Pathogenesis of Type 2 Diabetes Mellitus

DeFronzo, Ralph A.

doi:10.1007/978-3-319-45015-5_8

Cited by 30 publications

(35 citation statements)

References 500 publications

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“…Later on, the combination of further beta-cell dysfunction precipitates the development of diabetes due to the failure of the beta cells to compensate for more insulin release during insulin resistance [29]. Given that both insulin resistance and impaired β cell function constitute the hallmarks of the pathogenesis of human type 2 DM [30], high-fat diet-fed, streptozotocin-treated (HFD/STZ) rat model was used to establish a nongenetic rat model of type 2 DM in order to further mimic the pathology of such human disease. While HFD induces insulin resistance, the low dose of STZ causes mild impairment in β cell function [31].…”

Section: Discussionmentioning

confidence: 99%

The Biological Impacts of Sitagliptin on the Pancreas of a Rat Model of Type 2 Diabetes Mellitus: Drug Interactions with Metformin

Shawky

Morsi

Bana

et al. 2019

Biology

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Sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, is a beneficial class of antidiabetic drugs. However, a major debate about the risk of developing pancreatitis is still existing. The aim of the work was to study the histological and immunohistochemical effects of sitagliptin on both endocrine and exocrine pancreases in a rat model of type 2 diabetes mellitus and to correlate these effects with the biochemical findings. Moreover, a possible synergistic effect of sitagliptin, in combination with metformin, was also evaluated. Fifty adult male rats were used and assigned into five equal groups. Group 1 served as control. Group 2 comprised of untreated diabetic rats. Group 3 diabetic rats received sitagliptin. Group 4 diabetic rats received metformin. Group 5 diabetic rats received both combined. Treatments were given for 4 weeks after the induction of diabetes. Blood samples were collected for biochemical assay before the sacrification of rats. Pancreases were removed, weighed, and were processed for histological and immunohistochemical examination. In the untreated diabetic group, the islets appeared shrunken with disturbed architecture and abnormal immunohistochemical reactions for insulin, caspase-3, and inducible nitric oxide synthase (iNOS). The biochemical findings were also disturbed. Morphometrically, there was a significant decrease in the islet size and islet number. Treatment with sitagliptin, metformin, and their combination showed an improvement, with the best response in the combined approach. No evidence of pancreatic injury was identified in the sitagliptin-treated groups. In conclusion, sitagliptin had a cytoprotective effect on beta-cell damage. Furthermore, the data didn’t indicate any detrimental effects of sitagliptin on the exocrine pancreas.

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Section: Discussionmentioning

confidence: 99%

The Biological Impacts of Sitagliptin on the Pancreas of a Rat Model of Type 2 Diabetes Mellitus: Drug Interactions with Metformin

Shawky

Morsi

Bana

et al. 2019

Biology

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“…However, in some women the amount of insulin released cannot meet the increased requirements, resulting in GDM . The pathogenesis of GDM is similar to T2DM, which is also characterized by insulin resistance followed by a compensatory increase in insulin secretion that is unable to meet requirements …”

Section: Introductionmentioning

confidence: 99%

A genetic risk score that includes common type 2 diabetes risk variants is associated with gestational diabetes

Kawai

Levinson

Adefurin

et al. 2017

Clinical Endocrinology

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SUMMARY Objective Gestational diabetes (GDM) is characterized by maternal glucose intolerance that manifests during pregnancy. Because GDM resembles type 2 diabetes (T2DM), shared genetic predisposition is likely but has not been established. We tested the hypothesis that a genetic risk score (GRS) that included variants known to be associated with T2DM is associated with GDM. Study design We conducted a case-control study using the Vanderbilt Medical Center biobank (BioVU), and calculated a simple-count GRS using 34 variants previously associated with T2DM or fasting glucose in the general population, or with GDM or glucose intolerance in pregnancy. We assessed the association of the GRS with GDM adjusting for maternal age, parity, and body mass index (BMI) and calculated the area under the curve for the receiver-operating characteristic curve (c-statistic). Study population Among Caucasian women, we identified 458 cases of GDM and 1538 pregnant controls with normal glucose tolerance. Results Cases of GDM had a higher number of risk alleles compared to controls (38.9±4.0 vs. 37.4 ± 4.0 risk alleles, P=1.6x10−11). The GRS was significantly associated with GDM; the adjusted odds ratio associated with each additional risk allele was 1.10 (95% CI, 1.07-1.13, P=6x10−11). Clinical variables predicted the risk for GDM (c-statistic 0.67, 95% CI: 0.64 - 0.70), and adding the GRS modestly improved prediction (0.70, 95% CI: 0.67 - 0.73). Conclusions Among Caucasian women, a GRS that included common T2DM genetic risk variants was associated with increased risk of GDM but showed limited utility in the identification of GDM cases.

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“…Both the number of cases and the prevalence of diabetes have been steadily increasing over the past few decades. 1,2 Worldwide, almost 0.422 billion grown-ups are existing with T2DM in 2014, as compared to 0.108 billion in 1980. 3 The overall occurrence (age-standardized) of T2DM has approximately doubled since 1980, escalating from 4.7% towards 8.5% in 2014 in the population of adult.…”

Section: Introductionmentioning

confidence: 99%

Pharmacoinformatic Studies on 4-Thiazolyl-phenoxy Tail Containing Indanyl Acetic Acid Derivatives as PPAR-Pan Agonists as Potent Anti-Diabetic Agent

Verma¹,

Chouhan²

2019

IJPER

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Aim:The increasing incidences of type 2 diabetes mellitus, represents a considerable public health problem and characterized by loss in sensitivity of tissues to insulin which can be restored by activation of Peroxisome Proliferator-Activated Receptors (PPARs). The present work takes in consideration for the development of PPAR agonists, which can activate PPARs and is expected to lower LDL cholesterol and triglycerides, raise HDL cholesterol and normalize hyperglycaemia. Materials and Methods: Quantitative Structure-Activity Relationship (QSAR) study is performed by means of Multiple Linear Regression (MLR) analysis on a set of indanyl acetic acid derivatives followed by ADMET prediction and Docking Studies. Results: A good correlation is found by regression analysis between the observed and predicted activities as evident by their R 2 (0.81), Q 2 (0.81) and R 2 pred (0.86) for PPARα and R 2 (0.66), Q 2 (0.66) and R 2 pred (0.90) for PPARδ and R 2 (0.82), Q 2 (0.77) and R 2 pred (0.58) for PPARγ respectively. Molecular docking of the ligands qualifying all the Drug Likeness properties to the proteins PPARα (PDB ID: 3ET1), PPARδ (PDB ID: 3ET2) and PPARγ (PDB ID: 3ET3) with FlexX score -11.98, -9.69 and -21.48 respectively followed by core hoping. Conclusion: Docking studies revealed that hydrogen-bonding interactions are crucial for the binding of ligands with the target. Core replacement of the best-docked conformations of the selected ligand is performed in order to obtain more potent and novel ligands.

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Pathogenesis of Type 2 Diabetes Mellitus

Cited by 30 publications

References 500 publications

The Biological Impacts of Sitagliptin on the Pancreas of a Rat Model of Type 2 Diabetes Mellitus: Drug Interactions with Metformin

The Biological Impacts of Sitagliptin on the Pancreas of a Rat Model of Type 2 Diabetes Mellitus: Drug Interactions with Metformin

A genetic risk score that includes common type 2 diabetes risk variants is associated with gestational diabetes

Pharmacoinformatic Studies on 4-Thiazolyl-phenoxy Tail Containing Indanyl Acetic Acid Derivatives as PPAR-Pan Agonists as Potent Anti-Diabetic Agent

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