Homeostastic Model Assessment and Insulin Sensitivity/Resistance

Radziuk, J.

doi:10.2337/db14-0116

Cited by 40 publications

(28 citation statements)

References 35 publications

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“…We postulate that the glucose‐responsive PD effect of MK‐2640 in subjects with type 1 diabetes mostly represents hepatic insulin action. Dose‐response insulin regulation of hepatic glucose metabolism is considerably more sensitive (i.e., left‐shifted in dose‐response PD) relative to skeletal muscle, another key tissue determining insulin‐mediated glucose uptake . Based on the preclinical PK/PD studies, we posit that glucose‐responsive PK change for MK‐2640 in humans was principally generated across the hepatic bed and splanchnic tissues, but as measured in the larger systemic pool, likely were detected as smaller than what may have occurred in the key hepatic bed compartment.…”

Section: Discussionmentioning

confidence: 97%

Clinical Evaluation of MK‐2640: An Insulin Analog With Glucose‐Responsive Properties

Krug

Visser

Tsai

et al. 2018

Clin Pharma and Therapeutics

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The goal of this investigation was to examine clinical translation of glucose responsiveness of MK-2640, which is a novel insulin saccharide conjugate that can bind the insulin receptor or mannose receptor C type 1 (MRC1), the latter dependent upon glucose concentration. In a rising dose study in 36 healthy adults under euglycemic clamp conditions, rising exposures revealed saturation of MK-2640 clearance, likely due to saturation of clearance by MRC1. Potency of MK-2640 was ~25-fold reduced relative to regular human insulin. In a randomized, 2-period crossover trial in 16 subjects with type 1 diabetes mellitus to evaluate glucose-responsiveness of i.v. administered MK-2640, we were unable to demonstrate a glucose-dependent change in MK-2640 clearance, although a significant glucose-dependent augmentation of glucose infusion rate was observed. These pharmacokinetic (PK) and pharmacodynamic (PD) data provide crucial insights into next steps for developing an insulin saccharide conjugate as a clinically effective glucose-responsive insulin analog.

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Section: Discussionmentioning

confidence: 97%

Clinical Evaluation of MK‐2640: An Insulin Analog With Glucose‐Responsive Properties

Krug

Visser

Tsai

et al. 2018

Clin Pharma and Therapeutics

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“…These authors also demonstrated that VAT CSA was positively and negatively associated with fasting plasma glucose (FPG) and insulin concentrations, respectively, but not post-load indices of insulin resistance measured during an oral glucose tolerance test. As FPG concentrations have been shown to correlate with basal rates of hepatic glucose output [12] and HOMA-IR predominantly reflects hepatic insulin sensitivity [13], the associations between VAT and peripheral insulin resistance in persons with SCI remains to be assessed using a more sensitive measure of skeletal muscle/adipose tissue insulin sensitivity (i.e. intravenous glucose tolerance test; IVGTT).…”

Section: Introductionmentioning

confidence: 99%

Anthropometric cutoffs and associations with visceral adiposity and metabolic biomarkers after spinal cord injury

et al. 2018

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Background/ObjectivesTo examine associations of different anthropometric measurements of central adiposity to visceral adipose tissue (measured via multi-axial magnetic resonance imaging; MRI) and cardiometabolic disease risk factors in men with spinal cord injury (SCI). Additionally, to determine population-specific seated/supine waist and abdominal circumference cutoffs, which may identify men at increased risk of cardiometabolic disease.Participants/MethodsTwenty-two men with chronic SCI underwent MRI scans, anthropometric measurements along with assessments of various cardiometabolic risk biomarkers. Pearson/part (accounting for age as a covariate) correlation coefficients were calculated to determine the associations between study variables. Abdominal and waist circumference cutoffs were extrapolated using the slope of linear regression equations.ResultsSeated/supine abdominal and waist circumferences were (P < 0.01) associated with MRI visceral fat cross-sectional area (VATCSA), VAT volume and CSA:TotalCSA. Low density lipoprotein, non-high-density lipoprotein and total cholesterol were positively associated with seated/supine abdominal and waist circumferences after controlling for age; r = 0.50–0.61, r = 0.46–0.58, r = 0.52–0.58, P < 0.05, respectively. Tumor necrosis factor alpha was associated with seated/supine abdominal and waist circumferences after accounting for age; r = 0.49–0.51 and r = 0.48–0.56, P < 0.05 respectively. The population-specific cutoffs were 86.5cm and 88.3cm for supine waist and abdominal circumferences, respectively, as well as 89cm and 101cm for seated waist and abdominal circumferences, respectively. After dichotomizing VATCSA (< or ≥ 100cm2), peak oxygen uptake, triglycerides, insulin sensitivity and glycated hemoglobin were different (P < 0.05) between groups. After dichotomizing (< or ≥ 86.5cm) supine waist circumference, VATCSA, triglycerides and insulin sensitivity were different (P < 0.05) between groups.ConclusionsSeated/supine circumferences are associated with both central adiposity and biomarkers of cardiometabolic disease risk in persons with SCI. Population-specific cutoffs are proposed herein to identify central adiposity and potential cardiometabolic disease risk after SCI.

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“…The glucose disposal rate (GDR) was calculated during steady state conditions and is presented as milligrams of dextrose infused per kg of fat-free body mass per minute. The Insulin Sensitivity Index (ISI) is presented as the GDR of each individual normalized to her average steady state serum insulin concentration [20]. Insulin resistance was assessed for each participant using homeostatic model assessment of insulin resistance (HOMA-IR), which was calculated as the following: fasting glucose (mg/dl) × fasting insulin ( μ U/ml)/405 [21].…”

Section: Methodsmentioning

confidence: 99%

Effects of acute hyperinsulinemia on skeletal muscle mitochondrial function, reactive oxygen species production, and metabolism in premenopausal women

et al. 2017

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Background Acute metabolic demands that promote excessive and/or prolonged reactive oxygen species production may stimulate changes in mitochondrial oxidative capacity. Purpose To assess changes in skeletal muscle H2O2 production, mitochondrial function, and expression of genes at the mRNA and protein levels regulating energy metabolism and mitochondrial dynamics following a hyperinsulinemic-euglycemic clamp in a cohort of 11 healthy premenopausal women Methods Skeletal muscle biopsies of the vastus lateralis were taken at baseline and immediately following the conclusion of a hyperinsulinemic-euglycemic clamp. Mitochondrial production of H2O2 was quantified fluorometrically and mitochondrial oxidation supported by pyruvate, malate, and succinate (PMS) or palmitoyl carnitine and malate (PCM) was measured by high-resolution respirometry in permeabilized muscle fiber bundles. mRNA and protein levels were assessed by real time PCR and Western blotting. Results H2O2 emission increased following the clamp (P<0.05). Coupled respiration (State 3) supported by PMS and the respiratory control ratio (index of mitochondrial coupling) for both PMS and PCM were lower following the clamp (P<0.05). IRS1 mRNA decreased, whereas PGC1α and GLUT4 mRNA increased following the clamp (P≤0.05). PGC1α, IRS1, and phosphorylated AKT protein levels were higher after the clamp compared to baseline (P<0.05). Conclusions This study demonstrated that acute hyperinsulinemia induced H2O2 production and a concurrent decrease in coupling of mitochondrial respiration with ATP production in a cohort of healthy premenopausal women. Future studies should determine if this uncoupling ameliorates peripheral oxidative damage, and if this mechanism is impaired in diseases associated with chronic oxidative stress.

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Homeostastic Model Assessment and Insulin Sensitivity/Resistance

Cited by 40 publications

References 35 publications

Clinical Evaluation of MK‐2640: An Insulin Analog With Glucose‐Responsive Properties

Clinical Evaluation of MK‐2640: An Insulin Analog With Glucose‐Responsive Properties

Anthropometric cutoffs and associations with visceral adiposity and metabolic biomarkers after spinal cord injury

Effects of acute hyperinsulinemia on skeletal muscle mitochondrial function, reactive oxygen species production, and metabolism in premenopausal women

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