Glucose-Dependent Insulinotropic Polypeptide (GIP) Reduces Bone Resorption in Patients With Type 2 Diabetes

Abstract

Context In healthy individuals, GIP enhances insulin secretion and reduces bone resorption by up to 25% estimated by absolute placebo-corrected changes in carboxy-terminal type 1 collagen crosslinks (CTX) during GIP and glucose administration. In patients with type 2 diabetes (T2D), GIP’s insulinotropic effect is impaired and effects on bone may be reduced. Objective To investigate GIP’s effect on bone biomarkers in patients with T2D. Design Randomized, double-blinded, crossover study investigating six interventions. Patients Twelve male patients with T2D. Interventions A primed continuous 90-minute GIP-infusion (2 pmol/kg/min) or matching placebo (saline) administered at three plasma glucose (PG) levels i.e. paired days with ‘insulin-induced hypoglycemia’ (PG lowered to 3 mmol/l), ‘fasting hyperglycemia’ (mean PG ~8 mmol/l), or ‘aggravated hyperglycemia’ (mean PG ~12 mmol/l). Main Outcome Measures Bone biomarkers: CTX, Procollagen Type 1 N-terminal propeptide (P1NP) and PTH. Results On days with ‘insulin-induced hypoglycemia’ CTX was suppressed by up to 40±15% during GIP administration compared to 12±11% during placebo infusion (P<0.0001). On days with ‘fasting hyperglycemia’ CTX was suppressed by up to 36±15% during GIP administration, compared to 0±9% during placebo infusion (P<0.0001). On days with ‘aggravated hyperglycemia’ CTX was suppressed by up to 47±23% during GIP administration compared to 10±9% during placebo infusion (P=0.0005). At all glycemic levels, P1NP and PTH concentrations were similar between paired days after 90 minutes. Conclusions Short-term GIP infusions reduce bone resorption by more than a third (estimated by absolute placebo-corrected CTX reductions) in patients with T2DM suggesting preserved bone effects of GIP in these patients.

Associations between Postprandial Gut Hormones and Markers of Bone Remodeling

“…Our results from the mixed effect models showed that GIP and GLP-1 were positively associated with CTX, whereas PYY was inversely associated with CTX. These findings are in accordance with previous studies reporting a relationship of GLP-1 and especially GIP with bone turnover markers, including CTX [ 11 , 13 , 20 ]. Our study thus confirms gut hormones as likely critical bone turnover regulators, thereby representing a link between food intake and bone homeostasis.…”

“…Our study thus confirms gut hormones as likely critical bone turnover regulators, thereby representing a link between food intake and bone homeostasis. As opposed to other studies, which primarily used GIP and/or GLP-1 infusions [ 11 , 13 , 20 ], we used two different mixed meal types containing different amounts of calories: 260 kcal for granola bar vs. 498 kcal for standardized mixed meal. The combined association analysis of both mixed meal types is a strength of our study.…”

“…Postprandial GIP plasma levels correlate with bone remodeling, and recent studies have examined whether the intravenous administration of GIP or a GIP receptor antagonist affects the postprandial plasma levels of bone turnover markers. The studies reported that infusion with GIP caused a decrease in CTX and an increase in P1NP [ 12 , 13 , 20 ], whereas GIP receptor antagonism partly reversed the postprandial decrease in CTX [ 20 ]. Another study reported that GIP in combination with high plasma glucose acutely lowers CTX [ 21 ].…”

“…We did not observe any postprandial changes in the P1NP levels following the intake of either meal type and found no statistically significant associations between the iAUC for P1NP and the three gut hormones. While some studies reported decreased P1NP levels after food ingestion, which is indicative of decreased bone formation [ 26 , 27 , 28 ], others also found a lack of postprandial P1NP changes following oral glucose tolerance testing or GIP infusion [ 11 , 20 ]. In these studies, however, the meals consisted of more calories (up to 2150 kcal) compared to the number of calories in the present study (260/498 kcal).…”

Incretin Hormones and Type 2 Diabetes – Mechanistic Insights and Therapeutic Approaches

“…Reduced GIP receptor activity (due to a functional amino acid substitution) is associated with lower bone mineral density and an increased risk of bone fractures [144]. On the other hand, infusion with GIP both in lean and overweight/obese individuals as well as in T2DM patients is capable of inhibiting bone resorption [143,145]. Infusion with GLP-1 was also confirmed to increase bone formation in overweight/obese individuals [146].…”