Aila J. Ahola

The Association Between Dietary Sodium Intake, ESRD, and All-Cause Mortality in Patients With Type 1 Diabetes

OBJECTIVE Many guidelines recommend reduced consumption of salt in patients with type 1 diabetes, but it is unclear whether dietary sodium intake is associated with mortality and end-stage renal disease (ESRD). RESEARCH DESIGN AND METHODS In a nationwide multicenter study (the FinnDiane Study) between 1998 and 2002, 2,807 enrolled adults with type 1 diabetes without ESRD were prospectively followed. Baseline urinary sodium excretion was estimated on a 24-h urine collection. The predictors of all-cause mortality and ESRD were determined by Cox regression and competing risk modeling, respectively. RESULTS The median follow-up for survival analyses was 10 years, during which 217 deaths were recorded (7.7%). Urinary sodium excretion was nonlinearly associated with all-cause mortality, such that individuals with the highest daily urinary sodium excretion, as well as the lowest excretion, had reduced survival. This association was independent age, sex, duration of diabetes, the presence and severity of chronic kidney disease (CKD) (estimated glomerular filtration rate [eGFR] and log albumin excretion rate), the presence of established cardiovascular disease, and systolic blood pressure. During follow-up, 126 patients developed ESRD (4.5%). Urinary sodium excretion was inversely associated with the cumulative incidence of ESRD, such that individuals with the lowest sodium excretion had the highest cumulative incidence of ESRD. CONCLUSIONS In patients with type 1 diabetes, sodium was independently associated with all-cause mortality and ESRD. Although we have not demonstrated causality, these findings support the calls for caution before applying salt restriction universally. Clinical trials must be performed in diabetic patients to formally test the utility/risk of sodium restriction in this setting.

New susceptibility loci associated with kidney disease in Type 1 diabetes

Diabetic kidney disease, or diabetic nephropathy (DN), is a major complication of diabetes and the leading cause of end-stage renal disease (ESRD) that requires dialysis treatment or kidney transplantation. In addition to the decrease in the quality of life, DN accounts for a large proportion of the excess mortality associated with type 1 diabetes (T1D). Whereas the degree of glycemia plays a pivotal role in DN, a subset of individuals with poorly controlled T1D do not develop DN. Furthermore, strong familial aggregation supports genetic susceptibility to DN. However, the genes and the molecular mechanisms behind the disease remain poorly understood, and current therapeutic strategies rarely result in reversal of DN. In the GEnetics of Nephropathy: an International Effort (GENIE) consortium, we have undertaken a meta-analysis of genome-wide association studies (GWAS) of T1D DN comprising ∼2.4 million single nucleotide polymorphisms (SNPs) imputed in 6,691 individuals. After additional genotyping of 41 top ranked SNPs representing 24 independent signals in 5,873 individuals, combined meta-analysis revealed association of two SNPs with ESRD: rs7583877 in the AFF3 gene (P = 1.2×10−8) and an intergenic SNP on chromosome 15q26 between the genes RGMA and MCTP2, rs12437854 (P = 2.0×10−9). Functional data suggest that AFF3 influences renal tubule fibrosis via the transforming growth factor-beta (TGF-β1) pathway. The strongest association with DN as a primary phenotype was seen for an intronic SNP in the ERBB4 gene (rs7588550, P = 2.1×10−7), a gene with type 2 diabetes DN differential expression and in the same intron as a variant with cis-eQTL expression of ERBB4. All these detected associations represent new signals in the pathogenesis of DN.

Many patients with Type 1 diabetes estimate their prandial insulin need inappropriately

Background:  Many factors contribute to the need for prandial insulin in Type 1 diabetes. However, patients’ success in achieving normal postprandial glucose concentration is understudied. The aim of the present study was to determine how often patients with Type 1 diabetes achieve normal postprandial glucose concentrations and to evaluate factors associated with postprandial hypo‐ and hyperglycemia.

Sense of coherence, food selection and leisure time physical activity in type 1 diabetes.

Background: Successful management of type 1 diabetes depends on the self-care practices. Sense of coherence has been associated with various measures of lifestyle choices. We aimed to study the associations between sense of coherence and self-care practices in patients with type 1 diabetes. We hypothesized that patients with weak sense of coherence have less prudent food choices and lower physical activity. Methods: Cross-sectional data from 1104 patients (44% men, mean age 45±12 years) from the FinnDiane Study were available. Sense of coherence, dietary intake, and leisure time physical activity were evaluated using self-reported questionnaires. Diet score was calculated based on the degree to which food choices complied with dietary guidelines. Weekly metabolic equivalent hours were calculated by multiplying the activity duration by the activity- and intensity-specific metabolic equivalent. Results: The sense of coherence score correlated positively both with the diet score and the weekly metabolic equivalent hours. Those in the lowest sense of coherence tertile had both the lowest diet scores and the lowest weekly metabolic equivalent hours values. Among women, the sense of coherence score was associated with the diet score when adjusted for age, socioeconomic status, received dietary guidance, and nephropathy status. The sense of coherence score independently predicted the metabolic equivalent hours value in men. Conclusions : A higher sense of coherence score predicted more prudent food choices in women and higher physical activity in men. In the future, the health consequences associated with a weak sense of coherence should be studied prospectively. Also, the possibility to use the sense of coherence questionnaire as a screening instrument to identify patients who could benefit from intensified counseling should be investigated.

The serum uric acid concentration is not causally linked to diabetic nephropathy in type 1 diabetes

Previous studies have shown a relationship between uric acid concentration and progression of renal disease. Here we studied causality between the serum uric acid concentration and progression of diabetic nephropathy in 3895 individuals with type 1 diabetes in the FinnDiane Study. The renal status was assessed with the urinary albumin excretion rate and estimated glomerular filtration rate (eGFR) at baseline and at the end of the follow-up. Based on previous genomewide association studies on serum uric acid concentration, 23 single nucleotide polymorphisms (SNPs) with good imputation quality were selected for the SNP score. This score was used to assess the causality between serum uric acid and renal complications using a Mendelian randomization approach. At baseline, the serum uric acid concentration was higher with worsening renal status. In multivariable Cox regression analyses, baseline serum uric acid concentration was not independently associated with progression of diabetic nephropathy over a mean follow-up of 7 years. However, over the same period, baseline serum uric acid was independently associated with the decline in eGFR. In the cross-sectional logistic regression analyses, the SNP score was associated with the serum uric acid concentration. Nevertheless, the Mendelian randomization showed no causality between uric acid and diabetic nephropathy, eGFR categories, or eGFR as a continuous variable. Thus, our results suggest that the serum uric acid concentration is not causally related to diabetic nephropathy but is a downstream marker of kidney damage.

Patients with type 1 diabetes show signs of vascular dysfunction in response to multiple high-fat meals

BackgroundA high-fat diet promotes postprandial systemic inflammation and metabolic endotoxemia. We investigated the effects of three consecutive high-fat meals on endotoxemia, inflammation, vascular function, and postprandial lipid metabolism in patients with type 1 diabetes.MethodsNon-diabetic controls (n = 34) and patients with type 1 diabetes (n = 37) were given three high-caloric, fat-containing meals during one day. Blood samples were drawn at fasting (8:00) and every two hours thereafter until 18:00. Applanation tonometry was used to assess changes in the augmentation index during the investigation day.ResultsThree consecutive high-fat meals had only a modest effect on serum LPS-activity levels and inflammatory markers throughout the day in both groups. Of note, patients with type 1 diabetes were unable to decrease the augmentation index in response to the high-fat meals. The most profound effects of the consecutive fat loads were seen in chylomicron and HDL-metabolism. The triglyceride-rich lipoprotein remnant marker, apoB-48, was elevated in patients compared to controls both at fasting (p = 0.014) and postprandially (p = 0.035). The activities of the HDL-associated enzymes PLTP (p < 0.001), and CETP (p = 0.007) were higher and paraoxonase (PON-1) activity, an anti-oxidative enzyme bound to HDL, decreased in patients with type 1 diabetes (p = 0.027).ConclusionsIn response to high-fat meals, early signs of vascular dysfunction alongside accumulation of chylomicron remnants, higher augmentation index, and decreased PON-1 activity were observed in patients with type 1 diabetes. The high-fat meals had no significant impact on postprandial LPS-activity in non-diabetic subjects or patients with type 1 diabetes suggesting that metabolic endotoxemia may be more central in patients with chronic metabolic disturbances such as obesity, type 2 diabetes, or diabetic kidney disease.

Dietary patterns reflecting healthy food choices are associated with lower serum LPS activity

Gram-negative bacteria-derived lipopolysaccharides (LPS) are associated with various negative health effects. Whether diet is associated with LPS, is an understudied phenomenon. We investigated the association between diet and serum LPS activity in 668 individuals with type 1 diabetes in the FinnDiane Study. Serum LPS activity was determined using the Limulus Amoebocyte Lysate assay. Diet was assessed with a food frequency questionnaire (FFQ) section of a diet questionnaire and a food record. The food record was used to calculate energy, macronutrient, and fibre intake. In a multivariable model, energy, macronutrient, or fibre intake was not associated with the LPS activity. Using factor analysis, we identified seven dietary patterns from the FFQ data (“Sweet”, “Cheese”, “Fish”, “Healthy snack”, “Vegetable”, “Traditional”, and “Modern”). In a multivariable model, higher factor scores of the Fish, Healthy snack, and Modern patterns predicted lower LPS activity. The validity of the diet questionnaire was also investigated. The questionnaire showed reasonable relative validity against a 6-day food record. The two methods classified participants into the dietary patterns better than expected by chance. In conclusion, healthy dietary choices, such as consumption of fish, fresh vegetables, and fruits and berries may be associated with positive health outcomes by reducing systemic endotoxaemia.

Intestinal alkaline phosphatase at the crossroad of intestinal health and disease – a putative role in type 1 diabetes

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.

The association between macronutrient intake and the metabolic syndrome and its components in type 1 diabetes

Diet is a major modifiable lifestyle factor that may affect the components of the metabolic syndrome. We aimed to investigate the association between relative proportions of macronutrients and the components of the metabolic syndrome in a population of individuals with type 1 diabetes. In all, 791 individuals without nephropathy, with plausible energy intake and known metabolic syndrome status, taking part in the Finnish Diabetic Nephropathy Study were included in the analyses. Dietary data were collected with a diet record. The association between the relative macronutrient intake and the outcome variables were analysed using multivariable nutrient density substitution models. The relative proportions of dietary macronutrients or fatty acids were not associated with the presence of the metabolic syndrome. In men, however, favouring carbohydrates over fats was associated with lower odds of the waist component, whereas favouring either carbohydrates or fats over proteins was associated with lower odds of the blood pressure component of the metabolic syndrome. In women, substituting carbohydrates for fats was associated with lower HDL-cholesterol concentration. Substituting carbohydrates or fats for alcohol or protein was, in men, associated with lower systolic blood pressure. To conclude, the relative distribution of macronutrients may have some relevance for the metabolic syndrome.

Endotoxins are associated with visceral fat mass in type 1 diabetes

Bacterial lipopolysaccharides (LPS), potent inducers of inflammation, have been associated with chronic metabolic disturbances. Obesity is linked to dyslipidemia, increased body adiposity, and endotoxemia. We investigated the cross-sectional relationships between serum LPS activity and body adiposity as well as inflammation in 242 subjects with type 1 diabetes. Body fat distribution was measured by DXA and serum LPS activity by the limulus amebocyte lysate end-point assay. Since no interaction between visceral fat mass and sex was observed, data were pooled for the subsequent analyses. LPS was independently associated with visceral fat mass, when adjusted for traditional risk factors (age, sex, kidney status, hsCRP, insulin sensitivity). In the multivariate analysis, serum LPS activity and triglyceride concentrations had a joint effect on visceral fat mass, independent of these factors alone. A combination of high LPS and high hsCRP concentrations was also observed in those with the largest visceral fat mass. In conclusion, high serum LPS activity levels were associated with visceral fat mass in subjects with type 1 diabetes strengthening its role in the development of central obesity, inflammation and insulin resistance.