Impact of food intake on interstitial glucose
profiles after gastric bypass surgery
Impact of food intake on interstitial glucose profiles after gastric
bypass surgery
Acknowledgements
First of all, I would like to express my deepest gratitude to my advisor Prof. Mariana Monteiro for her guidance and motivation during all the process of elaboration of my thesis. Prof. Mariana is an example of leadership, multitasking, and working capacity; a true mentor and someone I aspire to be as a doctor and, perhaps, as a teacher.
I would also like to thank Prof. Marta Guimarães for her availability and to Dr. Mário Nora, director of Department of General Surgery at Hospital de São Sebastião.
I thank Sofia Pereira and Carolina Lobato, for their companionship and for all the help provided. I thank each and every one of my friends, especially the ones I’ve collected along the way, who made this journey worth every minute.
I am so grateful to my dear friends Joana and Álvaro for being the best partners and study buddies I could wish for and for making my days easier and funnier so many times.
To Maria and Cris, thank you for all the love and encouragement; no distance will ever be bigger than us.
Last but definitely not the least, there are not enough words to thank my beloved parents, my incredible sister and brother-in-law for their affection and unconditional support through all these years of study, helping and motivating me to pursue this dream of a lifetime of mine.
Resumo
Introdução/Objetivo: As hipoglicemias pós-bariátricas representam um desafio na prática clínica.
A sua fisiopatologia ainda não está completamente esclarecida e a abordagem terapêutica tem uma eficácia limitada. Contudo, a composição nutricional da alimentação parece ter impacto nas excursões glicémicas e na secreção de insulina. O objetivo do nosso estudo foi avaliar a influência da ingestão alimentar nos sintomas e no perfil de glicose intersticial em indivíduos previamente submetidos a bypass gástrico Y-de-Roux com e sem sintomas compatíveis com hipoglicemia.
Metodologia: Indivíduos previamente submetidos a bypass gástrico Y-de-Roux (n=17) foram
alocados em dois grupos, sintomáticos (n = 9) ou assintomáticos (n = 8). Foi colocado um sistema de monitorização flash de glicose durante 14 dias e fornecido um diário alimentar e de sintomas para registo detalhado, concomitantemente ao uso do dispositivo. Os dados da monitorização flash de glicose foram utilizados para calcular os perfis de glicose intersticial e a mean absolute glucose
change. Os diários alimentares foram revistos e analisados individualmente para obtenção da
composição nutricional das refeições.
Resultados: Os perfis de glicose intersticial, a mean absolute glucose change e o tempo passado em
cada intervalo glicémico foram semelhantes nos dois grupos. 70.5% dos indivíduos relataram sintomas compatíveis com hipoglicemia, 88.9% no grupo sintomático e 50% dos indivíduos anteriormente considerados assintomáticos; 91.1% dos quais ocorreram até 3 horas após a refeição e predominantemente após o pequeno-almoço, almoço e lanche da tarde; 31.9% e 4.7% dos eventos sintomáticos foram coincidentes com glicose intersticial < 70 mg/dl, no grupo sintomático vs assintomático respetivamente (p= 0.0110). Não foram encontradas diferenças significativas na ingestão diária de energia ou macronutrientes entre os dois grupos, embora ambos os grupos apresentassem uma ingestão de hidratos de carbono superior e de proteínas inferior ao recomendado. A composição nutricional das refeições que precederam os eventos sintomáticos foi similar, exceto a ingestão proteica no lanche da manhã, que foi significativamente menor (3.15 ± 1.01 g vs 7.71 ± 0.54 g, p = 0.0286) e a ingestão de açúcar ao almoço, que foi significativamente maior (11.55 ± 2.38 g vs 4.33 ± 0.92 g, p = 0.0333) no grupo sintomático.
Conclusões: Os sintomas pós-prandiais são frequentes em doentes submetidos a bypass gástrico
Y-de-Roux, embora ocorram em maior número em indivíduos que os reportam espontaneamente. Os eventos sintomáticos são mais frequentes após as refeições diurnas com maior teor de açúcar e menor teor de proteínas, que podem contribuir para o desencadear dos sintomas pós-prandiais.
Abstract
Background/Aim: Post-bariatric hypoglycemia is a challenging clinical condition. Its etiology is
uncertain, while management and treatment intervention are empirical and have limited effectiveness. Since meal nutritional composition is recognized to have a relevant impact on glucose excursions and insulin secretion, our aim of was to evaluate the influence of food intake on interstitial glucose profile and symptoms of patients previously submitted to Roux-en-Y gastric bypass with and without self-reported symptoms compatible with hypoglycemia.
Methods: Subjects previously submitted to Roux-en-Y gastric bypass (n=17) were allocated into two
groups symptomatic (n=9) or asymptomatic (n=8), according to spontaneous report of symptoms suggestive of hypoglycemia. Subjects were fitted with a flash glucose monitoring system for 14 days and provided with a food and symptom diary to record dietary intake and symptoms experienced, while using the flash glucose monitoring device. Flash glucose monitoring data was computed to obtain interstitial fluid glucose profiles and mean absolute glucose change. Dietary records were individually reviewed and analysed to obtain meal nutritional composition.
Results: Interstitial fluid glucose profiles, mean absolute glucose change and time spent on each
glycemic interval were similar in the two patient groups. No significant differences were found in daily energy or macronutrients intake between the two patient groups, despite presenting a higher carbohydrate and lower protein intake than recommended for this population. Symptoms compatible with hypoglycemia were reported by 70.5% of study subjects (88.9% of the symptomatic group and 50% of the group previously considered asymptomatic), 91.1% of the symptomatic events occurred up to 3 hours after a meal and predominantly after breakfast, lunch and afternoon snacks; 31.9% and 4.7% of symptomatic events were concurrent with interstitial fluid glucose < 70 mg/dl, in the symptomatic group vs asymptomatic controls, respectively (p= 0.0110). For symptomatic patient group, the nutritional composition of meals that preceded a symptomatic event was characterized by a significantly lower protein intake in the morning snacks (3.15 ± 1.01 g vs 7.71 ± 0.54 g, p=0.0286) and higher sugar intake during lunch (11.55 ± 2.38 g vs 4.33 ± 0.92 g, p=0.0333).
Conclusions: After Roux-en-Y gastric bypass, most patients present post-prandial symptoms,
although the frequency and concomitant low interstitial fluid glucose was higher in those that spontaneously report such complaints. Hypoglycemic events are more often after daytime meals
with higher sugar and lower protein content, which may contribute to triggering postprandial hypoglycemia symptoms.
Abbreviations
BMI Body mass index
DRI Dietary reference intake
FGM Flash glucose monitoring
FSD Food and symptom diary
GI Gastrointestinal
HOMA-IR Homeostasis model assessment of insulin resistance
IFG Interstitial fluid glucose
IQR Interquartile range
MAG Mean absolute glucose
PBH Post-bariatric hypoglycemia
RYGB Roux-en-Y gastric bypass
SEM Standard error of the mean
Table of contents
Acknowledgements ... i
Resumo ... ii
Abstract ... iv
Abbreviations ... vi
Table of contents ... vii
List of tables ... viii
Introduction ... 1 Methods ... 2 Results ... 4 Discussion ... 6 Conclusion ... 11 Bibliography ... 12 Tables ... 14
List of tables
Table I - Demographic, anthropometric, and clinical features of the two subject groups (mean ± SEM)
Table II - FGM profiles (median (IQR))
Table III - Daily energy and macronutrient intake
Table IV - Relative contribution of macronutrients to daily energy intake (%) Table IV - Frequency of symptoms suggestive of hypoglycemia
Table VI - Overall symptom report and temporal relationship with meals Table VII - Macronutrient composition of meals preceding symptomatic events Table VIII - Symptomatic events concurrent with IFG levels
Introduction
Bariatric surgery is the most effective treatment intervention for severe obesity and comorbid conditions1,2, as it results in considerable health gains that extend beyond weight loss, most
particularly for patients with type 2 diabetes1,3,4. Bariatric procedures comprise several different
surgical techniques that involve modification of gastrointestinal (GI) tract anatomy by diminishing stomach volume capacity and/or reducing intestinal absorptive capacity4. Roux-en-Y gastric bypass
(RYGB) is a widely performed bariatric procedure that rearranges the GI tract by excluding 95% of the stomach, the entire duodenum and part of the jejunum from alimentary transit, thus simultaneously resulting in restriction of gastric volume and intestinal malabsorption4-8. Despite the
very favorable outcomes and safety profile, bariatric surgery is not devoid of risks9,10. Late
complications, such as post-bariatric hypoglycemia (PBH) are becoming increasingly recognized9-11.
PBH is a clinical condition often under, over or even misdiagnosed, as clinical features can be highly nonspecific. PBH has been reported to occur in 0.1% up to one third of post-bariatric patients, depending on the criteria used for diagnosis11-15, therefore the actual prevalence is unknown.
Even though the underlying mechanisms have not been fully elucidated, PBH is known to be the end result of postprandial hyperinsulinemia16,17. Meal nutritional composition is recognized to have
a relevant impact on glucose excursions and insulin secretion, while reducing the meals carbohydrate content or glycemic index was demonstrated to decrease peak glucose and prevent reactive hypoglycemia9,18-21. Moreover, dietary counseling combined with an alpha-glucosidase
inhibitor acarbose was shown to limit glycemic variability as assessed by continuous glucose monitoring22. However, there are no established guidelines for PHB screening, nor universal criteria
for diagnosing the condition, or even specific nutritional, pharmacologic or surgical interventions widely accepted as being effective and recommended for clinical management. Hence, PBH remains a challenging condition that warrants further research efforts if progress in patient care is sought to be achieved.
The aim of this study was to gain further insights into this clinical condition by evaluating the influence of food intake nutritional composition on the symptoms and interstitial glucose profiles of patients previously submitted to RYGB with and without self-reported clinical features compatible with PBH.
Methods
Patients and methods
Subjects were selected from a larger post-bariatric surgery cohort under routine follow-up at a single bariatric surgical center. Prior to study enrollment subjects were submitted to laparoscopic RYGB for obesity treatment. RYGB procedure consisted in the creation of a 30 ml volume gastric pouch, which was anastomosed to a jejunum loop located at 60-100 cm from the ligament of Treitz while the biliopancreatic flow was restored by an entero-enteric anastomosis 120 cm distant from the gastro-enteric anastomosis, thereby resulting in the creation of a 120 cm long alimentary limb and a 60-100 cm long biliopancreatic limb.
Subjects (n=17) were allocated into two groups of symptomatic (n=9) or asymptomatic (n=8), according to the spontaneous report of symptoms compatible with hypoglycemia. Exclusion criteria included subjects submitted to bariatric procedures other than a standard RYGB procedure, including the 200 cm long biliopancreatic limb RYGB variant; symptomatic patients diagnosed with endocrine conditions causing hypoglycemia, such as neuro-endocrine tumours including insulinoma, adrenal insufficiency or hypopituitarism; patients with diabetes under insulin treatment or other anti-diabetic drugs responsible for causing hypoglycemia.
Subjects were fitted with a flash glucose monitoring (FGM) system (FreeStyle Libre®, Abbott, UK) by a specialist nurse according to the manufacturers’ instructions at the hospital facilities. The FGM system allows assessment of interstitial flash glucose (IFG) every 15 minutes for 14 consecutive days via a disposable subcutaneously implanted sensor with a storage capacity of IFG data for 8 hours. In addition, the FGM system enables the display of blood glucose estimates along with real time trends during the life-span of sensor use. All subjects received training on how to use the device to ensure correct data retrieval, including how to visualize and interpret IFG readings if symptomatic. No specific instructions were given on how to mitigate the symptoms or correct low glucose levels in case of occurrence other than subjects would usually do prior to study initiation. Subjects were asked to return to hospital facilities 14 days later to retrieve FGM raw data for statistical analysis. FGM data was computed to calculate median IFG, interquartile range (IQR) and mean percentage time (hours) spent <70 mg/dl and <55 mg/dl, within the 70 to 140 mg/dl interval and >140 mg/dl. In addition, mean absolute glucose (MAG) change, the sum of absolute differences between sequential readings divided by the time between the first and last blood glucose measurement, was calculated as a measure of glucose variability23,24.
On the same day and at the time of sensor fitting, subjects were provided with a food and symptom diary (FSD) and instructed on how to record dietary intake and symptoms experienced, while using the FGM device. Subjects were instructed to record every single meal, beverages and snacks consumed over the duration of FGM system usage. Recordings should include time (hours and
minutes) as displayed in the FGM device, detailed information on all food items consumed, including volumes, ingredients, preparation method for homemade meals and brand name for manufactured products. Subjects were specifically instructed to register food amounts either in grams, millilitres, weights from labels or household measures, such as spoons, cups and plates that were then converted into grams with the aid of the Food and Portion Sizes Manual25. Whenever
there was not sufficient information on the precise amounts of food consumed, for example “an apple”, an average portion size stipulated on the Food and Portion Sizes Manual was assumed. To estimate average total daily energy intake and macronutrient composition, dietary records were individually reviewed and analysed using a computer-based data evaluation system originally created for this study by an experienced Registered Dietitian. Meal macronutrient content calculations were performed with the aid of the Portuguese Food Composition Table26
complemented by other interactive tools used as need, thereby obtaining a database of 870 foods and beverages that enabled the quantitative analysis of food and nutrient intake. To standardize the number of days registered for each subject, the first and the last day of the FSD records coincident with FGM sensor placement and removal were discarded, thus resulting in 12 full days for data analysis.
Anthropometric and clinical data was retrieved from our bariatric cohort register. Data included age, gender, height, body weight, body mass index (BMI) before and after surgery, as well as time elapsed since surgery until symptoms onset. Excess BMI loss (%EBMIL) was calculated using the formula (preoperative BMI−postoperative BMI)/(preoperative BMI−25) × 100%). Insulin resistance was estimated by the homeostasis model assessment of insulin resistance (HOMA-IR) and calculated according to the formula [fasting glucose (mg/dl) × fasting insulin (mIU/l/405].
The study protocol including access to the patient register for data analysis were approved by the Centro Hospitalar de Entre o Douro e Vouga Institutional Ethical Review and Executive Boards.
Statistical analysis
Descriptive statistical analysis was used to describe the data. Continuous variables are presented as mean ± standard error of the mean (SEM) unless stated otherwise. Categorical variables are expressed as number of cases and percentage (%). D'Agostino & Pearson test was used to verify the normality of data. For continuous variables, the difference between two independent
Results
Seventeen subjects previously submitted to RYGB with self-reported symptoms compatible with hypoglycemia (n=9, 9 women) and asymptomatic controls (n=8, 1 man, 7 women) were included in this study.
There were no significant differences in demographics, anthropometric features before or after RYGB surgery, HOMA-IR, fasting plasma glucose and insulin and time elapsed since surgery between the two subject groups. After RYGB, both groups experienced significant weight loss, with a mean %EBMIL of over 78% when compared to baseline (Table I).
Two subjects in the symptomatic group were diagnosed with type 2 diabetes before RYGB, but both met clinical criteria of disease remission at the time of study enrollment, based on a HbA1c < 6% while off any active glucose lowering therapy for a minimum period of 1 year27.
An average number of valid IFG readings 1053.22 ± 40.17 and 977.63 ± 68.14 were retrieved in the symptomatic and asymptomatic subject groups, respectively. As IFG data was not normally distributed, summary statistics are presented as median (IQR). No significant differences were found for IFG profiles or glycemic variability, as expressed by MAG change, between the two groups (Table II). The mean percentage of time spent on each glycemic interval (<55 mg/dl, <70 mg/dl, 70-140 mg/dl and >70-140 mg/dl) in the two groups is also shown in Table II. Subjects spent most of the time on the normal glucose interval (74.64% vs 73.49% for symptomatic and asymptomatic subjects, respectively). No significant differences were found in the time spent on each glycemic interval between the two groups, although the asymptomatic controls spent more time on the glycemic range <70 mg/dl than the symptomatic group (18.19% vs 14.97%), whereas symptomatic subjects spent more time both on the glycemic range <55 mg/dl (2.37% vs 2.14%) and on the glycemic range >140 mg/dl (8.02% vs 6.18%).
The mean values for energy intake, protein, fat, carbohydrate and refined carbohydrate intake are depicted on Table III. No significant differences were found in daily energy or macronutrients intake between the two groups. Relative contribution of each macronutrient intake for the daily total energy intake was 51.02% carbohydrate, 29.59% fat and 19.39% protein vs 47.42% carbohydrate, 30.93% fat and 21.65% protein in the symptomatic group vs asymptomatic controls, respectively (Table IV).
Symptoms suggestive of hypoglycemia were reported by 70.5% of the subjects (12 individuals out of 17), 88.9% in the symptomatic subjects group (8/9), reporting a total of 69 episodes, while 50%
of subjects previously considered asymptomatic (4/8) also reporting a total of 21 symptomatic events. Symptoms were more frequently neuroglycopenic than autonomic, while some patients reported more than one symptom occurring at the same episode (Table V). Palpitations, irritability, blurred vision, headache and vomit were exclusively reported by the group of symptomatic subjects, whereas hunger feeling was more frequently reported by subjects of the asymptomatic group (75% vs 25%).
The large majority of symptoms (91.1%) occurred up to 3 hours after a meal in both groups with a mean time elapsed between the meal and symptoms of 01h44min and 01h35min for the symptomatic and asymptomatic group, respectively (Table VI). Symptoms occurred predominantly after breakfast, lunch and afternoon snacks, with no significant differences found on the event distribution between the two groups (Table VI).
The nutritional composition of meals preceding symptomatic events revealed that energy and macronutrient intake were not significantly different between the two groups, with the sole exceptions of protein intake in the morning snacks that was significantly lower in the symptomatic vs the asymptomatic group (3.15 ± 1.01 g vs 7.71 ± 0.54 g, p=0.0286) and sugar intake at the lunch meal that was significantly higher in the symptomatic vs the asymptomatic group (11.55 ± 2.38 g vs 4.33 ± 0.92 g, p=0.0333) (Table VII).
Comparing symptom report with FGM data, 31.9% and 4.8% of symptomatic events were concurrent with IFG < 70 mg/dl, in the symptomatic group vs asymptomatic controls, respectively (p= 0.0110) (Table VIII). Most hypoglycemic events occurred up to 3 hours after a meal, with the sole exception of one event in one subject in the control group, which occurred more than 3 hours after breakfast. A comparative statistical analysis of the nutritional composition of particular meals preceding symptomatic events with and without confirmed IFG < 70 mg/dl was not possible to perform due to limited number of meals in the first group.
Discussion
Bariatric surgery interventions result in significant weight loss and have a major impact in improving obesity-associated morbidities and life-expectancy28,29. However, procedure-related complications
that prompt early diagnosis and management also occur. PBH is considered a rare and late complication of bariatric surgery, most often reported to occur after RYGB. However, PBH prevalence is uncertain, since depending on the criteria used for diagnosis this can be widely variable, ranging from 0.1-1% until up to one third of patients, according several studies11,13-15. In
addition, as there are no nutritional, medical or surgical interventions with proven efficacy in the management of PBH, the condition remains a major challenge for the multidisciplinary teams. So, in order to gain further insights into the contribution of nutritional composition for the clinical manifestations and glucose profiles of patients with PBH, we performed a comprehensive evaluation of daily nutritional intake, interstitial glucose profile and symptoms report of subjects previously submitted to RYGB. For this, subjects with self-reported symptoms compatible with hypoglycemia in whom other causes of hypoglycemia had been previously excluded were evaluated and compared to a group of asymptomatic body weight matched controls.
In our study, 70.5% of the subjects reported symptoms compatible with hypoglycemia on the FSD. Although subjects with self-reported symptoms prior to study enrollment reported a higher number and frequency of symptoms, these also occurred in subjects previously considered asymptomatic. These data highlights that the prevalence of symptoms compatible with hypoglycemia in post-bariatric patients is high and underestimated when solely relied on self-reports. However, given the nonspecific nature of the majority of the symptoms, attrition to hypoglycemia must also be cautious in order to prevent over diagnosis of PBH. In fact, hypoglycemia symptoms include a broad mixture of autonomic manifestations, such as palpitations, tremor, anxiety, sweating, hunger and paresthesia; and neuroglycopenic manifestations that include confusion, weakness, light-headedness, dizziness, blurred vision, disorientation and, eventually, loss of consciousness9,10,30.
Severe hypoglycemia can lead to subsequent serious adverse events, such as seizures and syncope, while autonomic symptoms experienced at initial stages of hypoglycemia are responsible for subjective awareness, allowing intervention before the occurrence of severe neuroglycopenia14,30.
In our study, more than one symptom was reported as occurring at the same episode including neuroglycopenic manifestations, such as irritability, blurred vision and headaches, which were exclusively reported by subjects of the symptomatic group.
PBH manifestations may overlap with those of late dumping syndrome experienced by some post-bariatric patients. Dumping-related symptoms typically occur in the early postoperative period and are attributed to rapid gastric emptying and delivery to the small intestine of a significant quantity
of food, thus occurring within minutes to one hour after the meal and promptly recognized as early dumping syndrome31. In contrast, late dumping syndrome develops months to years after surgery
and symptoms typically occur 1 to 3 hours after meals enriched in refined carbohydrates9,10,31 ,
therefore with a clinical presentation similar to PBH. Since the large majority of symptoms reported by subjects in our study occurred within the postprandial state up to 3 hours after a meal were therefore compatible with either late dumping syndrome or PBH. The differential diagnosis between the two is established by the occurrence of hypoglycemia in the later condition. In fact, symptoms compatible with hypoglycemia concurrent with an IFG <70 mg/dl only occurred in about one third of symptomatic subjects, with a significantly lower ratio in the asymptomatic controls. These data reinforce the challenges of PBH diagnosis, given the nonspecific features suggestive of hypoglycemia, which can easily lead to over diagnosis. The presence of the Whipple’s triad consisting of low plasma glucose in the presence of compatible symptoms that are relieved by glucose correction is necessary to diagnose hypoglycemia. However, establishing a diagnosis of hypoglycemia can be further complicated by the fact that there is no universal consensus on the blood glucose threshold that should be used, which is defined as blood glucose bellow 70 mg/dl by the American Diabetes Association32 and a blood glucose below 55 mg/dl by the Endocrine
Society33.
Interstitial glucose profiles evaluated by FGM were not significantly different between the two groups of subjects, including the percentage of time spent on each glucose interval. Interestingly, less time was spent in the glycemic range <70 mg/dl by the symptomatic group as compared to the asymptomatic group, despite the higher number of symptoms reported in the diary. However, these symptomatic subjects did spend more time both on the severe hypoglycemia range (<55 mg/dl) and on the hyperglycemia range (>140 mg/dl) than the asymptomatic group. Also, no significant differences between the two groups of subjects were found in the median MAG change, despite the fact MAG change being superior to the upper limit of normality (MAG normal reference range 0.5 and 2.2)24 in both groups. Interestingly, MAG change was higher in the symptomatic group
when compared to asymptomatic controls. Overall, these data suggest that there could be a tendency for a greater glycemic variability in symptomatic patients that warrants further investigation in larger patient groups.
of 45% carbohydrate, 25% protein and 30% fat to the daily total energy intake27,35. In our study,
daily caloric intake and relative macronutrient composition were not significantly different between groups. Nevertheless, both groups had a higher carbohydrate and lower protein intake than recommended.
Post-bariatric patients are not only encouraged to meet carbohydrate dietary reference intake (DRI), but are also advised to meet the DRI by incorporating nutrient-dense complex carbohydrate and fiber, and discouraged to consume foods rich in refined carbohydrates and with a high glycemic index35,36. However, despite no significant differences were found between the study groups, both
exceed the DRI recommendations. Interestingly enough, total carbohydrate and sugar intake were respectively numerically higher and lower in symptomatic subjects when compared to asymptomatic controls. Hypoglycemia is recognized for promoting urgent seek for quick releasing sources of energy, which can contribute to weight regain after surgery10,37. However, since rapidly
absorbed carbohydrates are a strong stimulus for raising blood glucose and insulin secretion, its ingestion can perpetuate the exaggerated insulin response and thereby the risk of rebound hypoglycemia. In fact, carbohydrate restriction has proved to prevent postprandial hypoglycemia in post-bariatric patients20,21. Our data suggests that symptomatic subjects could have developed
sugar avoidance to prevent the vicious cycle, either by instinct or nutritional advice.
A protein intake of at least 60-80 g/day is recommended by The European Association for the Study of Obesity and The American Society of Metabolic and Bariatric Surgery2,38. Even though subjects
met the protein intake recommendations and no significant differences were found between groups, protein intake was lower in symptomatic when compared to the asymptomatic group. Whey protein preload before a mixed meal test was demonstrated to attenuate postprandial glycemia, reduce intestinal glucose absorption and potentiate the incretin response, without inducing more adverse postprandial GI symptoms39. Thus, increasing protein intake may also be
useful for management of PBH patients.
As the majority of symptomatic events occurred after breakfast, lunch or daytime snacks, we sought to perform a detailed analysis of the nutritional composition of the meals triggering symptomatic events. In fact, protein intake at morning snacks was found to be significantly lower, while sugar intake was identified as significantly higher at lunch in the symptomatic group as compared to asymptomatic controls. So these findings further reinforce the hypothesis that meals with a high sugar and a low protein content may contribute for triggering postprandial hypoglycemia symptoms. In addition, our findings also suggest that not only the nutritional composition of the meal is able to influence the clinical manifestations, but the timing of meal ingestion could also be an influential factor in triggering hypoglycemic events, as these were more often after breakfast, lunch or daytime snacks. These phenomena are potentially explained by altered patterns of insulin
sensitivity along the circadian clock in result of GI rearrangement induced by bariatric surgery. Indeed, there is a substantial intra and inter-individual variability in glucose levels, potentially related to the circadian system which is responsible for the coordination of many daily processes, including food intake, glucose absorption, insulin sensitivity and secretion and body weight balance40,41. Jakubowicz et al showed that greater caloric intake at breakfast vs dinner promotes
weight loss and improves fasting glucose levels, insulin sensitivity, and blood lipid profiles in obese women under isocaloric diet42. Thus, it should be counterintuitive that meal timing could also have
an impact on glycemic excursion patterns. Our findings could be particularly relevant for clinical management of PBH, by incorporating detailed nutritional strategies on the currently available recommendations, which should not only focus on the total caloric intake and macronutrient distribution, but also in the relative macronutrient proportion of each meal depending on the timing of food intake.
A few methodological limitations of our study must be acknowledged. The small sample size and use of an extensive food record instrument for collecting dietary data impose some restrictions on the possibility of extrapolation of our findings which requires additional validation in larger cohorts. In addition, the long duration of the dietary records may have limited the quality of data acquisition due to recording fatigue. Food diary is a quantitative method used to assess food and nutrient intake. Advantages of this method include the possibility to collect detailed information on food consumption habits, such as meal times and preparations used, and supposedly does not depends on memory. The main disadvantage of food diaries is that consumption can be misreported, especially when patients are able to recognize some foods as “unhealthy”. Other disadvantages include the time consumed, high level of motivation required and the difficulties that patients may experience in estimating portions sizes or using home measures.
Still, the major strengths of our current study must also be stressed. Clinical assessment is critical in the evaluation of patients with suspected PBH. In this study, glycemic excursions during routine everyday living in a representative time interval to reflect glucose variations that occur in a real-life scenario by including both week and week-end days were determined with the aid of a FGM system to retrieve detailed information on IFG profiles. In addition, since significant variability is observed in individuals’ response to foods and food combinations, a prolonged and detailed food dairy record for evaluation of total energy and macronutrient composition of each meal was used in parallel to
Despite such a comprehensive approach cannot be recommended for implementation in routine clinical practice, the evaluation in parallel of nutritional intake, glucose profile and clinical symptoms disclosed important clues, which if confirmed have the potential to significantly improvement the clinical management of PBH.
Conclusion
After RYGB, most patients present post-prandial symptoms, although the frequency and concomitant low IFG, is higher in those that spontaneously report such complaints.
Despite similar daily caloric intake and relative macronutrient composition, both groups of post-RYGB patients had a higher carbohydrate and lower protein intake than recommended. Hypoglycemic events are more often after daytime meals with a higher content of refined carbohydrate and lower protein. These findings may reinforce the hypothesis that meals with this specific nutrient distribution may contribute for triggering postprandial hypoglycemia symptoms, which could refine the clinical management and targeting nutritional invention of post-bariatric patients presenting with such challenging condition as PBH.
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Tables
Table I - Demographic, anthropometric, and clinical features of the two subject groups (mean ± SEM)
(*) Post-operative BMI vs pre-operative BMI (p<0.0001)
(#) Post-operative BMI vs pre-operative BMI (p<0.0001)
BMI: body mass index, EBMIL: excess of BMI loss; HOMA-IR: Homeostasis Model Assessment for Insulin Resistance
Symptomatic (n=9) Asymptomatic (n=8) p value
Gender (F/M) 9/0 7/1 Age 46.4 ± 1.66 42.1 ± 3.44 0.2590 Body weight (kg) 71.8 ± 3.20 75.3 ± 3.18 0.4634 Pre-operative BMI (kg/m2) 39.4 ± 1.85* 42.4 ± 1.16# 0.0592 Post-operative BMI (kg/m2) 28.4 ± 1.02* 28.3 ± 0.85# 0.9757 EBMIL (%) 78.8 ± 5.24 80.9 ± 5.32 0.7845
Fasting plasma glucose (mg/dl) 92.6 ± 2.85 91.4 ± 2.19 0.7551
Insulin (mIU/l) 7.06 ± 0.87 8.09 ± 1.06 0.4592
HOMA-IR 1.63 ± 0.24 1.86 ± 0.29 0.4807
Table II - FGM profiles (median (IQR))
IFG: interstitial fluid glucose, MAG change:mean absolute glucose change
Symptomatic (n=9) Asymptomatic (n=8) p value
IFG (mg/dl) 88 (77-109) 81 (71.5-97) 0.3831
MAG change (mmol/L*hour-1) 2.8 (2.4-3.0) 2.5 (2.3-2.5) 0.1181
Time (mean % hours)
> 140 mg/dl 8.02% 6.18%
0.9044
70-140 mg/dl 74.64% 73.49%
< 70 mg/dl 14.97% 18.19%
Table III - Daily energy and macronutrient intake
Symptomatic (n=9) Asymptomatic (n=8) p value
Energy (kcal) 1336.67 ± 103.95 1395.28 ± 98.70 0.6905
Protein (g) 63.05 ± 5.02 73.76 ± 7.47 0.2433
Fat (g) 43.54 ± 4.91 46.47 ± 3.61 0.6441
Carbohydrate (g) 167.29 ± 13.22 161.44 ± 13.89 0.7645
Table IV - Relative contribution of macronutrients to daily energy intake (%) Symptomatic (n=9) Asymptomatic (n=8) Protein 19.39 21.65 Fat 29.59 30.93 Carbohydrate 51.02 47.42
Table V - Frequency of symptoms suggestive of hypoglycemia
Symptomatic (n=9) Asymptomatic (n=8) Total
Autonomic Sweating 18 (90%) 2 (10%) 20 Palpitation 7 (100%) 0 (0%) 7 Tremor 10 (83%) 2 (17%) 12 Hunger feeling 1 (25%) 3 (75%) 4 Neuroglycopenic Confusion 14 (74%) 5 (26%) 19 Dizziness 30 (68%) 14 (32%) 44 Irritability 2 (100%) 0 (0%) 2 Blurred vision 7 (100%) 0 (0%) 7 Headache 24 (100%) 0 (0%) 24 Malaise Nausea 12 (86%) 2 (14%) 14 Vomit 5 (100%) 0 (0%) 5
Table VI - Overall symptom report and temporal relationship with meals
Symptomatic (n=9) Asymptomatic (n=8) Total (%) Mean time elapsed between meal
and symptoms 01h44min 01h35min
< 3 hours after meal 61 21 82 (91.1%)
Breakfast 10 (16.4%) 5 (23.8%) p=0.1649 Morning snack 4 (6.6%) 3 (14.3%) Lunch 13 (21.3%) 8 (38.1%) Afternoon snack 17 (27.8%) 4 (19.1%) Dinner 8 (13.1%) 1 (4.7%) Evening snack 9 (14.8%) 0 (0%)
> 3 hours after meal 8 0 8 (8.9%)
Table VII - Macronutrient composition of meals preceding symptomatic events
Breakfast Morning snack Lunch Afternoon snack
Symptomatic (n=10) Asymptomatic (n=5) p value Symptomatic (n=4) Asymptomatic (n=3) p value Symptomatic (n=13) Asymptomatic PBH (n=8) p value Symptomatic (n=17) Asymptomatic (n=5) p value Energy (kcal) 159.23 ± 9.07 191.14 ± 29.40 0.1538 128.82 ± 41.13 138.50 ± 21.65 0.3714 309.44 ± 59.56 331.81 ± 46.92 0.7948 160.08 ± 23.88 178.50 ± 47.29 0.6486 Protein (g) 5.30 ± 0.71 7.49 ± 1.19 0.1555 3.15 ± 1.01 7.71 ± 0.54 0.0286* 20.51 ± 4.96 17.62 ± 3.14 0.9155 5.834 ± 1.20 6.49 ± 2.97 0.9396 Fat (g) 3.49 ± 0.59 5.13 ± 0.79 0.0686 3.76 ± 1.25 1.38 ± 0.55 0.3714 10.89 ± 3.12 18.17 ± 3.11 0.0756 3.72 ± 0.75 2.84 ± 1.04 0.6486 Carbohydrate (g) 26.24 ± 1.02 28.40 ± 4.38 0.4935 20.82 ± 6.59 23.97 ± 0.98 0.3714 31.12 ± 4.88 21.45 ± 2.74 0.1608 25.42 ± 3.77 28.85 ± 8.31 0.7616 Refined carbohydrate (g) 6.85 ± 2.24 8.34 ± 2.42 0.4922 14.53 ± 6.09 16.68 ± 1.53 >0.9999 11.55 ± 2.38 4.33 ± 0.92 0.0333* 13.72 ± 2.71 17.95 ± 2.83 0.3512
Table VIII - Symptomatic events concurrent with IFG levels
IFG: interstitial fluid glucose
Symptomatic (n=9) Asymptomatic (n=8) Symptomatic events concurrent
with IFG < 70mg/dl 22 (31.9%) 1 (4.8%)
p=0.0110* Symptomatic events concurrent
with IFG > 70mg/dl 47 (68.12%) 20 (95.2%)
