Insulin and glucose metabolism with olanzapine and a combination of olanzapine and samidorphan: exploratory phase 1 results in healthy volunteers

A combination of olanzapine and samidorphan (OLZ/SAM) received US Food and Drug Administration approval in May 2021 for the treatment of adults with schizophrenia or bipolar I disorder. OLZ/SAM provides the efficacy of olanzapine, while mitigating olanzapine-associated weight gain. This exploratory study characterized the metabolic profile of OLZ/SAM in healthy volunteers to gain mechanistic insights. Volunteers received once-daily oral 10 mg/10 mg OLZ/SAM, 10 mg olanzapine, or placebo for 21 days. Assessments included insulin sensitivity during an oral glucose tolerance test (OGTT), hyperinsulinemic-euglycemic clamp, other measures of glucose/lipid metabolism, and adverse event (AE) monitoring. Treatment effects were estimated with analysis of covariance. In total, 60 subjects were randomized (double-blind; placebo, n = 12; olanzapine, n = 24; OLZ/SAM, n = 24). Olanzapine resulted in hyperinsulinemia and reduced insulin sensitivity during an OGTT at day 19, changes not observed with OLZ/SAM or placebo. Insulin sensitivity, measured by hyperinsulinemic-euglycemic clamp, was decreased in all treatment groups relative to baseline, but this effect was greatest with olanzapine and OLZ/SAM. Although postprandial (OGTT) glucose and fasting cholesterol concentrations were similarly increased with olanzapine or OLZ/SAM, other early metabolic effects were distinct, including post-OGTT C-peptide concentrations and aspects of energy metabolism. Forty-nine subjects (81.7%) experienced at least 1 AE, most mild or moderate in severity. OLZ/SAM appeared to mitigate some of olanzapine’s unfavorable postprandial metabolic effects (e.g., hyperinsulinemia, elevated C-peptide) in this exploratory study. These findings supplement the body of evidence from completed or ongoing OLZ/SAM clinical trials supporting its role in the treatment of schizophrenia and bipolar I disorder.

Short-Term SGLT2 Inhibitor Administration Does Not Alter Systemic Insulin Clearance in Type 2 Diabetes

Background: Decreased insulin clearance could be a relatively upstream abnormality in obesity, metabolic syndrome, and nonalcoholic fatty liver disease. Previous studies have shown that sodium-glucose cotransporter 2 inhibitor (SGLT2i) increases insulin–C-peptide ratio, a marker of insulin clearance, and improves metabolic parameters. We evaluated the effects of the SGLT2i tofogliflozin on metabolic clearance rate of insulin (MCRI) with a hyperinsulinemic euglycemic clamp study, the gold standard for measuring systemic insulin clearance. Methods: Study participants were 12 Japanese men with type 2 diabetes. We evaluated MCRI and tissue-specific insulin sensitivity with a hyperinsulinemic euglycemic clamp (insulin infusion rate, 40 mU/m2·min) before and immediately after a single dose (n = 12) and 8 weeks (n = 9) of tofogliflozin. We also measured ectopic fat in muscle and liver and the abdominal fat area using 1H-magnetic resonance spectroscopy and magnetic resonance imaging, respectively, before and after 8 weeks of tofogliflozin. Results: MCRI did not change after a single dose of tofogliflozin (594.7 ± 67.7 mL/min·m2 and 608.3 ± 90.9 mL/min·m2, p = 0.61) or after 8 weeks (582.5 ± 67.3 mL/min·m2 and 602.3 ± 67.0 mL/min·m2, p = 0.41). The 8-week treatment significantly improved glycated hemoglobin and decreased body weight (1.7%) and the subcutaneous fat area (6.4%), whereas insulin sensitivity and ectopic fat in muscle and liver did not change significantly. Conclusions: MCRI did not change after a single dose or 8 weeks of tofogliflozin. Increased MCRI does not precede a decrease in body fat or improved glycemic control.

Lipid accumulation product (LAP) as a potential index to predict risk of insulin resistance in young, non-obese Asian Indian males from Southern India: observations from hyperinsulinemic-euglycemic clamp studies

IntroductionWe aimed to compare the predictive accuracy of surrogate indices namely the lipid accumulation product (LAP) index, homeostatic model of assessment of insulin resistance (HOMA-IR), fasting glucose-insulin ratio (FG-IR) and the quantitative-insulin sensitivity check index (QUICKI), against the M value of hyperinsulinemic-euglycemic clamp (HEC), and to determine a cut-off value for the LAP index to predict risk of insulin resistance in non-obese (body mass index <21 kg/m2), normoglycemic, Asian Indian males from Southern India.Research design and methodsData of HEC studies performed in 108 non-obese, normoglycemic, Asian Indian males was obtained retrospectively and the M value (a measure of whole-body insulin sensitivity) was calculated. The M value is the rate of whole-body glucose metabolism at the hyperinsulinemic plateau (a measure of insulin sensitivity) and is calculated between 60 and 120 min after the start of the insulin infusion in the HEC procedure. The LAP index, the HOMA-IR, FG-IR and QUICKI were calculated. Spearman’s correlation and logistic regression analysis were performed. Cut-off value for the LAP index was obtained using receiver operating characteristics with area under curve (AUC) analysis at 95% CI. P value <0.05 was considered to be statistically significant.ResultsSignificant negative correlation was observed for the M value with LAP index (r=−0.39, p<0.001) while significant positive correlation was noted with FG-IR (r=0.25; p<0.01) and QUICKI (r=0.22; p<0.01). The LAP index cut-off value ≥33.4 showed 75% sensitivity and 75% specificity with AUC (0.72) to predict risk of insulin resistance in this cohort.ConclusionThe LAP index showed higher predictive accuracy for the risk of insulin resistance as compared with HOMA-IR, QUICKI and FG-IR in non-obese, normoglycemic Asian Indian males from Southern India.

Differential insulin sensitivity of NMR-based metabolomic measures in a two-step hyperinsulinemic euglycemic clamp study

Background Insulin is the key regulator of glucose metabolism, but it is difficult to dissect direct insulin from glucose-induced effects. We aimed to investigate the effects of hyperinsulemia on metabolomic measures under euglycemic conditions in nondiabetic participants. Methods We assessed concentrations of 151 metabolomic measures throughout a two-step hyperinsulinemic euglycemic clamp procedure. We included 24 participants (50% women, mean age = 62 [s.d. = 4.2] years) and metabolomic measures were assessed under baseline, low-dose (10 mU/m2/min) and high-dose (40 mU/m2/min) insulin conditions. The effects of low- and high-dose insulin infusion on metabolomic measures were analyzed using linear mixed-effect models for repeated measures. Results After low-dose insulin infusion, 90 metabolomic measures changed in concentration (p < 1.34e−4), among which glycerol (beta [Confidence Interval] = − 1.41 [− 1.54, − 1.27] s.d., p = 1.28e−95) and three-hydroxybutyrate (− 1.22 [− 1.36, − 1.07] s.d., p = 1.44e−61) showed largest effect sizes. After high-dose insulin infusion, 121 metabolomic measures changed in concentration, among which branched-chain amino acids showed the largest additional decrease compared with low-dose insulin infusion (e.g., Leucine, − 1.78 [− 1.88, − 1.69] s.d., P = 2.7e−295). More specifically, after low- and high-dose insulin infusion, the distribution of the lipoproteins shifted towards more LDL-sized particles with decreased mean diameters. Conclusion Metabolomic measures are differentially insulin sensitive and may thus be differentially affected by the development of insulin resistance. Moreover, our data suggests insulin directly affects metabolomic measures previously associated with increased cardiovascular disease risk.

The CREBRF diabetes-protective rs373863828-A allele is associated with enhanced early insulin release in men of Māori and Pacific ancestry

AimThe minor A allele of rs373863828 (CREBRF p.Arg457Gln) is associated with increased body mass index (BMI), but reduced risk of type 2 and gestational diabetes in Polynesian (Pacific peoples and Aotearoa New Zealand Māori) populations. This study investigates the effect of the A allele on insulin release and sensitivity in overweight/obese men without diabetes.MethodsA mixed meal tolerance test was completed by 172 men (56 with the A allele) of Māori or Pacific ancestry, and 44 (24 with the A allele) had a frequently sampled intravenous glucose tolerance test and hyperinsulinemic-euglycemic clamp. Mixed linear models with covariates age, ancestry and BMI were used to analyse the association between the A allele of rs373863828 and markers of insulin release and blood glucose regulation.ResultsThe A allele of rs373863828 is associated with a greater increase in plasma insulin 30 min following a meal challenge without affecting the elevation in plasma glucose or incretins GLP-1 or GIP. Consistent with this point, following an intravenous infusion of a glucose bolus, participants with an A allele had higher early (p<0.05 at 2 and 4 min) plasma insulin and C-peptide concentrations for a similar elevation in blood glucose as those homozygous for the major (G) allele. Despite increased plasma insulin, rs373863828 genotype was not associated with a significant difference (p>0.05) in insulin sensitivity index or glucose disposal during hyperinsulinemic-euglycemic clamp.Conclusion/interpretationrs373863828-A allele associates with increased glucose-stimulated insulin release without affecting insulin sensitivity, suggesting that CREBRF p.Arg457Gln may increase maximal ability for β-cells to release insulin to reduce the risk of type 2 diabetes.

Serum sclerostin is negatively associated with insulin sensitivity in obese but not lean women

Objective The mechanisms underlying the development of peripheral insulin resistance are complex. Several studies have linked sclerostin, an osteocyte-derived inhibitor of the Wnt/β-catenin pathway, to obesity and insulin resistance. The aim of this study was to investigate 1) whether serum sclerostin is associated with insulin sensitivity in lean and/or obese women; and 2) whether hyperinsulinemia affects serum sclerostin concentrations. Design A cross-sectional study. Methods Insulin sensitivity was measured in lean (BMI<25 kg·m-2) and obese (BMI > 30 kg·m-2) women using a hyperinsulinemic-euglycemic clamp. Serum sclerostin was measured at baseline and during the clamp procedure. Results We studied 21 lean and 22 obese women with a median age of 40 and 43 years and a median BMI of 22.4 and 33.5 kg·m-2, respectively. Obese women had higher serum sclerostin than lean women (122±33 vs 93±33 nmol/L, p<0.01). Higher serum sclerostin was associated with lower insulin sensitivity in obese, but not in lean individuals (difference in M value between highest and lowest quartile: -7.02 mg⋅kg−1⋅min−1, p = 0.03 and 1.59 mg⋅kg−1⋅min−1, p = 0.50, respectively). Hyperinsulinemia did not affect serum sclerostin in lean nor obese women (p>0.5). Conclusion Serum sclerostin is negatively associated with insulin sensitivity as measured with the hyperinsulinemic euglycemic clamp in obese, but not lean women. This indicates a potential role of the Wnt/β-catenin pathway in regulating insulin sensitivity particularly in obese individuals. Our findings remain hypothesis-generating and should be confirmed by additional studies.

Abstract 17025: Myeloid Rage Protects From Insulin Resistance in Mice Fed High Fat Diet

Introduction: Obesity is a major global health problem, with over one third of adults in the US classified as obese. Obesity often leads to a state of insulin resistance (IR), type 2 diabetes (T2D) and its complications. We previously showed that the receptor for advanced glycation end products (RAGE) and its ligands contribute to the pathogenesis of obesity and IR, as whole body and adipocyte-specific Ager (gene encoding RAGE) deleted mice fed a high fat diet (HFD) were significantly protected from weight gain and IR. Here, we hypothesize that myeloid RAGE contributed to IR upon HFD feeding. Methods: We generated mice with myeloid-specific (MDR) LyzMCre(+/+).Ager flox/flox and adipocyte and myeloid-specific (Double Knockouts) AdipoQCre(-/+)LyzMCre(+/+).Ager flox/flox deletion of Ager and LysMCre mice were used as control. Mice were fed either standard chow (LFD) or HFD (60% kcal/fat) for 3 months starting at age 6 weeks. Mice were assessed for body mass and composition, glucose and insulin sensitivity and whole body glucose metabolism by hyperinsulinemic-euglycemic clamp studies. Results: After 3 months HFD, there were no significant differences in body mass, body composition, food intake, energy expenditure and physical activity of the MDR mice vs. controls. Similar findings were observed in mice fed LFD. However, surprisingly, in HFD-fed mice, insulin tolerance tests and hyperinsulinemic-euglycemic clamp studies showed decreased insulin sensitivity and insulin action in the MDR vs. control mice, indicating that the MDR mice were more insulin resistant. The Double Knockout (myeloid/adipocyte) Cre (+) mice were more glucose tolerant and insulin sensitive compared to MDR mice, showing that deletion of Ager in the adipocytes rescued the adverse effects of Ager deletion in myeloid cells. Conclusions: Myeloid Ager protects from IR in mice fed HFD. Furthermore, in MDR mice, concomitant adipocyte-specific deletion of Ager rescues these mice from IR and, at the same time, reduces HFD-induced adiposity. The mechanisms underlying these findings are under active investigation.