To compare risk factors, stroke characteristics, and long-term prognosis between nondiabetic young ischemic stroke patients and similar patients having either type 1 diabetes mellitus (T1D) or type 2 ...diabetes mellitus (T2D) to provide information for patient management, counseling, and future research in these patient groups.
Our database comprised 1,008 consecutive patients aged 15 to 49 with first-ever ischemic stroke from 1994 to 2007. Primary outcome measures were 1) nonfatal or fatal recurrent ischemic stroke and 2) composite vascular endpoint (myocardial infarction, any stroke, revascularization, or vascular death).
Compared with nondiabetic stroke patients (n = 904), patients with T1D (44) or T2D (60) were more likely to have hypertension and stroke attributable to small-vessel disease (SVD). In addition, when compared with nondiabetic patients, those with T1D more frequently had coronary heart disease and peripheral arterial disease (PAD) and those with T2D more often had obesity, PAD, history of TIA, and stroke attributable to large-artery atherosclerosis, and T2D patients were also more likely to be older and male than were the nondiabetic patients. Mean follow-up in survivors was 9.0 (±3.8) years. Cumulative recurrent ischemic stroke rate at 10 years was 40.9% for T1D (14 events), 29.7% for T2D (15), and 12.0% for nondiabetic patients (94). Corresponding rates for the composite vascular endpoint were 65.1% for T1D (25), 46.9% for T2D (28), and 19.3% for nondiabetic patients (153).
Our findings suggest that ischemic stroke patients with T1D or T2D exhibit a distinct risk-factor and etiologic profile and a worse vascular prognosis than do nondiabetic patients.
Background
Patients with type 1 diabetes have shown an increase in circulating cytokines, altered lipoprotein metabolism and signs of vascular dysfunction in response to high‐fat meals. Intestinal ...alkaline phosphatase (IAP) regulates lipid transport and inflammatory responses in the gastrointestinal tract. We therefore hypothesized that changes in IAP activity could have profound effects on gut metabolic homeostasis in patients with type 1 diabetes.
Methods
Faecal samples of 41 nondiabetic controls and 46 patients with type 1 diabetes were analysed for IAP activity, calprotectin, immunoglobulins and short‐chain fatty acids (SCFAs). The impact of oral IAP supplementation on intestinal immunoglobulin levels was evaluated in C57BL/6 mice exposed to high‐fat diet for 11 weeks.
Results
Patients with type 1 diabetes exhibited signs of intestinal inflammation. Compared to controls, patients with diabetes had higher faecal calprotectin levels, lower faecal IAP activities accompanied by lower propionate and butyrate concentrations. Moreover, the amount of faecal IgA and the level of antibodies binding to oxidized LDL were decreased in patients with type 1 diabetes. In mice, oral IAP supplementation increased intestinal IgA levels markedly.
Conclusion
Deprivation of protective intestinal factors may increase the risk of inflammation in the gut – a phenomenon that seems to be present already in patients with uncomplicated type 1 diabetes. Low levels of intestinal IgA and antibodies to oxidized lipid epitopes may predispose such patients to inflammation‐driven complications such as cardiovascular disease and diabetic nephropathy. Importantly, oral IAP supplementation could have beneficial therapeutic effects on gut metabolic homeostasis, possibly through stimulation of intestinal IgA secretion.
Aims/hypothesis
Parental type 2 diabetes mellitus increases the risk of diabetic nephropathy in offspring with type 1 diabetes mellitus. Several single nucleotide polymorphisms (SNPs) that predispose ...to type 2 diabetes mellitus have recently been identified. It is, however, not known whether such SNPs also confer susceptibility to diabetic nephropathy in patients with type 1 diabetes mellitus.
Methods
We genotyped nine SNPs associated with type 2 diabetes mellitus in genome-wide association studies in the Finnish population, and tested for their association with diabetic nephropathy as well as with severe retinopathy and cardiovascular disease in 2,963 patients with type 1 diabetes mellitus. Replication of significant SNPs was sought in 2,980 patients from three other cohorts.
Results
In the discovery cohort, rs10811661 near gene
CDKN2A/B
was associated with diabetic nephropathy. The association remained after robust Bonferroni correction for the total number of tests performed in this study (OR 1.33 95% CI 1.14, 1.56,
p
= 0.00045,
p
36tests
= 0.016). In the meta-analysis, the combined result for diabetic nephropathy was significant, with a fixed effects
p
value of 0.011 (OR 1.15 95% CI 1.02, 1.29). The association was particularly strong when patients with end-stage renal disease were compared with controls (OR 1.35 95% CI 1.13, 1.60,
p
= 0.00038). The same SNP was also associated with severe retinopathy (OR 1.37 95% CI 1.10, 1.69
p
= 0.0040), but the association did not remain after Bonferroni correction (
p
36tests
= 0.14). None of the other selected SNPs was associated with nephropathy, severe retinopathy or cardiovascular disease.
Conclusions/interpretation
A SNP predisposing to type 2 diabetes mellitus, rs10811661 near
CDKN2A/B
, is associated with diabetic nephropathy in patients with type 1 diabetes mellitus.
Aims/hypothesis
Activation of the receptor for AGE (RAGE) is implicated in the development and progression of vascular complications of diabetes. In this study, we explore factors and mortality ...outcomes associated with soluble RAGE (sRAGE) in a multicentre nationwide cohort of Finnish adults with type 1 diabetes.
Methods
Baseline sRAGE concentrations were estimated in 3,100 adults with type 1 diabetes. Clinical and biological variables independently associated with sRAGE were identified using multivariate regression analysis. Independent predictors of mortality were determined using Cox and Fine–Gray proportional-hazards models.
Results
The main independent determinants of sRAGE concentrations were estimated glomerular filtration rate, albuminuria, body mass index, age, duration of diabetes, HbA
1c
and insulin dose (all
p
< 0.05). During a median of 9.1 years of follow-up there were 202 deaths (7.4 per 1,000 patient years). sRAGE was independently associated with all-cause (Cox model: HR 1.03) and cardiovascular mortality (Fine–Gray competing risks model: HR 1.06) such that patients with the highest sRAGE concentrations had the greatest risk of mortality, after adjusting for age, sex, macrovascular disease, HDL-cholesterol, HbA
1c
, triacylglycerol, high-sensitivity C-reactive protein (hsCRP) and the presence and severity of chronic kidney disease. Although polymorphisms in the gene coding for RAGE were significantly associated with sRAGE concentrations, none were associated with mortality outcomes.
Conclusions/interpretation
Increased concentrations of sRAGE are associated with increased all-cause and cardiovascular mortality in type 1 diabetes, potentially reflecting the activation and production of RAGE in the context of accelerated vascular disease. These novel findings highlight the importance of the RAGE activation in the prevention and management of diabetic complications.
Aims
Our aim was to evaluate the effect of the amount of alcohol consumption and the type of beverage on the risk of diabetic nephropathy and severe diabetic retinopathy.
Methods
The alcohol ...consumption data were available from 3608 patients with Type 1 diabetes participating in the Finnish Diabetic Nephropathy Study (FinnDiane). We assessed the cross‐sectional association between alcohol consumption and diabetic nephropathy as well as retinopathy. Patients were divided into different groups according to the amount of alcohol and the type of beverage they were consuming.
Results
In the multivariate analysis, the odds ratio for nephropathy was 1.39 (95% CI 1.05–1.84) for abstainers and 2.44 (95% CI 1.49–3.99) for former users compared with light consumers. The results were similar in retinopathy, with an odds ratio of 1.42 (95% CI 1.11–1.82) for abstainers and 1.73 (95% CI 1.07–2.79) for former users. No difference between light consumers and moderate or heavy consumers was observed. Compared with wine drinkers, men consuming mostly alcoholic spirits had a higher risk of nephropathy with an odds ratio of 2.80 (95% CI 1.15–6.81). In women, there was no difference in the risk of nephropathy between the different beverage types. Alcoholic spirit consumers had a higher risk of retinopathy with an odds ratio of 2.32 (95% CI 1.35–4.00). There was no difference between wine and beer consumers.
Conclusions
Alcoholic spirit drinkers carry a higher risk of nephropathy and severe retinopathy compared with wine drinkers. Lifelong abstainers and former users of alcohol have a higher risk of nephropathy and severe retinopathy compared with light consumers.
What's new?
Only a few studies have previously addressed the association between alcohol consumption and diabetic microvascular complications with conflicting results.
Our study shows an association with alcohol consumption and diabetic nephropathy and severe retinopathy.
The lifelong abstainers and former users of alcohol have a higher risk of nephropathy and severe retinopathy compared with light consumers.
Moderate and heavy consumers carry the same risk of nephropathy and severe retinopathy as the light consumers.
The previous studies have not compared different beverage types. In our study, consumers of alcoholic spirits have a higher risk of both nephropathy and severe retinopathy compared with wine drinkers.
Aims/hypothesis
This study aimed to investigate whether variation in long-term glycaemia in type 1 diabetes as measured by HbA
1c
variability is associated with the cumulative incidence and risk of ...retinopathy requiring laser treatment.
Methods
The effect of HbA
1c
variability was assessed in 2,019 Finnish Diabetic Nephropathy (FinnDiane) study patients. The patients were studied in two partially overlapping subcohorts with either verified first laser treatment (
n
= 1,459) or retinopathy severity graded from ophthalmic records with the Early Treatment of Diabetic Retinopathy Study (ETDRS) scale (
n
= 1,346). The ratio of intrapersonal SD and mean of serially measured HbA
1c
was considered an estimate of HbA
1c
variability.
Results
A subcohort of 1,459 patients did not have laser treatment prior to the first FinnDiane visit and 174 of these patients were treated during a mean follow-up period of 5.2 ± 2.2 years. The 5 year cumulative incidence of laser treatment was 19% (95% CI 15, 24) in the highest quartile of HbA
1c
variability and 10% (95% CI 7, 12) in the lowest quartile (
p
< 0.001, Gray’s test) with a corresponding HR of 1.6 (95% CI 1.1, 2.5;
p
= 0.02) adjusted for renal status, diabetes duration, mean HbA
1c
, blood pressure, sex and number of HbA
1c
measurements. In a subcohort of 1,346 patients, 434 patients had proliferative diabetic retinopathy (PDR). Patients in the highest quartile of HbA
1c
variability had an increased risk of PDR compared with the lowest quartile (HR 1.7 95% CI 1.3, 2.2;
p
< 0.001).
Conclusions/interpretation
HbA
1c
variability was associated with an increased cumulative incidence and risk of retinopathy requiring laser treatment in type 1 diabetes.
Aim
Acute oxygen inhalation and slow deep breathing improve measures of autonomic function transiently in individuals with short‐duration type 1 diabetes. Our aims were to examine these interventions ...and changes in autonomic function in individuals with long‐duration type 1 diabetes and to explore interactions with the presence of macroalbuminuria or existing cardiovascular autonomic neuropathy.
Methods
Individuals with type 1 diabetes (n = 54) were exposed to acute oxygen inhalation, slow deep breathing and a combination of both (hereafter ‘the combination’). Primary outcomes were change in baroreflex sensitivity and heart rate variability. Associations between changes in outcomes were evaluated using mixed effects models.
Results
Mean age ± sd was 60 ± 10 years and diabetes duration was 38 ± 14 years. Changes are presented as per cent difference from baseline with 95% confidence intervals. Acute oxygen inhalation, slow deep breathing and the combination increased baroreflex sensitivity by 21 (10, 34)%, 32 (13, 53)% and 30 (10, 54)%, respectively. Acute oxygen inhalation trended towards increasing heart rate variability 8 (−1, 17)% (P = 0.056), and slow deep breathing and the combination increased heart rate variability by 33 (18, 49)% and 44 (27, 64)% respectively. Macroalbuminuria or cardiovascular autonomic neuropathy did not modify results.
Conclusion
Autonomic function is improved transiently in individuals with long‐duration type 1 diabetes and normoalbuminuria or macroalbuminuria by acute oxygen inhalation and slow deep breathing. There is a risk of survival bias. Autonomic dysfunction might be a reversible condition, and hypoxia might represent a target of intervention.
What’s new?
Cardiovascular autonomic dysfunction is a risk factor for mortality in type 1 diabetes.
Hyperoxaemia can acutely improve autonomic function in individuals with short‐duration type 1 diabetes.
We explored the potential for improving autonomic function in long‐duration type 1 diabetes with macroalbuminuria, and found that autonomic function could be improved.
Autonomic dysfunction in type 1 diabetes might be a dynamic and reversible condition. Hypoxia might represent a target of intervention for attenuating progression of autonomic dysfunction in type 1 diabetes.
Increased concentrations of C-reactive protein and interleukin-6, a finding suggestive of the presence of inflammation, have been observed in Type 2 diabetes. In such patients, C-reactive protein was ...predictive of diabetic nephropathy. Studies on low-grade inflammatory markers and nephropathy in Type 1 diabetic patients have shown conflicting results. Therefore we studied whether low-grade inflammation is associated with diabetic nephropathy in Type 1 diabetic patients.
We divided 194 Type 1 diabetic patients into three groups from the Finnish Diabetic Nephropathy Study based upon their albumin excretion rate. Patients with normoalbuminuria (n=67) had no antihypertensive medication or signs of cardiovascular disease, while patients with microalbuminuria (n=64) or macroalbuminuria (n=63) were all treated with an angiotensin-converting enzyme inhibitor, a drug that could attenuate low-grade inflammation. As a measure of insulin sensitivity we used estimated glucose disposal rate. C-reactive protein was measured by radioimmunoassay and interleukin-6 by high sensitivity enzyme immunoassay.
C-reactive protein was higher in micro- and macroalbuminuric patients compared to normoalbuminuric patients (normoalbuminuria 2.0+/-1.7, microalbuminuria 2.6+/-1.7, macroalbuminuria 2.9+/-2.5 mg/l; p=0.016), while interleukin-6 increased in parallel with the severity of the renal disease (1.9+/-1.5, 2.9+/-3.3, 3.6+/-3.1 ng/l; p<0.0001). In multiple regression analysis albumin excretion rate was the only variable independently associated with C-reactive protein (p=0.03), whereas albumin excretion rate (p=0.0003), HDL-cholesterol (p=0.0135) and duration of diabetes (p=0.0176) were independently associated with interleukin-6.
Low-grade inflammatory markers are associated with diabetic nephropathy in Type 1 diabetic patients. The predictive value needs to be assessed.
Aims
Renal disease is a frequent comorbidity of type 2 diabetes mellitus (T2DM) and an important factor complicating the choice of glucose‐lowering drugs. The aim of this analysis was to evaluate the ...efficacy and safety of the dipeptidyl peptidase (DPP)‐4 inhibitor linagliptin (5 mg/day) in mono, dual or triple oral glucose‐lowering regimens in subjects with T2DM and mild or moderate renal impairment (RI).
Methods
In this pooled analysis of three 24‐week, placebo‐controlled, phase 3 trials, subjects with mild (estimated glomerular filtration rate (eGFR) 60–<90 ml/min/1.73 m2, n = 838) or moderate RI (30–<60 ml/min/1.73 m2, n = 93) were compared with subjects with normal renal function (≥90 ml/min/1.73 m2, n = 1212).
Results
Subjects with RI were older, had longer duration of diabetes, and increased prevalence of diabetes‐related comorbidities. After 24 weeks, linagliptin achieved consistent placebo‐corrected mean glycated haemoglobin (HbA1c) changes across the three renal function categories: normal (−0.63%; p < 0.0001), mild RI (−0.67%; p < 0.0001) and moderate RI (−0.53%; p < 0.01), with no inter‐group difference (p = 0.74). Renal function with linagliptin remained stable across all categories. In linagliptin‐treated subjects, overall adverse event (AE) rates and serious AE rates were similar to placebo. The incidence of hypoglycaemia with linagliptin and placebo was 11.1 versus 6.9%, 11.9 versus 9.0% and 15.9 versus 12.0% in the normal, mild RI and moderate RI categories, respectively.
Conclusions
This pooled analysis provides evidence that linagliptin is an effective, well‐tolerated and convenient treatment in subjects with T2DM and mild or moderate RI.
In the general population, habitual coffee consumption is inversely associated with the metabolic syndrome, a syndrome that is rather common also in patients with type 1 diabetes. However, whether ...coffee intake is beneficially related to the metabolic syndrome also in type 1 diabetes, is not known. We, therefore, studied the potential association between coffee consumption and the metabolic syndrome in a large population of individuals with type 1 diabetes. Furthermore, we investigated whether coffee consumption is associated with insulin resistance (estimated glucose disposal rate, eGDR), kidney function (estimated glomerular filtration rate, eGFR), and low-grade chronic inflammation (high-sensitivity C-reactive protein, hsCRP).
Data from 1040 participants in the Finnish Diabetic Nephropathy Study were included in these cross-sectional analyses. Metabolic syndrome was assumed if at least 3 of the following cardiovascular risk factors were present: central obesity, high blood pressure, low HDL-cholesterol concentration, high triglyceride concentration, and hyperglycaemia. Subjects were categorized based on self-reported daily coffee intake: non-consumers (<1 cup/d), low (≥1 cups/d < 3), moderate (≥3 cups/d < 5), and high coffee consumption (≥5 cups/d). In multivariable logistic regression analysis, moderate and high coffee consumption was associated with increased odds of the metabolic syndrome. Moreover, any level of coffee consumption was associated with increased risk of the blood pressure-component. An increasing trend was observed in the eGFR with increasing coffee consumption.
In type 1 diabetes, high coffee intake is associated with the metabolic syndrome, and especially its blood pressure-component.
•Coffee intake has been associated with health benefits in the general population.•Whether coffee exerts health benefits also in type 1 diabetes is not known.•High coffee consumption was associated with higher odds of metabolic syndrome.•All coffee intake levels were associated with increased risk of blood pressure component.•An increasing trend between eGFR and coffee consumption was observed.
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