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Context: The etiological mechanism of bile acid (BA) effects on insulin resistance and obesity is unknown., Objective: This work aimed to determine whether plasma BAs are elevated in human obesity and/or insulin resistance., Methods: This observational study was conducted at an academic research center. Seventy-one adult volunteers formed 4 groups: lean insulin-sensitive (body mass index [BMI] ≤ 25 kg/m2, Homeostatic Model Assessment of Insulin Resistance [HOMA-IR] < 2.0, n = 19), overweight/obese nondiabetic who were either insulin sensitive (Obsensitive, BMI > 25 kg/m2, HOMA-IR < 1.5, n = 11) or insulin resistant (Obresistant, BMI > 25 kg/m2, HOMA-IR > 3.0, n = 20), and type 2 diabetes (T2D, n = 21). Main outcome measures included insulin sensitivity by hyperinsulinemic-euglycemic clamp, body composition by dual energy x-ray absorptiometry, abdominal fat distribution, and liver density by computed tomography and plasma BA., Results: In the Obresistant group, glucose infusion rate/fat-free mass (GIR/FFM, an inverse measure of insulin resistance) was significantly lower, and visceral and liver fat higher, compared to lean and Obsensitive individuals, despite similar total adiposity in Obresistant and Obsensitive. Total BA concentrations were higher in Obresistant (2.62 ± 0.333 mmol/L, P = .03) and T2D (3.36 ± 0.582 mmol/L, P < .001) vs Obsensitive (1.16 ± 0.143 mmol/L), but were similar between Obsensitive and lean (2.31 ± 0.329 mmol/L) individuals. Total BAs were positively associated with waist circumference (R = 0.245, P = .041), visceral fat (R = 0.360, P = .002), and fibroblast growth factor 21 (R = 0.341, P = .004) and negatively associated with insulin sensitivity (R = -0.395, P = .001), abdominal subcutaneous fat (R = -0.352, P = .003), adiponectin (R = -0.375, P = .001), and liver fat (Hounsfield units, an inverse marker of liver fat, R = -0.245, P = .04). Conjugated BAs were additionally elevated in T2D individuals (P < .001)., Conclusions: BA concentrations correlated with abdominal, visceral, and liver fat in humans, though an etiological role in insulin resistance remains to be verified., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To determine whether routine blood glucose assessment of patients admitted to hospital from emergency departments (EDs) results in higher rates of new diagnoses of diabetes and documentation of follow-up plans., Design, Setting: Cluster randomised trial in 18 New South Wales public district and tertiary hospitals, 31 May 2011 - 31 December 2012; outcomes follow-up to 31 March 2016., Participants: Patients aged 18 years or more admitted to hospital from EDs., Intervention: Routine blood glucose assessment at control and intervention hospitals; automatic requests for glycated haemoglobin (HbA 1c ) assessment and notification of diabetes services about patients at intervention hospitals with blood glucose levels of 14 mmol/L or more., Main Outcome Measure: New diagnoses of diabetes and documented follow-up plans for patients with admission blood glucose levels of 14 mmol/L or more., Results: Blood glucose was measured in 133 837 patients admitted to hospital from an ED. The numbers of new diabetes diagnoses with documented follow-up plans for patients with blood glucose levels of 14 mmol/L or more were similar in intervention (83/506 patients, 16%) and control hospitals (73/278, 26%; adjusted odds ratio [aOR], 0.83; 95% CI 0.42-1.7; P = 0.61), as were new diabetes diagnoses with or without plans (intervention, 157/506, 31%; control, 86/278, 31%; aOR, 1.51; 95% CI, 0.83-2.80; P = 0.18). 30-day re-admission (31% v 22%; aOR, 1.34; 95% CI, 0.86-2.09; P = 0.21) and post-hospital mortality rates (24% v 22%; aOR, 1.07; 95% CI, 0.74-1.55; P = 0.72) were also similar for patients in intervention and control hospitals., Conclusion: Glucose and HbA 1c screening of patients admitted to hospital from EDs does not alone increase detection of previously unidentified diabetes. Adequate resourcing and effective management pathways for patients with newly detected hyperglycaemia and diabetes are needed., Trial Registration: Australian New Zealand Clinical Trials Registry, ACTRN12611001007921., (© 2019 AMPCo Pty Ltd.)

Background: Large cohort longitudinal studies have almost unanimously concluded that metabolic health in obesity is a transient phenomenon, diminishing in older age. We aimed to assess the fate of insulin sensitivity per se over time in overweight and obese individuals., Methods: Individuals studied using the hyperinsulinaemic-euglycaemic clamp at the Garvan Institute of Medical Research from 2008 to 2010 ( n = 99) were retrospectively grouped into Lean (body mass index (BMI) < 25 kg/m 2 ) or overweight/obese (BMI ≥ 25 kg/m 2 ), with the latter further divided into insulin-sensitive (Ob Sen ) or insulin-resistant (Ob Res ), based on median clamp M-value (M/I, separate cut-offs for men and women). Fifty-seven individuals participated in a follow-up study after 5.4 ± 0.1 years. Hyperinsulinaemic-euglycaemic clamp, dual-energy X-ray absorptiometry and circulating cardiovascular markers were measured again at follow-up, using the same protocols used at baseline. Liver fat was measured using computed tomography at baseline and proton magnetic resonance spectroscopy at follow-up with established cut-offs applied for defining fatty liver., Results: In the whole cohort, M/I did not change over time ( p = 0.40); it remained significantly higher at follow-up in Ob Sen compared with Ob Res ( p = 0.02), and was not different between Ob Sen and Lean ( p = 0.41). While BMI did not change over time ( p = 0.24), android and visceral fat increased significantly in this cohort ( p time ≤ 0.0013), driven by Ob Res ( p = 0.0087 and p = 0.0001, respectively). Similarly, systolic blood pressure increased significantly over time (p time = 0.0003) driven by Ob Res ( p = 0.0039). The best correlate of follow-up M/I was baseline M/I (Spearman's r = 0.76, p = 1.1 × 10 -7 )., Conclusions: The similarity in insulin sensitivity between the Ob Sen and the Lean groups at baseline persisted over time. Insulin resistance in overweight and obese individuals predisposed to further metabolic deterioration over time.

Introduction: When cervical lymph nodes are clinically positive for metastatic melanoma, surgeons may be hesitant to recommend a therapeutic complete lymph node dissection if the patient is elderly or has major comorbidities. A limited local node excision of the clinically positive nodes only, followed by adjuvant radiotherapy to the entire node field, may be an effective alternative in such patients., Methods: All patients who had presented with a primary head and neck melanoma or an unknown primary site and had subsequently undergone limited local node excision and adjuvant radiotherapy for macroscopically involved cervical nodes between 1993 and 2010 at a tertiary referral center were selected for study., Results: Twenty-eight patients were identified, with a median age of 78 years and a median of 2 major comorbidities. The 5-year regional control, disease-free survival, and overall survival rates were 69%, 44%, and 50%, respectively. At the time of data analysis, seven patients were alive without evidence of disease. Twenty-one patients had died: 11 of melanoma (4 with neck recurrence) and 10 of other causes (2 with neck recurrence)., Conclusions: Excision of clinically positive metastatic cervical lymph nodes followed by radiotherapy provides satisfactory regional disease control without risking serious morbidity or mortality in melanoma patients whose general condition is considered a contraindication for therapeutic complete lymph node dissection.

Obesity and osteoporosis are common public health problems. Paradoxically, while obesity is associated with higher bone density, type 2 diabetic obese individuals have an increased fracture risk. Although obesity and insulin resistance co-exist, some obese individuals remain insulin-sensitive. We suggest that the apparent paradox relating obesity, bone density and fracture risk in type 2 diabetes may be at least partly influenced by differences in bone strength and quality between insulin-resistant and insulin-sensitive obese individuals. In this review, we focus on the complex interplay between, adiposity, insulin resistance and osteoporotic fracture risk and suggest that this is an important area of study that has implications for individually tailored and targeted treatment to prevent osteoporotic fracture in obese type 2 diabetic individuals., (© 2018 World Obesity Federation.)

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., (© 2017 Royal Australasian College of Physicians.)

Context: The contribution of insulin resistance vs adiposity to bone mineral density (BMD), bone turnover, and fractures in humans remains unclear., Objective: To evaluate BMD and bone turnover markers (BTMs) in lean (n = 18) and overweight/obese individuals with (n = 17) and without (n = 34, insulin-sensitive [Obsensitive, n=15] or insulin-resistant [Obresistant, n=19] by homeostasis model assessment insulin resistance) diabetes mellitus., Design: Observational study., Outcome Measures: Insulin sensitivity was assessed using the hyperinsulinemic-euglycemic clamp; whole body BMD and fat mass (FM) using dual energy X-ray absorptiometry; and by measurement of BTMs [osteocalcin (OC), procollagen type 1 N-terminal propeptide (P1NP), and collagen type 1 cross-linked C-terminal telopeptide (CTx)], with the patient fasting and during clamp hyperinsulinemia., Results: Fasting BTMs correlated with glucose infusion rate/fat-free mass (GIR/FFM) and adiponectin and, inversely, with fasting insulin and visceral fat (P ≤ 0.04 for all). Obsensitive, Obresistant, and diabetic individuals were matched by their FM percentage. Clamp GIR/FFM was similar in the lean and Obsensitive subjects (P = 1) and approximately twofold greater (P < 0.001) than in the Obresistant and diabetic subjects. BMD was greater in Obresistant than in Obsensitive (P = 0.04) and lean (P = 0.001) subjects. At baseline, compared with Obsensitive and lean subjects, Obresistant and diabetic individuals had lower OC, P1NP, and CTx levels. This reached statistical significance for Obresistant vs lean and Obresistant vs Obsensitive for both OC and CTx and for diabetic vs lean for CTx (P ≤ 0.04 for all). During hyperinsulinemia, lean individuals suppressed CTx more than did diabetic individuals (P = 0.03). On multiple regression analysis, visceral adiposity explained 16.7% and 19.3% of the baseline OC and CTx variability, respectively., Conclusions: Increased visceral adiposity and higher fasting insulin in insulin-resistant states are associated with lower fasting OC and CTx and failure to further suppress with more insulin., (Copyright © 2017 by the Endocrine Society)

Objective: Alterations in lipids in muscle and plasma have been documented in insulin-resistant people with obesity. Whether these lipid alterations are a reflection of insulin resistance or obesity remains unclear., Methods: Nondiabetic sedentary individuals not treated with lipid-lowering medications were studied (n = 51). Subjects with body mass index (BMI) > 25 kg/m(2) (n = 28) were stratified based on median glucose infusion rate during a hyperinsulinemic-euglycemic clamp into insulin-sensitive and insulin-resistant groups (above and below median, obesity/insulin-sensitive and obesity/insulin-resistant, respectively). Lean individuals (n = 23) served as a reference group. Lipidomics was performed in muscle and plasma by liquid chromatography electrospray ionization-tandem mass spectrometry. Pathway analysis of gene array in muscle was performed in a subset (n = 35)., Results: In muscle, insulin resistance was characterized by higher levels of C18:0 sphingolipids, while in plasma, higher levels of diacylglycerol and cholesterol ester, and lower levels of lysophosphatidylcholine and lysoalkylphosphatidylcholine, indicated insulin resistance, irrespective of overweight/obesity. The sphingolipid metabolism gene pathway was upregulated in muscle in insulin resistance independent of obesity. An overweight/obesity lipidomic signature was only apparent in plasma, predominated by higher triacylglycerol and lower plasmalogen species., Conclusions: Muscle C18:0 sphingolipids may play a role in insulin resistance independent of excess adiposity., (© 2016 The Obesity Society.)

Background: Diabetic patients are commonly hyperglycaemic on presentation. Admission hyperglycaemia is associated with adverse outcomes, particularly prolonged hospitalisation. Improving inpatient glycaemia may reduce length of hospital stay (LOS) in diabetic patients., Aims: To determine whether in-hospital recognition and treatment of admission hyperglycaemia in diabetic patients is associated with reduced LOS., Methods: Medical records were reviewed from 1 November 2011 to 31 May 2012 for 162 diabetic patients admitted with a blood glucose level (BGL) ≥11.1mmol/L. In-hospital outcomes were compared. Stepwise multiple regression was used to evaluate factors contributing to LOS., Results: Compared to the untreated individuals (n=67), hyperglycaemia treatment (n=95) was associated with a longer LOS (median eight vs. four days, p<0.01), higher HbA1c (9.0 vs. 7.3 per cent, p<0.01), more infections (50 vs. 25 per cent, p<0.01), and more patients with follow-up plans (35 vs. 10 per cent, p<0.01). Higher HbA1c was significantly related to more follow-up (ρs=0.30, n=110, p<0.01) with a trend to lower re-admission in those with follow-up plans (ρs=-1.41, n=162, p=0.07)., Conclusion: Recognition and treatment of admission hyperglycaemia in diabetic patients was associated with longer LOS than if untreated. Contributory factors to LOS include: illness severity, infections, and higher HbA1c. Although follow-up plans were few (27 per cent) for diabetic patients with hyperglycaemia, it was significantly more likely in those with higher HbA1c. Diabetic patients' complexities require timely multidisciplinary team involvement. Improved follow-up care, particularly for hospitalised diabetic patients identified to have chronically poor glycaemic control, may help prevent future diabetic patient re-admissions.

Aims/hypothesis: Muscle insulin resistance, one of the earliest defects associated with type 2 diabetes, involves changes in the phosphoinositide 3-kinase/Akt network. The relative contribution of obesity vs insulin resistance to perturbations in this pathway is poorly understood., Methods: We used phosphospecific antibodies against targets in the Akt signalling network to study insulin action in muscle from lean, overweight/obese and type 2 diabetic individuals before and during a hyperinsulinaemic-euglycaemic clamp., Results: Insulin-stimulated Akt phosphorylation at Thr309 and Ser474 was highly correlated with whole-body insulin sensitivity. In contrast, impaired phosphorylation of Akt substrate of 160 kDa (AS160; also known as TBC1D4) was associated with adiposity, but not insulin sensitivity. Neither insulin sensitivity nor obesity was associated with defective insulin-dependent phosphorylation of forkhead box O (FOXO) transcription factor. In view of the resultant basal hyperinsulinaemia, we predicted that this selective response within the Akt pathway might lead to hyperactivation of those processes that were spared. Indeed, the expression of genes targeted by FOXO was downregulated in insulin-resistant individuals., Conclusions/interpretation: These results highlight non-linearity in Akt signalling and suggest that: (1) the pathway from Akt to glucose transport is complex; and (2) pathways, particularly FOXO, that are not insulin-resistant, are likely to be hyperactivated in response to hyperinsulinaemia. This facet of Akt signalling may contribute to multiple features of the metabolic syndrome.

Background: Diabetes diagnosis is delayed 4-7 years and 50% are undiagnosed. Forty percent of hospitalized patients with any blood glucose level (BGL) > or = 10 mmol/L have diabetes 3 months post-discharge, yet less than 5% are detected in hospital. We review identification of, and responses to, hyperglycaemia in inpatients at a teaching hospital., Methods: The world's largest retrospective review of medical records for inpatients with venous BGL > or = 11.1 mmol/L without known diabetes over 12 months (2005-2006). The primary outcome was recognition of hyperglycaemia; secondary outcomes were treatment and documentation of follow up. Logistic regression was performed with variables including BGL, admitting team, length of stay and endocrine team review., Results: Of 10 973 people screened, 162 were eligible. The median age was 58 years and BGL 13.3 mmol/L, with increased mortality and length of stay. Hyperglycaemia was noted as definitely in 26%, maybe in 24% and definitely not in 50%. Forty percent of patients were treated in hospital and 19% on discharge. Follow up was documented for 24%. A higher BGL and review by the endocrine team were strongly associated with clinical recognition on uni- and multivariate analyses. However, where an endocrine review was sought for non-hyperglycaemia reasons, similar rates of non-recognition occurred., Conclusion: Despite evidence for improved inpatient outcomes when treated, and high short-term progression to frank diabetes, inpatient hyperglycaemia remains frequently missed. In-hospital recognition is cheap, and vital for the implementation of activities to improve outcomes and prevent progression and complications. Changes to systems for checking pathology results, medical officer education and inpatient screening guidelines are indicated.