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

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.

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

Endocrinology ◽

10.1210/en.2012-1206 ◽

2012 ◽

Vol 153 (9) ◽

pp. 4216-4226 ◽

Cited By ~ 16

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.

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Peroxisome Proliferator-Activated Receptor-α Deficiency Does Not Alter Insulin Sensitivity in Mice Maintained on Regular or High-Fat Diet: Hyperinsulinemic-Euglycemic Clamp Studies

Endocrinology ◽

10.1210/en.2003-1015 ◽

2004 ◽

Vol 145 (4) ◽

pp. 1662-1667 ◽

Cited By ~ 29

Author(s):

Martin Haluzik ◽

Oksana Gavrilova ◽

Derek LeRoith

Keyword(s):

Insulin Sensitivity ◽

High Fat Diet ◽

Peroxisome Proliferator ◽

High Fat ◽

Peroxisome Proliferator Activated Receptor ◽

Euglycemic Clamp ◽

Hyperinsulinemic Euglycemic Clamp

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

Endocrine Connections ◽

10.1530/ec-13-0019 ◽

2013 ◽

Vol 2 (2) ◽

pp. 96-103 ◽

Cited By ~ 2

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.

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