Nutrition, Oral Health and Type 2 Diabetes
Condition: Inflammation
MeSH terms: Inflammation
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      Obesity continues to pose major public health challenges worldwide with cardiovascular
      damage, hypertension and diabetes as possible subsequent conditions. The obese are at risk
      for mortality and morbidity as they suffer from a high level of immune sensitivity with
      consequences related to damage to the circulation and microvasculature. The immune process
      itself is modulated by cytokines, which are small proteins which can modulate the spectrum of
      the inflammatory process. These proteins may act as biomarkers in the mouth.

      Diabetes is also a consequence of sustained obesity and this condition can strongly influence
      immune status. Diabetes is characterized by the failure to produce the hormone insulin or a
      loss of sensitivity to insulin. Without insulin high blood glucose results in the release of
      a series of pro-inflammatory factors, which lead to pathological processes in several organs
      leading to high mortality and morbidity. Periodontitis, a common complication of diabetes, is
      an inflammatory condition of the soft tissue of the periodontium, causing alveolar bone loss.
      The accessibility of the oral cavity facilitates the study of early inflammatory processes.

      Changes in diet may reduce inflammation, controlling gingival inflammation as well as
      clinical treatment. Since 2004 Igelösa Life Science AB has developed a modified Nordic diet
      based on evidence, primarily from the Japanese island of Okinawa, where the world's oldest
      and most healthy people live. In this study we will investigate the association between
      Igelösa dietary intake and measurements of inflammation in 30 overweight individuals with or
      without other systemic diseases.
    

Detailed description: 
      Obesity and diabetes mellitus Obesity is one of our most serious public health issues
      (National Food Agency, 2016). In the Swedish adult (16-84 years) population, about 35% are
      overweight and almost 15% are obese (Statistics Sweden). The most commonly used definition of
      obesity is based on the body mass index (BMI; overweight 25.0-29.9 kg/m2, obesity 30.0-39.9
      kg/m2 and severe obesity > 40 kg/m2) by the World Health Organization. Many studies have
      shown an increased risk of all-cause mortality with greater adiposity as measured by BMI. The
      share of overweight or obese inhabitants in Skåne has increased gradually over recent
      decades. Currently, more than half, (57%) of men are either overweight or obese and the
      corresponding figure for women is 41 percent. These obesity rates are somewhat higher than in
      the rest Sweden (Regional Folkhälsostrategi för Skåne, 2010). However, physical inactivity
      and sedentary behavior has not increased since 2000 (Regional Folkhälsostrategi för Skåne,
      2010). The consequences of obesity include increased risk of coronary heart disease, high
      blood pressure, stroke, and diabetes.

      Diabetes Diabetes is a major health problem and is characterized by elevated serum blood
      sugar levels (hyperglycaemia). Hyperglycemia can be the result of insulin resistance, as well
      as dysfunctional islet β-cells that are unable to secrete adequate insulin to regulate blood
      sugar levels. The financial burden to health care systems providing care to individuals with
      diabetes mellitus is considerable, as is the significant secondary damage to many organs of
      the body (Nolan et al., 2011). Recent estimates indicate that 8.3% of adults - 382 million
      people worldwide - have diabetes (diabetes mellitus type 1: T1D, or diabetes mellitus type 2:
      T2D) and this number may approach 600 million people in less than 25 years (Anonymous IDF
      2013). T2D is the predominant form of the condition and accounts for at least 90% of cases.
      The excess global mortality in 2000 attributed to T2D, was 2.9 million deaths. In the USA,
      diabetes is the leading cause of blindness, as well as causing around 40% of end-stage renal
      failure events and 60% of non-traumatic lower-limb amputations (Nolan et al., 2011).

      Periodontitis Periodontitis is a hallmark of diabetes mellitus (Loe, 1993) and is a chronic
      inflammatory disease of the gingiva (gum tissues), the teeth, and the supporting bone,
      leading to loss of connective tissue attachment to the teeth, and alveolar bone loss. The
      disease is a result of a complex interaction between bacteria and the host immune response
      (Salvi et al., 2005). Periodontal tissue destruction is caused by a host response to the
      development of a complex bacterial biofilm (Thomas et al., 2013). Periodontal infections
      trigger the release of pro-inflammatory cytokines IL1β, IL6, IL8 and TNFα, both at the site
      of the infection and through the endothelial cell system (Zdarilova et al., 2010; Kocgozlu et
      al., 2009). It is generally perceived that periodontitis is preceded by gingivitis, but the
      aetiology of the transition from gingivitis to periodontitis remains unknown. Gingivitis
      presents with swollen tissues and increased redness but with no loss of attachment of the
      teeth. Poor glycemic control in patients often presents with severely inflamed gum tissues
      and loss of tooth-supporting alveolar bone. Several studies have reported that chronic
      periodontitis is prevalent in patients with diabetes (Kim et al., 2013, Moodley et al.,
      2013). In poorly controlled type 2 diabetes pro-inflammatory cytokines and chemokines may
      partially explain the greater susceptibility of diabetic individuals to periodontal breakdown
      (Duarte et al., 2014). To identify bacterial pathogens responsible for periodontitis, one has
      to use both cultivation and molecular identification methods. No single or group of pathogens
      has been clearly identified as the causative agent or agents of gingivitis. Indeed, Kumar et
      al., (2003) showed 40% of organisms detected to be novel species based on ribosomal 16S
      cloning and sequencing. They also concluded that among the bacterial species identified in
      samples collected from both healthy and chronic periodontitis patients, about one third were
      more prevalent among non-healthy individuals. Treatment of periodontitis is usually focused
      on elimination of the infection by lowering the bacterial load using surgical, non-surgical
      or antibiotics. These treatments have considerable side effects, limited effect over time and
      are usually costly. However, another way to control the inflammation is through a radical
      change in diet.

      Okinawa and Igelösa Diet Prevention of high BMI and obesity requires a range of measures
      including moderate dietary habits. Research show that those who consume foods rich in fiber,
      like whole grain, vegetables, legumes, fruit, berries and nuts, more easily retain a stable
      weight (National Food Agency, 2016).

      Okinawa is an island in Japan that that has been top ranked in the world when it comes to
      longevity. The reasons behind the long lives of the original population on Okinawa is a
      combination of genetic and life style-related factors and it is impossible to entangle their
      separate roles (Steen, 2010). However, the traditional lifestyle in Okinawa is characterized
      by low levels of stress, natural exercise and a diet that can be described as mainly
      vegetarian with fish as a main source of animal protein and fat. Steen (2010) refers to the
      book "the Okinawa program" where the authors Suzuki, Willcox and Willcox describe "eating the
      Okinawa way". According to these authors food should be sourced directly from the nature, and
      should be made edible with as little intervention as possible. Comparable to the Swedish
      National Food Agency's recommendations vegetables and whole grain constitutes a large part of
      the natural diet, which further is characterized by its content of calcium, antioxidants in
      the form of flavonoids, omega-3. Another important principle is captured in the statement
      "weigh your options carefully" implying that most food can be consumed as long as certain
      foods, like animal protein and sweets are not overconsumed (Steen, 2010).

      Since 2004 Igelösa Life Science AB has developed a modified Nordic diet based on evidence,
      primarily from the diets of the Okinawa population. The Igelösa-diet consists of food without
      supplements, mainly based on locally produced traditional Nordic ingredients such as intact
      grain (oats, rye, barley, and wheat), vegetables, legumes, root vegetables, fish, poultry,
      fruit and nuts. At the same time, the diet restricts the intake of sugar, red meat,
      delicatessen and dairy products. The diet is nutritious but contains a lower number of
      calories than usual recommendations.

      Research within the field Changes in diet can reduce inflammation (Baumgartner et al., 2009),
      comparably with clinical intervention in the control of gingival inflammation (Widén et al.,
      2015). In 2015, a clinical nutrition study in 30 subjects with T2D was carried out in
      Kävlinge. For 12 weeks every individual received Igelösa diet free of charge. This consisted
      of two meals a day, ready to heat, including salad, fruit and snacks and breakfasts such as
      muesli and porridge. In the following 12 weeks individuals cooked their own food with the
      help of some key products. Individualized dietary advice was available. A research team at
      Skåne University Hospital in Malmö documented each individual's general condition and
      metabolic parameters of glucose, lipids and insulin. Blood, urine and faecal samples were
      collected at baseline and after 2, 12 and 24 weeks. The approach was effective and resulted
      in that several individuals no longer required insulin.

      Assessment of Periodontitis Since 1963, gingival inflammation has been determined through the
      incidence of bleeding on probing (BOP), that is, via a slight pressure of the gums to see if
      it causes bleeding (Loe & Silness, 1963). BOP bias can be avoided by using state-of-the-art
      laser-based measurement systems which exploit the Doppler Effect to record blood flow. Laser
      Doppler flow readings have been shown to be positively correlated with the degree of gingival
      inflammation (Gleissner et al, 2006, Patiño-Marín 2005). We will apply the Doppler technique
      in comparison with the traditional BOP method. Cytokines (immune system signals) are
      biomarkers of inflammation and these can be easily measured in fluid collected from the
      periodontal pockets.

      Aim of the Study The purpose of the study is to investigate the association between dietary
      intake, periodontal status, bacterial populations and measurements of inflammation in 30
      obese individuals.

      Specific objectives

        -  We wish to determine whether a change of diet leads to weight loss, a lower incidence of
           systemic and local inflammation, and less need for medication?

        -  Is this correlated with microbial population changes in the mouth?

        -  Is there a correlation between cytokine levels and bacterial numbers in samples of serum
           and gingival crevicular fluid from periodontal pockets?

        -  Are the Laser Doppler blood flow and measurements of pro-inflammatory cytokines better
           methods of assessing periodontal inflammation compared with bleeding on probing?
    

Intervention name(s): Diet
Intervention type(s): Dietary Supplement
Allocation: Non-Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Basic Science