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At least 19 recordsLinked to original sources
PubMed2026

Gut Microbiota, Lipidome, and Metabolites Mediate Immune Dysregulation in Diabetic Microvascular Disease: A Two-sample Mendelian Randomization and Mediation Analysis.

INTRODUCTION: Diabetic microvascular disease (DMiVD) involves dysregulated immune cell function, but the precise pathogenic mechanisms remain unclear. MATERIALS AND METHODS: We conducted a two-sample Mendelian randomization (MR) study using comprehensive GWAS and FinnGen summary statistics, encompassing 731 immune cell phenotypes, 473 gut microbial taxa, 91 inflammatory proteins, 179 lipid types, 1,400 plasma metabolites, 20 micronutrients, and DMiVD cases. The analysis aimed to evaluate causal associations between these variables and DMiVD. We further explored potential mediating roles of gut microbiota, plasma lipidome, and metabolites using mediation analysis, with multiple sensitivity tests confirming the robustness of our findings. RESULTS: We identified 20 immune cell phenotypes, 33 gut microbial taxa, 31 lipid types, and 83 plasma metabolites with significant causal associations with DMiVD. Mediation analysis revealed that the risk effect of CD3+ resting Tregs on diabetic nephropathy was partly mediated by phosphatidylcholine (16:0_18:2) (10.7%). Additionally, the protective effect of CX3CR1 on monocytes against DMiVD was partly mediated by Unclassified Bacilli A (35%), Species CAG-177 sp003538135 (22.6%), and triacylglycerol (52:6) (25.5%). DISCUSSION: These findings advance understanding of DMiVD pathogenesis, highlighting that modulation of key metabolic pathways and immune regulatory nodes may represent promising therapeutic strategies. Further experimental studies are needed to validate these potential causal relationships. CONCLUSION: Using causal inference approaches, this study identifies immune cell-mediated mechanisms underlying DMiVD, involving gut microbiota, plasma lipids, and metabolites. The results suggest potential intervention targets for mechanistic studies and therapeutic development.

Mendelian Randomization Analysis↗
PubMedDate not supplied

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↗
PubMed1979

The prognosis for diabetes.

Microvascular disease is the predominant manifestation of the juvenile-onset diabetic after the third decade of survival, while large vessel atheroma is the major problem in the long-term survival of the maturity-onset diabetic. From the experience of a diabetic-eye clinic, we would estimate that only about 3% of patients attending a hospital diabetic clinic would have a severe form of diabetic retinopathy which might need specialized ophthalmic photocoagulation treatment. The long-term visual prognosis for patients treated in this way remains under review. Among metabolic factors associated with vascular disease, a deficiency of HDL cholesterol may be important in the future prognosis of maturity-onset diabetes.

Arteriosclerosis↗
PubMed1977

Relationship of microvascular disease in diabetes to metabolic control.

Dogs were made alloxan-diabetic and randomly distributed into either of two prospective treatment groups. In one group it was intended that the metabolic signs of diabetes be controlled poorly, and commercial insulin was administered in doses inadequate to prevent chronic, severe hyperglycemia and glucosuria. In the other group it was intended that the metabolic disorder be well controlled, and the animals received food and commercial insulin twice daily such that the hyperglycemia and glucosuria became mild or infrequent. Experimental improvement of the carbohydrate disorder was accompanied by amelioration of hyperlipemia and other clinical signs of deficient insulin activity. By 60 months of diabetes, retinal capillary aneurysms, pericyte ghosts, obliterated vessels, and other microvascular abnormalities typical of diabetes were apparent in each animal of the poor-control group. Better control was found to reduce significantly the incidence and severity of microvascular lesions. The data suggest that the mechanism responsible for diabetic retinopathy is initiated as a result of deficient insulin activity and that the development of the microvascular complications of diabetes are preventable and may be inhibited by careful control of the metabolic disorder.

Animals↗
PubMed1978

Continuous subcutaneous insulin infusion: an approach to achieving normoglycaemia.

A study was performed to examine the feasibility of achieving long periods of near-normoglycaemia in patients with diabetes mellitus by giving a continuous subcutaneous infusion of insulin solution from a miniature, battery-driven, syringe pump. Twelve insulin-dependent diabetics had their insulin pumped through a subcutaneously implanted, fine nylon cannula; the basal infusion rate was electronically stepped up eightfold before meals. The blood glucose profile of these patients was closely monitored during the 24 hours of the subcutaneous infusion and compared with the profile on a control day, when the patients were managed with their usual subcutaneous insulin. Diet and exercise were standardised on both days. In five out of 14 studies the subcutaneous insulin infusion significantly lowered the mean blood glucose concentration without producing hypoglycaemic symptoms; in another six patients the mean blood glucose concentration was maintained. As assessed by the M value the level of control was statistically improved in six out of 14 studies by the infusion method and maintained in six other patients. To assess the effects of blood glucose control on diabetic microvascular disease it will be necessary to achieve long-term normoglycaemia in selected diabetics. The results of this preliminary study suggest that a continuous subcutaneous insulin infusion may be a means of maining physiological glucose concentrations in diabetics. Though several problems remain--for example, in determining the rate of infusion--longer-term studies with the miniature infusion pumps are now needed.

Adult↗
PubMed1979

Changes in red cell oxygen release capacity in diabetes mellitus.

Studies are summarized to indicate that diabetes is associated with a fluctuating disturbance in the oxygen release capacity of the erythrocytes. This disorder, present from the onset of the disease, is a consequence of excess hemoglobin AIc, and absolute or relative hypophosphatemia and acidosis that interfere with formation of the red cell metabolite 2,3-diphosphoglycerate. As a result frequent increases in hemoglobin--oxygen affinity are produced. Available evidence suggests that transient decreases in red cell oxygen delivery lead to dilatation of the venous part of the microcirculation associated with increased transcapillary plasma permeation. Combined with microrheologic alterations (increased red cell aggregation, increased blood viscosity, and decreased red cell deformability) these functional changes may over the years participate in the pathogenesis of the microvascular disease in diabetes.

Capillary Permeability↗
PubMed1977

Nature and nurture in the expression of diabetes mellitus and its vascular manifestations.

The prevailing concept of etiologic heterogeneity for the diabetes mellitus syndrome is one of multiple genetic factors interacting with a variety of environmental influences. Variation in expression of the disorder, particularly the need for insulin, does not correlate with known etiologic distinctions. There is much evidence for genetic heterogeneity, as well as phenotypic variation when etiology can be presumed to be identical. The vascular manifestations of diabetes include microangiopathy unique to diabetes and larger vessel disease that differs from that of normal aging only by its prematurity. There is as much evidence for heterogeneity of the vascular expression as there is for glucose intolerance. Approximately 25% of persons with insulin-dependent diabetes may never develop the microvascular disease. The pathogenesis of vascular disease in diabetes may involve a number of abnormalities of plasma, circulating cells, and vascular tissue. Were absolute control of glycemia possible, some of the contributing factors involved in vasculopathy would possibly be alleviated. In the absence of automated physiologic insulin replacement the potential deleterious effect of our current methods of treatment might be reduced by specific inhibition of excess catecholamine, growth hormone and/or glucagon responses.

Aging↗
PubMed1979

Oral glucose-tolerance tests and the diagnosis of diabetes: results of a prospective study based on the Whitehall survey.

Men who participated in the Whitehall survey and were found to be glucose intolerant have been studied 6--8 years later, together with a control group of men with normal screening blood-sugar levels. Ophthalmoscopically visible microvascular retinal disease was confined to men diagnosed as probably diabetic after the survey because their 2 h blood-sugar level (after a 50 g oral glucose load) in the survey examination or during a subsequent standard oral glucose-tolerance test was greater than or equal to 200 mg/dl (11.1 mmol/l). The lowest blood-sugar in a "diabetic" subsequently found to have retinopathy was 229 mg/dl. Men with lesser degrees of glucose intolerance, including 34 who had "worsened to diabetes", did not have visible retinovascular disease at follow-up. If diabetes implies a risk of specific microvascular complications in the medium term, then the findings in this study support proposals for the revision of diagnostic criteria based on glucose-tolerance tests.

Aged↗
PubMed1977

[Maintenance hemodialysis and renal transplantation in diabetic patients (author's transl)].

Maintenance hemodialysis and renal transplantation are increasingly used for treating diabetic patients with terminal uremia. Nowadays dialysis techniques may be considered for most of these patients, except those presenting with multiple severe disabling complications. Difficulties in control of glycaemia or of the uremic state or in the management of immunosuppressive drugs in transplanted patients do not, in themselves, constitute special problems in dialysis or transplantation. The high rate of complications and the excess mortality recorded in diabetics, compared with non-diabetic dialyzed or transplanted patients are closely related to the cardiovascular, neurological and microvascular disease that is present to various degress in all diabetic patients. Cardiac and cerebrovascular complications account for most of the deaths. Ocular and neurological status often worsen during dialysis but their stabilization usually occurs after successful transplantation. The choice between therapeutic methods in end-stage uremia must be an individual one for each patient" depending on age, medical and psychological factors and technical feasibility. Renal transplantation gives best results in patients aged less than 50 years and should be carried out early (creatinine clearance 15 - 10 ml/min.) before occurrence of the most disabling complications. If transplantation is not indicated or available, dialysis should be initiated when creatinine clearance is about 10 ml/min. Early multidisciplinary care of uremic diabetics will improve the results of maintenance hemodialysis, the problems and failures of which occur most frequently when treatment is commenced too late in patients with irreversible clinical and/or metabolic conditions.

Age Factors↗
PubMed2025

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↗
PubMed1977

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↗
PubMed1977

Diabetic microangiopathy: renal and retinal aspects.

Diabetic microangiopathy is a degenerative process specific to diabetes. Metabolic theory holds that the metabolic defect predisposes to vascular abnormalities, but other theory suggests that microangiopathy and metabolic disorders are of different origin. Metabolic and ultrastructural modifications in kidney and retina are reviewed. Human and animal studies suggest a specific organ response to fortuitous association of several factors leading to microvascular disease.

Animals↗
PubMed1976

Renin-angiotensin-aldosterone system in diabetes mellitus.

The renin-angiotensin-aldosterone system appears to function normally in uncomplicated diabetes mellitus. Alterations in this system, however, have been observed in several of the microvascular and electrolyte complications associated with this disease. Plasma renin activity (PRA) and aldosterone are decreased in diabetic with nephropathy and hypertension, in those with neuropathy including orthostatic hypotension, and in those with hypoaldosteronism. PRA is low in rats with uncontrolled, nonketotic diabetes, and pressor responsiveness to angiotension II is increased in patients with diabetic retinopathy. Potential mechanisms responsible for the decreased PRA include plasma volume expansion, hyalin destruction of the juxtaglomerular cells, defective synthesis of renin, and inadequate catecholamine stimulation of renin, and inadequant cathecholamine stimulation of renin release. In diabetic ketoacidosis, PRA and aldosterone are stimulated secondary to the associated dehydration with hypovolemia. This report reviews the current status of the function of the renin-angiotensin-aldosterone system in diabetes mellitus and proposes a possible role for the altered function of this system in the pathophysiology of several diabetic complications.

Aldosterone↗
PubMed1975

The problem of tissue oxygenation in diabetes mellitus. I. Its relation to the early functional changes in the microcirculation of diabetic subjects.

The underlying cause leading to the reversible functional changes in the microcirculation of insulin-dependent diabetic subjects early during the disease prior to any clinical signs of retinopathy and nephropathy (functional microangiopathy) is discussed. It is suggested that the initial microvascular dilation observed in diabetics is due to an autoregulatory response to relative tissue hypoxia providing an increased tissue perfusion in order to improve tissue oxygen delivery. Supporting evidence for this suggestion is derived from the findings that diabetics simultaneously may show increased tissue oxygen consumption and decreased ability of the circulating blood to release oxygen to the tissues. The latter defect is likely to be caused by two interrelated factors: 1. an increased proportion of haemoglobin A1c with high oxygen affinity, and 2. difficulties of maintaining a sufficiently high concentration of plasma inorganic phosphate in order to provide an optimal 2,3-diphosphoglycerate (2,3-DPG) content in the erythrocytes. The basal oxygen demand of diabetics may fluctuate even within a few hours dependent upon the state of metabolic control and is increased at times of poor regulation. Hence, diabetics may suffer from innumerable cellular hypoxic injuries, which during the first years of the disease are counteracted in the microcirculation by an autoregulatory response. These microvascular reactions associated with increased plasma permeation may over the years be of major importance for the development of the degenerative microangiopathy in diabetes.

Diabetes Mellitus↗
PubMed1976

Search for a biochemical basis of diabetic microangiopathy.

Diabetic microangiopathy, particularly as seen in the renal glomerulus, is characterized by morphological and biochemical alterations of the capillary basement membrane. Observations from a number of disciplines have indicated that the microvascular disease is not a separately inherited entity but a true consequence or "complication" of insulin deficiency. An evaluation of the biochemical events which could be responsible for the basement membrane lesions of diabetes indicates that the hyperglycemia or plasma somatotropin elevation of this disease alone, or in combination, may play an important role.

Animals↗
PubMedDate not supplied

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↗
PubMed2026

Adverse pregnancy outcomes and long-term cardiovascular disease risk.

Pregnancy provides a unique physiological stress test for the cardiovascular system, during which, adverse pregnancy outcomes (APOs) can unmask latent susceptibility to future disease. Common complications, including hypertensive disorders of pregnancy (HDP), gestational diabetes, and preterm birth (delivery before 37 weeks' gestation), identify women at substantially higher long-term risk of cardiovascular morbidity and mortality compared with women without a history of APOs. These excess risks likely reflect the combined effects of pre-existing cardiometabolic and genetic susceptibility, as well as the haemodynamic and metabolic stressors of pregnancy, heralding accelerated risk factor trajectories, relative impairment in endothelial and microvascular function, and early disease onset. This final Review in the Series extends the focus from cardiovascular disease during pregnancy and HDP to the long-term cardiovascular implications of APOs after delivery. We synthesise epidemiological data quantifying cardiovascular risk across major APO phenotypes and emerging evidence linking maternal APO history with cardiometabolic risk trajectories in offspring. We also delineate putative mechanistic pathways and summarise guidelines and consensus-informed recommendations for short-term and long-term follow-up after APOs. Finally, we propose practical approaches for integrating APO history into cardiovascular disease risk assessment and guideline-directed prevention across the female life course. We highlight key knowledge gaps, including uncertainty about optimal follow-up models, the limitations of current risk-stratification tools, and the absence of APO-specific prevention trials. We also outline priorities for mechanistic and implementation research. Positioning APOs as early, sex-specific indicators of cardiovascular risk offers a key window of opportunity to shift prevention upstream and improve cardiovascular health outcomes for women.

Humans↗