Search

ims/hypothesis: The aim of this study was to assess the association between lifelong cumulative glycaemia estimated by lens fluorometry and the presence of retinopathy in individuals with type 2 diabetes. Methods: We carried out a cross-sectional population-based study of 970 participants aged between 30 and 60 years, of which 170 were diagnosed with diabetes on screening (WHO 1999 criteria) and 35 had known type 2 diabetes. Procedures included clinical and laboratory examinations, non-invasive assessment of the intrinsic fluorescence of the lens of the eye, and seven-field fundus photography. Results: Retinopathy was found in 46 (22%) of 205 participants with type 2 diabetes. In a logistic regression analysis controlling for age, sex and diabetes status (screen-detected or known), a two-fold increase in lens fluorescence increased the odds for retinopathy by 3.46 (95% CI 1.25-9.55, p = 0.017). The association was marginally significant (OR 3.00 [95% CI 1.00-9.01], p = 0.050) when also adjusted for smoking, systolic blood pressure, body mass index and HbA. Conclusions/interpretation: Diabetic retinopathy was related to cumulative lifelong glycaemia as estimated by lens fluorometry in participants with type 2 diabetes. This supports the hypothesis that retinopathy is a marker of lifelong elevated glycaemia as well as of the unknown, pre-diagnostic duration of type 2 diabetes. The powerful association between lens fluorescence and retinopathy underscores the importance of strict long-term glycaemic control in the prevention of retinopathy in people with diabetes. [ABSTRACT FROM AUTHOR]

Aims/hypothesis. Fetal undernutrition can result in intrauterine growth restriction and increased incidence of Type 2 diabetes mellitus. Intrauterine malnutrition in form of an isocaloric low-protein diet given to female rats throughout gestation decreases islet-cell proliferation, islet size and pancreatic insulin content, while increasing the apoptotic rate and sensitivity to nitrogen oxide and interleukin-1β. Hence, the influence of a low-protein diet on the development of beta-cells and islets could also be of interest for the pathogenesis of Type 1 and Type 2 diabetes mellitus. We hypothesise that the effects of a low-protein diet in utero are caused by intrauterine programming of beta-cell gene expression. Methods. Pregnant Wistar rats were fed a low-protein diet (8% protein) or a control diet (20% protein) throughout gestation. At day 21.5 of gestation fetal pancreata were removed, digested and cultured for 7 days. Neoformed islets were collected and analysed by proteome analysis comprising 2-dimensional gel electrophoresis and mass spectrometry. Results. A total of 2810 different protein spots were identified, 70 of which were changed due to the low-protein diet. From 45 of the changed protein spots, identification was obtained by mass spectrometry (64% success rate). Proteins induced by the low-protein diet were grouped according to their biological functions, e.g. cell cycle and differentiation, protein synthesis and chaperoning. Conclusions/interpretation. Our study offers a possible explanation of the alterations induced by a low-protein diet in islets. It shows that in Wistar rats the intrauterine milieu could program islet gene expression in ways unfavourable for the future of the progeny. This could be important for our understanding of the development of Type 1 and Type 2 diabetes mellitus. [ABSTRACT FROM AUTHOR]

Aims/hypothesis. Type 2 diabetes is associated with impaired insulin action and secretion, including disturbed pulsatile release. Impaired pulsatility has been related to impaired insulin action, thus providing a possible link between release and action of insulin. Furthermore, progressive loss of beta-cell mass has been implicated in the pathogenesis of Type 2 diabetes. The aim of this study was to evaluate a possible link between loss of beta-cell mass and impaired pulsatile insulin secretion with special focus on glucose responsiveness of insulin secretion. Methods. The kinetic and dynamic profiles of insulin in Göttingen minipigs are favourable for studies on pulsatility and a model of diabetes with reduced beta-cell mass has recently been established. Pigs were studied before (n=14) and after (n=10) reduction of beta-cell mass by nicotinamide (67 mg/kg) and streptozotocin (125 mg/kg) from 17.7±4.7 (normal animals,n=5) to 6.1±2.0 mg/kg. Pulsatile insulin secretion was examined during basal (n=8 normal, n=6 beta-cell reduced) and glucose entrained (n=6 normal, n=4 beta-cell reduced) conditions. Insulin concentration time series were analysed by autocorrelation and spectral analyses for periodicities and regularity, and by deconvolution for pulse frequency, mass and amplitude. Results. Reduction of beta-cell mass and secondary hyperglycaemia resulted in correspondingly (r=0.7421, p=0.0275) reduced pulse mass (42% of normal during basal and 31% during entrained conditions) with normal periodicity (6.6±2.2 vs 5.8±2.4 min, p=0.50), regularity and entrainability of insulin secretion. Conclusion/interpretation. Neither beta-cell loss, nor 2 weeks of slight hyperglycaemia, as seen in the beta-cell-reduced minipig, probably accounts for the disturbed insulin pulsatility observed in human Type 2 diabetes. [ABSTRACT FROM AUTHOR]

Aims/hypothesis. With ageing the long-lived proteins of the human lens undergo denaturation by non-enzymatic glycation. The denaturated proteins are fluorescent, a property that can be assessed in vivo by fluorometry. Our aim was to examine the relative contribution of hereditary and environmental effects on the accumulation of fluorescent compounds in the lens. Methods. We examined 59 monozygotic and 55 dizygotic healthy twin pairs recruited from a population-based register of twins. Lens autofluorescence was measured on the undilated eye. All subjects underwent an OGTT and information on smoking habits was obtained. The genetic and environmental effects were estimated by structural equation modelling. Results. Lens autofluorescence was related to age (R2=53%), current glucose homeostasis (R2=10%) and smoking habits (R2=10%). After adjusting for these factors, interindividual variation in lens autofluorescence was statistically attributable to hereditary factors by approximately 28% as well as shared environment by 58% and non-shared environment by 14%. The hereditary factor seems not to be linked to a genetic predisposition to diabetes. Conclusion/interpretation. The correlation in lens fluorescence was greater in monozygotic twins than dizygotic twins indicating a genetically predetermined susceptibility for the accumulation of fluorophores in the lens, the relative importance of which was found to increase with age. Since fluorophore formation in the lens is attributable to non-enzymatic glycation our results support that genetic characteristics to some degree determine the susceptibility to glycation related diabetes complications and ageing processes. [ABSTRACT FROM AUTHOR]

Aims/hypothesis. Pulsatile secretion is important for insulin action and suitable animal models are important tools for examining the role of impaired pulsatile insulin secretion as a possible link between beta-cell mass, function and morphology and insulin resistance. This study examines the vascular sampling site, insulin kinetics, pulsatility and the response to glucose pulse entrainment to evaluate the Göttingen minipig as a model for studying pulsatile insulin secretion. Methods. Basal and glucose entrained insulin secretion was examined in normal minipigs and evaluated by autocorrelation, cross correlation and deconvolution. Results. Cross correlation showed a relation between oscillations in insulin concentrations in the portal and jugular vein in anaesthetised animals (p<0.001 in all animals), confirming the usefulness of jugular vein sampling for pulse detection. Jugular vein sampling in conscious animals showed obvious oscillations allowing estimates of burst shape and insulin kinetics. Glucose entrainment improved the pulsatile pattern (autocorrelation: 0.555±0.148 entrained vs 0.350±0.197 basal, p=0.054). Deconvolution analysis resolved almost all insulin release as secretory bursts (69±20 basal vs 99.5±1.2% entrained, p<0.01) with a pulse interval (min) of 6.6±2.2 (basal) and 9.4±1.5 (entrained) (p<0.05) and a pulse mass (pmol/l per pulse) which was higher after entrainment (228±117 vs 41.2±18.6 basal, p<0.001). Conclusion/interpretation. The ability to fit kinetic parameters directly by deconvolution of peripheral endogenous insulin concentration time series in combination with the suitability of jugular vein sampling, rapid kinetics and entrainability makes the Göttingen minipig ideal for mechanistic studies of insulin pulsatility and its effects on insulin action. [ABSTRACT FROM AUTHOR]

The effect of antihypertensive treatment on blood-retinal barrier leakage of fluorescein in background retinopathy was studied in nine hypertensive Type 1 (insulin-dependent) diabetic patients suffering from nephropathy. The patients were investigated before and after 7 (3 to 13) months of treatment with captopril ( n=8; 25 to 100 mg daily) and a diuretic, either frusemide ( n=4; 80 to 200 mg daily) or bendrofluazide ( n=2; 2.5 mg daily). Retinal function was assessed by fundus photography, fluorescein angiography, vitreous fluorometry, and renal function by glomerular filtration rate, and albuminuria. The antihypertensive treatment induced a significant reduction ( p<0.05) in: blood pressure from 152/97±14/8 mmHg to 134/82±11/6 mmHg; blood-retinal barrier leakage of fluorescein from 2.4 ±1.1 to 1.4±0.5·10 cm/second; albuminuria from 1391 (range: 168-4852) μg/min to 793 (range: 35-2081) ug/min. Glomerular filtration rate declined from 88±15 to 78±23 ml·min·1.73 m (0.05< p<0.10). The metabolic control of the patients as reflected by their blood glucose and HbA levels remained stable during the study. Our study suggests that systemic blood pressure elevation contributes to the abnormal blood-retinal barrier permeability to fluorescein characteristically found in diabetic background retinopathy and that this abnormality can be reversed during antihypertensive treatment. [ABSTRACT FROM AUTHOR]

A follow-up on three hundred and seven patients diagnosed before 1933 and before the patient was thirty-one years old was conducted as of 1.1.1973, i.e. after at least forty years of diabetes. All patients were seen at the Steno Memorial hospital and were referred from all parts of Denmark. A small proportion of the patients (5.9%) could not be traced. Of the remaining two hundred and eightynine patients 40% were alive. Three-hundred and six patients were insulin dependent, 87% being treated with insulin twice daily. More than 50% survived their diabetes for more than thirty-five years. The mortality rate was 2-6 times that in an age- and sexmatched non-diabetic population. In 31% of the deceased patients the cause of death was uraemia; in 25% myocardial infarction. The excess mortality among patients exhibiting persistent proteinuria before forty years of diabetes was 3-4 times higher than in patients who did not have proteinuria after forty years. 16% of the whole study population became blind, and another 14% had severely impaired vision; 21% exhibited objective signs of myocardial infarction, 10% of stroke, and 12% had gangrene or had undergone amputation of the foot or lower leg; 38% had proteinuria and 22% uraemia. Death with or from hypoglycaemia was more common than death in ketoacidotic coma. Clinical manifestations of late diabetic complications were considerably less common in patients who were still alive after more than forty years of diabetes than in patients who died before their fortieth year of diabetes. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: The aim of this parallel-group, double-blinded (study personnel and participants), randomised clinical trial was to assess the interaction between metformin and exercise training on postprandial glucose in glucose-intolerant individuals., Methods: Glucose-intolerant (2 h OGTT glucose of 7.8-11.0 mmol/l and/or HbA 1c of 39-47 mmol/mol [5.7-6.5%] or glucose-lowering-medication naive type 2 diabetes), overweight/obese (BMI 25-42 kg/m 2 ) individuals were randomly allocated to a placebo study group (PLA, n = 15) or a metformin study group (MET, n = 14), and underwent 3 experimental days: BASELINE (before randomisation), MEDICATION (after 3 weeks of metformin [2 g/day] or placebo treatment) and TRAINING (after 12 weeks of exercise training in combination with metformin/placebo treatment). Training consisted of supervised bicycle interval sessions with a mean intensity of 64% of Watt max for 45 min, 4 times/week. The primary outcome was postprandial glucose (mean glucose concentration) during a mixed meal tolerance test (MMTT), which was assessed on each experimental day. For within-group differences, a group × time interaction was assessed using two-way repeated measures ANOVA. Between-group changes of the outcomes at different timepoints were compared using unpaired two-tailed Student's t tests., Results: Postprandial glucose improved from BASELINE to TRAINING in both the PLA group and the MET group (∆PLA: -0.7 [95% CI -1.4, 0.0] mmol/l, p = 0.05 and ∆MET: -0.7 [-1.5, -0.0] mmol/l, p = 0.03), with no between-group difference (p = 0.92). In PLA, the entire reduction was seen from MEDICATION to TRAINING (-0.8 [-1.3, -0.1] mmol/l, p = 0.01). Conversely, in MET, the entire reduction was observed from BASELINE to MEDICATION (-0.9 [-1.6, -0.2] mmol/l, p = 0.01). The reductions in mean glucose concentration during the MMTT from BASELINE to TRAINING were dependent on differential time effects: in the PLA group, a decrease was observed at timepoint (t) = 120 min (p = 0.009), whereas in the MET group, a reduction occurred at t = 30 min (p < 0.001). V̇O 2peak increased 15% (4.6 [3.3, 5.9] ml kg -1  min -1 , p < 0.0001) from MEDICATION to TRAINING and body weight decreased (-4.0 [-5.2, -2.7] kg, p < 0.0001) from BASELINE to TRAINING, with no between-group differences (p = 0.7 and p = 0.5, respectively)., Conclusions/interpretation: Metformin plus exercise training was not superior to exercise training alone in improving postprandial glucose. The differential time effects during the MMTT suggest an interaction between the two modalities., Funding: The Beckett foundation, A.P Møller Foundation, DDA, the Research Foundation of Rigshospitalet and Trygfonden., Trial Registration: ClinicalTrials.gov (NCT03316690). Graphical abstract.

Aims/hypothesis: We aimed to investigate the short-term efficacy and safety of three glucose-lowering interventions in overweight or obese individuals with prediabetes defined by HbA 1c ., Methods: The PRE-D Trial was a randomised, controlled, parallel, multi-arm, open-label, non-blinded trial performed at Steno Diabetes Center Copenhagen, Gentofte, Denmark. One hundred and twenty participants with BMI ≥25 kg/m 2 , 30-70 years of age, and prediabetes (HbA 1c 39-47 mmol/mol [5.7-6.4%]) were randomised 1:1:1:1 to dapagliflozin (10 mg once daily), metformin (1700 mg daily), interval-based exercise (5 days/week, 30 min/session) or control (habitual lifestyle). Participants were examined at baseline and at 6, 13 and 26 weeks after randomisation. The primary outcome was the 13 week change in glycaemic variability (calculated as mean amplitude of glycaemic excursions [MAGE]) determined using a continuous glucose monitoring system (pre-specified minimal clinically important difference in MAGE ∼30%)., Results: One hundred and twelve participants attended the examination at 13 weeks and 111 attended the follow-up visit at 26 weeks. Compared with the control group, there was a small decrease in MAGE in the dapagliflozin group (17.1% [95% CI 0.7, 30.8], p = 0.042) and a small, non-significant, reduction in the exercise group (15.3% [95% CI -1.2, 29.1], p = 0.067), whereas MAGE was unchanged in the metformin group (0.1% [95% CI -16.1, 19.4], p = 0.991)). Compared with the metformin group, MAGE was 17.2% (95% CI 0.8, 30.9; p = 0.041) lower in the dapagliflozin group and 15.4% (95% CI -1.1, 29.1; p = 0.065) lower in the exercise group after 13 weeks, with no difference between exercise and dapagliflozin (2.2% [95% CI -14.8, 22.5], p = 0.815). One serious adverse event occurred in the control group (lung cancer)., Conclusions/interpretation: Treatment with dapagliflozin and interval-based exercise lead to similar but small improvements in glycaemic variability compared with control and metformin therapy. The clinical importance of these findings in prediabetes is uncertain., Trial Registration: ClinicalTrials.gov NCT02695810 FUNDING: The study was funded by the Novo Nordisk Foundation, AstraZeneca AB, the Danish Innovation Foundation, the University of Copenhagen and Ascensia Diabetes Care Denmark ApS Graphical abstract.

Aims/hypothesis: The aim was to investigate whether an intensive lifestyle intervention, with high volumes of exercise, improves beta cell function and to explore the role of low-grade inflammation and body weight., Methods: This was a randomised, assessor-blinded, controlled trial. Ninety-eight individuals with type 2 diabetes (duration <10 years), BMI of 25-40 kg/m 2 , no use of insulin and taking fewer than three glucose-lowering medications were randomised (2:1) to either the standard care plus intensive lifestyle group or the standard care alone group. Standard care consisted of individual guidance on disease management, lifestyle advice and blinded regulation of medication following a pre-specified algorithm. The intensive lifestyle intervention consisted of aerobic exercise sessions that took place 5-6 times per week, combined with resistance exercise sessions 2-3 times per week, with a concomitant dietary intervention aiming for a BMI of 25 kg/m 2 . In this secondary analysis beta cell function was assessed from the 2 h OGTT-derived disposition index, which is defined as the product of the Matsuda and the insulinogenic indices., Results: At baseline, individuals were 54.8 years (SD 8.9), 47% women, type 2 diabetes duration 5 years (IQR 3-8) and HbA 1c was 49.3 mmol/mol (SD 9.2); 6.7% (SD 0.8). The intensive lifestyle group showed 40% greater improvement in the disposition index compared with the standard care group (ratio of geometric mean change [RGM] 1.40 [95% CI 1.01, 1.94]) from baseline to 12 months' follow-up. Plasma concentration of IL-1 receptor antagonist (IL-1ra) decreased 30% more in the intensive lifestyle group compared with the standard care group (RGM 0.70 [95% CI 0.58, 0.85]). Statistical single mediation analysis estimated that the intervention effect on the change in IL-1ra and the change in body weight explained to a similar extent (59%) the variance in the intervention effect on the disposition index., Conclusions/interpretation: Our findings show that incorporating an intensive lifestyle intervention, with high volumes of exercise, in individuals with type 2 diabetes has the potential to improve beta cell function, associated with a decrease in low-grade inflammation and/or body weight., Trial Registration: ClinicalTrials.gov NCT02417012 Graphical abstract.

Aims/hypothesis: The aim of this study was to evaluate the effects of oxygen consumption-matched short-term interval walking training (IWT) vs continuous walking training (CWT) on glycaemic control, including glycaemic variability, in individuals with type 2 diabetes. We also assessed whether any training-induced improvements in glycaemic control were associated with systemic oxidative stress levels., Methods: Participants (n = 14) with type 2 diabetes completed a crossover trial using three interventions (control intervention [CON], CWT and IWT), each lasting 2 weeks. These were performed in a randomised order (computerised generated randomisation) and separated by washout periods of 4 or 8 weeks after CON or training interventions, respectively. Training included ten supervised treadmill sessions, lasting 60 min/session, and was performed at the research facility. CWT was performed at moderate walking speed (75.6% ± 2.5% of walking peak oxygen consumption [[Formula: see text]]), while IWT was performed as alternating 3 min repetitions at slow (58.9% ± 2.0% [Formula: see text]) and fast (90.0% ± 3.6% [Formula: see text]) walking speed. Before and after each intervention, the following was assessed: 24 h continuous glucose monitoring (CGM) and urinary free 8-iso prostaglandin F 2α (8-iso PGF 2α ; a marker for oxidative stress), physical fitness and body composition. Neither participants nor assessors were blinded to the interventions., Results: No intervention-induced changes were seen in physical fitness or body composition. Compared with baseline, IWT reduced mean glucose levels non-significantly (-0.7 ± 0.3 mmol/l, p = 0.08) and significantly reduced maximum glucose levels (-1.8 ± 0.5 mmol/l, p = 0.04) and mean amplitude of glycaemic excursions (MAGE; -1.7 ± 0.4 mmol/l, p = 0.02), whereas no significant within-group changes were seen with CON or CWT. Although 8-iso PGF 2α was associated with minimum glucose levels at baseline, no change in 8-iso PGF 2α was seen with any intervention, nor were there any associations between changes in 8-iso PGF 2α and changes in glycaemic control (p > 0.05 for all). No adverse effects were observed with any of the interventions., Conclusions/interpretation: Short-term IWT, but not CWT, improves CGM-derived measures of glycaemic control independent of changes in physical fitness and body composition in individuals with type 2 diabetes. Systemic oxidative stress levels are unaffected by short-term walking and changes in oxidative stress levels are not associated with changes in glycaemic control., Trial Registration: ClinicalTrials.gov NCT02320526 FUNDING : The Centre for Physical Activity Research (CFAS) is supported by a grant from TrygFonden. During the study period, the Centre of Inflammation and Metabolism (CIM) was supported by a grant from the Danish National Research Foundation (DNRF55). The study was further supported by grants from Diabetesforeningen, Augustinusfonden and Krista og Viggo Petersens Fond. CIM/CFAS is a member of the Danish Center for Strategic Research in Type 2 Diabetes (DD2; the Danish Council for Strategic Research, grant no. 09-067009 and 09-075724). MR-L was supported by a post-doctoral grant from the Danish Diabetes Academy supported by the Novo Nordisk Foundation.

Aims/hypothesis: A progressive loss of beta cell function and mass are important contributory factors in the development and progression of type 2 diabetes. The aim of this study was to evaluate the effects of a primary reduction in beta cell mass on beta cell function in vivo and in the perfused pancreas and to relate these characteristics to beta cell mass., Methods: The beta cell mass of six Göttingen minipigs was reduced chemically (using 67 mg/kg nicotinamide and 125 mg/kg streptozotocin). Six untreated minipigs were kept as control animals. Insulin responses were evaluated in vivo using the mixed meal tolerance test (2 g/kg oral glucose) and in the isolated perfused pancreata from the same animals by stimulation with glucose, glucagon-like peptide-1 or arginine., Results: Beta cell mass was reduced in the beta-cell-reduced animals compared with the control minipigs (182+/-76 vs 464+/-156 mg, p<0.01). AUC(glucose) was increased in the beta-cell-reduced animals (1383+/-385 vs 853+/-113 mmol.l(-1).min in control minipigs, p<0.01), as was the insulin response to oral glucose per unit of beta cell mass (123+/-84 vs 56+/-24 pmol.l(-1).min.mg(-1), p<0.05). Total in vitro insulin secretion was increased per unit of beta cell mass in nicotinamide + streptozotocin pancreata compared to controls (83.7+/-45.9 vs 34.6+/-14.4 nmol/mg beta cells, p<0.05) with responses to glucose and glucagon-like peptide-1 showing a partial compensation for reduced beta cell mass, whereas no compensation was seen in response to arginine., Conclusions/interpretation: A primary reduction in beta cell mass impairs glucose tolerance and leads to a compensatory increase in insulin secretion from the remaining beta cells after oral glucose in vivo, which is even more apparent in the perfused pancreas. It remains to be determined whether this compensation can be maintained in the long term.

Lens and cornea autofluorescence has been shown to be increased in patients with insulin-dependent diabetes mellitus and to be positively correlated to glycaemic control and duration of diabetes. We have studied lens and cornea autofluorescence at the clinical onset of non-insulin-dependent diabetes mellitus (NIDDM), in comparison with age-matched subjects with normal glucose tolerance. Fourteen subjects with NIDDM diagnosed less than 6 months prior to the examination were characterised by ocular fluorometry, glycosylated hemoglobin A1c, plasma lipid status, arterial blood pressure, and an oral glucose tolerance test (OGTT). Eleven age- and gender-matched healthy subjects without a family history of diabetes and with a normal glucose tolerance underwent the same examinations. In 11 of the 14 diabetic patients lens autofluorescence was increased to levels higher than the age-related mean + 2SD of healthy subjects. For the entire study population, control and diabetic subjects, lens fluorescence was positively correlated with HbA1c (p < 0.0001, r = 0.73), fasting plasma glucose (p = 0.002, r = 0.60) and the plasma glucose level 2 h after an OGTT (p = 0.004, r = 0.55). Cornea autofluorescence was also significantly increased in the group of newly diagnosed NIDDM patients, but only 9 patients had values above the mean + 2SD of the healthy subjects. NIDDM could be detected by ocular fluorometry with a sensitivity of 79% and a specificity of 100%. We conclude that lens and cornea autofluorescence is abnormally increased in the majority of patients with newly diagnosed NIDDM. The sensitivity and specificity of the method indicate that lens fluorometry may potentially be useful for screening for undiagnosed NIDDM in the general population. Additionally, we propose that the method may be a clinically useful indicator of cumulative glycaemia and risk of development of secondary complications in patients with diabetes.