Chronic Glycaemic Control Modulates the Relationship Between <scp>GIP</scp> and Glucagon Secretion Following Oral and Enteral Nutrients in Type 2 Diabetes

AIMS: Glucose-dependent insulinotropic polypeptide (GIP) may exert both insulinotropic and glucagonotropic effects. While its insulinotropic action is reportedly attenuated or abolished with worsening of glycaemic control in type 2 diabetes (T2D), the relationship between GIP and glucagon secretion across different levels of glycaemic control remains unclear. This study evaluated the relationship between postprandial GIP and glucagon responses to a mixed meal in T2D and to intraduodenal fat and glucose infusion in healthy and/or T2D individuals. MATERIALS AND METHODS: Data were analysed from three clinical studies: mixed-meal testing in T2D (n = 79), intraduodenal fat infusion (2 kcal/min over 120 min) in T2D (n = 15) and intraduodenal glucose infusion (2 kcal/min over 60 min) in health and T2D (n = 10 each). Relationships between postprandial GIP and glucagon or insulin following the mixed meal were also determined after stratification by HbA1c (< 6.5%, 6.5%-7.0%, > 7.0%). RESULTS: Following mixed-meal ingestion, early postprandial (0-30 min) glucagon secretion correlated positively with GIP, with the strength of this association increasing with higher HbA1c levels. In contrast, the insulinogenic index correlated with GIP only in subgroups with HbA1c < 6.5% and between 6.5%-7.0%. During intraduodenal fat infusion, glucagon and GIP responses correlated strongly in T2D. Following intraduodenal glucose infusion, early glucagon and GIP increments (0-15 min) were closely related in T2D, but not in healthy individuals. CONCLUSIONS: These observations indicate a glycaemia-dependent shift in endogenous GIP action in T2D, characterised by attenuation of insulinotropic effects and relative amplification of glucagonotropic effects with deteriorating glycaemic control. TRIAL REGISTRATION: ACTRN12614001131640, ACTRN12614001117606 and ACTRN12615001240538.