Metformin attenuates olanzapine-induced hepatic, but not peripheral insulin resistance

Abstract

Antipsychotics (APs) are linked to diabetes, even without weight gain. Whether anti-diabetic drugs are efficacious in reversing the direct effects of APs on glucose pathways is largely undetermined. We tested two metformin (Met) doses to prevent impairments seen following a dose of olanzapine (Ola) (3 mg/kg); glucokinetics were measured using the hyperinsulinemic-euglycemic clamp (HIEC). Met (150 mg/kg; nZ13, or 400 mg/kg; nZ11) or vehicle (Veh) (nZ11) was administered through gavage preceding an overnight fast, followed by a second dose prior to the HIEC. Eleven additional animals were gavaged with Veh and received a Veh injection during the HIEC (Veh/Veh); all others received Ola. Basal glucose was similar across treatment groups. The Met 400 group had significantly greater glucose appearance (R a ) in the basal period (i.e., before Ola, or hyperinsulinemia) vs other groups. During hyperinsulinemia, glucose infusion rate (GINF) to maintain euglycemia (reflective of whole-body insulin sensitivity) was higher in Veh/Veh vs other groups. Met 150/Ola animals demonstrated increased GINF relative to Veh/Ola during early time points of the HIEC. Glucose utilization during hyperinsulinemia, relative to basal conditions, was significantly higher in Veh/Veh vs other groups. The change in hepatic glucose production (HGP) from basal to hyperinsulinemia demonstrated significantly greater decreases in Veh/Veh and Met 150/Ola groups vs Veh/Ola. Given the increase in basal R a with Met 400, we measured serum lactate (substrate for HGP), finding increased levels in Met 400 vs Veh and Met 150. In conclusion, Met attenuates hepatic insulin resistance observed with acute Ola administration, but fails to improve peripheral insulin resistance. Use of supra-therapeutic doses of Met may mask metabolic benefits by increasing lactate.

Prolonged insulin treatment sensitizes apoptosis pathways in pancreatic β cells

“…Although the concentrations used in this study are unlikely to be attained in the blood during hyperinsulinemia, they are in accord with those used in other studies regarding insulin effects on its target tissues (Biswas et al 2007, Guillen et al 2008, Du & Ding 2009. Furthermore, some studies report levels as high as 700-800 pM (Movassat et al 1997, Remington et al 2015. Moreover, it should be noted that the concentration of insulin in the vicinity of the islets may be considerably higher than that in the serum.…”

Glucagon‐like peptide‐1 receptor agonists for antipsychotic‐associated cardio‐metabolic risk factors: A systematic review and individual participant data meta‐analysis

“…For instance, GLP‐1RAs normalize glucose tolerance and decrease body weight in rats treated with clozapine, providing mechanistic justification of their therapeutic potential in this context . By contrast, metformin only partially attenuates glucose dysregulation in animal models of antipsychotic metabolic abnormalities . To date, there have been no head‐to‐head studies of the effects of GLP‐1RAs versus metformin on body weight loss among overweight patients on antipsychotics.…”

“…22 By contrast, metformin only partially attenuates glucose dysregulation in animal models of antipsychotic metabolic abnormalities. 56 To date, there have been no head-to-head studies of the effects of GLP-1RAs versus metformin on body weight loss among overweight patients on antipsychotics.…”

Treatment of clozapine‐associated obesity and diabetes with exenatide in adults with schizophrenia: A randomized controlled trial (CODEX)

“…Although metformin is well tolerated, we found only modest weight loss in obese people using clozapine . Metformin only partially attenuates glucose dysregulation in animal models, highlighting the importance of investigating other interventions …”

“…6 Metformin only partially attenuates glucose dysregulation in animal models, highlighting the importance of investigating other interventions. 7 Although the physiological mechanisms underlying clozapine's metabolic adverse effects are not fully understood, recent preclinical models have suggested glucagon-like peptide-1 (GLP-1) is a key mediator. 8 GLP-1 is an endogenous peptide synthesized in the intestinal mucosa.…”