Insulin-Like Growth Factor 1 Predicts Post-Load Hypoglycemia following Bariatric Surgery: A Prospective Cohort Study
Stulnig TM (2014) Insulin-Like Growth Factor 1 Predicts Post-Load Hypoglycemia following Bariatric Surgery: A Prospective
Cohort Study. PLoS ONE 9(4): e94613. doi:10.1371/journal.pone.0094613
Insulin-Like Growth Factor 1 Predicts Post-Load Hypoglycemia following Bariatric Surgery: A Prospective Cohort Study
Bianca K. Itariu 0
Maximilian Zeyda 0
Gerhard Prager 0
Thomas M. Stulnig 0
Alan Stitt, Queen's University Belfast, United Kingdom
0 1 Division of Endocrinology and Metabolism, Department of Medicine III, Medical University Vienna , Vienna , Austria , 2 Christian Doppler Laboratory for Cardio-Metabolic Immunotherapy, Medical University Vienna , Vienna , Austria , 3 Department of Surgery, Medical University of Vienna , Vienna , Austria
Postprandial hypoglycemia is a complication following gastric bypass surgery, which frequently remains undetected. Severe hypoglycemic episodes, however, put patients at risk, e.g., for syncope. A major cause of hypoglycemia following gastric bypass is hyperinsulinemic nesidioblastosis. Since pancreatic islets in nesidioblastosis overexpress insulin-like growth factor 1 (IGF-1) receptor a and administration of recombinant IGF-1 provokes hypoglycemia, our main objective was to investigate the occurrence of post-load hypoglycemia one year after bariatric surgery and its relation to pre- and post-operative IGF-1 serum concentrations. We evaluated metabolic parameters including 2 h 75 g oral glucose tolerance test (OGTT) and measured IGF-1 serum concentration in thirty-six non-diabetic patients (29 f/7 m), aged 41.362.0 y with a median (IQR) BMI of 30.9 kg/m2 (27.5-34.3 kg/m2), who underwent elective bariatric surgery (predominantly gastric bypass, 83%) at our hospital. Post-load hypoglycemia as defined by a 2 h glucose concentration ,60 mg/dl was detected in 50% of patients. Serum insulin and C-peptide concentration during the OGTT and HOMA-IR (homeostatic model assessment-insulin resistance) were similar in hypoglycemic and euglycemic patients. Strikingly, pre- and post-operative serum IGF-1 concentrations were significantly higher in hypoglycemic patients (p = 0.012 and p = 0.007 respectively). IGF-1 serum concentration before surgery negatively correlated with 2 h glucose concentration during the OGTT (rho = 20.58, p = 0.0003). Finally, IGF-1 serum concentrations before and after surgery significantly predicted post-load hypoglycemia with odds ratios of 1.28 (95%CI:1.03-1.55, p = 0.029) and 1.18 (95%CI:1.03-1.33, p = 0.015), respectively, for each 10 ng/ml increment. IGF-1 serum concentration could be a valuable biomarker to identify patients at risk for hypoglycemia following bariatric surgery independently of a diagnostic OGTT. Thus, IGF-1 testing could help to prevent a significant complication of gastric bypass surgery.
Competing Interests: This work was partly supported by the Austrian National Bank Project. There are no patents, products in development or marketed
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Bariatric surgery is currently the most effective treatment to
achieve and maintain clinically significant long-term weight-loss in
severely obese subjects . The mortality rate from disease-related
causes decreases in surgically treated patients, but the rate of
nondisease deaths, caused by accidents, poisoning of undetermined
intent or suicide is twice as high in postoperative patients
compared to matched controls . Postprandial, severe and
recurrent hypoglycemia is a late complication of Roux-en-Y
gastric bypass surgery (RYGB)  and could contribute to the
post-operative increase in mortality unrelated to disease. Its
occurrence is increasingly reported in recent bariatric surgery
literature, with symptomatic or asymptomatic forms prevailing to
a similar extent . The published prevalence of hypoglycemia
following bariatric surgery varies greatly depending on the applied
definition with a range of 0.2% for patients requiring
hospitalisation for severe hypoglycemia to 72% for reactive hypoglycemia in
a glucose tolerance test [7,8]. Postoperative hypoglycemia seems to
be caused by post-prandial hyperinsulinemia, accompanied or not
by pancreatic nesidioblastosis , or altered incretin release
, even though other causes cannot be ruled out .
Hyperinsulinemic hypoglycemia has been described decades ago
as a complication of gastrectomy and can lead to life-threatening
neuroglycopenia . Therapeutic approaches to prevent
hypoglycemia following RYGB are not standardized and comprise
dietary interventions, drugs, such as acarbose, diazoxide or
verapamil as well as invasive procedures such as subtotal or total
pancreatectomy [16,17]. In order to prevent post-prandial
hypoglycemia, pre-operative individual risk assessment would be
imperative. However, factors predicting the onset of post-load
hypoglycemia following bariatric surgery are widely unknown.
Insulin-like growth factor-1 (IGF-1) is a hormone with structural
and functional similarities to insulin, whose main functions are
regulation of somatic growth, proliferation and apoptosis. IGF-1
enhances insulin sensitivity and lowers glycaemia by stimulating
glucose transport in muscle and adipose tissue via signalling
mechanisms linked to insulin receptor activation . It also
enhances glucose uptake into several cells including osteoblasts by
binding to the IGF-1 receptor . Some glucose-related effects
may be mediated through the IGF-2 and insulin receptors,
although the binding occurs with low affinity. Furthermore IGF-1
promotes bone formation, protein synthesis, neuronal survival and
also myelin synthesis . During periods of food deprivation
IGF-1 can reverse the negative nitrogen balance and inhibit
protein catabolism in muscle . Higher IGF-1 serum
concentrations are associated with a higher risk of breast cancer in
women and prostate cancer in men [21,22]. IGF-1 concentration
is directly related to insulin sensitivity, irrespective of confounders
such as age, BMI, WHR or glucose tolerance status, but its
association to insulin resistance seems U shaped [23,24]. Bariatric
surgery seems to have little effect on circulating IGF-1
concentrations [25,26]. Recombinant IGF-1 is used as a long-term
therapy in patients suffering from Laron Syndrome. Due to its
insulin-like action, the most common side-effect to exogenous
IGF1 is hypoglycemia, which occurs in a dose-dependent manner .
Insulin-like growth factor 1 (IGF-1) receptor a is overexpressed
in pancreatic islets in nesidioblastosis and administration of
recombinant IGF-1 causes hypoglycemia [27,28]. Given the direct
effect of IGF-1 on glucose metabolism we hypothesised that IGF-1
is an indicator for the occurrence of post-prandial hypoglycemia in
patients who underwent bariatric surgery. Consequently, high
IGF-1 serum levels would be associated with hypoglycemia before
and after bariatric surgery independent of insulin secretion.
Therefore, we aimed to investigate the occurrence of post-load
hypoglycemia by a 2 h OGTT and to assess the utility of IGF-1
serum levels before and after bariatric surgery as a biomarker for
post-load hypoglycemia. Our data identified IGF-1 as a novel
predicting factor for the occurrence of post-prandial hypoglycemia
following bariatric surgery.
Subjects and Methods
The study was conducted in compliance with the Declaration of
Helsinki and Good Clinical Practice guidelines at the Department
of Medicine III, Medical University of Vienna, and has been
previously approved by the Ethics Committee of the Medical
University of Vienna (EK Nr. 963/2009). All subjects provided
written informed consent.
In this prospective study, we performed longitudinal
measurements of metabolic and routine parameters in non-diabetic
patients shortly before and approximately one year after the
patients underwent elective bariatric surgery (mean follow up time
1461.9 months). Surgeries were performed at the Department of
Surgery of the Medical University of Vienna. We invited patients
.18 years of age, who participated in our previous studies [29,30]
and from which we collected preoperative anthropometric and
metabolic data (n = 55) to participate in this study. Patients were
excluded in case of acute illness within the last two weeks,
diagnosed type 2 diabetes, acquired immunodeficiency (HIV
infection, AIDS), significant liver disease, severe or untreated
cardiovascular, renal, pulmonary disease, active malignant disease,
etc. Pregnancy or breast feeding were also among the exclusion
criteria. Of the 55 patients we aimed to recruit, six patients did not
respond to our invitation, five patients refused to participate or did
not show up at the scheduled visit, one patient underwent surgery
due to complications related to the initial procedure, one patient
had died, and four patients were pregnant. We thus recruited 36
patients. Of these, 30 patients underwent RYGB, 3 patients
underwent gastric banding and 3 patients underwent sleeve
gastrectomy. None of the subjects were on oral antidiabetics of any
kind, insulin, or corticosteroids. Before surgery 6 patients were on
diuretics but treatment discontinued after surgery. One patient
was on antipsychotic mediation before and after surgery.
Antipsychotics can influence blood glucose concentration but the
medication was continuously administered at both time points,
before and after surgery. All samples and data were collected at the
Clinical Research Unit of the Division of Endocrinology and
Metabolism of the Medical University of Vienna. We advised
patients to fast overnight before the examination. Preoperatively
and at the follow-up visit, we performed anthropometric and
hemodynamic measurements (body mass index (BMI), waist and
hip circumference, systolic and diastolic blood pressure), blood
sampling for routine laboratory analyses and a standardized 75 g
2 h oral glucose tolerance test (OGTT). Due to technical reasons
we failed to perform the OGTT in one patient. After short venous
stasis and venipuncture, blood was collected into evacuated vials
and the samples were transferred to the Department of Laboratory
Medicine of the Medical University of Vienna, where serum
concentrations of triglycerides, total-, HDL- and LDL-cholesterol,
ALT, GGT, HbA1c, glucose, insulin and C-peptide were
determined by routine laboratory analyses.
Fasting serum concentrations of blood lipids (triglycerides,
cholesterol, high-density lipoprotein (HDL) cholesterol, low-density
lipoprotein (LDL) cholesterol), glucose, liver enzymes [alanine
transaminase (ALT), gamma-glutamyl-transferase (GGT)] as well as
hemoglobin A1c (HbA1c) were determined by routine laboratory
methods at the Department of Laboratory Medicine, Medical
University of Vienna; insulin and C-peptide were measured by
chemiluminescence immunoassays (Roche Diagnostics GmBH).
Insulin resistance was assessed by the homeostatic model
assessment index of insulin resistance (HOMA-IR) calculated as
the product of the fasting serum insulin concentration (in milliunits
per liter) and fasting plasma glucose concentration (in millimoles per
liter) divided by 22.5  and incremental area under the curve
(AUC) was calculated for the time course of glucose, insulin and
Cpeptide concentration during the OGTT. Post-load hypoglycemia
was defined by a blood glucose concentration,60 mg/dl
(3.3 mmol/l) in the 2nd hour of the OGTT. We calculated beta
cell function during the entire OGTT by calculating the dynamic
area under the curve of serum C-peptide concentrations as total
AUC-(1806 basal concentration) . Established OGTT-derived
indexes such as the Matsuda Index, the insulinogenic index and the
disposition index were calculated in order to assess insulin sensitivity
and beta cell function . Disposition index was calculated as
insulinogenic index * Matsuda index. Insulinogenic index was
calculated as [DInsulin30-0(microU/ml)/DGlucose300(mmol/
l)*18]. The C-peptide AUC to insulin AUC ratio was calculated
as a measure of hepatic insulin extraction.
Metabolic syndrome was assessed according to the of
International Diabetes Federation (IDF) consensus criteria published in
2006 , i.e. central obesity (waist .80 cm in women and .
94 cm in men), plus any two of the following criteria: raised
triglycerides ($150 mg/dl), reduced HDL-cholesterol (,50 mg/
dl in women and ,40 mg/dl in men), raised blood pressure
(systolic $130 mmHg or diastolic $85 mmHg or treatment for
previous diagnosed hypertension) or raised fasting plasma glucose
($100 mg/dl or previously diagnosed diabetes mellitus type 2).
Metabolic syndrome (IDF)a
Total cholesterol (mg/dl)
AUC glucose (mg/dl*2 h)
AUC insulin (mU/ml*2 h)
AUC C-peptide (ng/ml*2 h)
aMetabolic syndrome was defined according to IDF criteria;
ALT, alanine transaminase; BP, blood pressure; FLI, fatty liver index; GGT, gamma-glutamyl-transferase; HDL-C, high density lipoprotein cholesterol; LDL-C, low density
lipoprotein cholesterol, WHR, waist to hip ratio.
Serum IGF-1 concentration pre- and one year post surgery was
determined by chemiluminescent immunoassay on a Siemens
Immulite analyzer (Siemens Healthcare Medical Diagnostics, Bad
Nauheim, Germany). The assays were performed according to the
manufacturers recommendations by skilled technical laboratory
personal methods at the Department of Laboratory Medicine,
Medical University of Vienna. Interassay coefficients of variation
varied between 2.08.5% and the lowest detection limit was
The presence of fatty liver was calculated by an algorithm based
on BMI (in kg/m2), waist circumference (cm), serum triglycerides
(mg/dl) and GGT (U/l), called the fatty liver index (FLI), with
an accuracy in detecting fatty liver of 0.84 (95%CI: 0.810.87)
. FLI is calculated as (e(0.9536loge
Statistical analysis included all patients. Continuous variables
are presented as mean 6 SEM if normally distributed, otherwise
as median (IQR). Differences between continuous variables before
and one year after bariatric surgery were analyzed by paired t-test
or the non-parametric Wilcoxon signed rank test, as necessary.
Categorical variables were compared by chi-square test.
Differences between continuous variables in patients experiencing or not
post-load hypoglycemia were calculated by unpaired students
ttest for normally distributed variables otherwise by Mann Whitney
U-Test. Correlations were explored by Spearmans rank method.
Odds ratios were computed by logistic regression to estimate the
predictive value of IGF-1 on post-load hypoglycemia. The risk
estimation model for post-load hypoglycemia was calculated for
each participant using receiver operating characteristic (ROC)
curves. The ROC-AUC and 95% CIs were estimated by
nonparametric methods. All analyses were performed with IBM SPSS
Statistics 20.0 (IBM Corporation, New York, USA). Differences
were considered statistically significant with two sided p,0.05 and
there were no considerations to adjust for multiplicity.
Patients one year after bariatric surgery are at risk for
Post-operative changes in anthropometric and laboratory
parameters were dramatic (Table 1). Patients on average lost
Figure 1. Glucose, insulin and C-peptide concentration during pre-operative and post-operative OGTT. (A) Glucose concentrations
during the course of the pre-operative 2 h OGTT (n = 35, full lines) compared to the post-operative OGTT (n = 35, dashed lines). (B) Histogram of
postoperative 2 h glucose concentrations during the OGTT (n = 35). Post-load hypoglycemia was defined by a 2 h glucose concentration,60 mg/dl. (C)
Insulin and (D) C-peptide concentrations during the course of the pre-operative 2 h OGTT (n = 35, full lines) compared to the post-operative OGTT
(n = 35, dashed lines).
15.160.8 BMI units, corresponding to a mean weight loss of
43.262.5 kg. Parallel to the weight loss, we observed a significant
reduction in the number of patients with metabolic syndrome,
from 19 before surgery to 2 one year after (p,0.0001).
Accordingly, we detected a significant improvement in patients
lipid profiles (triglycerides, total, LDL- and HDL-cholesterol, all
p,0.01). Circulating concentration of liver enzymes ALT and
GGT was also reduced, as was the fatty liver index (FLI) (all p,
0.01), indicating a reduction of obesity-associated fatty liver
Plasma HbA1c concentration after surgery was lower than
before surgery and in the normal range at both time-points.
Fasting plasma glucose and fasting serum insulin concentrations
were significantly reduced after the surgery, as was HOMA-IR (all
p,0.0001). Glucose concentration during the course of the 2
hOGTT was drastically changed in the postoperative setting, with
significantly lower concentrations after the first hour, which is also
reflected by the reduced area under the curve (AUC) - Figure 1A,
Table 1. Moreover, post-load hypoglycemia as defined by blood
plasma glucose concentration ,60 mg/dl at 2 h of the OGTT
was detected in half (50%) of all patients (n = 18, Figure 1B). These
were mainly patients who underwent RYGB (n = 16). Surprisingly,
most patients who experienced post-load hypoglycemia reported
no complaints at all, including one patient whose blood glucose
concentration reached 14 mg/dl (0.78 mmol/l). First phase
insulin response to glucose load (calculated as the insulinogenic
index) remained similar to the response observed before surgery,
but insulin levels were significantly reduced during the second
hour of the OGTT (Figure 1C). The post-operative AUC for
insulin concentration was significantly lower than before surgery
(p = 0.019; Table 1). Interestingly, the C-peptide concentration at
30 minutes of the test was higher after compared to before the
operation (Figure 1D; p = 0.001), but the AUC for C-peptide
concentration was not significantly different (Table 1). Serum
IGF1 concentration increased after surgery by a mean of
20.5610.2 ng/dl and the increase was significant in trend
(p = 0.053).
Characteristics of patients with post-load hypoglycemia
We split patients into two groups according to their glycaemic
condition at 2 h during the post-operative OGTT (post-load
hypoglycemia/euglycemia) and compared the changes in glucose,
insulin and C-peptide concentrations and respective AUC. We
detected significant differences in glucose concentration at time
point 09, 909 and 1209 during the OGTT (p = 0.020, p = 0.003 and
p,0.0001 respectively, Figure 2A), but insulin or C-peptide
concentrations during the course of the OGTT were not altered
(Figure 2B,C) except for a slight elevation of C-peptide
concentration at 30 minutes (p = 0.06). The calculated AUC for glucose,
insulin and C-peptide were similar in both groups (Table 2). Beta
cell function as assessed by the dynamic AUC of serum C-peptide
was not significantly different between the two groups (p = 0.47).
There was no difference in the established OGTT-derived indices:
Matsuda index, insulinogenic index and disposition index between
the two groups (data not shown). Hepatic insulin extraction as
calculated by the C-peptide AUC to insulin AUC ratio was not
different between the groups (p = 0.24) and was not related to
IGF1 levels before or after surgery.
By comparing anthropometric and laboratory parameters of
patients with post-load hypoglycemia and patients with
euglycemia, we found that age, WHR, serum triglyceride, fasting plasma
glucose and IGF-1 serum concentrations were lower in patients
with post-load hypoglycemia - Table 2. Glucose concentration at
2 h during the OGTT correlated with post-operative WHR
(rho = 0.48, p = 0.004) and serum triglyceride concentration
(rho = 0.50; p = 0.002). Other parameters, including BMI, serum
lipids other than triglycerides, liver enzymes and FLI, did not
differ between the groups.
Differences between the two groups in baseline anthropometric
and laboratory parameters before surgery are presented in Table S1.
IGF-1 serum concentration before and after surgery
We hypothesised that increased IGF-1 concentration could
contribute to the susceptibility to develop post-load hypoglycemia.
As shown in Table 2, mean post-operative IGF-1 serum
concentration for all patients increased in trend, compared to
IGF-1 concentration measured before the operation (146612 vs.
12568 ng/ml; p = 0.0535). Notably, post-operative IGF-1
concentration was significantly higher in patients with post-load
hypoglycemia (n = 18) compared to patients with euglycemia
(n = 17, Figure 3A). Interestingly, patients with post-load
hypoglycemia had significantly higher serum IGF-1 concentrations
compared to patients with euglycemia, already before surgery
(145612 ng/dl vs. 10569 ng/dl respectively, p = 0.0122). When
we analysed other differences in other pre-operative parameters
with respect to post-load hypoglycemia, we found that only IGF-1
and age were significantly different between patients with
hypoglycemia and euglycemia. Pre-operative IGF-1 serum
Total cholesterol (mg/dl)
AUC glucose (mg/dl*2 h)
AUC insulin (mU/ml*2 h)
AUC C-peptide (ng/ml*2 h)
ALT, alanine transaminase; FLI, fatty liver index; GGT, gamma-glutamyl-transferase; HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein
cholesterol; WHR, waist to hip ratio.
centration correlated negatively with glucose concentration at 2 h
during the OGTT (rho = 20.58, p = 0.0003), whereas
postoperative IGF-1 concentration correlated only in trend (rho = 2
0.30, p = 0.08; Figure 3B,C). The risk of post-load hypoglycemia
one year after bariatric surgery increased by 28% with every
10 ng/ml increment of pre-operative IGF-1 serum concentration
(OR 1.28; 95%CI: 1.031.55; p = 0.0297) and by 18% with
postoperative IGF-1 concentrations (OR 1.18; 95%CI: 1.031.33;
p = 0.0155). Moreover, patients with a pre-operative serum IGF-1
concentration above the calculated median of the whole cohort of
111 ng/ml had a significantly higher risk of post-load
hypoglycemia (OR 4.8; 95%CI: 1.1520.1; p = 0.0275) while the median
cut-off value for post-operative IGF-1 concentration was not
significantly associated with a higher risk. Multiple logistic
regression for post-operative parameters including IGF-1, age,
triglycerides and WHR revealed that only IGF-1 significantly
predicted the occurrence of post-load hypoglycemia (OR 1.22;
95%CI: 1.021.42, p = 0.0300). The ROC analysis of the risk
estimation by pre-operative IGF-1 revealed an AUC of 0.79
(95%CI: 0.640.94, p = 0.0033) and hence showed a good
accuracy to detect hypoglycemia one year after bariatric surgery
(Figure 3D; ROC-AUC of 1.00 represents a perfect test and 0.50
an insignificant test).
The main finding of our study was that post-load hypoglycemia
approximately one year after bariatric surgery was closely
associated with increased circulating IGF-1 concentrations before
and after surgery. This could indicate that IGF-1 plays an
important role in glucose homeostasis following RYBG.
We noticed a trend increase in post-operative IGF-1 serum
concentration compared to pre-operative values. This increase
could be attributed to an improvement in liver function following
weight loss. Indeed obesity-associated fatty liver disease is likely to
improve after weight loss, as reflected by a reduction of BMI,
WHR, serum triglycerides and GGT, i.e. the most relevant
variables for determining the fatty liver index. However, the
reduction of hepatic steatosis, reflected by a reduced fatty liver
index, does not seem to affect the risk of hypoglycemia, since both
hypoglycemic as well as euglycemic patients had similar fatty liver
indices. Therefore, we believe that IGF-1 is in itself a good
predictor of post-load hypoglycemia, irrespective of improvements
in liver function.
Here we identified increased IGF-1 concentrations before and
after surgery as a major risk factor for post-load hypoglycemia.
IGF-1 is synthesized in the liver, has structural similarities to
proinsulin  and augments insulin actions such as stimulating
glucose uptake, via phosphorylation of IRS-1, and suppresses
hepatic gluconeogenesis [37,38]. Thus, IGF-1 is known to enhance
insulin sensitivity in humans and recombinant IGF-1 induces
hypoglycemia as does its ectopic secretion [30,39,40].
Interestingly, both pre- and post-operative IGF-1 serum concentrations were
significantly higher in subjects with post-load hypoglycemia and
the pre-operative levels correlated negatively with 2 h glucose
concentration. Thus, IGF-1 concentration was related to
hypoglycemia risk. Moreover pre-operative IGF-1 serum concentration
was the only parameter to be detected before surgery that
predicted post-load hypoglycemia. Post-operative IGF-1 serum
concentration was also predictive for the risk of hypoglycemia,
alone and even after adjustment for other potential risk factors
such as age, WHR and triglycerides. Higher IGF-1 concentrations
can be detected under physiologic conditions in the young and
pathologically in patients with growth hormone secreting pituitary
adenomas (acromegaly or gigantism), but these patients present
with hyperglycemia. IGF-1 secretion decreases with increasing age
and we also observed a negative correlation between pre and
postoperative IGF-1 concentration and age (r = -0.53, p = 0.0008 and
r = 20.41, p = 0.013, respectively). We found no association
between IGF-1 and serum triglycerides or IGF-1 and WHR,
similar to the findings of Gram et al . Furthermore,
triglycerides and WHR were no longer significant when added
to a multiple logistic regression for hypoglycemia risk, indicating
the independent relation of IGF-1 to hypoglycemia.
Patients suffering from hypoglycemia during the OGTT had a
similar BMI, but patients with hypoglycemia were younger, had
lower WHR, and lower serum triglyceride concentrations than
patients with euglycemia. This is partly consistent with work
suggesting that diabetes remission is more common in younger,
leaner, more insulin sensitive patients with adequate beta-cell
function at baseline . These latter correlations suggest that
reductions in abdominal fat may be important for decreasing
blood lipids and alleviating lipotoxicity effects on post-prandial
blood glucose regulation. A possible explanation for post-load
hypoglycemia may have been differences in insulin concentrations
, but we noticed similar insulin and C-peptide responses to the
oral glucose load in patients with hypoglycemia and patients with
euglycemia. Furthermore both groups were comparable with
respect to circulating serum total-, LDL- and HDL-cholesterol,
liver enzymes, hepatic insulin extraction and fatty liver index.
Since clinical predictors for post-operative hypoglycemia are
missing, we aimed to identify potential risk factors for post-load
hypoglycemia occurring one year after bariatric surgery, in a
cohort of non-diabetic patients. Strikingly, in an unexpectedly high
percentage, namely half of all patients, we detected moderate to
severe post-load hypoglycemia at 2 h during an OGTT. This
finding was surprising, as the frequency for hypoglycemia
following RYGB described in the literature is much lower
[1,4,79]. Emerging evidence of an increased susceptibility to
postprandial hypoglycemia following gastric bypass surgery 
points to the fact that hypoglycemia might contribute to the
increased risk of death from non-disease related causes, such as
accidental deaths and suicide [2,44], as hypoglycemia is known to
determine an increase in depressive symptoms . Similar to
patients under insulin treatment for type 1 or type 2 diabetes, most
of the patients we evaluated were completely unaware of
hypoglycemia during the test. Hence these patients could suffer
from hypoglycemia-related impairments of cognitive and motor
functions  without being aware of it. Therefore, we believe it is
crucial to identify patients at risk for post-prandial hypoglycemia
following bariatric surgery. We detected a clinically applicable
threshold of 111 ng/ml in pre-operative IGF-1 concentration
which can be somewhat useful in assessing the risk of
hypoglycemia. The association of insulin resistance with IGF-1
concentrations seems to be U shaped [23,24] in patients who did not
undergo bariatric surgery and there is not enough data to make
such an assumption for bariatric surgery patients. Nevertheless,
higher values are predictive of post-load hypoglycaemia following
bariatric surgery. Of note, serum IGF-1 concentration can be
determined independent of an elaborate and time-consuming oral
tolerance test, which further requires patient compliance. As an
additional advantage, IGF-1 concentration as a predictive marker
can be determined even before the operation and may hence
contribute to patient selection for gastric bypass surgery, while all
other parameters relating to post-operative hypoglycemia except
from age need to be determined in the post-operative setting,
thus demanding a strict follow-up of patients.
We are aware of some limitation to our study, including the
small sample size and the fact that we could not compare the
incidence of post-load hypoglycemia across a wider spectrum of
surgical techniques, since the most prevalent surgical procedure
performed in this cohort, was RYGB. Although the sample size
was modest, the differences we observed were consistent enough to
encourage further researcher. As for the operating technique,
RYGB is most representative, since it is the most commonly
performed bariatric procedure worldwide . Moreover, 80% of
the patients were women, which is a common finding in bariatric
surgery literature and we cannot make the assumption our findings
would be identical in men. Further work should be performed
including more men and also type two diabetics, since we included
only non-diabetic patients.
In conclusion, post- and particularly pre-operative IGF-1 serum
concentrations help in identifying patients at risk for developing
post-load hypoglycemia. Identification of patients at hypoglycemia
risk based on IGF-1 may improve patient selection for gastric
bypass surgery, help to tailor dietary recommendations, promote
awareness of patients and health-care professionals for this
complication, and may hence further improve the prognosis of
Table S1 Baseline characteristics (before surgery) of
patients who underwent post-load hypoglycemia and
euglycemia at 2h during the post-operative OGTT.
We thank the patients for participating in our study. We thank Dr.
Christian S. Gobl, from the Department of Gynecology and Obstetrics,
Medical University of Vienna, for helpful discussions regarding the
Conceived and designed the experiments: TMS BKI. Performed the
experiments: BKI GP. Analyzed the data: BKI MZ TMS. Contributed
reagents/materials/analysis tools: TMS MZ GP. Wrote the paper: BKI.
Critically reviewed the manuscript: TMS MZ GP.
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