Proceedings of the Kroc Foundation International Conference on Epidemiology of Diabetes and its Macrovascular Complication.
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Diabetic Angiopathies↗
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Epidemiology of diabetes and its macrovascular complications.
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Diabetes Complications↗
Integrative oral and gut microbiome profiling highlights microbial correlates of complications in type 1 diabetes: a cross-sectional analysis.
BACKGROUND/OBJECTIVE: Chronic vascular complications are the primary threat in long-standing type 1 diabetes (T1D) patients. We examined the associations between oral-gut microbiome dysbiosis and these complications, offering novel insights into therapeutic strategies and underlying mechanisms. METHODS: This cross-sectional study enrolled 75 T1D participants (disease duration ≥ 10 years) and 43 healthy controls who underwent comprehensive clinical assessment, including blood glucose, lipid profile, and complication-related examinations. Fecal and oral rinse samples were collected for shotgun metagenomic sequencing. T1D participants were stratified by the presence of microvascular (retinopathy, nephropathy, or neuropathy) or macrovascular complications separately. Microbial differences across groups were assessed. RESULTS: Significant differences in oral and gut microbiota compositions were observed between T1D participants with and without complications (both microvascular and macrovascular). A core set of 26 gut and 8 oral microbial species was specifically associated with vascular complications. Butyrate-producing gut bacteria (Blautia wexlerae, Anaerobutyricum hallii, Roseburia inulinivorans, A. soehngenii) and specific oral Neisseria species were enriched in T1D without complications individuals, suggesting protective effects against complications. Mediation analysis indicated associations consistent with partial mediation between certain microbial species and the relationships of glycemic control or insulin resistance (HbA1c, glucose risk index, estimated glucose disposal rate) with complication risk. Moreover, potential oral-gut microbiome interconnections were implicated in complication development. Finally, classification models integrating both oral and gut microbial features significantly outperformed models based on either site alone in distinguishing T1D patients with complications. CONCLUSIONS: Distinct oral and gut microbiome features are associated with chronic vascular complications in T1D. These findings highlight the potential of microbiome-targeted strategies for understanding and preventing T1D-related complications.
Humans↗
Diabetes mellitus and its vascular complications in Japanese migrants on the Island of Hawaii.
Japanese migrants and their offspring on the island of Hawaii and Japanese living in Hiroshima were examined for diabetes mellitus and its vascular complications. the same methods and investigators were used in both locations. Death certificates of Japanese and Caucasians dying on the island during the past 26 yr were analyzed. Diabetes, defined as a venous serum glucose concentration of at least 200 mg/dl 2 h after a 50-g oral glucose load, was significantly more common in the Hawaiian Japanese than in the Hiroshima Japanese subjects. This suggests that diabetes is more prevalent in Japanese in Hawaii than in Japan, although lack of knowledge about the total population of Japanese migrants in Hawaii makes this generalization uncertain. The proportion of deaths attributed to diabetes was much higher in Japanese migrants and their offspring in Hawaii than in Japan. During the 1950s, the proportional death rate from diabetes was about half as large in Japanese Hawaiians as in Caucasian Hawaiians, but it increased to become 1.6 times the Caucasian rate during the 1970s. A nutritional study revealed that the total caloric intake was similar in Japanese in Hawaii and Hiroshima, although the estimated level of physical activity was less in the Hawaiian subjects. Consumption of animal fat and simple carbohydrates (sucrose and fructose) were at least twice as high in Hawaiian as in Hiroshima Japanese. Conversely, Hiroshima Japanese consumed about twice the amount of complex carbohydrate as the Hawaiian Japanese. These observations support the hypothesis that a high fat, high simple carbohydrate, low complex carbohydrate diet and/or reduced levels of physical activity increase risk of diabetes. The proportion of deaths attributed to ischemic heart disease was higher in both diabetic and nondiabetic Japanese Hawaiians than in diabetic subjects in Japan. The rates were similar for Japanese and Caucasians in Hawaii. There was no evidence of an environmental influence on the development of microangiopathy (retinopathy) in diabetes, as the prevalence of diabetic retinopathy (stratified for diabetes duration) was similar in Japanese subjects in Hawaii and in Japan, and it was similar to previous reports from England. On the other hand, diabetes alone did not appear to account for the greater prevalence of macroangiopathy in Hawaiian Japanese than in Hiroshima. Thus environmental factors, possibly including diet, appear to be involved in the development of macrovascular complications of diabetes.
Adult↗
Epidemiology of diabetes and its macrovascular manifestations in Pacific populations: the medical effects of social progress.
Worldwide diabetes epidemiology studies have shown quite marked differences in diabetes prevalence rates between ethnic groups. This pattern holds true in the Pacific region and provides unique opportunities for comparative studies. Diabetes is rare in Melanesians, and also in Polynesians, Micronesians, and Australian Aboriginals who retain their traditional life-style. High prevalence rates of insulin-independent diabetes have been demonstrated in Polynesians, Micronesians, and Australian aboriginals who have adopted a Western life-style. Along with the Pima Indians, the Micronesian population of Nauru have the highest diabetes prevalence yet reported--40% of people aged 20 yr and over. As diabetes is rare in traditional living Polynesians and Micronesians, yet high in westernized populations of these ethnic groups, it appears these people may have a "diabetic genotype" that is unmasked by the change in life-style. Obesity, a high caloric Western diet, and reduced physical activity may be the major precipitating factors. Bimodality of glucose tolerance distributions has been demonstrated in both westernized Polynesians and Micronesians. The frequency distributions of both fasting and 2-h postload glucose levels allow separation of these populations into normal and hyperglycemic groups. The optimal cut-off levels between the two groups were a fasting plasma glucose congruent to 140 mg/dl and a 2-h level of congruent 20 mg/dl. These findings provide a valid basis for the diagnosis of diabetes mellitus to be based on the above levels. Only sparse information exists on the prevalence of microvascular and macrovascular complications of diabetes in these populations. However, there is clear evidence that they are occurring and they are similar in nature to the complications seen in Caucasian diabetic patients. Coronary artery disease is not yet a major problem in Pacific Islanders although most of the major risk factors are not present in urbanized communities. However, with increasing westernization, and given more time for the pathologic process of atheroma to develop, it can be expected that coronary artery disease will become a major cause of morbidity and mortality in Polynesians, Micronesians, and the Australian aboriginal.
Adult↗
Risk factors other than hyperglycemia in diabetic macrovascular disease.
A five-year prospective follow-up study was done on 10,000 adult males in Israel. The end-points of diabetes mellitus--clinical and unrecognized myocardial infarction, angina pectoris, sudden death, and hypertension--were examined. The incidence rates rise with age and vary significantly by areas of birth, with the Middle Eastern and North African subjects having the highest incidence of diabetes but the lowest cardiovascular rates. A developmental medical model based on a historical-societal perspective is proposed to explain these findings. The major factors found on multivariate analysis in the development of diabetes mellitus are compared with those of the other cardiovascular end-points mentioned above. The similarities and differences between these risk factors are discussed, and I conclude that the prevention or alleviation of diabetic macrovascular disease needs a multifactorial approach against the major risk factors of the macrovascular complications as well as those related to diabetes, in the individual, family, and community.
Adult↗
Longitudinal variability of lipoprotein(a) in youth-onset type 1 diabetes: implications for cardiovascular risk stratification.
BACKGROUND: Lipoprotein(a) [Lp(a)] is a genetically determined and independent cardiovascular risk factor, traditionally considered stable across the lifespan, supporting a single lifetime measurement strategy. However, its longitudinal behaviour during childhood and adolescence remains poorly characterised, particularly in individuals with type 1 diabetes who face a markedly increased lifetime risk of coronary artery disease. We therefore aimed to characterise intra- and inter-individual trajectories of Lp(a) in a paediatric type 1 diabetes cohort and to assess the implications of Lp(a) variability for cardiovascular risk classification. METHODS: We conducted a retrospective single-centre cohort study of children and adolescents with type 1 diabetes attending Geneva University Hospitals between 2012 and 2023. Annual fasting Lp(a) concentrations were analysed longitudinally. Variability was assessed in participants with ≥ 2 measurements. Clinically relevant thresholds were used to evaluate cardiovascular risk reclassification. Paired Wilcoxon tests, Pearson and Kendall correlations, and Holm-adjusted p-values (P < 0.05) were applied. Analyses were conducted in R. RESULTS: A total of 286 participants contributed 1403 Lp(a) measurements, with observation periods varying across individuals (median 6.2 years, IQR 2.9-9.6) and between 1 and 13 measurements per participant. At baseline, 26% had elevated Lp(a) (≥ 300 mg/l). Among participants with serial measurements, 32% showed intraindividual fluctuations exceeding 50% of their individual maximum value. Reclassification across the 300 mg/l cardiovascular risk threshold occurred in 11.9% of participants. Lp(a) concentrations peaked between ages 10 and 13 years and declined thereafter. Modest seasonal variation was observed, with higher concentrations in autumn and winter (P < 0.05). CONCLUSIONS: In youth with type 1 diabetes, Lp(a) is not as stable as previously assumed, exhibiting clinically relevant variability over time. These findings challenge the current paradigm of a single lifetime Lp(a) measurement and suggest that repeated assessment, particularly during adolescence, may improve early cardiovascular risk stratification.
Humans↗
Targeted proteomics of extreme vascular phenotypes in type 1 diabetes: the ESCAPER study.
Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in Type 1 Diabetes (T1D), but a subset of individuals remains free from macrovascular or renal complications despite decades of hyperglycaemia and a significant risk factor burden. We used a targeted proteomic approach (Olink Cardiovascular panel III, targeting 92 proteins) to characterize the proteomic profile of cardiovascular resilience in T1D by comparing 92 patients with long-standing T1D (age 59.8 [53.2, 69.1], duration 40.0 [35.0, 45.2] years) free from macrovascular complications or nephropathy against a reference group of 57 T1D patients with accelerated vascular pathology (age 42.0 [32.0, 56.0], duration 22.0 [18.0, 27.0] years), proliferative retinopathy and/or nephropathy in relation to diabetes duration, termed Rapid Progressors (RP). Twenty proteins differed significantly between RP and Escapers (False Discovery Rate [FDR] < 0.05) after adjustment for age, sex, HbA1c, and eGFR: Caspase-3 was significantly higher in RP (Adjusted difference: + 2.12 Normalized Protein eXpression [NPX], p < 0.001). Proteins associated with platelet activation and leukocyte adhesion with increased levels in RP included Junctional Adhesion Molecule A (+ 1.40 NPX), Glycoprotein VI (GP6: + 1.29 NPX), and P-Selectin (+ 0.82 NPX) (all p < 0.001). PECAM-1 (+ 0.55 NPX) and TNFRSF14 (+ 0.43 NPX), were also elevated. RP also showed higher levels of metabolic and tissue-remodelling proteins; Transferrin Receptor (+ 0.53 NPX) and Fatty Acid Binding Protein 4 (+ 0.52 NPX), as well as higher Bleomycin Hydrolase, Trefoil Factor 3, GDF-15, U-PAR, and Cystatin B. Conversely, von Willebrand Factor (vWF) levels (- 1.35 NPX, p < 0.001) and Paraoxonase 3 (PON3) was lower in RP (- 0.34 NPX, p = 0.003). In conclusion, escaping complications in long-term T1D appears to be associated with active molecular mechanisms. Progression is marked by apoptosis (Caspase-3), fibrosis (CHI3L1) and platelet activation (GP6), whereas resilience is associated with a distinct signature involving higher vWF and PON3. These findings highlight a profound biological divergence between extreme T1D phenotypes and provide a foundation for further research into vascular resilience.
Humans↗
Genetic predisposition and mediating pathways in ischemic stroke-induced cardiac arrhythmias: a genome-wide analysis.
INTRODUCTION: The clinical presentation of stroke-heart syndrome (SHS) underscores the interplay between the central nervous system and the cardiovascular system. While cardiac arrhythmia is the prevalent form of cardiac injury in SHS patients, the causal link between ischemic stroke and cardiac arrhythmia is still unclear. METHODS: Mendelian randomization analyses and genome-wide association studies data were used to investigate the causal role of ischemic stroke on cardiac complications. Mediation and colocalization analyses were used to identify potential pathways and shared genetic variants. Single nucleotide polymorphisms (SNPs) associated with arrhythmias and ischemic stroke were used for Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Gene expression omnibus (GEO) database from atrial fibrillation patients were used for validation. RESULTS: Mendelian randomization analyses showed a strong correlation between arrhythmias, including ventricular tachyarrhythmias and atrial fibrillation, with ischemic stroke. Diabetic microvascular (nephropathy, retinopathy) and macrovascular (cardiomyopathy, peripheral arterial disease) complications significantly mediated the effect of ischemic stroke on cardiac arrhythmias and atrial fibrillation, explaining 28.69 % and 20.48 % of the indirect effect, respectively. Colocalization analyses identified a shared causal variant in the Phosphodiesterase 3A (PDE3A) gene (rs11045239), providing genetic evidence for a shared pathogenic pathway between ischemic stroke and cardiac arrhythmias. Moreover, KEGG pathway enrichment analyses identified a role of the cyclic adenosine monophosphate (cAMP) signaling pathway in both ischemic stroke and arrhythmias. Validation using the GEO database confirmed a significant upregulation of the PDE3A gene expression in atrial fibrillation patients. CONCLUSION: This study demonstrated a causal link between ischemic stroke and cardiac arrhythmias, with diabetic complications as one mediating factor. The identification of a shared causal variant in the PDE3A gene and the role of the cAMP signaling pathway have the potential to improve prediction and management of SHS patients.
Humans↗
Prevalence of major vascular complications at the initial visit among Japanese diabetic patients.
The frequencies of retinopathy, proteinuria, hypertension, and electrocardiographic (ECG) abnormalities in 2025 diabetic subjects new to our clinic in Tokyo were analyzed in relation to status at initial visit with respect to age, estimated duration of diabetes, and fasting blood glucose. Frequency and severity of retinopathy increased markedly with duration of diabetes. A relationship was found between retinopathy at first visit and level of blood glucose at that time. Proteinuria also clearly increased with duration; its frequency was generally higher in older age groups. Frequency of hypertension increased with age up to 60 yr, but there was no association between prevalence of hypertension and duration of diabetes. ECG abnormalities also increased with age, although serious abnormalities were rare even in older subjects. Hypertension and ECG abnormalities were not more common in those with higher initial blood glucose values, and the frequencies of these aberrations did not increase with the duration of diabetes. ECG abnormalities were more common among hypertensives, especially in younger age groups. Despite the clear effect of degree and duration of hyperglycemia on microvascular complications, there was no evidence of a direct effect of hyperglycemia on macrovascular abnormalities in this study.
Adult↗
Intensive glycemic control in adults aged 80 years and older: A randomized trial evaluating diabetes complications and competing mortality.
AIMS: To evaluate whether intensive glycemic control reduces microvascular or macrovascular events compared with conservative glycemic targets in independently ambulatory adults aged 80 years or older with type 2 diabetes. METHODS: We conducted a prospective, randomized, open-label, single-center trial enrolling independently ambulatory adults aged ≥ 80 years with type 2 diabetes. Participants were assigned (1:1) to an intensive glycemic target (HbA1c < 7 %) or a conservative target (HbA1c < 9 %) and followed for 5 years. Primary outcomes were composite microvascular and macrovascular events. Analyses were done by intention to treat. Cause-specific Cox models and Fine-Gray subdistribution hazard models were used to account for all-cause mortality as a competing event. This trial is registered with ClinicalTrials.gov, NCT00850798. FINDINGS: 206 participants were randomly assigned to intensive (n = 102) or conservative (n = 104) treatment. At 5 years, mean HbA1c was lower in the intensive group than in the conservative group (7·42 % vs 8·21 %; p = 0·005). Intensive therapy did not reduce microvascular events (hazard ratio [HR] 1·24, 95 % CI 0·76-2·04) or macrovascular events (HR 1·02, 0·36-2·92). Competing risk analyses showed no reduction in cumulative incidence of vascular outcomes (subdistribution HR approximately 1·0 for both). The cumulative incidence of death exceeded that of vascular events, indicating that many participants died before potential glycemic benefits could be realized. Severe hypoglycemia requiring hospitalization was more frequent with intensive therapy (7 vs 1 event). INTERPRETATION: In adults aged 80 years or older with type 2 diabetes, intensive glycaemic control improved glycaemic levels but did not reduce vascular events and increased the risk of severe hypoglycaemia. High competing mortality substantially limits the potential long-term benefit of intensive treatment, supporting conservative and individualized glycemic targets in very old adults. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00850798.
Aged, 80 and over↗
Lipids and diabetes: the case for treatment of macrovascular disease.
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Arteriosclerosis↗
Epidemiologic methods in diabetic macrovascular disease.
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Cardiovascular Diseases↗
Pregnancy in diabetes complicated by vascular disease.
Over 50 years of experience with pregnancy in diabetic women is reviewed. In particular, the maternal and fetal survival in mothers with either microvascular or macrovascular disease is considered. This includes White classes E, F, R, RF, H, and T. In this group of patients with vascular disease, maternal survival during pregnancy is virtually 100 per cent with the exception of class H (ischemic heart disease). Fetal survival has steadily improved throughout the time period examined, but is still considerably below that of pregnancies occurring in women without vascular disease. Long-term maternal survival is adversely affected by the first decade after delivery.
Boston↗
The WHO multinational study of vascular disease in diabetes: 3. Microvascular disease.
A preliminary comparison and analysis of microvascular disease was performed in 14 stratified samples of diabetic subjects. Microvascular disease was assessed by estimating visual disabilities, by standardized examination of the optic fundus by direct ophthalmoscopy, by estimating proteinuria, and by measuring the serum creatinine concentration. Visual impairment by questionnaire positive varied considerably between centers, probably due to cultural differences in interpretation of the questions. Physician-assessed visual disability also yielded considerable differences in frequency; however, the frequency differences were unrelated to those observed for macrovascular disease. Retinopathy--the sum of all components--was related to duration of diabetes in each participating center. The apparent frequency of proteinuria varied considerably between centers. In general, the frequency of retinopathy was related to the level of systolic blood pressure, but there was no systematic association with cigarette smoking.
Diabetes Complications↗
The WHO multinational study of vascular disease in diabetes: 2. Macrovascular disease prevalence.
14 national groups have collaborated under WHO auspices to select, from local defined populations of individuals with clinical diabetes, groups of approximately 500 within the age range 35--55 yr stratified by age, sex, and known duration of diabetes. In each center, the selected patients were submitted to a standardized study protocol, which included systematic inquiry (WHO questionnaire) for the presence of symptoms of angina pectoris, history of myocardial infarction, presence of intermittent claudication, and cigarette smoking history. Examination included standard biometry, blood pressure measurement, 12-lead (centrally Minnesota coded) electrocardiography, and central laboratory measurement of serum cholesterol and creatine. Ophthalmoscopic and urinary examinations were also included. The prevalence of arterial disease symptoms and electrocardiographic abnormalities show very large variation between countries, the lowest rates generally being found in the Oriental samples and the highest in the European. "Risk factors" for arterial disease (blood pressure, serum cholesterol, and cigarette smoking) also vary widely between diabetic groups. Although data are not yet complete, these differences appear unlikely to explain the variation in the atherosclerotic morbidity observed. Diabetic women were at least as vulnerable to arterial disease as diabetic men. A high prevalence of nonspecific abnormalities of the repolarization phase of the ECG was found, even in groups where ischemic abnormalities were rare. The origin of these is uncertain; they may represent variable local changes or possibly diabetic cardiomyopathy. This preliminary report confirms and quantifies previous indications that the impact of atherosclerotic disease on persons with diabetes varies considerably between national groups, in broad terms, running parallel with the variations in prevalence in the populations in general and suggesting that cultural and/or ethnic factors are more important determinants of atherosclerosis in diabetic individuals than is the diabetic state per se.
Adult↗