olanzapine and Hyperinsulinism

Atypical antipsychotic drugs have been associated with the development of obesity and diabetes. In particular, olanzapine can induce peripheral insulin resistance and compensatory hyperinsulinemia independent of weight gain or psychiatric disease. To determine if this compensatory increase in insulin is mediated by parasympathetic muscarinic stimulation, we randomized 15 healthy subjects 2:1 to receive double-blind olanzapine or placebo for 9 days under diet- and activity-controlled inpatient conditions. Before and after 7 days of study drug administration, subjects underwent frequently sampled intravenous glucose tolerance tests with either saline or atropine infused on subsequent days to assess insulin secretion and hepatic insulin extraction in the absence or presence of muscarinic blockade. We found that olanzapine led to an increase in the acute insulin response to glucose, which was not seen with placebo, and was attenuated in the olanzapine group by atropine. Deconvolution of C-peptide data confirmed an increase in insulin secretion with olanzapine, which was blocked by atropine, with a modest reduction in hepatic insulin extraction with olanzapine. These results support the contribution of muscarinic augmentation of insulin secretion to olanzapine-induced hyperinsulinemia, and provide a mechanism for the compensatory hyperinsulinemia that normally serves to prevent deterioration of glucose tolerance under conditions of metabolic challenge.

Topics: Adolescent; Adult; Antipsychotic Agents; C-Peptide; Diet; Double-Blind Method; Female; Glucose Tolerance Test; Healthy Volunteers; Humans; Hyperinsulinism; Insulin Secretion; Liver; Male; Muscarinic Antagonists; Olanzapine; Weight Gain; Young Adult

The primary objective of this study was to evaluate insulin sensitivity in healthy subjects treated with olanzapine or risperidone. Subjects were randomly assigned to single-blind therapy with olanzapine (10 mg/d), risperidone (4 mg/d), or placebo for approximately 3 wk. Insulin sensitivity was assessed pre- and posttreatment using a 2-step, hyperinsulinemic, euglycemic clamp. Glucose and insulin responses were also assessed by a mixed meal tolerance test. Of the 64 subjects randomized, 22, 14, and 19 in the olanzapine, risperidone, and placebo groups, respectively, completed the study procedures. There were no significant within-group changes in the glucose disposal rate or the insulin sensitivity index for the active therapy groups. Further, the results of the mixed meal tolerance test did not demonstrate clinically significant changes in integrated glucose metabolism during treatment with these medications. In summary, this study did not demonstrate significant changes in insulin sensitivity in healthy subjects after 3 wk of treatment with olanzapine or risperidone.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Weight; Fasting; Fatty Acids, Nonesterified; Female; Food; Glucose Clamp Technique; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Male; Middle Aged; Olanzapine; Pirenzepine; Placebos; Reference Values; Risperidone

Atypical antipsychotics, such as olanzapine, are commonly prescribed to patients with schizophrenic symptoms and other psychiatric disorders. However, weight gain and metabolic disturbance cause adverse effects, impair patient compliance and limit clinical utility. Thus, a better understanding of treatment-acquired adverse effects and identification of targets for therapeutic intervention are believed to offer more clinical benefits for patients with schizophrenia. Beyond its nutritional effects, studies have indicated that supplementation of chromium brings about beneficial outcomes against numerous metabolic disorders. In this study, we investigated whether olanzapine-induced weight gain and metabolic disturbance involved chromium dynamic mobilization in a female Sprague-Dawley rat model, and whether a dietary supplement of chromium improved olanzapine-acquired adverse effects. Olanzapine medicated rats experienced weight gain and adiposity, as well as the development of hyperglycemia, hyperinsulinemia, insulin resistance, hyperlipidemia, and inflammation. The olanzapine-induced metabolic disturbance was accompanied by a decrease in hepatic Akt and AMP-activated Protein Kinase (AMPK) actions, as well as an increase in serum interleukin-6 (IL-6), along with tissue chromium depletion. A daily intake of chromium supplements increased tissue chromium levels and thermogenic uncoupling protein-1 (UCP-1) expression in white adipose tissues, as well as improved both post-olanzapine weight gain and metabolic disturbance. Our findings suggest that olanzapine medicated rats showed a disturbance of tissue chromium homeostasis by inducing tissue depletion and urinary excretion. This loss may be an alternative mechanism responsible for olanzapine-induced weight gain and metabolic disturbance.

Topics: Adipose Tissue, White; Adiposity; Administration, Oral; AMP-Activated Protein Kinases; Animals; Antipsychotic Agents; Chlorides; Chromium Compounds; Female; Gene Expression Regulation; Hyperglycemia; Hyperinsulinism; Hyperlipidemias; Inflammation; Insulin Resistance; Interleukin-6; Liver; Muscle, Skeletal; Olanzapine; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Signal Transduction; Uncoupling Protein 1; Weight Gain

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; n=13, or 400 mg/kg; n=11) or vehicle (Veh) (n=11) 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 (Ra) 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 Ra 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.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Glucose Clamp Technique; Hyperinsulinism; Hypoglycemic Agents; Insulin Resistance; Liver; Male; Metformin; Olanzapine; Rats; Rats, Sprague-Dawley

The second generation antipsychotic (SGA) drugs are widely used in psychiatry due to their clinical efficacy and low incidence of neurological side-effects. However, many drugs in this class cause deleterious metabolic side-effects. Animal models accurately predict metabolic side-effects for SGAs with known clinical metabolic liability. We therefore used preclinical models to evaluate the metabolic side-effects of glucose intolerance and insulin resistance with the novel SGAs asenapine and iloperidone for the first time. Olanzapine was used as a comparator.. Adults female rats were treated with asenapine (0.01, 0.05, 0.1, 0.5, 1.0 mg/kg), iloperidone (0.03, 0.5, 1.0, 5.0, 10.0 mg/kg) or olanzapine (0.1, 0.5, 1.5, 5.0, 10.0 mg/kg) and subjected to the glucose tolerance test (GTT). Separate groups of rats were treated with asenapine (0.1 and 1.0 mg/kg), iloperidone (1.0 and 10 mg/kg) or olanzapine (1.5 and 15 mg/kg) and tested for insulin resistance with the hyperinsulinemic-euglycemic clamp (HIEC).. Asenapine showed no metabolic effects at any dose in either test. Iloperidone caused large and significant glucose intolerance with the three highest doses in the GTT, and insulin resistance with both doses in the HIEC. Olanzapine caused significant glucose intolerance with the three highest doses in the GTT, and insulin resistance with the higher dose in the HIEC.. In preclinical models, asenapine shows negligible metabolic liability. By contrast, iloperidone exhibits substantial metabolic liability, comparable to olanzapine. These results emphasize the need for appropriate metabolic testing in patients treated with novel SGAs where current clinical data do not exist.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Dibenzocycloheptenes; Fasting; Female; Glucose Clamp Technique; Glucose Tolerance Test; Heterocyclic Compounds, 4 or More Rings; Hyperinsulinism; Insulin Resistance; Isoxazoles; Metabolism; Olanzapine; Piperidines; Rats; Rats, Sprague-Dawley

Olanzapine (OLZ) is known to cause weight gain and metabolic disturbances, which may have serious implications with respect to medical comorbidities such as metabolic syndrome and insulin resistance.. The aim of this study was to evaluate the effects of two angiotensin II type 1 receptor blockers (ARBs) which are widely used as antihypertensive agents, valsartan (VAL) and telmisartan (TEL), on insulin resistance in patients with schizophrenia treated with OLZ.. Thirty inpatients with schizophrenia with OLZ monotherapy over 8 weeks participated in this study. To assess insulin resistance, the homeostasis model assessment of insulin resistance (HOMA-IR), fasting plasma glucose (PG) levels and immunoreactive insulin (IRI) levels were measured [HOMA-IR = fasting PG level (mmol/L) x fasting IRI level (μU/ml)/22.5]. VAL add-on treatment was performed in insulin-resistant patients (HOMA-IR > 1.6) for 12 weeks. After a 12-week VAL washout period, TEL add-on treatment was carried out for 12 weeks. The effects of ARBs on insulin resistance and other metabolic variables were assessed.. In all 30 patients, both body mass index and abdominal circumference were strongly correlated with HOMA-IR. Twelve patients showed high HOMA-IR and were deemed to be insulin resistant. Add-on therapy of VAL and TEL resulted in a significant decrease in fasting IRI levels and HOMA-IR. No differences in any effects were observed between VAL and TEL. No adverse effects of either ARBs were observed in this study.. ARBs for patients treated with OLZ improved insulin sensitivity and attenuated insulin resistance.

Topics: Angiotensin II Type 1 Receptor Blockers; Antipsychotic Agents; Benzimidazoles; Benzoates; Benzodiazepines; Female; Humans; Hyperinsulinism; Insulin Resistance; Male; Middle Aged; Olanzapine; Receptor, Angiotensin, Type 1; Schizophrenia; Telmisartan; Tetrazoles; Valine; Valsartan

Olanzapine (OLZ) is an atypical antipsychotic whose clinical efficacy is hampered by side effects including weight gain and diabetes. Recent evidence shows that OLZ alters insulin sensitivity independent of changes in body weight and composition. The present study addresses whether OLZ-induced insulin resistance is driven by its central actions.. Sprague-Dawley rats received an intravenous (OLZ-IV group) or intracerebroventricular (OLZ-ICV group) infusion of OLZ or vehicle. Glucose kinetics were assessed before (basal period) and during euglycemic-hyperinsulinemic clamp studies.. OLZ-IV caused a transient increase in glycemia and a higher rate of glucose appearance (R(a)) in the basal period. During the hyperinsulinemic clamp, the glucose infusion rate (GIR) required to maintain euglycemia and the rate of glucose utilization (R(d)) were decreased in OLZ-IV, whereas endogenous glucose production (EGP) rate was increased compared with vehicle-IV. Consistent with an elevation in EGP, the OLZ-IV group had higher hepatic mRNA levels for the enzymes glucose-6-phosphatase and phosphoenolpyruvate carboxykinase. Phosphorylation of hypothalamic AMP-activated protein kinase (AMPK) was increased in OLZ-IV rats compared with controls. Similarly, an intracerebroventricular infusion of OLZ resulted in a transient increase in glycemia as well as a higher R(a) in the basal period. During the hyperinsulinemic period, OLZ-ICV caused a decreased GIR, an increased EGP, but no change in R(d). Furthermore, OLZ-ICV rats had increased hepatic gluconeogenic enzymes and elevated hypothalamic neuropeptide-Y and agouti-related protein mRNA levels.. Acute central nervous system exposure to OLZ induces hypothalamic AMPK and hepatic insulin resistance, pointing to a hypothalamic site of action for the metabolic dysregulation of atypical antipsychotics.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Carotid Arteries; DNA Primers; Glucose Clamp Technique; Glucose-6-Phosphatase; Hyperinsulinism; Infusions, Intravenous; Injections, Intraventricular; Insulin Resistance; Intracellular Signaling Peptides and Proteins; Jugular Veins; Kinetics; Liver; Male; Neuropeptides; Olanzapine; Orexins; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; Tubulin

Some atypical antipsychotics have been linked to an increased propensity for weight gain and metabolic disturbances, including type II diabetes. The objective of this study was to investigate an animal model to help understand the mechanisms underlying this phenomenon. Female, Sprague-Dawley rats were treated with olanzapine (2.0 or 7.5 mg/kg, via osmotic mini-pump) for 4 weeks, followed by the hyperinsulinemic/euglycemic and hyperglycemic clamp procedures to assess insulin sensitivity and secretion in vivo. Changes in body weight, visceral fat, food intake and locomotor activity were also assessed. Hepatic glucose production (R(A)) was increased in the hyperinsulinemic/euglycemic clamp for both treatment groups compared to control rats, while the high-dose olanzapine group had decreased peripheral glucose utilization (R(D)). No changes in insulin secretion were detected in the hyperglycemic clamp. Olanzapine did not change body weight or food intake, but did result in significant accumulation of visceral fat and decreases in locomotor activity. Like others, we found that a rodent model for antipsychotic-related weight gain per se is not tenable. However, chronic treatment with olanzapine was found to confer both hepatic and peripheral insulin resistance independent of weight gain, indicating a direct effect on glucose dysregulation.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus, Experimental; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Hyperinsulinism; Insulin Resistance; Locomotion; Olanzapine; Rats; Rats, Sprague-Dawley

The ability of clozapine to induce weight gain in female rats was investigated in three studies with progressively lowered doses of clozapine. In an initial preliminary high dose study, clozapine at 6 and 12 mg/kg (i.p., b.i.d.) was found to induce weight loss. In a subsequent intermediate dose study, we obtained no evidence for clozapine-induced weight gain despite using identical procedures and doses of clozapine (1-4 mg/kg, i.p., b.i.d.) with which we have observed olanzapine-induced weight gain, hyperphagia, enhanced adiposity and metabolic changes [Cooper G, Pickavance L, Wilding J, Halford J, Goudie A (2005). A parametric analysis of olanzapine-induced weight gain in female rats. Psychopharmacology; 181: 80-89.]. Instead, clozapine induced weight loss without alteration in food intake and muscle mass or changes in levels of glucose, insulin, leptin and prolactin. However, these intermediate doses of clozapine enhanced visceral adiposity and elevated levels of adiponectin. In a final study, low doses of clozapine (0.25-0.5 mg/kg, i.p, b.i.d.) induced weight loss. These data demonstrate that clozapine-induced weight gain can be much more difficult to observe in female rats than olanzapine-induced weight gain. Moreover, these findings contrast with clinical findings with clozapine, which induces substantial weight gain in humans. Clozapine-induced enhanced adiposity appears to be easier to observe in rats than weight gain. These findings, along with other preclinical studies, suggest that enhanced adiposity can be observed in the absence of antipsychotic-induced weight gain and hyperphagia, possibly reflecting a direct drug effect on adipocyte function independent of drug-induced hyperphagia [e.g. Minet-Ringuet J, Even P, Valet P, Carpene C, Visentin V, Prevot D, Daviaud D, Quignard-Boulange A, Tome D, de Beaurepaire R (2007). Alterations of lipid metabolism and gene expression in rat adipocytes during chronic olanzapine treatment. Molecular Psychiatry; 12: 562-571.]. These and other findings which show that the results of studies of antipsychotic treatment in animals do not always mimic clinical findings have important implications for the use of animal models of antipsychotic-induced weight gain. With regard to weight gain the results obtained appear to depend critically on the experimental procedures used and the specific drugs studied. Thus such models are not without limitations. However, they do consistently demonstrate the ability of various ant

Topics: Adiponectin; Adiposity; Animals; Antipsychotic Agents; Behavior, Animal; Benzodiazepines; Body Mass Index; Body Weight; Clozapine; Dose-Response Relationship, Drug; Eating; Female; Hyperinsulinism; Hyperphagia; Models, Animal; Olanzapine; Rats; Rats, Wistar; Research Design; Sex Factors; Weight Gain; Weight Loss

Some novel antipsychotics, including olanzapine, induce weight gain and metabolic abnormalities, which represent the major adverse effects of these drugs. However, the mechanism(s) involved in such effects are unclear.. The aim of this study was to develop, in female rats, a parametric model of olanzapine-induced weight gain and metabolic abnormalities and evaluate it against clinical findings.. Female rats were administered olanzapine b.i.d. at doses of 0, 1, 2 and 4 mg/kg over 20 days, and a wide range of variables were recorded during and after drug administration.. Olanzapine increased both 24 h and total food intake. This was associated with rapid onset weight gain and increased adiposity (assessed by visceral fat pad masses). Insulin, but not glucose, concentrations were elevated, with a significant increase in the HOMA-IR index, indicative of insulin resistance. A nonsignificant trend towards higher levels of leptin was observed. Paradoxically, there was a significant increase in adiponectin. All of these variables showed maximal increases at either 1 or 2 mg/kg and attenuated effects at 4 mg/kg. Prolactin levels were also increased by olanzapine. However, for this variable, there was a clear dose-response curve, with the maximal effect at the highest dose (4 mg/kg).. These data suggest that aspects of olanzapine-induced weight gain and metabolic abnormalities can possibly be modelled in female rats. It is suggested that olanzapine-induced hyperphagia acts as an initial stimulus which leads to weight gain, enhanced visceral adiposity and subsequent insulin resistance, although the latter may be ameliorated by compensatory responses in adiponectin levels. Prolactin elevation appears likely not to be involved in the weight gain, adiposity and metabolic changes seen in this model.

Topics: Adipose Tissue; Animals; Antipsychotic Agents; Benzodiazepines; Dose-Response Relationship, Drug; Drinking; Eating; Estradiol; Female; Homeostasis; Hyperinsulinism; Insulin Resistance; Leptin; Metabolic Diseases; Olanzapine; Prolactin; Rats; Rats, Wistar; Statistics as Topic; Weight Gain

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Fasting; Female; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Male; Mental Disorders; Olanzapine; Pirenzepine; Triglycerides