Diabetes Mortality Research Articles

Diabetes mortality: trends and multi-country analysis of the Americas from 2000 to 2019.

Diabetes has been increasing worldwide and is now among the 10 leading causes of death globally. Diabetic kidney disease (DKD), a complication of poorly managed diabetes, is related to high mortality risk. To better understand the situation in the Americas region, we evaluated diabetes and DKD mortality trends over the past 20 years. We analysed diabetes and DKD mortality for 33 countries in the Americas from 2000 to 2019. Data were extracted from the World Health Organization (WHO) Global Health Estimates and the World Population Prospects, 2019 Revision, estimating annual age-standardized mortality rates (ASMR) and gaps in the distribution of diabetes and DKD mortality by sex and country. Trend analyses were based on the annual average percentage of change (AAPC). From 2000 to 2019, the overall mortality trend from diabetes in the Americas remained stable [AAPC: -0.2% (95% CI: -0.4%-0.0%]; however, it showed important differences by sex and by country over time. By contrast, DKD mortality increased 1.5% (1.3%-1.6%) per year, rising faster in men than women, with differences between countries. Central America, Mexico and the Latin Caribbean showed significant increases in mortality for both diseases, especially DKD. In contrast in North America, diabetes mortality decreased whereas DKD mortality increased. The increase in DKD mortality is evidence of poorly controlled diabetes in the region. The lack of programmes on prevention of complications, self-care management and gaps in quality health care may explain this trend and highlight the urgent need to build more robust health systems based on primary care, prioritizing diabetes prevention and control.

Determining the Associations Between Glucocorticoid Use During Hematologic Chemotherapy Treatment and New-onset Diabetes and Hyperglycemia and Mortality: A Population-based Cohort Study

ObjectivesThe aim of this study was to determine the associations between glucocorticoid administration during chemotherapy for hematologic malignancy and hyperglycemia, new-onset diabetes, and mortality in Ontario, Canada. Hospitalization and emergency room utilization during the chemotherapy treatment period were also described. MethodsWe conducted a retrospective cohort study using health administrative data from ICES, Ontario, to assess risk of new-onset diabetes, new-onset hyperglycemia, and hyperglycemia for individuals with leukemia, non-Hodgkin lymphoma (NHL), and Hodgkin lymphoma (HL) receiving glucocorticoids during chemotherapy between 2006 and 2016. Using multivariable regression models, we determined the associations between glucocorticoid exposure and our outcomes of interest, controlling for age, sex, marginalization, and comorbidities. ResultsOur cohort included 19,530 individuals; 71.1% (n=13,893) received a glucocorticoid. The highest proportion of hyperglycemia occurred with leukemia (25.4%, n=1,301). Of the 15,580 individuals with no history of diabetes, those with leukemia had the highest rate of new-onset diabetes (7.1%, n=279) and new-onset hyperglycemia (18.1%, n=641), and glucocorticoid exposure increased the risk of new-onset diabetes (hazard ratio [HR] 1.29, 95% confidence interval [CI] 1.01 to 1.64, p=0.04) and new-onset hyperglycemia (HR 1.28, 95% CI 1.09 to 1.5, p=0.003). Hyperglycemia during chemotherapy increased the risk of all-cause mortality for the combined (HR 1.18, 95% CI 1.09 to 1.27, p<0.0001) and NHL (HR 1.16, 95% CI 1.04 to 1.28, p=0.007) cohorts. ConclusionsHyperglycemia is common during hematologic chemotherapy treatment and is associated with a modest increased risk of all-cause mortality. Routine screening, monitoring, and management of hyperglycemia should be an integral part of treatment plans for leukemia, NHL, or HL, with or without glucocorticoid administration.

Reduced Blood to Brain Glucose Transport as the Cause for Hyperglycemia: A Model That Resolves Multiple Anomalies in Type 2 Diabetes

Classically type 2 diabetes is believed to be a result of insulin resistance and relative insulin deficiency. However, evidences have been accumulating against the insulin resistance models. Absence of lasting hyperglycemia by insulin receptor knockouts or insulin suppression, evidence for hyperinsulinemia preceding insulin resistance, the perplexing hyperinsulinemic normoglycemic state, reduced glucose transport to the brain preceding hyperglycemia, signs of vasculopathy preceding hyperglycemia, absent or poor correlation between fasting glucose and insulin, very strong positive correlation between indices of insulin resistance and β cell function in population data are some of the anomalous findings which classical glucose homeostasis models have not addressed so far. With increasing evidence for neuronal involvement in glucose regulation, we propose a refined model of glucose regulation that considers brain glucose and insulin levels as the ultimate target of homeostasis and combines central and peripheral mechanisms of regulation. A model considering reduced rate of blood to brain transportation of glucose and insulin as primary pathology explains most of the patterns, with or without insulin resistance or any other defect in glucose regulation mechanisms. Apart from resolving multiple anomalies the model also accounts for the failure of glucose normalization in effectively reducing diabetic complications and mortality.

Plant-based diets, mediating biomarkers, and mortality risk among adults with diabetes or prediabetes.

Background: A healthy eating pattern characterized by a higher intake of healthy plant foods has been associated with a lower risk of premature mortality, but whether this applies to individuals with varying glycemic status remains unclear. Methods: This study included 4621 participants with diabetes and 8061 participants with prediabetes from the US National Health and Nutrition Examination Survey (2007-2016). Using the dietary data assessed by two 24 h dietary recalls, a healthful plant-based diet index (hPDI) and an unhealthful plant-based diet index (uPDI) were created based on 15 food groups and were assessed for their relationships with mortality risk. Results: Over a median follow-up of 7.2 years, there were 1021 deaths in diabetes and 896 deaths in prediabetes. A higher hPDI (highest vs. lowest quartile) was associated with a 41% (HR = 0.59, 95% CI: 0.49-0.72; P-trend < 0.001) lower risk of all-cause mortality in diabetes and a 31% (HR = 0.69, 95% CI: 0.55-0.85; P-trend < 0.001) lower risk in prediabetes. A higher uPDI was associated with an 88% (HR = 1.88, 95% CI: 1.55-2.28; P-trend < 0.001) higher risk of mortality in diabetes and a 63% (HR = 1.63, 95% CI: 1.33-1.99; P-trend < 0.001) higher risk in prediabetes. Mediation analysis suggested that C-reactive protein and γ-glutamine transaminase explained 6.0% to 10.9% of the relationships between hPDI or uPDI and all-cause mortality among participants with diabetes. Conclusions: For adults with diabetes as well as those with prediabetes, adhering to a plant-based diet rich in healthier plant foods is associated with a lower mortality risk, whereas a diet that incorporates less healthy plant foods is associated with a higher mortality risk.

Longer Multimorbidity Intervals Are Associated With Lower Mortality in Diabetes: A Whole-Population Nested Case-Control Study.

Approximately two-thirds of diabetes patients develop multimorbidity, which is associated with increased mortality. We aimed to examine whether, and to what extent, the time interval between pre-existing diabetes and a second chronic disease may be associated with the risk of mortality. We carried out a territory-wide nested case-control study using incidence density sampling, utilizing electronic health records from Hong Kong's public healthcare facilities. Among 158 732 patients first diagnosed with diabetes from January 1, 2010 to December 31, 2012 and subsequently developed multimorbidity as of December 31, 2019, we extracted those who died before December 31, 2019 as case participants. For each participant, we randomly matched with up to 4 people of the same sex, multimorbidity age, and second chronic condition who had not died after going through the same survival period of the case participant. Multimorbidity interval was included as a continuous variable. We used conditional logistic regression to estimate adjusted odds ratios (aOR) for mortality. In total, 3508 case participants were matched with 14 032 control participants. Conditional logistic regression showed there were 19%-reduced odds of mortality following the extension of multimorbidity interval by 1 year. Similar associations were observed in men, women, people aged 64 years or younger, and older people aged 65 years or more. Delayed multimorbidity among patients living with diabetes may be related to a lower risk of mortality. This study suggests that we should focus on mitigating and lowering the risk of multimorbidity in clinical management of diabetes to reduce further complication and mortality.

Predictive Value of Triglyceride-Glucose Index for All-Cause and Cardiovascular Mortality in Patients With Diabetes Mellitus: A Retrospective Study: TyG Index and Mortality in Diabetes.

Objective: To determine the associations between triglyceride-glucose (TyG) index and mortality from all causes and cardiovascular causes in diabetic population. Methods: 3349 participants with diabetes mellitus (DM) from the 1999-2014 National Health and Nutrition Examination Surveys (NHANES), aged 18-85 years were included and grouped based on the TyG index in quintiles. Mortality was followed up through December 31th, 2015. Cox proportional hazards models were used to assess the hazard ratios (HRs) and 95% confidence intervals (CIs). We clarified the shape of association between TyG index and mortality using restricted cubic splines and piecewise linear regression. Results: After a median follow-up period of 82 months, 800 (23.9%) deaths occurred, of which 190 (5.7%) were due to cardiovascular causes. Participants in the top quintile had higher risks of all-cause mortality (HR, 1.38; 95% CI, 1.04-1.48) and cardiovascular mortality (HR, 2.43; 95% CI, 1.32-4.45) than those in the lowest quintile. TyG index and all-cause mortality had a J-shaped relationship with a threshold value of 9.32, while TyG index and cardiovascular mortality had a reversed L-shaped relationship with a threshold value of 9.37. Higher TyG index was associated with increased risks of all-cause mortality (per SD increment, HR, 1.52; 95% CI, 1.27-1.82) and cardiovascular mortality (per SD increment, HR, 2.17; 95% CI, 1.54-3.04) when above the threshold values. The sensitivity analyses demonstrated similar findings. Conclusions: TyG index in diabetic patients was nonlinearly correlated with mortality risks, potentially predicting all-cause and cardiovascular mortality.

Endothelial Dysfunction in Type 2 Diabetes Patients and its Association with Microvascular Complications: A Cross-sectional Study

Introduction: The prevalence of Type 2 Diabetes Mellitus (T2DM) is increasing worldwide. Microangiopathic and macroangiopathic complications are the main causes of morbidity and mortality in diabetes. Endothelial dysfunction is important in the early pathophysiology of vascular complications. Screening is very important in order to prevent these complications. Aim: To investigate endothelial dysfunction, as measured by Flow Mediated Vasodilation (FMD) of the brachial artery, in diabetic individuals. It also aims to explore the correlation between FMD and Glycated Haemoglobin (HbA1c), as well as the association between FMD and microvascular complications such as diabetic neuropathy, diabetic retinopathy, and albuminuria. Materials and Methods: This cross-sectional study was conducted at Mahatma Gandhi Medical College and Research Institute, Puducherry, India, between 2020 and 2021 on 160 patients. All patients diagnosed with T2DM, attending the Outpatient Department (OPD) or admitted to the ward, were enrolled in the study using consecutive sampling. FMD was measured for each patient, and Urine Albumin Creatinine Ratio (UACR) was also assessed. Diabetic retinopathy was evaluated through fundus examination, and diabetic neuropathy was screened using the monofilament test. Statistical analysis was performed using Statistical Package for Social Sciences (SPSS) version 27.0 to determine the correlation between FMD and these variables. Results: A total of 160 patients were enrolled in this study, including 104 (65%) males and 56 (35%) females. The median age was 52 years, and the participants had a median Body Mass Index (BMI) of 29.5 kg/m2 . The median HbA1c was 8.7%. The median Fasting Blood Sugar (FBS) and Postprandial Blood Sugar (PPBS) levels were 145 mg/dL and 242 mg/dL, respectively. The median FMD among all patients was 5.6%, with an Interquartile Range (IQR) of 4.9% to 6.6%. There was an inverse correlation between HbA1C and FMD values, with a correlation coefficient of -0.718 (p-value &lt;0.01), indicating a strong and significant inverse correlation. Patients with significant macroalbuminuria had a lower median FMD compared to non albuminuric patients, and this difference was statistically significant. The median FMD was also lower in patients with diabetic neuropathy and retinopathy. Conclusion: The study findings suggest that endothelial dysfunction, as measured by FMD, is significantly impaired in patients with elevated HbA1c and microvascular complications of diabetes mellitus.

Admission blood glucose and 30-day mortality in patients with acute decompensated heart failure: prognostic significance in individuals with and without diabetes.

Diabetes is a significant risk factor for acute heart failure, associated with an increased risk of mortality. This study aims to analyze the prognostic significance of admission blood glucose (ABG) on 30-day mortality in Chinese patients with acute decompensated heart failure (ADHF), with or without diabetes. This retrospective study included 1,462 participants from the JX-ADHF1 cohort established between January 2019 to December 2022. We conducted multivariate cox regression, restricted cubic spline, receiver operating characteristic curve analysis, and mediation analysis to explore the association and potential mechanistic pathways (inflammation, oxidative stress, and nutrition) between ABG and 30-day mortality in ADHF patients, with and without diabetes. During the 30-day follow-up, we recorded 20 (5.36%) deaths in diabetic subjects and 33 (3.03%) in non-diabetics. Multivariate Cox regression revealed that ABG was independently associated with 30-day mortality in ADHF patients, with a stronger association in diabetics than non-diabetics (hazard ratio: Model 1: 1.71 vs 1.16; Model 2: 1.26 vs 1.19; Model 3: 1.65 vs 1.37; Model 4: 1.76 vs 1.33). Further restricted cubic spline analysis indicated a U-shaped relationship between ABG and 30-day mortality in non-diabetic ADHF patients (P for non-linearity < 0.001), with the lowest risk at ABG levels approximately between 5-7 mmol/L. Additionally, receiver operating characteristic analysis demonstrated that ABG had a higher predictive accuracy for 30-day mortality in diabetics (area under curve = 0.8751), with an optimal threshold of 13.95mmol/L. Finally, mediation analysis indicated a significant role of inflammation in ABG-related 30-day mortality in ADHF, accounting for 11.15% and 8.77% of the effect in diabetics and non-diabetics, respectively (P-value of proportion mediate < 0.05). Our study confirms that ABG is a vital indicator for assessing and predicting 30-day mortality risk in ADHF patients with diabetes. For ADHF patients, both with and without diabetes, our evidence suggests that physicians should be alert and closely monitor any changes in patient conditions when ABG exceeds 13.95 mmol/L for those with diabetes and 7.05 mmol/L for those without. Timely adjustments in therapeutic strategies, including endocrine and anti-inflammatory treatments, are advisable.

Plant but not animal sourced nitrate intake is associated with lower dementia-related mortality in the Australian Diabetes, Obesity, and Lifestyle Study.

Dietary nitrate is potentially beneficial for cardiovascular, cerebrovascular, and nervous systems due to its role as a nitric oxide (NO) precursor. Increased nitrate intake improves cardiovascular health and therefore could protect against dementia, given the cardiovascular-dementia link. To investigate the association between source-dependent nitrate intake and dementia-related mortality. As individuals with diabetes are at higher risk of dementia, a secondary aim was to investigate if the associations between nitrate and dementia varied by diabetes mellitus (DM) and pre-diabetes status. This study involved 9,149 participants aged ≥25 years from the well-characterised Australian Diabetes, Obesity, and Lifestyle (AusDiab) Study followed over a period of 17 years. Intakes of plant-sourced, vegetable-sourced, naturally occurring animal-sourced nitrate, and processed meat (where nitrate is an allowed additive)-sourced nitrate were assessed from a 74-item food frequency questionnaire completed by participants at baseline and nitrate databases were used to estimate nitrate from these different dietary sources. Associations between source-dependent nitrate intake and dementia-related mortality were assessed using multivariable-adjusted Cox proportional hazards models adjusted for demographics, lifestyle, and dietary factors. Over 17 years of follow-up, 93 (1.0%) dementia-related deaths occurred of 1,237 (13.5%) total deaths. In multivariable-adjusted models, participants with the highest intakes of plant-sourced nitrate (median intake 98 mg/day) had a 57% lower risk of dementia-related mortality [HR (95% CI): 0.43 (0.22, 0.87)] compared to participants with lowest intakes of plant-sourced nitrate (median intake 35 mg/day). A 66% lower risk was also seen for higher intakes of vegetable-sourced nitrate [HR (95% CI): 0.34 (0.17, 0.66)]. No association was observed for animal-sourced nitrate, but the risk was two times higher amongst those who consumed the most processed meat-sourced nitrate intake [HR (95%): 2.10 (1.07, 4.12)]. The highest intake of vegetable-sourced nitrate was associated with a lower risk of dementia-related mortality for those with and without DM and pre-diabetes. Encouraging the intake of nitrate-rich vegetables, such as green leafy vegetables and beetroot, may lower the risk of dementia-related mortality, particularly in individuals with (pre-) diabetes who are at a higher dementia risk.

Demographics, medication use, and admission characteristics of patients hospitalized with diabetes in Ontario, Canada: A retrospective cohort study.

In Canada, one in seven adults has diabetes (i.e., 2.3 million) and the lifetime risk of developing diabetes is approximately 30% by age 65. Although 30% of patients admitted to the hospital have diabetes, data from inpatient hospitalizations for patients with diabetes are lacking, both in Canada and globally. To validate International Classification of Diseases 10th edition Canadian version (ICD-10-CA) codes for the identification of patients with diabetes, to create a multicenter database of patients with diabetes hospitalized under internal medicine in Ontario, and to determine their baseline characteristics, medication use, and admission characteristics. We created a database of people who had diabetes and were hospitalized between 2010 and 2020 at 8 hospitals in Ontario that were part of the General Medicine Inpatient Initiative (GEMINI) hospital data-sharing network. Patients who had diabetes were identified using chart review, based upon either (i) a previous physician diagnosis of diabetes, (ii) a recorded hemoglobin A1c ≥ 6.5% or (iii) outpatient prescription of a diabetes medication preceding the hospitalization. The test characteristics of ICD-10-CA codes for diabetes were evaluated. We compared baseline demographics, medication use and hospitalization details among patients with and without diabetes. For hospitalization details, we collected information on the admission diagnosis, comorbidity index, length of stay, receipt of ICU-level care, and inpatient mortality. There were 384,588 admissions within the total study cohort, of which 118,987 (30.9%) had an ICD-10-CA diagnosis code of diabetes (E10.x, E11.x, E13.x, E14.x). The sensitivity and specificity of ICD-10-CA diagnostic codes was 95.9% and 98.8%, respectively. Most patients with an ICD-10-CA code for diabetes had a code for type 2 diabetes (93.9%) and a code for type 1 diabetes was rare (6.1%). The mean age was 66.4 years for patients without diabetes and 71.3 years for those with an ICD-10-CA diagnosis code for diabetes. Patients with diabetes had a higher prevalence of hypertension (64% vs. 37.9%), coronary artery disease (28.7% vs. 15.3%), heart failure (24.5% vs. 12.1%) and renal failure (33.8% vs. 17.3%) in comparison to those without diabetes. The most prevalent diabetes medications received in hospital were metformin (43%), DPP4 inhibitors (22.7%) and sulfonylureas (18.8%). The most common reason for admission among patients with diabetes was heart failure (9.0%), and among patients without diabetes was pneumonia (7.8%). Median length of stay was longer for patients with diabetes (5.5 vs. 4.5 days) and in-hospital mortality was similar between groups (6.8% with diabetes vs. 6.5% without diabetes). Diabetes is one of the most prevalent chronic medical conditions, affecting roughly one third of all patients hospitalized on an internal medicine ward and is associated with other comorbidities and longer hospital stays. ICD-10-CA codes were highly accurate in identifying patients with diabetes. The development of an inpatient cohort will allow for further study of in-hospital practices and outcomes among patients with diabetes.

Exploring mechanisms of insulin action and strategies to treat diabetes.

Insulin is a hormone that positively regulates anabolism and cell growth, whereas diabetes mellitus is a disease characterized by hyperglycemia associated with impaired insulin action. My colleagues and I have elucidated multifaceted insulin action in various tissues mainly by means of model mice. In the liver, insulin regulates endoplasmic reticulum (ER) stress response during feeding, whereas ER stress 'response failure' contributes to the development of steatohepatitis comorbid with diabetes. Not only the liver but also the proximal tubules of the kidney are important in the regulation of gluconeogenesis, and we revealed that insulin suppresses gluconeogenesis in accordance with absorbed glucose in the latter tissue. In skeletal muscle, another important insulin-targeted tissue, impaired insulin/IGF-1 signaling leads not only to sarcopenia, an aging-related disease of skeletal muscle, but also to osteopenia and shorter longevity. Aging is regulated by adipokines as well, and it should be considered that aging could be accelerated by 'imbalanced adipokines' in patients with a genetic background of progeria. Moreover, we reported the effects of intensive multifactorial intervention on diabetic vascular complications and mortality in patients with type 2 diabetes in a large-scale clinical trial, the J-DOIT3, and the results of subsequent sub-analyses of renal events and fracture events. Various approaches of research enable us of endocrinologists to elucidate the physiology of hormone signaling, the mechanisms underlying the development of endocrine diseases, and the appropriate treatment measures. These approaches also raise fundamental questions, but addressing them in an appropriate manner will surely contribute to the further development of endocrinology.

Geographic disparities and temporal changes of diabetes-related mortality risks in Florida: a retrospective study.

Over the last few decades, diabetes-related mortality risks (DRMR) have increased in Florida. Although there is evidence of geographic disparities in pre-diabetes and diabetes prevalence, little is known about disparities of DRMR in Florida. Understanding these disparities is important for guiding control programs and allocating health resources to communities most at need. Therefore, the objective of this study was to investigate geographic disparities and temporal changes of DRMR in Florida. Retrospective mortality data for deaths that occurred from 2010 to 2019 were obtained from the Florida Department of Health. Tenth International Classification of Disease codes E10-E14 were used to identify diabetes-related deaths. County-level mortality risks were computed and presented as number of deaths per 100,000 persons. Spatial Empirical Bayesian (SEB) smoothing was performed to adjust for spatial autocorrelation and the small number problem. High-risk spatial clusters of DRMR were identified using Tango's flexible spatial scan statistics. Geographic distribution and high-risk mortality clusters were displayed using ArcGIS, whereas seasonal patterns were visually represented in Excel. A total of 54,684 deaths were reported during the study period. There was an increasing temporal trend as well as seasonal patterns in diabetes mortality risks with high risks occurring during the winter. The highest mortality risk (8.1 per 100,000 persons) was recorded during the winter of 2018, while the lowest (6.1 per 100,000 persons) was in the fall of 2010. County-level SEB smoothed mortality risks varied by geographic location, ranging from 12.6 to 81.1 deaths per 100,000 persons. Counties in the northern and central parts of the state tended to have high mortality risks, whereas southern counties consistently showed low mortality risks. Similar to the geographic distribution of DRMR, significant high-risk spatial clusters were also identified in the central and northern parts of Florida. Geographic disparities of DRMR exist in Florida, with high-risk spatial clusters being observed in rural central and northern areas of the state. There is also evidence of both increasing temporal trends and Winter peaks of DRMR. These findings are helpful for guiding allocation of resources to control the disease, reduce disparities, and improve population health.

Electrocardiographic T Wave Abnormality and Associated Factors Among Type 2 Diabetic Patients: Multicenter Institution-Based Cross-Sectional Study

Introduction: T wave abnormalities are usually found on ECG and show abnormal ventricular repolarization. The presence and magnitude of T wave abnormality are often associated with cardiovascular disease and mortality in diabetes. However, there is no study about the electrocardiographic T wave abnormalities among type 2 DM patients in Ethiopia. Therefore, this study determined the overall prevalence and the associated factors of T wave abnormalities among people living with T2DM in Amhara National Regional State referral hospitals, Ethiopia. Methods: A multicenter institution-based cross-sectional study was conducted from 01 January to 30 March 2022. Simple random sampling and systematic sampling techniques were employed to select the referral hospitals and study participants, respectively. A digital electrocardiograph was used to measure the T wave patterns, and an interviewer-administered questionnaire to collect sociodemographic and some clinical factors. Epi-data version-4.6 and Stata-14 were used for data entry and statistical analysis, respectively. The descriptive statistics were presented with tables and graphs. A binary logistic regression model was fitted to identify associated factors of T wave abnormality. In the final model, statistical significance was decided at p&lt;0.05, and the strength of association was indicated using an adjusted odds ratio with 95% CI. Results: Two hundred and fifty-eight participants (response rate=99.6%) were included in the analysis. The prevalence of overall T wave abnormality was 21.7% (95% CI: 19, 29.2%). Higher monthly income (&gt;90$) (AOR=0.16 [0.06, 0.46]), hypertension 5.55 (AOR=5.55 [2.12, 14.49]), fasting blood sugar of &gt;130mg/dl 6.38 (AOR=6.38 [1.94, 20.94]), were statistically significant factors of T wave abnormality. Conclusions: Higher income, hypertension, and higher fasting blood sugar were significantly associated with ECG abnormality. The findings of this study suggest the need to institute routine ECG screening for all T2DM patients to reduce silent myocardial ischemia and further complications.

MASP-2 deficiency does not prevent the progression of diabetic kidney disease in a mouse model of type 1 diabetes.

Mannan-binding lectin (MBL) initiates the lectin pathway of complement and has been linked to albuminuria and mortality in diabetes. We hypothesize that MBL-associated serine protease 2 (MASP-2) deficiency will protect against diabetes-induced kidney damage. Male C57BL/6J MASP-2 knockout (Masp2-/-) mice and wildtype (WT) mice were divided into a diabetic group and a non-diabetic group. Renal hypertrophy, albumin excretion, mesangial area and specific mRNA expressions in the renal cortex were measured after 8 and 12 weeks of diabetes. By two-way ANOVA it was tested if MASP-2 modulated the renal effects of diabetes, that is interaction. After 12 weeks of diabetes Masp2-/- diabetic mice had a smaller mesangium at 21.1% of the glomerular area (95% CI 19.7, 22.6) compared with WT diabetic mice, 25.2% (23.2, 27.2), p(interaction) = 0.001. After 8 weeks of diabetes, plasma cystatin C was 261.5 ng/mL (229.6, 297.8) in the WT diabetic group compared to 459.9 ng/mL (385.7, 548.3) in non-diabetic WT mice, p < 0.001. By contrast, no difference in plasma cystatin C levels was found between the Masp2-/- diabetic mice, 288.2 ng/mL (260.6, 318.6) and Masp2-/- non-diabetic mice, 293.5 ng/mL (221.0, 389.7), p = 0.86 and p(interaction) = 0.001. We demonstrated a protective effect of MASP-2 deficiency on mesangial hypertrophy after 12 weeks of diabetes and an effect on plasma cystatin C level. MASP-2 deficiency did, however, fail to protect against diabetic-induced alterations of kidney weight, albuminuria and renal mRNA expression of fibrotic- and oxidative stress markers.

COMPARING THE ASSOCIATION BETWEEN DIABETES AND MORTALITY IN TWO INDEPENDENT BIRTH COHORT OF OLDER ADULTS IN MEXICO

Abstract The prevalence of diabetes among middle-aged and older adults in Mexico has nearly doubled since the year 2000. This increase is primarily due to healthcare reforms that promoted diabetes screening. Insulin use and other treatments have also increased during the same period. Early diagnosis and treatment can reduce diabetes mortality risk. However, it is unclear if the increased diagnosis and treatment of diabetes in Mexico have reduced the mortality risk associated with diabetes in older adults. We used the Mexican Health and Aging Study to compare the association between diabetes and 5-year mortality in two independent cohorts of adults aged 60-69 in 2001 (1932-1941) and 2012 (1943-1952). The final sample included 3,694 participants in 2001 and 4,769 in 2012. Demographic variables included age, gender, education, living in an urban community, and having health insurance coverage. Self-reported health conditions included diabetes, hypertension, stroke, and respiratory disease. We used cox-proportional hazard regression models that included an interaction term for diabetes by cohort and adjusted for demographic and self-reported health characteristics. Overall, diabetes was associated with 2.56 times higher mortality (95% CI=2.18-3.00). The 2012 cohort did not have significantly different mortality risk compared to the 2001 cohort (HR=0.91, 95% CI=0.77-1.07). The association between diabetes and mortality for participants in the 2001 cohort (HR=2.52, 95% CI=1.95-3.26) was not significantly different from the 2012 cohort (HR=2.58, 95% CI=2.09-3.17). Our results indicate that diabetes continues to be a major risk factor for mortality in Mexico despite the increase in screening and treatment.

Long-term effects of blood pressure 130–139/80–89 mmHg on all-cause and cardiovascular mortality among Chinese adults with different glucose metabolism

BackgroundThis study aimed to investigate the risks of all-cause and cardiovascular mortality associated with blood pressure (BP) levels of 130–139/80–89 mmHg in Chinese adults with different glucose metabolism, during a long-term follow-up of over 20 years.MethodsA prospective population-based cohort of 2,132 adults in Shanghai was established in 2002 and followed for 21 years. The association between BP categories and mortality was assessed, and the risk was further analyzed using multiple Cox regression analysis by combining BP and blood glucose categories.ResultsThe final analysis included 2,004 participants, with 397 all-cause and 166 cardiovascular mortality. The incidence of all-cause and cardiovascular mortality per 1,000 person-years for different BP categories were as follows: BP < 130/80 mmHg (4.5 and 1.3), 130–139/80–89 mmHg (7.7 and 2.9), and ≥ 140/90 mmHg or treated groups (19.9 and 8.7), respectively. After adjusting for age, sex, and other factors, BP ≥ 140/90 mmHg was significantly associated with a higher risk of mortality across different blood glucose categories. However, using BP < 130/80 mmHg and normoglycemia as the reference, a BP of 130–139/80–89 mmHg was significantly associated with higher risks of all-cause (hazard ratio 3.30 [95% confidence interval 1.48–7.38], P < 0.01) and cardiovascular mortality (9.60 [1.93–47.7], P < 0.01) in diabetes, but not in those with normoglycemia or prediabetes.ConclusionsBP of 130–139/80–89 mmHg may lead to a significantly higher risk of all-cause and cardiovascular mortality in Chinese adults with diabetes, but not in those with normoglycemia or prediabetes. This suggests that the targeted BP for people with diabetes should be < 130–139/80–89 mmHg.

Does Sugar Control Arrest Complications in Type 2 Diabetes? Examining the Rigour in Statistical Methods and Causal Inference in Clinical Trials.

BACKGROUND: In contrast to type 1 diabetes mellitus (T1DM), in type 2 (T2DM) the success of intensive glucose normalisation in arresting diabetic complications is marginal and inconsistent across multiple clinical trials. However, glucose regulation still largely remains the main target of treatment for T2DM in clinical practice. OBJECTIVES: We examine the possible causes of inconsistency across studies, the scientific rigour behind the design, conduct and inferences of 6 large institutional clinical trials targeting glucose normalisation and following up for diabetic complications and mortality. STUDY DESIGN: We enumerate the possible flaws in the design, statistical treatment of the results and possible logical traps in making inferences. Further, we evaluate whether the flaws can mislead the conclusions. We also suggest a more sound statistical treatment of the data and interpret results of the trials together in a coherent way. RESULTS: The clinical trials for intensive glucose control suffer from a number of common problems that have not been addressed. The most important being the failure to correct for multiple outcomes. This is recognised by some reviewers but no correction is attempted. The second is the interdependence of the outcomes, owing to which statistics based on the assumption of independence can be misleading. Simulations show that the apparent inconsistency or heterogeneity between trial results can be explained by the violation of assumed independence alone. Further, the problems with placebo control, failure to recognise alternative possibilities, inability to segregate clinical significance from statistical significance and misleading reporting formats point to conformity bias and publication bias. CONCLUSIONS: We find no support for the prevalent belief that glucose normalisation has any benefit in terms of reducing the frequency of any of the complications or mortality. It is time to reconsider the glucocentric line of treatment of T2DM. Rethinking some of the fundamental beliefs about the pathophysiology of diabetic complications and facilitating novel alternative lines of research is the need of the field.

Exploring mechanisms underlying diabetes comorbidities and strategies to prevent vascular complications.

It is important to prevent not only diabetic complications but also diabetic comorbidities in diabetes care. We have elucidated multifaceted insulin action in various tissues mainly by means of model mice, and it was revealed that insulin regulates endoplasmic reticulum (ER) stress response during feeding, whereas ER stress 'response failure' contributes to the development of steatohepatitis, one of the major diabetic comorbidities. Insulin regulates gluconeogenesis not only in the liver but also in the proximal tubules of the kidney, which is also suppressed by reabsorbed glucose in the latter. In skeletal muscle, another important insulin-targeted tissue, impaired insulin/IGF-1 signaling leads not only to sarcopenia, an aging-related disease, but also to bone loss and shorter longevity. Aging is regulated by adipokines as well, and it is deemed to be accelerated by 'imbalanced adipokines' in combination with genetic background of progeria. Moreover, we reported effects of intensive multifactorial intervention on diabetic complications and mortality in patients with type 2 diabetes in a large-scale clinical trial, the J-DOIT3, followed by reports of subsequent sub-analyses of renal events and fracture events. Various approaches to elucidate the mechanisms underlying the development of diabetes and how it should be treated are expected to help us improve diabetes management.

Trends in the mortality of diabetes in Mexico from 1998 to 2022: a joinpoint regression and age-period-cohort effect analysis

ObjectiveThe purpose was to analyze age-standardized trends in diabetes mortality rates (DMR) from 1998 to 2022, stratified by sex and Mexican state, and the effects attributable to age, period, and cohort by sex. Study designJoinpoint regression and age-period-cohort effect analysis. MethodsBased on the tenth revision of the International Classification of Diseases, E11, E12, E13, and E14 codes of the death certificate, a daily record of mortality was extracted from the death certificate attributable to diabetes as the main cause. From 1998 to 2022, sexes and ages (≥20 years) were used to calculate the crude mortality rates and standardized at the national and Mexican state levels. Additionally, the age-period-cohort model was used to examine age, period, and cohort effects. ResultsFrom 1998 to 2005, the age-adjusted DMR increased by 3.6% (95% confidence interval [CI]: 2.7, 4.5) for the total population, as shown by the joinpoint regression analysis at a national level; from 2017 to 2020, it increased by 7.4% (95% CI: 0.6, 14.8). The DMR with the highest increase during the study period came mainly from states in the country's southeastern region, 2.3% to 3.7% per year. The net age and period effects showed that mortality increased with advancing age and with going time, respectively; and the net cohort effect revealed that mortality increased in more recent birth cohorts, mainly in men Rate Ratio (RR) = 2.37 (95% CI: 2.29, 2.46) vs RR = 1.13 (95% CI: 1.09, 1.17). ConclusionThe DMR increased among older age groups. The period effect showed that mortality increased over time. Furthermore, the cohort effect showed that mortality increased in more recent birth cohorts, especially among men.

Effects of inappropriate cause-of-death certification on mortality from cardiovascular disease and diabetes mellitus in Tonga

BackgroundCardiovascular disease (CVD) and diabetes mellitus are major health issues in Tonga and other Pacific countries, although mortality levels and trends are unclear. We assess the impacts of cause-of-death certification on coding of CVD and diabetes as underlying causes of death (UCoD).MethodsTongan records containing cause-of-death data (2001–2018), including medical certificates of cause-of-death (MCCD), had UCoD assigned according to International Classification of Diseases 10th revision (ICD-10) coding rules. Deaths without recorded cause were included to ascertain total mortality. Diabetes and hypertension causes were reallocated from Part 1 of the MCCD (direct cause) to Part 2 (contributory cause) if potentially fatal complications were not recorded, and an alternative UCoD was assigned. Proportional mortality by cause based on the alternative UCoD were applied to total deaths then mortality rates calculated by age and sex using census/intercensal population estimates. CVD and diabetes mortality rates for unaltered and alternative UCoD were compared using Poisson regression.ResultsOver 2001–18, in ages 35–59 years, alternative CVD mortality was higher than unaltered CVD mortality in men (p = 0.043) and women (p = 0.15); for 2010–18, alternative versus unaltered measures in men were 3.3/103 (95%CI: 3.0–3.7/103) versus 2.9/103 (95%CI: 2.6–3.2/103), and in women were 1.1/103 (95%CI: 0.9–1.3/103) versus 0.9/103 (95%CI: 0.8–1.1/103). Conversely, alternative diabetes mortality rates were significantly lower than the unaltered rates over 2001–18 in men (p < 0.0001) and women (p = 0.013); for 2010–18, these measures in men were 1.3/103 (95%CI: 1.1–1.5/103) versus 1.9/103 (95%CI: 1.6–2.2/103), and in women were 1.4/103 (95%CI: 1.2–1.7/103) versus 1.7/103 (95%CI: 1.5–2.0/103). Diabetes mortality rates increased significantly over 2001–18 in men (unaltered: p < 0.0001; alternative: p = 0.0007) and increased overall in women (unaltered: p = 0.0015; alternative: p = 0.014).ConclusionsDiabetes reporting in Part 1 of the MCCD, without potentially fatal diabetes complications, has led to over-estimation of diabetes, and under-estimation of CVD, as UCoD in Tonga. This indicates the importance of controlling various modifiable risks for atherosclerotic CVD (including stroke) including hypertension, tobacco use, and saturated fat intake, besides obesity and diabetes. Accurate certification of diabetes as a direct cause of death (Part 1) or contributory factor (Part 2) is needed to ensure that valid UCoD are assigned. Examination of multiple cause-of-death data can improve understanding of the underlying causes of premature mortality to better inform health planning.