The Relationship between Dyslipidemia and Acute Axonal Function in Type 2 Diabetes Mellitus In Vivo.

OBJECTIVES:Diabetic peripheral neuropathy (DPN) is a common and debilitating complication of diabetes mellitus. Treatment largely consists of symptom alleviation and there is a need to identify therapeutic targets for prevention and treatment of DPN. The objective of this study was to utilise novel neurophysiological techniques to investigate axonal function in patients with type 2 diabetes and to prospectively determine their relationship to serum lipids in type 2 diabetic patients. METHODS:Seventy-one patients with type 2 diabetes were consecutively recruited and tested. All patients underwent thorough clinical neurological assessments including nerve conduction studies, and median motor axonal excitability studies. Studies were also undertaken in age matched normal control subjects(n = 42). Biochemical studies, including serum lipid levels were obtained in all patients. Patient excitability data was compared to control data and linear regression analysis was performed to determine the relationship between serum triglycerides and low density lipoproteins and excitability parameters typically abnormal in type 2 diabetic patients. RESULTS:Patient mean age was 64.2±2.3 years, mean glycosylated haemoglobin (HbA1c%) was 7.8±0.3%, mean triglyceride concentration was 1.6±0.1 mmol/L and mean cholesterol concentration was 4.1±0.2mmol/L. Compared to age matched controls, median motor axonal excitability studies indicated axonal dysfunction in type 2 diabetic patients as a whole (T2DM) and in a subgroup of the patients without DPN (T2DM-NN). These included reduced percentage threshold change during threshold electrotonus at 10-20ms depolarising currents (TEd10-20ms)(controls 68.4±0.8, T2DM63.9±0.8, T2DM-NN64.8±1.6%,P<0.05) and superexcitability during the recovery cycle (controls-22.5±0.9, T2DM-17.5±0.8, T2DM-NN-17.3±1.6%,P<0.05). Linear regression analysis revealed no associations between changes in axonal function and either serum triglyceride or low density lipoprotein concentration when adjusted for renal function, a separate risk factor for neuropathy development. Our findings indicate that acutely, serum lipids do not exert an acute effect on axonal function in type 2 diabetic patients: TEd(10-20ms)(1.2(-1.4,3.8);P = 0.4) and superexcitability (2.4(-0.05, 4.8);P = 0.06). CONCLUSIONS:These findings suggest that serum triglyceride levels are not related to axonal function in type 2 diabetic patients. Additional pathogenic mechanisms may play a more substantial role in axonal dysfunction prior to DPN development

Linear Regression model between serum LDL and excitability parameters typically abnormal in type 2 diabetic patients.

<p>Linear Regression model between serum LDL and excitability parameters typically abnormal in type 2 diabetic patients.</p

Clinical characteristics of the patient cohort.

<p>Clinical characteristics of the patient cohort.</p

Linear Regression model between serum triglycerides and excitability parameters typically abnormal in type 2 diabetic patients.

<p>Linear Regression model between serum triglycerides and excitability parameters typically abnormal in type 2 diabetic patients.</p

Axonal excitability parameters in patients vs controls.

<p>Axonal excitability parameters in patients vs controls.</p

Mean threshold electrotonus and recovery cycle plots from type 2 diabetic patients without neuropathy compared to matched normal controls.

<p>Type 2 diabetic patients (block lines) exhibited less threshold change during both threshold electrotonus (a) and the recovery cycle (b) compared to control subjects (dashed lines). Threshold electrotonus parameters are expressed as percentage threshold change during and after subthreshold depolarising and hyperpolarising currents up to 100ms whilst the recovery cycle is given as percentage threshold change at varying intervals after a supramaximal impulse. Significance is indicated by: *P<0.05, **P<0.005 and ***P<0.0005.</p

Routine glucose assessment in the emergency department for detecting unrecognised diabetes : a cluster randomised trial

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 (HbA1c) 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 HbA1c 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

Islet-1: A potentially important role for an islet cell gene in visceral fat

Objective: To examine differences in gene expression between visceral (VF) and subcutaneous fat (SF) to identity genes of potential importance in regulation of VF. Methods and Procedures: We compared gene expression (by DNA array and quantitative PCR (qPCR)) in paired VF and SF adipose biopsies from 36 subjects (age 54 15 years, 15 men/21 women) with varying degrees of adiposity and insulin resistance, in chow and fat fed mice (rosiglitazone treatment) and in c-Cbl−/− mice. Gene expression was also examined in 3T3-L1 preadipocytes during differentiation. Results: A twofold difference or more was found between VF and SF in 1,343 probe sets, especially for genes related to development, cell differentiation, signal transduction, and receptor activity. Islet-1 (ISL1), a LIM-homeobox gene with important developmental and regulatory function in islet, neural, and cardiac tissue, not previously recognized in adipose tissue was virtually absent in SF but substantially expressed in VF. ISL1 expression correlated negatively with BMI (r = −0.37, P = 0.03), abdominal fat (by dual energy X-ray absorptiometry, r = −0.44, P = 0.02), and positively with circulating adiponectin (r = 0.33, P = 0.04). In diet-induced obese mice, expression was reduced in the presence or absence of rosiglitazone. Correspondingly, expression was increased in the c-Cbl−/−mouse, which is lean and insulin sensitive (IS). ISL1 expression was increased sevenfold in 3T3-L1 preadipocytes during early (day 1) differentiation and was reduced by day 2 differentiation. Discussion: An important developmental and regulatory gene ISL1 is uniquely expressed in VF, probably in the preadipocyte. Our data suggest that ISL1 may be regulated by adiposity and its role in metabolic regulation merits further study.Haiyan Li, Leonie K. Heilbronn, Dachun Hu, Ann M. Poynten, Miriam A. Blackburn, Deepali P. Shirkhedkar, Warren H. Kaplan, Adamandia D. Kriketos, Jiming Ye and Donald J. Chishol