Individuals with type 2 diabetes mellitus (T2DM) are at risk for developing life-threatening comorbidities such as cardiovascular disease (CVD). As a consequence, T2DM is associated with increased morbidity and mortality and decreased quality of life, thus highlighting the importance of prevention of T2DM. Further, the prevalence of T2DM is substantially greater in rural populations compared to urban populations, making rural individuals particularly appropriate targets for T2DM prevention. T2DM is a largely preventable disease that is associated with modifiable risk factors such as poor diet, sedentary lifestyle, and obesity. Lifestyle interventions to improve these modifiable risk factors have been used to decrease the risk of developing T2DM. There is little evidence that supports lifestyle interventions as a means to decrease T2DM risk in rural populations with prediabetes, the precursor of T2DM. The purpose of this dissertation was to determine whether rural-living individuals with prediabetes would improve modifiable risk factors, specifically diet quality by following a lifestyle intervention; thereby, decreasing their risk of developing T2DM. Specific aims for this dissertation were to, 1) examine and synthesize data from dietary interventions used to reduce risk of T2DM in rural populations on order to identify gaps and guide future research, 2) critically evaluate validity and reliability of indices used to determine diet quality in research, and 3) determine the effect of a risk reduction program on improving diet quality and glucose control (as a measure of T2DM risk) in rural adults with prediabetes and CVD risk factors. Specific aim one was achieved by a review and synthesis of literature focused on lifestyle and dietary interventions used in rural populations to decrease the risk of developing T2DM. Common goals in these studies were a decrease in weight, decrease in dietary fat and calories, and an increase in physical activity. Decreased weight and increased physical activity were demonstrated in all eight studies, and a decrease in T2DM incidence was also demonstrated in one of the studies. However, diet quality was not adequately assessed in the majority of the studies. Furthermore, none of the studies were randomized controlled trials and only half used a control group. It was concluded that research using a more robust design is needed to determine the effect of lifestyle changes, specifically diet, on T2DM risk in rural populations. Specific aim two was addressed by a critical analysis of six common indices of dietary quality. Validity and reliability of the Healthy Eating Index, the Alternative Healthy Eating Index, the DASH diet score, the Diet Quality Index-Revised, the Healthy Diet Indicator, and the Diet Quality Score were examined. Five of the six indices are valid and reliable tools for measure diet quality but all five rely on an extensive food frequency questionnaire that may be burdensome for participants. The Diet Quality Score does not provide adequate evidence to support its use in research. It was concluded that a short, reliable, and validated diet screener may be useful in research. Specific aim three was addressed by a secondary data analysis of a longitudinal, randomized controlled study of rural residents with CVD risk factors and prediabetes. Diet quality, measured by the Mediterranean Diet Adherence Screener (MEDAS), and glucose control, measured by hemoglobin A1c, were analyzed in a subpopulation of 62 participants with prediabetes. Neither diet quality nor glucose control improved between baseline, four month, and 12 month post intervention. The reliability and validity of the MEDAS in this population is not known and may have been a factor in the lack of intervention effect related to diet quality. Participants were also not informed of their prediabetes status, thus it is not known if this knowledge would have made an impact on the outcomes of the study. In addition, the small sample size limits the statistical power to determine changes between the intervention and control groups. It was concluded that further research is needed to determine if a high quality diet will reduce T2DM risk in this rural population Considering the disproportionate prevalence of T2DM in rural populations compared to their urban counterparts, the results of this dissertation demonstrate a continued need for interventions that decrease modifiable risk factors associated with this disease. Interventions that target obesity, poor diet quality, and sedentary lifestyles in at-risk rural populations that are culturally tailored are needed to decrease risk of developing T2DM and the comorbidities associated with this preventable disease.

<p>Most human traits and common diseases have a complex genetic makeup involving more than one gene. The work presented in this thesis investigates standing body height and the common disease type 2 diabetes mellitus (T2DM). In study I we analyzed two single nucleotide polymorphisms (SNPs) in the TCF7L2 gene that had been shown to be associated with T2DM. Analysis was performed in the ULSAM population cohort of ~1500 males. We were able to replicate the association to type 2 diabetes and in addition to that we made a novel find, showing association between the risk alleles and increased proinsulin levels. In study II we analyzed four genes identified to be associated with T2DM in a genome-wide association study. We analyzed SNPs in these genes in the ULSAM population cohort and found an association between SNPs in the HHEX gene and insulin responses and insulin levels. </p><p>The aim of studies III-V was to identify genes affecting normal variation in standing body height. Using a candidate gene approach in study III, 17 genes were screened in the ULSAM population cohort using SNPs. A suggestive association of the ESR1 gene with height was found and confirmed as significant in males from the PIVUS population cohort. In study IV, as a part of the GenomEUtwin project, we performed genetic fine mapping of a linked locus for body height on the X-chromosome. By analyzing 1377 SNPs in 780 Finnish twins, we mapped a region spanning 65kb of this locus with linkage to body height in males. This region contains the GPC3 and PHF6 genes that have known connections to syndromes were standing body height is affected. In study V significant linkage and association to standing body height in males was found for the COL1A11 gene, using population cohorts from Finland and Iceland. </p>

Übergewicht, Diabetes oder Fettstoffwechselstörungen sind mit erniedrigten Adiponectinspiegeln assoziiert. Eine Modulation des Adiponectins kann durch genetische und metabolische Gegebenheiten erfolgen. Das Ziel dieser Arbeit war die Analyse von Faktoren, welche die Adiponectinspiegel beeinflussen können, sowie eine Charakterisierung der Oligomerverteilung unter verschiedenen metabolischen Bedingungen. In der MeSyBePo-Kohorte waren die zirkulierenden Adiponectinspiegel mit den Promotorpolymorphismen ADIPOQ -11377 C/G und ADIPOQ -11391 G/A im Adiponectingen assoziiert. Im Hinblick auf die metabolischen Faktoren korrelierte Adiponectin eng mit Parametern des Glukose- und Fettstoffwechsels sowie dem Übergewicht. Innerhalb von hyperinsulinämischen euglykämischen Clamps führte eine akute Hyperinsulinämie zu einer Abnahme der Adiponectinspiegel. Adiponectin zirkuliert im Serum als hochmolekulare (HMW), mittelmolekulare (MMW) und niedrigmolekulare (LMW) Spezies. Mit zunehmendem Körpergewicht konnte eine Verlagerung von HMW-Spezies hin zu den LMW-Spezies beobachtet werden. Durch eine moderate Gewichtsabnahme erhöhten sich die Anteile an HMW- und MMW-Adiponectin wieder. Während sich in Abhängigkeit vom Glukosemetabolismus keine Unterschiede in den Gesamtspiegeln ergaben, wurden bei Personen mit normaler Glukosetoleranz signifikant höhere Anteile an MMW-Adiponectin detektiert als bei Personen mit einem gestörten Glukosestoffwechsel. Insgesamt scheinen die HMW- und MMW-Spezies gegensätzlich zur LMW-Spezies reguliert zu werden. Die Arbeit unterstreicht die wichtige Rolle des Adiponectins im Glukose- und Fettstoffwechsel sowie bei einer Adipositas in vivo. Dabei waren Änderungen der Adiponectinspiegel bei Vorliegen von Insulinresistenz und Adipositas stets mit einer Umverteilung der Oligomerfraktionen verbunden. Vor allem die HMW- und MMW-Spezies des Adiponectins scheinen von entscheidender Bedeutung zu sein. / Experimental data suggest that a dysregulation of adiponectin might be involved in the development of the metabolic syndrome. Adiponectin circulates as a variety of multimeric forms and its concentration was found to be decreased in obesity, type 2 diabetes mellitus, and dyslipidemia. Polymorphisms within the adiponectin gene, as well as the metabolic status, may modulate the adiponectin level. The aim of this work was to evaluate factors that may modulate total adiponectin levels as well as the distribution of its multimeric complexes under specific metabolic conditions. In the caucasian MeSyBePo population, serum adiponectin concentrations were associated with two promoter polymorphisms, ADIPOQ -11377 C/G and ADIPOQ -11391 G/A, respectively. Mean serum adiponectin levels were related to obesity, glucose metabolism, and lipid metabolism. Additionally, hyperinsulinemic euglycemic clamps acutely lowered serum adiponectin concentration. Adiponectin circulates in serum as low-, medium-, and high-molecular-weight complexes (LMW, MMW, and HMW, respectively). Adiponectin oligomer composition was related to BMI, with decreased HMW and MMW fractions in case of high BMI levels. According to this, HMW and MMW adiponectin increased after moderate weight reduction. While total adiponectin levels were comparable between patients with type 2 diabetes and control subjects, a reduction of MMW oligomers was observed in patients with impaired glucose metabolism. Finally, these studies all suggested a differential regulation of HMW and MMW species compared to the LMW fraction. The data presented underline the important role of adiponectin within the glucose- and lipid metabolism as well as in obesity. We showed that modulation of total adiponectin levels in case of insulin resistance or obesity are always accompanied with changes of adiponectin oligomer composition. Thereby the HMW and MMW species seem to play a crucial role in affecting metabolic changes.

Most human traits and common diseases have a complex genetic makeup involving more than one gene. The work presented in this thesis investigates standing body height and the common disease type 2 diabetes mellitus (T2DM). In study I we analyzed two single nucleotide polymorphisms (SNPs) in the TCF7L2 gene that had been shown to be associated with T2DM. Analysis was performed in the ULSAM population cohort of ~1500 males. We were able to replicate the association to type 2 diabetes and in addition to that we made a novel find, showing association between the risk alleles and increased proinsulin levels. In study II we analyzed four genes identified to be associated with T2DM in a genome-wide association study. We analyzed SNPs in these genes in the ULSAM population cohort and found an association between SNPs in the HHEX gene and insulin responses and insulin levels. The aim of studies III-V was to identify genes affecting normal variation in standing body height. Using a candidate gene approach in study III, 17 genes were screened in the ULSAM population cohort using SNPs. A suggestive association of the ESR1 gene with height was found and confirmed as significant in males from the PIVUS population cohort. In study IV, as a part of the GenomEUtwin project, we performed genetic fine mapping of a linked locus for body height on the X-chromosome. By analyzing 1377 SNPs in 780 Finnish twins, we mapped a region spanning 65kb of this locus with linkage to body height in males. This region contains the GPC3 and PHF6 genes that have known connections to syndromes were standing body height is affected. In study V significant linkage and association to standing body height in males was found for the COL1A11 gene, using population cohorts from Finland and Iceland.

Type 2 diabetes mellitus (T2DM) ensues from diminished insulin sensitivity and abated compensatory insulin secretion. While diminished insulin secretion has a strong genetic origin, environmental factors are central in the development of insulin resistance; these include hyperinsulinemia and lipotoxicity. Insulin resistance results in the dysregulation of hypothalamic neurons that mediate its central actions: a key intermediary neuron is the neuropeptide Y/agouti-related peptide (NPY/AgRP) neuron. The hypothesis therefore was generated that insulin directly regulates NPY/AgRP neurons, and that prolonged insulin or palmitate, a prevalent free fatty acid (FFA), exposure inhibits neuronal insulin signaling. Using well characterized hypothalamic cell lines, mHypoE-46 or mHypoE-44, which express NPY, AgRP and insulin receptor signaling machinery, this hypothesis was examined in three studies. Correspondingly, insulin decreased NPY and AgRP mRNA expression in the mHypoE-46 cells, through an extracellular signal-regulated kinase (ERK) dependent mechanism; whereas prolonged exposure of NPY/AgRP cells to insulin or palmitate attenuated insulin signaling, determined by analysis of phosphorylated Akt. Insulin induced insulin receptor substrate-1 (IRS-1) serine 1101 phosphorylation in mHypoE-46 cells, utilizing the mTOR-S6K1 pathway, as the mTOR inhibitor rapamycin prevented IRS-1 serine phosphorylation. Insulin also decreased insulin receptor and IRS-1 protein levels; this was prevented by lysosomal and proteasomal pathway inhibitors, 3-methyladenine and epoxomicin, respectively. Importantly, rapamycin, epoxomicin or 3-methyladenine pre-treatment decreased the attenuation of insulin signaling during long-term insulin exposure. On the other hand, palmitate activated c-Jun N-terminal kinase (JNK), the apoptosis effector caspase 3, and induced endoplasmic reticulum (ER) stress in mHypoE-44 cells: JNK inhibition prevented ER stress. In an attempt to avert the deleterious effects of palmitate, the neuronal cells were treated with the 5`AMP-activated protein kinase (AMPK) activator AICAR, a possible insulin sensitizer. Interestingly, AICAR attenuated JNK and caspase 3 activation, and restored insulin signaling. These findings demonstrate that insulin directly regulates NPY/AgRP neuronal cells, and that insulin and palmitate provoke neuronal insulin resistance through different mechanisms. These findings substantiate the idea that environmental factors known to trigger peripheral insulin resistance may have consequences at the level of the individual hypothalamic neuron, which may ultimately contribute to the resulting pathophysiological states of obesity and T2DM.

Type 2 diabetes mellitus (T2DM) ensues from diminished insulin sensitivity and abated compensatory insulin secretion. While diminished insulin secretion has a strong genetic origin, environmental factors are central in the development of insulin resistance; these include hyperinsulinemia and lipotoxicity. Insulin resistance results in the dysregulation of hypothalamic neurons that mediate its central actions: a key intermediary neuron is the neuropeptide Y/agouti-related peptide (NPY/AgRP) neuron. The hypothesis therefore was generated that insulin directly regulates NPY/AgRP neurons, and that prolonged insulin or palmitate, a prevalent free fatty acid (FFA), exposure inhibits neuronal insulin signaling. Using well characterized hypothalamic cell lines, mHypoE-46 or mHypoE-44, which express NPY, AgRP and insulin receptor signaling machinery, this hypothesis was examined in three studies. Correspondingly, insulin decreased NPY and AgRP mRNA expression in the mHypoE-46 cells, through an extracellular signal-regulated kinase (ERK) dependent mechanism; whereas prolonged exposure of NPY/AgRP cells to insulin or palmitate attenuated insulin signaling, determined by analysis of phosphorylated Akt. Insulin induced insulin receptor substrate-1 (IRS-1) serine 1101 phosphorylation in mHypoE-46 cells, utilizing the mTOR-S6K1 pathway, as the mTOR inhibitor rapamycin prevented IRS-1 serine phosphorylation. Insulin also decreased insulin receptor and IRS-1 protein levels; this was prevented by lysosomal and proteasomal pathway inhibitors, 3-methyladenine and epoxomicin, respectively. Importantly, rapamycin, epoxomicin or 3-methyladenine pre-treatment decreased the attenuation of insulin signaling during long-term insulin exposure. On the other hand, palmitate activated c-Jun N-terminal kinase (JNK), the apoptosis effector caspase 3, and induced endoplasmic reticulum (ER) stress in mHypoE-44 cells: JNK inhibition prevented ER stress. In an attempt to avert the deleterious effects of palmitate, the neuronal cells were treated with the 5`AMP-activated protein kinase (AMPK) activator AICAR, a possible insulin sensitizer. Interestingly, AICAR attenuated JNK and caspase 3 activation, and restored insulin signaling. These findings demonstrate that insulin directly regulates NPY/AgRP neuronal cells, and that insulin and palmitate provoke neuronal insulin resistance through different mechanisms. These findings substantiate the idea that environmental factors known to trigger peripheral insulin resistance may have consequences at the level of the individual hypothalamic neuron, which may ultimately contribute to the resulting pathophysiological states of obesity and T2DM.

Es gibt widersprüchliche Befunde darüber, ob depressive Symptome Risikofaktoren für die Neumanifestation eines Diabetes sind oder ob umgekehrt auch Diabetes ein Risikofaktor für depressive Zustände ist. Daher untersuchen wir die längsschnittlichen wechselseitigen Assoziationen zwischen depressiven Symptomen und Typ-2-Diabetes (T2D) sowie die Auswirkungen des gemeinsamen Auftretens beider Erkrankungen auf die Mortalität anhand einer Stichprobe von Hausarztpatienten im Verlauf eines im Mittel 3,5-jährigen Beobachtungszeitraums. Die depressive Symptomatik wurde anhand des Depression Screening Questionnaire (DSQ) kategorial sowie dimensional betrachtet. Die Einteilung in Patienten mit normalem Nüchternblutzucker (NBZ), erhöhtem NBZ sowie T2D (unbehandelt, medikamentös, mit Insulin/kombiniert behandelt) erfolgte nach Arztangaben beziehungsweise nach Laborbefunden zur Baseline-Untersuchung. Die Inzidenz des T2D bei Patienten mit beziehungsweise ohne depressive Symptome betrug 25,6 und 20,9 pro 1000 Personenjahre. Bei dimensionaler Betrachtung des DSQ erhöhte sich das T2D-Risiko (unadjustiert) um das 1,03-Fache [KI (95%): 1,01–1,06] bei punktweisem Anstieg des DSQ. Die Inzidenz depressiver Symptome per 1000 Personenjahre betrug 30,5 für Patienten mit normalem, 34,2 für Patienten mit erhöhtem NBZ, 36,4 für unbehandelte, 32,3 für oral behandelte und 47,8 für insulinbehandelte T2D-Patienten. Verglichen mit Patienten mit einem normalen NBZ hatten insulinbehandelte Patienten ein höheres Risiko für depressive Symptome [HR: 1,71; KI (95%): 1,03–2,83] und oral behandelte T2D-Patienten ein niedrigeres Risiko [HR: 0,58; KI (95%): 0,36–0,96]. Verglichen mit Patienten ohne T2D und depressiver Symptomatik ist das Vorliegen beider Erkrankungen mit einer erhöhten Mortalität assoziiert [HR: 2,49; KI (95%):1,45–4,28]. Die Ergebnisse deuten an, dass vor allem eine Insulinbehandlung bei T2D-Patienten mit inzidenten depressiven Symptomen assoziiert ist. / It is unclear whether depressive symptoms are a risk factor for incident diabetes or diabetes is a risk factor for depressive conditions. Therefore, we examined the longitudinal bidirectional associations between depressive symptoms and type 2 diabetes (T2D) as well as the impact of both diseases on (all cause) mortality in a sample of primary care patients over a 3.5-years follow-up period on average. Depressive symptomatology, defined by the Depression Screening Questionnaire (DSQ), was examined both categorically and dimensionally. Patients were categorized as normal fasting glucose (NFG), impaired fasting glucose (IFG), and T2D (untreated, oral antidiabetics, insulin/combined treatment) according to physician ratings and baseline lab values. Incidence rates of T2D were 25.6 and 20.9 per 1000 person–years for those with and without depressive symptoms, respectively. The unadjusted risk of incident type 2 diabetes was 1.03 times higher (CI(95%): 1.01–1.06) for each 1-point increment in DSQ score. The incidence rates of elevated depressive symptoms per 1000 person–years were 30.5 for NFG, 34.2 for IFG, 36.4 for untreated T2D, 32.3 for oral treated T2D, and 47.8 for insulin/combined-treated T2D patients. Compared to NFG patients, insulin-treated patients had a higher risk of incident depressive symptoms (HR: 1.71; CI(95%): 1.03–2.83) and oral-treated patients had a lower risk (HR: 0.58; CI(95%): 0.36–0.96). Higher mortality rates were associated with both diseases compared to patients without T2D or depressive symptoms at baseline (HR: 2.49; CI(95%):1.45–4.28). Results indicate that especially insulin treatment in T2D patients is associated with incident depressive symptoms.

Adipositas ist besonders in den Industrienationen ein zunehmendes gesellschaftliches und ökonomisches Problem. Dabei sind vor allem die kardiovaskulären und metabolischen Begleiterkrankungen von entscheidender Bedeutung. In den letzten Jahren konnte gezeigt werden, dass verschiedene Adipozyten- und Hepatozyten-sezernierte Proteine Mediatoren von Insulinresistenz und Dyslipidämie darstellen. Kürzlich wurde Angiopoietin-related growth factor (AGF) als ein neues, von der Leber produziertes Protein, das potentiell Insulinresistenz und Adipositas antagonisiert, vorgestellt. Im Mausmodell waren AGF-überexprimierende Tiere schlanker und insulinsensitiver verglichen zu Kontrolltieren. Zudem entwickelten AGF-knockout-Mäuse eine Adipositas, Insulinresistenz sowie eine Leber- und Skelettmuskelverfettung. Weiterhin fand sich in epidermalen Keratinozyten eine Hypervaskularisierung bei transgenen Mäusen mit AGF-Expression. Dies macht AGF möglicherweise zu einem Zielgen in der Behandlung moderner Zivilisationskrankheiten, wie z.B. dem Diabetes mellitus Typ 2 (DMT2). Bisherige Publikationen über AGF basieren zumeist auf Tiermodellen. Über die Regulation beim Menschen existieren dagegen bislang nur wenige Studien. In der vorliegenden Arbeit wurde AGF im Serum verschiedener Patientenpopulationen mit einem erhöhten kardiovaskulären Risikoprofil (Patienten mit chronischer Dialysepflicht, DMT2, Präeklampsie [PE]) mittels enzyme-linked immunosorbent assay quantifiziert und mit Kontrollpatienten verglichen. Die Ergebnisse zeigen, dass AGF bei Patienten mit DMT2 im Vergleich zu Nichtdiabetikern signifikant erhöht ist. Bei terminal-niereninsuffizienten Patienten dagegen fanden sich signifikant niedrigere AGF-Konzentrationen im Serum. Bei PE-Patientinnen waren signifikant höhere AGF-Spiegel nachweisbar verglichen zu gesunden schwangeren Kontrollen. Die vorgestellten Daten weisen darauf hin, dass erhöhte AGF-Spiegel bei DMT2 und PE eine physiologische Gegenregulation darstellen könnten, die der Insulinresistenz bei DMT2 bzw. antiangiogenetischen Faktoren bei PE entgegenwirkt. Alternativ wäre – ähnlich der Insulinresistenz – eine Resistenz von Patienten mit DMT2 bzw. PE gegen AGF möglich mit einer reflektorischen Erhöhung dieses Hepatozyten-exprimierten Faktors. Die genaue Rolle von AGF bei kardiovaskulären Risikopatienten muss in zukünftigen Arbeiten noch weiter aufgeklärt werden.

The increased prevalence of obesity amongst adolescents is considered a worldwide epidemic. Within the black population of South Africa, obesity is significantly more prevalent amongst black girls than black boys. The high prevalence of obesity amongst children can be attributed to a combination of various lifestyle factors, namely a decrease in physical activity, an increase in television viewing, Westernization and increased food supply. The decrease in physical activity amongst adolescents over the last few decades has led to an increase in the number adolescents diagnosed with type 2 diabetes mellitus. Research has indicated that insulin sensitivity improves with regular physical endurance activity, irrespective of change in bodyweight. Regular physical exercise also lowers the risk of type 2 diabetes mellitus, and prevents the development of coronary heart diseases, hypertension and obesity. The primary goals of this study were two-fold: Firstly, to determine the relationship between BMI, percentage body fat and insulin sensitivity amongst black adolescents, and, secondly, to determine whether there exists a positive correlation between current cardiovascular fitness (V02-maximum),together with everyday physical activity status, and insulin sensitivity amongst black adolescents. One hundred and twenty-four (124) black boys and 148 black girls between the ages of 14 and 17 participated in the study. The BOD-POD was used to calculate percentage body fat, and blood analysis for fasting glucose and insulin were completed. Insulin sensitivity (QUIKI-index) and resistance (HOMA) were also calculated, and habitual physical activity was measured using the "Previous Day Physical Activity Recall" (pDPAR) questionnaire. Physical development was determined with the Tanner questionnaire, cardiovascular fitness (VO2-maximum) was determined using the "Bleep" test and anthropometry (mass, length, skin folds, waist and hip circumference) was measured to determine body composition. The results of this study found a statistically significant negative correlation between skin fold thickness, percentage body fat, BMI and insulin sensitivity in girls. A significant negative correlation between percentage body fat and V02-maximum was found in boys, while their self-reported activity (PDPAR) did not correlate with percentage body fat. Current cardiovascular fitness and habitual physical activity status (PDPAR) showed no significant relationship with insulin sensitivity. Amongst the girls there was however a tendency towards a positive correlation between insulin sensitivity and V02-maximum. / Thesis (M.Sc. (Human Movement Science))--North-West University, Potchefstroom Campus, 2006.

Type 2 diabetes is a significant health problem because of its high prevalence and strong association with cardiovascular morbidity and mortality. An increase of type 2 diabetes is predicted due to increasing obesity and sedentary lifestyle habits. The development from latent to diagnostic disease spans many years and during this time it is possible to prevent or postpone type 2 diabetes using lifestyle and pharmacological interventions. The objective of this thesis is to investigate and describe early patterns and risk indicators of type 2 diabetes. The focus is on type 2 diabetes as one component in metabolic syndrome, i.e. the clustering of several cardiovascular risk markers. Two studies based on the Västerbotten Intervention Programme (VIP) provided the data; one case-referent study nested within VIP which includes 237 diabetes cases that were clinically diagnosed 5.4 years after the health survey, each with two referents; and one panel study with 5 consecutive annual cohorts including subjects that participated in VIP between1990 and 1994 and returned to a follow-up after 10 years, a total of 16 492 individuals. Associations between risk markers and type 2 diabetes or metabolic syndrome are evaluated by several statistical techniques. A model of metabolic syndrome is hypothesized. A prediction model for developing type 2 diabetes among middle-aged individuals is proposed, where high risk is defined as having at least two out of three risk criteria (fasting plasma glucose ≥6.1 mmol/L, HbA1c ≥4.7% (Swedish Mono-S standard) and BMI ≥27 in men and BMI ≥30 in women). With positive predictive values of 32% in men and 46% in women, this model performs at least as well as other published prediction models. Information on family history of diabetes does not improve the result and the cumbersome oral glucose tolerance test is not needed. Therefore this model should be feasible for use in routine care. A model of metabolic syndrome with five composite factors, based on 14 variables including markers produced by adipose tissue and b-cells, suggest that obesity with insulin resistance and b-cell decompensation are the core perturbations in the early stages of type 2 diabetes, while inflammation and dyslipidemia could not be shown to be independent early risk indicators. The composite factors do not improve the prediction as compared to the single markers of fasting glucose, BMI and proinsulin and, possibly blood pressure values. Stress (measured as passive or tense working conditions) and weak social support (measured as emotional support), are suggested to be strong risk indicators along with high BMI for type 2 diabetes in women. In men BMI is predictive, but the stress variables are not shown to be associated with future type 2 diabetes. A social gap is indicated by double risk of metabolic syndrome among subjects with low (≤ 9 years at school) compared to high education (≥ 13 years). High consumption of Swedish smokeless tobacco, snuff (&gt;4 cans/week), is independently associated with metabolic syndrome, obesity and hypertriglyceridemia, but not with dysregulation of glucose. To conclude, single markers, that are commonly used in daily practice, are useful and sufficient for identification of subjects that are in the early stages of type 2 diabetes. Obesity with insulin resistance and b-cell decompensation are the core perturbations in early development to T2DM. Lifestyle, socioeconomic and psychosocial markers, in addition to biomarkers, are important determinants of future type 2 diabetes and metabolic syndrome, albeit not similarly among men and women.