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Identification of circulating miRNA alterations in diabetes patients excluding periodontitis effects: insights into target gene downregulation in diabetic complications.

BACKGROUND: Diabetes mellitus (DM) induces systemic complications through chronic metabolic dysregulation. Circulating exosomal microRNAs (miRNAs) are emerging as key regulators of post-transcriptional gene expression and may drive diabetes-associated pathologies. Although miRNAs have been widely studied in diabetes, the characterization of PD-independent miRNA signatures across tissues remains limited. This study aimed to identify DM-specific miRNA alterations and their contribution to systemic metabolic dysfunction independent of PD. METHODS: Exosomes were isolated from plasma samples, and small RNA sequencing was performed to identify differentially expressed miRNAs (DE-miRs) using the limma R package. Predicted target genes were identified using TargetScan and validated through bulk RNA sequencing datasets from four tissues-foot, kidney, pancreas, and retina. Differentially expressed genes (DEGs) were analyzed, followed by Gene Ontology Biological Process (GOBP) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment to elucidate diabetes-related mechanisms. RESULTS: We identified 9 upregulated and 6 downregulated DE-miRs specific to the diabetic group. TargetScan predicted 216 upregulated and 64 downregulated target genes. Functional validation revealed that these genes were enriched in pathways related to glucose metabolism, cellular stress response, and tissue repair. Notably, SREK1 and GLIPR1 were commonly detected across all four tissues, suggesting potential systemic regulators of diabetes-related complications. CONCLUSION: This study suggests that circulating exosomal miRNAs, independent of periodontitis, may function as systemic regulators in diabetes. Unlike previous studies, which did not distinguish co-morbid periodontitis, we specifically defined PD-independent miRNA signatures and validated their cross-organ regulatory effects on target genes. Our results revealed a cross-organ miRNA-mRNA regulatory network and identified common regulatory targets. These findings provide insights into both systemic and organ-specific mechanisms underlying diabetic complications and highlight the potential of miRNAs as biomarkers and therapeutic targets.

Humans

Large-scale multiethnic electronic health record resource for diabetes complications research: the North West London Diabetes Cohort (NWLDC) - cohort profile.

PURPOSE: The North West London Diabetes Cohort is established to provide systematic characterisation of a large diabetes population as a foundation for complications research and prognostic modelling. Many predictive modelling studies neglect the essential descriptive characterisation of underlying cohorts, focusing narrowly on model accuracy. This cohort profile addresses this gap by comprehensively describing the demographic composition, clinical characteristics and complication incidence patterns. The notably diverse, multiethnic population enables examination of ethnic disparities and supports future development of reliable prognostic models and evidence-based prevention strategies for diabetes complications. PARTICIPANTS: At baseline, 337 271 patients with diabetes were identified. It includes 279 067 patients with type 2 diabetes, 17 638 with type 1 diabetes, 33 590 with gestational diabetes and 6916 with unspecified diabetes. The earliest diabetes diagnosis dates to January 1932, with data updated to 27 May 2025. FINDINGS TO DATE: This cohort profile describes baseline characteristics of patients with comprehensive data collected on demographics (age, sex, Deprivation Index, ethnicity), clinical measures (glycated haemoglobin, body mass index, blood pressure, lipids and estimated glomerular filtration rate) and 14 major diabetes complications tracked longitudinally. Key findings for patients with type 2 diabetes reveal diabetic retinopathy as the most common complication (74.6 per 1000 person-years), followed by hypertension (51.0) and kidney disease (31.4). Cumulative incidence analyses using the Aalen-Johansen estimator, which accounts for mortality as a competing risk, demonstrated significant ethnic disparities, with black, Asian, mixed and other ethnic groups showing elevated risk compared with white patients. Time-varying Cox models identified strong clustering between cardiovascular and renal complications, confirming a cardiometabolic-renal syndrome. Mental health conditions (depression and anxiety) were prevalent throughout the disease timeline, occurring both before and after diabetes diagnosis. FUTURE PLANS: This cohort will be used as a platform for developing and validating prognostic models for diabetes complications, enabling risk stratification and targeted interventions. Future work will incorporate medication data to refine diabetes type classification, examine the effectiveness of antidiabetic medications in preventing different complications and address demographic differences in prognostic model performance and prediction accuracy. To better characterise lifestyle, further interrogation of electronic health record data will examine recording of advice given, including dietary advice, referral to weight management schemes and presence of alcohol consumption codes.

Humans

Rhegmatogenous retinal detachment complicating diabetic retinopathy.

Retinal detachment complicating proliferative diabetic retinopathy is being recognized with increasing frequency. Although one type of detachment is tractional and requires vitrectomy for hopeful repair, the other variety of detachment is rhegmatogenous. The rhegmatogenous form of retinal detachment does not generally require the radical surgical approach of vitrectomy. However, because of the unusual nature of the retinal detachment , a standard encircling scleral buckling procedure does not suffice to correct the problem. The unusual characteristics of this form of retinal detachment are discussed, and the criteria for types of surgical repair are considered. A modification of scleral buckling procedure which has been successful in anatomically reattaching most rhegmatogenous retinal detachments is described. The complications resulting from surgery are reviewed along with methods to avoid complications.

Diabetic Retinopathy

[Hyperglycemia and diabetic complications].

Are long-term complications secondary to diabetes or do they appear independently? This question has an important bearing, particularly for the physician and the patient who must achieve optimum control of hyperglycemia. Over the last 10 years, many epidemiological and biochemical studies have shown close links between hyperglycemia and the wide range of factors involved in the development of long-term complications.

Arteriosclerosis

Aldose reductase in diabetic complications of the eye.

Aldose reductase (AR) appears to initiate the cataractous process in galactosemic and diabetic animals. Sugars in excess are converted to polyols by lens AR. In sugar cataracts, polyols accumulate to levels substantial enough to cause a hypertonicity leading to lens fiber swelling. All other changes appear secondary to polyol accumulation and lens swelling. The development of sugar cataracts can be duplicated in organ culture. In culture, the various changes that occur were minimized or did not occur when inhibitors of AR were included in the medium. Moreover, AR inhibitors were shown to effectively delay the onset of sugar cataract development in animals. A defect in the corneal epithelium of diabetics became apparent in vitrectomy. One manifestation of this problem was the delay in the reepithelialization of denuded corneas. In examining this problem experimentally, the epithelium was removed from the corneas of diabetic and normal rats. The regeneration of epithelium in corneas of diabetic rats required a longer period than in the normal. The possibility that AR, active in the epithelium, was involved in this phenomenon was investigated. The corneal epithelium was removed from both eyes of a diabetic rat. One eye was treated topically with the AR inhibitor CP-45,634 while the other served as control. The eye treated with CP-45,635 regenerated epithelium much more quickly than the untreated eye. Other AR inhibitors had similar beneficial effects.

Aldehyde Reductase

Lactic acidosis complicating diabetic ketosis in a patient with hyperthyroidism.

The present report describes a patient with insulin-dependent diabetes who developed simultaneously lactic acidosis and ketoacidosis following insulin deprivation. Administration of insulin at low doses rapidly corrected both ketosis and lactic acidosis. There had been neither circulatory collapse, nor phenformin intake, and hepatic function was normal. The development of lactic acidosis in this case was possibly precipitated by hyperthyroidism. A review of the literature indicates that lactic acidosis is a very rare complication of diabetic ketosis per se.

Acidosis

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&#xa0;years or older with type 2 diabetes. METHODS: We conducted a prospective, randomized, open-label, single-center trial enrolling independently ambulatory adults aged&#xa0;&#x2265;&#xa0;80&#xa0;years with type 2 diabetes. Participants were assigned (1:1) to an intensive glycemic target (HbA1c&#xa0;<&#xa0;7&#xa0;%) or a conservative target (HbA1c&#xa0;<&#xa0;9&#xa0;%) and followed for 5&#xa0;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&#xa0;=&#xa0;102) or conservative (n&#xa0;=&#xa0;104) treatment. At 5&#xa0;years, mean HbA1c was lower in the intensive group than in the conservative group (7&#xb7;42&#xa0;% vs 8&#xb7;21&#xa0;%; p&#xa0;=&#xa0;0&#xb7;005). Intensive therapy did not reduce microvascular events (hazard ratio [HR] 1&#xb7;24, 95&#xa0;% CI 0&#xb7;76-2&#xb7;04) or macrovascular events (HR 1&#xb7;02, 0&#xb7;36-2&#xb7;92). Competing risk analyses showed no reduction in cumulative incidence of vascular outcomes (subdistribution HR approximately 1&#xb7;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&#xa0;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

[Acceptance of amino acids by transfer RNA in the liver of rabbits in experimental diabetes complicated by glucocorticoid administration].

Alloxan diabetic rabbits were injected with hydrocortisone acetate (1 mg/kg) daily for one week. This led to a more pronounced decrease of acception of 14C-lysine, 14C-alanine, and 14C-leucine by tRNAs as compared to the diabetic status. Diminution of formation of aminoacyl-tRNA in the liver of diabetic animals was the result not only of insulin deficiency, but also of the negative action of glucocorticoids.

Amino Acids

[Orthostatic hypotension in complicated diabetes mellitus: study of the renin-angiotensin-aldosterone system (author's transl)].

Plasma renin activity (P.R.A.) and plasma aldosterone (P.A.) were studied basally and after various stimuli in eight diabetic subjects with orthostatic hypotension and autonomic neuropathy. Five of them had chronic renal failure and proteinuria. On a diet containing 100 mEq Na/24 H, mean P.R.A. was 0,80 +/- 0,32 ng/ml/h in the supine position and 0,95 +/- 0,43 ng/ml/h in the upright position (N.S.); mean P.A. was 111 +/- 77 pg/ml in the supine position and 234 pg/ml in the upright position (p less than 0,01). On a diet containing 10 mEq Na/24 H, mean P.R.A. was 1,54 +/- 0,76 ng/ml/h in the supine position and 2,44 +/- 1,53 ng/ml/h in the upright position (N.S.). There was little stimulation of P. R. A. by low sodium intakes. After furosemide (n = 6), epinephrine + norepinephrine (n = 4) or diazoxide (n = 2), there was no stimulation of P.R.A. and P.A. Thus in diabetic patients with orthostatic hypotension and autonomic neuropathy basal values of P.R.A. and P.A. are in the normal range but there is dysregulation of renin-angiotensin-aldosterone system.

Adult