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.

Reduction in C-Peptide Levels and Influence on Pharmacokinetics and Pharmacodynamics of Insulin Preparations: How to Conduct a High-Quality Euglycemic Clamp Study

Objective: The aim of the study was to investigate the different extent of inhibition of endogenous insulin secretion by the reduction of C-peptide levels in an euglycemic clamp study and its effects on the evaluation of pharmacokinetics, pharmacodynamics of insulin preparations, and quality of clamp study to determine the best reduction range of C-peptide levels.Methods: Healthy Chinese male volunteers were enrolled and underwent a single-dose euglycemic clamp test. Participants were subcutaneously injected with long-acting insulin glargine (0.4 IU/kg). Blood samples were collected pretest and up to 24 h post-test to assess pharmacokinetics (PK), pharmacodynamics (PD), and C-peptide levels.Results: We divided the 39 volunteers enrolled in the study into three groups according to the reduction of C-peptide levels: group A (ratio of C-peptide reduction <30%, n = 13), group B (ratio of C-peptide reduction between ≥ 30% and <50%, n = 15), and group C (ratio of C-peptide reduction ≥50%, n = 11); there were significant differences in the three groups (p= 0.000). The upper and lower limits of blood glucose oscillation in group C was statistically lower than the other groups, the range of oscillating glucose levels in group C was −17.0 ± 6.6% to −1.1 ± 6.7%. The AUC0–24 h in groups A, B, and C were 9.7 ± 2.2, 11.0 ± 2.9, and 11.9 ± 2.1 ng/ml × min, respectively, which indicated an increasing trend in the three groups (Ptrend = 0.041). For quality assessment, the average glucose (p = 0.000) and MEFTG (p = 0.001) levels in three groups were significantly different.Conclusion: The different extent of inhibition of endogenous insulin will influence the PK/PD of insulin preparations and the quality of the euglycemic clamp. Furthermore, the ratio of C-peptide reduction should be above 50% to free from the interference of endogenous insulin, and the range of blood glucose levels should be consistently maintained at −10% to 0 in the euglycemic clamp.

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.

New Insights on the Interactions Between Insulin Clearance and the Main Glucose Homeostasis Mechanisms

<i>Objective</i> Endogenous insulin clearance (EIC) is physiologically reduced at increasing insulin secretion rate (ISR). Computing EIC at the prevailing ISR does not distinguish the effects of hypersecretion from those of other mechanisms of glucose homeostasis. We aimed to measure EIC in standardized ISR conditions (i.e., at fixed ISR levels) and to analyze its associations with relevant physiologic factors. <p><i>Research Design and Methods</i> We estimated standardized EIC (EIC_ISR) by mathematical modelling in 9 different studies with insulin and glucose infusions (N=2067). EIC_ISR association with various traits was analyzed by stepwise multivariable regression, in studies with euglycemic clamp and OGTT (N=1410). We also tested whether oral glucose ingestion, as opposed to intravenous infusion, has an independent effect on EIC (N=1555).</p> <p><i>Results</i> Insulin sensitivity (as M/I from the euglycemic clamp) is the strongest determinant of EIC_ISR, ~4 times more influential than insulin-resistance related hypersecretion. EIC_ISR independently associates positively with M/I, fasting and mean OGTT glucose or type 2 diabetes, and β-cell glucose sensitivity, and negatively with African American or Hispanic race, female sex, and female age. With oral glucose ingestion, an ISR-independent ~10% EIC reduction is necessary to explain the observed insulin concentration profiles.</p> <p><i>Conclusions</i> Based on EIC_ISR, we posit the existence of two adaptive processes involving insulin clearance: the first reduces EIC_ISR with insulin resistance (not with higher BMI <i>per se</i>) and is more relevant than the concomitant hypersecretion; the second reduces EIC_ISR with β-cell dysfunction. These processes are dysregulated in type 2 diabetes. Finally, oral glucose ingestion <i>per se</i> reduces insulin clearance.<br> </p>

New Insights on the Interactions Between Insulin Clearance and the Main Glucose Homeostasis Mechanisms

<i>Objective</i> Endogenous insulin clearance (EIC) is physiologically reduced at increasing insulin secretion rate (ISR). Computing EIC at the prevailing ISR does not distinguish the effects of hypersecretion from those of other mechanisms of glucose homeostasis. We aimed to measure EIC in standardized ISR conditions (i.e., at fixed ISR levels) and to analyze its associations with relevant physiologic factors. <p><i>Research Design and Methods</i> We estimated standardized EIC (EIC_ISR) by mathematical modelling in 9 different studies with insulin and glucose infusions (N=2067). EIC_ISR association with various traits was analyzed by stepwise multivariable regression, in studies with euglycemic clamp and OGTT (N=1410). We also tested whether oral glucose ingestion, as opposed to intravenous infusion, has an independent effect on EIC (N=1555).</p> <p><i>Results</i> Insulin sensitivity (as M/I from the euglycemic clamp) is the strongest determinant of EIC_ISR, ~4 times more influential than insulin-resistance related hypersecretion. EIC_ISR independently associates positively with M/I, fasting and mean OGTT glucose or type 2 diabetes, and β-cell glucose sensitivity, and negatively with African American or Hispanic race, female sex, and female age. With oral glucose ingestion, an ISR-independent ~10% EIC reduction is necessary to explain the observed insulin concentration profiles.</p> <p><i>Conclusions</i> Based on EIC_ISR, we posit the existence of two adaptive processes involving insulin clearance: the first reduces EIC_ISR with insulin resistance (not with higher BMI <i>per se</i>) and is more relevant than the concomitant hypersecretion; the second reduces EIC_ISR with β-cell dysfunction. These processes are dysregulated in type 2 diabetes. Finally, oral glucose ingestion <i>per se</i> reduces insulin clearance.<br> </p>

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.