Optimal Designs for Model‐Based Assessment of Insulin Sensitivity and Glucose Effectiveness

Context: Although metformin is widely used to improve insulin resistance in women with polycystic ovary syndrome (PCOS), its mechanism of action is complex, with inconsistent effects on insulin sensitivity and variability in treatment response. Objective: The aim of the study was to delineate the effect of metformin on glucose and insulin parameters, determine additional treatment outcomes, and predict patients with PCOS who will respond to treatment. Design and Setting: We conducted an open-label, interventional study at an academic medical center. Subjects: Women with PCOS (n = 36) diagnosed by the National Institutes of Health criteria participated in the study. Interventions: Subjects underwent fasting blood sampling, an IV glucose tolerance test, dual-energy x-ray absorptiometry scan, transvaginal ultrasound, and measurement of human chorionic gonadotropin-stimulated androgen levels before and after 12 weeks of treatment with metformin extended release 1500 mg/d. Interval visits were performed to monitor anthropometric measurements and menstrual cycle parameters. Main Outcome Measures: Changes in glucose and insulin parameters, androgen levels, anthropometric measurements, and ovulatory menstrual cycles were evaluated. Results: Insulin sensitivity did not change despite weight loss. Glucose effectiveness (P = .002) and the acute insulin response to glucose (P = .002) increased, and basal glucose levels (P = .001) decreased after metformin treatment. T levels also decreased. Women with improved ovulatory function (61%) had lower baseline T levels and lower baseline and stimulated T and androstenedione levels after metformin treatment (all P < .05). Conclusions: Using an IV glucose tolerance test, which distinguishes improvements in glucose effectiveness and insulin sensitivity, metformin does not improve insulin sensitivity in women with PCOS but does improve glucose effectiveness. The improvement in glucose effectiveness may be partially mediated by decreased glucose levels. T levels also decreased with metformin treatment. Ovulation during metformin treatment was associated with lower baseline T levels and greater T and androstenedione decreases during treatment, but not with insulin or LH levels. Thus, the action of metformin in PCOS primarily affects glucose levels and steroidogenesis, which may be mediated by mechanisms that affect both pathways, such as inhibition of mitochondrial complex I.

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Insulin sensitivity and sepsis score: A correlation between model-based metric and sepsis scoring system in critically ill patients

Biomedical Signal Processing and Control ◽

10.1016/j.bspc.2016.08.005 ◽

2017 ◽

Vol 32 ◽

pp. 112-123

Author(s):

Fatanah M. Suhaimi ◽

J. Geoffrey Chase ◽

Christopher G. Pretty ◽

Geoffrey M. Shaw ◽

Normy N. Razak ◽

...

Keyword(s):

Insulin Sensitivity ◽

Critically Ill ◽

Critically Ill Patients ◽

Scoring System ◽

Model Based ◽

Sepsis Score

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Effects of acute intermittent hypoxia on glucose metabolism in awake healthy volunteers

Journal of Applied Physiology ◽

10.1152/japplphysiol.91523.2008 ◽

2009 ◽

Vol 106 (5) ◽

pp. 1538-1544 ◽

Cited By ~ 198

Author(s):

Mariam Louis ◽

Naresh M. Punjabi

Keyword(s):

Obstructive Sleep Apnea ◽

Insulin Secretion ◽

Sleep Apnea ◽

Insulin Sensitivity ◽

Glucose Metabolism ◽

Healthy Volunteers ◽

Intermittent Hypoxia ◽

Metabolic Dysfunction ◽

Glucose Effectiveness ◽

Obstructive Sleep

Accumulating evidence suggests that obstructive sleep apnea is associated with alterations in glucose metabolism. Although the pathophysiology of metabolic dysfunction in obstructive sleep apnea is not well understood, studies of murine models indicate that intermittent hypoxemia has an important contribution. However, corroborating data on the metabolic effects of intermittent hypoxia on glucose metabolism in humans are not available. Thus the primary aim of this study was to characterize the acute effects of intermittent hypoxia on glucose metabolism. Thirteen healthy volunteers were subjected to 5 h of intermittent hypoxia or normoxia during wakefulness in a randomized order on two separate days. The intravenous glucose tolerance test (IVGTT) was used to assess insulin-dependent and insulin-independent measures of glucose disposal. The IVGTT data were analyzed using the minimal model to determine insulin sensitivity (SI) and glucose effectiveness (SG). Drops in oxyhemoglobin saturation were induced during wakefulness at an average rate of 24.3 events/h. Compared with the normoxia condition, intermittent hypoxia was associated with a decrease in SI [4.1 vs. 3.4 (mU/l)−1·min−1; P = 0.0179] and SG (1.9 vs. 1.3 min−1×10−2, P = 0.0065). Despite worsening insulin sensitivity with intermittent hypoxia, pancreatic insulin secretion was comparable between the two conditions. Heart rate variability analysis showed the intermittent hypoxia was associated with a shift in sympathovagal balance toward an increase in sympathetic nervous system activity. The average R-R interval on the electrocardiogram was 919.0 ms during the normoxia condition and 874.4 ms during the intermittent hypoxia condition ( P < 0.04). Serum cortisol levels after intermittent hypoxia and normoxia were similar. Hypoxic stress in obstructive sleep apnea may increase the predisposition for metabolic dysfunction by impairing insulin sensitivity, glucose effectiveness, and insulin secretion.

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Changes in Identified, Model-based Insulin Sensitivity can be used to Improve Risk and Variability Forecasting in Glycaemic Control

IFAC-PapersOnLine ◽

10.1016/j.ifacol.2018.09.153 ◽

2018 ◽

Vol 51 (15) ◽

pp. 311-316 ◽

Cited By ~ 1

Author(s):

Vincent Uyttendaele ◽

Jennifer L. Dickson ◽

Sophie Morton ◽

Geoffrey Shaw ◽

Thomas Desaive ◽

...

Keyword(s):

Insulin Sensitivity ◽

Glycaemic Control ◽

Model Based

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Modelling the effects of glucagon during glucose tolerance testing

Theoretical Biology and Medical Modelling ◽

10.1186/s12976-019-0115-3 ◽

2019 ◽

Vol 16 (1) ◽

Author(s):

Ross A. Kelly ◽

Molly J. Fitches ◽

Steven D. Webb ◽

S. R. Pop ◽

Stewart J. Chidlow

Keyword(s):

Insulin Sensitivity ◽

Glucose Tolerance ◽

Mathematical Models ◽

Linear Relationship ◽

Insulin Infusion ◽

Glucose Tolerance Test ◽

Tolerance Test ◽

Glucose Kinetics ◽

Glucose Effectiveness ◽

Tolerance Testing

Abstract Background Glucose tolerance testing is a tool used to estimate glucose effectiveness and insulin sensitivity in diabetic patients. The importance of such tests has prompted the development and utilisation of mathematical models that describe glucose kinetics as a function of insulin activity. The hormone glucagon, also plays a fundamental role in systemic plasma glucose regulation and is secreted reciprocally to insulin, stimulating catabolic glucose utilisation. However, regulation of glucagon secretion by α-cells is impaired in type-1 and type-2 diabetes through pancreatic islet dysfunction. Despite this, inclusion of glucagon activity when modelling the glucose kinetics during glucose tolerance testing is often overlooked. This study presents two mathematical models of a glucose tolerance test that incorporate glucose-insulin-glucagon dynamics. The first model describes a non-linear relationship between glucagon and glucose, whereas the second model assumes a linear relationship. Results Both models are validated against insulin-modified and glucose infusion intravenous glucose tolerance test (IVGTT) data, as well as insulin infusion data, and are capable of estimating patient glucose effectiveness (sG) and insulin sensitivity (sI). Inclusion of glucagon dynamics proves to provide a more detailed representation of the metabolic portrait, enabling estimation of two new diagnostic parameters: glucagon effectiveness (sE) and glucagon sensitivity (δ). Conclusions The models are used to investigate how different degrees of pax‘tient glucagon sensitivity and effectiveness affect the concentration of blood glucose and plasma glucagon during IVGTT and insulin infusion tests, providing a platform from which the role of glucagon dynamics during a glucose tolerance test may be investigated and predicted.

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