Kirsten A. McAuley

Overweight and obese children have low bone mass and area for their weight

OBJECTIVES: To determine whether girls and boys categorized from body mass index (BMI) values as overweight or obese for their age have lower bone mineral content (BMC) or lower bone area in relation to total body weight than children of normal adiposity.DESIGN: Cross-sectional study in a university bone research unit.SUBJECTS: Two hundred girls and 136 boys aged 3–19 y recruited from the general population by advertisement.MEASUREMENTS: Total body BMC (g) and bone area (cm2) measured by dual energy X-ray absorptiometry (DXA) in relation to body weight (kg), lean tissue mass (kg) and fat mass (kg) in boys and girls of three different BMI percentile groupings: normal weight (BMI<85th percentile); overweight (85 to 94th BMI percentile); obese (≥95th BMI percentile).RESULTS: Obese children had higher BMC, bone area, and fat mass for chronological age than those of normal body weight (P<0.001). In spite of this the observed values for age-adjusted total body BMC and bone area relative to body weight were each lower than predicted values, in both overweight and obese children (2.5–10.1% less, P<0.05) than in children of lower adiposity.CONCLUSION: In overweight and obese boys and girls there is a mismatch between body weight and bone development during growth: their bone mass and bone area are low for their body weight.

Long-term effects of popular dietary approaches on weight loss and features of insulin resistance

Objective:High-carbohydrate (HC)–high-fibre diets are recommended for weight loss and for treating and preventing diseases such as diabetes and cardiovascular disease. We report a randomised trial comparing high-fat (HF) and high-protein (HP) diets with the conventional approach.Research design and methods:A total of 93 overweight insulin-resistant women received advice following randomisation to HF, HP or HC dietary regimes, to achieve weight loss followed by weight maintenance over 12 months. Weight, body composition and measures of carbohydrate and lipid metabolism were investigated.Results:Retention rates were 93% for HP and 75% for HC and HF. Features of the metabolic syndrome improved in all groups during the first 6 months, to a greater extent on HF and HP than an HC. During the second 6 months the HF group had increases in waist circumference (mean difference 4.4 cm (95% CI 3.0, 5.8)), fat mass (2.3 kg (1.5, 3.1)), triglycerides (0.28 mmol/l (0.09, 0.46)) and 2 h glucose (0.70 mmol/l (0.22, 1.18)). Overall there was substantial sustained improvement in waist circumference, triglycerides and insulin in the HP group and sustained but more modest changes on HC. Dietary compliance at 12 months was poor in all groups.Conclusions:HP and HC approaches appear to be appropriate options for insulin-resistant individuals. When recommending HP diets appropriate composition of dietary fat must be ensured. HC diet recommendations must include advice regarding appropriate high-fibre, low glycaemic index foods.

Monte Carlo analysis of a new model-based method for insulin sensitivity testing

Insulin resistance (IR), or low insulin sensitivity, is a major risk factor in the pathogenesis of type 2 diabetes and cardiovascular disease. A simple, high resolution assessment of IR would enable earlier diagnosis and more accurate monitoring of intervention effects. Current assessments are either too intensive for clinical settings (Euglycaemic Clamp, IVGTT) or have too low resolution (HOMA, fasting glucose/insulin). Based on high correlation of a model-based measure of insulin sensitivity and the clamp, a novel, clinically useful test protocol is designed with: physiological dosing, short duration (<1 h), simple protocol, low cost and high repeatability. Accuracy and repeatability are assessed with Monte Carlo analysis on a virtual clamp cohort (N=146). Insulin sensitivity as measured by this test has a coefficient of variation (CV) of CV(SI)=4.5% (90% CI: 3.8-5.7%), slightly higher than clamp ISI (CV(ISI)=3.3% (90% CI: 3.0-4.0%)) and significantly lower than HOMA (CV(HOMA)=10.0% (90% CI: 9.1-10.8%)). Correlation to glucose and unit normalised ISI is r=0.98 (90% CI: 0.97-0.98). The proposed protocol is simple, cost effective, repeatable and highly correlated to the gold-standard clamp.

Thematic review series: Patient-Oriented Research. Nutritional determinants of insulin resistance

Interpreting the literature relating to the nutritional determinants of insulin resistance is complicated by the wide range of methods used to determine insulin sensitivity. Excess adiposity is unquestionably the most important determinant of insulin resistance, although the effect may be tempered by a relatively high proportion of lean body mass. Weight loss is associated with improved insulin sensitivity. Thus, diet-related factors that promote excessive energy intake may be regarded as promoters of insulin resistance. In the context of energy balance, diets characterized by high intakes of saturated fat and low intakes of dietary fiber are associated with reduced insulin sensitivity. Total fat intakes greater than the usually consumed range appear to promote insulin resistance, although the relative proportions of total fat and carbohydrate within the usual range appear unimportant. Monounsaturated fatty acids with a cis configuration and fiber-rich carbohydrate foods appear to be appropriate substitutes for saturated fatty acids and rapidly digested glycemic carbohydrates. In animal studies, n-3 unsaturated fatty acids have been shown to enhance insulin sensitivity and fructose and sucrose to increase insulin resistance. However, human data are limited. Large prospective studies currently being conducted should confirm the most appropriate macronutrient composition of diets for preventing and treating insulin resistance as well as establishing whether a range of candidate genes explains the variation in response to dietary change.

Determining optimal approaches for weight maintenance: a randomized controlled trial

Background: Weight regain often occurs after weight loss in overweight individuals. We aimed to compare the effectiveness of 2 support programs and 2 diets of different macronutrient compositions intended to facilitate long-term weight maintenance. Methods: Using a 2 × 2 factorial design, we randomly assigned 200 women who had lost 5% or more of their initial body weight to an intensive support program (implemented by nutrition and activity specialists) or to an inexpensive nurse-led program (involving “weigh-ins” and encouragement) that included advice about high-carbohydrate diets or relatively high-monounsaturated-fat diets. Results: In total, 174 (87%) participants were followed-up for 2 years. The average weight loss (about 2 kg) did not differ between those in the support programs (0.1 kg, 95% confidence interval [CI] −1.8 to 1.9, p = 0.95) or diets (0.7 kg, 95% CI −1.1 to 2.4, p = 0.46). Total and low-density lipoprotein (LDL) cholesterol levels were significantly higher among those on the high-monounsaturated-fat diet (total cholesterol: 0.17 mmol/L, 95% CI 0.01 to 0.33; p = 0.040; LDL cholesterol: 0.16 mmol/L, 95% CI 0.01 to 0.31; p = 0.039) than among those on the high-carbohydrate diet. Those on the high-monounsaturated-fat diet also had significantly higher intakes of total fat (5% total energy, 95% CI 3% to 6%, p < 0.001) and saturated fat (2% total energy, 95% CI 1% to 2%, p < 0.001). All of the other clinical and laboratory measures were similar among those in the support programs and diets. Interpretation: A relatively inexpensive program involving nurse support is as effective as a more resource-intensive program for weight maintenance over a 2-year period. Diets of different macronutrient composition produced comparable beneficial effects in terms of weight loss maintenance. ClinicalTrials.gov trial register no. NCT00128336.

Point: HOMA—Satisfactory for the Time Being HOMA: The best bet for the simple determination of insulin sensitivity, until something better comes along

There is no doubt that the cluster of clinical and metabolic features associated with insulin resistance predicts risk of developing type 2 diabetes and cardiovascular disease (CVD) (1); however, whether there is merit in defining a syndrome is less clear (2). There is also a lack of agreement regarding the value of measuring insulin sensitivity in clinical practice (3). The widely used criteria for defining the metabolic syndrome (those recommended by the World Health Organization [4] and the Adult Treatment Panel III [5]) includes a measure of insulin resistance in the definition of the syndrome. A very recent approach suggested by a group representing the International Diabetes Federation involves identifying individuals with central obesity and a range of clinical and metabolic parameters associated with insulin resistance; however, it does not include a direct measure of insulin sensitivity (6). It is argued that measures of insulin resistance do not predict CVD when other more easily measured components of the metabolic syndrome cluster are present, and these measures based on fasting insulin are unreliable (3). However, measurement of insulin sensitivity has greatly enhanced the understanding of the pathophysiology of diabetes and relationships to cardiovascular outcomes (7). Dismissing the assessment of insulin sensitivity because its measurement is too variable or difficult (3) is understandable, but hardly desirable, as one major dimension of altered metabolism will be omitted from research and clinical assessments. It may prove to be much the same as assessing cardiovascular risk without serum cholesterol. A truly reliable simple measure may prove to be more appropriate than an aggregation of surrogates in predicting subsequent development of diabetes and CVD and in further explaining disease progression and response to treatment. Several reviews (8,9) describe some of the numerous methods for measuring or estimating insulin sensitivity. The …

Design and clinical pilot testing of the model-based Dynamic Insulin Sensitivity and Secretion Test (DISST)

Background: Insulin resistance is a significant risk factor in the pathogenesis of type 2 diabetes. This article presents pilot study results of the dynamic insulin sensitivity and secretion test (DISST), a high-resolution, low-intensity test to diagnose insulin sensitivity (IS) and characterize pancreatic insulin secretion in response to a (small) glucose challenge. This pilot study examines the effect of glucose and insulin dose on the DISST, and tests its repeatability. Methods: DISST tests were performed on 16 subjects randomly allocated to low (5 g glucose, 0.5 U insulin), medium (10 g glucose, 1 U insulin) and high dose (20 g glucose, 2 U insulin) protocols. Two or three tests were performed on each subject a few days apart. Results: Average variability in IS between low and medium dose was 10.3% (p = .50) and between medium and high dose 6.0% (p = .87). Geometric mean variability between tests was 6.0% (multiplicative standard deviation (MSD) 4.9%). Geometric mean variability in first phase endogenous insulin response was 6.8% (MSD 2.2%). Results were most consistent in subjects with low IS. Conclusions: These findings suggest that DISST may be an easily performed dynamic test to quantify IS with high resolution, especially among those with reduced IS.

DISTq: An Iterative Analysis of Glucose Data for Low-Cost, Real-Time and Accurate Estimation of Insulin Sensitivity

Insulin sensitivity (SI) estimation has numerous uses in medical and clinical situations. However, highresolution tests that are useful for clinical diagnosis and monitoring are often too intensive, long and costly for regular use. Simpler tests that mitigate these issues are not accurate enough for many clinical diagnostic or monitoring scenarios. The gap between these tests presents an opportunity for new approaches. The quick dynamic insulin sensitivity test (DISTq) utilises the model-based DIST test protocol and a series of population estimates to eliminate the need for insulin or C-peptide assays to enable a high resolution, low-intensity, real-time evaluation of SI. The method predicts patient specific insulin responses to the DIST test protocol with enough accuracy to yield a useful clinical insulin sensitivity metric for monitoring of diabetes therapy. The DISTq method replicated the findings of the fully sampled DIST test without the use of insulin or C-peptide assays. Correlations of the resulting SI values was R=0.91. The method was also compared to the euglycaemic hyperinsulinaemic clamp (EIC) in an in-silico Monte-Carlo analysis and showed a good ability to re-evaluate SIEIC (R=0.89), compared to the fully sampled DIST (R=0.98) Population-derived parameter estimates using a-posteriori population-based functions derived from DIST test data enables the simulation of insulin profiles that are sufficiently accurate to estimate SI to a relatively high precision. Thus, costly insulin and C-peptide assays are not necessary to obtain an accurate, but inexpensive, real-time estimate of insulin sensitivity. This estimate has enough resolution for SI prediction and monitoring of response to therapy. In borderline cases, re-evaluation of stored (frozen) blood samples for insulin and C-peptide would enable greater accuracy where necessary, enabling a hierarchy of tests in an economical fashion.

The dynamic insulin sensitivity and secretion test--a novel measure of insulin sensitivity.

The objective was to validate the methodology for the dynamic insulin sensitivity and secretion test (DISST) and to demonstrate its potential in clinical and research settings. One hundred twenty-three men and women had routine clinical and biochemical measurements, an oral glucose tolerance test, and a DISST. For the DISST, participants were cannulated for blood sampling and bolus administration. Blood samples were drawn at t = 0, 10, 15, 25, and 35 minutes for measurement of glucose, insulin, and C-peptide. A 10-g bolus of intravenous glucose at t = 5 minutes and 1 U of intravenous insulin immediately after the t = 15 minute sample were given. Fifty participants also had a hyperinsulinemic-euglycemic clamp. Relationships between DISST insulin sensitivity (SI) and the clamp, and both DISST SI and secretion and other metabolic variables were measured. A Bland-Altman plot showed little bias in the comparison of DISST with the clamp, with DISST underestimating the glucose clamp by 0.1·10(-2)·mg·L·kg(-1)·min(-1)·pmol(-1) (90% confidence interval, -0.2 to 0). The correlation between SI as measured by DISST and the clamp was 0.82; the c unit for the receiver operating characteristic curve analysis for the 2 tests was 0.96. Metabolic variables showed significant correlations with DISST SI and the second phase of insulin release. The DISST also appears able to distinguish different insulin secretion patterns in individuals with identical SI values. The DISST is a simple, dynamic test that compares favorably with the clamp in assessing SI and allows simultaneous assessment of insulin secretion. The DISST has the potential to provide even more information about the pathophysiology of diabetes than more complicated tests.

Body mass index and waist circumference cutoffs to define obesity in indigenous New Zealanders

BACKGROUND The suggestion that body mass index (BMI) cutoffs to define obesity should differ in persons of Polynesian descent compared with Europeans is based principally on the observation that persons of Polynesian descent have a relatively higher proportion of lean body mass for a given BMI. OBJECTIVES The objectives were to determine whether the relation between BMI, waist circumference, and metabolic comorbidity differs in the 2 major ethnic groups in New Zealand and to ascertain whether ethnicity-specific BMI and waist circumference cutoffs for obesity are justified for Māori (indigenous New Zealanders). DESIGN Subjects included a convenience sample of 1539 men and women aged 17-82 y (47% Māori, 53% white) with measures of BMI, waist circumference, blood pressure, fasting insulin, glucose, and lipids. The sensitivity and specificity of BMI (in kg/m(2); 30 and 32), waist circumference (80 and 88 cm in women, 94 and 102 cm in men), and waist-to-height ratio (WHtR; > or =0.6) in relation to insulin sensitivity, insulin resistance, and the metabolic syndrome were determined. Receiver operating characteristic curves and areas under the curve (AUCs) were also calculated. RESULTS No ethnic or sex differences between AUCs were observed for BMI, waist circumference, or WHtR, which showed that these anthropometric measures perform similarly in Māori and European men and women and correctly discriminate between those with and without insulin resistance or the metabolic syndrome 79-87% of the time. Any increase in specificity from a higher BMI cutoff of 32 in Māori was offset by appreciable reductions in sensitivity. CONCLUSION These findings argue against having different BMI or waist circumference cutoffs for people of Polynesian descent.