Mozhgan Dorkhan

Novel subgroups of adult-onset diabetes and their association with outcomes: a data-driven cluster analysis of six variables

BACKGROUND Diabetes is presently classified into two main forms, type 1 and type 2 diabetes, but type 2 diabetes in particular is highly heterogeneous. A refined classification could provide a powerful tool to individualise treatment regimens and identify individuals with increased risk of complications at diagnosis. METHODS We did data-driven cluster analysis (k-means and hierarchical clustering) in patients with newly diagnosed diabetes (n=8980) from the Swedish All New Diabetics in Scania cohort. Clusters were based on six variables (glutamate decarboxylase antibodies, age at diagnosis, BMI, HbA1c, and homoeostatic model assessment 2 estimates of β-cell function and insulin resistance), and were related to prospective data from patient records on development of complications and prescription of medication. Replication was done in three independent cohorts: the Scania Diabetes Registry (n=1466), All New Diabetics in Uppsala (n=844), and Diabetes Registry Vaasa (n=3485). Cox regression and logistic regression were used to compare time to medication, time to reaching the treatment goal, and risk of diabetic complications and genetic associations. FINDINGS We identified five replicable clusters of patients with diabetes, which had significantly different patient characteristics and risk of diabetic complications. In particular, individuals in cluster 3 (most resistant to insulin) had significantly higher risk of diabetic kidney disease than individuals in clusters 4 and 5, but had been prescribed similar diabetes treatment. Cluster 2 (insulin deficient) had the highest risk of retinopathy. In support of the clustering, genetic associations in the clusters differed from those seen in traditional type 2 diabetes. INTERPRETATION We stratified patients into five subgroups with differing disease progression and risk of diabetic complications. This new substratification might eventually help to tailor and target early treatment to patients who would benefit most, thereby representing a first step towards precision medicine in diabetes. FUNDING Swedish Research Council, European Research Council, Vinnova, Academy of Finland, Novo Nordisk Foundation, Scania University Hospital, Sigrid Juselius Foundation, Innovative Medicines Initiative 2 Joint Undertaking, Vasa Hospital district, Jakobstadsnejden Heart Foundation, Folkhälsan Research Foundation, Ollqvist Foundation, and Swedish Foundation for Strategic Research.

Narrowband ultraviolet B three times per week is more effective in treating vitamin D deficiency than 1600 IU oral vitamin D-3 per day: a randomized clinical trial

Background  It is known that narrowband ultraviolet B (NB‐UVB) radiation and oral vitamin D3 supplementation can both improve serum levels of vitamin D, expressed as 25‐hydroxyvitamin D3 [25(OH)D3]. However, surprisingly few studies have compared the effects of the two interventions in treating vitamin D deficiency.

Treatment with a thiazolidinedione increases eye protrusion in a subgroup of patients with type 2 diabetes.

Objective  Changes in eye protrusion in patients treated with pioglitazone.

Glycaemic and nonglycaemic effects of pioglitazone in triple oral therapy of patients with type 2 diabetes

Objectives.  To examine pioglitazone as add‐on to metformin and insulin secretagogues in patients with type 2 diabetes and inadequate glycaemic control and its effect on glycaemic control, surrogate measures of insulin sensitivity (adiponectin) and β‐cell function (proinsulin/insulin) and fluid retention.

Differences in effects of insulin glargine or pioglitazone added to oral anti-diabetic therapy in patients with type 2 diabetes What to add-Insulin glargine or pioglitazone?

BACKGROUND While metformin is the first line treatment in type 2 diabetes, the best way to escalate therapy is not always clear, particularly whether to add one or two oral agents or to introduce insulin. METHODS Thirty-six patients inadequately controlled on metformin and sulfonylurea/meglitinide were randomized to receive add-on therapy with insulin glargine or pioglitazone for 26 weeks. Insulin was up-titrated to achieve fasting plasma glucose <6 mmol/l. Pioglitazone was increased to 45 mg/day after 16 weeks if HbA1c>6.2%. beta-Cell function and insulin sensitivity were assessed by measuring insulin, proinsulin and adiponectin, and in a subgroup using a combined glucagon-stimulated C-peptide test and insulin tolerance test (GITT). Lipids and natriuretic peptides were measured at start and end of study. RESULTS The reduction in HbA1c was slightly greater in the insulin glargine group and used as co-variate when analysing other variables. The effect on beta-cell function was more favourable with insulin glargine measured by proinsulin (42+/-48 to 19+/-16, p=0.01 vs. 36+/-26 to 27+/-16 p=0.04) while the improvement in insulin sensitivity measured by adiponectin (7.5+/-3.7 to 15+/-10, p<0.01 vs. 8.7+/-4 to 7.6+/-3, p=0.04) and HDL cholesterol (1.10+/-0.24 to 1.24+/-0.3, p<0.01 vs. 1.08+/-0.35 to 1.04+/-0.33, ns) (all p between groups <0.01) was more favourable in pioglitazone group. Pioglitazone caused significant increase in natriuretic peptides (BNP pmol/l 6.6+/-5.2 to 13.7+/-16.1, p=0.04 vs. 8.8+/-11.6 to 8.6+/-10.6, ns, p between groups 0.028). CONCLUSIONS The results demonstrate characteristic differences in the effects of insulin glargine vs. pioglitazone on measures of beta-cell function and insulin sensitivity as well as cardiac load.

Effect of pioglitazone versus insulin glargine on cardiac size, function, and measures of fluid retention in patients with type 2 diabetes

BackgroundBoth insulin and thiazolidinediones (TZDs) are effective in the treatment of hyperglycaemia and amelioration of insulin resistance in type 2 diabetes but have side effects including weight gain and fluid retention. The use of TZDs has been further hampered by the risk of adverse cardiovascular events including heart failure. The present study evaluated the effect of pioglitazone or insulin glargine on cardiac function and size as well as on surrogate markers of fluid retention such as weight, haemoglobin and natriuretic peptides.MethodsThirty patients with inadequate glycaemic control on metformin and sulfonylurea were randomised to receive add-on therapy with insulin glargine or pioglitazone for 26 weeks. Echocardiographic data and blood samples were collected from the two groups before the start of the treatment and after 26 weeks. Left ventricular end-diastolic and left atrial end-systolic volumes were quantified, weight measured and blood samples analyzed.ResultsAfter 26 weeks of treatment, the changes in HbA1c, weight and haemoglobin were similar between the two groups. HDL increased significantly in the pioglitazone group. While there was an increase in natriuretic peptides in the pioglitazone group (NT-proBNP 11.4 ± 19.6 to 22.8 ± 44.0, p = 0.046), the difference between the treatment groups was not significant. Left ventricular end-diastolic volume increased by 11% and left atrial end-systolic volume by 17% in the pioglitazone group (Both, p < 0.05, between treatment groups). There was a borderline significant increase in ejection fraction in the pioglitazone group.ConclusionThis randomised pilot-study showed that six-month treatment with pioglitazone induced significant increases in natriuretic peptides and alterations of cardiac size. These changes were not observed with insulin glargine, which also is known to induce fluid retention. Larger randomised trials are warranted to confirm these findings.

Coffee consumption and the risk of latent autoimmune diabetes in adults-results from a Swedish case-control study

Coffee consumption is associated with a reduced risk of Type 2 diabetes. Our aim was to investigate if coffee intake may also reduce the risk of latent autoimmune diabetes in adults, an autoimmune form of diabetes with features of Type 2 diabetes.

Relationship between natriuretic peptides and echocardiography parameters in patients with poorly regulated type 2 diabetes

This study evaluated the relationship between natriuretic peptide levels and a wide range of echocardiography parameters in a population of thirty-three patients with poorly regulated type 2 diabetes, and no known heart failure. Natriuretic peptides brain natriuretic peptide (BNP) and N-terminal prohormone BNP (NT-proBNP) were measured. Transthoracic echocardiography was performed and cardiac volumes and ejection fraction were measured. Doppler and tissue Doppler were measured and diastolic function was stratified according to recent guidelines. Very few echocardiography parameters were correlated with BNP or NT-proBNP levels. However, left atrial end-systolic volume indexed for body surface area was correlated with natural logarithm (ln) BNP and ln NT-proBNP (r = 0.62 and r = 0.60; P < 0.05). There were significant differences in ln BNP and ln NT-proBNP levels between those with normal and those with abnormal diastolic function (1.4 vs 3.1; P < 0.001 and 3.4 vs 5.8; P < 0.001). This study showed that very few echocardiography parameters were correlated with BNP or NT-proBNP levels in patients with poorly regulated type 2 diabetes, which in part contradicts previous studies in other diabetic populations. The exception was left atrial end-systolic volume that showed a moderate correlation with BNP or NT-proBNP levels. There were significant differences in BNP and NT-proBNP levels between the group with normal left ventricular diastolic function and the group with abnormal diastolic function.

Independent measures of insulin secretion and insulin sensitivity during the same test: the glucagon–insulin tolerance test

Background.  To validate a test for independent assessment of insulin secretion and insulin sensitivity during the same occasion for metabolic studies in clinical practice, i.e. combined glucagon‐stimulated C‐peptide test and insulin tolerance test (GITT).

Prevalence and risk factors for diabetic retinopathy at diagnosis (DRAD) in patients recently diagnosed with type 2 diabetes (T2D) or latent autoimmune diabetes in the adult (LADA)

PURPOSE To study prevalence of diabetic retinopathy (DR) at diagnosis (DRAD) and to estimate contributing risk by sociodemographic, cardiovascular and metabolic characteristics present in patients recently diagnosed with type 2 diabetes (T2D) or latent autoimmune diabetes in the adult (LADA). METHODS Patients (n=2174) recently diagnosed T2D (93%) or LADA (7%) were included upon arrival for their baseline DR screening. Fundus photographs of 4902 eyes were graded by a senior ophthalmologist according to the International Diabetic Retinopathy Disease Severity Scale. Official registers held by Statistics Sweden provided sociodemographic variables. The National Patient Register and Swedish Prescribed Drug Register were used to assess cardiovascular risk. Beta cell function (HOMA2%b) and insulin sensitivity (HOMA2%s) were estimated from fasting (f) C-Peptide using the homeostasis model assessment (HOMA) 2 calculator. Odds ratios (OR) for DRAD were estimated using generalized estimating equation models. RESULTS The prevalence of DRAD was 12% (7% mild and 5% moderate) and of diabetic macular edema it was 11% (all within vascular arch). The prevalence did not significantly differ between T2D and LADA. Due to sample size, the regression analysis of LADA patients did not yield any significant estimates. In T2D low educational level (≤9years) increased risk for DRAD by 44% (OR 1.44; 95% CI 1.07-1.93) and <50% beta-cell function adjusted for HbA1c and insulin sensitivity at diagnosis increased the risk by 77% (OR 1.77; 95% CI 1.28-2.44). For every unit increase in BMI, risk for DRAD decreased by 3% (OR 0.97; 95% CI 0.95-0.99). CONCLUSIONS DRAD prevalence in patients recently diagnosed with T2D or is 12%. Low educational level and low beta cell function at diagnosis are risk factors for DRAD. Estimation of beta cell function from (f)C-Peptide and (f)P-Glucose may be a valuable tool in identifying patients at risk for DRAD.