotheses to be tested were: 1) pretreatment with lispro insulin would prevent, or at least reduce, the occurrence of hypoglycemia; and 2) substitution of fructose for glucose in the test meal would prevent, or at least reduce, the occurrence of hypoglycemia. Study participants were 10 patients with post-gastric bypass hyperinsulinemic hypoglycemia who met the following criteria: 1) history of postprandial hypoglycemia with neuroglycopenia (confusion, seizure, loss of consciousness) occurring after gastric bypass surgery; 2) history of spontaneous correction of hypoglycemia; 3) normal fasting plasma glucose and serum insulin; 4) after a carbohydrate-containing mixed meal, demonstration at any time point of serum insulin ⬎ 50 mU/L and at any time point plasma glucose ⬍ 50 mg/dL. Treatments were separated by at least 24 hours but could be performed on consecutive days. Subjects fasted for at least 8 hours before the studies. For the control condition, subjects received a high-carbohydrate test meal composed of orange juice
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doi: 10.1210/jc.2015-1283
(8 oz), fat-free yogurt (6 oz), one piece of toasted wheat bread, margarine (1 teapoonful), and jam (2 teaspoonsful). The meal provided 403 cal from 74 g carbohydrate, 12 g protein, and 7 g fat. Of the 74 g carbohydrate, 12 g (16% of total carbohydrate) came from fructose. Ten minutes before the meal, subjects received a sc injection of saline. For the insulin condition, subjects received a test meal of the same composition, and 10 minutes before the meal, a sc injection of 1 U lispro insulin for each 15 kg of body weight. Subjects were masked as to treatment with saline or insulin. For the fructose condition, subjects received a test meal with similar amounts of carbohydrate, protein, and fat as in the control meal, but with fructose as the principal carbohydrate. The fructose meal was composed of an almond flour muffin made with fructose, lean ham (42 g), and Kool Aid made with fructose (18 oz). The meal provided 402 cal from 70 g carbohydrate, 10 g protein, and 10 g fat. Of the 70 g carbohydrate, 62 g (89% of total carbohydrate) came from fructose. Subjects received a stipend of $50 for each test day they completed and an additional $75 if they completed all three test days. The protocol was approved by the University of Minnesota Institutional Review Board, and informed consent was obtained from all subjects. Plasma glucose and serum insulin were sampled 15 minutes before and 15, 30, 45, 60, 75, 90, 105, 120, 135, 150, 180, 210, and 240 minutes after all test meals. Subjects and study staff were masked as to plasma glucose results. All blood specimens were held and sent to the laboratory after testing was completed. Before each blood draw, subjects were asked to name the date and identify their location. If they could not do so correctly, capillary blood glucose was tested. If plasma glucose was ⬍ 45 mg/dL, treatment was provided with three glucose tablets, and testing was stopped. If they could answer both questions correctly, testing continued regardless of other symptoms. After completion of the study, subjects were provided a low-carbohydrate snack and discharged. Plasma glucose and serum insulin were determined in the Clinical Chemistry Laboratory of the University of Minnesota Hospitals. The primary study endpoint was occurrence or not of plasma glucose ⬍ 60 mg/dL during the 4 hours after the test meal (binary endpoint). The control meal was compared to the insulin pretreated test meal and, in a separate comparison, to the fructose test meal. Secondary endpoints were comparisons between the control and active treatments in peak postprandial serum insulin, peak postprandial plasma glucose, nadir postprandial plasma glucose, and the 4-hour longitudinal time course of plasma glucose measurements. The three treatments were compared using standard methods for crossover designs that have binary or continuous outcomes; that is, within-person correlation was modeled, and both time and carryover effects were assessed. With 10 subjects, there was a 70% power to find a difference between the active and control treatments in the primary endpoint. Power was estimated by the percentage of significant type 3 tests for treatment. Calculations were performed in SAS version 9.3 (SAS Institute, Inc).
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Table 1. Baseline Characteristics of the 10 Study Participants Age, y Gender (female/male), n Pre-bariatric surgery weight, kg Pre-bariatric surgery BMI, kg/m2 Time from gastric bypass to study, y Weight at time of study, kg Weight loss at time of study, kg BMI at time of study, kg/m2 Time to onset of hypoglycemic episodes, y Frequency of hypoglycemic episodes, episodes/mo History of hypoglycemia causing confusion, n History of hypoglycemia causing loss of consciousness, n
48 (37– 60) 9/1 122.2 (94.5–144.1) 43.8 (32.7a-52.0) 7.6 (1.7–10.8) 78.4 (50.7–111.6) 43.8 (28.9 – 65.3) 28.2 (21.0 –36.1) 2.5 (1.0 – 8.5) 8 (1–20) 10 of 10 6 of 10
Data are expressed as mean (range) unless stated otherwise. a Gastric bypass was done in one participant for gastroesophageal reflux.
body mass index (BMI) 28.2 kg/m2 at the time of the study. All had undergone Roux-en-Y gastric bypass for weight loss, except for one subject who had gastric bypass because of gastroesophageal reflux. One subject had a laparoscopic band procedure before gastric bypass, and her pre-laparoscopic band weight was used as her preoperative weight. Mean preoperative weight and BMI were 122.2 kg and 43.8 kg/m2, respectively, and all subjects lost a substantial amount of weight after gastric bypass (mean weight loss at time of study, 43.8 kg). Symptoms of hypoglycemia started a mean of 2.5 years after bariatric surgery. No subject could recall having had symptoms of hypoglycemia in the first year after bariatric surgery. All 10 subjects had a history of hypoglycemia-induced confusion, and six subjects actually lost consciousness because of hypoglycemia. In all subjects, episodes of hypo-
Results Ten subjects completed the study. Baseline characteristics are summarized in Table 1. The subjects were one man and nine women with mean age 48 years, weight 78.4 kg, and
Figure 1. Plasma glucose values (mean ⫾ SE). *, P ⬍ .05, compared to control meal; †, P ⬍ .001, compared to control meal.
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Figure 2. Serum insulin values (mean ⫾ SE). *, P ⬍ .05, compared to control meal.
glycemia continued despite attempts to follow a lowcarbohydrate diet or to make other dietary modifications. Fasting and postprandial plasma glucose and serum insulin values for the three treatment conditions are shown in Figures 1 and 2. There were no differences among the three treatments in fasting values. After the high-carbohydrate, control meal with premeal saline injection, mean peak plasma glucose and serum insulin were 173 mg/dL and 134 mU/L, respectively (Table 2). The mean postprandial plasma glucose nadir was 44 mg/dL, and it came 132 minutes after starting the test meal. Eight of 10 subjects demonstrated a plasma glucose nadir ⬍ 60 mg/dL. Five subjects demonstrated a nadir ⬍ 40 mg/dL. The lowest plasma glucose observed was 22 mg/dL. Despite the low plasma glucose values, testing was not stopped because no subject developed evidence of neuroglycopenia during testing. As shown in Figures 1 and 2, insulin pretreatment did not prevent postprandial hyperglycemia, hyperinsulinemia, or subsequent hypoglycemia. After the high-carbohydrate meal with premeal insulin injection, mean peak postprandial plasma glucose and serum insulin were 182 Table 2.
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mg/dL and 148 mU/L, respectively, and not significantly different from the corresponding values after the control meal. All 10 subjects demonstrated a plasma glucose nadir ⬍ 60 mg/dL, and the mean plasma glucose nadir was 34 mg/dL. The mean plasma glucose nadir was significantly lower than the mean nadir after the control meal. Testing had to be stopped in one subject at 120 minutes because of confusion and a plasma glucose of 25 mg/dL. After subjects consumed the high-carbohydrate fructose meal, mean peak postprandial plasma glucose was 117 mg/dL, and mean peak postprandial serum insulin was 45 mU/L. Both values were significantly lower than during the control meal. Only two subjects demonstrated a plasma glucose nadir ⬍ 60 mg/dL, and the mean plasma glucose nadir was 67 mg/dL. The number of subjects with plasma glucose ⬍ 60 mg/dL was significantly fewer, and the mean plasma glucose nadir was significantly higher than during the control meal. Testing did not have to be stopped in any subject.
Discussion Although the prevalence of post-gastric bypass hyperinsulinemic hypoglycemia has not been established, it appears to be a serious postoperative complication. It remains unclear whether hypoglycemia results from rapid digestion and absorption of ingested nutrients (15, 16) or, alternatively, from an increase in functional insulin with or without an increase in -cell mass post-gastric bypass (2– 4). Regardless of which mechanism is responsible, reducing the rise in plasma glucose after a carbohydratecontaining meal should reduce endogenous insulin secretion and potentially prevent, or at least reduce, the severity of subsequent hypoglycemia. Accordingly, we pretreated people with this disorder with rapid-acting insulin before a high-carbohydrate test meal.
Fasting and Postprandial Test Values High-Carbohydrate High-Carbohydrate High-Carbohydrate Meal With Premeal Meal With Premeal Fructose Meal Saline Injection (Control) Insulin Injection (Insulin) (Fructose)
Fasting plasma glucose, mg/dL Fasting serum insulin, mU/L Peak postprandial plasma glucose, mg/dL Peak postprandial serum insulin, mU/L Postprandial plasma glucose ⬍ 60 mg/dL, n (%) Postprandial glucose nadir, mg/dL Time to glucose nadir, min
76 ⫾ 6 4⫾3 173 ⫾ 47 134 ⫾ 55 8 (80) 44 ⫾ 15 132 ⫾ 35
77 ⫾ 5 5⫾2 182 ⫾ 40 148 ⫾ 68 10 (100) 34 ⫾ 10a 125 ⫾ 27
81 ⫾ 8 4⫾3 117 ⫾ 20b 45 ⫾ 31b 2 (20)a 67 ⫾ 10b 126 ⫾ 28
Data are expressed as mean ⫾ SD, unless stated otherwise. a
P ⬍ .05 when compared to the control meal.
b
P ⬍ .001 when compared to the control meal.
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doi: 10.1210/jc.2015-1283
Insulin pretreatment did not prevent postprandial hypoglycemia. However, insulin pretreatment also did not reduce peak postprandial plasma glucose or serum insulin levels. This raises the possibility that the time interval between insulin injection and the test meal in our study (10 minutes) was too short or the dose of lispro insulin used (1 U/15 kg body weight) was too low. Had we waited longer after the insulin injection to start the test meal or provided a larger dose of insulin, we might have reduced the postprandial rise in plasma glucose, reduced the subsequent endogenous insulin response, and prevented hypoglycemia. These possibilities seem worthy of further study. Dietary fructose produces only a modest rise in plasma glucose and stimulates insulin secretion to a lesser degree than glucose or glucose-containing carbohydrates (21, 22). Thus, it seemed plausible that dietary fructose would be less likely than other carbohydrates to produce hypoglycemia in patients with post-gastric bypass hypoglycemia. Consistent with this, we found that a high-carbohydrate fructose test meal produced a lesser rise in plasma glucose and serum insulin than a high-carbohydrate test meal containing glucose, sucrose, and starch. The fructose test meal resulted in a plasma glucose nadir that was not as low as the high-carbohydrate control test meal nadir and fewer subjects (20%) with a postprandial plasma glucose nadir ⬍ 60 mg/dL. Our data suggest that fructose is a suitable carbohydrate for people with post-gastric bypass hypoglycemia and, perhaps, the preferred sweetening agent to be used in moderation in their diets. One of the surprising observations in our study was how well this group of patients tolerated hypoglycemia. Many times our subjects demonstrated plasma glucose values below 40 mg/dL and even below 30 mg/dL without confusion or other significant symptoms. This suggests that patients with this disorder have experienced frequent hypoglycemia and have adapted to it, a phenomenon known to happen in insulin-treated people with diabetes (23). Another observation of interest was the timing of hypoglycemia in our subjects. With all three treatments, the plasma glucose nadir was reached at about 130 minutes. This suggests that a small amount of carbohydrate taken about 90 minutes after a high-carbohydrate meal might prevent hypoglycemia. Based on this observation, we recommend to our patients with this disorder that they take one or two glucose tablets about 90 minutes after a carbohydrate-containing meal. In summary, our study demonstrated that fructose is a dietary carbohydrate that people with post-gastric bypass hypoglycemia can consume with little risk of subsequent hypoglycemia. We were not able to demonstrate that rapid-acting insulin treatment before a carbohydrate-containing meal prevented hypoglycemia, but it is possible
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that, with different timing or a different dose of insulin, hypoglycemia might be prevented.
Acknowledgments Address all correspondence and requests for reprints to: Anne E. Bantle, University of Minnesota, MMC 101, 420 Delaware Street SE, Minneapolis, MN 55455. E-mail: [email protected]. Trial Registration: Clinicaltrials.gov NCT 01933490. This work was supported by institutional funds. Disclosure Summary: The authors have nothing to disclose.
References 1. Service GJ, Thompson GB, Service FJ, Andrews JC, Collazo-Clavell ML, Lloyd RV. Hyperinsulinemic hypoglycemia with nesidioblastosis after gastric-bypass surgery. N Engl J Med. 2005;353:249 – 254. 2. Patti ME, McMahon G, Mun EC, et al. Severe hypoglycaemia postgastric bypass requiring partial pancreatectomy: evidence for inappropriate insulin secretion and pancreatic islet hyperplasia. Diabetologia. 2005;48:2236 –2240. 3. Clancy TE, Moore FD Jr, Zinner MJ. Post-gastric bypass hyperinsulinism with nesidioblastosis: subtotal or total pancreatectomy may be needed to prevent recurrent hypoglycemia. J Gastrointest Surg. 2006;10:1116 –1119. 4. Alvarez GC, Faria EN, Beck M, Girardon DT, Machado AC. Laparoscopic spleen-preserving distal pancreatectomy as treatment for nesidioblastosis after gastric bypass surgery. Obes Surg. 2007;17: 550 –552. 5. Bantle JP, Ikramuddin S, Kellogg TA, Buchwald H. Hyperinsulinemic hypoglycemia developing late after gastric bypass. Obes Surg. 2007;17:592–594. 6. Kellogg TA, Bantle JP, Leslie DB, et al. Postgastric bypass hyperinsulinemic hypoglycemia syndrome: characterization and response to a modified diet. Surg Obes Relat Dis. 2008;4:492– 499. 7. Z’graggen K, Guweidhi A, Steffen R, et al. Severe recurrent hypoglycemia after gastric bypass surgery. Obes Surg. 2008;18:981–988. 8. Salehi M, Gastaldelli A, D’Alessio DA. Altered islet function and insulin clearance cause hyperinsulinemia in gastric bypass patients with symptoms of postprandial hypoglycemia. J Clin Endocrinol Metab. 2014;99:2008 –2017. 9. Marsk R, Jonas E, Rasmussen F, Näslund E. Nationwide cohort study of post-gastric bypass hypoglycaemia including 5,040 patients undergoing surgery for obesity in 1986 –2006 in Sweden. Diabetologia. 2010;53:2307–2311. 10. Goldfine AB, Mun EC, Devine E, et al. Patients with neuroglycopenia after gastric bypass surgery have exaggerated incretin and insulin secretory responses to a mixed meal. J Clin Endocrinol Metab. 2007;92:4678 – 4685. 11. Rabiee A, Magruder JT, Salas-Carrillo R, et al. Hyperinsulinemic hypoglycemia after Roux-en-Y gastric bypass: unraveling the role of gut hormonal and pancreatic endocrine dysfunction. J Surg Res. 2011;167:199 –205. 12. Cui Y, Elahi D, Andersen DK. Advances in the etiology and management of hyperinsulinemic hypoglycemia after Roux-en-Y gastric bypass. J Gastrointest Surg. 2011;15:1879 –1888. 13. Drucker DJ. Glucagon-like peptides: regulators of cell proliferation, differentiation, and apoptosis. Mol Endocrinol. 2003;17:161–171. 14. Hadjiyanni I, Baggio LL, Poussier P, Drucker DJ. Exendin-4 modulates diabetes onset in nonobese diabetic mice. Endocrinology. 2008;149:1338 –1349.
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15. Meier JJ, Butler AE, Galasso R, Butler PC. Hyperinsulinemic hypoglycemia after gastric bypass surgery is not accompanied by islet hyperplasia or increased -cell turnover. Diabetes Care. 2006;29: 1554 –1559. 16. McLaughlin T, Peck M, Holst J, Deacon C. Reversible hyperinsulinemic hypoglycemia after gastric bypass: a consequence of altered nutrient delivery. J Clin Endocrinol Metab. 2010;95:1851–1855. 17. Moreira RO, Moreira RB, Machado NA, Gonçalves TB, Coutinho WF. Post-prandial hypoglycemia after bariatric surgery: pharmacological treatment with verapamil and acarbose. Obes Surg. 2008; 18:1618 –1621. 18. Valderas JP, Ahuad J, Rubio L, Escalona M, Pollak F, Maiz A. Acarbose improves hypoglycaemia following gastric bypass surgery without increasing glucagon-like peptide 1 levels. Obes Surg. 2012; 22:582–586. 19. de Heide LJ, Laskewitz AJ, Apers JA. Treatment of severe
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postRYGB hyperinsulinemic hypoglycemia with pasireotide: a comparison with octreotide on insulin, glucagon, and GLP-1. Surg Obes Relat Dis. 2014;10:e31– e33. Salehi M, Gastaldelli A, D’Alessio DA. Blockade of glucagon-like peptide 1 receptor corrects postprandial hypoglycemia after gastric bypass. Gastroenterology. 2014;146:669 – 680.e2. Jenkins DJ, Wolever TM, Taylor RH, et al. Glycemic index of foods: a physiological basis for carbohydrate exchange. Am J Clin Nutr. 1981;34:362–366. Bantle JP, Laine DC, Castle GW, Thomas JW, Hoogwerf BJ, Goetz FC. Postprandial glucose and insulin responses to meals containing different carbohydrates in normal and diabetic subjects. N Engl J Med. 1983;309:7–12. Seaquist ER, Anderson J, Childs B, et al. Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine Society. Diabetes Care. 2013;36:1384 –1395.
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ARTICLE
Post-Gastric Bypass Hyperinsulinemic Hypoglycemia: Fructose is a Carbohydrate Which Can Be Safely Consumed Anne E. Bantle, Qi Wang, and John P. Bantle Division of Endocrinology and Diabetes, Department of Medicine (A.E.B., J.P.B.), and Clinical and Translational Science Institute (Q.W.), University of Minnesota, Minneapolis, Minnesota 55455
Context: Postprandial hypoglycemia after gastric bypass surgery is a serious problem. Available treatments are often ineffective. Objective: The objective was to test the hypotheses that injection of rapid-acting insulin before a high-carbohydrate meal or replacement of other carbohydrates with fructose in the meal would prevent hypoglycemia. Design: This was a randomized, crossover trial comparing a high-carbohydrate meal with premeal saline injection (control), a high-carbohydrate meal with premeal insulin injection, and a highfructose meal with total carbohydrate content similar to the control meal. Setting: The setting was an academic medical center. Patients: Ten patients with post-gastric bypass hyperinsulinemic hypoglycemia participated. Interventions: Interventions included lispro insulin injected before test meals and replacement of other carbohydrates with fructose in test meals. Main Outcome Measure: The main outcome measure was plasma glucose ⬍ 60 mg/dL after test meals. Results: After the control meal, mean peak glucose and insulin were 173 ⫾ 47 mg/dL and 134 ⫾ 55 mU/L, respectively; mean glucose nadir was 44 ⫾ 15 mg/dL; and eight of 10 subjects demonstrated glucose ⬍ 60 mg/dL. Five subjects demonstrated a glucose nadir ⬍ 40 mg/dL. There were no significant differences in the corresponding values after premeal insulin treatment, except that the mean glucose nadir of 34 ⫾ 10 mg/dL was lower (P ⬍ .05). After the fructose meal, mean peak postprandial glucose and insulin were 117 ⫾ 20 mg/dL and 45 ⫾ 31 mU/L, respectively (both P ⬍ .001 for comparison with control), mean glucose nadir was 67 ⫾ 10 mg/dL (P ⬍ .001), and two of 10 subjects demonstrated glucose ⬍ 60 mg/dL (P ⬍ .05). Conclusions: People with post-gastric bypass hypoglycemia can consume a meal sweetened with fructose with little risk of hypoglycemia. Treatment with rapid-acting insulin before a carbohydrate-containing meal did not prevent hypoglycemia. (J Clin Endocrinol Metab 100: 3097–3102, 2015)
n 2005, Service et al (1) first described postprandial hypoglycemia causing neuroglycopenia after Roux-en-Y gastric bypass surgery. Several of their patients experi-
I
enced confusion and loss of consciousness during episodes. Subsequently, additional patients with this disorder have been described in small series and case reports (2– 8).
ISSN Print 0021-972X ISSN Online 1945-7197 Printed in USA Copyright © 2015 by the Endocrine Society Received February 1, 2015. Accepted May 28, 2015. First Published Online June 2, 2015
Abbreviations: BMI, body mass index; GLP-1, glucagon-like peptide 1.
doi: 10.1210/jc.2015-1283
J Clin Endocrinol Metab, August 2015, 100(8):3097–3102
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The prevalence of post-gastric bypass hyperinsulinemic hypoglycemia is unknown but is at least 0.36% of those patients having gastric bypass surgery (6). This is almost certainly an underestimate because it is likely that all patients with the syndrome were not identified. The syndrome appears to be specific for gastric bypass and does not occur after purely restrictive procedures such as adjustable gastric banding (9). The pathogenesis of post-gastric bypass hyperinsulinemic hypoglycemia has not been established. In the original report, Service et al (1) suggested that patients with this disorder developed hyperinsulinemia as a result of islet cell hyperplasia, perhaps due to an increase in glucagon-like peptide 1 (GLP-1) secretion. Postprandial serum insulin and GLP-1 responses are known to increase after gastric bypass surgery (10 –12), and GLP-1 has been shown to increase -cell mass in rodent models (13, 14). Several investigators, in addition to Service, have suggested that -cell mass is increased after gastric bypass (2– 4). However, this has not been a universal finding (7). Moreover, Meier et al (15) reexamined the pancreatic tissues of the patients in Service’s original report and found no evidence of increased -cell mass. They suggested that postprandial hypoglycemia after gastric bypass was due to the combination of gastric dumping and increased insulin secretion. Consistent with this, McLaughlin et al (16) described a unique patient with this disorder. The patient had a gastrostomy tube inserted into her remnant stomach. When she was given a standardized liquid test meal orally, she developed postprandial hyperglycemia and hyperinsulinemia, followed by hypoglycemia. However, when the standardized test meal was given through the gastrostomy tube into her remnant stomach, no postprandial hyperinsulinemia or hypoglycemia developed. Thus, it is not clear whether post-gastric bypass hypoglycemia results from rapid digestion and absorption of ingested nutrients or, alternatively, an increase in functional insulin secretion with or without an increase in -cell mass, perhaps induced by an increase in GLP-1 or other -cell trophic peptides. A variety of treatments for post-gastric bypass hyperinsulinemic hypoglycemia have been attempted. Service et al (1) employed an arterial calcium stimulation test to localize excessive pancreatic insulin secretion and subsequent subtotal pancreatic resection, with improvement in symptoms in some patients. However, total pancreatectomy has been required to eliminate hypoglycemia in other patients (3), resulting in iatrogenic, insulin-deficient diabetes mellitus. Gastric restriction by laparoscopic placement of a Silastic ring around the gastric pouch has been reported to be an effective treatment (7). Noninvasive treatments include low-carbohydrate diets (5, 6), coinges-
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tion of the medication acarbose with meals containing carbohydrate to retard carbohydrate digestion (17, 18), treatment in a single patient with the somatostatin analog pasireotide (19), and continuous infusion of the GLP-1 receptor antagonist exendin 9 –39 (20). However, these approaches have not been consistently effective or are not generally available. Patients with post-gastric bypass hyperinsulinemic hypoglycemia demonstrated a greater than normal rise in plasma glucose after eating carbohydrate-containing meals (5, 6, 8). This led to a robust insulin response, hyperinsulinemia, and subsequent hypoglycemia although insulin levels declined rapidly as plasma glucose fell. Thus, it is plausible that treatment that reduces the postprandial rise in plasma glucose after a carbohydrate-containing meal would also reduce the insulin response and, thereby, the risk of hypoglycemia. With this in mind, we studied two interventions intended to prevent postprandial hyperglycemia and subsequent hypoglycemia. The first was a rapid-acting insulin analog given before a high-carbohydrate meal. The second was replacement of glucose with fructose in a high-carbohydrate meal. In healthy subjects, ingestion of fructose has been shown to produce a more modest rise in plasma glucose than ingestion of a comparable amount of glucose or glucose-containing polysaccharides and, thereby, to stimulate insulin secretion to a lesser degree (21, 22).
Subjects and Methods Three treatments were compared in random order using a crossover design. The treatments were a high-carbohydrate test meal (control condition), a high-carbohydrate test meal after pretreatment with rapid-acting lispro insulin (insulin condition), and a high-fructose test meal that was low in glucose and glucosecontaining carbohydrates but with total carbohydrate and caloric content similar to the control meal (fructose condition). The hypotheses to be tested were: 1) pretreatment with lispro insulin would prevent, or at least reduce, the occurrence of hypoglycemia; and 2) substitution of fructose for glucose in the test meal would prevent, or at least reduce, the occurrence of hypoglycemia. Study participants were 10 patients with post-gastric bypass hyperinsulinemic hypoglycemia who met the following criteria: 1) history of postprandial hypoglycemia with neuroglycopenia (confusion, seizure, loss of consciousness) occurring after gastric bypass surgery; 2) history of spontaneous correction of hypoglycemia; 3) normal fasting plasma glucose and serum insulin; 4) after a carbohydrate-containing mixed meal, demonstration at any time point of serum insulin ⬎ 50 mU/L and at any time point plasma glucose ⬍ 50 mg/dL. Treatments were separated by at least 24 hours but could be performed on consecutive days. Subjects fasted for at least 8 hours before the studies. For the control condition, subjects received a high-carbohydrate test meal composed of orange juice
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doi: 10.1210/jc.2015-1283
(8 oz), fat-free yogurt (6 oz), one piece of toasted wheat bread, margarine (1 teapoonful), and jam (2 teaspoonsful). The meal provided 403 cal from 74 g carbohydrate, 12 g protein, and 7 g fat. Of the 74 g carbohydrate, 12 g (16% of total carbohydrate) came from fructose. Ten minutes before the meal, subjects received a sc injection of saline. For the insulin condition, subjects received a test meal of the same composition, and 10 minutes before the meal, a sc injection of 1 U lispro insulin for each 15 kg of body weight. Subjects were masked as to treatment with saline or insulin. For the fructose condition, subjects received a test meal with similar amounts of carbohydrate, protein, and fat as in the control meal, but with fructose as the principal carbohydrate. The fructose meal was composed of an almond flour muffin made with fructose, lean ham (42 g), and Kool Aid made with fructose (18 oz). The meal provided 402 cal from 70 g carbohydrate, 10 g protein, and 10 g fat. Of the 70 g carbohydrate, 62 g (89% of total carbohydrate) came from fructose. Subjects received a stipend of $50 for each test day they completed and an additional $75 if they completed all three test days. The protocol was approved by the University of Minnesota Institutional Review Board, and informed consent was obtained from all subjects. Plasma glucose and serum insulin were sampled 15 minutes before and 15, 30, 45, 60, 75, 90, 105, 120, 135, 150, 180, 210, and 240 minutes after all test meals. Subjects and study staff were masked as to plasma glucose results. All blood specimens were held and sent to the laboratory after testing was completed. Before each blood draw, subjects were asked to name the date and identify their location. If they could not do so correctly, capillary blood glucose was tested. If plasma glucose was ⬍ 45 mg/dL, treatment was provided with three glucose tablets, and testing was stopped. If they could answer both questions correctly, testing continued regardless of other symptoms. After completion of the study, subjects were provided a low-carbohydrate snack and discharged. Plasma glucose and serum insulin were determined in the Clinical Chemistry Laboratory of the University of Minnesota Hospitals. The primary study endpoint was occurrence or not of plasma glucose ⬍ 60 mg/dL during the 4 hours after the test meal (binary endpoint). The control meal was compared to the insulin pretreated test meal and, in a separate comparison, to the fructose test meal. Secondary endpoints were comparisons between the control and active treatments in peak postprandial serum insulin, peak postprandial plasma glucose, nadir postprandial plasma glucose, and the 4-hour longitudinal time course of plasma glucose measurements. The three treatments were compared using standard methods for crossover designs that have binary or continuous outcomes; that is, within-person correlation was modeled, and both time and carryover effects were assessed. With 10 subjects, there was a 70% power to find a difference between the active and control treatments in the primary endpoint. Power was estimated by the percentage of significant type 3 tests for treatment. Calculations were performed in SAS version 9.3 (SAS Institute, Inc).
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Table 1. Baseline Characteristics of the 10 Study Participants Age, y Gender (female/male), n Pre-bariatric surgery weight, kg Pre-bariatric surgery BMI, kg/m2 Time from gastric bypass to study, y Weight at time of study, kg Weight loss at time of study, kg BMI at time of study, kg/m2 Time to onset of hypoglycemic episodes, y Frequency of hypoglycemic episodes, episodes/mo History of hypoglycemia causing confusion, n History of hypoglycemia causing loss of consciousness, n
48 (37– 60) 9/1 122.2 (94.5–144.1) 43.8 (32.7a-52.0) 7.6 (1.7–10.8) 78.4 (50.7–111.6) 43.8 (28.9 – 65.3) 28.2 (21.0 –36.1) 2.5 (1.0 – 8.5) 8 (1–20) 10 of 10 6 of 10
Data are expressed as mean (range) unless stated otherwise. a Gastric bypass was done in one participant for gastroesophageal reflux.
body mass index (BMI) 28.2 kg/m2 at the time of the study. All had undergone Roux-en-Y gastric bypass for weight loss, except for one subject who had gastric bypass because of gastroesophageal reflux. One subject had a laparoscopic band procedure before gastric bypass, and her pre-laparoscopic band weight was used as her preoperative weight. Mean preoperative weight and BMI were 122.2 kg and 43.8 kg/m2, respectively, and all subjects lost a substantial amount of weight after gastric bypass (mean weight loss at time of study, 43.8 kg). Symptoms of hypoglycemia started a mean of 2.5 years after bariatric surgery. No subject could recall having had symptoms of hypoglycemia in the first year after bariatric surgery. All 10 subjects had a history of hypoglycemia-induced confusion, and six subjects actually lost consciousness because of hypoglycemia. In all subjects, episodes of hypo-
Results Ten subjects completed the study. Baseline characteristics are summarized in Table 1. The subjects were one man and nine women with mean age 48 years, weight 78.4 kg, and
Figure 1. Plasma glucose values (mean ⫾ SE). *, P ⬍ .05, compared to control meal; †, P ⬍ .001, compared to control meal.
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Figure 2. Serum insulin values (mean ⫾ SE). *, P ⬍ .05, compared to control meal.
glycemia continued despite attempts to follow a lowcarbohydrate diet or to make other dietary modifications. Fasting and postprandial plasma glucose and serum insulin values for the three treatment conditions are shown in Figures 1 and 2. There were no differences among the three treatments in fasting values. After the high-carbohydrate, control meal with premeal saline injection, mean peak plasma glucose and serum insulin were 173 mg/dL and 134 mU/L, respectively (Table 2). The mean postprandial plasma glucose nadir was 44 mg/dL, and it came 132 minutes after starting the test meal. Eight of 10 subjects demonstrated a plasma glucose nadir ⬍ 60 mg/dL. Five subjects demonstrated a nadir ⬍ 40 mg/dL. The lowest plasma glucose observed was 22 mg/dL. Despite the low plasma glucose values, testing was not stopped because no subject developed evidence of neuroglycopenia during testing. As shown in Figures 1 and 2, insulin pretreatment did not prevent postprandial hyperglycemia, hyperinsulinemia, or subsequent hypoglycemia. After the high-carbohydrate meal with premeal insulin injection, mean peak postprandial plasma glucose and serum insulin were 182 Table 2.
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mg/dL and 148 mU/L, respectively, and not significantly different from the corresponding values after the control meal. All 10 subjects demonstrated a plasma glucose nadir ⬍ 60 mg/dL, and the mean plasma glucose nadir was 34 mg/dL. The mean plasma glucose nadir was significantly lower than the mean nadir after the control meal. Testing had to be stopped in one subject at 120 minutes because of confusion and a plasma glucose of 25 mg/dL. After subjects consumed the high-carbohydrate fructose meal, mean peak postprandial plasma glucose was 117 mg/dL, and mean peak postprandial serum insulin was 45 mU/L. Both values were significantly lower than during the control meal. Only two subjects demonstrated a plasma glucose nadir ⬍ 60 mg/dL, and the mean plasma glucose nadir was 67 mg/dL. The number of subjects with plasma glucose ⬍ 60 mg/dL was significantly fewer, and the mean plasma glucose nadir was significantly higher than during the control meal. Testing did not have to be stopped in any subject.
Discussion Although the prevalence of post-gastric bypass hyperinsulinemic hypoglycemia has not been established, it appears to be a serious postoperative complication. It remains unclear whether hypoglycemia results from rapid digestion and absorption of ingested nutrients (15, 16) or, alternatively, from an increase in functional insulin with or without an increase in -cell mass post-gastric bypass (2– 4). Regardless of which mechanism is responsible, reducing the rise in plasma glucose after a carbohydratecontaining meal should reduce endogenous insulin secretion and potentially prevent, or at least reduce, the severity of subsequent hypoglycemia. Accordingly, we pretreated people with this disorder with rapid-acting insulin before a high-carbohydrate test meal.
Fasting and Postprandial Test Values High-Carbohydrate High-Carbohydrate High-Carbohydrate Meal With Premeal Meal With Premeal Fructose Meal Saline Injection (Control) Insulin Injection (Insulin) (Fructose)
Fasting plasma glucose, mg/dL Fasting serum insulin, mU/L Peak postprandial plasma glucose, mg/dL Peak postprandial serum insulin, mU/L Postprandial plasma glucose ⬍ 60 mg/dL, n (%) Postprandial glucose nadir, mg/dL Time to glucose nadir, min
76 ⫾ 6 4⫾3 173 ⫾ 47 134 ⫾ 55 8 (80) 44 ⫾ 15 132 ⫾ 35
77 ⫾ 5 5⫾2 182 ⫾ 40 148 ⫾ 68 10 (100) 34 ⫾ 10a 125 ⫾ 27
81 ⫾ 8 4⫾3 117 ⫾ 20b 45 ⫾ 31b 2 (20)a 67 ⫾ 10b 126 ⫾ 28
Data are expressed as mean ⫾ SD, unless stated otherwise. a
P ⬍ .05 when compared to the control meal.
b
P ⬍ .001 when compared to the control meal.
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Insulin pretreatment did not prevent postprandial hypoglycemia. However, insulin pretreatment also did not reduce peak postprandial plasma glucose or serum insulin levels. This raises the possibility that the time interval between insulin injection and the test meal in our study (10 minutes) was too short or the dose of lispro insulin used (1 U/15 kg body weight) was too low. Had we waited longer after the insulin injection to start the test meal or provided a larger dose of insulin, we might have reduced the postprandial rise in plasma glucose, reduced the subsequent endogenous insulin response, and prevented hypoglycemia. These possibilities seem worthy of further study. Dietary fructose produces only a modest rise in plasma glucose and stimulates insulin secretion to a lesser degree than glucose or glucose-containing carbohydrates (21, 22). Thus, it seemed plausible that dietary fructose would be less likely than other carbohydrates to produce hypoglycemia in patients with post-gastric bypass hypoglycemia. Consistent with this, we found that a high-carbohydrate fructose test meal produced a lesser rise in plasma glucose and serum insulin than a high-carbohydrate test meal containing glucose, sucrose, and starch. The fructose test meal resulted in a plasma glucose nadir that was not as low as the high-carbohydrate control test meal nadir and fewer subjects (20%) with a postprandial plasma glucose nadir ⬍ 60 mg/dL. Our data suggest that fructose is a suitable carbohydrate for people with post-gastric bypass hypoglycemia and, perhaps, the preferred sweetening agent to be used in moderation in their diets. One of the surprising observations in our study was how well this group of patients tolerated hypoglycemia. Many times our subjects demonstrated plasma glucose values below 40 mg/dL and even below 30 mg/dL without confusion or other significant symptoms. This suggests that patients with this disorder have experienced frequent hypoglycemia and have adapted to it, a phenomenon known to happen in insulin-treated people with diabetes (23). Another observation of interest was the timing of hypoglycemia in our subjects. With all three treatments, the plasma glucose nadir was reached at about 130 minutes. This suggests that a small amount of carbohydrate taken about 90 minutes after a high-carbohydrate meal might prevent hypoglycemia. Based on this observation, we recommend to our patients with this disorder that they take one or two glucose tablets about 90 minutes after a carbohydrate-containing meal. In summary, our study demonstrated that fructose is a dietary carbohydrate that people with post-gastric bypass hypoglycemia can consume with little risk of subsequent hypoglycemia. We were not able to demonstrate that rapid-acting insulin treatment before a carbohydrate-containing meal prevented hypoglycemia, but it is possible
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that, with different timing or a different dose of insulin, hypoglycemia might be prevented.
Acknowledgments Address all correspondence and requests for reprints to: Anne E. Bantle, University of Minnesota, MMC 101, 420 Delaware Street SE, Minneapolis, MN 55455. E-mail: [email protected]. Trial Registration: Clinicaltrials.gov NCT 01933490. This work was supported by institutional funds. Disclosure Summary: The authors have nothing to disclose.
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