Early Stages Of Type 2 Diabetes Research Articles

Assessment of Risk Factors for the Development of Diabetic Retinopathy in T2D

Objective: To estimate the risk factors that contributes to the incidence of diabetic retinopathy (DR) in type 2 diabetes (T2D). Methodology: We conducted serial fundus photography in individuals at high risk of developing type 2 diabetes, including after the onset of diabetes. The ETDRS (Early Treatment Diabetic Retinopathy Study) grading system was used to evaluate the fundus photographs. Results: A total of 400 participants with a 3:3.6 male-to-female ratio were included in this study. The T2 DM patients with mean age 48.73±9.24 and 47.53±8.53 years with and without retinopathy respectively were observed, which shows that there is a non-significant difference (p=0.801). The differences in weight and BMI in T2 D participants with and without diabetic retinopathy were also not significant. The study found that the history of pregnancy, history of gestational DM, measures of HOMA-B, HOMA-IR, insulin genic inde, oral disposition inde, urine albumin to creatinine ratio, and hs-CRP were not associated with the presence of retinopathy. Association of nonglycemic risk factors in T2D. The study found that mean HbA1c during follow-up was significantly associated (P 0.0001) with the prevalence of retinopathy, The study found that retinopathy was associated with measures of higher blood pressure (systolic blood pressure, diastolic blood pressure, and presence of hypertension) and lipid profile. Conclusions: The development of DR can occur in the early stages of T2D. Hemoglobin A1c was found to be a significant risk factor for the occurrence of DR across the intact glycemic range in patients with T2D.

Metabolic and Skeletal Characterization of the KK/Ay Mouse Model-A Polygenic Mutation Model of Obese Type 2 Diabetes.

Type 2 diabetes (T2D) increases fracture incidence and fracture-related mortality rates (KK.Cg-Ay/J. The Jackson Laboratory; Available from: https://www.jax.org/strain/002468 ). While numerous mouse models for T2D exist, few effectively stimulate persistent hyperglycemia in both sexes, and even fewer are suitable for bone studies. Commonly used models like db/db and ob/ob have altered leptin pathways, confounding bone-related findings since leptin regulates bone properties (Fajardo et al. in Journal of Bone and Mineral Research 29(5): 1025-1040, 2014). The Yellow Kuo Kondo (KK/Ay) mouse, a polygenic mutation model of T2D, is able to produce a consistent diabetic state in both sexes and addresses the lack of a suitable model of T2D for bone studies. The diabetic state of KK/Ay stems from a mutation in the agouti gene, responsible for coat color in mice. This mutation induces ectopic gene expression across various tissue types, resulting in diabetic mice with yellow fur coats (Moussa and Claycombe in Obesity Research 7(5): 506-514, 1999). Male and female KK/Ay mice exhibited persistent hyperglycemia, defining them as diabetic with blood glucose (BG) levels consistently exceeding 300mg/dL. Notably, male control mice in this study were also diabetic, presenting a significant limitation. Nevertheless, male and female KK/Ay mice showed significantly elevated BG levels, HbA1c, and serum insulin concentration when compared to the non-diabetic female control mice. Early stages of T2D are characterized by hyperglycemia and hyperinsulinemia resulting from cellular insulin resistance, whereas later stages may feature hypoinsulinemia due to β-cell apoptosis (Banday et al. Avicenna Journal of Medicine 10(04): 174-188, 2020 and Klein et al. Cell Metabolism 34(1): 11-20, 2022). The observed hyperglycemia, hyperinsulinemia, and the absence of differences in β-cell mass suggest that KK/Ay mice in this studyare modeling the earlier stages of T2D. While compromised bone microarchitecture was observed in this study, older KK/Ay mice, representing more advanced stages of T2D, might exhibit more pronounced skeletal manifestations. Compared to the control group, the femora of KK/Ay mice had higher cortical area and cortical thickness, and improved trabecular properties which would typically be indicative of greater bone strength. However, KK/Ay mice displayed lower cortical tissue mineral density in both sexes and increased cortical porosity in females. Fracture instability toughness of the femora was lower in KK/Ay mice overall compared to controls. These findings indicate that decreased mechanical integrity noted in the femora of KK/Ay mice was likely due to overall bone quality being compromised.

Elucidating the sex differences in a translational mouse model of diabetic cardiomyopathy

Obesity is a major risk factor for type 2 diabetes (T2D) and related cardiovascular diseases including diabetic cardiomyopathy (DbCM), which is often asymptomatic during the early stages of T2D. Increased cardiovascular risk associated with diabetes is more prominent in women, but an understanding of the pathology of DbCM in females is lacking, as most of the reported mechanistic studies have been performed in male rodents.

Organ-Specific Metabolic Pathways Distinguish Prediabetes, Type 2 Diabetes and Normal Tissues

Defects in pancreatic islets and the progression of multi-tissue insulin resistance in combination with environmental factors are the main causes of type 2 diabetes (T2D). Mass spectrometry-based proteomics of five key-metabolic tissues on a cohort of 42 multi-organ donors provided deep coverage of the proteomes of pancreatic islets, visceral adipose tissue (VAT), liver, skeletal muscle and serum. Enrichment analysis of gene ontology (GO) terms built a tissue-specific map of the chronological order of altered biological processes across healthy controls (CTRL), pre-diabetes (PD) and T2D subjects. This unique dataset allowed us to explore alterations of entire biological pathways and individual proteins in multiple tissues. We confirmed the significant decrease of the citric acid cycle and the respiratory electron transport in VAT and muscle of T2D and we provided a thorough visual representation of the complete set of downregulated proteins. Importantly, we found widespread novel alterations in relevant biological pathways including the increase in hemostasis in pancreatic islets of PD, the increase in the complement cascade in liver and pancreatic islets of PD and the elevation in cholesterol biosynthesis in liver of T2D. Overall, our findings suggest inflammatory, immune and vascular impairments in pancreatic islets as potentially causal factors of insufficient insulin production and increased glucagon levels in the early stages of T2D. In contrast alterations in lipid metabolism and mitochondrial function in the liver and VAT/muscle, respectively, became evident later in manifest T2D. This first multi-tissue proteomic map indicates the temporal order of tissue-specific metabolic dysregulation in T2D development.

The modern paradigm of pathophysiology, prevention and treatment of heart failure in type 2 diabetes mellitus

Prevention and choice of therapeutic strategies in patient,s with type 2 diabetes (T2D) and heart failure (HF) is an urgent problem. This review presents a modern concept for HF development from early stages of T2D. Glucose-lowering and cardiac medications for the prevention and treatment of HF depending on its phenotypes were considered.

Insulin Inhibits Aβ42 Aggregation and Prevents Aβ42-Induced Membrane Disruption.

Alzheimer's disease (AD) is associated with self-assembly of amyloid β-protein (Aβ) into soluble oligomers. Of the two predominant Aβ alloforms, Aβ40 and Aβ42, the latter is particularly strongly linked to AD. Longitudinal studies revealed a correlation between AD and type 2 diabetes (T2D), characterized by abnormal insulin levels and insulin resistance. Although administration of intranasal insulin is explored as a therapy against AD, the extent to which insulin affects Aβ dynamics and activity is unclear. We here investigate the effect of insulin on Aβ42 self-assembly and characterize the capacity of insulin, Aβ42, and Aβ42 co-incubated with insulin to disrupt the integrity of biomimetic lipid vesicles. We demonstrate that quiescently incubated insulin, which does not form amyloid fibrils, over time develops membrane-disrupting capacity, which we propose to originate in misfolded insulin monomers. These hypothetically toxic misfolded monomers might contribute to the development of insulin resistance in early stages of T2D that are associated with abnormally high insulin levels. We show that in contrast to quiescent incubation, insulin incubated under agitated conditions readily forms amyloid fibrils, which protect against membrane permeation. Insulin quiescently incubated with Aβ42 attenuates both Aβ42 fibril formation and the ability of Aβ42 to disrupt membranes in a concentration-dependent manner. Our findings offer insights into interactions between insulin and Aβ42 that are relevant to understanding the molecular basis of intranasal insulin as a therapy against Aβ-induced AD pathology, thereby elucidating a plausible mechanism underlying the observed correlations between AD and T2D.

Pathological Between-Network Positive Connectivity in Early Type 2 Diabetes Patients Without Cerebral Small Vessel Diseases.

Background and PurposePrevious neuroimaging studies have demonstrated type 2 diabetes (T2D)-related brain structural and functional changes are partly associated with cognitive decline. However, less is known about the underlying mechanisms. Chronic hyperglycemia and microvascular complications are the two of most important risk factors related to cognitive decline in diabetes. Cerebral small vessel diseases (CSVDs), such as those defined by lacunar infarcts, white matter hyperintensities (WMHs) and microhemorrhages, are also associated with an increased risk of cognitive decline and dementia. In this study, we examined brain magnetic resonance imaging (MRI) changes in patients in the early stages of T2D without CSVDs to focus on glucose metabolism factors and to avoid the interference of vascular risk factors on T2D-related brain damage.MethodsT2D patients with disease durations of less than 5 years and without any signs of CSVDs (n = 34) were compared with healthy control subjects (n = 24). Whole-brain region-based functional connectivity was analyzed with network-based statistics (NBS), and brain surface morphology was examined. In addition, the Montreal Cognitive Assessment (MoCA) was conducted for all subjects.ResultsAt the whole-brain region-based functional connectivity level, thirty-three functional connectivities were changed in T2D patients relative to those in controls, mostly manifested as pathological between-network positive connectivity and located mainly between the sensory-motor network and auditory network. Some of the connectivities were positively correlated with blood glucose level, insulin resistance, and MoCA scores in the T2D group. The network-level analysis showed between-network hyperconnectivity in T2D patients, but no significant changes in within-network connectivity. In addition, there were no significant differences in MoCA scores or brain morphology measures, including cortical thickness, surface area, mean curvature, and gray/white matter volume, between the two groups.ConclusionThe findings indicate that pathological between-network positive connectivity occurs in the early stages of T2D without CSVDs. The abnormal connectivity may indicate that the original balance of mutual antagonistic/cooperative relationships between the networks is broken, which may be a neuroimaging basis for predicting cognitive decline in early T2D patients.

Phenolic linked anti-hyperglycemic bioactives of barley (Hordeum vulgare L.) cultivars as nutraceuticals targeting type 2 diabetes

Barley (Hordeum vulgare L.) is an important commercial and industrial crop rich in phenolic bioactives and dietary antioxidants and can be targeted for developing non-food nutraceuticals and functional ingredients to counteract diet-linked chronic diseases such as type 2 diabetes (T2D). In this study 13 barley cultivars were screened for phenolic-linked functionalities targeting antioxidant and anti-hyperglycemic properties using in vitro assay models. Total soluble phenolics (TSP) content, individual phenolic acid profile, and antioxidant activity of barley extracts (hot water, cold water, and 12% ethanol) were evaluated. The α-amylase and α-glucosidase inhibitory activities of barley extracts were also evaluated using in vitro assays. The TSP content of barley varied between 0.44 and 0.63mg/g gallic acid equivalent (GAE) on a dry weight basis across cultivars and extraction types, with hot water extracts having highest TSP content. Across barley cultivars, cv. Pinnacle had the highest antioxidant activity, while among extraction types ethanol extracts had highest antioxidant activity. Cold water and ethanol extracts of most barley cultivars had significantly high α-amylase inhibitory activity; however, significant differences were not observed among most cultivars. The black barley cultivar had the highest α-glucosidase inhibitory activity (34%) across all extraction types, and a dose-dependent pattern was observed in all barley cultivars. Therefore, barley cultivars with significant potential to modulate the activity of key enzymes that regulate carbohydrate metabolism were screened and identified in this in vitro study. Consequently, grains of such cultivars may be utilized for further clinical and animal studies to develop phenolic bioactive-rich non-food type nutraceuticals and bioactive functional ingredients that can be used to complement current drug design strategies to offset hyperglycemia and oxidative stress associated with early stages of T2D.

Reversal of β cell de-differentiation by a small molecule inhibitor of the TGFβ pathway.

Dysfunction or death of pancreatic β cells underlies both types of diabetes. This functional decline begins with β cell stress and de-differentiation. Current drugs for type 2 diabetes (T2D) lower blood glucose levels but they do not directly alleviate β cell stress nor prevent, let alone reverse, β cell de-differentiation. We show here that Urocortin 3 (Ucn3), a marker for mature β cells, is down-regulated in the early stages of T2D in mice and when β cells are stressed in vitro. Using an insulin expression-coupled lineage tracer, with Ucn3 as a reporter for the mature β cell state, we screen for factors that reverse β cell de-differentiation. We find that a small molecule inhibitor of TGFβ receptor I (Alk5) protects cells from the loss of key β cell transcription factors and restores a mature β cell identity even after exposure to prolonged and severe diabetes.

Mitochondrial quality control systems sustain brain mitochondrial bioenergetics in early stages of type 2 diabetes.

Mitochondria have a crucial role in the supply of energy to the brain. Mitochondrial alterations can lead to detrimental consequences on the function of brain cells and are thought to have a pivotal role in the pathogenesis of several neurologic disorders. This study was aimed to evaluate mitochondrial function, fusion-fission and biogenesis and autophagy in brain cortex of 6-month-old Goto-Kakizaki (GK) rats, an animal model of nonobese type 2 diabetes (T2D). No statistically significant alterations were observed in mitochondrial respiratory chain and oxidative phosphorylation system. A significant decrease in the protein levels of OPA1, a protein that facilitates mitochondrial fusion, was observed in brain cortex of GK rats. Furthermore, a significant decrease in the protein levels of LC3-II and a significant increase in protein levels of mTOR phosphorylated at serine residue 2448 were observed in GK rats suggesting a suppression of autophagy in diabetic brain cortex. No significant alterations were observed in the parameters related to mitochondrial biogenesis. Altogether, these results demonstrate that during the early stages of T2D, brain mitochondrial function is maintained in part due to a delicate balance between mitochondrial fusion-fission and biogenesis and autophagy. However, future studies are warranted to evaluate the role of mitochondrial quality control pathways in late stages of T2D.

Metabolomics study of type 2 diabetes using ultra-performance LC-ESI/quadrupole-TOF high-definition MS coupled with pattern recognition methods

Type 2 diabetes (T2D), called the burden of the twenty-first century, is growing with an epidemic rate. Here, we explored the differences in metabolite concentrations between T2D patients and healthy volunteers. Metabolomics represents an emerging discipline concerned with comprehensive analysis of small molecule metabolites and provides a powerful approach to discover biomarkers in biological systems. The acquired data were analyzed by ultra-performance liquid chromatography-electrospray ionization/quadrupole time-of-flight high-definition mass spectrometry coupled with pattern recognition approach [principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA)] to identify potential disease-specific biomarkers. PCA showed satisfactory clustering between patients and healthy volunteers. Biomarkers reflected the biochemical events associated with early stages of T2D which were observed in PLS-DA loading plots. These urinary differential metabolites, such as adiponectin, acylcarnitines, citric acid, kynurenic acid, 3-indoxyl sulfate, urate, and glucose, were identified involving several key metabolic pathways such as taurine and hypotaurine metabolism; cysteine and methionine metabolism; valine, leucine, and isoleucine biosynthesis metabolism, etc. Our data suggest that robust metabolomics has the potential as a noninvasive strategy to evaluate the early diagnosis of T2D patients and provides new insight into pathophysiologic mechanisms and may enhance the understanding of its cause of disease.

Insulin Therapy for Pre-Hyperglycemic Beta-Cell Endoplasmic Reticulum Crowding

Insulin therapy improves β-cell function in early stages of diabetes by mechanisms that may exceed alleviation of glucotoxicity. In advance type 2 diabetes, hyperglycemia causes β-cell damage and ultimately β-cell loss. At such an advanced stage, therapeutic modalities are often inadequate. Growing evidence indicates that in early stages of type-2 diabetes and some types of monogenic diabetes linked with malfunctioning endoplasmic-reticulum (ER), the β-cell ER fails to process sufficient proinsulin once it becomes overloaded. These changes manifest with ER distention (ER-crowding) and deficiency of secretory granules. We hypothesize that insulin therapy may improves β-cell function by alleviating ER-crowding. To support this hypothesis, we investigated pre-diabetic β-cell changes in hProC(A7)Y-CpepGFP transgenic mice that develop prolonged pre-diabetes due to proinsulin dysmaturation and ER-crowding. We attenuated the β-cell ER proinsulin synthesis with a treat-to-target insulin therapy while avoiding hypoglycemia and weight gain. Alleviation of ER-crowding resulted in temporary improvement in proinsulin maturation, insulin secretion and glucose tolerance. Our observations suggest that alleviation of pre-diabetic ER-crowding using a treat-to-target insulin therapy may improve β-cell function and may prevent further metabolic deterioration.

The role of the nurse practitioner in the diagnosis and early management of type 2 diabetes

Abstract Purpose: To review the early diagnosis and early effective treatment of type 2 diabetes and its role in reducing the risk of complications. This article discusses the diagnosis of T2D and the initial stages of disease management with oral monotherapy.Data sources: Extensive literature review of textbooks and clinical, medical, and nursing journals.Conclusions: There are clear evidence‐based recommendations for disease management in the early stages of T2D, with therapy focusing on implementation of lifestyle changes and use of pharmacologic monotherapy. A vital part of early T2D treatment is patient education, which can lay the foundation for treatment throughout the disease continuum. The lifestyle changes recommended for management of T2D can be difficult for patients to sustain, and treatment regimens are often complex.Implications for practice: Type 2 diabetes (T2D) is a progressive disease, associated with a long‐term risk of morbidity and mortality. Therefore, it is important that treatment is individualized, and that ongoing support is provided to maximize the possibility of achieving treatment goals. Current standards for T2D treatment are designed for a patient‐centered treatment approach managed by team of healthcare practitioners, in which the nurse practitioner (NP) is central.