Higher Prevalence Of Type 2 Diabetes Research Articles

Use of SGLT2 Inhibitors in Frail Older Adults is Associated with Increased Survival: A Retrospective Study.

In recent years, sodium-glucose co-transporter 2 inhibitors (SGLT2i) have emerged as a valuable treatment for type 2 diabetes (T2D) and heart failure. Despite these medications seeming to be safe in older people, the literature about SGLT2i and frailty is still limited. This study aims to evaluate whether SGLT2i use is associated with increased survival in older adults and if frailty can affect the findings. We enrolled over 65 patients admitted to the Geriatrics Wards at the University Hospital 'P. Giaccone' in Palermo, Italy, between December 2022 and May 2023. After 12 months of follow-up, various outcomes were assessed, including mortality, hospitalization, glycemic dysregulation, urinary tract infections, and falls. The association between SGLT2i use and mortality was analyzed and reported as hazard ratios (HRs) with their 95% confidence intervals (CIs). A total of 80 patients were included in the study (mean age 79.5 ± 8.5 years; 50% were women). Patients using SGLT2i had a higher prevalence of T2D (p = 0.02) and cirrhosis (p = 0.001). After adjusting for potential confounders, SGLT2i use was significantly associated with a reduced mortality risk (HR = 0.53; 95% CI: 0.20-0.93; p = 0.02). When stratified by the presence of multidimensional frailty, SGLT2i use was significantly associated with a lower risk of mortality in frail patients (HR = 0.27; 95% CI: 0.06-0.88; p = 0.008), but not in robust ones. In older frail patients, the use of SGLT2i is associated with reduced mortality after 12 months of follow-up. Further larger studies are needed to evaluate the role of these medications in older adults.

Metabolic and hepatic phenotypes in sarcopenic obesity and impact of bariatric surgery

Background & AimsSarcopenic obesity (SO) is associated with cardiometabolic disorders and steatotic liver disease and carries major health risks. We assessed the hepatic and metabolic clinical phenotype associated with SO in patients with obesity undergoing bariatric surgery (BS). We also evaluated whether weight-loss and metabolic improvement post-surgery differ between patients with and without SO. Methods972 consecutive patients from a single-center BS cohort who underwent whole-body dual-energy X-ray absorptiometry (DXA) and peri-operative liver biopsy were included. SO was diagnosed using the AIM-SO score, an AI-assisted unbiased clustering algorithm based on body composition. One-year post-surgery, 862 patients were reassessed for AIM-SO score changes. ResultsPre-operatively, 207 (21.3%) patients were diagnosed with SO. These patients had significantly higher prevalence of type-2 diabetes (T2D), arterial hypertension and obstructive sleep apnea (OSA) compared to patients without SO (all p≤0.003). Patients with SO had more severe liver damage: higher grades of moderate/advanced steatosis (64.2% vs. 47.3%), steatohepatitis (44.4% vs. 32.3%) and advanced fibrosis (12.1% vs. 6.0%) (all p≤0.01). One-year post-BS, 58.5% of patients had remission of SO. Patients with persistent SO exhibited less weight-loss than those with SO remission (–23.8 kg vs. –29.1 kg, p<0.001) and had lower rates of remission for T2D (41.9% vs. 69.8%), arterial hypertension (20.8% vs. 45.3%), and metabolic syndrome (47.6% vs. 75.0%) (all p≤0.009). ConclusionThe DXA-based AIM-SO score identifies patients with SO who are at greater risk of hepatic and cardiometabolic comorbidities, and predicts less favorable weight-loss and metabolic improvements post-BS.

The Glycemic Index of Gayam (Inocarpus fagifer Forst) Cookies as a High Dietary Fiber Food

The type 2 diabetes (T2D) is still one of the world's public health problems. It needs serious handling and prevention efforts in the nutritional aspect. The high prevalence of T2D is related to the low intake of dietary fiber. This type of food has a low glycemic index (GI). Gayam is a high-dietary fiber material that can be used for the manufacture of flour and as processed food material for the high-dietary fiber cookies. The objectives of this research were to study the GI evaluation of cookies from gayam flour. Cookies were tested for chemical composition, and glycemic index. The glycemic index evaluation test used 12 volunteers taken from the healthy group/nondiabetic, normal nutritional status (BMI: 18.5-22.9), and age 19-55 years. The results of this study indicate the dietary fiber content of gayam cookies was 4.57 g/100 g and included in the category of high dietary fiber food. The glycemic index of gayam cookies was 43 and the low glycemic index category. The obtained results show for the first time the potential of gayam cookies in hyperglycaemia management. The conclusion of this study was that gayam cookies has high dietary fiber content and low GI level. Gayam cookies can be used as an alternative snack to control blood glucose levels in the prevention of diabetes mellitus.

Effect of circadian clock disruption on type 2 diabetes.

Type 2 diabetes (T2D) is the predominant form of diabetes mellitus and is among the leading causes of death with an increasing prevalence worldwide. However, the pathological mechanism underlying T2D remains complex and unclear. An increasing number of studies have suggested an association between circadian clock disruption and high T2D prevalence. This review explores the physiological and genetic evidence underlying T2D symptoms associated with circadian clock disturbances, including insulin secretion and glucose metabolism. Notably, circadian clock disruption reduces insulin secretion and insulin sensitivity and negatively affects glucose homeostasis. The circadian clock regulates the hypothalamic-pituitary-adrenal axis, an important factor that regulates glucose metabolism and influences T2D progression. Therefore, circadian clock regulation is an attractive, novel therapeutic approach for T2D, and various circadian clock stabilizers play therapeutic roles in T2D. Lastly, this review suggests novel therapeutic and preventive approaches using circadian clock regulators for T2D.

An Economic Evaluation of the Relationship Between Glycemic Control and Total Healthcare Costs for Adults with Type2 Diabetes: Retrospective Cohort Study.

Glycemic control is associated with better outcomes among individuals with type2 diabetes (T2D). This research examines total US all-cause medical costs for adults with T2D with recommended glycemic control (HbA1c < 7%) compared to poor glycemic control (HbA1c ≥ 7%). The study used administrative claims data linked to HbA1c laboratory test results from January1, 2015 through June30, 2021 to identify adults with T2D with a recorded HbA1c test. Patients with recommended glycemic control at index date were propensity score matched to patients with poor glycemic control. General linear models and two-part models were used to compare all-cause outpatient, drug, acute care and total costs for 1year post index date. The study included 59,830 propensity-matched individuals. Results indicate that recommended glycemic control, compared to poor glycemic control, was associated with statistically significantly lower all-cause acute care ($23,868 ± $21,776 vs. $24,352 ± $22,223), drug ($10,277 ± $14,671 vs. $10,540 ± $14,928), and total medical costs ($41,381 ± $42,757 vs. $42,054 ± $43,422) but significantly higher outpatient costs ($7290 ± $12,028 vs. $7026 ± $11,587) (all p < 0.0001). Sensitivity analyses examined results based upon alternative HbA1c thresholds of ≤ 6.5% and < 8%. Results were generally robust to alternative HbA1c thresholds, with higher HbA1c thresholds associated with higher all-cause total costs as well as increased savings for having HbA1c below threshold. Glycemic control was associated with significantly lower all-cause total, drug, and acute care medical costs. Given the high prevalence of T2D in the USA, our results suggest potential economic benefits associated with glycemic control for healthcare providers.

Ancestry-attenuated effects of socioeconomic deprivation on type 2 diabetes disparities in the All of Us cohort

BackgroundDiabetes is a common disease with a major burden on morbidity, mortality, and productivity. Type 2 diabetes (T2D) accounts for roughly 90% of all diabetes cases in the USA and has a greater observed prevalence among those who identify as Black or Hispanic.MethodsThis study aimed to assess T2D racial and ethnic disparities using the All of Us Research Program data and to measure associations between genetic ancestry (GA), socioeconomic deprivation, and T2D. We used the All of Us Researcher Workbench to analyze T2D prevalence and model its associations with GA, individual-level (iSDI), and zip code-based (zSDI) socioeconomic deprivation indices among participant self-identified race and ethnicity (SIRE) groups.ResultsThe study cohort of 86,488 participants from the four largest SIRE groups in All of Us: Asian (n = 2311), Black (n = 16,282), Hispanic (n = 16,966), and White (n = 50,292). SIRE groups show characteristic genetic ancestry patterns, consistent with their diverse origins, together with a continuum of ancestry fractions within and between groups. The Black and Hispanic groups show the highest levels of socioeconomic deprivation, followed by the Asian and White groups. Black participants show the highest age- and sex-adjusted T2D prevalence (21.9%), followed by the Hispanic (19.9%), Asian (15.1%), and White (14.8%) groups. Minority SIRE groups and socioeconomic deprivation, both iSDI and zSDI, are positively associated with T2D, when the entire cohort is analyzed together. However, SIRE and GA both show negative interaction effects with iSDI and zSDI on T2D. Higher levels of iSDI and zSDI are negatively associated with T2D in the Black and Hispanic groups, and higher levels of iSDI and zSDI are negatively associated with T2D at high levels of African and Native American ancestry.ConclusionsSocioeconomic deprivation is associated with a higher prevalence of T2D in Black and Hispanic minority groups, compared to the majority White group. Nonetheless, socioeconomic deprivation is associated with reduced T2D risk within the Black and Hispanic groups. These results are paradoxical and have not been reported elsewhere, with possible explanations related to the nature of the All of Us data along with SIRE group differences in access to healthcare, diet, and lifestyle.

1476-P: Genetic Relationships between Puberty Onset and Type 2 Diabetes

Early puberty onset is a risk factor for type 2 diabetes (T2D). In this study we aimed to determine whether these phenotypes are associated via genetic variation that contributes to both T2D and puberty onset. We, thus, investigated the associations of a polygenic score (PS) for T2D and a PS for age of menarche (AAM) with parameters of adolescent growth and T2D status in an Indigenous population from the Southwestern US with a high T2D prevalence. Genotypic and clinical data were obtained from a longitudinal study. Two key parameters of the adolescent growth spurt, including age at take-off (ATO) and age at peak velocity (APV), were derived from the Preece-Baines growth model, a parametric growth curve for longitudinal height data. PSs were constructed using imputed genotypes, where variants for the T2D-PS (n=289) and the AAM-PS (n= 275) were selected from genome-wide significant variants in European meta-analyses (DIAGRAM Consortium and Reprogen Consortium, respectively). Associations between PS and T2D status (N=7659) were adjusted for age, sex, birth year and the first 5 genetic PCs. Associations with ATO and APV (N=787) were adjusted for birth year, sex, maternal diabetes and the first 5 genetic principal components (PCs). Associations were calculated using linear mixed models, accounting for genetic relationships. The T2D-PS had a significant, positive association with T2D (OR=1.47 per SD [95% CI 1.38, 1.57]; p=4.05×10−30). We found no association of the T2D-PS with ATO (p=0.11) nor APV (p=0.20). Conversely, genetically-predicted later puberty onset (AAM-PS) had a significant, inverse association with T2D (OR=0.92 per SD [95% CI 0.86, 0.98]; p=0.0194). The AAM-PS also associated with ATO (r=0.11, p=0.0013) and APV (r=0.13, p=1.8×10−04). Our results suggest that many variants that associate with AAM and T2D in large European cohorts also affect these traits in this Indigenous population. They also support the notion that variants that associate with early puberty onset also confer susceptibility to T2D. Disclosure M.J.Ramirez-luzuriaga: None. S.Kobes: None. L.E.Wedekind: None. W.Hsueh: None. L.Baier: None. R.L.Hanson: None.

1480-P: Mitochondrial Haplogroup H Is Protective against Type 2 Diabetes in Arabs from Gulf Region

Background: Mitochondrial dysfunction is implicated in the pathogenesis of type 2 diabetes (T2D) via impaired glucose-stimulated insulin secretion in pancreatic beta cells and decreased oxidative phosphorylation in insulin target tissues. Several global studies have been performed to delineate the genetic associations of mitochondrial DNA (mtDNA) haplogroups and variants with T2D incidence. Maternal haplogroups F, D, M9 and N9a and a rare variant (mtDNA 3243 A&amp;gt;G) and a common variant (mtDNA 16189 T&amp;gt;C) were associated with increased risk of T2D in different populations. It is worth noting that some of these proposed associations were not consistent across populations. Since the Gulf Cooperation Council (GCC) countries are marked by high prevalence of T2D, we aim to study association of mitochondrial haplogroups and variants in Arabs from GCC region. Methods: We examined mitochondrial haplogroups and variants in 1,112 Kuwaiti and Qatari native individuals using whole exome sequencing data. The cohort was divided into T2D cases (685) and non-T2D controls (427). Results: The association tests indicated that individuals with haplogroup H have a protective effect against T2D with a suggestive significance [odds ratio (OR) = 0.65; P = 0.022]. The haplogroup H association remained significant even after adjusting for age, sex, and body mass index (BMI) (OR= 0.607; P= 0.021). We also identified mtDNA variants with suggestive significance of association (adjusting for covariates) with T2D. Conclusion: The study demonstrates that maternal H haplogroup, which we previously identified as protective towards obesity in Kuwaiti Arabs, is a protective haplogroup for T2D in Arabs from GCC. Further, the mtDNA variants delineated as associated with T2D are from genes involved in cell energy production. Disclosure M.H.Dashti: None. N.Ali: None. H.Alsaleh: None. R.Nizam: None. F.Almulla: None. A.T.Thangavel: None.

671-P: Obesity in African Immigrants Is Associated with Body Size Dissatisfaction and Poor Cardiometabolic Health

In African immigrants, the relationship between obesity and body size dissatisfaction and cardiometabolic health is unknown. Hence, we assessed body size dissatisfaction and cardiometabolic health in 352 African-born Blacks living in the Washington DC area (female: 39% (137/352) age 40±11y (mean±SD)). Using the Stunkard Figure Rating Scale, participants ranked their perceived body size and wish body size. Body size dissatisfaction was defined as the difference between perceived and wish body size. Adverse cardiometabolic health was determined by the presence of type 2 diabetes (T2D) or elevated BP (BP≥120/80) or elevated non-HDL cholesterol levels. Obesity prevalence was 27% (94/352) and higher in women than men (38% (52/137) vs 20% (42/215) P&amp;lt;0.01). Body size dissatisfaction was also higher in women than men (83% vs 69% P&amp;lt;0.01). However, among participants with obesity there was no sex difference in body size dissatisfaction (94% vs 91% P=0.49). Persons with obesity judged themselves to be: Too Large (92%) Just Right (7%) or Too Small (1%) (Figure). Obesity was associated with a higher prevalence of T2D (14% vs 5% P&amp;lt;0.01) elevated BP (51% vs 41% P=0.02) and higher non-HDL cholesterol (121±34 vs 113±33 mg/dL P=0.06). Obesity is viewed negatively by African immigrants and is associated with poor cardiometabolic health. Disclosure J.Hurston: None. C.C.Worthy: None. E.Shoup: None. J.Gatete: None. B.R.Schenk: None. L.Mabundo: None. C.Dubose: None. R.Jagannathan: None. M.F.Horlyck-romanovsky: None. A.E.Sumner: None.

1470-P: Novel Associations of Glycometabolic Traits in Ethnically Diverse Africans

Prior studies have identified genetic factors that impact an individual’s risk of developing type 2 diabetes (T2D). However, African ancestry is underrepresented in genetic studies despite the higher prevalence of T2D in African Americans compared to European or Asian Americans. To better understand risk factors for this health disparity, we used a unique dataset of T2D biomarkers (C-peptide and standing glucose) and ~5 million single nucleotide polymorphism genotypes from an ethnically diverse sampling of sub-Saharan Africans (N~1,250) to identify genetic variants associated with these traits. Because the individuals in our dataset practice traditional subsistence patterns and live in rural settings, there is less environmental heterogeneity than observed in urban settings. Between both traits, we uncovered hundreds of novel marginal associations (p&amp;lt;10−5) and three genome-wide significant associations (p&amp;lt;5×10−8), one with C-peptide (rs147703855, in DAAM1) and two with glucose (rs74085215, near KLC1; rs951516, intergenic). The minor alleles for these three associations are rare outside of Africa (&amp;lt;0.1%) but attain frequencies ~5-10% in at least one African ancestry group. Although none of these associations have been previously reported, the genes near the marginal C-peptide associations (&amp;lt;200kbp) are enriched for variants with previously reported T2D associations (GWAS catalogue), as well as chylomicron, VLDL, and triglyceride associations. The genes near our marginal glucose associations were not found to be enriched for previously reported T2D associations (p&amp;gt;0.05), though they were significantly enriched for body size, chylomicron, and triglyceride associations (p&amp;lt;0.006). We are following up this preliminary study with an expanded GWAS using a new proteomics dataset in ~500 subjects, and a metabolomics dataset in ~700 subjects. These data will be used to construct polygenic risk scores for biomarkers of T2D that are more effective in people of recent African descent. Disclosure M.Hansen: None. D.Harris: None. A.M.Harris: None. T.B.Nyambo: None. G.Belay: None. S.Mpoloka: None. C.Burant: Research Support; Rhythm Pharmaceuticals, Inc. S.A.Tishkoff: None. Funding American Diabetes Association (1-19-VSN-02 to S.A.T.); National Institutes of Health (R35GM134922)

#6054 CLINICAL CHARACTERISTICS AND RENAL RISK OF PATIENTS WITH CHRONIC KIDNEY DISEASE: REAL-WORLD EVIDENCE FROM THE ICAREME GLOBAL REGISTRY

Abstract Background and Aims Chronic kidney disease (CKD) has emerged as a leading global public health concern due to its growing prevalence and associated morbidity and mortality. Throughout the disease progression, CKD is associated with a substantial health and socio-economic burden on patients, families, and healthcare systems worsened by complex interactions with type 2 diabetes (T2D), hypertension (HTN), and heart failure (HF). To help current and future patients get the best possible care, it is of the greatest importance to better understand how they are managed routinely, but real-world data on coexisting cardiovascular, renal, and metabolic diseases are scarce or non-existent in many countries. The iCaReMe Global Registry aims to address these knowledge gaps by providing observational data on patients’ characteristics, risk factors, management patterns, disease progression, and outcomes related to CKD and associated comorbidities namely: T2D, HTN, and HF. Method The iCaReMe Global Registry (NCT03549754) is a prospective, investigator-led, multinational, observational registry relying on voluntary participation by treating physicians to assess the management and quality of care through socio-demographic and clinical characteristics, disease management patterns (including screening, diagnosis, treatment approaches), healthcare resource utilization and clinical outcomes in patients with CKD, T2D, HTN, and/or HF. Eligible and consented patients were enrolled during routine clinical practice based on the physician's discretion and were followed up per routine clinical care. We present the descriptive analysis of baseline clinical and demographic characteristics of the CKD cohort enrolled in the iCaReMe Global Registry from February 2018 to December 2022. Results Overall 2977 patients with CKD have been enrolled from 21 countries (Argentina, Costa Rica, Egypt, Ethiopia, Georgia, Greece, Hong Kong, Indonesia, India, Jordan, Kenya, Lebanon, Malaysia, Mexico, Russia, South Africa, Thailand, The Philippines, Turkey, Ukraine, and the United Arab Emirates). At baseline, the mean ± standard deviation (SD) age was 60.4 ± 13.8 years and 54.6% were males. The mean ± SD systolic and diastolic blood pressures of the cohort were 120.4 ± 43.6 and 70.5 ± 25.6 mmHg and the mean ± SD body mass index was 21.6 ± 12.9 kg/m2. 68.9% had T2D and 68.3% had hypertension. Diabetic kidney disease and hypertensive kidney disease were the most common etiologies in 78.8% of the patients (Figure 2). Serum creatinine was reported in 85.3% of patients and urine albumin-creatinine ratio (UACR) in 30.5% and only 25.9% had both. The prevalence of KDIGO GFR categories G3-5 based on estimated glomerular filtration rate (eGFR) using CKD-EPI was 72.5% and the prevalence of albuminuria A2/A3 was 75.9%. In total, 7.9% patients were undergoing dialysis. In patients with T2D (n = 2051); 69.1% (1250/1808) had G3-5 GFR category and 76.1% (484/636) had albuminuria stage A2 and A3. In patients with HTN (n = 2033); 77.6% (1367/1761) had G3-5 GFR category and 76.6% (485/633) had albuminuria stage A2 and A3. Conclusion At baseline most of iCaReMe Registry CKD cohort fall within the KDIGO high or very high risk of outcomes associated with a high prevalence of T2D and HTN. Our results also indicate an underutilization of albuminuria testing despite its critical role in diagnosis, risk stratification and follow up which raises concerns about CKD early detection, management, and prognosis.

Differences in HDL-Bound Apolipoproteins in Patients With Advanced Liver Fibrosis Due to Nonalcoholic Fatty Liver Disease.

The mechanisms leading to increased cardiovascular disease in patients with nonalcoholic fatty liver disease (NAFLD) and advanced liver fibrosis remain incompletely understood. This study assessed HDL-bound proteins in patients with NAFLD with or without advanced fibrosis. This cross-sectional study at a university hospital included 185 patients with or without type 2 diabetes (T2D). Patients underwent liver proton magnetic resonance spectroscopy to measure intrahepatic triglyceride accumulation and those with NAFLD underwent a percutaneous liver biopsy. Advanced lipid testing with lipoprotein subfraction measurements and targeted proteomics of HDL-bound proteins was performed. Patients with and without advanced fibrosis had similar clinical characteristics, except for lower HDL-C (34 ± 8 vs 38 ± 9 mg/dL, P = 0.024) and higher prevalence of T2D in advanced fibrosis. Patients with advanced fibrosis had lower HDL particle number. A panel of 28 HDL-bound proteins were targeted and quantified by multiple reaction monitoring liquid chromatography-tandem mass spectrometry. Five proteins were found to be decreased in patients with advanced fibrosis (ApoC-I [P < 0.001], ApoC-IV [P = 0.012], ApoM [P = 0.008], LCAT [P = 0.014], and SAA4 [P = 0.016]). No differences were observed in these proteins in patients with vs without NAFLD or steatohepatitis. The pCAD index, associated with coronary artery disease and cardiovascular mortality, was significantly higher in patients with advanced fibrosis (97 ± 5 vs 86 ± 25, P = 0.04). Patients with NAFLD with advanced fibrosis showed significant differences in HDL-bound protein levels; this translated into increased cardiovascular risk based on pCAD index. Different lipoprotein composition and function may explain the link between liver disease and increased cardiovascular mortality in these patients.

225-LB: Impaired Microvascular Responses May Explain Health Disparities and Impaired Metabolic Flexibility in Hispanic Residents of the Rio Grande Valley

Purpose: Impaired skeletal muscle microvascular blood flow (MBF) is one of the earliest pathophysiologies of type 2 diabetes (T2D) . People with a family history of T2D (FH+ are at greater risk for developing T2D than those with no family history (FH-) . Further, we have shown that normoglycemic Caucasian FH+ individuals have impaired skeletal muscle microvascular responses and metabolic flexibility (MF - ability to switch substrate oxidation upon stimulation) to a mixed meal challenge (MMC) when compared with matched FH- (p&amp;lt;0.01) , suggesting early vascular insulin resistance. Mexican Hispanic individuals have the highest prevalence of T2D in the US and make up ∼95% of Hispanic residents of the Rio Grande Valley (HRGV) where T2D diagnosis rates are ∼3x the national average. Therefore, we sought to determine if impaired MBF responses are present in healthy HRGV. Methods: 15 FH- and 13 FH+ HRGV were recruited to assess MF and MBF responses to a MMC. MF was measured via indirect calorimetry and MBF via contrast-enhanced ultrasound while fasting and again 60-min post MMC. Results: No changes in skeletal MBF were noted in FH- (1.21 ± 0.53 SEM and 0.86 ± 0.23 SEM fasting and postprandial MBF respectively) or FH+ (2.17 ± 0.98 SEM and 1.49 ± 0.66 SEM fasting and postprandial MBF respectively) groups. Abdominal adipose MBF responses increased in FH+ (-2.3 ± 0.71 SEM, p=0.004) , but not in FH- (-0.49 ± 0.39 SEM p=0.39) . FH+ display impaired postprandial metabolic flexibility (MF) responses during 60-min of testing post-MMC. Neither blood glucose responses (99.3 ± 1.3 SEM and 102.27 ± 2.1 SEM fasting and post-prandial respectively, p=0.2) nor body composition differed between FH groups. Conclusions: HRGV display impaired skeletal muscle MBF responses, indicating early vascular insulin resistance. Further, the impairment in MF in FH+ may be partially explained by increased adipose MBF responses, as adipose is less metabolically active than skeletal muscle. Disclosure R. D. Russell: None. Y. Tai: None. S. Marupudi: None.

Analyzing Type 2 Diabetes Associations with the Gut Microbiome in Individuals from Two Ethnic Backgrounds Living in the Same Geographic Area.

It is currently unknown whether associations between gut microbiota composition and type 2 diabetes (T2D) differ according to the ethnic background of individuals. Thus, we studied these associations in participants from two ethnicities characterized by a high T2D prevalence and living in the same geographical area, using the Healthy Life In Urban Settings (HELIUS) study. We included 111 and 128 T2D participants on metformin (Met-T2D), 78 and 49 treatment-naïve T2D (TN-T2D) participants, as well as a 1:1 matched group of healthy controls from, respectively, African Surinamese and South-Asian Surinamese descent. Fecal microbiome profiles were obtained through 16S rRNA gene sequencing. Univariate and machine learning analyses were used to explore the associations between T2D and the composition and function of the gut microbiome in both ethnicities, comparing Met-T2D and TN-T2D participants to their respective healthy control. We found a lower α-diversity for South-Asian Surinamese TN-T2D participants but no significant associations between TN-T2D status and the abundance of bacterial taxa or functional pathways. In African Surinamese participants, we did not find any association between TN-T2D status and the gut microbiome. With respect to Met-T2D participants, we identified several bacterial taxa and functional pathways with a significantly altered abundance in both ethnicities. More alterations were observed in South-Asian Surinamese. Some altered taxa and pathways observed in both ethnicities were previously related to metformin use. This included a strong negative association between the abundance of Romboutsia and Met-T2D status. Other bacterial taxa were consistent with previous observations in T2D, including reduced butyrate producers such as Anaerostipes hadrus. Hence, our results highlighted both shared and unique gut microbial biomarkers of Met-T2D in individuals from different ethnicities but living in the same geographical area. Future research using higher-resolution shotgun sequencing is needed to clarify the role of ethnicity in the association between T2D and gut microbiota composition.

1132-P: Genetic Relationships between Birth Weight and Type 2 Diabetes

There is considerable evidence that birth weight is associated with increased risk of type 2 diabetes (T2D) in adulthood. However, evidence from populations with high prevalence of T2D on the genetic relationships between birth weight and T2D is limited. Data were obtained from a genome-wide association study (GWAS) in an Indigenous population from the Southwest US with high prevalence of T2D in which the relationship of T2D with birth weight is “U-shaped." Weighted polygenic scores (PSs) were constructed using imputed genotypes for genome-wide significant single-nucleotide polymorphisms (SNPs) from GWAS meta-analyses for birth weight (EGG Consortium, 126 SNPs) and T2D (DIAGRAM Consortium, 293 SNPs). Associations of birth weight PS and T2D PS with T2D and birth weight were calculated, accounting for participants’ pairwise relationships, using linear mixed models. Birth weight data (n=3700) were normalized separately by sex and analyzed for associations, adjusted for birth year, gestational age and the first 5 genetic principal components (PCs). T2D (n=7659) data were analyzed for associations, adjusted for age, sex, birth year and the first 5 genetic PCs. Birth weight PS had a significant, positive association with birth weight (β=0.134 SD birth weight per SD PS (95% CI 0.101, 0.168); p=4.1×10-15). The T2D PS was likewise significantly, positively associated with T2D (OR=1.48 per SD (1.38, 1.58); p=8.1×10-31). The birth weight PS was significantly, inversely associated with T2D (OR=0.91 (0.85, 0.97); p=0.0043); we found no evidence for a non-linear relationship between birth weight PS and T2D (p=0.80). The T2D PS was not significantly associated with birth weight (β=-0.005 (-0.040, 0.030); p=0.80). Results indicate that genetic variants that associate with birth weight and T2D from larger European GWAS largely also influence these traits in this Indigenous population. Current findings also support the notion that many variants conferring susceptibility to low birth weight also confer susceptibility to T2D. Disclosure L. E. Wedekind: None. W. Hsueh: None. M. Olaiya: None. S. Kobes: None. L. Baier: None. W. C. Knowler: None. A. Mahajan: Employee; Self; Genentech, Inc. M. Mccarthy: Employee; Self; Genentech, Inc. R. L. Hanson: None.

Current type 2 diabetes, rather than previous gestational diabetes, is associated with liver disease in U.S. Women

AimTo investigate the relative contribution of previous gestational diabetes mellitus (GDM) and current type 2 diabetes (T2D) on the development of liver fibrosis, the strongest predictor of end-stage liver disease. MethodsThis is a population-based cross-sectional study based on data from the 2017–2018 cycle of the National Health and Nutrition Examination Survey. We included women age ≥ 20 years that had delivered at least one live birth and had available data on vibration-controlled transient elastography (VCTE). Liver steatosis and fibrosis were assessed by the median value of controlled attenuation parameter (CAP) and liver stiffness measurement (LSM), respectively. ResultsAmong the 1699 women included in the study, 144 (10.1%, 95% CI 7.7–13.2) reported a previous diagnosis of GDM. Women with previous GDM were younger, had a higher BMI, a higher prevalence of T2D and were significantly older at the time they had the last live birth. Univariate analysis did not show a significant difference between women with and without a prior history of GDM in terms of both steatosis (44.8% vs 39.4%, p = 0.464) and fibrosis (7.5% vs 7.6%, p = 0.854). Multivariable logistic regression analysis showed that BMI, γ-glutamyltranspeptidase levels, T2D (OR 2.96, 95% CI 1.48–5.93, p < 0.01), HBV and HCV infection were associated with higher odds of significant fibrosis, while previous GDM showed a neutral effect. ConclusionsWomen with previous GDM that do not develop overt T2D might not experience a poor hepatic prognosis.

The Utility of a Type 2 Diabetes (T2D) Polygenic Score in Addition to Clinical Variables for Prediction of T2D Incidence in Birth, Youth, and Adult Cohorts

Background: There is limited information on how polygenic scores (PSs) — based on variants from genome-wide association studies (GWAS) of T2D — add to clinical variables in predicting T2D incidence. Methods: For participants in a longitudinal study in an Indigenous population from the Southwest United States (US) with high T2D prevalence, we analyzed 10 constructions of PS using publicly available GWAS summary statistics. T2D incidence was examined in three cohorts of individuals without T2D at baseline. The adult cohort, comprised of 2333 participants followed from age≥20y, had 640 T2D cases. The youth cohort was comprised of 2229 participants followed from age 5-19y (228 cases). The birth cohort was comprised of 2894 participants followed from birth (438 cases). We assessed contributions of the PS and clinical variables in predicting T2D incidence. Results: Of the 10 PS constructions, a PS using 293 genome-wide significant variants from a large T2D GWAS meta-analysis in European-ancestry populations performed best. In the adult cohort, area under the receiver operating characteristic curve (AUC) for clinical variables for prediction of T2D incidence was 0·728; with the PS, 0·735. The PS’s hazard ratio (HR) was 1.27 per SD (p=1·6×10-8; 95% CI 1·17-1·38). In the youth cohort, the analogous model’s AUC was 0·805; with the PS, 0·812. The PS’s HR was 1·49 (p=4·3×10-8; 95% CI 1·29-1·72). In the birth cohort, AUC for the clinical variables was 0·614; with the PS, 0·685. The PS’s HR was 1·48 (p=2·8×10-16; 95% CI 1·35-1·63). To further assess the potential impact of including PS for assessing individual T2D risk, the net reclassification improvement (NRI) was calculated: NRI for the PS was 0·264, 0·249, and 0·309 for adult, youth, and birth cohorts, respectively. For comparison, NRI for HbA1c was 0·292 and 0·150 for adult and youth cohorts, respectively. Across all cohorts, as estimated using decision curve analyses, the net benefit of including the PS in addition to clinical variables was most pronounced at moderately stringent threshold probability (pt) values for instituting a preventive intervention. Discussion: This study demonstrates that the PS contributes significantly to prediction of T2D incidence in addition to the information provided by clinical factors; however, overall improvement of the prediction model was modest. Discriminatory power of the PS for predicting incident T2D was similar to that of other commonly measured clinical factors (e.g. HbA1c). Including T2D PS in addition to clinical factors may be clinically beneficial for identifying individuals at higher risk for T2D, especially at younger ages. Funding Statement: This study used computational resources of the Biowulf system at the National Institutes of Health (NIH), Bethesda, MD. The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Intramural Research Program provided support for NIDDK-based coauthors. The NIH Oxford-Cambridge Scholars Program provided funding support for L.E.W.’s doctoral programme. M.I.M. was a Wellcome Senior Investigator and an NIHR Senior Investigator. This work was funded in Oxford by the Wellcome Trust (098381, 106130, 203141), NIH (U01- DK105535; U01-DK085545) and National Institute for Health Research (NIHR) (NF-SI-0617- 10090) and Oxford Biomedical Research Centre (BRC). Declaration of Interests: The views expressed in this article are those of the author(s) and not necessarily those of NIH, NHS, NIHR, or UK Department of Health. M.I.M. has served on advisory panels for Pfizer, Novo Nordisk, and Zoe Global; has received honoraria from Merck, Pfizer, Novo Nordisk, and Eli Lilly; and research funding from Abbvie, Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, NovoNordisk, Pfizer, Roche, Sanofi Aventis, Servier, and Takeda. As of June 2019, M.I.M. and A.M. are employees of Genentech and holders of Roche stock. Ethics Approval Statement: Protocols were approved by the institutional review board of the National Institute of Diabetes and Digestive and Kidney Diseases.

Assessment of genetic risk of type 2 diabetes among Pakistanis based on GWAS-implicated loci

Genome-wide association studies (GWAS) have identified multiple type 2 diabetes (T2D) loci, mostly among populations of European descent. There is a high prevalence of T2D among Pakistanis. Both genetic and environmental factors may be responsible for this high prevalence. In order to understand the shared genetic basis of T2D among Pakistanis and Europeans, we examined 77 genome-wide significant variants previously implicated among European populations. We genotyped 77 single-nucleotide polymorphisms (SNPs) by iPLEX® Gold or TaqMan® assays in a case-control sample of 1,683 individuals. Association analysis was performed using logistic regression. A total of 16 SNPs (TCF7L2/rs7903146, GLIS3/rs7041847, CHCHD9/rs13292136, PLEKHA1/rs2292626, FTO/rs9936385, CDKAL1/rs7756992, KCNJ11/rs5215, LOC105372155/rs12970134, KCNQ1/rs163182, CTRB1/rs7202877, ST6GAL1/rs16861329, ADAMTS9-AS2/rs6795735, LOC105370275/rs1359790, C5orf67/rs459193, ZBED3-AS1/rs6878122 and UBE2E2/rs7612463) showed statistically significant associations after controlling for the false discovery rate. While KCNQ1/rs163182 and ZBED3-AS1/rs6878122 showed opposite allelic effects, the remaining significant SNPs had the same allelic effects as reported previously. Our data indicate that a selected number of T2D loci previously identified among populations of European descent also affect the risk of T2D in the Pakistani population.

Prevalence of type 2 diabetes mellitus in a representative sample of Greek adults and its association with modifiable risk factors: results from the Hellenic National Nutrition and Health Survey

ObjectiveDiabetes mellitus is a disease associated with many complications leading to premature death. The aim of this study was to estimate prevalence of type 2 diabetes (T2D), and the proportion of the population unaware of the condition, in association with modifiable risk factors. Study designData from the Hellenic National Nutrition and Health Survey were used (n = 3773 adults, 40.8% men) and were obtained by trained personnel. MethodsDiabetes mellitus disease status was categorized as per the International Classification of Diseases codes (10th version). A subsample from the two main metropolitan areas was used to assess T2D and impaired fasting glucose (IFG) (n = 990; 38.2% men) from plasma analysis. ResultsThe prevalence of T2D in the population was 5.2% in total, reaching 13.7% in adults aged >60 years (no sex differences). IFG was observed in 27.3% of adults in the two metropolitan areas, and 40% were unaware of having T2D in this subsample. The likelihood of having T2D significantly increased with age and body weight, whereas it decreased with higher educational level and physical activity (P for all <0.001). ConclusionThe high T2D prevalence in adults, especially among the older age-groups, suggests a major public health problem in Greece.

Mitoprotective Clinical Strategies in Type 2 Diabetes and Fanconi Anemia Patients: Suggestions for Clinical Management of Mitochondrial Dysfunction.

Oxidative stress (OS) and mitochondrial dysfunction (MDF) occur in a number of disorders, and several clinical studies have attempted to counteract OS and MDF by providing adjuvant treatments against disease progression. The present review is aimed at focusing on two apparently distant diseases, namely type 2 diabetes (T2D) and a rare genetic disease, Fanconi anemia (FA). The pathogenetic links between T2D and FA include the high T2D prevalence among FA patients and the recognized evidence for OS and MDF in both disorders. This latter phenotypic/pathogenetic feature—namely MDF—may be regarded as a mechanistic ground both accounting for the clinical outcomes in both diseases, and as a premise to clinical studies aimed at counteracting MDF. In the case for T2D, the working hypothesis is raised of evaluating any in vivo decrease of mitochondrial cofactors, or mitochondrial nutrients (MNs) such as α-lipoic acid, coenzyme Q10, and l-carnitine, with possibly combined MN-based treatments. As for FA, the established knowledge of MDF, as yet only obtained from in vitro or molecular studies, prompts the requirement to ascertain in vivo MDF, and to design clinical studies aimed at utilizing MNs toward mitigating or delaying FA’s clinical progression. Altogether, this paper may contribute to building hypotheses for clinical studies in a number of OS/MDF-related diseases.