Incretin effect in prediabetic subjects

Abstract

The global prevalence of diabetes mellitus (DM) is increasing and rising rate is higher in developing countries. The favorable influence of gut hormones GIP and GLP-1 (7 – 36) on metabolic disorders of DM has provided the mainstay of incretin based therapy of type 2 DM. Reduced incretin effect is a specific, important and early characteristic of type 2 DM and is associated with β cell failure. However, the interrelationship between incretins, insulin secretory dysfunction and insulin resistance in isolated IGT is still controversial and poorly understood. Increased insulin resistance in isolated IGT in Bangladeshi population has been reported. but its associated abnormalities in the secretion of gut hormones have not yet been investigated. In the present study, gut hormones (incretins) secretion in isolated IGT were evaluated by plasma concentrations of total GIP and GLP-1(7 – 36) to explore their relationship with insulin secretory capacity and insulin sensitivity. Thirty four isolated IGT subjects and equal number of age-sex matched controls were recruited from the OPD of BIHS hospital. Blood specimens and anthropometric data were collected after obtaining written consent. Plasma glucose, lipid parameters, serum ALT and serum creatinine concentrations were measured by standard methods. Plasma concentrations of the gut hormones total GIP and GLP-1 (7 – 36), were determined by enzyme linked immunosorbent assay (ELISA). Results are expressed as median (range) analyzed by appropriated statistical tests. According to inclusion criteria of the study subjects, acute and chronic glycemic status differed significantly (p<0.001) between control and isolated IGT groups. Fasting and postprandial TGs were found to be higher in isolated IGT compared to control. HDL cholesterol levels were significantly lower in isolated IGT subjects. Total cholesterol and LDL cholesterol levels were similar in control and isolated IGT subjects. Fasting and postprandial insulin levels were found to be 64.2 % [10.9 (2.8 – 25.6) μIU/ml vs 17.9 (7.7 – 44.8) μIU/ml and p<0.001] and 16.6% [69.4 (34 – 211) μIU/ml vs 80.9 (22 – 217) μIU/ml and p<0.046)] higher in isolated IGT groups compared to control. Postprandial insulin levels compared to fasting levels were also found to be higher in both controls [10.9 vs 69.4 μIU/ml] and IGT subjects (17.9 vs 80.9 μIU/ml) and the changes in insulin levels were remarkably lower in IGT compared to control (6.2 fold vs 4.5 fold). In subjects with IGT, insulin secretory capacity was found to be significantly higher compared to control (147.3 vs 164.3, p<0.05), insulin sensitivity was found to be significantly lower (63.9 vs 38.4) and insulin resistance was significantly higher (1.6 vs 2.6) compared to control. Fasting GIP concentrations were 58% higher in isolated IGT compared to control (99.9 vs 158.1 pg/mL, p<0.01), but postprandial GIP concentrations were similar in both groups (only 2% lower in IGT, p = 0.864). The changes in plasma GIP after mixed breakfast was 50% lower in isolated IGT compared to control (control vs IGT: 851% vs 424%). When GIP concentrations per unit of glucose were compared between control and IGT, fasting GIP per unit of glucose was 32% higher in IGT whereas postprandial GIP was 27% lower compared to control. Compared to control, increase in GIP concentration per unit of glucose was 50% lower in isolated IGT after mixed breakfast. Insulin concentrations per unit of GIP showed no significant difference between control and IGT in fasting state and postprandial state. On correlation analysis, fasting GIP showed no significant relationship with insulin secretory capacity, insulin sensitivity and insulin resistance. Fasting concentrations of GLP-1 (7 – 36) was found to be 58% lower in isolated IGT compared to control (3.3 vs 1.4 pmol/L, p<0.05). However, postprandial GLP-1 showed no significant differences between IGT and control subjects. The incretin effect in terms of plasma GLP-1 (7 – 36) showed no significant difference between fasting and postprandial state (p>0.05) in control. Whereas, GLP-1 (7 – 36) concentration in postprandial state in isolated IGT was found to be significantly higher compared to fasting state. GLP-1 (7 – 36) per unit of glucose was significantly lower in IGT compared to that of control; it was also significantly reduced in postprandial state compared to fasting state in both control and IGT. Insulin secretory capacity showed a significant positive relationship with fasting GLP-1 (7 – 36), postprandial GLP-1 (7 – 36) and BMI only in isolated IGT. Insulin sensitivity in isolated IGT was found to be inversely related to fasting GLP-1 (7 – 36), postprandial GLP-1 (7 – 36) and BMI. But in control insulin sensitivity showed no such relationship. GLP-1 (7 – 36) inversely related to insulin sensitivity and positively related to insulin resistance in IGT. It may be concluded from this study that • Isolated IGT is a hyperinsulinemic state and it is associated with insulin resistance. • Hypersecretion of GIP and deficient secretion of GLP-1 in the fasting states are ssociated with isolated IGT. • Insulin secretory dysfunction and insulin resistance can develop in the absence of any impairment of GIP secretions but they may be associated with defective GLP-1 secretion from the gut.