Effects of Marked Weight Loss Induced by Gastric Bypass Surgery or Low-Calorie Diet Alone on Postprandial Glucose Disposal in Type 2 Diabetes

Abstract

We used a dual (intravenous and oral) glucose tracer protocol to evaluate rates of glucose appearance in the circulation, insulin-mediated glucose disposal (IMGD), and noninsulin-mediated glucose disposal (NIMGD) for 4 h after consumption of a mixed meal in people with obesity and type 2 diabetes before and after marked (∼20%) weight loss, induced by behavioral diet therapy (BDT, n = 11) or Roux-en-Y gastric bypass (RYGB) surgery (n = 9). Total postprandial glucose appearance rate was lower after compared with before weight loss in both the BDT and RYGB groups because of a decrease in endogenous glucose production, without a difference between groups. However, the decreases in total and incremental postprandial plasma glucose concentration areas under the curve were greater in the BDT group than the RYGB group because IMGD doubled in the BDT group but did not change in the RYGB group. These results demonstrate that the improvement in postprandial glycemia is greater after marked, matched weight loss induced by BDT compared with RYGB in people with obesity and type 2 diabetes, because of increased IMGD after BDT but not RYGB. Nonetheless, these findings do not diminish the potent therapeutic effect of RYGB surgery on glycemic control and even achieving remission of type 2 diabetes.

Article Highlights

• In people with obesity and diabetes, marked (∼20%) weight loss induced by behavioral diet therapy (BDT) causes a greater decrease in postprandial plasma glucose area under the curve than matched weight loss after Roux-en-Y gastric bypass (RYGB), even though insulin sensitivity and postprandial plasma insulin area under the curve are the same in both groups.

• We studied the effects of marked weight loss after BDT or RYGB on insulin-mediated glucose disposal (IMGD) and non–insulin-mediated glucose disposal.

• Weight loss induced by BDT, but not RYGB, increased IMGD.

• Postprandial glycemia improves more after marked weight loss induced by BDT than by RYGB because of increased IMGD after BDT but not RYGB.

Graphical Abstract

Introduction

Postprandial hyperglycemia is a pathognomonic feature of type 2 diabetes that is caused by impaired disposal of ingested glucose due to insulin resistance and inadequate insulin secretion (1–3). The defects in insulin action and secretion increase the importance of insulin-independent glucose disposal to regulate postprandial glycemia. In fact, postprandial non–insulin-mediated glucose disposal (NIMGD, defined as glucose disposal at basal plasma insulin) is the major mechanism for glucose disposal in people with diabetes and helps compensate for the defect in insulin-mediated glucose disposal (IMGD, i.e., glucose disposal driven by the postprandial increase in plasma insulin above basal values) (4).

Weight loss has profound therapeutic effects on postprandial glucose homeostasis in people with obesity and type 2 diabetes (5). We recently found that marked (∼20%) weight loss, induced by either behavioral diet therapy (BDT) or Roux-en-Y gastric bypass (RYGB) surgery, caused a large decrease in postprandial plasma glucose (4-h area under the curve [AUC] after a mixed meal) (5), and the decrease was greater after BDT than RYGB, even though the improvements in insulin sensitivity (assessed by using the hyperinsulinemic-euglycemic clamp procedure [HECP]), total postprandial plasma insulin concentration, and total glucose appearance rate in the systemic circulation were not different between the BDT and RYGB groups. The reason(s) for the difference in postprandial plasma glucose concentration between these two weight loss therapies is not clear but is likely related to differences in the delivery of ingested glucose into the systemic circulation and the subsequent differences in plasma glucose and insulin dynamics that can affect insulin action on glucose disposal (6).

The purpose of the current study was to evaluate the effects of marked weight loss on the rates of IMGD and NIMGD after mixed-meal ingestion in people with obesity and type 2 diabetes who lost weight by BDT alone or in conjunction with RYGB surgery. We hypothesized that weight loss would increase IMGD postprandially in both groups, but the increase would be greater in the BDT group than the RYGB group.

Research Design and Methods

Study Participants

The data in this paper represent a secondary analysis of data obtained from 20 participants (three men and eight women in the BDT group; three men and six women in the RYGB group) who participated in a study (clinicaltrials.gov reg. no. NCT02207777) that evaluated the effect of weight loss induced by BDT or RYGB surgery on multiorgan metabolic function before and after ∼20% weight loss in people with obesity and type 2 diabetes. Participants’ body composition and metabolic characteristics before and after weight loss are shown in Table 1. A detailed description of the study protocol and participant selection criteria was previously published (5). Potential participants were excluded if they 1) had a disease other than type 2 diabetes or were taking medication(s) that could affect the study outcome measures, 2) had previous bariatric surgery, or 3) consumed excessive amounts of alcohol. All participants provided written informed consent before enrolling in the study, which was approved by the Washington University Institutional Review Board (St. Louis, MO).

Table 1.

Body composition and metabolic characteristics of the participants before and after weight loss

	BDT			RYGB
	Beforea	Aftera	Change (%)b	Beforea	Aftera	Change (%)b	Group differencec
Age (years)	55 ± 7	—		50 ± 10	—
BMI (kg/m2)	43 ± 9	35 ± 7	17.8 (−18.6, −17.0)	43 ± 6	35 ± 3	−18.4 (20.1, 16.7)	0.31 (−0.61, 1.23)
Weight (kg)	114 ± 16	95 ± 13*	−17.0 (−18.6, −15.4)	123 ± 18	100 ± 15	−18.6 (−21.0, −17.0)	1.30 (−1.88, 4.49)
Fat-free mass (kg)	58 ± 13	54 ± 9*	−7.3 (−9.3, −5.3)	63 ± 12	58 ± 12	−9.1 (−10.9, −7.3)	0.57 (−1.11, 2.25)
Body fat (%)	48 ± 6	43 ± 6*	−11.3 (−13.9, −8.7)	47 ± 3	44 ± 6	−9.5 (−12.9, −6.1)	−0.75 (−2.48, 0.98)
Basal glucose (mg/dL)	164 ± 39	107 ± 10*	−31.9 (−40.2, −23.6)	153 ± 30	106 ± 15	−29.9 (−35.5, −24.3)	−1.1 (−11.7, 9.5)
Basal insulin (mU/L)	18 ± 7	11 ± 3	−41.8 (−56.1, −27.4)	27 ± 12	9 ± 6	−61.6 (−71.9, −51.3)	3.3 (−1.1, 7.6)
Basal glucose Ra (µmol/kg FFM/min)	17.8 ± 3.6	15.0 ± 2.6	−14.8 (−29, 6.0)	18.2 ± 3.6	15.2 ± 1.5	−15.3 (−24.7, −5.9)	−0.31 (−2.6, 2.0)
Glucose Rd/I HECP ([nmol/kg FFM/min]/[mU/L])	250 ± 114	536 ± 162	121 (162, 80)	273 ± 108	535 ± 190	116 (185, 48)	22 (−128, 171)
HbA1c (%)	8.7 ± 2.2	5.7 ± 0.7	−32 (−40, −24)	7.2 ± 1.4	5.9 ± 0.6	−14 (−24, −3)	−0.78 (−1.65, 0.08)

CIs that do not include zero are statistically significant at the P < 0.05 level. BDT n = 11; RYGB n = 9. FFM, fat-free mass; Rd, disposal rate; Rd/I, disposal rate in relationship to plasma insulin.

^aBefore and after values are expressed as means ± SD.

^bChange values are expressed as means (95% CI).

^cGroup difference refers to the difference between the group means (95% CI) of the values after weight loss, adjusted for the values before weight loss.

Experimental Protocol

Body composition was determined by using dual energy X-ray absorptiometry (Lunar iDXA; GE Healthcare, Madison, WI). All participants completed an HECP with stable isotopically labeled glucose infusion to determine basal and insulin-stimulated glucose disposal rates as a measure of insulin sensitivity (5). In addition, participants completed a dual tracer ([6,6-²H₂]glucose given intravenously, [U-¹³C₆]glucose given orally) 200-mL liquid mixed-meal test after they fasted for ∼12 h overnight. The meal contained 49.9 g (277 mmol) of glucose (49 g unlabeled glucose and 0.9 g [U-¹³C₆]glucose), 18 g of fat, and 22 g of protein, and provided 450 kcal of energy both before and after the intervention. The [6,6-²H₂]glucose tracer infusion was started 3 h before ingesting the mixed meal, which was consumed in seven equal aliquots every 5 min over 30 min, and continued for 4 h after mixed-meal ingestion (5). Blood samples were obtained before starting the tracer infusion, at 20 min, 10 min, and immediately before ingesting the mixed meal, and then every 10 min for the first 60 min and every 20 min for the next 180 min after mixed-meal ingestion (5). The average values obtained from the blood samples during the 20-min period before initiating meal ingestion were used as basal (t = 0) values. Participants were instructed to stop taking glucagon-like peptide 1 receptor agonists for 2 weeks, oral diabetes medications for 3 days, and insulin for 1 day before admission to the research unit the night before the mixed-meal test.

Weight loss was initiated in all participants within a few weeks after baseline testing. Laparoscopic RYGB surgery was performed by using standard techniques. Participants in both the BDT and RYGB groups participated in a supervised dietary weight loss program designed to achieve 20% weight loss within 4–6 months, followed by a weight maintenance diet (<2% change in body weight) for at least 2 weeks. Repeat metabolic testing was conducted when participants were weight-stable (average weight change: −0.5 ± 0.4% per week in the RYGB group,−0.4 ± 0.1% per week in the BDT group), which occurred at about 4 months after surgery in the RYGB group and about 6 months after initiating diet therapy in the BDT group (Supplementary Fig. 1).

Postprandial Glucose Kinetics Modeling

We used a published mathematical model (4) that is described in detail in the Supplementary Material to evaluate IMGD and NIMGD rates after glucose ingestion. By fitting the plasma insulin and glucose concentrations and the plasma glucose tracer enrichments to the model, the model describes the rates of endogenous glucose production (EGP) and oral glucose appearance in the systemic circulation, IMGD (glucose disposal that is attributable to the postprandial rise in plasma insulin above basal postabsorptive insulin values), and NIMGD (glucose disposal that is not attributable to the postprandial rise in insulin). Modeling of the data was performed by using SAAM II version 1.2.1 (SAAM Institute, University of Washington).

Statistical Analysis

ANOVA was used to evaluate differences in metabolic outcomes between the BDT and RYGB groups at baseline and after the interventions (with after values adjusted for baseline values). All summary data are presented as mean ± SEM unless otherwise noted. A P value of ≤0.05 was considered statistically significant.

Data and Resource Availability

Data generated from this study are available from the corresponding author upon reasonable request. No resources were generated.

Results

Plasma Glucose and Insulin Concentrations and Insulin Sensitivity

At baseline, insulin sensitivity of glucose disposal assessed by using HECP, basal (overnight fasted condition) and postprandial plasma glucose and insulin concentrations, and HbA_1c were not statistically significantly different between the BDT and RYGB groups (Table 1 and Fig. 1A and B). Weight loss increased insulin sensitivity and decreased basal plasma glucose and insulin concentrations, without a difference between groups (Table 1). Weight loss also decreased HbA_1c in both groups; the relative decrease was greater in the BDT group than the RYGB group (−32 ± 4% vs. −14 ± 6%, P < 0.05), and the absolute decrease tended to be greater (P = 0.051) in the BDT group (Table 1). About a quarter of the participants in both the RYGB group (n = 2 of 9, 22%) and the BDT group (n = 3 of 11, 27%) achieved diabetes remission (HbA_1c <6.0% without diabetes medication) after weight loss. The 4-h postprandial insulin and glucose AUCs were lower after than before weight loss in both groups (Fig. 1A–C). However, the decreases in glucose total AUC and incremental AUC (iAUC) were greater in the BDT group than the RYGB group (group × time interaction, P < 0.05) (Fig. 1C), whereas the decreases in the insulin AUC were not different between groups (effect of time, P < 0.05; no significant group × time interaction) (Fig. 1C).

Figure 1.

Plasma insulin (A) and glucose (B) concentrations and model fit to the glucose concentration data immediately before (−30 to 0 min) and for 4 h after (0–240 min) meal ingestion, glucose and insulin total and incremental AUC (C), and total (endogenously produced and meal-derived) and endogenously produced glucose appearance rates in the systemic circulation immediately before (−30 to 0 min) and for 4 h after meal ingestion (0–240 min) (D) in the BDT group (n = 11, left) and the RYGB group (n = 9, right) before and after weight loss. Data are expressed as mean ± SEM and include individual level data in C. *Value significantly different from corresponding before value, P < 0.05. †Greater weight loss–induced decrease in the BDT group than the RYGB group, P < 0.05.

Model Fit to the Data and Glucose Appearance Rate in the Systemic Circulation

The model we used to determine glucose kinetics provided an excellent fit to the plasma glucose concentrations and the [6,6-²H₂]glucose and [U-¹³C₆]glucose tracer-to-tracee ratios before and after weight loss in both the BDT and RYGB groups (Fig. 1B and Supplemental Fig. 2). Before weight loss, the total appearance rate (Ra) of glucose (derived from EGP and the ingested glucose) in the systemic circulation increased rapidly after initiating meal ingestion and peaked at about 30 min in both the BDT and RYGB groups (Fig. 1D). Basal glucose Ra (i.e., basal EGP) (Table 1), total postprandial EGP (AUC), and total postprandial glucose Ra (AUC) during the 4-h period after starting meal ingestion were lower after than before weight loss in both the BDT and RYGB groups, without a difference between groups (effect of time, P < 0.05; no significant group × time interaction) (Fig. 1D). The time-course pattern of the total glucose Ra response to the meal did not change after weight loss in the BDT group, whereas postprandial total glucose Ra increased more rapidly and to a higher peak after than before weight loss in the RYGB group (Fig. 1D). However, the total incremental increase in glucose Ra during the 4-h postprandial period was not different before and after the intervention in either group (BDT group: 120 ± 10 and 126 ± 10 mmol, respectively; RYGB group: 110 ± 10 and 116 ± 12 mmol, respectively). Before weight loss, ingested glucose was the main source of total glucose Ra during the first 2.5 h after initiating meal ingestion in both the BDT and RYGB groups (Fig. 1D). After weight loss, ingested glucose was the main source of total glucose Ra during the first 2.5 h postprandially in the BDT group, whereas the appearance of ingested glucose in the systemic circulation was nearly complete within the first hour in the RYGB group (Fig. 1D).

Total Postprandial Glucose Disposal Rate

Total postprandial glucose disposal represents the sum of NIMGD and IMGD and includes the disposal of endogenously produced and ingested glucose. Before weight loss, the postprandial total glucose disposal (TGD) rate increased from 0 to 60 min, reached a plateau from 60 to 140 min, and slowly declined to basal values between 140 and 240 min in both the BDT and RYGB groups (Fig. 2A). The postprandial increase in total glucose Ra during the first hour after initiating meal ingestion was much greater than the increase in TGD rate (Fig. 3A, left), causing a positive glucose net balance (Fig. 3B) and a rise in plasma glucose concentration (Fig. 1B), whereas during the final 2 h of the meal test, TGD rate (total glucose Rd) exceeded total glucose Ra (Fig. 3A, left), causing a return of plasma glucose toward basal values (Fig. 1B) without a difference between groups.

Figure 2.

Total glucose disposal rate before and after the interventions (A), insulin-mediated and non-insulin–mediated glucose disposal rate before the intervention (B), insulin-mediated and non-insulin–mediated glucose disposal rate after the intervention (C), and the proportional contribution of insulin-mediated glucose disposal to total glucose disposal (D) in the BDT group (n = 11, left) and the RYGB group (n = 9, right) before and after weight loss. Data are expressed as mean ± SEM. *Value significantly different from corresponding before value, P < 0.05.

Figure 3.

Total glucose appearance and disappearance rates (A) and glucose net balance (difference between total glucose appearance rate and total glucose disappearance rate) (B) before and after weight loss in the BDT group (n = 11) and the RYGB group (n = 9). Ra, appearance rate; Rd, disappearance rate (equivalent to total glucose disposal rate, i.e., TGD rate). Data are expressed as mean ± SEM.

Compared with baseline (before weight loss), weight loss caused a ∼30% decrease in basal (before meal ingestion) glucose disposal (basal TGD) rate (which equals basal glucose Ra) in both the BDT and the RYGB groups, without a difference between groups (main effect of time, P < 0.05; no significant group × time interaction) (Table 1 and Fig. 2A). The postprandial rise in TGD during the 4-h meal test (iAUC) was ∼45% higher after compared with before weight loss in the BDT group but did not change with weight loss in the RYGB group (group × time interaction, P < 0.05) (Fig. 2A). In addition, weight loss caused a change in the time-course pattern of the postprandial TGD curve in both the BDT and RYGB groups. TGD rate after meal ingestion increased above basal values and returned to basal values more rapidly after than before weight loss in both the BDT and RYGB groups, but the peak postprandial TGD values occurred much earlier in the RYGB group (at ∼60 min after initiating meal ingestion) than in the BDT group (at ∼100 min) (Fig. 2A). In the BDT group, the difference between the postprandial rise in total glucose Ra and TGD rate was smaller (less net-positive) after than before weight loss (Fig. 3B, left), causing the smaller postprandial increase in plasma glucose concentration after than before weight loss (P < 0.05) (Fig. 1B and C). In the RYGB group, the postprandial rise in TGD rate after weight loss was much less than the initial several-fold increase in glucose Ra (Fig. 3A, right), resulting in a greater positive glucose net balance after compared with before weight loss (Fig. 3B, right) and a 2.5-fold increase in plasma glucose concentration above basal values early after meal ingestion (Fig. 1B, right). The marked differences in glucose dynamics between the BDT and RYGB groups after weight loss (Fig. 3A, right) resulted in different plasma glucose net balance profiles between the BDT and RYGB groups (Fig. 3B) and overall smaller decreases in plasma glucose concentration AUC and iAUC after compared with before weight loss in the RYGB group compared with the BDT group (Fig. 1B and C).

Insulin-Mediated and Non–Insulin-Mediated Glucose Disposal Rates

In the model we used, IMGD is defined as the glucose disposal rate that is attributable to the postprandial rise in insulin above basal insulin, and NIMGD is the glucose disposal rate that is not attributable to the postprandial rise in insulin. Together, IMGD and NIMGD comprise TGD. Accordingly, glucose disposal rate during basal postabsorptive conditions is also defined as noninsulin-mediated and does not include an insulin-mediated component. Before weight loss, IMGD started with a delay of about 30 min, and the relative contributions of IMGD and NIMGD to TGD for 4 h after initiating meal ingestion were ∼15% and ∼85%, respectively, in both the BDT and RYGB groups (Fig. 2B and D). In the BDT group, IMGD AUC during the 4-h postprandial period increased from 38 ± 14 mmol before weight loss to 85 ± 19 mmol after weight loss (Fig. 2B and C, left), and the relative contribution of IMGD to postprandial TGD doubled (from ∼15% to ∼30%) (Fig. 2D, left). In contrast, in the RYGB group, IMGD AUC during the 4-h postprandial period did not increase after weight loss (45 ± 16 mmol before and 39 ± 19 mmol after; group × time interaction, P < 0.05) (Fig. 2B and C, right), and the relative contribution of IMGD to postprandial TGD did not change (Fig. 2D, right). NIMGD AUC was significantly lower after compared with before weight loss in the BDT group (236 ± 15 mmol after, 316 ± 23 mmol before, P < 0.05) but did not significantly change after weight loss in the RYGB group (286 ± 20 mmol after, 323 ± 24 mmol before, P = 0.11). The difference in NIMGD between the groups after weight loss was due to the difference in the plasma glucose load and was not caused by a difference in the weight loss–induced change in the glucose effectiveness rate constant (GE, 10⁻³ × min⁻¹), which increased by ∼50% in both groups (BDT: 8.2 ± 1.8 before, 12.5 ± 3.8 after; RYGB: 7.1 ± 1.3 before, 10.6 ± 2.8 after).

Discussion

Postprandial plasma glucose concentration is an important measure of metabolic health (1–3); it is primarily determined by the rates at which ingested glucose is delivered to and removed from the systemic circulation. We evaluated NIMGD and IMGD after consumption of a mixed meal in people with obesity and type 2 diabetes before and after marked (20%) weight loss induced by either BDT or RYGB surgery to help explain the greater decrease in postprandial plasma glucose concentration after matched, marked weight loss induced by BDT compared with RYGB. We found IMGD increased in the BDT group but not in the RYGB group, and the increase in IMGD induced by weight loss in the BDT group was entirely due to increased insulin sensitivity rather than an increase in postprandial plasma insulin concentration, which was lower after than before weight loss. Weight loss induced by RYGB did not increase IMGD, even though the increase in insulin sensitivity and the decrease in total postprandial plasma insulin concentrations were the same in the BDT and RYGB groups, presumably because the accelerated delivery of ingested glucose into the systemic circulation prevented an adequate increase in IMGD. The results from our study demonstrate marked differences in postprandial glucose disposal after weight loss induced by RYGB surgery compared with BDT and support the use of low-glycemic meals after RYGB surgery to reduce postprandial glycemia.

Weight loss induced by RYGB surgery was not as effective in lowering postprandial plasma glucose concentration as the same weight loss induced by BDT. The decreases in total 4-h postprandial plasma glucose concentration AUC and iAUC were greater in the BDT group than the RYGB group because IMGD increased only after weight loss in the BDT group, even though insulin sensitivity (glucose disposal during the HECP) and total postprandial plasma insulin concentration were not different between the two groups. Although the rapid and large postprandial increase in glucose appearance in plasma caused an increase in NIMGD in the RYGB group, the increase in NIMGD did not fully compensate for the failure to increase IMGD. These results are consistent with the data from a study that evaluated the effect of varying the rates of glucose delivery into the small intestine on plasma glucose and insulin concentrations (6). Infusing glucose into the duodenum at a high rate (3 kcal/min) for 15 min followed by a low rate (0.71 kcal/min) for 105 min resulted in greater initial and total plasma glucose and insulin concentration AUCs than providing the same total amount of glucose at a moderate rate (1 kcal/min) for 120 min (6). We also found there was about a 30-min delay in increasing IMGD after initiating meal ingestion despite a large increase in plasma insulin, presumably because of the time it takes insulin to travel across the capillary endothelium and interstitial fluid before reaching cell surface insulin receptors (7–9) and subsequent GLUT4 recruitment to the plasma membrane (10,11). In fact, during a rapid and sustained (square wave) experimental increase in plasma insulin within the normal physiological range, the increase in glucose disposal lags behind the increase in plasma insulin, requiring at least 2 h until final plateau values in glucose disposal are achieved (12). Therefore, a normal delay in IMGD after the rapid rise in plasma insulin likely contributed to the early postprandial hyperglycemia in the RYGB group because of limited insulin action when glucose appearance in plasma was increasing rapidly. In addition, it is likely that the early marked increase in plasma glucose after RYGB surgery blunted postprandial insulin-mediated glucose clearance, because plasma glucose clearance at any plasma insulin concentration is lower at high compared with low plasma glucose concentrations (13–15). Together, these results demonstrate that the rate of delivery of ingested glucose into the small intestine is an important determinant of postprandial glycemia. The rapid rate of intestinal glucose delivery after RYGB surgery overwhelms the ability of insulin to dispose of glucose and the ability of NIMGD to adequately compensate. These data also demonstrate that it is not possible to extrapolate dynamic postprandial IMGD rates from the IMGD rate obtained during an HECP procedure that evaluates glucose disposal during prolonged steady insulin exposure and fixed plasma insulin and glucose concentrations. It is possible that potential differences in plasma hormones, such as glucagon, or nonglucose substrate oxidation or substrate competition also contributed to the difference in postprandial glucose handling between groups.

We are aware of only four studies that compared the effect of weight loss induced by RYGB surgery with the same weight loss induced by either a low-calorie diet alone or by laparoscopic adjustable gastric banding (LAGB) on postprandial glycemia in people with obesity and type 2 diabetes (16–19). The results from these studies show conflicting results. Studies that evaluated postprandial glycemia after an oral glucose challenge found that moderate (∼10%) weight loss after RYGB surgery caused a greater decrease in total 3-h postprandial glucose AUC than the same amount of weight loss induced by a low-calorie diet alone (18) or after LAGB (19). However, the superiority of the effect of RYGB on postprandial glycemia was not sustained after marked (20%), matched weight loss and even 1 year after RYGB surgery, when weight loss was much greater in the RYGB group than the LAGB group (30% and 17%, respectively) (19). In contrast, studies that evaluated postprandial glycemia after consuming a liquid mixed meal found no difference in the decrease in the 3-h postprandial plasma glucose AUC between the RYGB and diet therapy groups after moderate (∼7% and ∼10%) weight loss (16,17). The results from our study demonstrate that the decline in postprandial glycemia during 4 h after mixed-meal ingestion is greater after BDT- than RYGB-induced marked weight loss followed by at least 2 weeks of weight maintenance. Moreover, in the parent study (4), we observed about a 20% greater improvement in 24-h plasma glucose concentration AUC in the BDT group compared with the RYGB group, but the difference did not reach statistical significance (between-group difference with 95% CI: 32 [−1 to 66] mg/dL × min × 10³), most likely because of insufficient statistical power because of the small sample size and because the hourly 24-h blood sampling protocol did not provide a robust assessment of glucose kinetics. The different outcomes among studies are likely because of the type of metabolic challenge (glucose versus mixed-meal ingestion), the amount or duration of weight loss, the duration of postprandial measurements, and, possibly, the stability of body weight, medication use, and glycemic control before the testing procedures.

Our study complements two studies that evaluated the effect of RYGB surgery on glucose effectiveness in people with type 2 diabetes but did not include a diet-alone comparator group (20,21). One study found that RYGB surgery caused a significant increase in glucose effectiveness, assessed by using an oral glucose tolerance test and the oral minimal model, 2 months after RYGB surgery (13% weight loss) (20). The other study found no change in glucose effectiveness, assessed by using a standard (not insulin-modified) intravenous glucose tolerance test, 3 months after RYGB surgery (∼15% weight loss) (21). However, the data from that study might not be robust because of the very small endogenous insulin secretion response in the study participants, which is common in people with diabetes but is insufficient without additional exogenous insulin to obtain reliable glucose disposal results (22–24).

Our study has some limitations. First, the small sample size limits the generalizability of the results. Second, our study did not determine potential additional mechanisms (e.g., additional hormones, potential substrate competition) responsible for differences in glucose disposal between the BDT and RYGB groups. Third, it is possible that the difference in time to achieve target weight loss between groups could influence the outcomes. However, this seems unlikely, because the improvement in insulin sensitivity was the same in both groups and the rapid delivery of ingested glucose into the systemic circulation is caused by the permanent change in intestinal anatomy. Fourth, even though we slowed weight loss to 0.5% per week before metabolic testing, this does not ensure a metabolic steady state, because participants were not absolutely weight-stable. Fifth, our model is a whole-body model and cannot determine the sites of postprandial glucose disposal. Lastly, the model-derived values are estimates and involve a degree of uncertainty. However, the overall conclusions from the data are robust, because the key finding from our modeling analysis is supported by the plasma insulin and glucose concentration measurements. Those data show that the weight loss–induced increase in insulin action on glucose metabolism was greater in the BDT group than the RYGB group, because the decrease in postprandial plasma glucose concentration AUC was greater in the BDT group than the RYGB group, even though there was no difference in the weight loss–induced change in plasma insulin AUC between the two groups.

In summary, the current study demonstrates that the decrease in postprandial glycemia after marked (∼20%) weight loss in people with obesity and type 2 diabetes is greater when weight loss is induced by BDT than RYGB surgery. The difference in plasma glucose between groups is likely a result of the rapid delivery of ingested glucose into the systemic circulation after RYGB, which prevents the increase in IMGD observed after BDT, even though the improvement in insulin sensitivity and total postprandial plasma insulin concentrations were the same in both groups. Despite more favorable changes in postprandial glucose after matched weight loss in the BDT group compared with the RYGB in our study, RYGB is more effective than lifestyle therapy in lowering HbA_1c and achieving glycemic control (diabetes remission) in clinical practice, because RYGB causes a more marked and sustained decrease in body weight (25–28).

This article contains supplementary material online at https://doi.org/10.2337/figshare.30521024.

Funding Statement

This study was supported by National Institutes of Health grants R01 DK101578, P30 DK056341 (Washington University School of Medicine Nutrition and Obesity Research Center), P30 DK020579 (Washington University School of Medicine Diabetes Research Center), and UL1 TR000448 (Washington University School of Medicine Institute of Clinical and Translational Sciences) and a grant from the Longer Life Foundation.