Online appendix Table A1 lists the studies in which data on insulin sensitivity have been reported for obese type 2 diabetic patients undergoing bariatric surgery. With the proviso that our literature search has likely missed diabetic patients included in series that did not provide results separately for diabetic and nondiabetic subjects, the studies in online appendix Table A1 include ~450 type 2 diabetic patients reported over a period of ~25 years. As can be appreciated, type of surgery, duration of follow-up, and methodology vary enough to preclude precise quantitation of the impact of weight loss on insulin sensitivity. Nevertheless, some information can be derived from these data (with no pretense of bona fide meta-analysis). Thus, the weighted mean of preoperative BMI in all 423 patients was 46.4 kg/m2
, which reflects the current indications for bariatric surgery (BMI ≥40 kg/m2
or ≥35 kg/m2
in complicated obesity). In the 204 patients in whom homeostasis model assessment (HOMA) (HOMA of insulin resistance, in this case) was used to assess changes in insulin sensitivity ≥4 months after surgery (weighted mean 12 months), insulin sensitivity improved by 51% for a mean BMI drop of 32% (~40 kg). The percent changes in BMI and HOMA across the different studies were loosely related to one another. In the 79 patients in whom HOMA was measured <4 months after surgery (weighted mean 1.5 months), insulin sensitivity improved by 49% for a BMI decrease of 10% (with no correlation between the respective decrements). The few studies in online appendix Table A1 using different methods of estimating insulin sensitivity (insulin sensitivity test, insulin tolerance test, frequently sampled intravenous glucose tolerance test, and clamp [60
]) do not in general run contrary to this result. Therefore, with all the approximations of this sort of analysis, the notions emerge that 1
) bariatric surgery is capable of improving the insulin resistance of type 2 diabetes by ~50% while at the same time causing a ~30% decrease in BMI and 2
) this improvement of insulin sensitivity may be seen already ~6 weeks following surgery, at which time BMI may be decreased by only 11%. The latter apparent paradox may result from the use of surrogate measures of insulin sensitivity (HOMA). It can also be at least partly explained by the fact that early after surgery, caloric restriction per se (whether achieved by lower intake as per restrictive procedures or reduced absorption as with malabsorptive operations) plays a major role in improving insulin action. Months to years after surgery, weight loss has generally leveled off; a quantitative relationship between the changes in BMI and insulin sensitivity is now usually evident. The weakness of the correlation between the loss of weight and the gain in insulin sensitivity has been repeatedly noted. For example, in a nonrandomized study comparing LAGB and RYGB in a large number of nondiabetic patients (66
), HOMA at 30 months postsurgery was similar but RYGB induced a significantly larger weight loss than LAGB (−33 vs. −22%). It should be considered that, in addition to the confounding factors mentioned in the previous section, an important determinant of weight loss is the initial body weight. For example, in a prospective 2-year follow-up of 107 men and women undergoing BPD at one center, there was a strong correlation (r
= 0.68) between initial weight and achieved weight loss, which was entirely driven by initial fat mass (r
= 0.64) and not fat-free mass (FFM) (67
). This phenomenon is reminiscent of the common clinical observation that with any treatment the response is proportional to the initial height of the abnormality (e.g., A1C or arterial blood pressure). As with these other variables, the biology underlying this apparent rule is unclear.
The questions now arise 1) whether insulin sensitivity is fully restored despite the fact that postoperative BMI typically remains in the obese range, 2) whether the heightened insulin sensitivity is alone responsible for the resolution/improvement of hyperglycemia, and 3) whether the different surgical approaches differ from one another in their insulin-sensitizing power.
Some relevant information can be derived from the few studies that have employed the clamp technique to directly measure insulin sensitivity. In two different databases using the same exogenous insulin infusion rate, the dependency of whole-body insulin sensitivity on BMI is best described by curvilinear fits (online appendix Fig. A2). Both in the European Group for the Study of Insulin Resistance (EGIR) cohort (20
) and in the study by Muscelli et al. (68
), a 30% reduction in BMI (from 46 kg/m2
) predicts a 50% increase in insulin sensitivity. However, both interpolating functions also predict that insulin sensitivity would not be fully restored by a 30% weight decrement (to the level of 42 μmol · kgFFM−1
associated with a BMI of 25 kg/m2
We then used these cross-sectional relationships to scale the results of insulin clamp studies in subjects losing weight by different approaches. In nondiabetic subjects on a calorie-restricted diet (69
) or undergoing RYGB (68
), the data fall well within the 95% CIs of the fit ()—in other words, when weight-stabilized subjects had gained insulin sensitivity in exact proportion to the weight change. Strikingly similar results are obtained when plotting data from two other clamp studies, using caloric restriction (38
) or RYGB (70
). In contrast, in 107 patients, 35 of whom with type 2 diabetes, undergoing BPD and restudied 2 years later, the increase in insulin sensitivity definitely exceeded the prediction; i.e., insulin resistance was normal or supernormal at BMI values still in the obese range (67
). Furthermore, in one study (71
) where insulin sensitivity was estimated at variable (but not sequential) time intervals following BPD, completely normal rates of insulin-mediated glucose clearance were found as early as 10 days after surgery; at this time, marked insulin resistance was present in a control group of morbidly obese patients undergoing major nonbariatric abdominal surgery.
With regard to hepatic insulin resistance, we could find no study that measured endogenous glucose production in obese diabetic patients before and after surgery. However, given that hepatic and peripheral insulin resistance correlate with each other, the pattern of results outlined for insulin-mediated glucose uptake can probably be extrapolated to the effects of insulin on endogenous (hepatic) insulin sensitivity. As for fat distribution, in a large cohort of subjects (including type 2 diabetic patients) undergoing LAGB, the ratio of visceral to subcutaneous abdominal fat (measured by ultrasound) was significantly reduced 1 year postoperatively in concomitance with a weight loss of 8 BMI units (43
). This finding is consistent with the notion that fat is more rapidly lost from visceral than subcutaneous depots. Whereas this fat redistribution may contribute to the improvement of other metabolic abnormalities, it is doubtful that selective fat removal in very obese subjects who lose substantial portions of excess weight affects insulin action over and above what is engendered by weight loss itself.
Patients with diabetes appear to lose significantly less weight than equally obese nondiabetic subjects following gastric bypass (72
). Whether the gain in insulin sensitivity in obese type 2 diabetic patients is any different from that of the nondiabetic obese individuals for the same weight reduction has not been examined systematically. In one series (71
), insulin sensitivity was fully restored in subjects with normal glucose tolerance, impaired glucose tolerance, or type 2 diabetes following BPD; because type 2 diabetic patients had lower presurgery levels of insulin sensitivity, their gain was the highest.
The picture emerging from this analysis is as follows: Surgical procedures that greatly restrain food intake (RYGB) or absorption (BPD) may induce some recovery of insulin sensitivity before any large weight loss has occurred. However, when tested under conditions of stable energy balance, insulin resistance is increased by surgically induced weight loss quantitatively. Therefore, long-term–postsurgery morbidly obese patients (nondiabetic and diabetic alike) are likely to retain a degree of insulin resistance if their BMI is still in the overweight/obese range. Malabsorptive procedures take exception in that they may improve insulin sensitivity beyond the effect of weight loss. This fundamental difference between mainly restrictive and malabsorptive procedures needs to be proven by prospective, randomized studies.