京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19892号 / 医博第4141号 / 新制||医||1016(附属図書館) / 32969 / 京都大学大学院医学研究科医学専攻 / (主査)教授 川村 孝, 教授 横出 正之, 教授 妹尾 浩 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Type 2 diabetes mellitus (T2DM) is a global health concern affecting six to ten percent of adults worldwide, with the number of diagnosed individuals projected to double in the next 25 years. However, effective public health strategies can help mitigate its impact on quality of life, morbidity, mortality and the associated social and economic burden. In Sweden, screening programs classify individuals with Impaired fasting glucose (IFG) as high-risk individuals, however scholars argue that preventative measures should also include those at lower fasting plasma glucose (FPG) concentrations as some evidence suggests that the disease begins developing several years before the current threshold. A systematic review and meta-analysis of cohort and case-control studies was conducted with the purpose of exploring the IFG threshold from a longitudinal perspective. Eleven studies on the incidence rates of T2DM in normoglycemic individuals and seven studies on pre-diagnostic trajectories of FPG concentrations were analyzed. Incidence rates increased progressively across the normoglycemic range, with a twelve-fold difference between the low and high end. FPG concentrations in eventual progressors and non-diabetic controls were significantly different twelve years prior to diagnosis. Mildly increasing FPG concentrations were observed in eventual progressors until three years before diagnosis, at which a larger increase followed. In the last year before diagnosis, FPG concentrations rose dramatically in this group. The findings imply that a lowering of the threshold would extend the time spent in the IFG state, allowing for earlier identification of at-risk individuals. In addition, further stratification of normoglycemic range may enhance the accuracy of T2DM risk assessment.

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.

<p>Diet is the number one leading modifiable cause of poor health globally, with poor diets accounting for 10.9 million (22%) of all deaths among adults in 2017. In addition, one of our generation’s forthcoming challenges is the rapid expansion of the population aged 60 years and older. Although people are living longer, there is an associated increase in the prevalence of aged-related chronic diseases and functional impairment, such as cardiometabolic diseases and sarcopenia. As such, dietary components can play a role in positively or negatively influencing the prevention and treatment of chronic cardiometabolic diseases and sarcopenia. One such dietary component is dietary protein, which is essential throughout the life course, from gestation through old age. Evidence supports dietary protein playing an important role in reducing the risk of developing age-related chronic diseases such as sarcopenia and cardiometabolic diseases. </p> <p><em><strong>     Study 1, Chapter 2:</strong></em> The Dietary Guidelines for Americans (DGA) recommends consuming a variety of “Protein Foods” based on “ounce equivalent” (oz-eq) portions. In addition, the 2020-2030 Strategic Plan for NIH Nutrition Research includes to “define the role of nutrition across the lifespan” with an objective to “assess the role of nutrition in older adults to promote healthy aging.” However, there is a paucity of primary research that directly compares EAAs bioavailability between young and older adults consuming the same oz-eq portions of varied Protein Foods. No study has assessed the same oz-eq portions of animal- versus plant-based Protein Foods on essential amino acids (EAAs) bioavailability for protein anabolism in young and older adults. Therefore, we conducted two sequential randomized, investigator-blinded, crossover, acute feeding trials with the same study design; first in a cohort of young adults and second in a cohort of older adults. The primary objective of this project was to assess the effect of consuming two oz-eq portions of animal-based (unprocessed lean pork or whole eggs) vs. plant-based (black beans or sliced almonds) Protein Foods as part of a mixed whole foods meal on plasma EAAs bioavailability for protein anabolism. Consistent with our hypotheses, participant age did not affect postprandial EAAs bioavailability, and consuming a meal with two oz-eq of unprocessed lean pork or whole eggs resulted in greater postprandial EAAs bioavailability compared to a meal with two oz-eq of black beans or raw sliced almonds in 1) young adults; 2) older adults; and 3) young and older adults combined. These findings show on the same oz-eq basis, consuming these animal- vs. plant-based Protein Foods more effectively provide bioavailable EAAs for protein anabolism. </p> <p><em><strong>     Study 2, Chapter 3:</strong></em> Poultry meat is the most consumed type of meat worldwide and in the US. Poultry is generally considered to be a “healthy” meat as it is a high-quality protein source and provides other essential nutrients. However, research assessing poultry and its effects on and relations with chronic diseases in humans is sparse, and the forms of poultry typically consumed in the US, are not necessarily in line with recommendations provided by the DGA. Therefore, we conducted a scoping review to systematically search and chronicle scientific literature pertinent to poultry intake and human health. Main findings from this project were 1) historically, little research, especially randomized diet-controlled feeding trials, has been conducted to understand associations between and effects of consuming poultry products on human health; 2) the majority of research is from observational studies assessing relationships between poultry intake and risks of morbidity and mortality from various types of cancer; 3) a paucity of research exists to support chicken as a health-promoting food in children; and 4) research taking into account poultry product processing and cooking methods is needed. Science and health professionals, the poultry industry, and the public will benefit from new observational and experimental research to address cutting-edge scientific, public policy, and consumer topics pertinent to poultry intake and human health. </p> <p><em><strong>     Study 3, Chapter 4:</strong></em> Emerging research on whey protein supplementation suggests it may be a potential modifier of type 2 diabetes mellitus (T2DM) risk factors, including glucose control. As systematic reviews and/or meta-analyses of randomized controlled trials are gaining importance in nutrition literature, we conducted an umbrella systematic review to search for and chronicle published systematic reviews and/or meta-analyses of randomized controlled trials pertinent to whey protein supplementation and T2DM modifiable risk factors (study 3, Chapter 4). Among the 13 systematic reviews, including 12 meta-analyses critically assessed for this umbrella review, no reviews reported any adverse effects of whey protein on any reported T2DM-related risk factor. Collectively, a preponderance of evidence indicates whey protein supplementation improves multiple clinical indicators of glucose control in apparently healthy adults and those at increased risk for type 2 diabetes mellitus. </p>

Our study provided an analysis and comparison of specific blood values, dietary intake, body composition, and inflammatory markers (high sensitivity-C-reactive protein (HS-CRP), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6)) between adults with type 2 diabetes mellitus (T2DM) and prediabetes (PDM) to adults without diabetes. A total of 22 participants (PDM/T2DM n=12, controls n=10) in the San Luis Obispo, CA area completed the study prior to our ending recruitment due to Covid-19. Body composition data were collected through DXA scans. Dietary intake was assessed using a 3-day food record survey and nutritional analysis conducted using ESHA food processing software. In addition, participants completed an overnight fast and early morning blood draw for evaluation of blood glucose regulation, blood lipid profile and inflammatory biomarkers. Analysis included a series of randomization tests that were conducted to determine possible statistical differences between the mean of basic characteristics (age, BMI, weight, HbA1C, fasting plasma glucose, fasting insulin, triglycerides, LDL, HDL, and total cholesterol levels) of the control group and the PDM/T2DM group. Secondly, 2-way ANOVA statistical analyses were conducted to determine the interaction between sex and diabetes status on caloric intake, macronutrient distribution, quality of fat intake, visceral adipose tissue (VAT), and inflammatory biomarkers. We found there was a significant difference in fasting plasma glucose (FPG) and hemoglobin A1C (HbA1C) between the control group and the PDM/T2DM group. We did not find a statistically significant difference in caloric intake, macronutrient distribution, quality of fat intake, visceral adipose tissue (VAT), and inflammatory biomarkers between the PDM/T2DM and control group. Due to the lack of studies that include adults with PDM, we concluded additional future research needs to focus on blood biochemistry values, dietary intake, body composition, and inflammatory markers health-risk factors in both adults with PDM and T2DM since these values can improve diagnosis and treatment of T2DM.

Background Type 2 diabetes mellitus (T2DM) is a globally prevalent disease anticipated to double from 500 million diagnosed cases in 2021 to more than one billion by 2050. The investigation of the potentially protective effects of skeletal muscle mass on glucose intolerance may lead to the development of more precise screening protocols. Purpose This thesis aimed to address the lack of clear consensus in existing literature by exploring the relationship between skeletal muscle mass and glucose intolerance. Methods Fifteen healthy young adults were recruited to partake in a prospective correlational study. The participants underwent anthropometric measurements and an oral glucose tolerance test (OGTT). Anthropometric data was collected using an bioelectrical impedance analysis (BIA) scale. Blood glucose levels were measured using capillary sampling before and after ingestion of a 75 g/200 mL glucose solution. Statistical analysis included Spearman’s rank correlation test and Pearson’s correlation coefficient test. Results All associations between skeletal muscle mass and glucose intolerance were of moderate strength. Skeletal muscle mass (SMM) correlated significantly with glucose concentrations two hours (2hPG) following ingestion of the glucose solution and an adjusted measure of SMM was significantly associated with glucose area under the curve (AUC). Statistical significance was also found between Sex and incremental glucose area under the curve (iAUC). Conclusion This thesis suggests an inverse relationship between skeletal muscle mass and glucose intolerance in a group of healthy young adults. The results imply the potential usefulness of incorporating muscle mass when determining the glucose load during an OGTT, especially in preventive contexts. Nevertheless, further research with larger samples is crucial to establish precise cutoff levels for clinical applications. / Bakgrund Typ 2 diabetes mellitus (T2DM) är en global sjukdom och antalet diagnostiserade individer förväntas fördubblas från 500 miljoner fall 2021 till över en miljard år 2050. En undersökning av muskelmassans potentiellt skyddande effekt på glukostolerans kan leda till utvecklandet av noggrannare screeningmetoder. Syfte Syftet med denna uppsats var att bemöta den bristfälliga konsensus som råder bland befintlig forskning genom att undersöka sambandet mellan muskelmassa och glukosintolerans. Metod Femton friska yngre vuxna rekryterades för att delta i en prospektiv korrelationsstudie. Deltagarna genomgick antropometriska mätningar samt ett oralt glukostoleranstest (OGTT). Antropometriska värden mättes med hjälp av en bioelektrisk impedansanalysvåg. Blodglukosnivåer mättes kapillärt före och efter intag av en 75 g/200 mL glukoslösning. Statistisk analys inkluderade Spearmans rangkorrelationstest och Pearsons korrelationskoefficientstest. Resultat Alla samband mellan muskelmassa och glukosintolerans var av måttlig styrka. Muskelmassa (SMM) korrelerade signifikant med blodglukos två timmar (2hPG) efter intag av glukoslösningen och ett justerat SMM-mått (adjSMM) var signifikant associerat med arean under glukoskurvan (AUC). Statistisk signifikans hittades även mellan kön och den inkrementella arean under glukoskurvan (iAUC). Slutsats Resultaten från denna uppsats antyder att ett omvänt samband existerar mellan muskelmassa och glukosintolerans hos en grupp friska yngre vuxna. Resultatet innebär en potentiell möjlighet att använda muskelmassan vid bestämmandet av mängden glukos som administreras vid ett OGTT, särskilt i preventiva syften. Ytterligare forskning med fler studiedeltagare är avgörande för att fastställa exakta gränsvärden för klinisk tillämpning.

Current screening tests for type 2 diabetes mellitus (T2DM) identify less than 50% of undiagnosed T2DM patients and provide no information about how the disease will develop in prediabetic patients. Here, twenty-nine protein glycation sites were quantified after tryptic digestion of plasma samples at the peptide level using tandem mass spectrometry and isotope-labelled peptides as internal standard. The glycation degrees were determined in three groups, i.e., 48 patients with a duration of T2DM exceeding ten years, 48 non-diabetic individuals matched for gender, BMI, and age, and 20 prediabetic men. In long-term controlled diabetic patients, 27 glycated peptides were detected at significantly higher levels, providing moderate diagnostic accuracies (ACCs) from 61 to 79%, allowing a subgrouping of patients in three distinct clusters. Moreover, a feature set of one glycated peptides and six established clinical parameters provided an ACC of 95%. The same number of clusters was identified in prediabetic males (ACC of 95%) using a set of eight glycation sites (mostly from serum albumin). All patients present in one cluster showed progression of prediabetic state or advanced towards diabetes in the following five years. Overall, the studied glycation sites appear to be promising biomarkers for subgrouping prediabetic patients to estimate their risk for the development of T2DM.

Introduction The prevalence of prediabetes in adults aged 18 or older was as high as 38% between 2017-2020. Youth-onset T2DM is a more aggressive phenotype than T2DM that occurs later in life. Young adults with T2DM have poorer health outcomes, lose an average of 15 years of life, all resulting in significant economic burden impacting the person. Current self-management interventions do not improve health outcomes in young adults with T2DM. Purpose The purpose of this research was to explore the self-care experiences of young adults living with T2DM. Methods Existential hermeneutic phenomenology informed the research. Inclusion criteria as follows: adults aged 18 to 30 with a self-reported diagnosis of T2DM, physical presence in the United States, English proficiency. Purposive and snowball sampling were used. Nineteen participants were interviewed: 16 self-identified as Black, 2 as White, and 1 as Latino. Interviews were transcribed verbatim. Transcripts were analyzed using an iterative approach for meaning units and themes. Thematic meanings were identified from the data. Results The grand theme my journey and two themes: finding out and navigating, three subthemes include distress, around me, and my duties. The second subtheme, around me, included two micro themes: support and juggling. The third subtheme, my duties, included three micro themes: exercise, education, and trigger surveillance. Several factors were unique to young adults' perception of self-care. Perceptions of time, support networks, novel coping strategies, and search for disease literacy impacted self-care perceptions and understanding. Results suggest the need for future person-centered, self-care intervention research with young adults that could result in improved health outcomes.

Bakgrund: Diabetes är en folksjukdom som ökar i världen. För en framgångsrik behandling behöver personer med diagnosen diabetes typ 2 förutom medicinsk vård även ändra sin livsstil vilket främst innefattar förändrade vanor kring kost och fysisk aktivitet.  Syfte: Syftet med denna studie var att beskriva personers upplevelser av livsstilsförändringar vid diabetes typ 2. Metod: Allmän litteraturöversikt. Systematiska sökningar gjordes i databaserna CINAHL och PubMed. Kvalitativ innehållsanalys genomfördes för analys. En tematisk analys gjordes av nio forskningsartiklar och dess resultat. Resultat: Resultatet genererade två teman med respektive två subteman, Motivation - Motiverade till livsstilsförändringar och Omotiverade till livsstilsförändringar, Ändra och bibehålla vanor - Beteendeförändringar och Praktiska utmaningar  Slutsats: Resultaten pekade på att motivation, bibehållandet av livsstilsförändringar över tid, känslor relaterade till diagnosen och socialt sammanhang var avgörande för livsstilsförändring. Sjuksköterskor har en viktig funktion att förstå patienters unika livssituationer och levnadsvillkor för att effektivt kunna stödja dem i att göra nödvändiga livsstilsförändring. Fortsatt forskning: Studien understryker även behovet av fortsatt forskning för personer med diabetes typ 2 med fokus på den yngre befolkningens omvårdnadsbehov och livsstilsförändringar. Nyckelord: Diabetes mellitus typ 2, livsstilsförändring, omvårdnad, personer, personcentrerad vård, upplevelser / Background: Diabetes is a common disease that is increasing worldwide. For successful treatment, individuals diagnosed with type 2 diabetes need not only medical care but also to change their lifestyle, which mainly involves changing habits related to diet and physical activity. Purpose: The purpose of this study was to describe individuals' experiences with lifestyle changes in type 2 diabetes. Method: General literature review. Systematic searches were conducted in the CINAHL and PubMed databases. Qualitative content analysis was performed for analysis. A thematic analysis was done of nine research articles and their results. Results: The results generated four themes two subthemes each, Motivation - Motivated for Lifestyle Changes and Unmotivated for Lifestyle Changes, Changing and Maintaining Habits - Behavioral Changes and Practical Challenges.  Conclusion: The results indicated that motivation, maintaining lifestyle changes over time, emotions related to the diagnosis, and social context was crucial for succeeding with lifestyle changes. Nurses play a significant role in understanding patients' unique life situations and living conditions to effectively support them in making necessary lifestyle changes. Continued Research: The study also emphasizes the need for further research on individuals with type 2 diabetes, focusing on the care needs and lifestyle changes of the younger population. Keywords: Experiences, lifestyle changes, nursing, person-centered care, persons, type 2 diabetes mellitus.

Coronary artery disease (CAD), Hypertension (Ht) and Type 2 Diabetes Mellitus (T2DM) are all global health problems. This is particularly evident amongst South Asian population groups. The conventional risk factors do not fully explain the higher prevalence of these diseases among South Asians. The endothelial Nitric Oxide Synthase (eNOS) gene is responsible for the production of Nitric Oxide (NO), which may contribute to the physiology of all three disease states. Endothelial dysfunction (which is characterised by a reduction in basal NO) has been shown to be present in, or prior to all three diseases. Numerous variations exist within the eNOS gene, of these variations three have been shown to have a possible functional effect. The first is the Glu298Asp polymorphism within the exon region of the gene, resulting in an amino acid substitution of Glutamate (Glu) to Aspartate (Asp). The second, known as the T-786C polymorphism, is a thymine to cytosine mutation at position -786 in the promoter region. Finally a VNTR polymorphism in Intron 4 causes either a 4 27bp repeat or a 5 27bp repeat. It is hypothesised that these variations could have an effect on the ability of eNOS to produce NO and thus may increase the risk or contribute to the development of the diseases. Previous studies on these variants have shown conflicting results and further studies are warranted to understand and confirm the role of eNOS gene polymorphisms in cardio-metabolic diseases. There is very limited research into the distributions of these genetic variants and their interaction in diseases processes in North Indian populations. Objectives: 1. To analyse through a case control study three different polymorphisms of the eNOS gene for possible association with Coronary Artery Disease (CAD), Hypertension (Ht) and Type 2 Diabetes Mellitus (T2DM) in North Indian population groups. 2. To statistically evaluate descriptive statistics including; age, gender, smoking, dietary behaviours and lipid parameters for possible influence on disease and potential interaction with genetic polymorphisms. 3. To evaluate linkage disequilibrium between the three eNOS variants and carryout haplotype analysis to work out haplotype risk in different diseases. 4. To analyse through a case control study the deletion variant of the Angiotensin-converting enzyme (ACE) gene for possible association with Coronary Artery Disease (CAD), Hypertension (Ht) and Type 2 Diabetes Mellitus (T2DM) in North Indian population groups. 5. To determine a possible interactive effect of the eNOS polymorphisms with the ACE polymorphism. Subjects and Methods: The Glu298Asp and Intron 4 variants were genotyped using a PCR-RFLP technique, the T-786C variant was genotyped using a real time-PCR technique. The ACE deletion variant was also genotyped using a standard PCR technique. The genotyping was undertaken in a total of 457 CAD patients and 220 matched controls from Lucknow, Uttar Pradesh in North India, 319 T2DM patients and 307 matched controls from Punjab, North India and 210 Ht and 162 matched controls, also from Punjab, North India. Results: CAD: The Glu298Asp was significantly associated with CAD among smokers (TT+GT vs. GG OR=2.84 (CI: 1.61-5.0), p<0.001). The Intron 4 variant was also significantly associated with CAD in a smoking dependent manner (4aa+4ab vs. 4bb OR=0.56 (CI: 0.33-0.96). The T-786C variant showed no overall influence on CAD risk. There was also evidence for both synergistic and haplotypic effects of the eNOS gene on CAD status (haplotype G-C-4b OR=4.76 (CI: 1.43-15.78), p<0.001). The ACE genetic variant was confirmed to be a strong independent risk factor for CAD under a dominant model (OR=2.18 (CI: 1.46-3.25), p<0.001). There was no evidence for an interactive effect between the ACE deletion and any of the three eNOS variants incorporated in the current study. Ht: The Glu298Asp variant was not shown to increase Ht risk, with a reduced risk association found under a recessive model (OR=0.316 (CI:0.089-1.116)), p=0.061). The T-786C variant s role in disease remained unclear with the findings showing a non significant increased risk. The Intron 4 variant was also shown to increase Ht risk, in a non significant manner. Sufficiently powered studies would be required to clarify these possible associations. The combined analysis, using logistic regression and haplotype analysis revealed no significant associations, but there was a possible protective effect of the T-C-4b haplotype (OR=0.46 (CI: 0.21-1.01), p=0.054). The ACE gene variant was confirmed to be a strong independent risk factor for Ht under a recessive model (OR=1.81 (CI: 1.20-2.74), p=0.01). Again there was no evidence for an interactive effect between the ACE deletion and any of the three eNOS variants in hypertension. T2DM: The Glu298Asp variant was found to be associated with T2DM under a dominant model, the protective effect remained significant following adjustment for conventional risk factors and other gene variants (OR=0.407 (CI: 0.231-0.717), p=0.002). The T-786C variant showed no overall influence on T2DM risk. The Intron 4 variant also found no overall influence. Haplotype analysis found the T-T-4b was found to be significantly protective for T2DM (OR=0.41 (CI: 0.26-0.65), p=0.0002). Finally the ACE gene variant was confirmed to be a risk factor for T2DM under a dominant model (OR=2.62 (CI: 1.51-4.54), p=0.001). Overall Conclusions: To conclude, this study successfully identified the frequency of three eNOS gene variants and the ACE deletion variant in three complex diseases within north Indian populations. There is a clear role of the eNOS gene in all three diseases and consequently the genetic variants have susceptible/protective associations. The association with disease was found to be present at an individual level, in association with risk factors and at a haplotypic level. These findings warrant further studies to confirm and untangle the genetics of complex diseases and genetic risk profiles calculations which will contribute to the field of medical genomics/personalised medicare and interventions among North Indian populations.