Finnish Diabetes Prevention Study Research Articles

Diabetes Prevention in Australia: 10 Years Results and Experience.

Clinical trials have demonstrated the efficacy of lifestyle modification for the prevention of type 2 diabetes mellitus but it was achieved at higher cost than can be sustained in routine health services. The first clinical trial to report was the Finnish Diabetes Prevention Study. This paper describes how Australia worked with Finnish colleagues to adapt the findings of that study to achieve a statewide diabetes prevention program. Small evaluative, effectiveness trials have been conducted in a number of countries to see if the results of the clinical trials can be replicated in routine health services. The Australian evaluative trial, Greater Green Triangle Diabetes Prevention Program is described in detail to demonstrate the ingredients for success in moving a program from one country to another. Few countries have managed to scale up from evaluative trials to statewide or national programs. The Australian experience is described in detail including lessons learned about what reduced the effectiveness, particularly the need for policy makers in government, people from the implementing organisation and researchers to work together from the start of the evaluative trial and throughout the first 5 years of a national program.

Imbalance of bacteriome profiles within the Finnish Diabetes Prediction and Prevention study: Parallel use of 16S profiling and virome sequencing in stool samples from children with islet autoimmunity and matched controls.

We set out to explore associations between the stool bacteriome profiles and early-onset islet autoimmunity, taking into account the interactions with the virus component of the microbiome. Serial stool samples were longitudinally collected from 18 infants and toddlers with early-onset islet autoimmunity (median age 17.4 months) followed by type 1 diabetes, and 18 tightly matched controls from the Finnish Diabetes Prediction and Prevention (DIPP) cohort. Three stool samples were analyzed, taken 3, 6, and 9 months before the first detection of serum autoantibodies in the case child. The risk of islet autoimmunity was evaluated in relation to the composition of the bacteriome 16S rDNA profiles assessed by mass sequencing, and to the composition of DNA and RNA viromes. Four operational taxonomic units were significantly less abundant in children who later on developed islet autoimmunity as compared to controls-most markedly the species of Bacteroides vulgatus and Bifidobacterium bifidum. The alpha or beta diversity, or the taxonomic levels of bacterial phyla, classes or genera, showed no differences between cases and controls. A correlation analysis suggested a possible relation between CrAssphage signals and quantities of Bacteroides dorei. No apparent associations were seen between development of islet autoimmunity and sequences of yet unknown origin. The results confirm previous findings that an imbalance within the prevalent Bacteroides genus is associated with islet autoimmunity. The detected quantitative relation of the novel "orphan" bacteriophage CrAssphage with a prevalent species of the Bacteroides genus may exemplify possible modifiers of the bacteriome.

Following in the Footsteps of the North Karelia Project: Prevention of Type 2 Diabetes.

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 cardiovascular diseases, and increasing type 2 diabetes prevalence has also been suggested to lead to a new upward turn in cardiovascular diseases. Therefore, it is important to implement activities to prevent type 2 diabetes. We present the trial evidence for the prevention of type 2 diabetes with emphasis on the Finnish Diabetes Prevention Study findings. Furthermore, we discuss the practical implementation of screening of individuals for high type 2 diabetes risk and prevention of type 2 diabetes in Finland at the population level and describe how they have contributed to European level initiatives.

The effect of dietary counselling on food intakes in pregnant women at risk for gestational diabetes: a secondary analysis of a randomised controlled trial RADIEL.

The prevalence of gestational diabetes mellitus (GDM) is increasing worldwide. GDM may be prevented by improving the diets of pregnant women. The objective of this study was to evaluate the effect of dietary counselling on the diets of pregnant women at GDM risk. This study was a secondary analysis of a randomised controlled trial the Finnish gestational diabetes prevention study (RADIEL) in which pre-pregnant and pregnant women with previous GDM or BMI ⩾30 kg/m(2) were allocated into two groups, namely the control and the intervention groups. The control group received standard antenatal dietary counselling according to the Finnish Nutrition Recommendations. The intervention group participated in one individual dietary counselling session and one group dietary counselling session in addition to the standard counselling. This study included women who were recruited during pregnancy. To assess changes in food intake, food-intake questionnaires were collected during the first and the second trimester of pregnancy. Bootstrap type analysis of covariance was used, and 242 participants were included in the final analysis to study changes in food intake. The intakes of low-fat cheese (baseline adjusted mean 0.09 times/day; 95% confidence interval (CI) 0.07, 0.24; P=0.040) and fish (baseline adjusted mean 0.28 times per week; 95% CI 0.08, 0.49; P=0.011) showed a significant increase in the intervention group compared with the control group. This study showed that dietary counselling in early pregnancy can lead to modest dietary improvements in pregnant women at GDM risk.

In high-risk pregnant women, an individualized lifestyle intervention reduced gestational diabetes mellitus.

Source Citation Koivusalo SB, Rono K, Klemetti MM, et al. Gestational diabetes mellitus can be prevented by lifestyle intervention: the Finnish Gestational Diabetes Prevention study (RADIEL): a ran...

Prevention of type 2 diabetes through lifestyle modification: is there a role for higher-protein diets?

Type 2 diabetes (T2D) incidence is increasing worldwide, driven by a rapidly changing environment and lifestyle and increasing rates of overweight and obesity. Prevention of diabetes is key and is most likely achieved through prevention of weight gain and/or successful long-term weight loss maintenance. Weight loss is readily achievable but there is considerable challenge in maintaining that weight loss over the long term. Lower-fat carbohydrate-based diets are widely used for T2D prevention. This is supported primarily by 3 successful long-term interventions, the US Diabetes Prevention Program, the Finnish Diabetes Prevention Study, and the Chinese Da Qing Study, but evidence is building in support of novel higher-protein (>20% of energy) diets for successful weight loss maintenance and prevention of T2D. Higher-protein diets have the advantage of having relatively low energy density, aiding longer-term appetite suppression, and preserving lean body mass, all central to successful weight loss and prevention of weight regain. Here, we review the carbohydrate-based intervention trials and present mechanistic evidence in support of increased dietary protein for weight loss maintenance and a possible novel role in prevention of dysglycemia and T2D.

Diabetes, glycaemia, and cognition-a secondary analysis of the Finnish Diabetes Prevention Study.

Type 2 diabetes is linked with cognitive dysfunction and dementia in epidemiological studies, but these observations are limited by lack of data on the exact timing of diabetes onset. We investigated diabetes, dysglycaemia, and cognition in the Finnish Diabetes Prevention Study, in which the timing and duration of diabetes are well documented. The Finnish Diabetes Prevention Study comprised middle-aged, overweight participants with impaired glucose tolerance but no diabetes at baseline (n = 522), randomized to lifestyle intervention or a control group. After an intervention period (mean duration 4 years) and follow-up (additional 9 years), cognitive assessment with the CERAD test battery and Trail Making Test A (TMT) was executed twice within a 2-year interval. Of the 364 (70%) participants with cognitive assessments, 171 (47%) had developed diabetes. Cognitive function did not differ between those who developed diabetes and those who did not. Lower mean 2-h glucose at an oral glucose tolerance test (OGTT) and HbA1C during the intervention period predicted better performance in the TMT (p = 0.012 and 0.024, respectively). Those without diabetes or with short duration of diabetes improved in CERAD total score between the two assessments (p = 0.001) whereas those with long duration of diabetes did not (p = 0.844). Better glycemic control among persons with baseline impaired glucose tolerance predicted better cognitive performance 9 years later in this secondary analysis of the Finnish Diabetes Prevention Study population. In addition, learning effects in cognitive testing were not evident in people with long diabetes duration. Copyright © 2015 John Wiley & Sons, Ltd.

Gestational Diabetes Mellitus Can Be Prevented by Lifestyle Intervention: The Finnish Gestational Diabetes Prevention Study (RADIEL): A Randomized Controlled Trial.

To assess whether gestational diabetes mellitus (GDM) can be prevented by a moderate lifestyle intervention in pregnant women who are at high risk for the disease. Two hundred ninety-three women with a history of GDM and/or a prepregnancy BMI of ≥30 kg/m(2) were enrolled in the study at <20 weeks of gestation and were randomly allocated to the intervention group (n = 155) or the control group (n = 138). Each subject in the intervention group received individualized counseling on diet, physical activity, and weight control from trained study nurses, and had one group meeting with a dietitian. The control group received standard antenatal care. The diagnosis of GDM was based on a 75-g, 2-h oral glucose tolerance test at 24-28 weeks of gestation. A total of 269 women were included in the analyses. The incidence of GDM was 13.9% in the intervention group and 21.6% in the control group ([95% CI 0.40-0.98%]; P = 0.044, after adjustment for age, prepregnancy BMI, previous GDM status, and the number of weeks of gestation). Gestational weight gain was lower in the intervention group (-0.58 kg [95% CI -1.12 to -0.04 kg]; adjusted P = 0.037). Women in the intervention group increased their leisure time physical activity more and improved their dietary quality compared with women in the control group. A moderate individualized lifestyle intervention reduced the incidence of GDM by 39% in high-risk pregnant women. These findings may have major health consequences for both the mother and the child.

Association of Long-Term Dietary Fat Intake, Exercise, and Weight with Later Cognitive Function in the Finnish Diabetes Prevention Study.

To investigate associations of long-term nutrient intake, physical activity and obesity with later cognitive function among the participants in the Finnish Diabetes Prevention Study, in which a lifestyle intervention was successful in diabetes prevention. An active lifestyle intervention phase during middle age (mean duration 4 years) and extended follow-up (additional 9 years) with annual lifestyle measurements, followed by an ancillary cognition assessment. 5 research centers in Finland. Of the 522 middle-aged, overweight participants with impaired glucose tolerance recruited to the study, 364 (70%) participated in the cognition assessment (mean age 68 years). A cognitive assessment was executed with the CERAD test battery and the Trail Making Test A on average 13 years after baseline. Lifestyle measurements included annual clinical measurements, food records, and exercise questionnaires during both the intervention and follow-up phase. Lower intake of total fat (p=0.021) and saturated fatty acids (p=0.010), and frequent physical activity (p=0.040) during the whole study period were associated with better cognitive performance. Higher BMI (p=0.012) and waist circumference (p=0.012) were also associated with worse performance, but weight reduction prior to the cognition assessment predicted worse performance as well (decrease vs. increase, p=0.008 for BMI and p=0.002 for waist). Long-term dietary fat intake, BMI, and waist circumference have an inverse association with cognitive function in later life among people with IGT. However, decreases in BMI and waist prior to cognitive assessment are associated with worse cognitive performance, which could be explained by reverse causality.

Longitudinal associations of serum fatty acid composition with type 2 diabetes risk and markers of insulin secretion and sensitivity in the Finnish Diabetes Prevention Study.

To examine the longitudinal associations of serum fatty acid composition with type 2 diabetes, insulin secretion and insulin sensitivity over several years. We conducted a prospective cohort study derived from the randomized Finnish Diabetes Prevention Study. Total serum fatty acid composition was measured using gas chromatography in 407 overweight, middle-aged people with impaired glucose tolerance at baseline (1993-1998) and annually during the intervention period (1994-2000). Longitudinal associations of 20 fatty acids and three desaturase activities (Δ5 (20:4n-6/20:3n-6, D5D), Δ6 (18:3n-6/18:2n-6, D6D), stearoyl-CoA desaturase-1 (16:1n-7/16:0, SCD-1)) with type 2 diabetes incidence, and estimates of insulin sensitivity (Matsuda), secretion (ratio of insulin and glucose concentrations) and β-cell function (disposition index) by an oral glucose tolerance test were analyzed using Cox regression and linear mixed models. We validated estimated D5D and D6D using a known FADS1 gene variant, rs174550. The baseline proportions of 20:5n-3, 22:5n-3 and 22:6n-3, and D5D were associated with lower incidence of type 2 diabetes during a median follow-up of 11 years (HR per 1SD: 0.72, 0.74, 0.73, 0.78, respectively, P ≤ 0.01). These long-chain omega-3 fatty acids and D5D were associated with higher insulin sensitivity in subsequent years but not with disposition index. Saturated, monounsaturated and trans fatty acids and 18:3n-3, 18:2n-6, SCD-1 and D6D were inconsistently associated with type 2 diabetes or related traits. Serum long-chain omega-3 fatty acids and D5D predicted lower type 2 diabetes incidence in people at a high risk of diabetes attending to an intervention study; a putative mechanism behind these associations was higher insulin sensitivity.

Markers of cholesterol metabolism as biomarkers in predicting diabetes in the Finnish Diabetes Prevention Study

Background and aimsWe examined the effect of serum markers of cholesterol synthesis and absorption on the incidence of type 2 diabetes (T2D) in the randomized Finnish Diabetes Prevention Study (DPS). We also explored a possible interaction of ABCG8 rs4299376 on sterol levels and lifestyle intervention. Methods and resultsWe conducted a prospective cohort study including overweight, middle-aged people with impaired glucose tolerance at baseline who participated in the randomized DPS. The primary outcome of the DPS was the diagnosis of T2D based on repeated oral glucose tolerance tests (OGTTs). After active intervention (median of four years, 1994–2001), non-T2D participants were further followed until T2D diagnosis, dropout or the end of 2009. Of these, 340 participants who had β-sitosterol, campesterol, lathosterol and desmosterol measured by gas chromatography-mass spectrometry during the active four-year follow-up and who were not using cholesterol lowering medications were analysed. Surrogate indexes of insulin sensitivity (IS) and secretion were calculated from an OGTT. In adjusted models, plant sterols during the four-year follow-up were associated with lower T2D incidence during the extended eight-year follow-up (HR for 1-SD change in β-sitosterol and campesterol: 0.76 [0.63–0.92], and 0.81 [0.67–0.99], respectively). Lathosterol levels were associated with higher T2D incidence (HR: 1.35 [1.13–1.62]). These associations, though, were not independent of IS. There was an interaction between rs4299376 and study group on β-sitosterol (p = 0.001) and campesterol (p = 0.004) levels during the follow-up. ConclusionsMarkers of low absorption and high synthesis of cholesterol were associated with the risk of developing T2D, mostly ascribed to IS.

Cognition in the Finnish Diabetes Prevention Study

We studied cognition in the Finnish Diabetes Prevention Study (DPS), a trial of lifestyle intervention that prevented diabetes in persons with impaired glucose tolerance. Cognition was similar in the randomization arms 9 years after the intervention in 364 participants, suggesting that the intervention did not benefit cognition.

Prevention of type 2 diabetes - where is the evidence?

Diabetes is an “old disease”. The first description of diabetes written on papyrus about 3500 years ago is found in the Ebers papyrus, which was discovered in Egypt in 1873 by the German archeologist Georg Ebers. Humans, like most mammals, may develop diabetes, if sufficient environmental exposure to physical inactivity, unhealthy diet and obesity are present. Genetic effects are important for the individual risk of type 2 diabetes (T2D) but twin studies have shown that the genetic effects combined explain less than 50% of the risk of T2D (1). Today we know almost 100 susceptibility genes associated with T2D but the relative importance of each of these genes is low (2), and together they explain only a small part of the disease risk. Thus, genetic screening cannot be used for the prediction of T2D for individuals. On the other hand, healthy lifestyle can also prevent T2D in people who are genetically at high risk, e.g. those with positive family history (3). Thus, the importance of lifestyle factors for the development and prevention of T2D is overwhelming. The strongest evidence in medicine is considered to come from randomized controlled trials (RCTs). They are also important in providing the link to causal inference that in most observational studies cannot be derived. At the same time, observational studies are necessary for the identification of factors associated with an increased or decreased risk of a disease, and for generation of hypotheses on potential means for prevention based on modifiable risk factors. Observational studies have by now identified a large number of factors that are associated with the development of T2D or with the protection against it. Most of them are related to physical activity, diet and obesity. It has also been shown unequivocally that exposures (poor nutrition, infections, smoking, etc.) during fetal life and early infancy resulting in insufficient development (often shown as low birth weight) also predict T2D later in life (4). Traditionally, T2D has been considered to be a disease of the elderly. However, with increasing obesity and sedentary lifestyle in children, there are increasing numbers of cases of T2D already occurring at a young age in many populations (5). In the past two decades several innovative RCTs have repeatedly shown that interventions on modifiable risk factors can reduce the incidence of diabetes in high-risk groups. The evidence has been summarized in several systematic reviews and meta-analyses (6,7). There is compelling scientific evidence from RCTs that T2D can be prevented or its onset delayed. The key for prevention is a multimodal package of lifestyle changes that is a sum outcome of dietary and physical activity behaviours. The power of lifestyle was dramatically illustrated by the Finnish Diabetes Prevention Study (DPS) that explicitly showed that when the study participants with impaired glucose tolerance reached all five modest lifestyle intervention targets, none of them progressed to T2D (8). Importantly, lifestyle intervention lasting for 3–6 years has been shown to have a carry-over effect on T2D incidence that lasts for several years; up to 15 in the Finnish Diabetes Prevention Study (9) and 20 years in the China Da Qing Diabetes Prevention Study (10). The observed sustained risk reduction seems to be a result of sustained lifestyle changes, but the legacy effect of improved glycaemia during the early intervention may also have contributed to the long-term effect. The follow-up data from the Chinese study indicate moreover that vascular risks are also reduced by lifestyle management. Several prognostic questionnaires exist for detecting people at risk of T2D (11). One of the screening tools with an adequately high sensitivity and specificity is the Finnish Diabetes Risk Score (FINDRISC) developed in Finland (12). The FINDRISC has been successfully implemented in the Finnish primary health care system and used also in many other countries. The FINDRISC was also tested in the Omani population and as a result a slightly modified Omani Diabetes Risk Score was developed (13) which may be a suitable screening tool for the Arab populations in the Middle East. Lifestyle interventions aiming at translating evidence from efficacy RCTs on T2D prevention into “real world” intervention programmes have also been carried out in various populations. Such data were recently combined in a meta-analysis considering the relationship between intervention effectiveness and adherence to guidelines (14). The primary meta-analysis included 22 studies with outcome data for weight loss at 12 months. The pooled result of the direct pairwise meta-analysis shows that lifestyle

Prevention of diabetes: How far have we gone?

Prevention of diabetes: How far have we gone?

Human parechovirus and the risk of type 1 diabetes

Human parechoviruses (HPeVs) are RNA viruses associated mainly with mild gastrointestinal and respiratory infections in children and also cause neonatal sepsis and CNS infections. Human enteroviruses, close relatives of HPeVs, associate with the development of type 1 diabetes. In this study, the potential role of HPeV infections in promoting beta cell autoimmunity was investigated by analyzing stool samples of 54 prediabetic case and 134 healthy control children for the presence of HPeV RNA and comparing the derived infection frequencies. All 188 children were participants of the Finnish prospective Diabetes Prediction and Prevention study. Viral RNA was screened for using an HPeV-specific RT-PCR method coupled to liquid hybridization of the PCR product. The overall HPeV infection frequency did not differ between prediabetic case and control children. However, case boys had more HPeV positive samples in the 6-month period before becoming autoantibody positive, when compared to the matching time-period in controls (P < 0.01). HPeV infection at a young age does not appear to play a major role in the development of beta-cell autoimmunity. In boys, however, HPeVs showed time-dependent association with the first detection of diabetes-associated autoantibodies. Thus, in boys, HPeV infections cannot be excluded as a gender-specific risk factor which promotes the development of type 1 diabetes.

Genetic predisposition to obesity and lifestyle factors – the combined analyses of twenty-six known BMI- and fourteen known waist:hip ratio (WHR)-associated variants in the Finnish Diabetes Prevention Study

Recent genome-wide association studies have identified multiple loci associated with BMI or the waist:hip ratio (WHR). However, evidence on gene-lifestyle interactions is still scarce, and investigation of the effects of well-documented dietary and other lifestyle data is warranted to assess whether genetic risk can be modified by lifestyle. We assessed whether previously established BMI and WHR genetic variants associate with obesity and weight change in the Finnish Diabetes Prevention Study, and whether the associations are modified by dietary factors or physical activity. Individuals (n 459) completed a 3 d food record and were genotyped for twenty-six BMI- and fourteen WHR-related variants. The effects of the variants individually and in combination were investigated in relation to obesity and to 1- and 3-year weight change by calculating genetic risk scores (GRS). The GRS were separately calculated for BMI and the WHR by summing the increasing alleles weighted by their published effect sizes. At baseline, the GRS were not associated with total intakes of energy, macronutrients or fibre. The mean 1- and 3-year weight changes were not affected by the BMI or WHR GRS. During the 3-year follow-up, a trend for higher BMI by the GRS was detected especially in those who reported a diet low in fibre (P for interaction=0·065). Based on the present findings, it appears unlikely that obesity-predisposing variants substantially modify the effect of lifestyle modification on the success of weight reduction in the long term. In addition, these findings suggest that the association between the BMI-related genetic variants and obesity could be modulated by the diet.

Culturally adapting the prevention of diabetes and obesity in South Asians (PODOSA) trial

Type 2 diabetes is extremely common in South Asians, e.g. in men from Pakistani and Indian populations it is about three times as likely as in the general population in England, despite similarities in body mass index. Lifestyle interventions reduce the incidence of diabetes. Trials in Europe and North America have not, however, reported on the impact on South Asian populations separately or provided the details of their cross-cultural adaptation processes. Prevention of diabetes and obesity in South Asians (PODOSA) is a randomized, controlled trial in Scotland of an adapted, lifestyle intervention aimed at reducing weight and increasing physical activity to reduce type 2 diabetes in Indians and Pakistanis. The trial was adapted from the Finnish Diabetes Prevention Study. We describe, reflect on and discuss the following key issues: The core adaptations to the trial design, particularly the delivery of the intervention in homes by dietitians rather than in clinics. The use of both a multilingual panel and professional translators to help translate and/or develop materials. The processes and challenges of phonetic translation. How intervention resources were adapted, modified, newly developed and translated into Urdu and Gurmukhi (written Punjabi). The insights gained in PODOSA (including time pressures on investigators, imperfections in the adaptation process, the power of verbal rather than written information, the utilization of English and the mother-tongue languages simultaneously by participants and the costs) might help the research community, given the challenge of health promotion in multi-ethnic, urban societies.

Reducing the Risk of Developing Diabetes

Reducing the Risk of Developing Diabetes

Importance of Weight Loss Maintenance and Risk Prediction in the Prevention of Type 2 Diabetes: Analysis of European Diabetes Prevention Study RCT

BackgroundPrevalence of type 2 diabetes (T2D) is increasing worldwide. T2D prevention by lifestyle intervention is effective. Pragmatic scalable interventions are needed, with evidence to efficiently target and monitor such interventions. We report pooled analyses of data from three European trial cohorts: to analyse T2D incidence, sustained weight loss and utility of risk predictors.MethodsWe analysed data on 749 adults with impaired glucose tolerance (278 men and 471 women, mean age 56 years, mean BMI 31 kgm−2) recruited between 1993 and 2003, and randomised to intensive lifestyle intervention (I) or lifestyle advice control (C). The intervention aimed to increase physical activity, modify diet, and promote weight loss≥5%. Using Cox-regression survival analysis, we assessed T2D incidence and the impact on T2D incidence of sustained weight loss, and of baseline cut-point values of FINDRISC score, fasting plasma glucose (FPG), and HbA1c.ResultsMean follow-up duration was 3.1 years. T2D was diagnosed in 139 participants (I = 45/379, C = 94/370). Cumulative T2D incidence was 57% lower in the intervention compared with the control group (HR 0.42 (95% CI 0.29 to 0.60) P<0.001). Participants with ≥5% weight loss at one year had 65% lower T2D incidence (HR 0.35 (95% CI 0.22 to 0.56) P<0.001); maintaining ≥5% weight loss for two and three years further reduced T2D incidence. Recommended cut-points to identify those at high risk for T2D would have identified different proportions of European Diabetes Prevention Study (EDIPS) participants with similar hazard-ratios for intervention effect.ConclusionsPooled analysis of EDIPS trial data reinforces evidence for T2D prevention by lifestyle intervention. Analysis showed the preventive effect of ≥5% weight loss, especially if maintained long term, which has utility for intervention monitoring. Analysis of proposed cut-points demonstrates difficulties in balancing risk and benefit, to efficiently target interventions and suggests evidence is needed to define clinical policy.Trial registrationsThe Finnish Diabetes Prevention study, Helsinki, Finland: ClinicalTrials.gov; NCT00518167 The SLIM diabetes prevention study, Maastricht, The Netherlands: Clinical Trials.gov; NCT00381186 The EDIPS-Newcastle diabetes prevention study, Newcastle upon Tyne, UK: International Standard Randomised Controlled Trial Number; ISRCTN15670600.

LRP6 Enhances Glucose Metabolism by Promoting TCF7L2-Dependent Insulin Receptor Expression and IGF Receptor Stabilization in Humans

Common genetic variations in Wnt signaling genes have been associated with metabolic syndrome and diabetes by mechanisms that are poorly understood. A rare nonconservative mutation in Wnt coreceptor LRP6 (LRP6(R611C)) has been shown to underlie autosomal dominant early onset coronary artery disease, type 2 diabetes, and metabolic syndrome. We examined the interplay between Wnt and insulin signaling pathways in skeletal muscle and skin fibroblasts of healthy nondiabetic LRP6(R611C) mutation carriers. LRP6 mutation carriers exhibited hyperinsulinemia and reduced insulin sensitivity compared to noncarrier relatives in response to oral glucose ingestion, which correlated with a significant decline in tissue expression of the insulin receptor and insulin signaling activity. Further investigations showed that the LRP6(R611C) mutation diminishes TCF7L2-dependent transcription of the IR while it increases the stability of IGFR and enhances mTORC1 activity. These findings identify the Wnt/LRP6/TCF7L2 axis as a regulator of glucose metabolism and a potential therapeutic target for insulin resistance.