Fasting and stimulated glucagon-like peptide-1 exhibit a compensatory adaptive response in diabetes and pre-diabetes states: A multi-ethnic comparative study

Abstract

BackgroundImpaired secretion of glucagon-like peptide-1 (GLP-1) among Caucasians contributes to reduced incretin effect in type 2 diabetes mellitus (T2DM) patients. However, studies emanating from East Asia suggested preserved GLP-1 levels in pre-diabetes (pre-DM) and T2DM. We aimed to resolve these conflicting findings by investigating GLP-1 levels during oral glucose tolerance test (OGTT) among Malay, Chinese, and Indian ethnicities with normal glucose tolerance (NGT), pre-DM, and T2DM. The association between total GLP-1 levels, insulin resistance, and insulin sensitivity, and GLP-1 predictors were also analyzed.MethodsA total of 174 subjects were divided into NGT (n=58), pre-DM (n=54), and T2DM (n=62). Plasma total GLP-1 concentrations were measured at 0, 30, and 120 min during a 75-g OGTT. Homeostasis model assessment of insulin resistance (HOMA-IR), HOMA of insulin sensitivity (HOMA-IS), and triglyceride–glucose index (TyG) were calculated.ResultsTotal GLP-1 levels at fasting and 30 min were significantly higher in T2DM compared with pre-DM and NGT (27.18 ± 11.56 pmol/L vs. 21.99 ± 10.16 pmol/L vs. 16.24 ± 7.79 pmol/L, p=0.001; and 50.22 ± 18.03 pmol/L vs. 41.05 ± 17.68 pmol/L vs. 31.44 ± 22.59 pmol/L, p<0.001; respectively). Ethnicity was a significant determinant of AUCGLP-1, with the Indians exhibiting higher GLP-1 responses than Chinese and Malays. Indians were the most insulin resistant, whereas Chinese were the most insulin sensitive. The GLP-1 levels were positively correlated with HOMA-IR and TyG but negatively correlated with HOMA-IS. This relationship was evident among Indians who exhibited augmented GLP-1 responses proportionately to their high insulin-resistant states.ConclusionThis is the first study that showed GLP-1 responses are augmented as IR states increase. Fasting and post-OGTT GLP-1 levels are raised in T2DM and pre-DM compared to that in NGT. This raises a possibility of an adaptive compensatory response that has not been reported before. Among the three ethnic groups, the Indians has the highest IR and GLP-1 levels supporting the notion of an adaptive compensatory secretion of GLP-1.

Endogenous GLP-1 levels play an important role in determining the efficacy of DPP-IV Inhibitors in both prediabetes and type 2 diabetes

“…However, very little is known about the effects of endogenous GLP-1 levels in determining the efficacy of DPP-IV inhibition in these individuals. In our previous study (submitted for publication) we have shown that prediabetes and T2D subjects have higher GLP-1 levels compared to normal glucose tolerance ( 30 ). Hence there is a need to determine if this higher GLP-1 levels in these prediabetes and T2D subjects translate into a better efficacy with DPP-IV inhibition.…”

Dietary impact on fasting and stimulated GLP-1 secretion in different metabolic conditions – a narrative review

“…Although some studies showed decreased GLP-1 secretion in patients with IGT and T2DM after both OGTT [ 39 , 45 , 46 , 48 ] and MMTT or challenge meals [ 44 , 56 ], others reported an increased [ 42 , 44 , 50 , 55 ] or unchanged [ 47 , 49 , 58 , 69 ] GLP-1 response in the IGT and T2DM groups after OGTT or MMTT/challenge meals. The conflicting nature of the results is also evident from studies reporting increased fasting but decreased meal- or glucose-related GLP-1 concentrations in T2DM [ 38 ] and nonspecified diabetes [ 51 ], or unchanged fasting but reduced early postprandial GLP-1 concentrations in participants with low insulin sensitivity than in those with high insulin sensitivity [ 57 ].…”

“…Table 1 [ [41] , [42] , [43] , [44] , [45] , [46] , [47] , [48] , [49] , [50] , [51] , [52] , [53] ] provides an overview of the results of the 13 studies included on fasting and peak values of glucose-stimulated GLP-1, the delta between both values, the time at which peak concentration is achieved, GLP-1 concentrations at selected time points, and the AUC or iAUC values (the GLP-1 concentrations measured at all time points are shown in Supplemental Table 2 ). In addition, details of the assays used for GLP-1 measurements are presented.…”

“… - ↑ fasting levels in DM compared with NGT - ↓ postprandial levels in DM compared with NGT DM ( n = 548, BMI: 28.7 kg/m 2 ) # 9 16 120 7 Chong et al. 2022 [ 50 ] n = 174 ELISA (Millipore) 5 NGT ( n = 58, BMI: 24 kg/m 2 ) # 16 31 24 30 15 120 min: AUC: 3266 (pmol/L∗min) # - ↑ levels at fasting, after 30 min and AUC in T2DM compared with IGT and NGT - ↑ levels at fasting, after 30 min and AUC in IGT compared with NGT IGT ( n = 54, BMI: 26.2 kg/m 2 ) # 22 41 25 30 19 120 min: AUC: 3994 (pmol/L∗min) # T2DM ( n = 62, BMI: 26.7 kg/m 2 ) # 27 50 28 30 23 120 min: AUC: 4698 (pmol/L∗min) # GLP-1 concentrations for selected time points of blood sampling, time-to-peak as well as peak (peak concentration – fasting concentration), and—if available—AUC or iAUC values are listed. Under “results,” only significant results are listed.…”

“…

FIGURE 1 Glucagon-like peptide 1 concentrations during oral glucose tolerance tests in different metabolic conditions. Mean fasting and postprandial values of participants with normal glucose tolerance, impaired glucose tolerance, isolated impaired glucose tolerance, impaired fasting glucose or isolated impaired fasting glucose, type 2 diabetes mellitus or diabetes mellitus, normal weight, and overweight in 13 studies [ 39 , [42] , [43] , [44] , [45] , [46] , [47] , [48] , [49] , [50] , [51] , [52] , [53] ].

…”