Dietary Modulation of Gene Expression and Metabolic Pathways in Glucose Metabolism (Sysdimet)

Systems Biology Approach to Understand Dietary Modulation of Gene Expression and Metabolic Pathways in Subjects With Abnormal Glucose Metabolism (Sysdimet)

Professor Matti Uusitupa, University of Kuopio, Department of Clinical Nutrition (www.uku.fi) Docent Matej Oresic, VTT (www.vtt.fi) Ursula Schwab, PhD, Docent, Marjukka Kolehmainen, PhD, Docent, Leena Pulkkinen, PhD, Docent, David Laaksonen, MD, PhD, MPH, Docent, Kaisa Poutanen, DSc (Tech), Research Professor

ABSTRACT

The metabolic syndrome (MS) and type 2 diabetes (T2DM) are the most important health problems worldwide. In Finland the prevalence of T2DM is 12-15% among middle-aged people. The prevalence of less marked disturbances in glucose metabolism and MS is 30-40%. Because MS and T2DM are important risk factors for cardiovascular diseases (CVD), the leading cause of death in western countries, all efforts to reverse the epidemic increase in the incidence of MS and T2DM are warranted. The investigators have focused for years on the prevention and non-pharmacological treatment of T2DM and its complications including studies on genetic regulation of glucose and lipid metabolism after dietary modifications. In the investigators' recent projects, the investigators have studied the effects of long-term dietary interventions on gene expression profiles of fat tissue in subjects who are at risk of T2DM. The ultimate goal of these projects has been to identify genes and gene clusters and their biological pathways that respond to dietary modification and modulate glucose and lipid metabolism, and to develop dietary strategies for prevention of T2DM. The main goal of this project is to find nutrition related early biomarkers for progression of MS to T2DM by using modern technologies of systems biology (transcriptomics, metabolomics) of carefully conducted dietary interventions involving subjects with MS. The data will be analysed by using bioinformatics. The investigators reflect these new data to well-known risk factors for T2DM and CVD, e.g., insulin sensitivity, insulin secretion, serum lipids and inflammatory factors among others. In addition to interventions conducted earlier, a new intervention with a whole grain-berry-fish diet and a whole grain diet compared to a control diet with refined foods will be performed. The aim is to increase the investigators' understanding on the synergistic effects of these foods, because the investigators' previous interventions have shown that these individual foods have beneficial effects on glucose and lipid metabolism. On the contrary, diets with refined foods may be harmful in long-term due to its high insulin response, which may through chronic stress lead to both insulin resistance and beta-cell damage.

The significance of this project is to increase understanding of the pathophysiology of MS, T2DM and CVD in physiological, cellular and genetic systems, which may lead to more effective and individualised strategies for treatment and prevention, and better identification of high-risk individuals responsive to specific dietary modifications. Increasing knowledge of dietary factors involved in the progression of MS to T2DM and CVD offers new opportunities to individually tailored diets in the management and prevention of these disorders. The results will also be beneficial for the food industry in developing new functional foods. These results and actions may help delay or even stop the epidemic of MS and T2DM and their negative effect on public health currently seen in Finland and worldwide.

Study Overview

• Status: Completed
• Conditions: Obesity; Metabolic Syndrome; Impaired Glucose Tolerance; Impaired Fasting Glucose
• Intervention / Treatment: Dietary supplement: Diet with increased intake of rye bread, berries and fish; Dietary supplement: Increased intake of whole grain and rye bread; Dietary supplement: Control diet with decreased intake of rye bread, berries and fish

• Study Type: Interventional
• Enrollment (Actual): 106
• Phase: Phase 2

Contacts and Locations

Study Locations

• Finland
  • Kuopio, Finland, 70211
    • University of Kuopio, Department of Clinical Nutrition

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• impaired glucose tolerance (oral glucose tolerance test with 2-h glucose concentration 7,8-11,0 mmol/l) OR
• impaired fasting glucose fasting plasma glucose concentration 5,6-6,9 mmol/l = IFG)
• and two of the criteria for metabolic syndrome:
• BMI 26-39 kg/m2
• Waist circumference > 102 cm (men) or > 88 cm (women)
• hypertriglyceridemia (fasting serum triglyceride conc > 1,7 mmol/l),
• HDL-cholesterol (fasting serum HDL conc < 1,0 mmol/l for men and < 1,3 mmol/l for women)
• Blood pressure ≥ 130/≥ 85 mmHg

Exclusion Criteria:

• BMI > 40 kg/m2
• fasting serum triglyceride conc > 3.5 mmol/l
• fasting serum cholesterol > 8 mmol/l
• type 1 or 2 diabetes
• abnormal liver, kidney or thyroid function
• large alcohol intake (women >16, men > 24 doses (4cl liquor or equivalent) during week)
• inflammatory bowel disease
• disease that prevents participation
• neuroleptic neuroleptic cortisone medication

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: A; Diet with increased intake of rye bread, berries and fish	Dietary supplement: Diet with increased intake of rye bread, berries and fish; Dietary modification with commercial food items
Experimental: B; Increased intake of whole grain and rye bread	Dietary supplement: Increased intake of whole grain and rye bread; Dietary modification with commercial food items
Active Comparator: C; Control diet with decreased intake of rye bread, berries and fish	Dietary supplement: Control diet with decreased intake of rye bread, berries and fish; Dietary modification with commercial food items

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Changes in glucose metabolism, changes in transcriptomic and metabolomic profiles	By 2010

Secondary Outcome Measures

Outcome Measure	Time Frame
Interaction between the diet and genetic factors within treatment groups	By 2010

Collaborators and Investigators

• Sponsor: Marjukka Kolehmainen
• Collaborators: Wageningen University; VTT Technical Research Centre, Finland
• Investigators: Study Director: Matti IJ Uusitupa, professor, rector, University of Kuopio, Department of Clinical Nutrition

Publications and helpful links

General Publications

• Karkkainen O, Lankinen MA, Vitale M, Jokkala J, Leppanen J, Koistinen V, Lehtonen M, Giacco R, Rosa-Sibakov N, Micard V, Rivellese AAA, Schwab U, Mykkanen H, Uusitupa M, Kolehmainen M, Riccardi G, Poutanen K, Auriola S, Hanhineva K. Diets rich in whole grains increase betainized compounds associated with glucose metabolism. Am J Clin Nutr. 2018 Nov 1;108(5):971-979. doi: 10.1093/ajcn/nqy169.
• Lankinen MA, Hanhineva K, Kolehmainen M, Lehtonen M, Auriola S, Mykkanen H, Poutanen K, Schwab U, Uusitupa M. CMPF does not associate with impaired glucose metabolism in individuals with features of metabolic syndrome. PLoS One. 2015 Apr 15;10(4):e0124379. doi: 10.1371/journal.pone.0124379. eCollection 2015.
• Hanhineva K, Lankinen MA, Pedret A, Schwab U, Kolehmainen M, Paananen J, de Mello V, Sola R, Lehtonen M, Poutanen K, Uusitupa M, Mykkanen H. Nontargeted metabolite profiling discriminates diet-specific biomarkers for consumption of whole grains, fatty fish, and bilberries in a randomized controlled trial. J Nutr. 2015 Jan;145(1):7-17. doi: 10.3945/jn.114.196840. Epub 2014 Nov 12.
• Lankinen M, Kolehmainen M, Jaaskelainen T, Paananen J, Joukamo L, Kangas AJ, Soininen P, Poutanen K, Mykkanen H, Gylling H, Oresic M, Jauhiainen M, Ala-Korpela M, Uusitupa M, Schwab U. Effects of whole grain, fish and bilberries on serum metabolic profile and lipid transfer protein activities: a randomized trial (Sysdimet). PLoS One. 2014 Feb 28;9(2):e90352. doi: 10.1371/journal.pone.0090352. eCollection 2014.
• Lappi J, Salojarvi J, Kolehmainen M, Mykkanen H, Poutanen K, de Vos WM, Salonen A. Intake of whole-grain and fiber-rich rye bread versus refined wheat bread does not differentiate intestinal microbiota composition in Finnish adults with metabolic syndrome. J Nutr. 2013 May;143(5):648-55. doi: 10.3945/jn.112.172668. Epub 2013 Mar 20.
• Lankinen M, Schwab U, Kolehmainen M, Paananen J, Poutanen K, Mykkanen H, Seppanen-Laakso T, Gylling H, Uusitupa M, Oresic M. Whole grain products, fish and bilberries alter glucose and lipid metabolism in a randomized, controlled trial: the Sysdimet study. PLoS One. 2011;6(8):e22646. doi: 10.1371/journal.pone.0022646. Epub 2011 Aug 25.
• de Mello VD, Schwab U, Kolehmainen M, Koenig W, Siloaho M, Poutanen K, Mykkanen H, Uusitupa M. A diet high in fatty fish, bilberries and wholegrain products improves markers of endothelial function and inflammation in individuals with impaired glucose metabolism in a randomised controlled trial: the Sysdimet study. Diabetologia. 2011 Nov;54(11):2755-67. doi: 10.1007/s00125-011-2285-3. Epub 2011 Aug 26.

Study record dates

Study Major Dates

• Study Start: September 1, 2007
• Primary Completion (Actual): June 1, 2009
• Study Completion (Actual): June 1, 2009

Study Registration Dates

• First Submitted: December 13, 2007
• First Submitted That Met QC Criteria: December 13, 2007
• First Posted (Estimate): December 14, 2007

Study Record Updates

• Last Update Posted (Estimate): April 17, 2012
• Last Update Submitted That Met QC Criteria: April 16, 2012
• Last Verified: April 1, 2012

More Information

Terms related to this study

• Keywords: Metabolic syndrome; Atherosclerosis; Metabolomics; Type 2 Diabetes; Gene expression; Fat tissue; Nutrigenomics; Systems biology; Peripheral mononuclear cells; Gene clusters; Gene expression profiles; Personal diets
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Insulin Resistance; Hyperinsulinism; Hyperglycemia; Metabolic Syndrome; Glucose Intolerance
• Other Study ID Numbers: 56/2007; 117844 by Finnish Academy