Frail hypertensive older adults with prediabetes and chronic kidney disease: insights on organ damage and cognitive performance - preliminary results from the CARYATID study.

BACKGROUND: Hypertension and chronic kidney disease (CKD) pose significant public health challenges, sharing intertwined pathophysiological mechanisms. Prediabetes is recognized as a precursor to diabetes and is often accompanied by cardiovascular comorbidities such as hypertension, elevating the risk of pre-frailty and frailty. Albuminuria is a hallmark of organ damage in hypertension amplifying the risk of pre-frailty, frailty, and cognitive decline in older adults. We explored the association between albuminuria and cognitive impairment in frail older adults with prediabetes and CKD, assessing cognitive levels based on estimated glomerular filtration rate (eGFR). METHODS: We conducted a study involving consecutive frail older patients with hypertension recruited from March 2021 to March 2023 at the ASL (local health unit of the Italian Ministry of Health) of Avellino, Italy, followed up after three months. Inclusion criteria comprised age over 65 years, prior diagnosis of hypertension without secondary causes, prediabetes, frailty status, Montreal Cognitive Assessment (MoCA) score < 26, and CKD with eGFR > 15 ml/min. RESULTS: 237 patients completed the study. We examined the association between albuminuria and MoCA Score, revealing a significant inverse correlation (r: 0.8846; p < 0.0001). Subsequently, we compared MoCA Score based on eGFR, observing a significant difference (p < 0.0001). These findings were further supported by a multivariable regression analysis, with albuminuria as the dependent variable. CONCLUSIONS: Our study represents the pioneering effort to establish a significant correlation between albuminuria and eGFR with cognitive function in frail hypertensive older adults afflicted with prediabetes and CKD.

Association of combined healthy lifestyle with risk of adverse outcomes in patients with prediabetes.

OBJECTIVE: Prediabetes and lifestyle factors have been associated with the risks of multiple adverse outcomes, but the effect of a healthy lifestyle on prediabetes-related complications remains unknown. We aimed to investigate whether the risks of multiple adverse outcomes including incident type 2 diabetes mellitus (T2DM), cardiovascular disease (CVD), and chronic kidney disease (CKD) among individuals with prediabetes can be offset by a broad combination of healthy lifestyle factors. METHODS: This prospective study used data from the UK Biobank cohort. An overall lifestyle score ranging from 0 to 6 was created with 1 point for each of the 6 healthy lifestyle factors: no current smoking, moderate alcohol consumption, regular physical activity, healthy diet, no overweight or obese, and adequate sleep duration. T2DM, CVD, and CKD were ascertained during a median follow-up of 14 years. Cox proportional hazard regression models were used to estimate the associations. Sensitivity analyses were performed to test the robustness of the results. RESULTS: We included 202,993 participants without T2DM, CVD, and CKD at baseline (mean age 55.5 years [SD 8.1]; 54.7% were women). Among these participants, 6,745, 16,961, and 6,260 participants eventually developed T2DM, CVD, and CKD, respectively. Compared with the participants with normoglycaemia, those with prediabetes showed a higher risk of these adverse outcomes. In addition, those prediabetic participants with a lifestyle score of 0-1 had a significantly higher risk of T2DM (hazard ratio [HR] 16.73, 95% CI 14.24, 19.65), CVD (HR 1.96, 95% CI 1.74, 2.21), and CKD (HR 1.92, 95% CI 1.58, 2.34) compared with those with no prediabetes and a score of 5-6. Moreover, among the participants with prediabetes, the HRs for T2DM, CVD, and CKD comparing a lifestyle score of 5-6 versus 0-1 decreased to 0.43 (95% CI 0.36, 0.51), 0.52 (95% CI 0.44, 0.62), and 0.60 (95% CI 0.46, 0.79), respectively. CONCLUSIONS: Combined healthy lifestyle factors were associated with a significantly lower risk of multiple adverse outcomes, including T2DM, CVD, and CKD. This indicates that prioritising multifactorial approaches to behavioural lifestyle modification is crucial for preventing and postponing the development of complications related to prediabetes.

Lipidome characterisation and sex-specific differences in type 1 and type 2 diabetes mellitus.

BACKGROUND: In this study, we evaluated the lipidome alterations caused by type 1 diabetes (T1D) and type 2 diabetes (T2D), by determining lipids significantly associated with diabetes overall and in both sexes, and lipids associated with the glycaemic state. METHODS: An untargeted lipidomic analysis was performed to measure the lipid profiles of 360 subjects (91 T1D, 91 T2D, 74 with prediabetes and 104 controls (CT)) without cardiovascular and/or chronic kidney disease. Ultra-high performance liquid chromatography-electrospray ionization mass spectrometry (UHPLC-ESI-MS) was conducted in two ion modes (positive and negative). We used multiple linear regression models to (1) assess the association between each lipid feature and each condition, (2) determine sex-specific differences related to diabetes, and (3) identify lipids associated with the glycaemic state by considering the prediabetes stage. The models were adjusted by sex, age, hypertension, dyslipidaemia, body mass index, glucose, smoking, systolic blood pressure, triglycerides, HDL cholesterol, LDL cholesterol, alternate Mediterranean diet score (aMED) and estimated glomerular filtration rate (eGFR); diabetes duration and glycated haemoglobin (HbA1c) were also included in the comparison between T1D and T2D. RESULTS: A total of 54 unique lipid subspecies from 15 unique lipid classes were annotated. Lysophosphatidylcholines (LPC) and ceramides (Cer) showed opposite effects in subjects with T1D and subjects with T2D, LPCs being mainly up-regulated in T1D and down-regulated in T2D, and Cer being up-regulated in T2D and down-regulated in T1D. Also, Phosphatidylcholines were clearly down-regulated in subjects with T1D. Regarding sex-specific differences, ceramides and phosphatidylcholines exhibited important diabetes-associated differences due to sex. Concerning the glycaemic state, we found a gradual increase of a panel of 1-deoxyceramides from normoglycemia to prediabetes to T2D. CONCLUSIONS: Our findings revealed an extensive disruption of lipid metabolism in both T1D and T2D. Additionally, we found sex-specific lipidome changes associated with diabetes, and lipids associated with the glycaemic state that can be linked to previously described molecular mechanisms in diabetes.

Effect and safety of electroacupuncture on weight loss in obese patients with pre-diabetes: study protocol of a randomised controlled trial.

INTRODUCTION: Obesity has been identified as a significant risk factor for several chronic conditions, including diabetes, tumours and cardiovascular disease, and has been associated with increased mortality rates. Despite the well-established clinical practice of electroacupuncture (EA) as a potential treatment option for obesity, its efficacy remains questionable, primarily due to the paucity of empirical evidence supporting its therapeutic benefits. METHODS AND ANALYSIS: The present study aims to investigate the efficacy and safety of EA for weight loss in obese individuals with pre-diabetes, using a randomised, placebo-controlled clinical trial design. A total of 256 eligible patients will be randomly assigned to one of two groups: EA (comprising EA treatment with health education) or superficial acupuncture (SA) (comprising SA treatment with health education). The intervention will be administered three times per week for the initial 12 weeks, two times per week for the subsequent 8 weeks and one time per week for the final 4 weeks, with a 24-week follow-up period. The primary outcome measure will be the percentage of patients who achieve a reduction of 10% or more in their body weight at week 24. Secondary outcome measures will include changes in body weight and body mass index, blood test results, data collected by the body composition analyser, size of adipose tissue scanned by MRI of the abdomen and the Impact of Weight on Quality of Life, the 21-item Three-Factor Eating Questionnaire-Revised and the Food Craving Questionnaire-Trait. The Treatment Emergent Symptom Scale will be employed to monitor every adverse reaction from baseline to follow-up. ETHICS AND DISSEMINATION: This trial has received ethical clearance from the Ethics Committee of Shanghai Municipal Hospital of Traditional Chinese Medicine under the registration number 2021SHL-KY-74. All participants will provide their written informed consent prior to their enrolment. The findings of this investigation will be disseminated through peer-reviewed publications and scholarly conferences. TRIAL REGISTRATION NUMBER: NCT05237089.

Home-based Intervention with Semaglutide Treatment of Neuroleptic-Related Prediabetes (HISTORI): protocol describing a prospective, randomised, placebo controlled and double-blinded multicentre trial.

INTRODUCTION: Subjects with schizophrenia have a 2-3 fold higher mortality rate than the general population and a reduced life expectancy of 10-20 years. Approximately one-third of this excess mortality has been attributed to obesity-related type 2 diabetes (T2D) and to cardiovascular disease. Glucagon-like peptide-1 (GLP-1) analogues increase satiety and delay gastric emptying, thereby reducing food intake and weight. GLP-1 analogues also exert beneficial effects on cardiovascular outcomes in high-risk patients with T2D.Our aim is to investigate whether 30 weeks add-on treatment with the GLP-1 analogue semaglutide can reduce HbA1c sufficiently to reverse pre-diabetes and the metabolic syndrome in overweight schizophrenic patients. METHODS AND ANALYSIS: We will perform a 30 week, two-armed, multicentre, superiority, double-blinded, randomised trial investigating the effect of weekly injections of semaglutide versus placebo in mental health facilities in Region of Southern Denmark and Region of Zealand, Denmark. In total, 154 adults with schizophrenia spectrum disease, aged 18-60 years treated with second generation antipsychotic treatment, HbA1c 39-47 mmol/mol and body mass index >27 kg/m2 will be randomised to injections of 1.0 mg semaglutide or placebo. The primary outcome is changes in HbA1c. Secondary outcomes encompass metabolic measures, psychotic symptoms and quality of life. Exploratory outcomes encompass insulin sensitivity, cardiovascular risk profile, medication adherence, general well-being and physical activity. ETHICS AND DISSEMINATION: This study will be carried out in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. This research has obtained approval from both the Danish Medicines Agency and The Regional Committees on Health Research Ethics for Southern Denmark. TRIAL REGISTRATION NUMBER: NCT05193578 European Clinical Trials Database Number (EudraCT) 2020-004374-22, Regional Ethical Committee number S-20200182.

Does metformin reduce the risk of cancer in obesity and diabetes? A systematic review and meta-analysis.

AIM: To evaluate the effect of metformin on cancer incidence in subjects with overweight/obesity and/or prediabetes/diabetes. MATERIALS AND METHODS: We searched MEDLINE, Embase and CENTRAL for randomized controlled trials (RCTs) in adults with overweight/obesity and/or prediabetes/diabetes that compared metformin to other interventions for ≥24 weeks. Independent reviewers selected and extracted data including population and intervention characteristics and new diagnoses of cancer. We used the RoB 2.0 risk-of-bias tool and the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework to assess risk of bias and certainty of evidence. RESULTS: From 14 895 records after removal of duplicates, 27 trials were included, providing a total of 10 717 subjects in the metformin group and 10 003 in the control group, with 170 and 208 new cases of cancer, respectively. Using a random-effects model, the relative risk was 1.07 (95% confidence interval 0.87-1.31), with similar results in subgroup analyses by study duration or effect of control intervention on weight. Risk of bias in most studies was low, and no evidence of publication bias was found. Trial sequential analysis provided evidence that the cumulative sample size was large enough to exclude a significant effect of metformin on cancer incidence. CONCLUSIONS: Metformin did not reduce cancer incidence in RCTs involving subjects with overweight/obesity and/or prediabetes/diabetes.

Correlation of serum uric acid levels with certain anthropometric parameters in prediabetic and drug-naive diabetic subjects.

Introduction: Uric acid is produced during the metabolism of nucleotide and adenosine triphosphate and contains the final product of human purine metabolism. It acts both as an antioxidant and pro-inflammatory marker and has a positive association with visceral fat in overweight subjects. The aim of the present study is to find an association of uric acid level with certain anthropometric parameters in subjects having type 2 diabetes. Materials and Methods: The study included 124 urban drug-naive diabetic Indian subjects above 18 years of age from the general population of the city of North India. Uric acid concentrations were estimated by the uricase method. Fasting plasma glucose (FPG) concentrations were estimated by the glucose oxidase-peroxidase method. Anthropometric measurements and information on lifestyle factors and disease history were collected through in-person meeting. Results: All participants of the study subjects had a body mass index (BMI) of more than 23.5. BMI, waist-to-hip ratio (WHR), waist-to-height ratio, waist circumference, neck circumference, weight, age, sagittal abdominal diameter (SAD), skinfold thickness, and body roundness index were positively correlated with the serum uric acid level. The correlation of weight, BMI, SAD, and WHR was statistically significant. Conclusion: We found that serum uric acid level increases as body fat content increases. Statistical data show remarkable results for a significant correlation of uric acid level with BMI, WHR, SAD, and FPG. Hypertrophy occurs as a result of inflammatory processes and oxidative stress when the supply of energy starts to exceed the storage capacity of adipocytes, as a result, adipokines such as interleukin (IL)-1, IL-6, and tumor-necrosis factor-alpha are released more frequently which lead to low-grade chronic inflammation. Uric acid levels are much lean toward visceral obesity than overall body fat content.

Résumé Introduction: L'acide urique est produit lors du métabolisme des nucléotides et de l'adénosine triphosphate, et il représente le produit final du métabolisme des purines chez l'homme. Il agit à la fois comme un antioxydant et un marqueur pro-inflammatoire, et il est positivement associé à la graisse viscérale chez les sujets en surpoids. L'objectif de la présente étude est de rechercher une association entre le taux d'acide urique et certains paramètres anthropométriques chez des sujets atteints de diabète de type 2. Matériels et méthodes: L'étude a inclus 124 sujets diabétiques urbains indiens, naïfs aux médicaments, âgés de plus de 18 ans, issus de la population générale de la ville du nord de l'Inde. Les concentrations d'acide urique ont été estimées par la méthode de l'uricase. Les concentrations de glucose plasmatique à jeun (FPG) ont été estimées par la méthode glucose oxydase-peroxydase. Les mesures anthropométriques et les informations sur les facteurs de mode de vie et les antécédents médicaux ont été recueillies lors de rencontres en personne. Résultats: Tous les participants de l'étude présentaient un indice de masse corporelle (IMC) supérieur à 23,5. L'IMC, le rapport taille-hanche (WHR), le rapport taille-hauteur, la circonférence de taille, la circonférence du cou, le poids, l'âge, le diamètre abdominal sagittal (SAD), l'épaisseur des plis cutanés et l'indice de rondeur corporelle étaient corrélés positivement avec le taux d'acide urique sérique. La corrélation du poids, de l'IMC, du SAD et du WHR était statistiquement significative. Conclusion: Nous avons constaté que le taux d'acide urique sérique augmente avec l'augmentation de la teneur en graisse corporelle. Les données statistiques montrent des résultats remarquables pour une corrélation significative du taux d'acide urique avec l'IMC, le WHR, le SAD et le FPG. L'hypertrophie se produit en raison de processus inflammatoires et de stress oxydatif lorsque l'apport d'énergie dépasse la capacité de stockage des adipocytes. Par conséquent, des adipokines telles que l'interleukine (IL)-1, l'IL-6 et le facteur alpha de nécrose tumorale sont libérées plus fréquemment, ce qui entraîne une inflammation chronique de bas grade. Les niveaux d'acide urique sont davantage associés à l'obésité viscérale qu'à la teneur globale en graisse corporelle. Mots-clés: Anthropométrique, syndrome métabolique, microalbuminurie, acide urique sérique.

The association between type 2 diabetes mellitus/prediabetes status and femoral neck bone mineral density in old adults.

BACKGROUND: The prevalence of both type 2 diabetes mellitus (T2DM) and osteoporosis has been increasing among older individuals, with these two health conditions often coexisting. Our aim in this study was to evaluate the association between T2DM status and bone mineral density (BMD) of the femoral neck among older adults in the United States. METHODS: This was a retrospective analysis of the data from 5695 adults, 60-80 years of age. The data were obtained from the National Health and Nutrition Examination Survey, for the following years: 2005-2006, 2007-2008, 2009-2010, 2013-2014, and 2017-2018. Weighted multivariable regression analyses, with subgroup analyses as appropriate, were performed to identify an association between T2DM/prediabetes status and femoral BMD and mediating factors. RESULTS: There was a significant positive association between T2DM/prediabetes status and femoral neck BMD among older women, but not men, after adjusting for body mass index (BMI). On subgroup analysis, stratified by BMI, the significant positive association was retained for T2DM women with a BMI of 25-29.9 kg/m2 (ß, 0.030; 95% CI, 0.007-0.052) or ≥30 kg/m2 (ß, 0.029; 95% CI, 0.007-0.05), and for prediabetes women with a BMI of 25-29.9 kg/m2 (ß, 0.016; 95% CI, 0.001-0.030). CONCLUSIONS: The association between a positive T2DM/prediabetes status and femoral neck BMD differed by sex among older individuals, with the association being further modulated by BMI. For women with a BMI of 25-29.9 kg/m2 or ≥30 kg/m2, T2DM was associated with a significantly higher femoral neck BMD, compared to the non-diabetes group.

Remission of type 2 diabetes: always more questions, but enough answers for action.

The concept of type 2 diabetes remission is evolving rapidly, and gaining wide public and professional interest, following demonstration that with substantial intentional weight loss almost nine in ten people with type 2 diabetes can reduce their HbA1c level below the diagnostic criterion (48 mmol/mol [6.5%]) without glucose-lowering medications, and improve all features of the metabolic syndrome. Pursuing nomoglycaemia with older drugs was dangerous because of the risk of side effects and hypoglycaemia, so the conventional treatment target was an HbA1c concentration of 53 mmol/mol (7%), meaning that diabetes was still present and allowing disease progression. Newer agents may achieve a normal HbA1c safely and, by analogy with treatments that send cancers or inflammatory diseases into remission, this might also be considered remission. However, although modern glucagon-like peptide-1 receptor agonists and related medications are highly effective for weight loss and glycaemic improvement, and generally safe, many people do not want to take drugs indefinitely, and their cost means that they are not available across much of the world. Therefore, there are strong reasons to explore and research dietary approaches for the treatment of type 2 diabetes. All interventions that achieve sustained weight loss of >10-15 kg improve HbA1c, potentially resulting in remission if sufficient beta cell capacity can be preserved or restored, which occurs with loss of the ectopic fat in liver and pancreas that is found with type 2 diabetes. Remission is most likely with type 2 diabetes of short duration, lower HbA1c and a low requirement for glucose-lowering medications. Relapse is likely with weight regain and among those with a poor beta cell reserve. On current evidence, effective weight management should be provided to all people with type 2 diabetes as soon as possible after diagnosis (or even earlier, at the stage of prediabetes, defined in Europe, Australasia, Canada [and most of the world] as ≥42 and <48 mmol/mol [≥6.0 and <6.5%], and in the USA as HbA1c ≥39 and <48 mmol/mol [≥5.7 and <6.5%]). Raising awareness among people with type 2 diabetes and their healthcare providers that remission is possible will enable earlier intervention. Weight loss of >10 kg and remission lasting 1-2 years may also delay vascular complications, although more evidence is needed. The greatest challenge for research is to improve long-term weight loss maintenance, defining cost-effective approaches tailored to the preferences and needs of people living with type 2 diabetes.

Insulin-like growth factor-1 and cognition in normoglycemia, prediabetes, and type 2 diabetes mellitus.

BACKGROUND: The relationship between insulin-like growth factor-1 (IGF-1) and cognition has been studied in healthy individuals, but not extensively with regards to insulin resistance and type 2 diabetes mellitus (T2DM). In this retrospective observational study, we investigated relationships of IGF-1 with memory and executive function across people with normoglycemia, prediabetes, and T2DM. METHODS: Data from the Midlife in the United States (MIDUS) study were used. Episodic memory and executive function were assessed using the Brief Test of Adult Cognition by Telephone approximately 21.42 ± 12.10 months prior to measuring IGF-1 levels from a fasting blood sample. Normoglycemia was identified as individuals without a physician diagnosis of diabetes and glycated hemoglobin (HbA1c) ≤5.6%. Prediabetes was identified as those without a physician diagnosis of diabetes and HbA1c between 5.7%-6.4%. T2DM was identified as anyone with a physician diagnosis of diabetes, or HbA1c ≥6.5%, or anyone using an oral hypoglycemic medication. The associations were assessed using linear regressions controlling for age, sex, education, body mass index, C-reactive protein, HbA1c or homeostatic model of insulin resistance, MIDUS wave, exercise, smoking status, sleep quality, alcohol intake, oral hypoglycemic use, and insulin use. RESULTS: The study included 1400 participants, which consisted of 583 normoglycemic (48.4% female, mean age 51.0 ± 12.2 years), 512 prediabetes (58.4% female, mean age 57.3 ± 11.8 years), and 305 T2DM participants (53.8% female, mean age 57.6 ± 11.5 years). Peripheral IGF-1 concentrations were lower (F2,1397 = 28.29, p < 0.001) in people with prediabetes or T2DM, vs. normoglycemia. Participants with prediabetes or T2DM had lower episodic memory (F2,1397 = 9.21, p < 0.001) and executive function (F2,1397 = 20.29, p < 0.001) composite z-scores than people with normoglycemia. Higher IGF-1 concentrations were associated with better executive performance in individuals with prediabetes (ß = 0.115 [0.028, 0.202], p = 0.010), but not in individuals with normoglycemia or T2DM. An interaction between IGF-1 and sex in predicting executive function was observed in the prediabetes group (ß = -0.344, p = 0.042), where the relationship was weaker in females (ß = 0.106 [-0.012, 0.224], p = 0.077) than males (ß = 0.251 [0.123, 0.380], p < 0.001). No associations were seen between IGF-1 and memory. CONCLUSION: The results suggest that peripheral IGF-1 concentrations may be related to executive function, and that the relationship may be sex-specific and dependent on diabetes status.

Association between prediabetes and breast cancer: a comprehensive meta-analysis.

BACKGROUND: Breast cancer accounts for up to 30% of cancer cases in women in the US. Diabetes mellitus has been recognized as a risk factor for breast cancer. Some studies have suggested that prediabetes may also be associated with breast cancer whereas other studies have shown no or an inverse association; thus, we conducted a meta-analysis to assess the risk of breast cancer in prediabetes. METHODS: We searched PubMed/Medline, EMBASE, Google Scholar, and Scopus to identify studies that reported breast cancer risks in patients having prediabetes compared to normoglycemic patients. Binary random-effects model was used to calculate a pooled odds ratio (OR) with 95% confidence intervals. I2 statistics were used to assess heterogeneity. Leave-one-out sensitivity analysis and subgroup analyses were performed. RESULTS: We analyzed 7 studies with 24,586 prediabetic and 224,314 normoglycemic individuals (783 and 5739 breast cancer cases, respectively). Unadjusted odds ratio (OR) for breast cancer was 1.45 (95% CI = 1.14, 1.83); adjusted OR was 1.19 (95% CI = 1.07, 1.34) in prediabetes. Subgroup analysis revealed a higher breast cancer risk in individuals aged less than 60 years (OR = 1.86, 95% CI = 1.39, 2.49) than in those aged 60 years or more (OR = 1.07, 95% CI = 0.97, 1.18). Subgroup analysis by median follow-up length indicated a higher risk of breast cancer for follow-ups of less than or equal to 2 years (OR = 2.34, 95% CI = 1.85, 2.95) than in those of over 10 years (OR = 1.1, 95% CI = 0.99, 1.23) and 6 to 10 years (OR = 1.03, 95% CI = 0.88, 1.21). CONCLUSIONS: In conclusion, individuals with prediabetes have higher risk of developing breast cancer than those with normoglycemia, especially younger prediabetes patients. These individuals may benefit from early identification, monitoring, and interventions to reverse prediabetes.

Salivary and crevicular fluid proinflammatory cytokines and advanced glycation end products in patients with different glycemic levels undergoing fixed orthodontic treatment.

OBJECTIVE: To examine whether patients with different blood glycemic levels undergoing fixed orthodontic therapy demonstrate changes in the biochemical profiles of crevicular fluid and salivary advanced glycation end products (AGEs) and proinflammatory cytokine levels in comparison with nondiabetic healthy subjects. MATERIALS AND METHODS: Prediabetic subjects, subjects with type 2 diabetes mellitus (T2DM), and subjects without a diabetes mellitus diagnosis undergoing fixed orthodontic therapy with MBT prescription brackets (0.022-inch brackets and 0.019 × 0.025-inch stainless steel archwires) were included in the study. The following clinical periodontal parameters were evaluated: (1) plaque score (PS), (2) probing depth (PD), (3) bleeding on probing (BOP), and (4) clinical attachment loss. Crevicular fluid and saliva specimens were collected during regular orthodontic visits. Salivary and crevicular fluid tumor necrosis factor alpha, interleukin-6, ghrelin, resistin, AGEs, and receptor activator of nuclear factor κΒ ligand were evaluated using a human magnetic Luminex multiplex assay. RESULTS: BOP scores were significantly higher among T2DM subjects (19.2%) than among nondiabetic subjects (11.2%) and prediabetic subjects (15.9%). Comparable values were demonstrated by all three study groups regarding PD scores and PSs. T2DM subjects demonstrated higher scores for gingival crevicular fluid (GCF) chemokines than nondiabetic and prediabetic subjects. A statistically significant difference was found in the levels of AGEs and resistin among the three study groups. The scores revealed for the levels of GCF resistin and AGEs versus periodontal BOP demonstrated a significant positive association by the Pearson correlation test. CONCLUSIONS: T2DM patients demonstrated significantly higher levels of GCF resistin and AGEs during fixed orthodontic therapy. Chronic hyperglycemic patients undergoing orthodontic therapy demonstrated a proinflammatory response.

Coronary Artery Calcium and Cognitive Decline in the Diabetes Prevention Program Outcomes Study.

Background Our aim was to investigate the association of coronary artery calcium (CAC) with cognitive function in adults with impaired glucose tolerance or type 2 diabetes. Methods and Results The Diabetes Prevention Program was a randomized controlled trial comparing an intensive lifestyle intervention, metformin, or placebo for prevention of type 2 diabetes among patients with prediabetes. After 3 years, intensive lifestyle intervention and placebo were stopped, the metformin arm was unmasked, and participants continued in the DPPOS (Diabetes Prevention Program Outcomes Study). Approximately 14 years after randomization (Y14), CAC (Agatston score) was assessed with computed tomography, and cognitive performance was assessed with the Spanish English Verbal Learning Test (SEVLT) and Digit Symbol Substitution Test. SEVLT and Digit Symbol Substitution Test were reassessed 5 years later (Y19) along with the Modified Mini-Mental State Exam. We examined cross-sectional and longitudinal associations between CAC and cognition among 1931 participants using linear and logistic regression. In unadjusted analyses, compared with no calcification, CAC score >300 was associated with decreased performance on all cognitive tests at Y14 in both sexes. Additionally, CAC >300 was associated with a greater 5-year decline in SEVLT Immediate Recall in both sexes and SEVLT Delayed Recall in women. After adjustment for demographic, genetic, metabolic, vascular, and behavioral covariates, CAC score >300 remained associated with greater decline in only SEVLT Delayed Recall in women. Conclusions In women with prediabetes or diabetes, CAC >300, compared with no calcification, was independently associated with greater decline in verbal memory. Registration information clinicaltrials.gov. Identifier: NCT00038727.

Diabetes and the risk of cirrhosis and HCC: An analysis of the UK Biobank.

BACKGROUND: Diabetes increases the risk of cirrhosis and HCC. We aimed to assess such associations given different diabetes statuses. METHODS: We included 449,497 participants in the UK Biobank cohort (mean age 56.7±8.0 y; 45.5% male) and assessed the association between preclinical diabetes (prediabetes, having a high risk of diabetes), clinical diabetes (presence, duration, or glycemic control of type 2 diabetes), and incident liver cirrhosis and HCC by the Cox regression. Liver diseases were ascertained through inpatient records and national death registration. Gene-environment interaction was examined using the polygenic risk scores of cirrhosis and HCC. RESULTS: Compared with normoglycemia, having <5 years,≥5 years of diabetes showed adjusted HRs (aHRs) of cirrhosis as 2.85 (2.45-3.32) and 3.43 (2.92-4.02), respectively, which was similarly observed in HCC. In diabetes, a level of hemoglobin A1c ≥ 7.5% showed aHRs of 1.37 (1.07-1.76) and 1.89 (1.10-3.25) for cirrhosis and HCC, respectively, compared with hemoglobin A1c < 6.5%. In non-diabetes, prediabetes presented aHRs of 1.41 (1.14-1.73) and 1.80 (1.06-3.04) of cirrhosis and HCC, respectively. Participants with a high risk of diabetes at baseline showed an aHR of 3.31 (2.65-4.13) for cirrhosis and 2.09 (1.15-3.80) for HCC. In those with a high genetic risk of HCC, having an increased risk of diabetes posed a significantly higher risk of HCC (aHR: 1.93, 1.45-2.58, Pinteraction=0.005), compared with those without a high genetic risk of HCC. CONCLUSIONS: Not only diabetes but preclinical diabetes, longer diabetes duration, and higher baseline hemoglobin A1c were associated with an increased risk of incident cirrhosis and HCC in the general population.

Resting heart rate and the risk of incident type 2 diabetes mellitus among non-diabetic and prediabetic Iranian adults: Tehran lipid and glucose study.

BACKGROUND: Resting heart rate (RHR) has been found to be a potential risk factor for developing type 2 diabetes mellitus (T2DM), with a highly significant heterogeneity among previous studies. Therefore, we examined the association of RHR and risk of incident T2DM among non-diabetic and prediabetic adults. METHODS: The study population included 2431 men and 2910 women aged ≥ 20 years without T2DM at baseline (2001-2005). Participants were followed for incident T2DM by about 3-year intervals up to April 2018. The multivariable Cox proportional models were applied to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs). The models were adjusted for age, body mass index, waist circumference, educational level, physical activity, smoking, hypertension, family history of diabetes, triglycerides/ high-density lipoprotein cholesterol ratio, and fasting plasma glucose. RESULTS: During a median follow-up of 12.2 years, 313 men and 375 women developed T2DM. Interestingly, a significant sex-difference was found (all P-values for sex interaction < 0.025). Among men, compared to the first quintile (< 68 bpm: beats per minute), those who had RHR of over 84 bpm were at higher T2DM risk with a HR (95%CI) of 1.69 (1.16-2.47). Furthermore, considering RHR as a continuous variable, an increase of 10 bpm caused 17% significantly higher risk among men with a HR of 1.17 (1.05-1.30). However, among women, there was no significant association between incident T2DM and RHR. Moreover, among prediabetic participants at baseline, the association of RHR and risk of T2DM progression was generally similar to the general population, which means higher RHR increased the risk of T2DM development only among men with a HR of 1.26 (1.09-1.46) for 10 bpm increase. CONCLUSIONS: Among men, being either non-diabetic or prediabetic at baseline, higher RHR can be associated with incident T2DM; however, women didn't show a significant association. Further studies are needed to determine the added value of RHR as a potential modifiable risk factor in screening and risk prediction of incident T2DM.

Design and rationale of the myocardial infarction and new treatment with metformin study (MIMET) - Study protocol for a registry-based randomised clinical trial.

AIMS: To investigate if addition of metformin to standard care (life-style advice) reduces the occurrence of cardiovascular events and death after myocardial infarction (MI) in patients with newly detected prediabetes. METHODS: The Myocardial Infarction and new treatment with Metformin study (MIMET) is a large multicentre registry-based randomised clinical trial (R-RCT) within the SWEDEHEART registry platform expected to include 5160 patients with MI and newly detected prediabetes (identified with fasting blood glucose, HbA1c or 2-h glucose on oral glucose tolerance test) at ∼20 study sites in Sweden. Patients 18-80 years, without known diabetes and naïve to glucose lowering therapy, will be randomised 1:1 to open-label metformin therapy plus standard care or standard care alone. OUTCOMES: Patients will be followed for 2 years for the primary outcome new cardiovascular event (first of death, non-fatal MI, hospitalisation for heart failure or non-fatal stroke). Secondary endpoints include individual components of the primary endpoint, diabetes diagnosis, initiation of any glucose lowering therapy, cancer, and treatment safety. Events will be collected from national healthcare registries. CONCLUSIONS: The MIMET study will investigate if metformin is superior to standard care after myocardial infarction in preventing cardiovascular events in patients with prediabetes (Clinicaltrials.gov identifier: NCT05182970; EudraCT No: 2019-001487-30).

Diabetes detection in women with gestational diabetes and polycystic ovarian syndrome.

Gestational diabetes mellitus (GDM) and polycystic ovarian syndrome (PCOS) represent two of the highest risk factors for development of type 2 diabetes mellitus in young women. As these increasingly common conditions generally affect younger women, early detection of dysglycemia is key if preventative measures are to be effective. While international guidance recommends screening for type 2 diabetes, current screening strategies suffer from significant challenges.First, guidance lacks consensus in defining which tests to use and frequency of monitoring, thereby sending mixed messages to healthcare professionals.Second, conformity to guidance is poor, with only a minority of women having tests at the recommended frequency (where specified). Approaches to improve conformity have focused on healthcare related factors (largely technology driven reminder systems), but patient factors such as convenience and clear messaging around risk have been neglected.Third, and most critically, current screening strategies are too generic and rely on tests that become abnormal far too late in the trajectory towards dysglycemia to offer opportunities for effective preventative measures. Risk factors show wide interindividual variation, and insulin sensitivity and ß cell function are often abnormal during pre-diabetes stage, well before frank diabetes.New, consistent, targeted screening strategies are required that incorporate early, prevention focused testing and personalised risk stratification.

Obesity Associated with Prediabetes Increases the Risk of Breast Cancer Development and Progression-A Study on an Obese Rat Model with Impaired Glucose Tolerance.

Patients with comorbidities of obesity and diabetes are recognized to be at high risk of breast cancer development and face worse breast cancer outcomes. Though several reports showed the reinforced link between obesity, diabetes, and prediabetes with breast cancer, the underlying molecular mechanisms are still unknown. The present study aimed to investigate the underlying molecular link between increased risks of breast cancer due to coincident diabetes or obesity using a spontaneous obese rat model with impaired glucose tolerance (WNIN/GR-Ob rat). A single dose of solubilized DMBA suspension (40 mg/kg body weight) was orally administered to the animals at the age of 60 days to induce breast tumors. The tumor incidence, latency period, tumor frequency, and tumor volume were measured. Histology, immunohistochemistry, and immunoblotting were performed to evaluate the tumor morphology and expression levels of signal molecules. The development of mammary tumors in GR-Ob rats was characterized by early onset and shorter latency periods compared to control lean rats. While 62% of obese rats developed breast tumors, tumor development in lean rats was only 21%. Overexpression of ER, PR, Ki67, and p53 markers was observed in tumor tissues of obese rats in comparison with lean rats. The levels of the hallmarks of cell proliferation and angiogenesis involved in IGF-1/PI3K/Akt/GSK3ß/ß-catenin signaling pathway molecules were upregulated in obese rat breast tumors compared to lean rats. Furthermore, obesity with prediabetes is associated with changes in IGF-1 signaling and acts on PI3K/Akt/GSK3ß/ß-catenin signaling, which results in rapid cell proliferation and development of breast tumors in obese rats than the lean rats. These results indicate that tumor onset and development were faster in spontaneous obese rat models with impaired glucose tolerance than in their lean counterparts.

Prediabetes and the risk of lung cancer incidence and mortality: A meta-analysis.

AIMS/INTRODUCTION: There has been conflicting evidence regarding the role of prediabetes as a risk factor of lung cancer. A systemic review and meta-analysis was conducted to determine the relationship between prediabetes and lung cancer incidence and mortality in general adult populations. MATERIALS AND METHODS: Observational studies relevant to the objective were found in Medline, Embase, Cochrane Library, and Web of Science. By incorporating potential heterogeneity into the model, a randomized-effects model was selected. RESULTS: Ten cohort studies were included. People with prediabetes were associated with a mildly increased risk of lung cancer incidence compared with controls with normoglycemia (risk ratio [RR]: 1.09, 95% confidence interval [CI]: 1.01-1.18, P = 0.03; I2 = 79%), which was mainly observed in men rather than in women (RR: 1.07 vs 0.99, P for subgroup difference < 0.001). Prediabetes was related to a higher risk of lung cancer mortality (RR: 1.19, 95% CI: 1.02-1.39, P = 0.03; I2 = 52%), and the results were consistent in both men and women (P for subgroup difference = 0.67). The association between prediabetes and lung cancer incidence or mortality did not appear to be significantly affected by different definitions of prediabetes (P for subgroup difference = 0.27 and 0.37). CONCLUSIONS: Prediabetes might be associated with a mildly increased risk of lung cancer incidence in men, but not in women. In addition, prediabetes may be related to a higher risk of lung cancer mortality in the adult population.

Serum 25(OH)D Concentration, Vitamin D Supplementation, and Risk of Cardiovascular Disease and Mortality in Patients with Type 2 Diabetes or Prediabetes: a Systematic Review and Dose-Response Meta-Analysis.

BACKGROUND: Evidence is uncertain about the association between serum 25-hydroxyvitamin D (25(OH)D) concentration and health outcomes in people with type 2 diabetes. OBJECTIVES: We aimed to assess the association between vitamin D status and all-cause mortality and cardiovascular disease in people with type 2 diabetes. METHODS: We did a systematic search in PubMed, Scopus, CENTRAL, and Web of Science until May 2022. We selected 1) cohort studies investigating the association between serum 25(OH)D concentration and mortality or cardiovascular disease in people with type 2 diabetes or prediabetes and 2) randomized trials of vitamin D supplementation in these patients. We used random-effects pairwise meta-analyses to calculate summary relative risks (RRs) and 95% confidence intervals (CI). RESULTS: 21 cohort studies and 6 randomized trials were included. Compared with sufficient vitamin D status (≥50 nmol/L), the RR of all-cause mortality was 1.36 (95% CI: 1.23, 1.49; n = 11 studies, GRADE = moderate) for vitamin D insufficiency (25 to <50 nmol/L), and 1.58 (1.33, 1.83; n = 16, GRADE = moderate) for deficiency (<25 nmol/L). Similar findings were observed for cardiovascular mortality and morbidity but not for cancer mortality. The certainty of evidence ranged from very low to moderate. Dose-response meta-analyses indicated nonlinear associations, with the lowest risk at 25(OH)D ∼60 nmol/L for all-cause and cardiovascular mortality. Supplementation with vitamin D did not reduce the risk of all-cause mortality (RR: 0.96, 95% CI: 0.79, 1.16; risk difference per 1000 patients: 3 fewer, 95% CI: 16 fewer, 12 more; n = 6 trials with 7316 participants; GRADE = low) or the risk of cardiovascular mortality and morbidity (very low- to low-certainty evidence). CONCLUSIONS: Vitamin D deficiency and insufficiency are associated with a higher risk of all-cause and cardiovascular mortality in patients with type 2 diabetes or prediabetes. Vitamin D deficiency should be corrected in patients with type 2 diabetes to reach normal serum 25(OH)D concentrations, preferably 60 nmol/L. SYSTEMATIC REVIEW REGISTRATION: This systemic review was registered at PROSPERO as CRD42022326429 (=https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=326429).