Non-alcoholic fatty liver disease and risk of type 2 diabetes

Non-alcoholic fatty liver disease (NAFLD) covers a spectrum of liver disease from simple steatosis to non-alcoholic steatohepatitis (NASH) and cirrhosis. NAFLD is commonly associated with features of the metabolic/insulin resistance syndrome ('Metabolic/Obese NAFLD') and may therefore predict type 2 diabetes (T2DM). For this review, we searched for prospective studies examining whether NAFLD predicts T2DM, and if so, whether this occurs independently of factors such as age and obesity. These studies included NAFLD diagnosed by ultrasonography (n = 6) or liver enzymes (n = 14). All ultrasonography studies found NAFLD to predict the risk of T2DM independently of age, and in 4 out of 6 studies NAFLD was also a predictor independently of BMI. NAFLD was a predictor of T2DM in all 14 studies where NAFLD was diagnosed by liver enzymes. In 12 of these studies, ALT or AST or GGT were significant predictors of T2DM risk, independently of age and BMI. NAFLD, however, is heterogeneous and may also be caused by common genetic variants. The I148M variant in PNPLA3 and the E167K variant in TM6SF2 are both associated with increased liver fat content, but not features of the metabolic/insulin resistance syndrome. These genetic forms of NAFLD predict NASH and cirrhosis but not T2DM. Taken together these data imply that 'Metabolic/Obese NAFLD' predicts T2DM independently of age and obesity and support the role of hepatic insulin resistance in the pathogenesis of this disease. (C) 2016 Elsevier Ltd. All rights reserved.Peer reviewe

Contact frequency determines outcome of basal insulin initiation trials in type 2 diabetes

Aims/hypothesis The aim of the present study was to investigate whether predetermined contact frequency with the study teamand endpoint insulin dose are associated with study outcomes in basal insulin initiation trials in type 2 diabetes. Methods A systematic Medline search was performed. Using data from the selected studies, contact frequency was plotted against HbA(1c) reduction and endpoint insulin dose. The importance of face-to-face vs telephone contact was also analysed. Insulin dose was plotted against HbA(1c) reduction, hypoglycaemia rate and weight gain. To investigate non-specific study effects, the relationship between contact frequency and HbA(1c) was also assessed in dipeptidyl peptidase-4 (DPP-4) inhibitor trials. Results The reduction in HbA(1c) was highly correlated with contact frequency and endpoint insulin dose (r(2)=0.751, p<0.001 and r(2)=0.433, p=0.008, respectively). However, after adjusting for contact frequency, the relationship between insulin dose and HbA(1c) reduction was no longer significant (p=0.270). The frequency of both clinical and telephone contacts were independent predictors of HbA(1c) improvement (p=0.010 and p<0.001, respectively). We found no dose response relationship between end-of-study insulin dose and hypoglycaemia or weight gain. In DPP-4 inhibitor studies, contact frequency was not positively associated with HbA(1c). Conclusions/interpretation The frequency of contact with the study team is highly correlated with the improvement in HbA(1c) achieved in basal insulin initiation trials in type 2 diabetic patients. This has important implications for trial design and interpretation, as well as for clinical car

Hypoglycaemia in Type 2 diabetes

The primary cause of hypoglycaemia in Type 2 diabetes is diabetes medication—in particular, those which raise insulin levels independently of blood glucose, such as sulphonylureas (SUs) and exogenous insulin. The risk of hypoglycaemia is increased in older patients, those with longer diabetes duration, lesser insulin reserve and perhaps in the drive for strict glycaemic control. Differing definitions, data collection methods, drug type/regimen and patient populations make comparing rates of hypoglycaemia difficult. It is clear that patients taking insulin have the highest rates of self-reported severe hypoglycaemia (25% in patients who have been taking insulin for > 5 years). SUs are associated with significantly lower rates of severe hypoglycaemia. However, large numbers of patients take SUs in the UK, and it is estimated that each year > 5000 patients will experience a severe event caused by their SU therapy which will require emergency intervention. Hypoglycaemia has substantial clinical impact, in terms of mortality, morbidity and quality of life. The cost implications of severe episodes—both direct hospital costs and indirect costs—are considerable: it is estimated that each hospital admission for severe hypoglycaemia costs around £1000. Hypoglycaemia and fear of hypoglycaemia limit the ability of current diabetes medications to achieve and maintain optimal levels of glycaemic control. Newer therapies, which focus on the incretin axis, may carry a lower risk of hypoglycaemia. Their use, and more prudent use of older therapies with low risk of hypoglycaemia, may help patients achieve improved glucose control for longer, and reduce the risk of diabetic complications

Gene Expression and Immunohistochemistry in Adipose Tissue of HIV Type 1-Infected Patients with Nucleoside Analogue Reverse-Transcriptase Inhibitor-Associated Lipoatrophy

BackgroundLong-term use of both zidovudine (AZT) and stavudine (d4T) is associated with lipoatrophy, but it occurs possibly through different mechanisms MethodsSurgical biopsy specimens of subcutaneous adipose tissue were obtained from 18 human immunodeficiency virus type 1 (HIV-1)-infected lipoatrophic patients (the LA+ group) who were treated with either zidovudine (the AZT+LA+ group; n=10) or stavudine (the d4T+LA+ group; n=8) and from 10 nonlipoatrophic HIV-1-infected patients (the LA− group) who received antiretroviral therapy. Mitochondrial DNA (mtDNA) copy numbers, gene expression, and immunohistochemistry data were analyzed ResultsmtDNA copy numbers were significantly reduced in the LA+ group, compared with the LA− group, and in the d4T+LA+ group, compared with the AZT+LA+ group. The ratio of mtDNA-encoded cytochrome COX3 to nuclear DNA-encoded COX4 expression was significantly lower in the LA+ group than in the LA− group. Compared with the LA− group, the LA+ group had significantly lower expression of genes involved in adipogenesis (SREBP1cand CEBPB) lipid (fatty acid synthase), and glucose (GLUT4) metabolism. Expression of genes involved in mitochondrial biogenesis (PGC1B) apoptosis (FAS) inflammation (IL1B) oxidative stress (PCNA and SOD1) and lamin B was significantly higher in the LA+ group than in the LA− group. The d4T+LA+ group had significantly lower expression of genes involved in mitochondrial biogenesis (POLG1) energy metabolism (the COX3/COX4 ratio), adipogenesis (SREBP1c and CEBPA) perilipin, and hexokinase than did the AZT+LA+ group. There were 7-fold more macrophages in adipose tissue specimens obtained from patients in the LA+ group, compared with the LA− group ConclusionsLipoatrophy is characterized by mtDNA depletion, inflammation, and signs of apoptosis. Changes were more profound in the d4T+LA+ group than in the AZT+LA+ grou

Glycaemic control and hypoglycaemia with new insulin glargine 300 U/ml versus insulin glargine 100 U/ml in people with type 2 diabetes using basal insulin and oral antihyperglycaemic drugs: the EDITION 2 randomized 12-month trial including 6-month extension

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Comparison of insulin glargine and liraglutide added to oral agents in patients with poorly controlled type 2 diabetes

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Observational study of the association of first insulin type in uncontrolled type 2 diabetes with macrovascular and microvascular disease

&lt;p&gt;Aims: To compare the risk of vascular disease, HbA1c and weight change, between first prescribed insulins in people with type 2 diabetes.&lt;/p&gt; &lt;p&gt;Methods: People included in THIN United Kingdom primary care record database who began insulin (2000–2007) after poor control on oral glucose-lowering agents (OGLD) were grouped by the number of OGLDs in their treatment regimen immediately before starting insulin (n = 3,485). Within OGLD group, Cox regression compared macrovascular (all-cause mortality, myocardial infarction, acute coronary syndrome and stroke) and microvascular disease (peripheral neuropathy, nephropathy, and retinopathy) between insulin type (basal, pre-mix or Neutral Protamine Hagedorn, NPH) while ANCOVAs compared haemoglobin A1c (HbA1c) and weight change.&lt;/p&gt; &lt;p&gt;Results: Mean follow-up was 3.6 years. Rates of incident macrovascular events were similar when basal insulin was compared to pre-mix or NPH, adjusted hazard ratio versus basal: pre-mix 1.08 (95% CI 0.73, 1.59); NPH 1.00 (0.63, 1.58) after two OGLDs, and pre-mix 0.97 (0.46, 2.02); NPH 0.77 (0.32, 1.86) after three OGLDs. An increased risk of microvascular disease in NPH versus basal after 3 OGLDs, adjusted hazard ratio1.87 (1.04, 3.36), was not seen after two agents or in comparisons of basal and pre-mix. At one year, after two OGLDs, weight increase was less with basal compared with pre-mix. After three OGLDs, mean HbA1c had reduced less in basal versus pre-mix or NPH at 6–8 and at 9–11 months, and versus pre-mix at 12–14 months.&lt;/p&gt; &lt;p&gt;Conclusion: We found no difference in the risk of macrovascular events between first insulins in the medium term when started during poor glycaemia control. The increased risk of microvascular events with NPH warrants further study. In certain groups, first use of basal insulin was associated with less gain in weight and decrease in HbA1c compared to other insulins.&lt;/p&gt

Exenatide twice-daily does not affect renal function or albuminuria compared to titrated insulin glargine in patients with type 2 diabetes mellitus : A post-hoc analysis of a 52-week randomised trial

Aims: To compare the effects of long-term treatment with the GLP-1RA exenatide twicedaily versus titrated insulin glargine (iGlar) on renal function and albuminuria in type 2 diabetes (T2DM) patients. Methods: We post-hoc evaluated renal outcome-data of 54 overweight T2DM patients (mean +/- SD age 60 +/- 8 years, HbA1c 7.5 +/- 0.9%, eGFR 86 +/- 16 mL/min/1.73m(2), median [IQR] urinary albumin-to-creatinine-ratio (UACR) 0.75 [0.44-1.29] mg/mmol) randomised to exenatide 10 mg twice-daily or titrated iGlar on-top-of metformin for 52-weeks. Renal efficacy endpoints were change in creatinine clearance (CrCl) and albuminuria (urinary albuminexcretion [UAE] and UACR) based on 24-h urines, collected at baseline and Week-52. eGFR and exploratory endpoints were collected throughout the intervention-period, and after a 4-week wash-out. Results: HbA1c-reductions were similar with exenatide (mean +/- SEM -0.80 +/- 0.10%) and iGlar (-0.79 +/- 0.14%; treatment-difference 0.02%; 95% CI - 0.31 to 0.42%). Change from baseline to Week-52 in CrCl, UAE or UACR did not statistically differ; only iGlar reduced albuminuria (P <0.05; within-group). eGFR decreased from baseline to Week-4 with exenatide (-3.9 +/- 2.1 mL/min/1.73 m(2); P = 0.069) and iGlar (-2.7 +/- 1.2 mL/min/1.73 m(2); P = 0.034), without treatment-differences in ensuing trajectory. Exenatide versus iGlar reduced bodyweight (-5.4 kg; 2.9-7.9; P <0.001), but did not affect blood pressure, lipids or plasma uric acid. Conclusions: Among T2DM patients without overt nephropathy, one-year treatment with exenatide twice-daily does not affect renal function-decline or onset/progression of albuminuria compared to titrated iGlar. (C) 2019 Elsevier B.V. All rights reserved.Peer reviewe