Table 4.

Acute preclinical studies examining direct effects of antipsychotics on glucose metabolism.

A. Female Models
STUDY	MODEL	AP DOSE	EFFECT ON GLUCOSE METABOLISM
Albaugh et al. (2006) [33]	Female Sprague-Dawley rats	Olanzapine; oral gavage 4 mg/kg 4 doses over 29 h	• Basal fasting glucose was significantly decreased by olanzapine • Olanzapine improved glucose tolerance (via OGTT administered 1-h after last dose) • Matched by significant increase in serum insulin in response to glucose bolus (attenuated compared to vehicle treated rats)
Boyda et al. (2012) [76]	Female Sprague-Dawley rats	Olanzapine; I.P. 7.5, 15 mg/kg, Once	• Increased fasting glucose levels, increased serumin insulin levels • Significantly impaired glucose tolerance (ipGTT)
Boyda et al. (2014) [77]	Female Sprague-Dawley rats	Olanzapine; I.P.; 7.5, 15 mg/kg; Once	• No effect on fasting blood glucose levels • Significantly increased fasting serum insulin • Olanzapine decreased glucose tolerance (7.5, 15 mg/kg; ipGTT)
Houseknecht et al. (2007) [60]	Female CD/Sprague-Dawley Rats	• Olanzapine; S.C. • 10 mg/kg; Once (60 min before dissection/ex vivo incubation) • Clozapine; S.C.; 10 mg/kg; Once (60 min before dissection/ex vivo incubation)	• No effect on in vitro basal or insulin-stimulated glucose uptake in isolated epitrochlearis muscle
Jassim et al. (2012) [78]	Female Sprague-Dawley rats	• Olanzapine; I.P.; 5 mg/kg • Clozapine; I.P.; 25 mg/kg	• Increased serum glucose approximately 1 h posttreatment (olanzapine increased approximately 1 mmol/L (resolved by next time point-3 h)) • Olanzapine: No significant effect on serum insulin, or serum glucagon, slightly decreased gluconeogenic precursors • Clozapine: increased glucagon 30 min posttreatment, increased gluconeogenic precursors
Martins et al. (2010) [79]	Female C57/BL6 Mice	Olanzapine; I.P.; 4.5 mg/kg Once	• Olanzapine increased blood glucose • Serum insulin levels not reported
Wu et al. (2014) [80]	Female Sprague-Dawley Rats	Olanzapine; S.C. 10 mg/kg (for ipGTT) 1.5 mg/kg, 15 mg/kg (for HIEC) Once	• No effect on fasting (overnight) blood glucose • Large increase in fasting insulin levels • Decreased glucose tolerance (ipGTT) • High dose (15 mg.kg) but not low dose (1.5 mg/kg) increased insulin resistance (HIEC)
B. Male Models
STUDY	MODEL	AP DOSE	EFFECT ON GLUCOSE METABOLISM
Albaugh et al. (2011) [48]	Male Sprague-Dawley rats	Olanzapine; Oral gavage 10 mg/kg 2 Doses (PM + AM 2 h preceding experiments)	• Increased blood glucose 2 h post-treatment in fed and fasted (5 h, 15 h) rats • Increased insulin in fasted state, no affect in fed state • Impaired insulin sensitivity (HIEC) but insulin signaling remained intact in response to hyperinsulinemia
Albaugh et al. (2012) [81]	Male Sprague-Dawley rats	Olanzapine; Oral gavage 4 mg/kg 2 doses (PM and AM 1 h preceding experiment)	• Increased fasting glucose levels • Decreased glucose tolerance (OGTT) and insulin tolerance (ITT) • Plasma insulin did not change during OGTT or in response to olanzapine
Bush et al. (2018) [82]	Male C57BL6J mice	Olanzapine; I.P. 5 mg/kg; Once	• Increased blood glucose immediately posttreatment Prevented via activation of liver AMPK (via AICAR)
Castellani et al. (2017) [83]	Male C57BL6J mice + male Grgrc−/−mice	Olanzapine; I.P. 5 mg/kg; Once	• Increased blood glucose immediately posttreatment • No change in serum insulin, increased serum glucagon • Glucagon receptor knockout mice protected from olanzapine-induced increase in blood glucose, but not olanzapine-induced reductions insulin tolerance
Castellani et al. (2018) [84]	Male C57BL6J mice	Olanzapine; I.P.; 5 mg/kg; Once	• Increased blood glucose immediately post-treatment, no change in serum insulin
Chintoh et al. (2008) [85]	Male Sprague-Dawley rats	Olanzapine; S.C. 3 mg/kg; Once	• Increased blood glucose • Decreased insulin release in response to glucose bolus (lower insulin and c-peptide levels during hyperglycemic clamp) • Increased insulin resistance (HIEC-increased glucose production/decreased glucose uptake)
Chintoh et al., (2009) [86]	Male Sprague-Dawley rats	• Clozapine; S.C.; 10 mg/kg • Olanzapine; S.C.; 3.0 mg/kg • Risperidone; S.C.; 1 mg/kg • Ziprasidone; S.C.; 3 mg/kg • Haloperidol; S.C.; 0.25 mg/kg Once	• Olanzapine and clozapine decreased insulin sensitivity (HIEC), increased hepatic glucose production • Olanzapine and clozapine decreased insulin secretion in response to glucose bolus (hyperglycemic clamp)
Girault et al. (2012) [87]	Male Wistar Han rats	• Olanzapine; intragastirc; 3 mg/kg/h; Once • Olanzapine; ICV; 30 mg/kg/h, Once	• Increased blood glucose levels, no change in plasma insulin, corticosterone • ICV olanzapine had no effect on blood glucose levels or endogenous glucose production, insulin, corticosterone levels
Hahn et al. (2014) [88]	Male Sprague-Dawley rats	Olanzapine; ICV; 75 ug; Once	• Decreased insulin secretion (decreased insulin and c-peptide levels during hyperglycemic clamp) • Increased blood glucose levels (lower glucose infusion rate to reach hyperglycemia in response to olanzapine treatment) • No effect on insulin resistance (HIEC)
Houseknecht et al. (2007) [60]	Male Wistar Han rats	• Clozapine; S.C.; 1, 3.2, 10 mg/kg; Once • Olanzapine; S.C.; 1, 3.2, 10 mg/kg; Once • Risperidone; S.C.; 2 mg/kg; Once • Ziprasidone; S.C.; 3.2, 10, 32 mg/kg; Once	Clozapine (3.2, 10 mg/kg): Increased insulin resistance (HIEC) • Olanzapine (3.2, 10 mg/kg): Increased insulin resistance (HIEC) • Risperidone: No effect on insulin sensitivity (HIEC) • Ziprasidone: No effect on insulin sensitivity (HIEC)
Ikegami et al. (2013) [89]	Male ICR Mice	Olanzapine; ICV; 5, 10, 15 nmol; Once	• Dose dependent increase in blood glucose at doses of 10 and15 nmol • No change in blood insulin
Ikegami et al. (2013) [90]	Male ICR mice	• Olanzapine; I.P; 0.3,1,3,5 mg/kg, Once • Olanzapine; ICV; 10, 15 nmol; Once	• I.P. dose (3,5 mg/kg): Decreased glucose tolerance (ipGTT) • ICV dose: Decreased glucose tolerance (ipGTT) Changes involve activation of hypothalamic AMPK • No effect of olanzapine on insulin or glucagon levels (20 min post-treatment)
Ikegami et al. (2013) [91]	Male ICR mice,6 weeks old	• Olanzapine; I.P; 0.3,1,3,5 mg/kg, Once • Olanzapine; ICV; 10, 15 nmol; Once	• I.P. treatment increased blood glucose in fed and overnight fasted mice • ICV treatment increased blood glucose in fed mice only • Involves AMPK activation at hypothalamus and beta-adrenergic activation
Klingerman et al. (2015) [92]	Male Sprague-Dawley rats	• Olanzapine; ICV (3rd ventricle); 0.1, 0.2, 0.3, 0.44 mg/kg • Olanzapine; ICV (lateral ventricle); 0.44, 1.8 mg/kg • Olanzapine; Oral gavage; 0.44, 1, 3,10 mg/kg)	• ICV: Increased blood glucose 30 min posttreatment to 3rd ventricle (0.3 mg/kg, 0.44 mg/kg) • ICV: Increased blood glucose 30 min posttreatment to lateral ventricle (1.8 mg/kg) • Increased blood glucose in fasted (4-h) rats 30 min post-treatment (3 mg/kg, 10 mg/kg) and 1 h post-treatment (10 mg/kg)
Kowalchuk et al. (2017) [93]	Male Sprague-Dawley rats	Olanzapine; S.C.; 2 mg/kg Once	• No effect of olanzapine during euglycemic-pancreatic clamp (somatostatin to block endogenous insulin secretion, exogenous insulin replaced at basal levels)
Martins et al. (2010) [79]	Male Sprague-Dawley Rats	• Olanzapine; primed continuous IV infusion;1 mg/kg/h Once • Olanzapine; ICV; a bolus of 110 g and 73.4 g/h Once	• Increased blood glucose levels, no change in plasma insulin • Increased rate of glucose production, decreased rate of uptake (HIEC) • Increased endogenous glucose production at liver and increased p-AMPK at hypothalamus
Nagata et al. (2016) [94]	Male Wistar Rats	Olanzapine; I.V.; 2.5, 5, 10 mg/kg Once	• High dose of olanzapine (10 mg/kg) increased blood glucose and blood insulin (max ~1 h post-AP) • Increased blood cortisol but no change in serum glucagon • Effect blocked by treatment with adrenergic receptor antagonist propranolol
Smith et al. (2008) [54]	Male Sprague-Dawley rats	• Haloperidol; 0.25 mg/kg • Quetiapine;10 mg/kg • Clozapine;10 mg/kg 28 days	• Blood glucose and plasma insulin levels were significantly increased by 1 h after haloperidol, quetiapine or clozapine injections • Decreased glucose tolerance (via decreased glucose clearance in response to quetiapine and clozapine) • Increased hepatic glucose output (PTT)
Townsend et al. (2018) [61]	Male C57BL6J mice	Olanzapine; I.P.; 5 mg/kg Once	• Increased blood glucose post-treatment • Potentiated with 4 week high fat feeding • Increased gluconeogenesis, decreased insulin sensitivity and signaling

AP: antipsychotic, iPGTT: intraperitoneal glucose tolerance test, HIEC: hyperinsulinemic-euglycemic clamp, PTT: pyruvate tolerance test.