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

2021 ◽  
Author(s):  
Frederico G. S. Toledo ◽  
William F. Martin ◽  
Linda Morrow ◽  
Carine Beysen ◽  
Daiva Bajorunas ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Healthy Volunteers ◽  
Exploratory Study ◽  
The Body ◽  
Metabolic Effects ◽  
Oral Glucose ◽  
C Peptide ◽  
Bipolar I Disorder ◽  
Euglycemic Clamp ◽  
Hyperinsulinemic Euglycemic Clamp

AbstractA 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.

scholarly journals Chronic kidney disease and obesity bias surrogate estimates of insulin sensitivity compared with the hyperinsulinemic euglycemic clamp

2017 ◽  
Vol 312 (3) ◽  
pp. E175-E182 ◽  
Author(s):  
Iram Ahmad ◽  
Leila R. Zelnick ◽  
Nicole R. Robinson ◽  
Adriana M. Hung ◽  
Bryan Kestenbaum ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Insulin Sensitivity ◽  
Kidney Disease ◽  
Oral Glucose ◽  
Cross Sectional ◽  
Euglycemic Clamp ◽  
Insulin Kinetics ◽  
Hyperinsulinemic Euglycemic Clamp ◽  
Sensitivity Indices ◽  
Organ Specific

Insulin sensitivity can be measured by procedures such as the hyperinsulinemic euglycemic clamp or by using surrogate indices. Chronic kidney disease (CKD) and obesity may differentially affect these measurements because of changes in insulin kinetics and organ-specific effects on insulin sensitivity. In a cross-sectional study of 59 subjects with nondiabetic CKD [estimated glomerular filtration rate: (GFR) <60 ml·min−1·1.73 m2] and 39 matched healthy controls, we quantified insulin sensitivity by clamp (SIclamp), oral glucose tolerance test, and fasting glucose and insulin. We compared surrogate insulin sensitivity indices to SIclamp using descriptive statistics, graphical analyses, correlation coefficients, and linear regression. Mean age was 62.6 yr; 48% of the participants were female, and 77% were Caucasian. Insulin sensitivity indices were 8–38% lower in participants with vs. without CKD and 13–59% lower in obese compared with nonobese participants. Correlations of surrogate indices with SIclamp did not differ significantly by CKD or obesity status. Adjusting for SIclamp in addition to demographic factors, Matsuda index was 15% lower in participants with vs. without CKD ( P = 0.09) and 36% lower in participants with vs. without obesity ( P = 0.0001), whereas 1/HOMA-IR was 23% lower in participants with vs. without CKD ( P = 0.02) and 46% lower in participants with vs. without obesity ( P < 0.0001). We conclude that CKD and obesity do not significantly alter correlations of surrogate insulin sensitivity indices with SIclamp, but they do bias surrogate measurements of insulin sensitivity toward lower values. This bias may be due to differences in insulin kinetics or organ-specific responses to insulin.

scholarly journals The influence of reduced insulin sensitivity via short-term reductions in physical activity on cardiac baroreflex sensitivity during acute hyperglycemia

2015 ◽  
Vol 119 (12) ◽  
pp. 1383-1392 ◽  
Author(s):  
S. W. Holwerda ◽  
L. J. Reynolds ◽  
R. M. Restaino ◽  
D. P. Credeur ◽  
H. J. Leidy ◽  
...  
Keyword(s):  
Physical Activity ◽  
Insulin Sensitivity ◽  
Healthy Subjects ◽  
Baroreflex Sensitivity ◽  
Glucose Consumption ◽  
Oral Glucose ◽  
Short Term ◽  
Acute Hyperglycemia ◽  
Euglycemic Clamp ◽  
Hyperinsulinemic Euglycemic Clamp

Reduced insulin sensitivity and impaired glycemic control are among the consequences of physical inactivity and have been associated with reduced cardiac baroreflex sensitivity (BRS). However, the effect of reduced insulin sensitivity and acute hyperglycemia following glucose consumption on cardiac BRS in young, healthy subjects has not been well characterized. We hypothesized that a reduction in insulin sensitivity via reductions in physical activity would reduce cardiac BRS at rest and following an oral glucose tolerance test (OGTT). Nine recreationally active men (23 ± 1 yr; >10,000 steps/day) underwent 5 days of reduced daily physical activity (RA5) by refraining from planned exercise and reducing daily steps (<5,000 steps/day). Spontaneous cardiac BRS (sequence technique) was compared at rest and for 120 min following an OGTT at baseline and after RA5. A substudy ( n = 8) was also performed to independently investigate the influence of elevated insulin alone on cardiac BRS using a 120-min hyperinsulinemic-euglycemic clamp. Insulin sensitivity (Matsuda index) was significantly reduced following RA5 (BL 9.2 ± 1.3 vs. RA5 6.4 ± 1.1, P < 0.001). Resting cardiac BRS was unaffected by RA5 and significantly reduced during the OGTT similarly at baseline and RA5 (baseline 0 min, 28 ± 4 vs. 120 min, 18 ± 4; RA5 0 min, 28 ± 4 vs. 120 min, 21 ± 3 ms/mmHg). Spontaneous cardiac BRS was also reduced during the hyperinsulinemic-euglycemic clamp ( P < 0.05). Collectively, these data demonstrate that acute elevations in plasma glucose and insulin can impair spontaneous cardiac BRS in young, healthy subjects, and that reductions in cardiac BRS following acute hyperglycemia are unaffected by reduced insulin sensitivity via short-term reductions in physical activity.

A Novel Use of the Hyperinsulinemic-Euglycemic Clamp Technique to Estimate Insulin Sensitivity of Systemic Lipolysis

2001 ◽  
Vol 33 (2) ◽  
pp. 89-95 ◽  
Author(s):  
M Stumvoll ◽  
H G Wahl ◽  
K Löblein ◽  
R Becker ◽  
A Volk ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Euglycemic Clamp ◽  
Clamp Technique ◽  
Hyperinsulinemic Euglycemic Clamp

scholarly journals Superimposition of Postnatal Calorie Restriction Protects the Aging Male Intrauterine Growth- Restricted Offspring from Metabolic Maladaptations

Endocrinology ◽  
2012 ◽  
Vol 153 (9) ◽  
pp. 4216-4226 ◽  
Author(s):  
Yun Dai ◽  
Shanthie Thamotharan ◽  
Meena Garg ◽  
Bo-Chul Shin ◽  
Sherin U. Devaskar
Keyword(s):  
Physical Activity ◽  
Insulin Sensitivity ◽  
Postnatal Growth ◽  
Growth Restriction ◽  
Fine Tuning ◽  
Whole Body ◽  
Aging Male ◽  
Intrauterine Growth ◽  
Euglycemic Clamp ◽  
Hyperinsulinemic Euglycemic Clamp

Intrauterine growth restriction (IUGR) results in dysregulated glucose homeostasis and adiposity in the adult. We hypothesized that with aging, these perturbations will wane, and superimposition of postnatal growth restriction (PNGR) on IUGR [intrauterine and postnatal growth restriction (IPGR)] will reverse the residual IUGR phenotype. We therefore undertook hyperinsulinemic-euglycemic clamp, energy balance, and physical activity studies during fed, fasted, and refed states, in light and dark cycles, on postweaned chow diet-fed more than 17-month aging male IUGR, PNGR, and IPGR vs. control (CON) rat offspring. Hyperinsulinemic-euglycemic clamp revealed similar whole-body insulin sensitivity and physical activity in the nonobese IUGR vs. CON, despite reduced heat production and energy expenditure. Compared with CON and IUGR, IPGR mimicking PNGR was lean and growth restricted with increased physical activity, O2 consumption (VO2), energy intake, and expenditure. Although insulin sensitivity was no different in IPGR and PNGR, skeletal muscle insulin-induced glucose uptake was enhanced. This presentation proved protective against the chronologically earlier (5.5 months) development of obesity and dysregulated energy homeostasis after 19 wk on a postweaned high-fat diet. This protective role of PNGR on the metabolic IUGR phenotype needs future fine tuning aimed at minimizing unintended consequences.

scholarly journals Ghrelin- and GH-induced insulin resistance: no association with retinol-binding protein-4

2013 ◽  
Vol 2 (2) ◽  
pp. 96-103 ◽  
Author(s):  
Esben Thyssen Vestergaard ◽  
Morten B Krag ◽  
Morten M Poulsen ◽  
Steen B Pedersen ◽  
Niels Moller ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Binding Protein ◽  
Human Subjects ◽  
Retinol Binding Protein ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Retinol Binding Protein 4 ◽  
Euglycemic Clamp ◽  
Hyperinsulinemic Euglycemic Clamp

ObjectiveSupraphysiological levels of ghrelin and GH induce insulin resistance. Serum levels of retinol-binding protein-4 (RBP4) correlate inversely with insulin sensitivity in patients with type 2 diabetes. We aimed to determine whether ghrelin and GH affect RBP4 levels in human subjects.Materials and methodsTo study GH-independent effects of ghrelin, seven hypopituitary men undergoing replacement therapy with GH and hydrocortisone were given ghrelin (5 pmol/kg per min) and saline infusions for 300 min in a randomized, double-blind, placebo-controlled, crossover design. Circulating RBP4 levels were measured at baseline and during a hyperinsulinemic–euglycemic clamp on both study days. To study the direct effects of GH, nine healthy men were treated with GH (2 mg at 2200 h) and placebo for 8 days in a randomized, double-blind, placebo-controlled, crossover study. Serum RBP4 levels were measured before and after treatment, and insulin sensitivity was measured by the hyperinsulinemic–euglycemic clamp technique.ResultsGhrelin acutely decreased peripheral insulin sensitivity. Serum RBP4 concentrations decreased in response to insulin infusion during the saline experiment (mg/l): 43.2±4.3 (baseline) vs 40.4±4.2 (clamp), P<0.001, but this effect was abrogated during ghrelin infusion (mg/l): 42.4±4.5 (baseline) vs 42.9±4.7 (clamp), P=0.73. In healthy subjects, serum RBP4 levels were not affected by GH administration (mg/l): 41.7±4.1 (GH) vs 43.8±4.6 (saline), P=0.09, although GH induced insulin resistance.Conclusionsi) Serum RBP4 concentrations decrease in response to hyperinsulinemia, ii) ghrelin abrogates the inhibitory effect of insulin on circulating RBP4 concentrations, and iii) ghrelin as well as GH acutely induces insulin resistance in skeletal muscle without significant changes in circulating RBP4 levels.

Pancreas and gut hormone responses to oral glucose and intravenous glucagon in cystic fibrosis patients with normal, impaired, and diabetic glucose tolerance

1993 ◽  
Vol 128 (3) ◽  
pp. 207-214 ◽  
Author(s):  
Susanne Lanng ◽  
Birger Thorsteinsson ◽  
Michael E Røder ◽  
Cathrine Ørskov ◽  
Jens J Holst ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Pancreatic Polypeptide ◽  
Oral Glucose ◽  
C Peptide ◽  
Control Subjects ◽  
Gut Hormone ◽  
Patient Groups ◽  
Hormone Responses

Pancreatic and gut hormone responses to oral glucose, and insulin sensitivity were studied in cystic fibrosis patients with normal (N= 14), impaired (N=4), and diabetic (N= 12) glucose tolerance, and in 10 control subjects, and beta cell responses to oral glucose and intravenous glucagon were compared. Compared to control subjects, initial insulin and C-peptide responses to oral glucose were lower in all patient groups, and decreased with decreasing glucose tolerance. Insulin sensitivity in patients with impaired and diabetic glucose tolerance was lower than in control subjects. The 6 min post-glucagon C-peptide concentration was positively correlated with the initial insulin response to oral glucose. Fasting levels of pancreatic polypeptide, pancreatic glucagon, total glucagon, glucagon-like peptide-1 7-36 amide, and gastric inhibitory polypeptide were normal in all patient groups. Following oral glucose, pancreatic polypeptide responses were absent in all patients, suppressibility of pancreatic glucagon secretion was increasingly impaired with decreasing glucose tolerance, and gut hormone levels were normal. In conclusion, at cystic fibrosis (a) insulin secretion is impaired even when glucose tolerance and insulin sensitivity are within the normal range, (b) the glucagon test gives valid estimates of residual beta cell function, (c) pancreatic polypeptide response to oral glucose is absent, (d) glucagon suppressibility decreases with decreasing glucose tolerance, and (e) the enteroinsular axis is intact.

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