Pathophysiology-based phenotyping in type 2 diabetes: A clinical classification tool.

BACKGROUND: Type 2 diabetes may be a more heterogeneous disease than previously thought. Better understanding of pathophysiological subphenotypes could lead to more individualized diabetes treatment. We examined the characteristics of different phenotypes among 5813 Danish patients with new clinically diagnosed type 2 diabetes. METHODS: We first identified all patients with rare subtypes of diabetes, latent autoimmune diabetes of adults (LADA), secondary diabetes, or glucocorticoid-associated diabetes. We then used the homeostatic assessment model to subphenotype all remaining patients into insulinopenic (high insulin sensitivity and low beta cell function), classical (low insulin sensitivity and low beta cell function), or hyperinsulinemic (low insulin sensitivity and high beta cell function) type 2 diabetes. RESULTS: Among 5813 patients diagnosed with incident type 2 diabetes in the community clinical setting, 0.4% had rare subtypes of diabetes, 2.8% had LADA, 0.7% had secondary diabetes, 2.4% had glucocorticoid-associated diabetes, and 93.7% had WHO-defined type 2 diabetes. In the latter group, 9.7% had insulinopenic, 63.1% had classical, and 27.2% had hyperinsulinemic type 2 diabetes. Classical patients were obese (median waist 105 cm), and 20.5% had cardiovascular disease (CVD) at diagnosis, while insulinopenic patients were fairly lean (waist 92 cm) and 17.5% had CVD (P = 0.14 vs classical diabetes). Hyperinsulinemic patients were severely obese (waist 112 cm), and 25.5% had CVD (P < 0.0001 vs classical diabetes). CONCLUSIONS: Patients clinically diagnosed with type 2 diabetes are a heterogeneous group. In the future, targeted treatment based on pathophysiological characteristics rather than the current "one size fits all" approach may improve patient prognosis.

Missing portion sizes in FFQ--alternatives to use of standard portions.

OBJECTIVE: Standard portions or substitution of missing portion sizes with medians may generate bias when quantifying the dietary intake from FFQ. The present study compared four different methods to include portion sizes in FFQ. DESIGN: We evaluated three stochastic methods for imputation of portion sizes based on information about anthropometry, sex, physical activity and age. Energy intakes computed with standard portion sizes, defined as sex-specific medians (median), or with portion sizes estimated with multinomial logistic regression (MLR), 'comparable categories' (Coca) or k-nearest neighbours (KNN) were compared with a reference based on self-reported portion sizes (quantified by a photographic food atlas embedded in the FFQ). SETTING: The Danish Health Examination Survey 2007-2008. SUBJECTS: The study included 3728 adults with complete portion size data. RESULTS: Compared with the reference, the root-mean-square errors of the mean daily total energy intake (in kJ) computed with portion sizes estimated by the four methods were (men; women): median (1118; 1061), MLR (1060; 1051), Coca (1230; 1146), KNN (1281; 1181). The equivalent biases (mean error) were (in kJ): median (579; 469), MLR (248; 178), Coca (234; 188), KNN (-340; 218). CONCLUSIONS: The methods MLR and Coca provided the best agreement with the reference. The stochastic methods allowed for estimation of meaningful portion sizes by conditioning on information about physiology and they were suitable for multiple imputation. We propose to use MLR or Coca to substitute missing portion size values or when portion sizes needs to be included in FFQ without portion size data.

Accurate Post-Calibration Predictions for Noninvasive Glucose Measurements in People Using Confocal Raman Spectroscopy.

In diabetes prevention and care, invasiveness of glucose measurement impedes efficient therapy and hampers the identification of people at risk. Lack of calibration stability in non-invasive technology has confined the field to short-term proof of principle. Addressing this challenge, we demonstrate the first practical use of a Raman-based and portable non-invasive glucose monitoring device used for at least 15 days following calibration. In a home-based clinical study involving 160 subjects with diabetes, the largest of its kind to our knowledge, we find that the measurement accuracy is insensitive to age, sex, and skin color. A subset of subjects with type 2 diabetes highlights promising real-life results with 99.8% of measurements within A + B zones in the consensus error grid and a mean absolute relative difference of 14.3%. By overcoming the problem of calibration stability, we remove the lingering uncertainty about the practical use of non-invasive glucose monitoring, boding a new, non-invasive era in diabetes monitoring.

Plasma osteoprotegerin is related to carotid and peripheral arterial disease, but not to myocardial ischemia in type 2 diabetes mellitus.

BACKGROUND: Cardiovascular disease (CVD) is frequent in type 2 diabetes mellitus patients due to accelerated atherosclerosis. Plasma osteoprotegerin (OPG) has evolved as a biomarker for CVD. We examined the relationship between plasma OPG levels and different CVD manifestations in type 2 diabetes. METHODS: Type 2 diabetes patients without known CVD referred consecutively to a diabetes clinic for the first time (n = 305, aged: 58.6 ± 11.3 years, diabetes duration: 4.5 ± 5.3 years) were screened for carotid arterial disease, peripheral arterial disease, and myocardial ischemia by means of carotid artery ultrasonography, peripheral ankle and toe systolic blood pressure measurements, and myocardial perfusion scintigraphy (MPS). In addition, plasma OPG concentrations and other CVD-related markers were measured. RESULTS: The prevalence of carotid arterial disease, peripheral arterial disease, and myocardial ischemia was 42%, 15%, and 30%, respectively. Plasma OPG was significantly increased in patients with carotid and peripheral arterial disease compared to patients without (p < 0.001, respectively), however, this was not the case for patients with myocardial ischemia versus those without (p = 0.71). When adjusted for age, HbA1c and U-albumin creatinine ratio in a multivariate logistic regression analysis, plasma OPG remained strongly associated with carotid arterial disease (adjusted OR: 2.12; 95% CI: 1.22-3.67; p = 0.008), but not with peripheral arterial disease or myocardial ischemia. CONCLUSIONS: Increased plasma OPG concentration is associated with carotid and peripheral arterial disease in patients with type 2 diabetes, whereas no relation is observed with respect to myocardial ischemia on MPS. The reason for this discrepancy is unknown.

A Validated Prediction Model for End-Stage Kidney Disease in Type 1 Diabetes.

OBJECTIVE: End-stage kidney disease (ESKD) is a life-threatening complication of diabetes that can be prevented or delayed by intervention. Hence, early detection of people at increased risk is essential. RESEARCH DESIGN AND METHODS: From a population-based cohort of 5,460 clinically diagnosed Danish adults with type 1 diabetes followed from 2001 to 2016, we developed a prediction model for ESKD accounting for the competing risk of death. Poisson regression analysis was used to estimate the model on the basis of information routinely collected from clinical examinations. The effect of including an extended set of predictors (lipids, alcohol intake, etc.) was further evaluated, and potential interactions identified in a survival tree analysis were tested. The final model was externally validated in 9,175 adults from Denmark and Scotland. RESULTS: During a median follow-up of 10.4 years (interquartile limits 5.1; 14.7), 303 (5.5%) of the participants (mean [SD] age 42.3 [16.5] years) developed ESKD, and 764 (14.0%) died without having developed ESKD. The final ESKD prediction model included age, male sex, diabetes duration, estimated glomerular filtration rate, micro- and macroalbuminuria, systolic blood pressure, hemoglobin A1c, smoking, and previous cardiovascular disease. Discrimination was excellent for 5-year risk of an ESKD event, with a C-statistic of 0.888 (95% CI 0.849; 0.927) in the derivation cohort and confirmed at 0.865 (0.811; 0.919) and 0.961 (0.940; 0.981) in the external validation cohorts from Denmark and Scotland, respectively. CONCLUSIONS: We have derived and validated a novel, high-performing ESKD prediction model for risk stratification in the adult type 1 diabetes population. This model may improve clinical decision making and potentially guide early intervention.

Critical-depth Raman spectroscopy enables home-use non-invasive glucose monitoring.

One of the most ambitious endeavors in the field of diabetes technology is non-invasive glucose sensing. In the past decades, a number of different technologies have been assessed, but none of these have found its entry into general clinical use. We report on the development of a table-top confocal Raman spectrometer that was used in the home of patients with diabetes and operated for extended periods of time unsupervised and without recalibration. The system is based on measurement of glucose levels at a 'critical depth' in the skin, specifically in the interstitial fluid located below the stratum corneum but above the underlying adipose tissue layer. The region chosen for routine glucose measurements was the base of the thumb (the thenar). In a small clinical study, 35 patients with diabetes analyzed their interstitial fluid glucose for a period of 60 days using the new critical-depth Raman (CD-Raman) method and levels were correlated to reference capillary blood glucose values using a standard finger-stick and test strip product. The calibration of the CD-Raman system was stable for > 10 days. Measurement performance for glucose levels present at, or below, a depth of ~250µm below the skin surface was comparable to that reported for currently available invasive continuous glucose monitors. In summary, using the CD-Raman technology we have demonstrated the first successful use of a non-invasive glucose monitor in the home.

AKA-TPG: a program for kinetic and epidemiological analysis of data from labeled glucose investigations using the two-pool model and database technology.

BACKGROUND: The Two-Pool Glucose (TPG) model has an important role to play in diabetes research since it enables analysis of data obtained from the frequently sampled labeled (hot) glucose tolerance test (FSHGT). TPG modeling allows determination of the separate effects of insulin on the disposal of glucose and on the hepatic production of glucose. It therefore provides a basis for the accurate estimation of glucose effectiveness, insulin sensitivity, and the profile of the rate of endogenous glucose production. Until now, there has been no program available dedicated to the TPG model, and a number of technical reasons have deterred researchers from performing TPG analysis. METHODS AND RESULTS: In this paper, we describe AKA-TPG, a new program that combines automatic kinetic analysis of the TPG model data with database technologies. AKA-TPG enables researchers who have no expertise in modeling to quickly fit the TPG model to individual FSHGT data sets consisting of plasma concentrations of unlabeled glucose, labeled glucose, and insulin. Most importantly, because the entire process is automated, parameters are almost always identified, and parameter estimates are accurate and reproducible. AKA-TPG enables the demographic data of hundreds of individual subjects, their individual unlabeled and labeled glucose and insulin data, and each subject's parameters and indices derived from AKA-TPG to be securely stored in, and retrieved from, a database. We describe how the stratification and population analysis tools in AKA-TPG are used and present population estimates of TPG model parameters for young, healthy (without diabetes) Nordic men. CONCLUSION: Researchers now have a practical tool to enable kinetic and epidemiological analysis of TPG data sets.

Plasma copeptin as marker of cardiovascular disease in asymptomatic type 2 diabetes patients.

Recently, copeptin was found associated with cardiovascular disease (CVD) and all-cause mortality in type 2 diabetes mellitus (T2DM) patients treated in primary care. This study aimed to evaluate whether plasma copeptin correlated to CVD in asymptomatic T2DM patients intensively investigated for sub-clinical CVD. A total of 302 T2DM patients referred to the Diabetes Clinic at Odense University Hospital, Denmark, entered the study. None of the patients had known or suspected CVD. As a control group, 30 healthy adults were recruited from the DanRisk study - a random sample of middle-aged Danes. A variety of clinical investigations were performed, including blood pressure measurements, carotid intima media thickness evaluation and myocardial perfusion scintigraphy. Blood sample analyses included copeptin measurements. Median plasma copeptin concentrations were similar in the T2DM group and the control group. However, men had significantly higher copeptin concentrations than women in the T2DM group (p < 0.001), and also, T2DM men had significantly higher copeptin concentrations than men without T2DM (p = 0.038). Copeptin correlated significantly with a number of variables, but the strongest correlation was with creatinine (R = 0.432, p < 0.001), and in multiple regression analysis, only this correlation remained significant. When association with clinical scores were investigated, plasma copeptin remained significantly associated with peripheral arterial disease (PAD) (p = 0.01). We found correlations between creatinine, copeptin levels and PAD in T2DM patients, and if confirmed, plasma copeptin combined with plasma creatinine could be a candidate for PAD screening in T2DM patients.

Metformin, but not rosiglitazone, attenuates the increasing plasma levels of a new cardiovascular marker, fibulin-1, in patients with type 2 diabetes.

OBJECTIVE The extracellular matrix protein fibulin-1 is upregulated in the arterial wall in type 2 diabetes (T2D) and circulates in increased concentrations in diabetes. Metformin is an antidiabetic drug with beneficial cardiovascular disease effects in diabetes. We hypothesized that metformin would influence the increased level of plasma fibulin-1 in diabetes. RESEARCH DESIGN AND METHODS After a 4-week run-in period, 371 eligible patients with T2D were randomized to treatment groups in a factorial design including insulin alone (control), +metformin, +rosiglitazone, or +both metformin and rosiglitazone. Plasma fibulin-1 was analyzed at the beginning of the study and after 18 and 24 months. RESULTS Plasma fibulin-1 increased in all groups throughout the 2-year period; however, the increase was strongly attenuated among patients treated with metformin. A highly significant difference was observed when the mean change in plasma fibulin-1 was compared between metformin- and non-metformin-treated individuals both at 18 and 24 months of treatment, but rosiglitazone had no effect. Metformin and rosiglitazone alone reduced the HbA1c levels to comparable levels and in combination even further. CONCLUSIONS Metformin attenuates the increase in plasma fibulin-1 concentrations in T2D, independently of glycemic effects. Changes in fibulin-1 may reflect an important element in diabetic arteriopathy that can be influenced by metformin.

Low dose spironolactone reduces blood pressure in patients with resistant hypertension and type 2 diabetes mellitus: a double blind randomized clinical trial.

BACKGROUND: The increased risk of cardiovascular morbidity and mortality associated with arterial hypertension is particularly pronounced in patients with type 2 diabetes mellitus. Blood pressure control is, therefore, decisively important but often not sufficiently achieved. OBJECTIVE: The primary objective of this study was to evaluate the antihypertensive effect of low dose spironolactone added to triple therapy for resistant hypertension in patients with type 2 diabetes measured by ambulatory monitoring. Secondary objectives were to evaluate the effects on glycaemic control and urinary albumin excretion as well as adverse effects. METHODS: In a multicentre, double-blind, randomized, placebo-controlled study 119 patients with blood pressure at or above 130/80 mmHg despite triple antihypertensive therapy were included. One tablet of 25 mg spironolactone or placebo was added to previous treatment and increased to two if blood pressure below 130/80 mmHg was not achieved after 4 weeks. Blood pressure was measured by ambulatory monitoring at baseline and after 16 weeks. RESULTS: The study was completed by 112 patients, 57 randomized to spironolactone and 55 to placebo. Average daytime placebo-corrected blood pressure was reduced by 8.9 (4.7-13.2)/3.7 (1.5-5.8) mmHg. Also office blood pressure, night-time, 24-h and pulse pressures were reduced significantly. Urinary albumin/creatinine ratio was significantly reduced in the spironolactone group. Glycaemic control remained unchanged. Hyperkalemia was the most frequent adverse event leading to dose reduction in three cases and discontinuation in one, whereas gynaecomastia was not reported. CONCLUSION: Low dose spironolactone exerts significant BP and urinary albumin creatinine ratio lowering effects in high-risk patients with resistant hypertension and type 2 diabetes mellitus.