Developmental Programming: Impact of Prenatal Testosterone Excess and Postnatal Weight Gain on Insulin Sensitivity Index and Transfer of Traits to Offspring of Overweight Females

Abstract:Background:A combination of olanzapine and samidorphan (OLZ/SAM) is in development for schizophrenia to provide the efficacy of olanzapine while mitigating olanzapine-associated weight gain. The objective of this phase 1 exploratory study was to assess metabolic treatment effects of OLZ/SAM.Methods:Healthy, non-obese adults (18–40 years) were randomized 2:2:1 to once-daily OLZ/SAM, olanzapine, or placebo for 21 days. Assessments included oral glucose tolerance test (OGTT), hyperinsulinemic-euglycemic clamp, weight gain, and adverse event (AE) monitoring. Treatment effects were estimated with analysis of covariance.Results:Sixty subjects were randomized (OLZ/SAM, n=24; olanzapine, n=24; placebo, n=12); 19 (79.2%), 22 (91.7%), and 11 (91.7%), respectively, completed the study. In the OGTT, olanzapine led to significant hyperinsulinemia (P<0.0001) and significantly reduced insulin sensitivity (2-hour Matsuda index) at day 19 vs baseline (P=0.0012), changes not observed with OLZ/SAM. No significant between-group differences were observed for change from baseline in clamp-derived insulin sensitivity index at day 21. Least squares mean weight change from baseline was similar with OLZ/SAM (3.16 kg) and olanzapine (2.87 kg); both were significantly higher than placebo (0.57 kg; both P<0.01). Caloric intake significantly decreased from baseline to day 22 with OLZ/SAM (P=0.015) but not with olanzapine or placebo. Forty-nine subjects (81.7%) experienced ≥1 AE (OLZ/SAM, 87.5%; olanzapine, 79.2%; placebo, 75.0%).Conclusions:In this exploratory study, hyperinsulinemia and decreased insulin sensitivity were observed in the OGTT with olanzapine but not with OLZ/SAM or placebo. Clamp-derived insulin sensitivity index and weight changes were similar with OLZ/SAM and olanzapine in healthy subjects during the 3-week study.Funding Acknowledgements:This study was funded by Alkermes, Inc.

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Subdiaphragmatic vagal deafferentation affects body weight gain and glucose metabolism in obese male Zucker (fa/fa) rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00736.2004 ◽

2005 ◽

Vol 289 (4) ◽

pp. R1027-R1034 ◽

Cited By ~ 18

Author(s):

Bettina Ferrari ◽

Myrtha Arnold ◽

Richard D. Carr ◽

Wolfgang Langhans ◽

Giovanni Pacini ◽

...

Keyword(s):

Body Weight ◽

Weight Gain ◽

Insulin Sensitivity ◽

Food Intake ◽

Plasma Glucose ◽

Body Weight Gain ◽

Zucker Rats ◽

Sensitivity Index ◽

Insulin Sensitivity Index ◽

Obese Rats

We investigated the effect of subdiaphragmatic vagal deafferentation (SDA) on food intake, body weight gain, and metabolism in obese ( fa/ fa) and lean ( Fa/?) Zucker rats. Before and after recovery from surgery, food intake and body weight gain were recorded, and plasma glucose and insulin were measured in tail-prick blood samples. After implantation of a jugular vein catheter, an intravenous glucose tolerance test (IVGTT) was performed, followed by minimal modeling to estimate the insulin sensitivity index. Food intake relative to metabolic body weight (g/kg0.75) and daily body weight gain after surgery were lower ( P < 0.05) in SDA than in sham obese but not lean rats. Before surgery, plasma glucose and insulin concentrations were lower ( P < 0.05) in lean than in obese rats but did not differ between surgical groups within both genotypes. Four weeks after surgery, plasma glucose and insulin were still similar in SDA and sham lean rats but lower ( P < 0.05) in SDA than in sham obese rats. IVGTT revealed a downward shift of the plasma insulin profile by SDA in obese but not lean rats, whereas the plasma glucose profile was unaffected. SDA decreased ( P < 0.05) area under the curve for insulin but not glucose in obese rats. The insulin sensitivity index was higher in lean than in obese rats but was not affected by SDA in both genotypes. These results suggest that elimination of vagal afferent signals from the upper gut reduces food intake and body weight gain without affecting the insulin sensitivity index measured by minimal modeling in obese Zucker rats.

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Equivalence of the insulin sensitivity index in man derived by the minimal model method and the euglycemic glucose clamp.

Journal of Clinical Investigation ◽

10.1172/jci112886 ◽

1987 ◽

Vol 79 (3) ◽

pp. 790-800 ◽

Cited By ~ 481

Author(s):

R N Bergman ◽

R Prager ◽

A Volund ◽

J M Olefsky

Keyword(s):

Insulin Sensitivity ◽

Minimal Model ◽

Glucose Clamp ◽

Sensitivity Index ◽

Insulin Sensitivity Index ◽

Model Method

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Postprandial glucose fluxes and insulin sensitivity during exercise: A study in healthy individuals

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00182.2013 ◽

2013 ◽

Vol 305 (4) ◽

pp. E557-E566 ◽

Cited By ~ 22

Author(s):

Michele Schiavon ◽

Ling Hinshaw ◽

Ashwini Mallad ◽

Chiara Dalla Man ◽

Giovanni Sparacino ◽

...

Keyword(s):

Insulin Sensitivity ◽

Healthy Subjects ◽

Acute Exercise ◽

Glucose Production ◽

Endogenous Glucose Production ◽

Fat Free Mass ◽

Glucose Turnover ◽

Sensitivity Index ◽

Moderate Exercise ◽

Insulin Sensitivity Index

Quantifying the effect size of acute exercise on insulin sensitivity (SIexercise) and simultaneous measurement of glucose disappearance (Rd), endogenous glucose production (EGP), and meal glucose appearance in the postprandial state has not been developed in humans. To do so, we studied 12 healthy subjects [5 men, age 37.1 ± 3.1 yr, body mass index 24.1 ± 1.1 kg/m2, fat-free mass (FFM) 50.9 ± 3.9 kg] during moderate exercise at 50% V̇o2max for 75 min, 120–195 min after a triple-tracer mixed meal consumed at time 0. Tracer infusion rates were adjusted to achieve constant tracer-to-tracee ratio and minimize non-steady-state errors. Glucose turnover was estimated by accounting for the nonstationary kinetics introduced by exercise. Insulin sensitivity index was calculated in each subject both in the absence [time ( t) = 0–120 min, SIrest] and presence ( t = 0–360 min, SIexercise) of physical activity. EGP at t = 0 min (13.4 ± 1.1 μM·kg FFM−1·min−1) fell at t = 120 min (2.4 ± 0.4 μM·kg FFM−1·min−1) and then rapidly rose almost eightfold at t = 180 min (18.2 ± 2.6 μM·kg FFM−1·min−1) before gradually falling at t = 360 min (10.6 ± 0.9 μM·kg FFM−1·min−1). Rd rapidly peaked at t = 120 min at the start of exercise (89.5 ± 11.6 μM·kg FFM−1·min−1) and then gradually declined at t = 195 min (26.4 ± 3.3 μM·kg FFM−1·min−1) before returning to baseline at t = 360 min. SIexercise was significantly higher than SIrest (21.6 ± 3.7 vs. 12.5 ± 2.0 10−4 dl·kg−1·min−1 per μU/ml, P < 0.0005). Glucose turnover was estimated for the first time during exercise with the triple-tracer technique. Our results, applying state-of-the-art techniques, show that moderate exercise almost doubles postprandial insulin sensitivity index in healthy subjects.

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Associations of phthalate exposure with lipid levels and insulin sensitivity index in children: A prospective cohort study

The Science of The Total Environment ◽

10.1016/j.scitotenv.2019.01.151 ◽

2019 ◽

Vol 662 ◽

pp. 714-721 ◽

Cited By ~ 5

Author(s):

Hyejin Han ◽

Hye Ah Lee ◽

Bohyun Park ◽

Bomi Park ◽

Young Sun Hong ◽

...

Keyword(s):

Cohort Study ◽

Insulin Sensitivity ◽

Prospective Cohort Study ◽

Prospective Cohort ◽

Sensitivity Index ◽

Lipid Levels ◽

Insulin Sensitivity Index ◽

Phthalate Exposure

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Genome-Wide Association Study of the Modified Stumvoll Insulin Sensitivity Index Identifies BCL2 and FAM19A2 as Novel Insulin Sensitivity Loci

Diabetes ◽

10.2337/db16-0199 ◽

2016 ◽

Vol 65 (10) ◽

pp. 3200-3211 ◽

Cited By ~ 37

Author(s):

Geoffrey A. Walford ◽

Stefan Gustafsson ◽

Denis Rybin ◽

Alena Stančáková ◽

Han Chen ◽

...

Keyword(s):

Insulin Sensitivity ◽

Association Study ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

Sensitivity Index ◽

Insulin Sensitivity Index ◽

Genome Wide

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Relation between Birth Weight and the Insulin Sensitivity Index in a Population Sample of 331 Young, Healthy Caucasians

American Journal of Epidemiology ◽

10.1093/oxfordjournals.aje.a009188 ◽

1997 ◽

Vol 146 (1) ◽

pp. 23-31 ◽

Cited By ~ 59

Author(s):

J. O. Clausen ◽

K. Borch-Johnsen ◽

O. Pedersen

Keyword(s):

Birth Weight ◽

Insulin Sensitivity ◽

Population Sample ◽

Sensitivity Index ◽

Insulin Sensitivity Index

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The association of hyperglycaemia and insulin resistance with incident depressive symptoms over 4 years of follow-up: The Maastricht Study

Diabetologia ◽

10.1007/s00125-020-05247-9 ◽

2020 ◽

Vol 63 (11) ◽

pp. 2315-2328 ◽

Cited By ~ 2

Author(s):

Anouk F. J. Geraets ◽

Sebastian Köhler ◽

Rutendo Muzambi ◽

Casper G. Schalkwijk ◽

Anke Oenema ◽

...

Keyword(s):

Insulin Resistance ◽

Depressive Symptoms ◽

Insulin Sensitivity ◽

Cox Regression ◽

Temporal Association ◽

Sensitivity Index ◽

Skin Autofluorescence ◽

Insulin Sensitivity Index ◽

Increased Risk

Abstract Aims/hypothesis Depression is twice as common in individuals with type 2 diabetes as in the general population. However, it remains unclear whether hyperglycaemia and insulin resistance are directly involved in the aetiology of depression. Therefore, we investigated the association of markers of hyperglycaemia and insulin resistance, measured as continuous variables, with incident depressive symptoms over 4 years of follow-up. Methods We used data from the longitudinal population-based Maastricht Study (n = 2848; mean age 59.9 ± 8.1 years, 48.8% women, 265 incident depression cases, 10,932 person-years of follow-up). We assessed hyperglycaemia by fasting and 2 h post-load OGTT glucose levels, HbA1c and skin autofluorescence (reflecting AGEs) at baseline. We used the Matsuda insulin sensitivity index and HOMA-IR to calculate insulin resistance at baseline. Depressive symptoms (nine-item Patient Health Questionnaire score ≥10) were assessed at baseline and annually over 4 years. We used Cox regression analyses, and adjusted for demographic, cardiovascular and lifestyle risk factors. Results Fasting plasma glucose, 2 h post-load glucose and HbA1c levels were associated with an increased risk for incident depressive symptoms after full adjustment (HR 1.20 [95% CI 1.08, 1.33]; HR 1.25 [1.08, 1.44]; and HR 1.22 [1.09, 1.37] per SD, respectively), while skin autofluorescence, insulin sensitivity index and HOMA-IR were not (HR 0.99 [0.86, 1.13]; HR 1.02 [0.85, 1.25]; and HR 0.93 [0.81, 1.08], per SD, respectively). Conclusions/interpretation The observed temporal association between hyperglycaemia and incident depressive symptoms in this study supports the presence of a mechanistic link between hyperglycaemia and the development of depressive symptoms.

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Validation of Insulin Sensitivity Indices from Oral Glucose Tolerance Test Parameters in Obese Children and Adolescents

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2003-031503 ◽

2004 ◽

Vol 89 (3) ◽

pp. 1096-1101 ◽

Cited By ~ 210

Author(s):

Catherine W. Yeckel ◽

Ram Weiss ◽

James Dziura ◽

Sara E. Taksali ◽

Sylvie Dufour ◽

...

Keyword(s):

Insulin Sensitivity ◽

Glucose Tolerance ◽

Glucose Tolerance Test ◽

Tolerance Test ◽

Oral Glucose ◽

Sensitivity Index ◽

Intramyocellular Lipid ◽

Insulin Sensitivity Index ◽

Obese Youth ◽

Intramyocellular Lipid Content

Abstract Given the extreme increase in prediabetes, type 2 diabetes, and the potential for metabolic syndrome in obese youth, identifying simplified indexes for assessing stimulated insulin sensitivity is critical. The purpose of this study was validation of two surrogate indexes of insulin sensitivity determined from the oral glucose tolerance test (OGTT): the composite whole body insulin sensitivity index (WBISI) and the insulin sensitivity index (ISI). An obese population (aged 8–18 yr) of normal and impaired glucose tolerance individuals was studied. One group (n = 38) performed both the euglycemic-hyperinsulinemic clamp and OGTT for comparison of insulin sensitivity measurements as well as 1H-magnetic resonance spectroscopy estimates of intramyocellular lipid content. Another larger (n = 368) cohort participated only in an OGTT. Both the WBISI and ISI represented good estimates (r = 0.78 and 0.74; P < 0.0005) for clamp-derived insulin sensitivity (glucose disposed, M-value), respectively. In the large cohort, the surrogate indexes demonstrated the shift toward poorer function and increased risk profile as a function of insulin resistance. Additionally, the WBISI and ISI correlated with intramyocellular lipid content (r = −0.74 and −0.71; P < 0.0001), a tissue marker for insulin resistance. Insulin sensitivity can be estimated using plasma glucose and insulin responses derived from the OGTT in obese youth with normal and impaired glucose tolerance.

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