Abstract #236: Sudden Rapid Progression to Insulin Dependence Post Treatment with Antipd1 Monoclonal Antibodies in Pre-existing Type 2 Diabetes

Abstract Background Type 2 diabetes in obese (≥ 25 and ≥ 30 kg/m2) patients is the foremost cause of cardiovascular complications like stroke, osteoarthritis, cancers (endometrial, breast, ovarian, liver, kidney, colon, and prostate), and vascular complications like diabetic neuropathy, diabetic and retinopathy, and diabetic nephropathy. It is recognized as a global burden disorder with high prevalence in middle-income nations which might lead to a double burden on health care professionals. Hence, this review emphasizes on understanding the complexity and vital signaling tracts involved in diabetic complications for effective treatment. Main body Type 2 diabetes in overweight patients induces the creation of specific ROS that further leads to changes in cellular proliferation, hypothalamus, and fringe. The resistin, TLR4, and NF-κB signalings are mainly involved in the progression of central and fringe changes such as insulin resistance and inflammation in diabetic patients. The overexpression of these signals might lead to the rapid progression of diabetic vascular complications induced by the release of proinflammatory cytokines, chemokines, interleukins, and cyclooxygenase-mediated chemicals. Until now, there has been no curative treatment for diabetes. Therefore, to effectively treat complications of type 2 diabetes, the researchers need to concentrate on the molecular mechanisms and important signaling tracts involved. Conclusion In this review, we suggested the molecular mechanism of STZ-HFD induced type 2 diabetes and the vital roles of resistin, TLR4, and NF-κB signalings in central, fringe changes, and development diabetic complications for its effective treatment. Graphical abstract

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Kidney Biopsy in Type 2 Diabetes: A Multicenter Cross-Sectional Study

American Journal of Nephrology ◽

10.1159/000514259 ◽

2021 ◽

pp. 1-10

Author(s):

Jonathan M. Chemouny ◽

Mickaël Bobot ◽

Aurélie Sannier ◽

Valentin Maisons ◽

Noémie Jourde-Chiche ◽

...

Keyword(s):

Type 2 Diabetes ◽

Total Population ◽

Cross Sectional Study ◽

Rapid Progression ◽

Hypertensive Nephropathy ◽

Cross Sectional ◽

Recent Onset ◽

Atypical Features ◽

Retinal Examination

Introduction: Kidney biopsies (KBs) are performed in patients with type 2 diabetes (T2D) to diagnose non-diabetic or hypertensive kidney disease (NDHKD) potentially requiring specific management compared to diabetic and or hypertensive nephropathy (absence of NDHKD). Indications for KB are based on the presence of atypical features compared to the typical course of diabetic nephropathy. In this study, we assessed the association of different patterns of atypical features, or KB indications, with NDHKD. Methods: Native KBs performed in patients with T2D were analyzed. Data were collected from the patients’ records. KB indications were determined according to the presence of different atypical features considered sequentially: (1) presence of any feature suggesting NDHKD which is not among the following ones, (2) recent onset of nephrotic syndrome, (3) low or rapidly declining estimated glomerular filtration rate (eGFR), (4) rapid increase in proteinuria, (5) short duration of diabetes, (6) presence of hematuria, or (7) normal retinal examination. Results: Among the 463 KBs analyzed, NDHKD was diagnosed in 40% of the total population and 54, 40, 24, and 7% of the KBs performed for indications 1–4 respectively. Conversely, no patient who underwent KB for indications 5–7 displayed NDHKD. Logistic regression analyses identified eGFRCKD-EPI >15 mL/min/1.73 m2, urinary protein-to-Cr ratio <0.3 g/mmol, hematuria, HbA1c <7%, and diabetes duration <5 years as predictors of NDHKD, independently from the indication group. Conclusion: NDHKD is frequent in T2D. Despite the association of hematuria with NDHKD, our results suggest that presence of hematuria and absence of DR are insufficient to indicate KB in the absence of concurrent atypical features. Conversely, rapid progression of proteinuria and rapid deterioration of eGFR are major signals of NDHKD.

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Secreted modular calcium-binding protein 1 binds and activates thrombin to account for platelet hyperreactivity in diabetes

Blood ◽

10.1182/blood.2020009405 ◽

2021 ◽

Vol 137 (12) ◽

pp. 1641-1651

Author(s):

Fredy Delgado Lagos ◽

Amro Elgheznawy ◽

Anastasia Kyselova ◽

Dagmar Meyer zu Heringdorf ◽

Corina Ratiu ◽

...

Keyword(s):

Type 2 Diabetes ◽

Monoclonal Antibodies ◽

Platelet Function ◽

Calcium Binding ◽

Transforming Growth Factor ◽

Binding Protein ◽

Calcium Binding Protein ◽

Matricellular Protein

Abstract Secreted modular calcium-binding protein 1 (SMOC1) is an osteonectin/SPARC-related matricellular protein, whose expression is regulated by microRNA-223 (miR-223). Given that platelets are rich in miR-223, this study investigated the expression of SMOC1 and its contribution to platelet function. Human and murine platelets expressed SMOC1, whereas platelets from SMOC1+/− mice did not present detectable mature SMOC1 protein. Platelets from SMOC1+/− mice demonstrated attenuated responsiveness to thrombin (platelet neutrophil aggregate formation, aggregation, clot formation, Ca2+ increase, and β3 integrin phosphorylation), whereas responses to other platelet agonists were unaffected. SMOC1 has been implicated in transforming growth factor-β signaling, but no link to this pathway was detected in platelets. Rather, the SMOC1 Kazal domain directly bound thrombin to potentiate its activity in vitro, as well as its actions on isolated platelets. The latter effects were prevented by monoclonal antibodies against SMOC1. Platelets from miR-223–deficient mice expressed high levels of SMOC1 and exhibited hyperreactivity to thrombin that was also reversed by preincubation with monoclonal antibodies against SMOC1. Similarly, SMOC1 levels were markedly upregulated in platelets from individuals with type 2 diabetes, and the SMOC1 antibody abrogated platelet hyperresponsiveness to thrombin. Taken together, we have identified SMOC1 as a novel thrombin-activating protein that makes a significant contribution to the pathophysiological changes in platelet function associated with type 2 diabetes. Thus, strategies that target SMOC1 or its interaction with thrombin may be attractive therapeutic approaches to normalize platelet function in diabetes.

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Pathophysiology-based subphenotyping of individuals at elevated risk for type 2 diabetes

10.1101/2020.10.12.20210062 ◽

2020 ◽

Author(s):

Robert Wagner ◽

Martin Heni ◽

Adam G. Tabak ◽

Jürgen Machann ◽

Fritz Schick ◽

...

Keyword(s):

Type 2 Diabetes ◽

Fat Distribution ◽

Elevated Risk ◽

Liver Fat ◽

Oral Glucose ◽

Rapid Progression ◽

Increased Risk ◽

Glucose Tolerance Tests ◽

Definition Of

AbstractThe state of intermediate hyperglycemia is indicative of elevated risk of developing type 2 diabetes1. However, the current definition of prediabetes neither reflects subphenotypes of pathophysiology of type 2 diabetes nor is it predictive of future metabolic trajectories. We used partitioning on variables derived from oral glucose tolerance tests, MRI measured body fat distribution, liver fat content, and genetic risk in a cohort of extensively phenotyped individuals who are at increased risk for type 2 diabetes2,3 to identify six distinct clusters of subphenotypes. Three of the identified subphenotypes have increased glycemia (clusters 3, 5 and 6), but only individuals in clusters 5 and 3 have immanent diabetes risks. By contrast, those in cluster 6 have moderate risk of type 2 diabetes, but an increased risk of kidney disease and all-cause mortality. Findings were replicated in an independent cohort using simple anthropomorphic and glycemic constructs4. This proof-of-concept study demonstrates that pathophysiological heterogeneity exists before diagnosis of type 2 diabetes and highlights a group of individuals who have an increased risk of complications without rapid progression to overt type 2 diabetes.

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Effect of Vitamin C as an Adjunct in Nonsurgical Periodontal Therapy in Uncontrolled Type 2 Diabetes Mellitus Patients

European Journal of Dentistry ◽

10.1055/s-0039-1693207 ◽

2019 ◽

Vol 13 (03) ◽

pp. 444-449 ◽

Cited By ~ 3

Author(s):

Piyapat Kunsongkeit ◽

Nis Okuma ◽

Supanee Rassameemasmaung ◽

Pechngam Chaivanit

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Vitamin C ◽

Test Group ◽

Post Treatment ◽

Periodontal Therapy ◽

Plasma Vitamin ◽

Significant Difference

Abstract Objective The main purpose of this article is to evaluate periodontal parameters of chronic periodontitis patients with uncontrolled type 2 diabetes mellitus after initial periodontal therapy plus vitamin C. Materials and Methods A double-blind, placebo-controlled, clinical trial was conducted. Subjects received initial periodontal therapy plus 500 mg/day vitamin C for 2 months (n = 15) or placebo (n = 16). Fasting blood sugar (FBS), hemoglobin A1c (HbA1C), and plasma vitamin C level were assessed at baseline and 2 months post-treatment. Plaque Index, Sulcus Bleeding Index, Gingival Index, pocket depth, and clinical attachment level were measured at baseline, 1 month, and 2 months post-treatment. Results Almost all subjects had low level of plasma vitamin C at baseline. In the test group, plasma vitamin C was significantly increased to an adequate level at the end of 2 months. After periodontal treatment, FBS and HbA1c were not significantly different compared with baseline in the test group. In the control group, FBS was significantly decreased from baseline. However, no significant difference between groups was found either in FBS or HbA1c. All periodontal parameters were significantly improved from baseline in both groups. However, no significant difference was found between groups. Conclusion Supplementation of 500 mg/day vitamin C did not give an additional benefit in promoting periodontal status in periodontitis patients with uncontrolled type 2 diabetes mellitus.

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