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Prader-Willi syndrome (PWS) is the predominant genetic cause of obesity in humans. Recent clinical reports have suggested that micro-deletion of the Snord116 gene cluster can lead to PWS, however, the extent of the contributions of the encoded snoRNAs is unknown. Here we show that mice lacking Snord116 globally have low birth weight, increased body weight gain, energy expenditure and hyperphagia. Consistent with this, microarray analysis of hypothalamic gene expression revealed a significant alteration in feeding related pathways that was also confirmed by in situ hybridisation. Importantly, selective deletion of Snord116 only from NPY expressing neurons mimics almost exactly the global deletion phenotype including the persistent low birth weight, increased body weight gain in early adulthood, increased energy expenditure and hyperphagia. Mechanistically, the lack of Snord116 in NPY neurons leads to the upregulation of NPY mRNA consistent with the hyperphagic phenotype and suggests a critical role of Snord116 in the control of NPY neuronal functions that might be dysregulated in PWS.

Prader-Willi syndrome (PWS) is the predominant genetic cause of obesity in humans and is associated with several behavioural phenotypes such as altered motoric function, reduced activity, and learning disabilities. It can include mood instability and, in some cases, psychotic episodes. Recently, the Snord116 gene has been associated with the development of PWS, however, it's contribution to the behavioural aspects of the disease are unknown. Here we show that male and female mice lacking Snord116 on both alleles exhibit normal motor behaviours and exploration but do display task-dependent alterations to locomotion and anxiety-related behaviours. Sociability is well developed in Snord116 deficient mice as are social recognition memory, spatial working memory, and fear-associated behaviours. No sex-specific effects were found. In conclusion, the biallelic Snord116 deficiency mouse model exhibits particular endophenotypes with some relevance to PWS, suggesting partial face validity for the syndrome.

Adiponectin has anti-inflammatory and anti-atherogenic properties in addition to its acknowledged roles in insulin sensitivity and energy homeostasis. These properties include the suppression of lipopolysaccharide [LPS]-mediated inflammatory events. We demonstrated that both recombinant and native adiponectin directly bind LPS derived from three different bacteria. The interaction occurred at pH 5.0–6.0 and was inhibited by the presence of Ca2+ and Mg2+, but enhanced by the sequestration of these cations. Maximal binding occurred at pH 6.0 in the presence of ethylenediaminetetraacetic acid. Lipid A and C1q were not inhibitory, although LPS, heparin, zymosan, and individual sugars all inhibited the reaction. Periodate-mediated deglycosylation of adiponectin, and reduction and alkylation also inhibited binding. Since adiponectin infiltrates into [relatively] acidic sites of inflammation, it may act as a scavenging anti-inflammatory agent in atherosclerosis and vascular damage where LPS [and other pro-inflammatory molecules] are present.

Objective: Little is known of the metabolism of different isoforms of adiponectin. We therefore (a) characterised the size distribution of human adiponectin in relation to gender, body composition and following a challenge with a fat meal or oral glucose in humans, and (b) studied the metabolism of isoforms of human adiponectin in rabbits.Method: Electrophoresis, blotting and chromatography were used to characterise human adiponectin in 36 healthy subjects, including 15 with at least two first-degree relatives with type 2 diabetes, before and after consumption of a fatty meal or glucose. The metabolism of column-fractionated human adiponectin was studied in rabbits, some of which were coinjected with insulin.Results: Females had a higher proportion of high molecular weight (HMW) and hexameric adiponectin (P= 0.002 and 0.004 respectively), and a lower proportion of trimers (P< 0.0001) than males. Females also showed a strong negative relationship between body fat measures and the proportion of HMW adiponectin. There were no differences in isoforms between insulin-resistant and -sensitive subjects, or following oral glucose or a fat meal. Adiponectin in rabbits had an extravascular/intravascular ratio of 0.71, and a half-life (T1/2) of 14.3 h. Metabolism was not influenced by insulin or reduction of sulphydryl bonds. HMW and trimeric isoforms had a significantly different T1/2 of 13.0 and 17.5 h respectively (P< 0.05), and these isoforms did not interconvertin vivo.Conclusions: Human adiponectin is present as trimers, hexamers and HMW forms. Females had a higher proportion and absolute amount of HMW species compared with males, and female, but not male, subjects showed a strong negative relationship between measures of body fat, and the proportion of HMW species. These isoforms did not respond to challenge in man with a fatty meal or oral glucose, and in the rabbit, to injected insulin. HMW adiponectin was more rapidly metabolised than the trimeric form, but both were stablein vivo, and did not interconvert. We conclude that human adiponectin is much longer-lived than is the case with other hormones, a finding with positive implications for the potential to supplement levels of adiponectin in man.

Renal failure is associated with a range of metabolic abnormalities including insulin resistance and dyslipidemia. We examined the role of creatinine clearance (CrCl) and body composition in the development of insulin resistance in patients with primary renal disease and a variable degree of renal failure. We also determined the effect of a high-fat meal on postprandial triglyceride levels in a subgroup of these patients.Forty-four patients with primary renal disease (men, 25; women, 19; age, 21-75 years) were compared to 44 controls matched for age, sex, and body composition. Renal biochemistry, plasma glucose, insulin, lipids, and nonesterified fatty acids were measured in the fasting state. Insulin sensitivity was calculated using the Homeostasis Model Assessment for Insulin Resistance (HOMA-R), and pancreatic beta-cell secretory capacity by HOMA- beta . Fourteen normotriglyceridemic subjects from each group consumed an 80-g fat meal to examine their postprandial metabolic response.Although there was no significant difference between HOMA-R for the controls and the entire patient group ( P = .06), HOMA-R was significantly higher in patients with CrCl less than 60 mL/min than those with CrCl greater than 60 mL/min or control subjects ( P.01 for each pair). Exponential analysis of the relationship between CrCl and HOMA-R and - beta showed a line of best fit that was superior to that obtained by linear regression analysis ( P.01 and P.005, respectively). HOMA-R in renal patients was correlated with several parameters of body composition, including central fat (kilogram) ( P.005). There was no difference in body fat parameters or HOMA-R for the patient and control subgroups undergoing a fat meal challenge. However, the patient subgroup showed a greater postprandial incremental rise in plasma triglycerides compared to controls ( P.02).Patients with renal disease exhibit metabolic features typically associated with the metabolic syndrome. Insulin resistance increased with decline in renal function and was significantly higher in patients with CrCl less than 60 mL/min compared to subjects with CrCl greater than 60 mL/min or carefully matched controls. Renal patients also showed significant postprandial hypertriglyceridemia.

Background Higher postprandial triglyceride responses reported in first degree relatives of people with type 2 diabetes (REL) were postulated to be the result of an early, possibly intrinsic, defect in oral lipid handling. The postprandial triglyceride response to high fat meals (HFM) in normal subjects is reduced by the insulin response to dietary carbohydrate (CHO) in the meal. The aims of this study were to examine whether (1) insulin resistance is associated with an intrinsic defect in triglyceride handling in insulin-resistant REL and (2) insulin resistance is associated with altered triglyceride handling after HFM with high CHO content. Materials and methods Postprandial responses to a HFM in normolipidaemic, normoglycaemic REL were compared with subjects without a family history of diabetes mellitus (CON). Over 6 h, the insulin, glucose, triglyceride and nonesterified fatty acid (NEFA) responses after a high fat (80 g fat), low CHO (HFM-LC; 20 g CHO, 4250 kJ) meal and a high fat, high CHO (HFM-HC; 100 g CHO, 5450 kJ) meal were examined. Results The 10 (7F/3M) REL were significantly more insulin-resistant, determined by glucose infusion during a hyperinsulinaemic euglycaemic clamp than the 10 (5F/5M) CON (glucose infusion rate 44·6 ± 4·9 vs. 60·0 ± 4·8 µmol min−1 kg FFM−1, P = 0·037). Subjects were similar for age and body mass index (BMI). The triglyceride increments after the HFM-LC were similar in both, peaking at 180–240 min (Δ0·77 ± 0·11 mmol L−1), demonstrating no postprandial defect in REL, despite insulin resistance. There was a significantly lower postprandial triglyceride response in CON following the HFM-HC compared with the HFM-LC, but not in REL. In contrast, the higher insulin level during the HFM-HC was associated with significantly greater NEFA level suppression than in the HFM-LC (2·13 ± 0·51 vs. 0·70 ± 0·35 mmol L−1, P = 0·03), only in the REL. Conclusions These results are inconsistent with a primary aetiological role for postprandial hypertriglyceridaemia in already insulin resistant type 2 diabetic REL, but raise the possibility that this potentially atherogenic manifestation is secondary to insulin resistance lessening VLDL production and/or release from the liver.

The aims of this study were to determine the influence of smoking, alcohol consumption, physical activity and hormone replacement therapy (HRT) on lipids, independently of genetic factors, and to detect whether gene-environment interactions influence these associations.Fasting plasma total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, apolipoproteins AI and B and lipoprotein(a) were measured in 685 female twins (96 monozygotic, 230 dizygotic pairs and 33 singletons).Smokers had higher triglyceride and lower HDL cholesterol levels than never-smokers (P0.001). After controlling for genetic influences, smoking accounted for 0.35 mmol L(-1) and 0.22 mmol L(-1) differences in triglyceride and HDL cholesterol levels, respectively (P0.005), remaining significant after excluding alcohol-discordant twin pairs. In a gene-environment interaction analysis, the association between smoking and triglycerides was exaggerated in subjects at high genetic risk of hypertriglyceridaemia (interaction P=0.04). All levels of alcohol consumption were associated with higher HDL cholesterol levels than abstinence, but only moderate alcohol consumers had lower LDL cholesterol and triglyceride levels. In monozygotic twins concordant for smoking, an alcohol intake10 units week(-1) accounted for a 0.32 mmol L(-1) difference in LDL cholesterol, independently of genetic effects (P=0.04). In postmenopausal women, those using HRT had 0.54 mmol L(-1) lower LDL cholesterol and 0.21 micromol L(-1) lower lipoprotein(a) levels than nonusers (P0.001 and P=0.04, respectively); these differences were attenuated after accounting for genetic effects in monozygotic twins. Although physically active subjects had higher levels of HDL cholesterol than nonactive subjects, this was nonsignificant after adjusting for genetic factors.Smoking-induced aberrations in HDL cholesterol and triglycerides and alcohol-related differences in LDL cholesterol were independent of genetic influences. The association between smoking and hypertriglyceridaemia was accentuated in high genetic risk individuals.

OBJECTIVE—Inflammatory markers such as C-reactive protein (CRP) are associated with insulin resistance, adiposity, and type 2 diabetes. Whether inflammation causes insulin resistance or is an epiphenomenon of obesity remains unresolved. We aimed to determine whether first-degree relatives of type 2 diabetic subjects differ in insulin sensitivity from control subjects without a family history of diabetes, whether first-degree relatives of type 2 diabetic subjects and control subjects differ in CRP, adiponectin, and complement levels, and whether CRP is related to insulin sensitivity independently of adiposity. RESEARCH DESIGN AND METHODS—We studied 19 young normoglycemic nonobese first-degree relatives of type 2 diabetic subjects and 22 control subjects who were similar for age, sex, and BMI. Insulin sensitivity (glucose infusion rate [GIR]) was measured by the euglycemic-hyperinsulinemic clamp. Dual-energy X-ray absorptiometry determined total and abdominal adiposity. Magnetic resonance imaging measured abdominal adipose tissue volumes. RESULTS—First-degree relatives of type 2 diabetic subjects had a 20% lower GIR than the control group (51.8 ± 3.9 vs. 64.9 ± 4.6 μmol · min−1 · kg fat-free mass−1, P = 0.04). However, first-degree relatives of subjects with type 2 diabetes and those without a family history of diabetes had normal and comparable levels of CRP, adiponectin, and complement proteins. When the cohort was examined as a whole, CRP was inversely related to GIR (r = −0.33, P = 0.04) and adiponectin (r = −0.34, P = 0.03) and positively related to adiposity (P < 0.04). However, CRP was not related to GIR independently of fat mass. In contrast to C3 (r = 0.41, P = 0.009) and factor B (r = 0.43, P = 0.005), CRP was unrelated to factor D. CONCLUSIONS—The insulin-resistant state is not associated with changes in inflammatory markers or complement proteins in subjects at high risk of type 2 diabetes. Our study confirms a strong relationship between CRP and fat mass. Increasing adiposity and insulin resistance may interact to raise CRP levels.

Type II diabetes is a common, complex and heterogeneous group of disorders of growing public health concern. Paradoxically, rare monogenic forms of diabetes mellitus have been the most informative regarding diabetes pathophysiology to date. We discuss disappointing results of genetic approaches thus far, emphasizing the genetic heterogeneity underlying the common phenotypic endpoint of elevated blood glucose level and the phenotypic misclassification in large studies resulting from this admixture and from the obligatory use of epidemiological or clinical surrogate measures. We suggest that novel approaches that take explicit account of the phenotypic, environmental and genetic complexities of type II diabetes are needed and discuss some principles that might underlie such approaches.

Objective: Abdominal fat and myocyte triglyceride levels relate negatively to insulin sensitivity, but their interrelationships are inadequately characterized in the overweight. Using recent methods for measuring intramyocyte triglyceride, these relationships were studied in men with a broad range of adiposity. Research Methods and Procedures: Myocyte triglyceride content (1H-magnetic resonance spectroscopy of soleus and tibialis anterior muscles and biochemical assessment of vastus lateralis biopsies), regional fat distribution (DXA and abdominal magnetic resonance imaging), serum lipids, insulin action (euglycemic hyperinsulinemic clamp), and substrate oxidation rates (indirect calorimetry) were measured in 39 nondiabetic men (35.1 ± 7.8 years) with a broad range of adiposity (BMI 28.6 ± 4.1 kg/m2, range 20.1 to 37.6 kg/m2). Results: Relationships between insulin-stimulated glucose disposal and regional body fat depots appeared more appropriately described by nonlinear than linear models. When the group was subdivided using median total body fat as the cut-point, insulin-stimulated glucose disposal correlated negatively to all regional body fat measures (all p ≤ 0.004), serum triglycerides and free fatty acids (p < 0.02), and both soleus intramyocellular lipid (p = 0.003) and vastus lateralis triglyceride (p = 0.04) in the normal/less overweight group. In contrast, only visceral abdominal fat showed significant negative correlation with insulin-stimulated glucose disposal in more overweight men (r = −0.576, p = 0.01), some of whom surprisingly had lower than expected myocyte lipid levels. These findings persisted when the group was subdivided using different cut-points or measures of adiposity. Discussion: Interrelationships among body fat depots, myocyte triglyceride, serum lipids, and insulin action are generally absent with increased adiposity. However, visceral abdominal fat, which corresponds less closely to total adiposity, remains an important predictor of insulin resistance in men with both normal and increased adiposity.

It has been noted since the earliest European contact that Polynesian body shape and size differ from those of Europeans. The muscular build of Polynesians, such as Tongans, raises questions as to the accuracy of simple anthropometric indicators, validated for use in European populations, in Polynesians. Body mass index (BMI), total body fat and an abdominal fat window were measured in a sample of Tongan [28 male (M), 28 female (F)] and Australian Caucasian adults (39 M, 46 F), with standard anthropometric and densitometric methods. Tongan males (BMI, 32.8+/-4.6 kg/m(2)) were heavier than Australian males (BMI, 27.1+/-3.7 kg/m(2)); but differences in total body percent fat (28.9+/-8.3 vs. 25.9+/-8.1, p=0.15), abdominal fat (1.84+/-0.69 vs. 1.55+/-0.60 kg, p=0.07) and abdominal percent fat (30.3+/-8.6 vs. 28.5+/-8.3, p=0.40) were non-significant. Tongan females (BMI, 34.3+/-5.5 kg/m(2)) were also heavier than their Australian counterparts (BMI, 26.2+/-6.3 kg/m(2)); with the difference in total body percent fat (41.9+/-5.2 vs. 38.7+/-8.9, p=0.05) and abdominal percent fat (39.3+/-4.8 vs. 33.6+/-8.9, p=0.001) less than expected, given the difference in BMI. This study demonstrates significant body composition variations between Tongans and Caucasians.

OBJECTIVE—To investigate 1) associations between environmental factors (alcohol consumption, hormone replacement therapy [HRT], and physical activity) and insulin resistance and secretion, independent of genetic influences; 2) the contribution of abdominal adiposity to these relationships; and 3) whether gene-environment interactions mediate these associations. RESEARCH DESIGN AND METHODS—Reported effects of lifestyle factors on insulin resistance and secretion are inconsistent, possibly due to difficulty in dissecting environmental from genetic influences and to confounding by adiposity. We examined these relationships in 798 nondiabetic female twins. Insulin resistance and secretion were estimated by modified homeostasis model assessment (HOMA-R′ and HOMA-β′, respectively). Percent total body fat and percent central abdominal fat (CAF) were measured by dual-energy X-ray absorptiometry. RESULTS—All categories of alcohol consumption were associated with lower insulin levels and HOMA-β′ than abstinence. Only moderate alcohol consumers (11–20 units/week) had lower HOMA-R′ than abstainers (−0.16 ± 0.09 vs. 0.14 ± 0.13 SD, P = 0.048). This difference was attenuated after controlling for percent CAF (P = 0.57), which was lower in moderate drinkers. Controlling for genetic and smoking effects in cotwin case-control analysis, monozygotic pairs discordant for alcohol consumption had greater within-pair differences in HOMA-R′ than concordant pairs (P = 0.02). Postmenopausal women using estrogen-only HRT had lower HOMA-R′ than non–HRT users (−0.33 ± 0.16 vs. 0.17 ± 0.08 SD, P = 0.003), even after controlling for percent CAF. Lower fasting glucose levels and insulin resistance and secretion indexes in physically active subjects were partly explained by lower abdominal adiposity. CONCLUSIONS—Moderate alcohol consumption, estrogen replacement, and physical activity are associated with increased insulin sensitivity in female twins. The favorable effects of moderate alcohol consumption and physical activity on insulin sensitivity are partly mediated by lower abdominal adiposity.

OBJECTIVE: To investigate whether normal glucose-tolerant and type II diabetic overweight adults differ in response to weight regain with regard to substrate oxidation and metabolic parameters. METHODS: A total of 15 overweight-obese subjects: seven normal glucose tolerant (NGT) and eight with type II diabetes (DM) were restudied 5 y after significant weight loss. Prediet, after 28 days calorie restriction and at 5 y, subjects were characterised for weight, height, waist-to-hip ratio (WHR) and body composition by dual-energy X-ray absorptiometry. Fasting glucose, insulin, leptin and lipid levels were measured and subjects underwent euglycaemic–hyperinsulinaemic clamp (insulin 0.25 U/kg/h for 150 min). Indirect calorimetry was performed resting and in the final 30 min of the clamp. Dietary assessment was by 4-day diet-diary. RESULTS: Both NGT and DM groups regained weight at 5 y and were not different to prediet. Total body fat (%) and WHR were higher at 5 y compared to prediet in both groups. Fasting glucose was increased in NGT subjects at 5 y, and fasting insulin was higher in both groups at 5 y compared to prediet. Insulin sensitivity (GIR) was similar at 5 y compared to prediet, but at 5 y DM subjects were more insulin resistant than NGT subjects. At 5 y, both DM and NGT groups had significantly reduced basal fat oxidation and no significant suppression of fat oxidation with insulin. Clamp respiratory quotient levels at 5 y were significantly higher in NGT compared to DM subjects. CONCLUSION: Reduced basal fat oxidation, and reduced variation in substrate oxidation in response to insulin develop with fat regain and fasting hyperinsulinaemia in both NGT and DM obese adults.

OBJECTIVE: Adiponectin is an adipose-specific protein with short-term effects in vivo on glucose and fatty acid levels. We studied the plasma concentration and the proteolytic activation status of adiponectin following the consumption of a high-fat, low-carbohydrate meal. DESIGN: Analysis of adiponectin concentration and polypeptide structure after consumption of a fat meal. SUBJECTS: Normal subjects (n=24) and first-degree relatives of patients with type II diabetes (n=20). MEASUREMENTS: All subjects had a normal fasting plasma glucose and glucose tolerance. Blood was collected for the determination of plasma insulin, adiponectin, triglyceride, and free fatty acids. Body composition was assessed with dual-energy X-ray absorptiometry and whole-body insulin sensitivity with a euglycaemic, hyperinsulinaemic clamp. Postprandial response over 6 h was determined for plasma adiponectin, glucose, insulin, triglyceride, and free fatty acids. Adiponectin was measured by commercial RIA and its polypeptide structure examined by Western blotting. RESULTS: The relatives were more insulin resistant and had increased adiposity compared with control subjects. There was no significant difference in postprandial response in fatty acids, triglyceride, or insulin between the groups. Postprandial levels of adiponectin measured by radioimmunoassay were not significantly different from fasting levels, and no breakdown products of adiponectin were detectable in postprandial samples by Western blotting. CONCLUSIONS: Levels of circulating adiponectin do not alter in response to a fat meal, despite evidence in mice that acute changes in adiponectin significantly affect postprandial fatty acid flux. Moreover, a fat meal challenge did not lead to significant activation of adiponectin by proteolytic conversion.

Background The postprandial triglyceride response following a meal high in fat (HFM) has been related to atherogenesis and insulin resistance. We examined the influence of dietary carbohydrate and the accompanying insulin secretory response on the postprandial triglyceride response following a HFM. Materials and design High-fat meals of equal fat content (fat 80 g) containing either 20 g (low) or 100 g (high) of carbohydrate (HFM-LC and HFM-HC, respectively), and therefore not isocaloric (4250 kJ of HFM-LC and 5450 kJ of HFM-HC), were consumed by seven (four male, three female) normolipidaemic subjects (aged 32·9 ± 3·7 years, BMI 24·7 ± 1·8 kg m−2). Blood and indirect calorimetry data were collected at 0–4 h. Results HFM-HC produced a significant rise in plasma glucose (Δ0·54 ± 0·23 mmol L−1, P = 0·05) at 2 h, while a HFM-LC elicited no mean change from baseline. Following a HFM-LC, the plasma insulin incremental area under the curve (AUC) was significantly lower (31·3 ± 6·7 vs. 83·2 ± 11·9 mU l−1 h−1, P

Aims To examine the relationships between body composition and changes in fasting glycaemia, and in indices of insulin secretion and insulin action over 6 years in females with a family history of Type 2 diabetes with or without prior gestational diabetes (‘at risk’ group, AR) and control females (control group, C). Methods At baseline and at follow-up, an oral glucose tolerance test and dual energy X-ray absorptiometry assessment of body composition were performed. Indices of insulin resistance (HOMA R′) and insulin secretion (HOMA β′) were obtained from fasting insulin and glucose concentrations. Results At baseline, the groups were similar for age, body mass index, fasting levels of plasma glucose and insulin, HOMA R′ and HOMA β′. Despite similar total body fatness, AR had significantly greater waist circumference and central fat (both P

OBJECTIVE—To investigate the reproducibility of the plasma glucose (PG) response to exercise in subjects with type 1 diabetes on a nonintensive insulin regimen. RESEARCH DESIGN AND METHODS—Subjects cycled for 45 min at 50% Vo2max on two occasions (studies 1 and 2) either 1 h after lunch and usual insulin (protocol A) or after overnight fasting without morning insulin (protocol B). Identical diet, activity, and insulin (twice daily neutral and intermediate) were maintained before and during each study day. A total of 13 type 1 diabetic subjects (6 men and 7 women, BMI 24.0 ± 0.9 kg/m2 [means ± SE], age 42.6 ± 2.7 years, diabetes duration 14.1 ± 2.8 years) completed protocol A, and 7 (3 men and 4 women, BMI 25.8 ± 1.3 kg/m2, age 39.7 ± 1.3 years, diabetes duration 14 ± 4.4 years) completed protocol B. RESULTS—In protocol A (fed), the fall in PG during exercise was 4.5 ± 1.0 and 5.0 ± 0.8 mmol/l in studies 1 and 2, respectively, whereas in protocol B (fasted), it was 0.6 ± 0.8 and 3.4 ± 1.6 mmol/l. Regression analysis of the change in PG in protocol A in study 1 versus study 2 showed poor reproducibility (r2 = 0.12, P = 0.25) despite uniform conditions. In protocol B, the fall in PG was more reproducible (r2 = 0.81, P = 0.006). In fed subjects, there was better (P = 0.01) and clinically useful reproducibility of the PG at exercise completion (r2 = 0.77, P = 0.0001) compared with preexercise. CONCLUSIONS—These results indicate poor reproducibility of the change in PG during exercise after feeding in type 1 diabetes on nonintensive insulin regimens but reasonable reproducibility when fasting. Exercise apparently decreases the glycemic variability after feeding, so that PG concentrations after exercise seek a reproducible “target.” Thus, the absolute PG level after a typical bout of exercise in the fed state should be a good guide to carbohydrate or insulin adjustment on subsequent occasions.

An increase in muscle lipid content has been postulated to relate closely to the evolution of insulin resistance. We aimed to test whether the multiple indexes of lipid supply within man [namely, circulating triglycerides, skeletal muscle triglycerides (SMT), total and central fat mass, and circulating leptin] were independent predictors of insulin resistance, or whether triglycerides from different sources are additive in their influence on whole body insulin sensitivity. Whole body insulin sensitivity, body composition, and SMT content were determined in 49 sedentary, nondiabetic males (age, 20–74 yr; body mass index, 20–38 kg/m2). Insulin sensitivity was inversely associated with central abdominal fat (r2 = 0.38; P < 0.0001), total body fat (r2 = 0.21; P = 0.0003), SMT content (r2 = 0.16; P = 0.005), and fasting triglycerides (r2 = 0.24; P = 0.0003), nonesterified free fatty acid (r2 = 0.19; P = 0.002), and leptin (r2 = 0.35; P < 0.0001) levels. However, only central abdominal fat was significantly related to SMT content (r2 = 0.10; P = 0.03). SMT content, circulating triglycerides, and measurements of total or central adiposity were independent predictors of whole body insulin sensitivity.

Objective: Computed tomography (CT) and magnetic resonance imaging, the most accurate methods of abdominal fat measurement, have been applied using a number of protocols, ranging from single-slice area determination to multiple-slice volume calculation. The aim of this study was to assess the validity of single-slice CT for abdominal fat area measurement by estimating the intra-subject variability in abdominal fat areas and comparing the ranking of subjects across four contiguous abdominal levels. Research Methods and Procedures: Nineteen premenopausal women (age, 35.3 ± 1.4 years; mean ± SE) were studied. CT was used to measure intra-abdominal fat (IAF) area, percentage of total intra-abdominal area (%IAF), subcutaneous abdominal fat (SAF) area, and IAF/SAF at four adjacent cross-sectional lumbar levels (L2–L4). Intra-subject variability (percentage) was defined as SD/mean × 100. Total body fat was measured by DXA, which was further analyzed for central abdominal fat. Results: Mean body mass index was 24.9 ± 1.0 kg/m2. The average (range) intra-subject variability was 28% (8% to 61%) for IAF, 46% (19% to 124%) for %IAF, 26% (14% to 38%) for SAF area, and 19% (7% to 71%) for IAF/SAF. The pattern of this variability was not uniform between subjects, because their ranking by IAF area was markedly different at each CT level. Discussion: We demonstrated significant intra-subject variability in CT-measured adipose tissue areas across four predetermined sites. This resulted in a difference in the ordering of subjects by IAF at each of the four imaging sites, suggesting that the usefulness of single-slice CT in the assessment of abdominal adiposity in premenopausal women may be limited, particularly when performed for the purpose of making comparisons between subjects based on abdominal fat area.

Perilipin 1 is a lipid droplet coat protein predominantly expressed in adipocytes, where it inhibits basal and facilitates stimulated lipolysis. Loss-of-function mutations in the PLIN1 gene were recently reported in patients with a novel subtype of familial partial lipodystrophy, designated as FPLD4. We now report the identification and characterization of a novel heterozygous frameshift mutation affecting the carboxy-terminus (439fs) of perilipin 1 in two unrelated families. The mutation cosegregated with a similar phenotype including partial lipodystrophy, severe insulin resistance and type 2 diabetes, extreme hypertriglyceridemia, and nonalcoholic fatty liver disease in both families. Poor metabolic control despite maximal medical therapy prompted two patients to undergo bariatric surgery, with remarkably beneficial consequences. Functional studies indicated that expression levels of the mutant protein were lower than wild-type protein, and in stably transfected preadipocytes the mutant protein was associated with smaller lipid droplets. Interestingly, unlike the previously reported 398 and 404 frameshift mutants, this variant binds and stabilizes ABHD5 expression but still fails to inhibit basal lipolysis as effectively as wild-type perilipin 1. Collectively, these findings highlight the physiological need for exquisite regulation of neutral lipid storage within adipocyte lipid droplets, as well as the possible metabolic benefits of bariatric surgery in this serious disease.

Individuals with Prader-Willi syndrome (PWS) are commonly restricted to 60-75% of height-appropriate calorie intake because they rapidly become obese on a normal diet. This study measured changes in energy expenditure, glucose and lipid homeostasis, and metabolic flexibility in response to a meal in PWS adults.11 adults with PWS were compared with 12 adiposity-matched and 10 lean subjects. Indirect calorimetry was conducted at baseline and 210 min after a standardized 600 kCal breakfast to assess energy expenditure and substrate utilization. Circulating glucose, insulin, C-peptide, glucagon, nonesterified fatty acids, and triglycerides were measured up to 240 min. Insulin sensitivity and insulin secretion rate were assessed by HOMA-IR and C-peptide deconvolution, respectively. Body composition was determined by dual-energy X-ray absorptiometry.The PWS group had lower lean mass than the obesity control group. Corrected for lean mass, there were no differences between the PWS and obesity groups in resting metabolic rate or metabolic flexibility. Total and abdominal fat mass, insulin sensitivity, and insulin secretion rate were also similar between these groups.This study did not detect an intrinsic metabolic defect in individuals with PWS. Rather, lower lean mass, combined with lower physical activity, may contribute to weight gain on an apparent weight-maintenance diet.

The Diabetes Control and Complications Trial and United Kingdom Prospective Diabetes Study (UKPDS) trials have provided evidence for the pivotal importance of optimizing glycaemic control to prevent complications in type 1 and 2 diabetes mellitus. Both patients and diabetes professionals consider lifestyle change and appropriate medication as cornerstones for achieving good glycaemic control. The frequent reversals in the recommended diabetic diet in the past century warn that in the nutritional area the hypotheses are many, but the proofs are few. In type 1 diabetes, the patient is still advised to spread out carbohyrate foods during the day with three short-acting insulin injections at meal times to minimize postprandial hyperglycaemia. In type 2 diabetes, weight loss is the major target, because 80% of patients are overweight or obese. However, it is salutory to note that in the UKPDS trial, no modality of treatment delayed the relentless deterioration of glycaemic control in type 2 diabetes, the extent of which was predicted by the insulin secretion. Controversy still exists regarding whether lowering the dietary fat enhances weight loss of itself and whether dietary carbohydrate, fat and fibre influence insulin sensitivity and glycaemia. The American Diabetes Association's evidence-based recommendations currently offer a choice between a high carbohyrate and modified fat diet, with monounsaturated fat replacing the saturated fat instead of carbohydrate. The role of omega-3 fatty acids in man is not resolved. The reason for the surprising lack of definitive evidence lies in the limitations of nutritional research. Under-reporting of diet is common and dietary assessment tools are often inaccurate. Sustained weight loss is unattainable by the majority of patients, perhaps because of the strongly genetic nature of obesity and the sedentary lifestyle. Compliance may be improved by suggesting small, sustained dietary changes, setting small weight loss targets and encouraging a permanent increase in total activity.

Objective: Insulin resistance is closely associated with two disparate aspects of lipid storage: the intracellular lipid content of skeletal muscle and the magnitude of central adipose beds. Our aim was to determine their relative contribution to impaired insulin action. Research Methods and Procedures: Eighteen older (56 to 75 years of age) men were studied before elective knee surgery. Insulin sensitivity (M/ΔI) was determined by hyperinsulinemic–euglycemic clamp. Central abdominal fat (CF) was assessed by DXA. Skeletal muscle was excised at surgery and assayed for content of metabolically active long-chain acyl-CoA esters (LCAC). Results: Significant inverse relationships were observed between LCAC and M/ΔI (R2 = 0.34, p = 0.01) and between CF and M/ΔI (R2 = 0.38, p = 0.006), but not between CF and LCAC (R2 = 0.0005, p = 0.93). In a multiple regression model (R2 = 0.71, p < 0.0001), both CF (p = 0.0006) and LCAC (p = 0.0009) were independent statistical predictors of M/ΔI. Leptin levels correlated inversely with M/ΔI (R2 = 0.60, p = 0.0002) and positively with central (R2 = 0.41, p = 0.006) and total body fat (R2 = 0.63, p = 0.0001). Discussion: The mechanisms by which altered lipid metabolism in skeletal muscle influences insulin action may not be related directly to those linking central fat and insulin sensitivity. In particular, it is unlikely that muscle accumulation of lipids directly derived from labile central fat depots is a principal contributor to peripheral insulin resistance. Instead, our results imply that circulating factors, other than nonesterified fatty acids or triglyceride, mediate between central fat depots and skeletal muscle tissue. Leptin was not exclusively associated with central fat, but other factors, secreted specifically from central fat cells, could modulate muscle insulin sensitivity.

Although prevention is clearly a logical first step in the management of the obese Type 2 diabetic patient, such programmes have had little long-term success. Diet, exercise and behavioural modification still form the cornerstones of treatment and relatively small weight loss results in improvement of all major obesity-related co-morbidities, including Type 2 diabetes. The obese diabetic patient faces extra impediments to weight loss, including the adverse effects of diabetic medication, poor glycaemic control and diabetes-related complications. New drugs may offer some additional help, in general by providing the benefit associated with the weight loss as such. Bariatric surgery can produce major long-term weight loss in the severely obese.

To the Editor: The recent publication in Diabetologia ofbaseline results from two large-scale longitudinal studiesprovides welcome confirmation of the association ofimpaired beta cell function and glucose intolerance outsidethe diabetic range and promises useful information whenfollow-up studies are completed regarding factors related toprogression of glucose intolerance [1, 2]. While bothstudies conclude that beta cell function is the dominantdeterminant of glucose tolerance, they differ in onesignificant detail. Mari et al. [1] conclude that variationsin their primary index of insulin secretion (glucosesensitivity) are not associated with variations in whole-body insulin sensitivity and therefore are not related to anyfeedback relationship between beta cell function and insulinsensitivity. On the contrary, DeFronzo et al. [2] concludefrom their primary index of insulin secretion (a dispositionindex [DI]), that impairments do represent a failure offeedback between insulin sensitivity and insulin secretion.We present here an argument that the two differentinterpretations reflect the same underlying reality, which isclosest to the interpretation of Mari et al., and that theapparent difference is due to a misinterpretation of thephysiological and statistical relationships between insulinsecretion, insulin sensitivity and glucose tolerance (or othermeasures of glycaemia).We have shown elsewhere [3], using published data fromsome of the authors of Mari et al. and DeFronzo et al. [4],that glycaemic responses to an OGTT conform closely to asimple HOMA-like model [5] relating insulin secretion,insulin sensitivity and glycaemia. The model can beexpressed as:lnðÞ¼b lnðÞR

Fetuin-A is a liver secretory glycoprotein that has been linked to the development of insulin resistance in animal models (1). Recent work suggests that free fatty acids (FFAs) and fetuin-A interact to induce insulin resistance in animal models (1) and humans (2). However, short-term overfeeding increases peripheral insulin resistance without significant increases in the levels of circulating FFAs in healthy humans (3,4). Thus, short-term overfeeding studies provide an ideal model with which to evaluate the relationships between fetuin-A and insulin resistance, independent of FFAs. We examined the effects of 28-day overfeeding (1,100 ± 100 kcal/day above baseline energy requirement, increasing mean [±SEM] dietary fat intake from 34 ± 1% to 45 ± 1% of energy intake) on circulating levels of fetuin-A, FFAs, and proinflammatory markers in healthy men and women (BMI 25.6 ± 0.6; age 37 ± 2 years; n = 40 [20 men]). The study protocol was described in detail previously (3 …

Baker IDI Heart and Diabetes Institute, Australia Monash University, Australia WHO Collaborating Centre for the Epidemiology of Diabetes Mellitus, Australia Garvan Institute, Australia The University of NSW, Australia The Diabetes Centre, St Vincent’s Hospital, Australia Wellington Hospital, Australia Dept. of Endocrinology, Royal Prince Alfred Hospital Sydney, Australia Sydney Medical School, The University of Sydney, Australia Discipline of Medicine, University of Adelaide, Australia Royal Adelaide Hospital, Australia Sir Edward Dunlop Medical Research Foundation, Australia tal

Diabetic lower-limb problems result in significant social, medical and economic consequences and are the most common cause of hospitalisation for people with diabetes. In people with diabetes, amputations are 15 times more common than in people without diabetes, and 50% of all amputations occur in people with diabetes. Peripheral neuropathy, vascular disease, infection and deformity of the feet are the major predisposing factors leading to ulceration or amputation. All people with diabetes should receive basic footcare education, and regular foot examinations. The risk for the development of ulceration can be assessed by basic clinical examination of the foot. Management strategies depend on the risk category, and range from basic education and annual review to specialist care by a multidisciplinary team.

Homeostasis model assessment (HOMA) provides indices of insulin secretion (β) and insulin resistance (R) derived from fasting plasma glucose (FPG) and fasting plasma insulin (FPI) levels. However, these indices could not account for a significant heritability of fasting plasma glucose (FPG) (h2 = 0.75, P < 0.01) in a group of 214 female twins. This result is consistent with a misclassification between effects due to insulin secretion and resistance in the HOMA indices. We report here evidence of such misclassification in the HOMA indices and describe a minor modification to the model which corrects it. Direct measures of insulin resistance (euglycaemic clamp) and secretion (i.v. glucose bolus) were obtained in 43 non-diabetic subjects. Heritability was estimated by statistical modelling of genetic and environmental influences in data from 214 non-diabetic female subjects. Modified HOMA (HOMA′) indices were obtained from β′ = (Ln(FPI)–c)/FPG and R′ = (Ln(FPI)–c)* FPG where c is a constant derived from regression analysis of Ln(FPI) vs FPG. Indices from both models correlated with the direct measures similarly (r = 0.63 (R), 0.49 (R′), 0.45 (β), 0.39 (β′), all P < 0.01). Directly measured insulin resistance and secretion were not significantly correlated (r = 0.13, P = 0.21). However, unmodified HOMA- and R were strongly related (r = 0.78, P < 0.0001 vs 0.13) demonstrating substantial misclassification. The relationship between β′ and R′ (r = 0.13) was not different from that between the two direct measures and significant heritability of β′ (h2 = 0.68, P < 0.01) and R′ (h2 = 0.59, P < 0.05) was evident in the twin data. The proposed modification to HOMA significantly reduces misclassification and reveals separate components of insulin resistance and insulin secretion in the heritability of FPG. Twin Research (2000) 3, 148–151.

Homeostasis model assessment (HOMA) provides indices of insulin secretion (β) and insulin resistance (R) derived from fasting plasma glucose (FPG) and fasting plasma insulin (FPI) levels. However, these indices could not account for a significant heritability of fasting plasma glucose (FPG) (h2 = 0.75, P < 0.01) in a group of 214 female twins. This result is consistent with a misclassification between effects due to insulin secretion and resistance in the HOMA indices. We report here evidence of such misclassification in the HOMA indices and describe a minor modification to the model which corrects it. Direct measures of insulin resistance (euglycaemic clamp) and secretion (i.v. glucose bolus) were obtained in 43 non-diabetic subjects. Heritability was estimated by statistical modelling of genetic and environmental influences in data from 214 non-diabetic female subjects. Modified HOMA (HOMA′) indices were obtained from β′ = (Ln(FPI)–c)/FPG and R′ = (Ln(FPI)–c)* FPG where c is a constant derived from regression analysis of Ln(FPI) vs FPG. Indices from both models correlated with the direct measures similarly (r = 0.63 (R), 0.49 (R′), 0.45 (β), 0.39 (β′), all P < 0.01). Directly measured insulin resistance and secretion were not significantly correlated (r = 0.13, P = 0.21). However, unmodified HOMA- and R were strongly related (r = 0.78, P < 0.0001 vs 0.13) demonstrating substantial misclassification. The relationship between β′ and R′ (r = 0.13) was not different from that between the two direct measures and significant heritability of β′ (h2 = 0.68, P < 0.01) and R′ (h2 = 0.59, P < 0.05) was evident in the twin data. The proposed modification to HOMA significantly reduces misclassification and reveals separate components of insulin resistance and insulin secretion in the heritability of FPG. Twin Research (2000) 3, 148–151.

Summary Aims To establish the incidence of post-transplant diabetes mellitus (PTDM) and factors predictive of its development. Methods This was a retrospective review (using hospital records and transplant database) of 97 consecutive adult patients who underwent cardiac transplantation at St Vincent’s Hospital, Sydney, Australia. Results Mean follow-up was 27 months. Excluding five patients who had pre-existing diabetes, the cumulative incidence of PTDM was 15.7%. Pre-transplant random blood glucose (5.6 ± 0.8 vs. 5.2 ± 0.6 mmol/l, P

OBJECTIVE: To determine the phenotypic and dietary characteristics of energy underreporters in a healthy population of middleaged women using accurate body composition measures. DESIGN: Cross-sectional study of 436 healthy middleaged female volunteers, unaware of any hypotheses regarding diet and body fat: mean age 58 y (39–70 y), body mass index (BMI) 24.3 kg/m2 (17.0–41.9 kg/m2). The prevalence of overweight (25.0>BMI>29.9 kg/m2) and obesity (BMI>30 kg/m2) were 30% and 5% respectively. MEASUREMENTS:Dietary intake by food frequency questionnaire (FFQ) (n=436), 197 subjects also completed seven-day food records; body composition by dual energy X-ray absorptiometry (DXA); physical activity by standardised questionnaire. Underreporters were subjects whose estimated energy expenditure (EE) exceeded reported energy intake (EI). Three cut-off levels of underreporting were determined from estimates of EE utilising DXA body composition measures: basal, and two including EE from physical activity (using the ratio 1.35 or ratios from reported physical activity level). RESULTS: Underreporters had significantly greater weight (P

Obesity, insulin resistance and disturbed glucose metabolism cluster within the Insulin Resistance Syndrome (IRS). Whether this reflects shared genetic or environmental factors detectable in ‘normal’ populations (not selected for IRS features) is unknown. This study estimated (i) genetic influences on IRS traits and (ii) shared and specific genetic and environmental factors on the relationships between these traits in healthy female twins. Fasting insulin, glucose, total and central fat were measured in 59 monozygotic (MZ) and 51 dizygotic (DZ) female twin pairs aged ( ± SD) 52 ± 13 years. Body fat was measured by dual-energy X-ray absorptiometry, insulin resistance and secretion by a modified homeostasis model assessment. Using intraclass correlation coefficients and univariate model-fitting analyses, genetic influences were found in total fat, central fat, insulin resistance, fasting glucose and insulin secretion, with genetic factors explaining 64, 57, 59, 75 and 68% of their variance, respectively, using the latter technique. In matched analysis intra-pair differences in total and central fat related to intra-pair differences in insulin resistance (r2 = 0.19, P < 0.001). Multivariate model-fitting showed a close genetic relationship between total and central fat (r = 0.88). The genetic correlation between IR and central fat (0.41) was significantly greater than that for total fat (0.24), suggesting that central fat is not only a predictor of, but shares considerable genetic influence with, insulin resistance. In Cholesky analysis, these genetic influences were separate from those shared between central and total fat. In conclusion, both shared and specific genetic factors regulate components of the IRS in healthy females. However, there were discrete genetic influences on -cell insulin secretion, not shared with other IRS components, suggesting that a separate genetic propensity exists for Type2 diabetes. These findings suggest we may understand the genetic and environmental influences on IRS from the study of the normal population.

Individuals with type 2 diabetes mellitus (n = 105; age 36-71 years) on diet therapy alone, and with quite good glycaemic control (mean HbA1c approximately 7.0%) were randomized to receive acarbose (100 mg three times daily) or placebo for 16 weeks, and changes in clinical and metabolic parameters indicative of Syndrome X were monitored. Fasting levels of glucose, glycosylated haemoglobin (HbA1c), true insulin, proinsulin, fibrinogen and lipids were measured four times weekly, and glucose, insulin, proinsulin and triglyceride responses to a standardized 1.6 MJ breakfast were determined at 0, 1 and 2 h post meal. Analysis was on an intention-to-treat basis. Fasting levels of glucose (P0.0001), triglycerides (P = 0.03) and HbA1c (P = 0.003) were reduced by acarbose over the 16 weeks of treatment. The mean change in HbA1c from week 0 to 16 differed by 0.4% (P = 0.003) between the two groups. Insulin (P = 0.06), proinsulin (P = 0.07) and glucose (P0.0001) responses to the standard meal were reduced. These data show that acarbose reduces fasting glucose and triglyceride levels, lowers HbA1c and limits the glycaemic and insulin response to food in individuals with type 2 diabetes mellitus with Syndrome X. Pharmacological agents that improve the metabolic environment and reduce insulin resistance have the potential to limit the progression of atherogenesis associated with type 2 diabetes mellitus.

Elevated non-esterified fatty acid (NEFA) levels may influence insulin secretion and contribute to the development of Type 2 DM. We investigated the effects of acute NEFA elevation in controls (n = 6) and subjects predisposed to Type 2 DM (n = 6) on basal insulin levels, and following glucose and arginine stimulation. Each subject had one study with a triglyceride (TG) plus heparin infusion (elevated NEFA levels) and another with normal saline. Twenty minutes after the TG or saline infusion began a glucose bolus was given and 10 min later a 90-min hyperglycaemic clamp (approximately 9 mmol l(-1)) was started. Intravenous arginine was given at 110 min. Elevated NEFA levels (approximately 4000 micromol l(-1)) did not enhance basal or first phase glucose stimulated insulin levels. During hyperglycaemia, NEFA elevation further increased insulin levels in both groups by 20-44% (p < 0.05) and C-peptide levels by 17-25% (p < 0.05). The post-arginine insulin levels during hyperglycaemia were increased by 45% in the Type 2 DM-risk group (p < 0.02). The glucose infusion rate maintaining matched hyperglycaemia was similar during NEFA elevation and for saline control for both groups. We conclude that acute elevation of NEFA levels enhances glucose and non-glucose-induced insulin secretion.

The known postmenopausal increase in cardiovascular risk may relate in part to changes in fat distribution. Environmental factors which are known to influence cardiovascular disease risk may do so in part by influencing body fat and its distribution.To determine the relationships between tobacco smoking, oestrogen replacement (ERT) and body fat and its distribution in postmenopausal women, independent of genetic factors, physical activity, diet composition and socioeconomic factors.Cross-sectional study in normal post menopausal twins.712 postmenopausal female twins (aged 58.7 +/- 0.2 y, body mass index (BMI) 24.4 +/- 0.1 kg/m2).Anthropometry; body composition and fat distribution by dual energy x-ray absorptiometry; physical activity, muscle strength, socioeconomic status, dietary composition and dehydroepiandrosterone sulfate (DHEAS).In monozygotic pairs discordant for smoking, intrapair differences in total and central fat were greater than that in concordant pairs, with the lower fat mass in the smoking twin. Overall, smokers had a lower weight, BMI, total and central abdominal fat, despite a higher total and saturated dietary fat intake and similar DHEAS levels. The reduction in central fat was not independent of that in total fat. In monozygotic twins discordant for ERT-use the intrapair differences in total and central body fat were significantly greater than in concordant pairs, with the lower fat measure in the ERT-using twin. Overall, current ERT-users had similar body weight, BMI and total fat compared to non-users but had lower central fat. There were no differences in activity levels, diet or socioeconomic factors between ERT-users and non-users.Smoking and ERT-use are associated with lower total and central fat in monozygotic postmenopausal twins. In current smokers, the lower central adiposity appears related to its influence on total body fat. In ERT-users, lower central fat may contribute to the reduced cardiovascular risk associated with postmenopausal oestrogen use.

Insulin resistance is considered a core component in the pathophysiology of the metabolic syndrome. Some clinicians measure serum insulin concentrations in the mistaken belief that they can be used to diagnose insulin resistance. Serum insulin levels are poor measures of insulin resistance. Furthermore, there is no clinical benefit in measuring insulin resistance in clinical practice. Measurements of fasting serum insulin levels should be reserved for large population-based epidemiological studies, where they can provide valuable data on the relationship of insulin sensitivity to risk factors for diabetes and cardiovascular disease. Clinicians should shift from identifying "insulin resistance" to identifying risk factors, such as fasting glucose and lipid levels, hypertension and central obesity. These proven risk factors converge within the metabolic syndrome. Individuals "at risk" of diabetes and atherosclerotic cardiac disease can be identified simply and inexpensively, using classic clinical techniques, such as history-taking, physical examination, and very basic investigations.

Central adiposity carries an increased risk of non-insulin dependent diabetes mellitus (NIDDM), cardiac disease, hypertension and death, and is closely related to insulin resistance. Genetic factors explain a large proportion of the population variance in central adiposity, although the genotypic characteristics remain obscure. Hormonal factors such as endogenous sex steroid levels, the menopause, hormone replacement therapy and cortisol may influence body fat partitioning. The link between dietary factors and central adiposity is controversial, with contradictory results in the literature. Smoking is associated with lower total body fat, but investigations of its influence on central adiposity have also yielded contradictory results. Higher levels of physical activity are associated with lesser amounts of central fat, both cross-sectionally and in intervention studies. Some of the contradictory results regarding putative influences on central adiposity may be due to limitations of some of the anthropometric parameters of central adiposity, such as the waist-hip ratio. Further research is required to clarify the relationships between many of these factors and with both compartments of central adiposity: subcutaneous abdominal and intraabdominal adipose tissue.

Central adiposity is a strong predictor of cardiovascular disease in women. We studied postmenopausal twins to explore the strength and the relationship between genetic influences on body fat and its distribution in a group where cardiovascular disease is the major cause of mortality. Healthy twin women were recruited from a national media campaign. One hundred nineteen monozygotic (MZ) and 97 dizygotic twin pairs were studied (mean ± se age 60 ± 0.3 yr, 10 ± 0.4 yr post menopausal). Total and central body fat were measured by dual-energy x-ray absorptiometry. Intrapair resemblance was significantly greater in MZ pairs for total fat (MZ vs. dizygotic, r = 0.70 ± 0.05 vs. r = 0.46 ± 0.08, P = 0.005) and central fat (r = 0.62 ± 0.06 vs. r = 0.35 ± 0.09, P = 0.005), suggesting a strong genetic influence on these traits. Model-fitting analysis indicated that genetic factors contribute up to 60% of total population variance in both total and central body fat. The heritability of central fat remained, after adjustment for the heritability of total fat, suggesting an independent genetic influence on fat distribution. These results were unchanged after adjusting for the effects of estrogen replacement and smoking. In conclusion, total adiposity and central abdominal fat mass in normal postmenopausal women are under strong genetic influence. The data suggest that some of the genes responsible for central adiposity and its metabolic sequelae will be different from those responsible for total adiposity.

The response of serum leptin to short (4 days) and prolonged (28 days) energy restriction (50 % reduction in energy intake) was determined in 18 (9 male, 9 female) moderately obese humans (body mass index 32.0 ± 0.6 kg/m2 mean ± SEM), 9 of whom had mild non-insulin-dependent diabetes mellitus (NIDDM). Body composition was assessed before and at the end of the energy restriction using DEXA. The subjects lost a measured 2.6 ± 0.4 kg of body fat after 28 days and an estimated 0.3 kg at 4 days. Serum leptin fell to 64 ± 3 % of baseline levels at day 4 and further to 46 ± 4 % at day 28. In a multiple correlation analysis, the change in leptin concentration at day 4 was significantly related to the change in dietary carbohydrate intake (partial r = 0.68, p < 0.005) but not to changes in fat (r = 0.12) or protein (r = 0.02) intakes. There was a 1 : 1 relationship between the changes in leptin and dietary carbohydrate (regression slope = 1.0 ± 0.3). Gender, or the presence of NIDDM had no effects on these responses. This pronounced fall in serum leptin in association with reduced carbohydrate intake before substantial loss of body fat suggests a role for leptin in defending the body's carbohydrate stores and implicates leptin in the satiating effects of carbohydrate. Dietary or other interventions which maintain leptin levels during weight reduction may lead to improvements in weight loss. [Diabetologia (1997) 40: 348–351]

Type 2 diabetes predicts accelerated cognitive decline and brain atrophy. We hypothesized that impaired fasting glucose (IFG) and incident glucose disorders have detrimental effects on global cognition and brain volume. We further hypothesized that metabolic and inflammatory derangements accompanying hyperglycaemia contribute to change in brain structure and function. This was a longitudinal study of a community-dwelling elderly cohort with neuropsychological testing (n = 880) and brain volumes by magnetic resonance imaging (n = 312) measured at baseline and 2 years. Primary outcomes were global cognition and total brain volume. Secondary outcomes were cognitive domains (processing speed, memory, language, visuospatial and executive function) and brain volumes (hippocampal, parahippocampal, precuneus and frontal lobe). Participants were categorised as normal, impaired fasting glucose at both assessments (stable IFG), baseline diabetes or incident glucose disorders (incident diabetes or IFG at 2 years). Measures included inflammatory cytokines and oxidative metabolites. Covariates were age, sex, education, non-English speaking background, smoking, blood pressure, lipid-lowering or antihypertensive medications, mood score, apolipoprotein E genotype and baseline cognition or brain volume. Participants with incident glucose disorders had greater decline in global cognition and visuospatial function compared to normal, similar to that observed in baseline diabetes. Homocysteine was independently associated with the observed effect of diabetes on executive function. Apolipoprotein E genotype did not influence the observed effects of diabetes on cognition. Incident glucose disorders and diabetes were also associated with greater 2-year decline in total brain volume, compared to normal (40.0 ± 4.2 vs. 46.7 ± 5.7 mm(3) vs. 18.1 ± 6.2, respectively, p 0.005). Stable IFG did not show greater decline in global cognition or brain volumes compared to normal. Incident glucose disorders, like diabetes, are associated with accelerated decline in global cognition and brain volumes in non-demented elderly, whereas stable IFG is not. Preventing deterioration in glucose metabolism in the elderly may help preserve brain structure and function.

Aim. Adiponectin has demonstrated anti-inflammatory and insulin sensitising properties, and low circulating levels may be an important risk factor for diabetes. We examined levels of adiponectin and its insulin-sensitising HMW isoform and their relationship with metabolic parameters in Tongans, a population prone to type II diabetes. Methods. Adiponectin and its HMW isoform were quantitated by Elisa in specimens from a randomly recruited, multistage cluster population survey of Tongans and from a group of Caucasians. Anthropometric, clinical, and biochemical data were collected on each subject. Results. Both male and female Tongans had lower levels of total and HMW adiponectin than their Caucasian counterparts. Levels of total and HMW adiponectin were higher in females than males in each group. Adiponectin levels were inversely related to BMI, weight, and HOMA in Tongan males and females, as well as to dyslipidemia in both sexes. Conclusion. Tongans had lower levels of both total and HMW adiponectin than Caucasians population, even after matching Tongans to their Caucasian counterparts based on BMI, age, and sex. These findings may reflect differences in body composition between the populations not adequately assessed by BMI, lifestyle factors, or a genetic variant likely in a genetically homogenous population.

While chronic obesity is associated with alterations in circulating glycerolipids, sphingolipids and plasmalogens, the effects of short-term overfeeding in humans are unclear.Healthy individuals (n = 40) were overfed by 1,250 kcal day(-1) for 28 days. Insulin sensitivity (hyperinsulinemic-euglycemic clamp), abdominal fat distribution and serum lipidomics (mass spectrometry) were assessed.Overfeeding increased liver fat, insulin resistance, serum C-reactive protein and urinary F2-isoprostanes. HDL increased (11% ± 2%, P0.001) while LDL, triglycerides and nonesterified fatty acids were unchanged. Three hundred and thirty three serum lipids were detected, of which 13% increased and 20% decreased with overfeeding. Total diacylglycerol and lysoalkylphosphatidylcholine (LPC(O)) concentrations decreased (P0.01), while total ceramide, Cer22:0 and Cer24:0 increased (P ≤ 0.01). The most notable increases were observed in the HDL-associated phosphatidylethanolamine-based plasmalogens and their precursors alkylhosphatidylethanolamine (18 ± 5% and 38 ± 8% respectively, P ≤ 0.01).Overfeeding led to weight gain and changes in the serum lipid profile. Increases in ceramides were noted, which left unchecked may promote systemic insulin resistance. Uniform increases were observed in plasmalogens and their precursors. Because plasmalogens are powerful antioxidants, this may be an appropriate response against increased oxidative stress generated by over-nutrition. The metabolic consequences of changes in concentrations of many circulating lipid species with overfeeding require further study. Copyright © 2013 The Obesity Society.

Context: Circulating levels of metabolically protective and adverse cytokines are altered in obese humans and rodent models. However, it is not clear whether these cytokines are altered rapidly in response to over-nutrition, or as a later consequence of the obese state. Methods: Forty sedentary healthy individuals were examined prior to and at 3 and 28 days of high fat overfeeding (+1250 kCal/day, 45% fat). Insulin sensitivity (hyperinsulinaemic-euglycaemic clamp), adiposity, serum levels of adiponectin and fibroblast growth factor-21 (FGF21), fatty acid binding protein-4 (FABP4), lipocalin-2 and plasminogen activator factor-1 (PAI1) were assessed. Statistics were performed by repeated measures ANOVA. Results: Overfeeding increased weight, body fat and liver fat, fasting glucose, insulin and reduced insulin sensitivity by clamp (all P

OBJECTIVE Subjects with IDDM should take carbohydrate before exercise to avoid hypoglycemia. However, there is little information on the glycemic effect of recommended supplementation. This study is aimed to determine the glycemic effects of oral glucose or bread (30 g carbohydrate) before 45 min of moderate exercise. RESEARCH DESIGN AND METHODS Nine subjects with uncomplicated IDDM did 45 min of bicycle ergometer exercise at 60% VO2max in the morning before insulin injection on three occasions: 1) with no carbohydrate supplement, 2) with 30 g glucose in water at −5 min, and 3) with 30 g carbohydrate as white bread with water at −20 min. The glycemic responses were determined. The glycemic responses to glucose and bread were also determined without exercise in six subjects. RESULTS Without carbohydrate, exercise caused a small fall (−1.2 ± 0.6 mmol/l, mean ± SE) in plasma glucose (PG). With either glucose or bread, PG rose (the change in plasma glucose relative to basal [Δ PG] = 5.1 ± 0.8 and 2.6 ± 0.8, respectively). The rise was greater (P < 0.01) without exercise (Δ PG = 6.9 ± 0.7 and 4.5 ± 0.7, respectively). During exercise, glucose increased PG levels more than bread increased glucose levels P < 0.05). CONCLUSIONS Before morning insulin injection, the fall in PG during moderate exercise in IDDM subjects is generally small or absent. The glycemic effects of complex carbohydrate are slightly < glucose before exercise. Under these circumstances, the usually recommended amount of carbohydrate tends to cause an unwanted elevation of PG; thus, IDDM subjects should anticipate reducing or even omitting carbohydrate supplementation after monitoring their individual glycemic response.

Insulin resistance appears to be central to obesity, NIDDM, hyperlipidemia, and cardiovascular disease. While obese women with abdominal (android) fat distribution are more insulin resistant than those with peripheral (gynecoid) obesity, in nonobese women, the relationship between abdominal fat and insulin resistance is unknown. By measuring regional adiposity with dual-energy X-ray absorptiometry and insulin sensitivity by euglycemic-hyperinsulinemic clamp in 22 healthy women, with a mean ± SE body BMI of 26.7 ± 0.9 kg/m2 and differing risk factors for NIDDM, we found a strong negative relationship between central abdominal (intra-abdominal plus abdominal subcutaneous) fat and whole-body insulin sensitivity (r = −0.89, P < 0.0001) and nonoxidative glucose disposal (r = −0.77, P < 0.001), independent of total adiposity, family history of NIDDM, and past gestational diabetes. There was a large variation in insulin sensitivity, with a similar variation in central fat, even in those whose BMI was