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Introduction Clinician-led diabetes education is a fundamental component of care to assist people with Type 1 diabetes (T1D) self-manage their disease. Recent initiatives to incorporate a more patient-centered approach to diabetes education have included recommendations to make such education more individualized. Yet there is a dearth of research that identifies patients’ perceptions of clinician-led diabetes education. We aimed to describe the experience of diabetes education from the perspective of young adults with T1D. Methods We designed a self-reported survey for Australian adults, aged 18–35 years, with T1D. Participants (n = 150) were recruited by advertisements through diabetes consumer-organizations. Respondents were asked to rate aspects of clinician-led diabetes education and identify sources of self-education. To expand on the results of the survey we interviewed 33 respondents in focus groups. Results Survey: The majority of respondents (56.0%) were satisfied with the amount of continuing clinician-led diabetes education; 96.7% sought further self-education; 73.3% sourced more diabetes education themselves than that provided by their clinicians; 80.7% referred to diabetes organization websites for further education; and 30.0% used online chat-rooms and blogs for education. Focus groups: The three key themes that emerged from the interview data were deficiencies related to the pedagogy of diabetes education; knowledge deficiencies arising from the gap between theoretical diabetes education and practical reality; and the need for and problems associated with autonomous and peer-led diabetes education. Conclusion Our findings indicate that there are opportunities to improve clinician led-diabetes education to improve patient outcomes by enhancing autonomous health-literacy skills and to incorporate peer-led diabetes education and support with clinician-led education. The results provide evidence for the potential value of patient engagement in quality improvement and health-service redesign. Electronic supplementary material The online version of this article (doi:10.1007/s13300-014-0056-0) contains supplementary material, which is available to authorized users.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is prevalent in patients undergoing heart transplant, and in those without preexisting T2DM, posttransplant diabetes mellitus may develop. Both T2DM and posttransplant diabetes mellitus have been associated with increased morbidity and mortality following heart transplantation. Empagliflozin is an effective glucose-lowering therapy that reduces the incidence of major cardiovascular events in patients with T2DM. The safety and efficacy of empagliflozin in transplant patients with diabetes mellitus has yet to be established. METHODS: Clinical outcomes were retrospectively examined in 22 heart transplant recipients treated with empagliflozin and compared with those of 79 heart transplant patients with diabetes mellitus receiving alternative glucose-lowering therapies. RESULTS: Three adverse events were recorded in empagliflozin-treated patients, leading to treatment discontinuation in 1. There were no genitourinary infections. Treatment with empagliflozin for 12 months was associated with reductions in weight, body mass index, glycated hemoglobin, and frusemide dose that were not seen in the control group. There were no large changes observed in blood pressure (systolic or diastolic) or renal function (serum urea, creatinine, or estimated glomerular filtration rate) after 12 months of treatment with empagliflozin or alternative glucose-lowering therapies. CONCLUSIONS: Empagliflozin appears safe and effective in the management of selected patients with diabetes mellitus following heart transplantation.

OBJECTIVE The metabolic effects of low-dose prednisolone and optimal management of glucocorticoid-induced diabetes are poorly characterized. The aims were to investigate the acute effects of low-dose prednisolone on carbohydrate metabolism and whether long-term low-dose prednisolone administration increases visceral adiposity, amplifying metabolic perturbations. RESEARCH DESIGN AND METHODS Subjects with inflammatory rheumatologic disease without diabetes mellitus were recruited. Nine subjects (age, 59 ± 11 years) not using oral glucocorticoids were studied before and after a 7- to 10-day course of oral prednisolone 6 mg daily. Baseline data were compared with 12 subjects (age, 61 ± 8 years) using continuous long-term prednisolone (6.3 ± 2.2 mg/day). Basal endogenous glucose production (EGP) was estimated by 6,6-2H2 glucose infusion, insulin sensitivity was estimated by two-step hyperinsulinemic-euglycemic clamp, insulin secretion was estimated by intravenous glucose tolerance test, and adipose tissue areas were estimated by computed tomography. RESULTS Prednisolone acutely increased basal EGP (2.44 ± 0.46 to 2.65 ± 0.35 mg/min/kg; P = 0.05) and reduced insulin suppression of EGP (79 ± 7 to 67 ± 14%; P = 0.03), peripheral glucose disposal (8.2 ± 2.4 to 7.0 ± 1.6 mg/kg/min; P = 0.01), and first-phase (5.9 ± 2.0 to 3.9 ± 1.6 mU/mmol; P = 0.01) and second-phase (4.6 ± 1.7 to 3.6 ± 1.4 mU/mmol; P = 0.02) insulin secretion. Long-term prednisolone users had attenuated insulin suppression of EGP (66 ± 14 vs. 79 ± 7%; P = 0.03) and nonoxidative glucose disposal (44 ± 24 vs. 62 ± 8%; P = 0.02) compared with nonglucocorticoid users, whereas basal EGP, insulin secretion, and adipose tissue areas were not significantly different. CONCLUSIONS Low-dose prednisolone acutely perturbs all aspects of carbohydrate metabolism. Long-term low-dose prednisolone induces hepatic insulin resistance and reduces peripheral nonoxidative glucose disposal. We conclude that hepatic and peripheral insulin sensitivity should be targeted by glucose-lowering therapy for glucocorticoid-induced diabetes.

Human adiposity has long been associated with insulin resistance and increased cardiovascular risk, and abdominal adiposity is considered particularly adverse. Intra-abdominal fat is associated with insulin resistance, possibly mediated by greater lipolytic activity, lower adiponectin levels, resistance to leptin, and increased inflammatory cytokines, although the latter contribution is less clear. Liver lipid is also closely associated with, and likely to be an important contributor to, insulin resistance, but it may also be in part the consequence of the lipogenic pathway of insulin action being up-regulated by hyperinsulinemia and unimpaired signaling. Again, intramyocellular triglyceride is associated with muscle insulin resistance, but anomalies include higher intramyocellular triglyceride in insulin-sensitive athletes and women (vs men). Such issues could be explained if the “culprits” were active lipid moieties such as diacylglycerol and ceramide species, dependent more on lipid metabolism and partitioning than triglyceride amount.Subcutaneous fat, especially gluteofemoral, appears metabolically protective, illustrated by insulin resistance and dyslipidemia in patients with lipodystrophy. However, some studies suggest that deep sc abdominal fat may have adverse properties.Pericardial and perivascular fat relate to atheromatous disease, but not clearly to insulin resistance.There has been recent interest in recognizable brown adipose tissue in adult humans and its possible augmentation by a hormone, irisin, from exercising muscle. Brown adipose tissue is metabolically active, oxidizes fatty acids, and generates heat but, because of its small and variable quantities, its metabolic importance in humans under usual living conditions is still unclear.Further understanding of specific roles of different lipid depots may help new approaches to control obesity and its metabolic sequelae.

Objectives While chronic obesity is associated with alterations in circulating glycerolipids, sphingolipids and plasmalogens, the effects of short-term overfeeding in humans are unclear. Design and Methods 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. Results Overfeeding increased liver fat, insulin resistance, serum C-reactive protein and urinary F2-isoprostanes. HDL increased (11% ± 2%, P < 0.001) 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 (P < 0.01), 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). Conclusions 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

OBJECTIVE Glutamine reduces postprandial glycemia when given before oral glucose. We evaluated whether this is mediated by stimulation of insulin and/or slowing of gastric emptying. RESEARCH DESIGN AND METHODS Ten healthy subjects were studied during intraduodenal (ID) infusion of glutamine (7.5 or 15 g) or saline over 30 min, followed by glucose (75 g over 100 min), while recording antropyloroduodenal pressures. Ten patients with type 2 diabetes mellitus (T2DM) were also studied with 15 g glutamine or saline. RESULTS ID glutamine stimulated glucagon-like peptide 1 (GLP-1; healthy: P < 0.05; T2DM: P < 0.05), glucose-dependent insulinotropic polypeptide (GIP; P = 0.098; P < 0.05), glucagon (P < 0.01; P < 0.001), insulin (P = 0.05; P < 0.01), and phasic pyloric pressures (P < 0.05; P < 0.05), but did not lower blood glucose (P = 0.077; P = 0.5). CONCLUSIONS Glutamine does not lower glycemia after ID glucose, despite stimulating GLP-1, GIP, and insulin, probably due to increased glucagon. Its capacity for pyloric stimulation suggests that delayed gastric emptying is a major mechanism for lowering glycemia when glutamine is given before oral glucose.

Lactic acidosis is an adverse event associated with metformin usage. Patients with metformin-associated lactic acidosis (MALA), however, often have other conditions contributing to the event. The relative contribution of metformin is often unclear. MALA is usually diagnosed without measuring the plasma concentrations of metformin. The objectives of this study were, first, to examine the plasma concentrations of metformin, lactate and creatinine and the arterial pH of patients with suspected MALA and, second, to review critically the mechanisms of MALA. Patients who were suspected of having MALA were identified during the period October 2008–September 2011. Repeated blood samples were collected to determine the plasma concentrations of lactate, metformin and creatinine. The pH of arterial blood was also measured on several occasions in each patient. Patients (n = 15; 9 female, 6 male) were 70 ± 12 years of age. There was one acute metformin overdose (estimated dose 5 g). Metformin was undetectable in one patient and one patient had therapeutic concentrations of metformin on admission (

Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are an increasingly prescribed class of medication for type 2 diabetes mellitus. Euglycaemic diabetic ketoacidosis (euDKA) has been reported in association with SGLT2i use. Clinicians need to understand how to recognise and treat this complication. We describe three cases of euDKA in patients treated with SGLT2i.

The study aimed to (1) determine the trends in the utilisation of metformin in Australia, (2) determine the appropriateness of metformin dosing in an Australian teaching hospital and (3) gather the opinions of prescribers on the relationship between metformin dose and renal function. National prescription data between 1990 and 2012 were accessed. A retrospective audit (2008–2012) of metformin doses and patient renal function (20 % random sample of all in-patients prescribed metformin) was conducted at St Vincent’s Hospital (SVH), Sydney. Prescribers of metformin were interviewed (semi-structured; consultants at SVH) or surveyed (Australian endocrinologists) to gather their understanding of metformin dosing in relation to renal function. Metformin utilisation increased fivefold nationally between 1995 and 2012. Metformin tended to be under-dosed in SVH patients with normal renal function (83.5 %) and over-dosed in patients with impaired renal function (estimated glomerular filtration rate (eGFR)

Maturity onset diabetes of the young (MODY), the most common monogenic form of diabetes, accounts for 1-2% of all diabetes diagnoses. Glucokinase (GCK)-MODY (also referred to as MODY2) constitutes 10-60% of all MODY cases and is inherited as an autosomal dominant heterozygous mutation, resulting in loss of function of the GCK gene. Patients with GCK-MODY generally have mild, fasting hyperglycaemia that is present from birth, are commonly leaner and diagnosed at a younger age than patients with type 2 diabetes, and rarely develop complications from diabetes. Hence, treatment is usually unnecessary and may be ceased. Therefore, genetic screening is recommended in all young patients (

Objective The development of skeletal muscle insulin resistance is an early physiological defect, yet the intracellular mechanisms accounting for this metabolic defect remained unresolved. Here, we have examined the role of glucose-6-phosphate dehydrogenase (G6PDH) activity in the pathogenesis of insulin resistance in skeletal muscle. Methods Multiple mouse disease states exhibiting insulin resistance and glucose intolerance, as well as obese humans defined as insulin-sensitive, insulin-resistant, or pre-diabetic, were examined. Results We identified increased glucose-6-phosphate dehydrogenase (G6PDH) activity as a common intracellular adaptation that occurs in parallel with the induction of insulin resistance in skeletal muscle and is present across animal and human disease states with an underlying pathology of insulin resistance and glucose intolerance. We observed an inverse association between G6PDH activity and nitric oxide synthase (NOS) activity and show that increasing NOS activity via the skeletal muscle specific neuronal (n)NOSμ partially suppresses G6PDH activity in skeletal muscle cells. Furthermore, attenuation of G6PDH activity in skeletal muscle cells via (a) increased nNOSμ/NOS activity, (b) pharmacological G6PDH inhibition, or (c) genetic G6PDH inhibition increases insulin-independent glucose uptake. Conclusions We have identified a novel, previously unrecognized role for G6PDH in the regulation of skeletal muscle glucose metabolism., Highlights • Defective skeletal muscle G6PDH activity in multiple insulin resistant animal models. • Demonstration of defective skeletal muscle G6PDH activity in pre-diabetic individuals. • Identification of nNOSμ as a regulator of G6PDH activity in skeletal muscle. • G6PDH activity modulates insulin-independent glucose uptake in skeletal muscle.

Background: Spontaneous hyperinsulinaemic hypoglycaemia following gastric bypass surgery (GBS) is increasingly recognised. However, its pathophysiology remains unclear. Some patients require pancreatectomy. Medical therapy with calcium channel blockers, acarbose and diazoxide has been reported to be beneficial but has variable adherence and response. Method: We demonstrate the role of GLP1, counter-regulatory hormones and the subsequent response of GLP1 to somatostatin analogue therapy in a 42-year-old woman with persistent neuroglycopaenia 6 years after GBS. Plasma GLP1, insulin and glucose were measured for 5 h on three settings: i) a 75 g oral glucose tolerance test (OGTT); ii) a standard liquid test meal (LTM); and iii) an OGTT 30 min after a s.c. injection of 100 mg octreotide. Results: In comparison with obese non-diabetic controls, the patient had an elevated fasting and a markedly enhanced GLP1 response during the OGTT, followed by an exaggerated insulin response and a subsequent low glucose level. The GLP1 response to a LTM was similar but greater. Octreotide given prior to the OGTT attenuated both the GLP1 and insulin responses and abolished hypoglycaemia. Octreotide therapy significantly improved the patient’s neuroglycopaenic symptoms. The hormone profile was reassessed after 6 months following the LTM preceded by octreotide injection. Peak GLP1 and insulin responses were less pronounced than pretreatment responses and without hypoglycaemia. The patient was treated with lanreotide and had remained symptom-free and euglycaemic for 4 years. Conclusion: An exaggerated incretin response following altered gastrointestinal anatomy was the likely cause of hypoglycaemia in our GBS patient. Somatostatin successfully suppressed this response acutely and in the long term, thereby avoiding pancreatectomy and its sequelae.

Recreational drug use during 'rave' parties is increasingly popular, but the impact of recreational drug use in type 1 diabetes (T1D) is not known. We determined the self-reported pattern and effects of recreational/illicit drug use in Australians with T1D people by inviting people with T1D to participate in an anonymous online/paper survey of drug use, through national radio broadcast and online/hospital advertising. Of the people with T1D who responded to our survey, more than three quarters reported having used recreational/illicit drug, but few people had informed health professionals about drug use. Drug use was associated with worse glycaemic control and higher risk of diabetic ketoacidosis. Medical awareness of common, currently underreported, drug use in young people with T1D is essential. It offers the possibility of helping such patients improve related suboptimal metabolic control.

Positron emission tomography (PET)-computed tomography (CT) has identified metabolically active supraclavicular fat in adult humans based on uptake of labeled glucose and confirmed to be brown adipose tissue (BAT) histologically. However, PET-CT has estimated a prevalence of BAT as low as 5% in adult humans, casting doubt on its significance. The true prevalence of BAT is unknown because of the suboptimal sensitivity of standard PET-CT.The objective of the study was to determine whether BAT is present in PET-negative supraclavicular fat.This was a prospective cohort study.The study was conducted at a tertiary referral hospital.Seventeen patients who underwent preoperative PET-CT for staging of head and neck malignancy participated in the study.The main outcome was signature BAT gene transcripts and protein in biopsies of supraclavicular fat with sc fat as negative control.PET-CT was positive in three and negative in 14 patients. PET-positive fat harbored multilobulated lipid droplets and stained strongly for uncoupling protein 1 (UCP1). These features are absent in sc fat. By contrast, PET-negative fat contained a predominance of cells with unilobulated lipid droplets, with scattered cells containing multilobulated lipid droplets and variable UCP1 staining. Molecular analyses of fat biopsies showed lower but clear expression of UCP1, NDUFS3 (NADH dehydrogenase (ubiquinone) iron-sulfur protein 3), β₃-adrenoceptor, and PRDM16 (PR domain containing 16) transcripts.BAT is present in supraclavicular fat, regardless of PET status. BAT is highly prevalent in adult humans, and its abundance determines PET status.

Obesity has reached epidemic proportions worldwide. Sympathetic nervous system activation has been shown to play a major role linking obesity to the development of associated metabolic complications, such as hypertension. Recent evidence has implicated central melanocortin signalling in the regulation of blood pressure in rodents and humans. The importance of sympathetic neural activity in mediating this association has been highlighted. Humans with loss-of-function mutations in the melanocortin 4 receptor (MC4R) are an ideal group of subjects in whom the importance of melanocortin signalling in linking obesity to hypertension can be studied. Consistent with rodent studies, it was recently demonstrated that humans with MC4R deficiency have lower blood pressure, less hypertension, lower 24-h urinary catecholamine excretion, lower resting heart rate and attenuated insulin-mediated sympathetic activation compared to equally-obese humans. In overweight and obese humans without MC4R mutations, the infusion of a highly-selective MC4R agonist led to dose-dependent increases in blood pressure and heart rate. All effects were independent of insulin. This evidence supports the notion that the melanocortin system regulates blood pressure and sympathetic neural function. The results obtained in rodent and human studies, in relation to blood pressure and sympathetic function, may limit the use of MC4R agonists for the treatment of obesity. Future studies will determine whether MC4R deficiency is associated with protection from development of the detrimental cardiovascular consequences that accompany obesity.

Brown adipose tissue (BAT) plays a major role in energy homeostasis in animals. Detection of BAT using positron emission tomography (PET)-CT in humans has challenged the view that BAT disappears after infancy. Several recent studies, based on analysis of single scans, have reported a low prevalence of only 5–10% in humans, casting doubt on its significance. We undertook a critical analysis of the sensitivity, reproducibility, and accuracy of PET-CT to deduce the prevalence of BAT and factors associated with its detection in adult humans. In a retrospective evaluation of PET-CT, using [18F]fluorodeoxyglucose, performed in 2,934 patients, BAT was identified in 250 patients, yielding an apparent prevalence of 8.5%. Among those patients with BAT, 145 were scanned more than once. The frequency of another scan being positive increased from 8 to 65% for one to more than four additional studies. The average probability of obtaining another positive scan among patients with BAT is 13%, from which the prevalence of BAT is estimated at 64%. BAT was more commonly detected in women, in younger (36 ± 1 vs. 52 ± 1 years, P < 0.001) and leaner (20.1 ± 0.9 vs. 24.9 ± 0.9 kg/m2, P < 0.01) individuals. Fasting glucose was lower in those with BAT than those without (4.9 ± 0.1 vs. 5.5 ± 0.1 mmol/l, P < 0.01). Among patients scanned more than once, BAT was detected when body weight and fasting glucose were lower (54.9 ± 0.5 vs. 58.2 ± 0.8 kg, P < 0.001 and 4.9 ± 0.3 vs. 5.5 ± 0.3 mmol/l, P = 0.03). We conclude that BAT is present in the majority of adult humans. Presence of BAT correlates negatively with body mass index and glucose concentration. BAT may play an important role in energy homeostasis in adults.

The purpose of the study was to test prospectively whether healthy individuals with a family history of type 2 diabetes are more susceptible to adverse metabolic effects during experimental overfeeding. We studied the effects of 3 and 28 days of overfeeding by 5,200 kJ/day in 41 sedentary individuals with and without a family history of type 2 diabetes (FH+ and FH− respectively). Measures included body weight, fat distribution (computed tomography) and insulin sensitivity (hyperinsulinaemic–euglycaemic clamp). Body weight was increased compared with baseline at 3 and 28 days in both groups (p

BACKGROUND Obesity is associated with increased cardiovascular morbidity. The skin is a unique site allowing simple, noninvasive assessment of capillary density and endothelial function. In the present study, we measured skin capillary density and endothelial function in a group of normotensive overweight/obese nondiabetic individuals and healthy lean controls. METHODS AND RESULTS We examined 120 relatively insulin-sensitive overweight individuals (BMI 27.9 +/- 2.7 kg/m, mean +/- SD) with normal blood pressure and fasting plasma glucose and 130 lean (BMI 22.4 +/- 1.7 kg/m) controls. We used video microscopy to measure skin capillary density in the resting state and during venous occlusion. Laser Doppler flowmetry, combined with iontophoresis of acetylcholine (endothelial-dependent vasodilation) and following skin heating (endothelial-independent dilation), was performed. Resting capillary density was negatively correlated with BMI (r = -0.130, P < 0.05). Resting capillary density (mean +/- SE) was lower, however nonsignificantly, in overweight as compared with the lean individuals (88.6 +/- 1.5 vs. 91.8 +/- 1.4, P = 0.117). Capillary recruitment, defined as the percentage increase in capillary density during venous congestion, was higher in overweight (9.5 +/- 1.0%) than in controls (5.4 +/- 0.9%, P = 0.003), which remained significant after adjustment for age, sex, mean arterial pressure and fasting glucose. As a consequence, capillary density during venous occlusion was similar between the groups. Endothelial-dependent and independent cutaneous vasodilation was also similar between groups. No correlations were found between capillary density and plasma markers of adiposity, inflammation or endothelial dysfunction. CONCLUSION BMI was inversely correlated with resting capillary density. This suggests a lower baseline tissue perfusion associated with higher vasomotor tone. Despite this, capillary recruitment was higher in overweight as compared with lean individuals, resulting in similar capillary density during venous congestion. Our results suggest that skin microcirculation abnormalities, in the absence of endothelial dysfunction, may be one of the earliest detectable alterations in vascular function in overweight individuals.

The metabolic syndrome (MetS) is associated with increased risk of type-2 diabetes and cardiovascular disease (CVD). We hypothesized that both small and large arteries may be impaired in subjects with the MetS, even in the absence of known CVD or diabetes. We compared both skin capillary density (CD) and pulse-wave velocity (PWV) in 36 cases with the MetS with those from 108 age- and gender-matched controls from the SU.VIM.AX-2 cohort. Compared with controls, MetS subjects demonstrated increased PWV (12.2+/-2.8 vs. 10.7+/-1.9 m s(-1), P=0.005) and lower functional CD (83.1+/-15.7 vs. 89.4+/-14.2 capillaries per mm(2), P=0.03). Functional CD was inversely related to fasting glucose, triglycerides (TGs) and HOMA-IR (all P0.05). On the other hand, no association was found between CD and BP or with PWV. In multivariate models, the odds ratios (95% confidence interval) for one standard deviation change, for having an impaired PWV (or=12 m s(-1), n=44), were: 1.65 (1.11-2.45) for systolic BP and 1.93 (1.25-2.99) for TG only. For impaired CD (or=80 capillaries per mm(2)), the odds ratios (95% confidence interval) were 1.45 (1.00-2.08) for TG and 1.65 (1.13-2.43) for fasting glucose, only. In conclusion, MetS subjects exhibited evidence of macro- and microcirculatory dysfunction, even in the absence of diabetes and CVD. The common mechanism linking MetS components to CVD risk through small- and large-artery dysfunctions may be mediated through metabolic factors related to insulin resistance, not to increased BP.

OBJECTIVE Chronic low-grade inflammation is a feature of obesity and is postulated to be causal in the development of insulin resistance and type 2 diabetes. The aim of this study was to assess whether overfeeding induces peripheral insulin resistance in lean and overweight humans, and, if so, whether it is associated with increased systemic and adipose tissue inflammation. RESEARCH DESIGN AND METHODS Thirty-six healthy individuals undertook 28 days of overfeeding by +1,250 kcal/day (45% fat). Weight, body composition, insulin sensitivity (hyperinsulinemic-euglycemic clamp), serum and gene expression of inflammation markers, immune cell activation, fat cell size, macrophage and T-cell numbers in abdominal subcutaneous adipose tissue (flow cytometry and immunohistochemistry) were assessed at baseline and after 28 days. RESULTS Subjects gained 2.7 ± 1.6 kg (P < 0.001) and increased fat mass by 1.1 ± 1.6% (P < 0.001). Insulin sensitivity decreased by 11% from 54.6 ± 18.7 to 48.9 ± 15.7 μmol/(kg of FFM)/min (P = 0.01). There was a significant increase in circulating C-reactive protein (P = 0.002) and monocyte chemoattractant protein-1 (P = 0.01), but no change in interleukin-6 and intercellular adhesion molecule-1. There were no changes in fat cell size, the number of adipose tissue macrophages or T-cells, or inflammatory gene expression and no change in circulating immune cell number or expression of their surface activation markers after overfeeding. CONCLUSIONS Weight gain-induced insulin resistance was observed in the absence of a significant inflammatory state, suggesting that inflammation in subcutaneous adipose tissue occurs subsequent to peripheral insulin resistance in humans.

Background: Secondary prevention of ischaemic stroke (IS) and transient ischaemic attack (TIA) mandates identification and treatment of multiple metabolic risk factors. The aim was to determine the prevalence of abnormal glycaemia, hypertension and dyslipidaemia in patients presenting to an Acute Stroke Unit of a tertiary referral teaching hospital with IS or TIA. Methods: We reviewed the clinical characteristics of consecutive patients presenting with symptoms of acute stroke or TIA between 1 February 2006 and 30 June 2007 to determine the prevalence of diabetes, impaired fasting glucose (IFG), post-stroke dysglycaemia (PSD), hypertension and dyslipidaemia. Results: Mean age ± SD of the 224 patients (84 female) was 71 ± 15 years. Seventy per cent (n= 157) of patients presented with IS and 30% (n= 67) with TIA. Of the cohort, 15% (n= 33) had previously diagnosed diabetes, 10% (n= 22) were diagnosed with diabetes during admission and 19% (n= 42) had IFG diagnosed during admission. A further 4% (n= 9) were classified as having PSD. Sixty-two per cent (n= 139) of patients had previously diagnosed hypertension; another 7% (n= 15) were diagnosed during admission. Eighty-eight per cent (n= 197) of patients had dyslipidaemia. Thirty per cent had all three risk factors concurrently. Conclusion: Abnormal glycaemia was present in almost half the patients presenting with IS/TIA, with the majority of cases undiagnosed. One-third of patients had abnormal glycaemia, hypertension and dyslipidaemia concurrently. Patients presenting with stroke should be routinely screened for abnormal glycaemia in concert with other vascular risk factors.

Weight gain and weight loss are associated with changes in blood pressure through unknown mechanisms. Central melanocortinergic signaling is implicated in the control of energy balance and blood pressure in rodents, but there is no information regarding such an association with blood pressure in humans.We assessed blood pressure, heart rate, and urinary catecholamines in overweight or obese subjects with a loss-of-function mutation in MC4R, the gene encoding the melanocortin 4 receptor, and in equally overweight control subjects. We also examined the effects of an MC4R agonist administered for 7 days in 28 overweight or obese volunteers.The prevalence of hypertension was markedly lower in the MC4R-deficient subjects than in the control subjects (24% vs. 53%, P=0.009). After the exclusion of subjects taking antihypertensive medications, blood-pressure levels were significantly lower in MC4R-deficient subjects than in control subjects, with mean (+/-SE) systolic blood pressures of 123+/-14 mm Hg and 131+/-12 mm Hg, respectively (P=0.02), and mean diastolic blood pressures of 73+/-10 mm Hg and 79+/-7 mm Hg, respectively (P=0.03). As compared with control subjects, MC4R-deficient subjects had a lower increase in heart rate on waking (P=0.007), a lower heart rate during euglycemic hyperinsulinemia (P0.001), and lower 24-hour urinary norepinephrine excretion (P=0.04). The maximum tolerated daily dose of 1.0 mg of the MC4R agonist led to significant increases of 9.3+/-1.9 mm Hg in systolic blood pressure and of 6.6+/-1.1 mm Hg in diastolic blood pressure (P0.001 for both comparisons) at 24 hours, as compared with placebo. Differences in blood pressure were not explained by changes in insulin levels; there were no significant adverse events.Results of our genetic and pharmacologic studies implicate melanocortinergic signaling in the control of human blood pressure through an insulin-independent mechanism.

Weight loss is associated with improvements in glycaemic control and cardiovascular disease risk factors. However, in the diabetic population, weight management is more challenging, in part because of the weight-promoting effects of the majority of glucose-lowering therapies. This review summarizes evidence from 23 placebo-controlled randomized trials, of at least 1 year duration, on the effects of drugs promoting weight loss (orlistat, sibutramine and rimonabant) on glycaemic variables, diabetes incidence and diabetes control. Fifteen studies of non-diabetic subjects were found, eight of which included a longer treatment period. Eight studies in diabetic patients were reviewed. In non-diabetic subjects, weight loss agents led to a significant improvement in fasting glucose, fasting insulin and insulin resistance. In the diabetic population, glycated haemoglobin decreased by 0.28-1.1% with orlistat and 0.6% with sibutramine and rimonabant. Orlistat reduces progression to diabetes in patients with glucose intolerance treated for 4 years (risk reduction of 45%). In summary, despite leading to only modest weight loss after 12 months, agents promoting weight loss have beneficial effects on glycaemic parameters, glycaemic control and progression to diabetes. These additional benefits of weight loss agents need to be highlighted in order to increase their judicious use in clinical practice, although this may be limited by their well-known adverse side effects. The longer-term safety of these agents beyond a few years is yet to be established.

FGF21 mimetics are a promising therapeutic tool, believed to exert their anti-obesity effect partly through browning of white fat. Veniant et al. (2015) and Samms et al. (2015) present evidence arguing against fat browning as the primary mechanism causal to weight loss following FGF21-based treatment in mice.

Addison's disease is associated with low bone mineral density and increased risk of hip fractures. Causes are multifactorial, contributed by underlying adrenocortical hormonal deficiency, associated autoimmune endocrinopathies, electrolyte disturbances and, in some patients, supraphysiologic glucocorticoid replacement. Recent realization of physiologic cortisol production rate has revised downwards glucocorticoid replacement dosages. Meanwhile, new research has emerged suggesting complex interplay between sodium and calcium homoeostasis under the influence of mineralocorticoid and parathyroid hormone that may impact bone health. As the prevalence of Addison's disease is rising, and osteoporosis and fractures are associated with significant morbidity and increased mortality, attention to bone preservation in Addison's disease is of clinical relevance and importance. We suggest an approach to bone health in Addison's disease integrating physiologic adrenocortical hormonal replacement with electrolyte and mineral homoeostasis optimization.

We describe a case of severe hyperglycaemia resulting in diabetic ketoacidosis secondary to L-asparaginase. There are few reports of this potentially life-threatening complication, particularly in the English literature. Awareness and recognition of this preventable and manageable problem will improve safe delivery of this anti-leukaemic drug.

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.

Summary The thiazolidinediones (or ‘glitazones’) are a new class of drugs for the treatment of type 2 diabetes. They bind avidly to peroxisome proliferator-activated receptor gamma in adipocytes to promote adipogenesis and fatty acid uptake (in peripheral but not visceral fat). By reducing circulating fatty acid concentrations and lipid availability in liver and muscle, the drugs improve the patient’s sensitivity to insulin. Thiazolidinediones favourably alter concentrations of the hormones secreted by adipocytes, particularly adiponectin. They increase total body fat and have mixed effects on circulating lipids.

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.

Metformin therapy is limited in patients with chronic kidney disease (CKD) due to the potential risk of lactic acidosis. This open-label observational study investigated metformin and lactate concentrations in patients with CKD (n = 22; creatinine clearances 15–40 ml/min) and in two dialysed patients. Patients were prescribed a range of metformin doses (250–2000 mg daily) and metformin concentrations were compared with data from healthy subjects (scaled to 1500 mg twice daily). A subset of patients (n = 7) was controlled on low doses of metformin (250 or 500 mg daily). No correlation between metformin and lactate concentrations was observed. Three patients had high lactate concentrations (>2.7 mmol/l) and two had high metformin concentrations (3–5 mg/l), but none had any symptoms of lactic acidosis. Reducing metformin dosage and monitoring metformin concentrations will allow the safe use of metformin in CKD, provided that renal function is stable.

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.

Diabetes and hyperglycemia are important causes of morbidity and mortality worldwide. Type 2 diabetes (approximately 90 % of diabetes cases) results from impaired insulin action on target tissues, termed insulin resistance, and is associated with excess body weight and physical inactivity [1, 2]. Defective insulin secretion is a key impairment in type 2 diabetes, contributing to hyperglycemia [3, 4]. Current research is focused on developing treatments that could potentially increase insulin secretion and improve glycemia in response to a meal in type 2 diabetes.

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.

To compare the pharmacokinetics of metformin between diabetic Indigenous (Aboriginal and Torres Strait Islander) and non-Indigenous patients.An observational, cross-sectional study was conducted on type 2 diabetic Indigenous and non-Indigenous patients treated with metformin. Blood samples were collected to determine metformin, lactate, creatinine and vitamin B12 concentrations and glycosylated haemoglobin levels. A population model was used to determine the pharmacokinetic parameters.The Indigenous patients (median age 55 years) were younger than the non-Indigenous patients (65 years), with a difference of 10 years (95% confidence interval 6-14 years, P0.001). The median glycosylated haemoglobin was higher in the Indigenous patients (8.5%) than in the non-Indigenous patients (7.2%), with a difference of 1.4% (0.8-2.2%, P0.001). Indigenous patients had a higher creatinine clearance (4.3 l h(-1) ) than the non-Indigenous patients (4.0 l h(-1) ), with a median difference of 0.3 l h(-1) (0.07-1.17 l h(-1) ; P0.05). The ratio of the apparent clearance of metformin to the creatinine clearance in Indigenous patients (13.1, 10.2-15.2; median, interquartile range) was comparable to that in non-Indigenous patients (12.6, 9.9-14.9). Median lactate concentrations were also similar [1.55 (1.20-1.88) vs. 1.60 (1.35-2.10) mmol l(-1) ] for Indigenous and non-Indigenous patients, respectively. The median vitamin B12 was 306 pmol l(-1) (range 105-920 pmol l(-1) ) for the Indigenous patients.There were no significant differences in the pharmacokinetics of metformin or plasma concentrations of lactate between Indigenous and non-Indigenous patients with type 2 diabetes mellitus. Further studies are required in Indigenous patients with creatinine clearance30 ml min(-1) .

Background and Aims L-glutamine is an efficacious glucagon-like peptide (GLP)-1 secretagogue in vitro. When administered with a meal, glutamine increases GLP-1 and insulin excursions and reduces postprandial glycaemia in type 2 diabetes patients. The aim of the study was to assess the efficacy and safety of daily glutamine supplementation with or without the dipeptidyl peptidase (DPP)-4 inhibitor sitagliptin in well-controlled type 2 diabetes patients. Methods Type 2 diabetes patients treated with metformin (n = 13, 9 men) with baseline glycated hemoglobin (HbA1c) 7.1±0.3% (54±4 mmol/mol) received glutamine (15 g bd)+ sitagliptin (100 mg/d) or glutamine (15 g bd) + placebo for 4 weeks in a randomized crossover study. Results HbA1c (P = 0.007) and fructosamine (P = 0.02) decreased modestly, without significant time-treatment interactions (both P = 0.4). Blood urea increased (P

Background This research examined whether young adults with Type 1 diabetes engage with the multidisciplinary consultation process and if not, then why. Methods We designed a web-based self-reported survey, available online from February to May 2011, for Australian adults 18–35 years with Type 1 diabetes. Respondents were asked about which clinicians they consulted to assist with self-management. To expand on the results of the survey, we interviewed 33 respondents. Results Survey: Respondents (n = 150) consulted with the following clinicians: endocrinologist and diabetes educators: 23.3%; endocrinologist only: 18.0%; endocrinologist, diabetes educators and dieticians: 14.6%; endocrinologist, diabetes educators, dietician and general practitioners (GP): 11.3%; endocrinologist and GP: 10.6%; GP only: 4.6%; all clinicians recommended to assist with self-management: 1.3%; 2.7% did not consult any clinician. Interview: Participants (n = 33) reported eight key disincentives to consultation with multidisciplinary clinicians. These were time constraints; provision of conflicting advice; inaccessibility of health services; variation in service standards; cost constraints; failure of clinicians to refer to other clinicians; lack of opportunity to build a therapeutic relationship; and failure of clinicians to engage in shared decision making. Conclusion Our results indicate that high attrition rates of young adults with Type 1 diabetes from recommended diabetes health services is linked to the failure of those services to meet the needs and preferences of their patients. The identified needs and preferences included joint consultation with multi-disciplinary team clinicians; flexible access to advice by email or telephone consultation; and shared decision making. Patient engagement in health-service re-design has implications for improved health-service delivery and enhanced treatment outcomes.

Distal tibial fractures are often the result of high-energy impacts combined with excessive soft tissue injury. Treatment options include either open reduction and internal fixation usually as a mi...

Metformin is contraindicated in patients with renal impairment; however, there is poor adherence to current dosing guidelines. In addition, the pharmacokinetics of metformin in patients with significant renal impairment are not well described. The aims of this study were to investigate factors influencing the pharmacokinetic variability, including variant transporters, between healthy subjects and patients with type 2 diabetes mellitus (T2DM) and to simulate doses of metformin at varying stages of renal function.Plasma concentrations of metformin were pooled from three studies: patients with T2DM (study A; n = 120), healthy Caucasian subjects (study B; n = 16) and healthy Malaysian subjects (study C; n = 169). A population pharmacokinetic model of metformin was developed using NONMEM(®) version VI for both the immediate-release (IR) formulation and the extended-release (XR) formulation of metformin. Total body weight (TBW), lean body weight (LBW), creatinine clearance (CLCR; estimated using TBW and LBW) and 57 single-nucleotide polymorphisms (SNPs) of metformin transporters (OCT1, OCT2, OCT3, MATE1 and PMAT) were investigated as potential covariates. A nonparametric bootstrap (n = 1,000) was used to evaluate the final model. This model was used to simulate 1,000 concentration-time profiles for doses of metformin at each stage of renal impairment to ensure metformin concentrations do not exceed 5 mg/l, the proposed upper limit.Creatinine clearance and TBW were clinically and statistically significant covariates with the apparent clearance and volume of distribution of metformin, respectively. None of the 57 SNPs in transporters of metformin were significant covariates. In contrast to previous studies, there was no effect on the pharmacokinetics of metformin in patients carrying the reduced function OCT1 allele (R61C, G401S, 420del or G465R). Dosing simulations revealed that the maximum daily doses in relation to creatinine clearance to prescribe to patients are 500 mg (15 ml/min), 1,000 mg (30 ml/min), 2,000 mg (60 ml/min) and 3,000 mg (120 ml/min), for both the IR and XR formulations.The population model enabled doses of metformin to be simulated for each stage of renal function, to ensure the concentrations of metformin do not exceed 5 mg/l. However, the plasma concentrations of metformin at these dosage levels are still quite variable and monitoring metformin concentrations may be of value in individualising dosage. This study provides confirmatory data that metformin can be used, with appropriate dosage adjustment, in patients with renal impairment.

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.