General description of the data
The basic data for the included patients is shown in Table
1. The majority of the patients were females (71.5 %), but sex distribution differs significantly between non- diabetics and diabetics, where the two genders were equally represented in the last group. Thirty percent of the patients were classified as diabetics, when both categories of diabetics were included. The age at surgery was significantly lower in the non-diabetic group (NDM) group compare to the two diabetic groups.
Table 1
Clinical status. Age at surgery and time to post-surgery non-diabetic state for pre-surgery diabetic subjects
Diabetics (DM) | 223 | | | | | | | | |
By glycemic status | 100 | | | | | | | | |
NDM post surgery | 48 | | | | | | | | |
DMT2 post surgery | 34 | | | | | | | | |
NDM post/treat DMT2 | 17 | (see text) | | | |
By treatment only | 123 | | | | | | | | |
NDM post surgery | 112 | | | | | | | | |
DMT2 post surgery | 11 | | | | | | | | |
Non-diabetics (NDM) | 518 | | | | | | | | |
Not determined glycemic | 5 | | | | | | | | |
Not determined glycemic/treat DMT2 | 1 | | | | | | | | |
Total | 747 | | | | | | | | |
Fraction diabetics | 0.3 | | | | | | | | |
Females | 530 | | | | | | | | |
Males | 217 | | | | | | | | |
Age at surgery | Glycemic DMT2 | | Treatment DMT2 | | NDM | | |
| Females | Males | Females % | Females | Males | Females % | Females | Males | Females % |
Number | 54 | 46 | 54.0 % | 70 | 53 | 56.9 % | 402 | 116 | 77.6 % |
Mean | 49.58 | 50.31 | | 48.55 | 48.5 | | 41.97 | 41.02 | |
Minimum | 30.79 | 30.29 | | 27.08 | 27.49 | | 18.97 | 19.05 | |
Maximum | 64.65 | 65.53 | | 61.95 | 61.83 | | 65.37 | 59.18 | |
Variance | 71.66 | 50.14 | | 77.68 | 69.14 | | 91.38 | 83.39 | |
Std | 8.47 | 7.08 | | 8.81 | 8.31 | | 9.56 | 9.13 | |
Females-Males. p-value* | | 0.642 | | | 0.975 | | | 0.33 | |
Compare clinical status | Females | Males | | | | | | | |
NDM-Glycemic | <0.001 | <0.001 | | | | | | | |
NDM-Treatment | <0.001 | <0.001 | | | | | | | |
Glycemic-Treatment | 0.512 | 0.248 | | | | | | | |
Days to NDM after surgery | Glycemic DMT2 | | Treatment DMT2 | | | | |
| Females | Males | | Females | Males | | | | |
Number | 33 | 32 | | 59 | 41 | | | | |
Mean | 202.55 | 201.94 | | 146.64 | 178.61 | | | | |
Minimum | 42 | 84 | | 11 | 66 | | | | |
Maximum | 708 | 696 | | 451 | 751 | | | | |
Variance | 21040 | 18975 | | 8088 | 23356 | | | | |
Std | 145 | 137 | | 90 | 153 | | | | |
Females-Males. p-value | | 0.986 | | | 0.239 | | | | |
Almost half of the glycaemic diabetics, DMT2, turned non-diabetics after surgery, NDM, (DMT2-NDM sub-population) to which may be added the 17 patients receiving post-surgery (but not pre-surgery) anti-diabetic treatment. This number may be even higher as the 34 patients still diabetics (DMT2-DMT2) according to the HbA1c levels may have shorter follow-up times and with time and weight loss may actually convert to a non-diabetic state. The average time for conversion in this group was 202 days (range 42 to 708 days) as judged from the HbA1c levels. Notably, this observation may, at least in part, be explained by the half-life of HbA1c and time span between outpatient visits, since weight loss is ongoing the first 1–2 years after RYGB. The fate of the treatment DM group differs from the glycaemic DM group: the time to NDM-conversion was shorter and more than 91 % did convert to NDM post-surgery, while only 65 % converted in the glycaemic DM group (including the 17 subjects prescribed anti-diabetic treatment post-surgery, Table
1). The post-surgery NDM status in this group was defined as HbA1cIFCC values below 48
and medical treatment withdrawn. There were no differences between genders within each sub-population.
The actual diabetic status of the treatment DM group was not unambiguously defined and for some variables this group was similar to the glycaemic DM groups, in others to the NDM group (see also Additional file
1: Table S1). Therefore the treatment DM group was not further included in interpretation of the RYGB data.
All data for all the variables in each sub-population are listed in Additional file
1: Table S1. An excerpt of the primary outcome variables (HbA1c, insulin and glucose) is tabulated in Table
2 (see also Additional file
2: Table S2). The relative changes (pre- to post-surgery) were significant for weight, BMI and the HbA1c measures in all populations (NDM, DMT2-NDM and DMT2-DMT2). The average weight loss and decrease in BMI were approximately 25 %, but varies considerably from almost no decrease up to more than 50 %, suggesting very heterogeneous sub-populations of weight loss responders. The changes in the NDM and the DMT2-NDM sub-populations were marginal significantly different for weight and BMI for females but not for males.
Table 2
Maximal changes in glucose-related variables
HBA1CIFCC (mmol/mol) Range <48 |
| NDM | DMT2-NDM | DMT2-DMT2 |
| Pre-surgery | Pre-surgery | Pre-surgery | Post-surgery | Pre-surgery | Post-surgery |
Number of subjects | 179 | | 47 | | 8 | |
Mean | 37 | 32 | 63 | 38 | 84 | 53 |
Range | 27–47 | 24–43 | 42–113 | 28–46 | 54–122 | 48–70 |
Comparison of conditions,
|
p-values*
| | | | |
| Pre-surgery | Post-surgery | | | | |
NDM v DMT2-NDM | <0.001 | <0.001 | | | | |
NDM v DMT2-DMT2 | <0.001 | <0.001 | | | | |
DMT2-NDM v DMT2-DMT2 | 0.031 | <0.001 | | | | |
Glucose (mmol/L) Range 4.2–6.1 |
| NDM | DMT2-NDM | DMT2-DMT2 |
| Pre-surgery | Post-surgery | Pre-surgery | Post-surgery | Pre-surgery | Post-surgery |
Number of subjects | 182 | | 43 | | 7 | |
Mean | 5.4 | 4.9 | 8.8 | 5.8 | 9.8 | 6.4 |
Range | 3.9–8.0 | 1.3–7.1 | 3.3–24 | 4.1–9.1 | 3.4–19 | 4.8–8.4 |
Comparison of conditions,
|
p-values
| | | | |
| Pre-surgery | Post-surgery | | | | |
NDM v DMT2-NDM | <0.001 | <0.001 | | | | |
NDM v DMT2-DMT2 | 0.070 | 0.032 | | | | |
DMT2-NDM v DMT2-DMT2 | 0.647 | 0.323 | | | | |
Insulin (pmol/L) Range 10–125 |
| NDM | DMT2-NDM | DMT2-DMT2 |
| Pre-surgery | Post-surgery | Pre-surgery | Post-surgery | Pre-surgery | Post-surgery |
Number of subjects | 177 | | 42 | | 7 | |
Mean | 113 | 41 | 150 | 50 | 69 | 32 |
Range | 23–486 | 1–112 | 13–494 | 2–11 | 4–167 | 1–53 |
Comparison of conditions,
|
p-values
| | | | |
| Pre-surgery | Post-surgery | | | | |
NDM v DMT2-NDM | 0.020 | 0.019 | | | | |
NDM v DMT2-DMT2 | 0.074 | 0.176 | | | | |
DMT2-NDM v DMT2-DMT2 | 0.007 | 0.022 | | | | |
HOMA-IR |
| NDM | DMT2-NDM | DMT2-DMT2 |
| Pre-surgery | Post-surgery | Pre-surgery | Post-surgery | Pre-surgery | Post-surgery |
Number of subjects | 175 | | 42 | | 7 | |
Mean | 28.1 | 9.5 | 59.1 | 13.5 | 36.8 | 9.3 |
Range | 4.7–164.0 | 0.3–28.7 | 1.9–199.0 | 0.6–36.7 | 0.6–107.6 | 0.3–15.4 |
Comparison of conditions,
|
p-values
| | | | |
| Pre-surgery | Post-surgery | | | | |
NDM v DMT2-NDM | <0.001 | <0.001 | | | | |
NDM v DMT2-DMT2 | 0.564 | 0.925 | | | | |
DMT2-NDM v DMT2-DMT2 | 0.190 | 0.082 | | | | |
HOMA-BETA |
| NDM | DMT2-NDM | DMT2-DMT2 |
| Pre-surgery | Post-surgery | Pre-surgery | Post-surgery | Pre-surgery | Post-surgery |
Number of subjects | 174 | | 41 | | 6 | |
Mean | 1303 | 489 | 869 | 430 | 239 | 261 |
Range | 236–5215 | 40–2072 | 113–1101 | 8–1184 | 88–369 | 121–546 |
Comparison of conditions,
|
p-values
| | | | |
| Pre-surgery | Post-surgery | | | | |
NDM v DMT2-NDM | 0.023 | 0.204 | | | | |
NDM v DMT2-DMT2 | <0.001 | 0.020 | | | | |
DMT2-NDM v DMT2-DMT2 | 0.001 | 0.063 | | | | |
The relative changes in HbA1c were significant except for the DMT2-DMT2 females. Pre- to post-surgery changes in HbA1c values differed significantly between the NDM and DMT2-NDM sub-populations, and to a lesser extent between the NDM and DMT2-DMT2, although the values were highly variable. The difference of post-surgery levels NDM and DMT2-NDM sub-populations compared to DMT2-DMT2 is of course due to the classification criteria (see
Methods). The relative changes were 2.6 to 3.8 fold higher in the diabetic sub-populations than in the non-diabetic sub-population, but nevertheless the change in the NDM group was significant and the metabolic state was “improved” in this otherwise non-diabetic sub-population. The post-surgery levels of HbA1c in both the diabetic groups approached pre-surgery but not the post-surgery levels in the non-diabetics.
Insulin decreased 45–60 % post-surgery irrespective of the pre-surgery levels and glucose tolerance, except for females in the DMT2-DMT2 sub-population (Additional file
2: Table S2). There were no significant differences of the relative changes in level between the sub-populations and all post-surgery levels were within the normal range. However, the pre-surgery levels showed a complex pattern: the mean levels were increased in DMT2-NDM sub-population and the male NMD sub-population, but not in in the female NDM sub-population and in the DMT2-DMT2 sub-populations (Table
2 and Additional file
2: Table S2). Also, some subjects in the NDM sub-populations had increased pre-surgery insulin levels, suggesting that the metabolic steady state in the non-diabetic subjects (as judge by the HbA1c levels) were heterogeneous i.e. may be defined as pre-diabetics.
A similar pattern was observed for fasting glucose levels with significant differences between pre- and post-surgery levels and relative changes (8 % in the non-diabetic sub-population up to 26 % in the DMT2-NDM sub-populations, Additional file
2: Table S2). On average, glucose levels were normalized in the NDM and DMT2-NDM sub-populations, but not in the DMT2-DMT2 sub-population and some subjects did have persistent hyperglycemia post-surgery in all sub-populations. Importantly, the post-surgery level in diabetics did not reach the pre-surgery level of the non-diabetics and not at all the non-diabetic post-surgery level for at least some of the subjects in the diabetic sub-populations.
The HOMA-beta and HOMA-IR indices decreased 53–60 % in the NDM sub-populations irrespective of gender (Table
2). No significant changes were seen in the diabetic sub-populations except for HOMA-IR in the male DMT2-NDM sub-population (Additional file
3: Table S3). The trends were however similar for HOMA-IR in all sub-populations with a substantial increase in insulin sensitivity. Importantly, the pre- and post-surgery levels of HOMA-IR were significantly different comparing NDM and DMT2-NDM (Table
2). The NDM and DMT2-NDM sub-population had similar levels of HOMA-beta values and seemed distinctively different from the DMT2-DMT2 sub-population, but these differences did not reach statistical significance. It should be noted that the number of subjects in the DMT2-DMT2 sub-population was low and variances rather high.
C-peptide decreased 34–44 % post-surgery with no difference in the NDM and DMT2-NDM sub-populations. The decreases in post-surgery levels in the DMT2-DMT2 sub-population were notable, but did not reach significance. The C-peptide levels were only marginal different when the NDM and DMT2-NDM subpopulations were compared (Additional file
2: Tables S2).
The changes in lipids were rather complex. Cholesterol decreased 17–26 % after surgery in the NDM and female DMT2-NDM sub-populations, and although substantial decreases were also seen in the DMT2-DMT2 sub-populations they did not reach significance. A similar pattern was seen for LDL-cholesterol. Triglyceride and VLDL-cholesterol levels decreased substantially in all sub-populations although the decreases were only marginal in the DMT2-DMT2 sub-populations. Small increases of HDL-cholesterol were detected. HDL-cholesterol was within the normal range except for a few subjects deviating slightly from the normal range.
The low-grade inflammatory parameter C-reactive protein decreased to a large extend in all sub-populations and gender (56–79 %), although the changes did not reach significance in the male DMT2-DMT2 sub-population. The decrease was much less for leukocytes (14–25 %) but still significant except for DMT2-DMT2 sub-populations. With a few exceptions all subjects were within the normal range for C-reactive protein and leukocytes.
A summary of the relative changes for all the variables is shown in Additional file
3: Table S3. The significance of the relative changes were high (
p <0.001) for most of the variables in the non-diabetic sub-population particular for women and with high power (>0.95). A similar pattern was seen for the DMT2-NDM sub-population, but important differences were observed. The most striking observation was the high responsiveness of the NDM sub-population to RYGB where many variables were “normalized” compared to the DMT2-NDM sub-populations and in particularly to the DMT2-DMT2 sub-populations in which only minor changes occurred (the number of subjects is small and variances may be large reducing the reliability of the statistics).
Trait distributions
The Kolmogorov-Smirnov analyses of similarity of trait distributions are very complex. If a level of acceptance of similarity is set at 0.05 then 311 similarities were observed among all the patients. However, such a level translates into low correlation. The more stringent level of 0.9 reduced the number of similarity of two-trait distributions to 55 (44 unique) as shown in Additional file
4: Table S4. Only the weight-BMI association was observed for all sub-populations. Taken all together, most of the associations were consistent with the concept of the metabolic syndrome including insulin, C-peptide, lipids and inflammatory markers.
The comparison of trait distributions within gender between the NDM and DMT2-NDM sub-populations are shown in Additional file
5: Table S5. The similarity
p-values were significant for all traits in the female population, but 13 traits in the male populations were not significant. Except for the HOMA indices and TSH significant differences were observed for in at least one of the genders. Thus, the vast majority of trait distributions do not emerge from a common distribution, suggesting basic differences in metabolic physiology in non-diabetics and diabetics even if the latter turned non-diabetic after surgery.