c-peptide and Schizophrenia

Hyperglycemia and type 2 diabetes mellitus are more common in schizophrenia than in the general population. Glucoregulatory abnormalities have also been associated with the use of antipsychotic medications themselves. While antipsychotics may increase adiposity, which can decrease insulin sensitivity, disease- and medication-related differences in glucose regulation might also occur independent of differences in adiposity.. Modified oral glucose tolerance tests were performed in schizophrenic patients (n = 48) receiving clozapine, olanzapine, risperidone, or typical antipsychotics, and untreated healthy control subjects (n = 31), excluding subjects with diabetes and matching groups for adiposity and age. Plasma was sampled at 0 (fasting), 15, 45, and 75 minutes after glucose load.. Significant time x treatment group interactions were detected for plasma glucose (F(12,222) = 4.89, P<.001) and insulin (F(12,171) = 2.10, P =.02) levels, with significant effects of treatment group on plasma glucose level at all time points. Olanzapine-treated patients had significant (1.0-1.5 SDs) glucose elevations at all time points, in comparison with patients receiving typical antipsychotics as well as untreated healthy control subjects. Clozapine-treated patients had significant (1.0-1.5 SDs) glucose elevations at fasting and 75 minutes after load, again in comparison with patients receiving typical antipsychotics and untreated control subjects. Risperidone-treated patients had elevations in fasting and postload glucose levels, but only in comparison with untreated healthy control subjects. No differences in mean plasma glucose level were detected when comparing risperidone-treated vs typical antipsychotic-treated patients and when comparing typical antipsychotic-treated patients vs untreated control subjects.. Antipsychotic treatment of nondiabetic patients with schizophrenia can be associated with adverse effects on glucose regulation, which can vary in severity independent of adiposity and potentially increase long-term cardiovascular risk.

Topics: Adult; Antipsychotic Agents; Body Mass Index; Brief Psychiatric Rating Scale; C-Peptide; Diabetes Mellitus, Type 2; Female; Glucagon; Glucose; Humans; Hydrocortisone; Insulin; Male; Obesity; Schizophrenia

Treatment with most antipsychotics is associated with an increased risk of weight gain and metabolic disturbances. In a randomized trial, we previously demonstrated that 16 weeks of glucagon-like peptide-1 receptor agonist liraglutide treatment vs. placebo significantly reduced glucometabolic disturbances and body weight in prediabetic, overweight/obese schizophrenia-spectrum disorder patients treated with clozapine or olanzapine. The aim of this study was to investigate whether the beneficial effects of the 16-week intervention were sustained beyond the intervention period.. One year after completion of the intervention, we investigated changes in body weight, fasting glucose, glycated hemoglobin, C-peptide, and lipids comparing 1-year follow-up levels to end of treatment (week 16) and baseline (week 0) levels.. From end of treatment to the 1-year follow-up, body weight had increased in the liraglutide-treated group. However, compared to baseline levels, the placebo-subtracted body weight loss remained significantly reduced (-3.8 kg, 95% CI: -7.3 to -0.2, P = 0.04). Fasting glucose, glycated hemoglobin, C-peptide, and lipids had each returned to baseline levels 1 year after stopping liraglutide.. The body weight reduction during 16 weeks of liraglutide treatment was partially sustained 1 year after the intervention was completed. However, the improvements in other metabolic parameters returned to baseline levels.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Blood Glucose; Body Weight; C-Peptide; Clozapine; Denmark; Fasting; Female; Follow-Up Studies; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Lipid Metabolism; Liraglutide; Male; Middle Aged; Obesity; Olanzapine; Overweight; Placebos; Prediabetic State; Schizophrenia; Young Adult

The present study was to investigate the sex difference in effects of clozapine, olanzapine, risperidone, and sulpiride on glucose and lipid metabolism in first-episode schizophrenia.. One hundred twelve patients with schizophrenia were assigned randomly to receive clozapine, olanzapine, risperidone, or sulpiride for 8 weeks. Planned assessments included body mass index, waist-hip ratio, fasting glucose, insulin, C-peptide, insulin resistance index (IRI), cholesterol and triglyceride levels. All measures were collected at baseline and at the end of the 8-week treatment.. After treatment, waist-hip ratio and triglyceride and IRI levels of men were increased higher than that of women in clozapine and olanzapine groups. In sulpiride group, body mass index and triglyceride, insulin, and IRI levels of women increased higher than those of men. There was no significant sex difference for all assessments in risperidone group. Insulin, C-peptide, and IRI, but not fasting glucose levels, were significantly increased in the 4 groups. Cholesterol and triglyceride levels were significantly increased in the clozapine and olanzapine groups. Patients treated with clozapine and olanzapine had higher fasting insulin, C-peptide, and IRI levels than those treated with risperidone and sulpiride.. These results suggest that clozapine, olanzapine, and sulpiride had effects on glucose and lipid metabolism in first-episode schizophrenia with sex difference. Clozapine and olanzapine seem to have the greatest potential to induce glucose and lipid metabolism abnormalities, and risperidone has the least.

Topics: Adult; Antipsychotic Agents; Blood Glucose; Body Mass Index; Body Weight; C-Peptide; Cholesterol; Female; Homeostasis; Humans; Insulin; Lipid Metabolism; Longitudinal Studies; Male; Prospective Studies; Schizophrenia; Sex Characteristics; Triglycerides

Glucose and lipid metabolism dysfunction is a significant side effect associated with antipsychotics. Although there are many studies about the linkages between drugs and metabolic dysfunction, most of these studies have compared the effects of two antipsychotics on only one metabolic measure: either glucose or lipid metabolism.. The present study aimed to investigate the effects of clozapine, olanzapine, risperidone, and sulpiride on glucose and lipid metabolism in first-episode schizophrenia.. One hundred twelve schizophrenics were assigned randomly to receive clozapine, olanzapine, risperidone, or sulpiride for 8 weeks. Planned assessments included body mass index (BMI), waist-to-hip ratio, fasting glucose, insulin, C-peptide, insulin resistance index (IRI), cholesterol, and triglyceride. All measures were collected at baseline and at the end of the 8-week treatment.. After treatment, insulin, C-peptide, and IRI were significantly increased in the four groups, but not fasting glucose levels. Cholesterol and triglyceride levels were significantly increased in the clozapine and olanzapine groups. Patients treated with clozapine and olanzapine had higher fasting insulin, C-peptide, and IRI levels than those treated with risperidone and sulpiride. Among the four antipsychotics, the increases of mean BMI from high to low were as follows: clozapine, olanzapine, sulpiride, and risperidone.. This study confirmed that the four antipsychotic drugs were associated with an increase of insulin, C-peptide, and IRI. It was found that clozapine and olanzapine were associated with an increase in cholesterol and triglyceride levels. The effects of clozapine and olanzapine on the glucose and lipid metabolism outweighed those of risperidone and sulpiride.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Mass Index; C-Peptide; Cholesterol; Clozapine; Female; Homeostasis; Humans; Insulin; Insulin Resistance; Lipid Metabolism; Male; Metabolic Syndrome; Olanzapine; Prospective Studies; Risperidone; Schizophrenia; Sulpiride; Triglycerides; Waist-Hip Ratio

Schizophrenia is a psychotic disorder with high heritability. There are also indications that impaired cellular signalling via the insulin receptor-A and the insulin-like growth factor 1 receptor may play a role in its pathogenesis. Insulin, and possibly also C-peptide, are ligands to these receptors. The insulin gene, coding both insulin and C-peptide, has however not been genetically studied in schizophrenia. Therefore, this study was undertaken to investigate the involvement of this gene in schizophrenia susceptibility.. For identification of single nucleotide polymorphisms (SNPs) of interest, the whole insulin gene and parts of its promoter region were first DNA sequenced in two subgroups of the study population (37 schizophrenia patients with heredity for schizophrenia or related psychosis, and 25 controls), and mapped to the reference sequence. Then, 7 identified SNPs of potential interest were typed by TaqMan® SNP Genotyping Assays in the whole study population, consisting of 94 patients with schizophrenia and 60 controls.. Allele frequencies tended to differ between patients and controls for two of the 7 SNPs, rs5505 and rs3842749 (p=0.077 and p=0.078, respectively), whereas subgroup analyses of diabetes mellitus (type 1 or 2) and/ or heredity for diabetes mellitus (type 1 or 2) in patients and controls showed overall significant differences in genotype/ allele frequencies solely for rs5505 (p=0.021/ 0.023).. These findings are of interest, as the two SNPs - rs5505 and rs3842749 - may have regulatory function on the coding of insulin and C-peptide, against which increased antibody reactivity has been previously reported in schizophrenia.

Topics: C-Peptide; Diabetes Mellitus, Type 1; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Insulin; Polymorphism, Single Nucleotide; Schizophrenia

Numerous membrane-bound proteins undergo regulated intramembrane proteolysis. Regulated intramembrane proteolysis is initiated by shedding, and the remaining stubs are further processed by intramembrane-cleaving proteases (I-CLiPs). Neuregulin 1 type III (NRG1 type III) is a major physiological substrate of β-secretase (β-site amyloid precursor protein-cleaving enzyme 1 (BACE1)). BACE1-mediated cleavage is required to allow signaling of NRG1 type III. Because of the hairpin nature of NRG1 type III, two membrane-bound stubs with a type 1 and a type 2 orientation are generated by proteolytic processing. We demonstrate that these stubs are substrates for three I-CLiPs. The type 1-oriented stub is further cleaved by γ-secretase at an ϵ-like site five amino acids N-terminal to the C-terminal membrane anchor and at a γ-like site in the middle of the transmembrane domain. The ϵ-cleavage site is only one amino acid N-terminal to a Val/Leu substitution associated with schizophrenia. The mutation reduces generation of the NRG1 type III β-peptide as well as reverses signaling. Moreover, it affects the cleavage precision of γ-secretase at the γ-site similar to certain Alzheimer disease-associated mutations within the amyloid precursor protein. The type 2-oriented membrane-retained stub of NRG1 type III is further processed by signal peptide peptidase-like proteases SPPL2a and SPPL2b. Expression of catalytically inactive aspartate mutations as well as treatment with 2,2'-(2-oxo-1,3-propanediyl)bis[(phenylmethoxy)carbonyl]-l-leucyl-l-leucinamide ketone inhibits formation of N-terminal intracellular domains and the corresponding secreted C-peptide. Thus, NRG1 type III is the first protein substrate that is not only cleaved by multiple sheddases but is also processed by three different I-CLiPs.

Topics: Amino Acid Sequence; Amino Acid Substitution; Animals; Aspartic Acid Endopeptidases; C-Peptide; Cell Membrane; HEK293 Cells; Humans; Molecular Sequence Data; Mutation; Neuregulin-1; Neurons; Peptide Hydrolases; Peptides; Polymorphism, Single Nucleotide; Protein Structure, Tertiary; Proteolysis; Rats; Schizophrenia; Substrate Specificity

Molecular abnormalities in metabolic, hormonal and immune pathways are present in peripheral body fluids of a significant subgroup of schizophrenia patients. The authors have tested whether such disturbances also occur in psychiatrically ill and unaffected siblings of schizophrenia patients with the aim of identifying potential contributing factors to disease vulnerability. The subjects were recruited as part of the Genetic Risk and OUtcome of Psychosis (GROUP) study. The authors used multiplexed immunoassays to measure the levels of 184 molecules in serum from 112 schizophrenia patients, 133 siblings and 87 unrelated controls. Consistent with the findings of previous studies, serum from schizophrenia patients contained higher levels of insulin, C-peptide and proinsulin, decreased levels of growth hormone and altered concentrations of molecules involved in inflammation. In addition, significant differences were found in the levels of some of these proteins in siblings diagnosed with mood disorders (n=16) and in unaffected siblings (n=117). Most significantly, the insulin/growth hormone ratio was higher across all groups compared with the controls. Taken together, these findings suggest the presence of a molecular endophenotype involving disruption of insulin and growth factor signaling pathways as an increased risk factor for schizophrenia.

Topics: Adolescent; Adult; C-Peptide; Endophenotypes; Female; Genetic Predisposition to Disease; Human Growth Hormone; Humans; Inflammation Mediators; Insulin; Intracellular Signaling Peptides and Proteins; Male; Proinsulin; Reference Values; Risk Factors; Schizophrenia; Young Adult

To compare the difference in body mass index (BMI), waist-to-hip ratio (WHR), and glucose and lipid metabolism parameters between drug-naïve, first-episode schizophrenia patients and healthy controls matched for age, ethnicity and gender, we conducted a test including BMI, WHR, and fasting glucose and lipid metabolism parameters in both 70 drug-naïve, first-episode schizophrenia patients, having not a single day of cumulative exposure to antipsychotic medications and 44 normal healthy controls at baseline. Student's t tests (two tailed) were conducted to examine between group differences. We found that drug-naïve first-episode schizophrenia patients had higher insulin, insulin resistance and C-peptide levels, and had lower total cholesterol (TC), high density lipoprotein cholesterol (HDL-c) and apolipoproteinA1 levels. Simultaneously, drug-naïve, first-episode schizophrenia patients show a potential tendency of WHR enlargement, although there were no statistically significant differences between groups (mean=0.82, SD=0.06, for the patients versus mean=0.79, SD=0.06, for the health subjects). These results suggest that drug-naïve, first-episode schizophrenia patients do differ from healthy controls in their fasting glycometabolism parameters and lipid profiles, including fasting plasma levels of insulin, C-peptide, TC, HDL-c, and apolipoproteinA1, and patients are more insulin resistant before the onset of antipsychotic medication treatment.

Topics: Adolescent; Adult; Apolipoproteins A; Blood Glucose; Body Mass Index; C-Peptide; Chi-Square Distribution; Cholesterol, HDL; Fasting; Female; Humans; Insulin Resistance; Lipid Metabolism; Lipids; Male; Observation; Prospective Studies; Schizophrenia; Waist-Hip Ratio; Young Adult

Several studies have shown increased rates of hyperglycemia and diabetes in schizophrenic patients treated with olanzapine. However, the underlying mechanism is poorly understood. Glucose-dependent insulinotropic polypeptide (GIP) is known to affect insulin secretion by pancreatic β cells. Recently, a meta-analysis study reported an association between a GIP receptor (GIPR) gene polymorphism (rs10423928) and insulin secretion measured by an oral glucose tolerance test (OGTT). We assessed the influence of this GIPR gene polymorphism on glucose metabolism in 60 schizophrenic patients treated with olanzapine and 103 healthy controls. The GIPR gene polymorphism was determined using TaqMan methods. We performed repeated-measures analysis of variance (ANOVA) and one-way ANOVA for the glucose and insulin levels during OGTTs in four groups divided by the GIPR gene polymorphism and cohort (schizophrenia or control). We found significant effects of the GIPR gene and cohort on the insulin levels at 30 min. Our findings suggest that schizophrenic patients with the A allele of GIPR rs10423928 are at risk of developing hyperinsulinemia when treated with antipsychotics.

Topics: Adult; Antipsychotic Agents; Area Under Curve; Benzodiazepines; C-Peptide; Female; Genotype; Glucose Tolerance Test; Humans; Insulin; Male; Middle Aged; Olanzapine; Polymorphism, Genetic; Receptors, Gastrointestinal Hormone; Schizophrenia

Topics: Adult; C-Peptide; Female; Humans; Insulin Resistance; Male; Middle Aged; S100 Proteins; Schizophrenia

Topics: Adolescent; Adult; Bipolar Disorder; Blood Glucose; C-Peptide; Chromogranin A; Enzyme-Linked Immunosorbent Assay; Female; Humans; Insulin; Male; Neuropeptides; Proinsulin; Retrospective Studies; Schizophrenia; Young Adult

While most of the second generation antipsychotic agents are associated with abnormal glucose metabolism, previous studies have shown that risperidone has relatively little effect upon blood glucose levels. This study aimed to explore the effect of risperidone on the glucose-regulating mechanism of patients with schizophrenia by using the oral glucose tolerance test (OGTT), measuring insulin and C-peptide levels.. Thirty inpatients with schizophrenia taking risperidone were studied. All the patients were given a simplified OGTT at baseline and six weeks after treatment. Plasma glucose, insulin, and C-peptide concentrations were measured at fasting, then 1 and 2h after OGTT respectively. Other data, including demographic characteristics and plasma drug concentrations, were also recorded.. (1) There was no significant increase in the proportion of patients demonstrating abnormal plasma glucose levels compared with baseline (p=1.000, McNemar test); (2) risperidone was associated with elevated insulin concentrations (p=0.013), C-peptide levels (p=0.020), insulin/glucose ratio (p=0.020) and BMI (p<0.01); (3) no sex differences in glucose-related measures were observed.. Risperidone treatment may be associated with alterations in glucose-regulating mechanisms in patients with schizophrenia.

Topics: Adult; Antipsychotic Agents; Blood Glucose; Body Mass Index; C-Peptide; China; Cohort Studies; Female; Glucose Tolerance Test; Humans; Insulin; Male; Prospective Studies; Risperidone; Schizophrenia

Weight gain is a commonly observed adverse effect of atypical antipsychotic medications, but associated changes in energy balance and body composition are not well defined. The authors report here the effect of olanzapine on body weight, body composition, resting energy expenditure, and substrate oxidation as well as leptin, insulin, glucose, and lipid levels in a group of outpatient volunteers with first-episode psychosis.. Nine adults (six men and three women) experiencing their first psychotic episode who had no previous history of antipsychotic drug therapy began a regimen of olanzapine and were studied within 7 weeks and approximately 12 weeks after olanzapine initiation.. After approximately 12 weeks of olanzapine therapy, the median increase in body weight was 4.7 kg, a significant increase of 7.3% from first observation. Body fat, measured by dual-energy x-ray absorptiometry, increased significantly, with a propensity for central fat deposition. Lean body mass and bone mineral content did not change. Resting energy expenditure, measured by indirect calorimetry, did not change. Respiratory quotient significantly increased 0.12 with olanzapine and was greatest in those who gained >5% of their initial weight. Fasting insulin, C-peptide, and triglyceride levels significantly increased, but there were no changes in glucose levels; total, high density lipoprotein, or low density lipoprotein cholesterol levels; or leptin levels.. Olanzapine appears to have induced an increase in central body fat deposition, insulin, and triglyceride levels, suggesting the possible development of insulin resistance. The decrease in fat oxidation may be secondary or predispose patients to olanzapine-induced weight gain.

Topics: Adipose Tissue; Adult; Antipsychotic Agents; Benzodiazepines; Body Composition; Body Weight; C-Peptide; Energy Metabolism; Female; Humans; Insulin; Male; Obesity; Olanzapine; Oxidation-Reduction; Psychotic Disorders; Respiratory Physiological Phenomena; Schizophrenia; Triglycerides

The onset of diabetes and impaired glucose metabolism among schizophrenic patients has been the topic of numerous recently published articles, with research implicating weight gain, the use of antipsychotic medication, history of diabetes mellitus in family members, and the diagnosis of schizophrenia itself as risk factors. Therefore, it was the aim of this study to determine the glucose metabolism parameters in noncompliant unmedicated schizophrenic patients (antipsychotic-free) and first-episode antipsychotic-naive schizophrenic patients to investigate whether there is a preexisting impairment of glucose metabolism in never-medicated schizophrenic patients.. Plasma glucose, insulin, C-peptide, and leptin concentrations were determined in 50 antipsychotic-free and 50 antipsychotic-naive DSM-IV schizophrenia patients and 50 healthy control subjects. Insulin resistance was calculated through the homeostatic model assessment (HOMA). The General Linear Model (univariate) procedure was used to perform analysis of covariance. Patients were recruited from July 2001 to December 2002.. Antipsychotic-free patients showed significantly increased insulin (p = .001) and C-peptide (p = .02) concentrations and a significantly higher degree of insulin resistance (p = .003), as measured with the HOMA index, in comparison with the antipsychotic-naive patients and the control group. Significantly increased leptin concentrations (p = .000) were also noted in the antipsychotic-free patients and were attributed to the effects of body mass index (p = .000) and sex (p = .000).. The results reported in this study suggest the effect of previous antipsychotic treatment on glucose metabolism parameters and weight-related hormones such as leptin, while ruling out a preexisting impairment of glucose metabolism in never-medicated first-episode schizophrenic patients.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Blood Glucose; Body Mass Index; C-Peptide; Female; Glucose; Humans; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Psychiatric Status Rating Scales; Schizophrenia; Treatment Refusal

Recent results suggest that treatment with the atypical antipsychotics clozapine and olanzapine is associated with increased insulin and lipid levels.. The aim of the present study was to investigate potential relationships between insulin or other hormones related to glucose-insulin homeostasis or lipids and steady-state serum concentrations of clozapine or olanzapine in patients on therapeutic doses.. Thirty-four patients, diagnosed with schizophrenia or related psychoses according to the DSM-IV criteria and treated with clozapine ( n=18) or olanzapine ( n=16), were studied. Median treatment time with the antipsychotics was 5.3 years (range 0.5-16.3 years). Fasting blood samples for insulin, C-peptide, insulin-like growth factor I, insulin-like growth factor binding protein-1, leptin, glucose and lipids were analyzed and investigated in relation to the patients' drug serum concentrations.. Hyperinsulinemia was found in 30-60% of the patients, hyperglycemia in 10-30%, hyperlipidemia in 40-60% and hyperleptinemia in 10-20%. Moreover, levels of insulin, C-peptide and triglycerides correlated positively to the clozapine serum concentration and to the ratio of olanzapine to N-desmethylolanzapine concentrations. In contrast, levels of C-peptide, leptin and blood glucose were inversely correlated to the serum concentration of the metabolite N-desmethylolanzapine.. Metabolic abnormalities (i.e. hyperinsulinemia, hyperlipidemia and hyperleptinemia) and insulin resistance were associated with both clozapine and olanzapine treatments. Levels of insulin and triglycerides increased by increasing clozapine serum concentration and by increasing ratio of olanzapine to N-desmethylolanzapine; the last due to the metabolite N-desmethylolanzapine probably having an inverse effect to the main compound olanzapine. Thus, the metabolic abnormalities induced by these two drugs are clozapine-concentration dependent in clozapine-treated patients, and ratio of olanzapine to N-desmethylolanzapine-concentration dependent in olanzapine-treated patients.

Topics: Adult; Benzodiazepines; Blood Glucose; Body Mass Index; C-Peptide; Chromatography, High Pressure Liquid; Clozapine; Diabetes Mellitus, Type 2; Diagnostic and Statistical Manual of Mental Disorders; Dose-Response Relationship, Drug; Female; Hormones; Humans; Insulin; Lipids; Male; Middle Aged; Olanzapine; Radioimmunoassay; Schizophrenia; Smoking; Statistics as Topic; Triglycerides

Although there have been several reports that clozapine precipitated hyperglycemia and diabetic ketoacidosis in some patients, the mechanism by which clozapine impairs glucose metabolism is not known. This study investigated the effect of clozapine on glucose metabolism in six schizophrenic patients while they were free of medication and receiving 200 mg/d and 450 mg/d of clozapine. Clozapine increased mean levels of blood glucose, insulin and C-peptide. It is possible, based on these findings, that the glucose intolerance was due to increased insulin resistance.

Topics: Adult; Antipsychotic Agents; Blood Glucose; C-Peptide; Clozapine; Female; Glucose Tolerance Test; Humans; Insulin; Male; Middle Aged; Schizophrenia