Insulin resistance and systemic metabolic changes in oral glucose tolerance test in 5340 individuals: an interventional study

Abstract

Background: Insulin resistance (IR) is predictive for type 2 diabetes and associated with various metabolic abnormalities in fasting conditions. However, limited data are available on how IR affects metabolic responses in a non-fasting setting, yet this is the state people are mostly exposed to during waking hours in the modern society. Here, we aim to comprehensively characterise the metabolic changes in response to an oral glucose test (OGTT) and assess the associations of these changes with IR.

Methods: Blood samples were obtained at 0 (fasting baseline, right before glucose ingestion), 30, 60, and 120 min during the OGTT. Seventy-eight metabolic measures were analysed at each time point for a discovery cohort of 4745 middle-aged Finnish individuals and a replication cohort of 595 senior Finnish participants. We assessed the metabolic changes in response to glucose ingestion (percentage change in relative to fasting baseline) across the four time points and further compared the response profile between five groups with different levels of IR and glucose intolerance. Further, the differences were tested for covariate adjustment, including gender, body mass index, systolic blood pressure, fasting, and 2-h glucose levels. The groups were defined as insulin sensitive with normal glucose (IS-NGT), insulin resistant with normal glucose (IR-NGT), impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and new diabetes (NDM). IS-NGT and IR-NGT were defined as the first and fourth quartile of fasting insulin in NGT individuals.

Results: Glucose ingestion induced multiple metabolic responses, including increased glycolysis intermediates and decreased branched-chain amino acids, ketone bodies, glycerol, and triglycerides. The IR-NGT subgroup showed smaller responses for these measures (mean + 23%, interquartile 9-34% at 120 min) compared to IS-NGT (34%, 23-44%, P < 0.0006 for difference, corrected for multiple testing). Notably, the three groups with glucose abnormality (IFG, IGT, and NDM) showed similar metabolic dysregulations as those of IR-NGT. The difference between the IS-NGT and the other subgroups was largely explained by fasting insulin, but not fasting or 2 h glucose. The findings were consistent after covariate adjustment and between the discovery and replication cohort.

Conclusions: Insulin-resistant non-diabetic individuals are exposed to a similar adverse postprandial metabolic milieu, and analogous cardiometabolic risk, as those with type 2 diabetes. The wide range of metabolic abnormalities associated with IR highlights the necessity of diabetes diagnostics and clinical care beyond glucose management.

Keywords: Impaired fasting glucose; Impaired glucose tolerance; Insulin resistance; Metabolic profiling; Oral glucose tolerance test; Type 2 diabetes.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1

Mean concentration of insulin and glucose at 0, 30, 60, and 120 min during an oral glucose tolerance test. Insulin and glucose trajectories for insulin-sensitive subgroup of normal glucose tolerance (IS-NGT, dashed blue, n = 708), insulin-resistant subgroup of normal glucose tolerance (IR-NGT, solid blue, n = 713), impaired fasting glucose (IFG, green, n = 1380), impaired glucose tolerance (purple, n = 412), and newly-diagnosed type 2 diabetes (red, NDM, n = 106) are shown. IS-NGT was defined as the bottom quartile of fasting insulin within NGT, and IR-NGT was defined as the top quartile. The dots denote mean absolute concentrations. Interquartile ranges are listed in Table 1

Fig. 2

Selected metabolic changes in response to an oral glucose tolerance test in individuals with normal glucose tolerance. The dots and error bars denote mean percent change and 95%CI. Percent change is defined as the absolute change in relative to baseline. a Glycolysis-related and ketone bodies. b Amino acids. c Lipoprotein lipids and others

Fig. 3

Metabolic trajectoires compared between insulin-resistant and insulin-sensitive individuals in the normal glucose tolerance group. IS-NGT, indiviudals with normal glucose tolerance and in the first quartile of fasting insulin (n = 708); IR-NGT, individuals with normal glucose tolerance and in the top quartile of fasting insulin (n = 713). The dots and error bars denote mean percentage changes and 95% confidence intervals, respectively. The asterisk denotes that there are signficiant differences between IS-NGT and IR-NGT at corresponding time point. a Insulin and glucose. b Glycolysis-related. c Branched-chain amino acids. d Ketone bodies. e Triglycerides-related

Fig. 4

Metabolic trajectories compared between insulin-resistant individuals in the normal glucose tolerance group (blue) and those with 2-h impaired glucose tolerance (red). IR-NGT, indiviudals with normal glucose tolerance and in the top quartile of fasting insulin (n = 713); IGT/NDM, Individuals with 2-h impaired glucose tolerance, including those with impaired glucsoe tolerance and new onset of type 2 diabetes (n = 518). The dots and error bars denote mean percentage changes and 95% confidence intervals, respectively. The asterisk denotes that there are signficiant differences between IR-NGT and those with IGT or NDM at corresponding time point. a Insulin and glucose. b Glycolysis-related. c Branched-chain amino acids. d Ketone bodies. e Triglycerides-related

Fig. 5

Summary and replication. a Estimated insulin resistance in IS-NGT (grey), IR-NGT (blue), and pooled of IFG, IGT, and NDM (red) in NFBC66. b Two-hour metabolic responses associated with IR with or without glucose abnormality in NFBC66 (purple) and replicated in Oulu45 (red). Groups were compared by linear regression models with the 2-h concentration change as the response variable. Baseline and 2-h metabolite concentrations were log-transformed, and the changes between 2-h and baseline metabolite concentrations were scaled to baseline SD. Group sizes within NFBC66: n = 708 in IS-NGT, n = 713 in IR-NGT, and n = 1898 in combined IFG, IGT, and NDM. Group sizes within Oulu1945: n = 62 in IS-NGT, n = 64 in IR-NGT, and n = 343 in combined IFG, IGT, and NDM

Fig. 6

Group comparison adjusted for baseline factors in the NFBC66 cohort. a Differences in 2-h changes between the IR-NGT (n = 713) and the IS-NGT group (n = 708). b Differences in 2-h changes in the combined IFG, IGT, and NDM (n = 1898) and the IS-NGT group (n = 708). Groups were compared by linear regression models with the 2-h concentration change as the response variable. Baseline and 2-h metabolite concentrations were log-transformed, and the changes between 2-h and baseline metabolite concentrations were scaled to baseline SD. Insulin was log-transformed