Matti I J Uusitupa

• MD, PhD
• Professor Emeritus at University of Eastern Finland

In interventional health studies, causal mediation analysis can be employed to investigate mechanisms through which the intervention affects the targeted health outcome. Identifying direct and indirect (i.e. mediated) effects from empirical data, however, becomes complicated if the mediator-outcome association is confounded by a variable itself aff...

Aims/hypothesis Vitamin D insufficiency is associated with an elevated risk of type 2 diabetes, but evidence from randomised trials on the benefits of vitamin D supplementation is limited, especially for average-risk populations. The Finnish Vitamin D Trial (FIND) investigated the effects of vitamin D3 supplementation at two different doses on the...

Context Lifestyle intervention prevents or delays type 2 diabetes (T2D) in subjects at a high risk of T2D. However, it is not known whether genetic variants modify the effect on incident T2D during lifestyle intervention. Objective To investigate whether a low or high genetic risk has effects on incident T2D in a group-based lifestyle intervention...

Context Lifestyle intervention reduces the incidence of type 2 diabetes (T2D) in people with impaired glucose tolerance (IGT). Objective This work aimed to find out whether participation in an earlier lifestyle intervention had an effect on the occurrence of clinically diagnosed diabetic retinopathy (DR) during a median of 22 years of follow-up ti...

Distinct tissue-specific mechanisms mediate insulin action in fasting and postprandial states. Previous genetic studies have largely focused on insulin resistance in the fasting state, where hepatic insulin action dominates. Here we studied genetic variants influencing insulin levels measured 2 h after a glucose challenge in >55,000 participants fr...

Type 2 diabetes (T2D) is a heterogenous disease regarding its phenotype and genotype [...]

Background Behavioral processes through which lifestyle interventions influence risk factors for type 2 diabetes (T2DM), e.g., body weight, are not well-understood. We examined whether changes in psychological dimensions of eating behavior during the first year of lifestyle intervention would mediate the effects of intervention on body weight durin...

Background: The effects of different dietary fatty acids (FA) on cardiovascular risk still needs clarification. Plasma lipids composition may be a biomarker of FA dietary intake. Purpose: To evaluate in a composite population the relationships between changes in dietary fat intake and changes in FA levels in serum cholesterol esters. Methods:...

Type 2 diabetes (T2D) can be prevented or postponed by lifestyle modifications as shown by previous intervention studies. In most of these studies, participants have received resource-demanding individual counseling. In the 3-year T2D-GENE trial with lifestyle intervention, we investigated whether a less resource-demanding form of group and interne...

The prevention of type 2 diabetes (T2D) in high-risk people with lifestyle interventions has been demonstrated by several randomized controlled trials. The intervention effect has sustained up to 20 years in post-trial monitoring of T2D incidence. In 2000, Finland launched the national T2D prevention plan. For screening for high T2D risk, the non-l...

OBJECTIVE Combined low-risk lifestyle behaviors (LRLBs) have been associated with a reduction in type 2 diabetes risk. This relationship has not been systematically quantified. RESEARCH DESIGN AND METHODS A systematic review and meta-analysis was conducted to assess the association of combined LRLBs with type 2 diabetes. Databases were searched up...

Objective To assess the prospective associations of circulating levels of omega 3 polyunsaturated fatty acid (n-3 PUFA) biomarkers (including plant derived α linolenic acid and seafood derived eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid) with incident chronic kidney disease (CKD). Design Pooled analysis. Data sources A...

An intricate relationship between gut microbiota, diet, and the human body has recently been extensively investigated. Gut microbiota and gut-derived metabolites, especially, tryptophan derivatives, modulate metabolic and immune functions in health and disease. One of the tryptophan derivatives, indolepropionic acid (IPA), is increasingly being stu...

Aims/hypothesis Nordic dietary patterns that are high in healthy traditional Nordic foods may have a role in the prevention and management of diabetes. To inform the update of the EASD clinical practice guidelines for nutrition therapy, we conducted a systematic review and meta-analysis of Nordic dietary patterns and cardiometabolic outcomes. Meth...

Background: n-3 and n-6 PUFAs have physiologic roles in sleep processes, but little is known regarding circulating n-3 and n-6 PUFA and sleep parameters. Objectives: We sought to assess associations between biomarkers of n-3 and n-6 PUFA intake with self-reported sleep duration and difficulty falling sleeping in the Fatty Acids and Outcome Resea...

Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) associated with waist circumference and waist-to-hip ratio adjusted for body mass index (WCadjBMI, WHRadjBMI), but it remains unclear whether these SNPs relate to change in WCadjBMI or WHRadjBMI with lifestyle intervention. We hypothesized that polygenic scores (...

Background Vitamin D insufficiency is associated with risk of cardiovascular diseases (CVD) and cancer in observational studies, but evidence for benefits with vitamin D supplementation is limited. Objectives To investigate the effects of vitamin D3 supplementation on CVD and cancer incidence. Design The study was a 5-year randomized placebo-cont...

Diabetic retinopathy (DR) is the most common microvascular complication of diabetes, and retinal microaneurysms (MA) are one of the first detected abnormalities associated with DR. We recently showed elevated serum triglyceride levels to be associated with the development of MA in the Finnish Diabetes Prevention Study (DPS). The purpose of this met...

Background & Aims Intake assessment in multicenter trials is challenging, yet important for accurate outcome evaluation. The present study aimed to characterize a multicenter randomized controlled trial with a healthy Nordic diet (HND) compared to a Control diet (CD) by plasma and urine metabolic profiles and to associate them with cardiometabolic...

Objective . The strongest locus which associated with type 2 diabetes (T2D) by the common variant rs7903146 is the transcription factor 7-like 2 gene ( TCF7L2 ). We aimed to quantify the interaction of diet/lifestyle interventions and the genetic effect of TCF7L2 rs7903146 on glycemic traits, body weight, or waist circumference in overweight or obe...

Objective: Prospective associations between n-3 fatty acid biomarkers and type 2 diabetes (T2D) risk are not consistent in individual studies. We aimed to summarize the prospective associations of biomarkers of α-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA) with T2D risk through an...

Aims The Finnish National Diabetes Prevention Program (FIN-D2D) was the first large-scale diabetes prevention program in a primary health care setting in the world. The risk reduction of type 2 diabetes was 69% after one-year intervention in high-risk individuals who were able to lose 5% of their weight. We investigated long-term effects of one-yea...

Background De novo lipogenesis (DNL) is the primary metabolic pathway synthesizing fatty acids from carbohydrates, protein, or alcohol. Our aim was to examine associations of in vivo levels of selected fatty acids (16:0, 16:1n7, 18:0, 18:1n9) in DNL with incidence of type 2 diabetes (T2D). Methods and findings Seventeen cohorts from 12 countries (...

Objectives To assess associations between individual and total circulating n-3 fatty acids (FAs) with self-reported sleep duration and difficulty sleeping in the Fatty Acids and Outcome Research Consortium (FORCE). Methods De novo harmonized individual-level analyses were performed and pooled in 10 prospective studies (N = 22,717) with data on sle...

One of the special issues in Nutrients in 2020 focuses on the nutritional therapy for diabetes mellitus [...]

The recommended amount and quality of protein in diets of diabetic patients are highly controversial. In order to provide evidence-based information, the Diabetes Nutrition Study Group (DNSG) used a grading procedure used for quality of evidence and strength of recommendations (GRADE). A protein intake of 10% to 20% of energy intake (E%) or about 0...

A healthy dietary pattern is associated with a lower risk of metabolic syndrome (MetS) and reduced inflammation. To explore this at the molecular level, we investigated the effect of a Nordic diet (ND) on changes in the gene expression profiles of inflammatory and lipid-related genes in peripheral blood mononuclear cells (PBMCs) of individuals with...

Prevention of type 2 diabetes (T2D) is a great challenge worldwide. The aim of this evidence synthesis was to summarize the available evidence in order to update the European Association for the Study of Diabetes (EASD) clinical practice guidelines for nutrition therapy. We conducted a systematic review and, where appropriate, meta-analyses of rand...

Background: Recently, a group of betainized compounds have been suggested to play a role in health effects in relation to a whole-grain-rich diet. Objectives: The aims of this study were to develop a quantitative mass spectrometric method for selected betainized compounds in human plasma, and to investigate their association with nutrient intake...

The aim of the study was to find out whether participation in earlier intervention had an effect on the occurrence of retinopathy in study participants. We also examined risk factors (age, sex, weight, fasting and 2 h glucose, fasting insulin, blood pressure, serum lipids) for early retinal changes. The study included 522 individuals (mean 55 years...

Low-grade inflammation (LGI) has been suggested to be involved in the development of chronic diseases. Healthy dietary patterns, such as the Mediterranean diet (MD), may decrease the markers of LGI. Healthy Nordic diet (HND) has many similarities with MD, but its effects on LGI are less well known. Both of these dietary patterns emphasize the abund...

Scope To explore the effect of a healthy Nordic diet on the global transcriptome profile in peripheral blood mononuclear cells (PBMCs) of subjects with the metabolic syndrome. Methods and Results Subjects with the metabolic syndrome underwent an 18/24 week randomized intervention study comparing an isocaloric healthy Nordic diet with an average ha...

Background: Saturated fatty acids (SFAs) of different chain lengths have unique metabolic and biological effects, and a small number of recent studies suggest that higher circulating concentrations of the very-long-chain SFAs (VLSFAs) arachidic acid (20:0), behenic acid (22:0), and lignoceric acid (24:0) are associated with a lower risk of diabete...

Abstract Aims Low-density lipoprotein (LDL) particles cause atherosclerotic cardiovascular disease (ASCVD) through their retention, modification, and accumulation within the arterial intima. High plasma concentrations of LDL drive this disease, but LDL quality may also contribute. Here, we focused on the intrinsic propensity of LDL to aggregate up...

The fatty acid compositions of plasma lipids and cell membranes of certain tissues are modified by dietary fatty acid composition. Furthermore, many other factors (age, sex, ethnicity, health status, genes, and gene × diet interactions) affect the fatty acid composition of cell membranes or plasma lipid compartments. Therefore, it is of great impor...

Background We aimed to investigate prospective associations of circulating or adipose tissue odd-chain fatty acids 15:0 and 17:0 and trans-palmitoleic acid, t16:1n-7, as potential biomarkers of dairy fat intake, with incident type 2 diabetes (T2D). Methods and findings Sixteen prospective cohorts from 12 countries (7 from the United States, 7 from...

Background: Epidemiologic evidence suggests that diets rich in whole grains are associated with a reduced risk of developing chronic diseases and all-cause mortality. However, the molecular mechanisms behind these beneficial metabolic effects are poorly understood. Objective: Our aim was to investigate novel trimethylated (betainized) compounds...

We recently reported using non-targeted metabolic profiling that serum indolepropionic acid (IPA), a microbial metabolite of tryptophan, was associated with a lower likelihood of developing type 2 diabetes (T2D). In the present study, we established a targeted quantitative method using liquid chromatography with mass spectrometric detection (HPLC-Q...

Aims: Body iron inhibits the metabolism of adiponectin, an insulin sensitizing adipokine. We investigated the relationships of baseline and average of 4-year change in values of serum adiponectin (sA), serum ferritin (sF) and sA/sF ratio on type 2 diabetes (T2D) risk and insulin sensitivity (Matsuda ISI) and secretion (disposition index; DI30). M...

Objectives: Several studies have reported that the intestinal microbiota composition of celiac disease (CD) patients differs from healthy individuals. The possible role of gut microbiota in the pathogenesis of the disease is, however, not known. Here, we aimed to assess the possible differences in early fecal microbiota composition between children...

Background The effects of obesity surgery on serum and adipose tissue fatty acid (FA) profile and FA metabolism may modify the risk of obesity-related diseases. Methods We measured serum (n=122) and adipose tissue (n=24) FA composition and adipose tissue mRNA expression of genes regulating FA metabolism (n=100) in participants of the Kuopio Obesit...

Scope: Urinary hippuric acid has been proposed as a biomarker for fruit, vegetable and polyphenol consumption. We assessed how serum hippuric acid changes after a bilberry-enriched diet (BB; high anthocyanin intake) and another berry diet including strawberries, raspberries and cloudberries (SRC; lower anthocyanin intake) and how these changes ass...

Wide-scale profiling technologies including metabolomics broaden the possibility of novel discoveries related to the pathogenesis of type 2 diabetes (T2D). By applying non-targeted metabolomics approach, we investigated here whether serum metabolite profile predicts T2D in a well-characterized study population with impaired glucose tolerance by exa...

To identify novel coding association signals and facilitate characterization of mechanisms influencing glycemic traits and type 2 diabetes risk, we analyzed 109,215 variants derived from exome array genotyping together with an additional 390,225 variants from exome sequence in up to 39,339 normoglycemic individuals from five ancestry groups. We ide...

Academy of Finland (129293, 128315, 129330, 131593, 139635, 139635, 121584, 126925, 124282, 129378, 258753); Action on Hearing Loss (G51); Ahokas Foundation; American Diabetes Association (#7-12-MN-02); Atlantic Canada Opportunities Agency; Augustinus foundation; Becket foundation; Benzon Foundation; Biomedical Research Council; British Heart Found...

Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derive...

Supplementary Figures 1-7, Supplementary Tables 1-5

Transferability of novel loci in other anthropometric GWAS

Phenotype summary statistics of all studies in 1st and 2nd stage analyses.

Association results for 189 GWAS-significant loci.

Genotyping description for all studies in 1st and 2nd stage analyses.

Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derive...

Purpose To investigate whether obesity-related genes affect a visual outcome of anti-VEGF-treatment in wet AMD. Methods Thirty-seven patients with wet AMD (mean age: 77.0 years) in Kuopio University Hospital, Finland, solely treated with anti-VEGF as needed, were genotyped for 40 recently associated obesity-related loci using the Sequenom iPlex pl...

To dissect the genetic architecture of blood pressure and assess effects on target organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry, and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure–associated loci, of which 17 were n...

High blood pressure is a major risk factor for cardiovascular disease and premature death. However, there is limited knowledge on specific causal genes and pathways. To better understand the genetics of blood pressure, we genotyped 242,296 rare, low-frequency and common genetic variants in up to 192,763 individuals and used ~155,063 samples for ind...

Objective To assess the effect of the FTO genotype on weight loss after dietary, physical activity, or drug based interventions in randomised controlled trials. Design Systematic review and random effects meta-analysis of individual participant data from randomised controlled trials. Data sources Ovid Medline, Scopus, Embase, and Cochrane from in...

Supplementary file: supplementary appendices 1-8

High blood pressure is a major risk factor for cardiovascular disease and premature death. However, there is limited knowledge on specific causal genes and pathways. To better understand the genetics of blood pressure, we genotyped 242,296 rare, low-frequency and common genetic variants in up to 192,763 individuals and used ∼155,063 samples for ind...

To dissect the genetic architecture of blood pressure and assess effects on target organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry, and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure-associated loci, of which 17 were n...

[This corrects the article DOI: 10.1371/journal.pgen.1005378.].

Consortia members and extended acknowledgments. (DOCX)

The prevalence as well as actual number of people with type 2 diabetes has been increasing in Finland during the past decades, in parallel with an increase in overweight and obesity. Besides obesity, population aging is among the main drivers of increasing numbers of diabetic patients. Type 2 diabetes brings along complications, most importantly ca...

The maintenance of normal body weight is disrupted in patients with anorexia nervosa (AN) for prolonged periods of time. Prior to the onset of AN, premorbid body mass index (BMI) spans the entire range from underweight to obese. After recovery, patients have reduced rates of overweight and obesity. As such, loci involved in body weight regulation m...

Background: Diet has a great impact on the risk of developing features of metabolic syndrome (MetS), type 2 diabetes mellitus (T2DM), and cardiovascular diseases (CVD). We evaluated whether a long-term healthy Nordic diet (ND) can modify the expression of inflammation and lipid metabolism-related genes in peripheral blood mononuclear cells (PBMCs)...

A scavenger that protects the heart Coronary heart disease is a tale of two forms of plasma cholesterol. In contrast to the well-established effects of “bad” cholesterol (LDL-C), the role of “good” cholesterol (HDL-C) is mysterious. Elevated HDL-C correlates with a lower risk of heart disease, yet drugs that raise HDL-C levels do not reduce risk. Z...

Background: A healthy Nordic diet is associated with improvements in cardiometabolic risk factors, but the effect on lipidomic profile is not known. Objective: The aim was to investigate how a healthy Nordic diet affects the fasting plasma lipidomic profile in subjects with metabolic syndrome. Methods: Men and women (n = 200) with features of...

High blood pressure is a major risk factor for cardiovascular disease and premature death. However, there is limited knowledge on specific causal genes and pathways. To better understand the genetics of blood pressure, we genotyped 242,296 rare, low-frequency and common genetic variants in up to ~192,000 individuals, and used ~155,063 samples for i...

Human and animal studies suggest an interaction between the Pro12Ala polymorphism of PPARG and dietary fat. In this randomized crossover clinical trial, we investigated whether subjects with the Pro12Pro and Ala12Ala genotypes of PPARG respond differently to a diet supplemented with high saturated (SAFA) or polyunsaturated fatty acid (PUFA).We recr...

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for ag...

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for ag...

Scope: Limited information exists on how the relationship between dietary intake of fat and fatty acids in erythrocytes and plasma is modulated by polymorphisms in the FADS gene cluster. We examined gene-diet interaction of total marine PUFA intake with a known gene encoding Δ-5 desaturase enzyme (FADS1) variant (rs174550) for fatty acids in eryth...

Alkylresorcinols (ARs) have been suggested as biomarkers of whole-grain wheat and rye intake. Plasma AR concentrations have a short half-life; hence, long-term biomarkers are needed. This study evaluated the responsiveness of ARs in adipose tissue biopsies as biomarkers after a whole-grain intake intervention. Samples and data of 27 participants fr...

Our aim was to investigate the fasting proportions of fatty acids and estimated desaturase and elongase activities in three different lipid fractions in plasma, phospholipids (PLs), cholesteryl esters (CEs) and triacylglycerols (TGs), as predictors for the worsening of glycaemia (area under the glucose curve in an OGTT [glucose AUC]) and incident t...