“Inflammaging” as a Druggable Target: A Senescence-Associated Secretory Phenotype—Centered View of Type 2 Diabetes

Aging is a complex phenomenon driven by a variety of molecular alterations. A relevant feature of aging is chronic low-grade inflammation, termed “inflammaging.” In type 2 diabetes mellitus (T2DM), many elements of aging appear earlier or are overrepresented, including consistent inflammaging. T2DM patients have an increased death rate, associated with an incremented inflammatory score. The source of this inflammation is debated. Recently, the senescence-associated secretory phenotype (SASP) has been proposed as the main origin of inflammaging in both aging and T2DM. Different pathogenic mechanisms linked to T2DM progression and complications development have been linked to senescence and SASP, that is, oxidative stress and endoplasmic reticulum (ER) stress. Here we review the latest data connecting oxidative and ER stress with the SASP in the context of aging and T2DM, with emphasis on endothelial cells (ECs) and endothelial dysfunction. Moreover, since current medical practice is insufficient to completely suppress the increased death rate of diabetic patients, we propose a SASP-centered view of T2DM as a futuristic therapeutic option, possibly opening new prospects by moving the attention from one-organ studies of diabetes complications to a wider targeting of the aging process.

Download Full-text

Lipotoxic Stress Induces Pancreaticβ-Cell Apoptosis through Modulation of Bcl-2 Proteins by the Ubiquitin-Proteasome System

Journal of Diabetes Research ◽

10.1155/2015/280615 ◽

2015 ◽

Vol 2015 ◽

pp. 1-16 ◽

Cited By ~ 11

Author(s):

Sara A. Litwak ◽

Jibran A. Wali ◽

Evan G. Pappas ◽

Hamdi Saadi ◽

William J. Stanley ◽

...

Keyword(s):

Type 2 Diabetes ◽

Cell Death ◽

Er Stress ◽

Ubiquitin Proteasome System ◽

Diabetic Patients ◽

Type 2 Diabetic Patients ◽

Ubiquitin Proteasome

Pancreaticβ-cell loss induced by saturated free fatty acids (FFAs) is believed to contribute to type 2 diabetes. Previous studies have shown induction of endoplasmic reticulum (ER) stress, increased ubiquitinated proteins, and deregulation of the Bcl-2 family in the pancreas of type 2 diabetic patients. However, the precise mechanism ofβ-cell death remains unknown. In the present study we demonstrate that the FFA palmitate blocks the ubiquitin-proteasome system (UPS) and causes apoptosis through induction of ER stress and deregulation of Bcl-2 proteins. We found that palmitate and the proteasome inhibitor MG132 induced ER stress inβ-cells, resulting in decreased expression of the prosurvival proteins Bcl-2, Mcl-1, and Bcl-XL, and upregulation of the prodeath BH3-only protein PUMA. On the other hand, pharmacological activation of the UPS by sulforaphane ameliorated ER stress, upregulated prosurvival Bcl-2 proteins, and protectedβ-cells from FFA-induced cell death. Furthermore, transgenic overexpression of Bcl-2 protected islets from FFA-induced cell deathin vitroand improved glucose-induced insulin secretionin vivo. Together our results suggest that targeting the UPS and Bcl-2 protein expression may be a valuable strategy to preventβ-cell demise in type 2 diabetes.

Download Full-text

A study of prevalence of metabolic syndrome in patients with type 2 diabetes mellitus in a tertiary care referral hospital in West Bengal

International Journal of Basic & Clinical Pharmacology ◽

10.18203/2319-2003.ijbcp20194268 ◽

2019 ◽

Vol 8 (10) ◽

pp. 2262

Author(s):

Tamoghna Maiti ◽

Sonai Mandal ◽

Ratul Banerjee ◽

Somenath Das ◽

Amrita Panda

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Metabolic Syndrome ◽

West Bengal ◽

Cardiac Risk Factor ◽

Diabetic Patients ◽

Low Grade ◽

The Metabolic Syndrome ◽

Increased Risk

Background: The terms "metabolic syndrome", "insulin resistance syndrome" and "syndrome X" are now used specifically to define a constellation of abnormalities that is associated with increased risk for the development of type 2 diabetes and atherosclerotic vascular disease. It is a state of chronic low grade inflammation with the profound systemic effects. Several organisations gave several criteria to diagnose it. Effective preventive approaches include lifestyle changes, primarily weight loss, diet, and exercise, the appropriate use of pharmacological agents to reduce the specific risk factors.Methods: A cross-sectional study was done to evaluate the co-morbidity profile of patients, with metabolic syndrome and correlate clinical manifestations with specific components or metabolic syndrome, at the OPD of Bankura Sammilani Medical College and Hospitals, West Bengal. American Association of Clinical Endocrinologists criteria were chosen for diagnosis.Results: 100 patients were recruited having type II diabetes mellitus. Most of the patients were male between 20-70 years and maximum was on oral hypoglycemic agent with app 40% patient was without any glycemic control. In comorbidities hypertension was highest, followed by coronary artery disease, hypothyroidism and cerebrovascular accident. Waist-hip ratio was highest in female. All of the patients were having some cardiac risk factor assessed by ECG, echocardiography and thread mill test.Conclusions: The data demonstrates that metabolic syndrome is extremely common among diabetic patients. Frequency was much higher in women than men. Obesity is a key element in causing the metabolic syndrome and this factor was also more common in women.

Download Full-text

Elevated Serum TNF-α Is Related to Obesity in Type 2 Diabetes Mellitus and Is Associated with Glycemic Control and Insulin Resistance

Journal of Obesity ◽

10.1155/2020/5076858 ◽

2020 ◽

Vol 2020 ◽

pp. 1-5 ◽

Cited By ~ 7

Author(s):

Hana Alzamil

Keyword(s):

Diabetes Mellitus ◽

Insulin Resistance ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Chronic Inflammation ◽

Affinity Column ◽

Diabetic Patients ◽

Low Grade ◽

Model Assessment

Background. Diabetes and obesity are very common associated metabolic disorders that are linked to chronic inflammation. Leptin is one of the important adipokines released from adipocytes, and its level increases with increasing body mass index (BMI). Tumor necrosis factor alpha (TNF-α) is a cytokine that is released by adipocytes and inflammatory cells in response to chronic inflammation. Type 2 diabetes mellitus (T2DM) is believed to be associated with low-grade chronic inflammation. The current study aims to investigate the involvement of leptin and TNF-α in T2DM associated with obesity. Methodology. This is a cross-sectional study involving 63 healthy volunteers and 65 patients with T2DM. Body composition was measured, and fasting venous blood samples were analyzed for blood glucose, glycosylated hemoglobin (HbA1c), basal insulin, leptin, and TNF-α. HbA1c was measured by the affinity column method. Insulin, leptin, and TNF-α immunoassays were performed by the ELISA technique. Insulin resistance and beta-cell function were assessed using the homeostasis model assessment (HOMA-IR and HOMA-B). Results. Our study showed a significantly higher level of TNF-α in T2DM patients compared to controls (7.51 ± 2.48 and 6.19 ± 3.01, respectively; p=0.008). In obese diabetic patients, the serum level of TNF-α was significantly higher in comparison with nonobese diabetic patients (p<0.018) and obese nondiabetic group (p<0.001). TNF-α correlated positively with HbA1c (r = 0.361, p=0.003) and HOMA-IR (r = 0.296, p=0.017) in patients with T2DM. Conclusion. TNF-α is associated with concurrent obesity and T2DM and correlates with HbA1c. This suggests that TNF-α needs further investigation to explore if it has a role in monitoring the effectiveness of management in individuals with obesity and T2DM.

Download Full-text

Updated Review: Improved Glycemic Control with Repaglinide-Metformin in Fixed Combination for Patients with Type 2 Diabetes

Clinical Medicine Insights Endocrinology and Diabetes ◽

10.4137/cmed.s5094 ◽

2011 ◽

Vol 4 ◽

pp. CMED.S5094 ◽

Cited By ~ 1

Author(s):

John W. Richard ◽

Philip Raskin

Keyword(s):

Type 2 Diabetes ◽

Combination Therapy ◽

Therapeutic Option ◽

Diabetic Patients ◽

Combination Regimen ◽

Combination Therapies ◽

Insulin Sensitizer ◽

Oral Medications ◽

Glucose Output

As the prevalence of type 2 diabetes continues to rise, new drug therapies will need to be explored to prevent morbidity and mortality associated with diabetes as well as growing health care costs. Type 2 diabetes is characterized by decreased insulin secretion and sensitivity. Numerous oral medications are currently approved for the treatment of type 2 diabetes. A treat-to-failure approach has traditionally been adopted with step-wise additions of oral medications; however, a growing frequency of treatment failures with monotherapy has led to the use of combination therapies earlier in the treatment of type 2 diabetes. One such combination regimen is repaglinide (a prandial glucose optimizer that increases insulin release) plus metformin (an insulin sensitizer that inhibits hepatic glucose output and increases peripheral glucose uptake while minimizing weight gain). Findings from several clinical trials have shown repaglinide plus metformin combination therapy to be superior to either monotherapy with significant reductions in hemoglobin A1C and fasting glucose values. Repaglinide used in combination also has shown less incidence of hypoglycemia compared with other combination therapies such as sulphonylureas plus metformin. Repaglinide plus metformin combination therapy appears to be a valuable therapeutic option for type 2 diabetic patients seeking a less complex drug regimen while potentially achieving better glucose control if currently inadequately controlled on monotherapy.

Download Full-text

Diabetes mellitus quality care management: The promise of herbal supplementation

GSC Advanced Research and Reviews ◽

10.30574/gscarr.2021.9.1.0197 ◽

2021 ◽

Vol 9 (1) ◽

pp. 007-012

Author(s):

Arar K ◽

Ghouini A

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Blood Sugar ◽

Therapeutic Option ◽

Quality Care ◽

Nutritional Supplementation ◽

Diabetic Patients ◽

Glucose Levels ◽

Sugar Levels

Overcoming diabetes is a major health challenge of the 21st century. WHO predicts that by 2030 it will be the seventh leading cause of death in the world and calls for global action to stop its rise and improve care. Actually, Herbal and nutritional supplementation is required in the management of diabetic patients, a finding shared unanimously by scientists. Recently diabetologists have come to the evidence that a therapeutic supplement consisting of nutrients and herbal is necessary to optimize the treatment of diabetes. The treatment of Type 2 diabetes mellitus, which is very often associated with overweight, is based on hygiene and dietetic measures and, where appropriate, on taking oral antidiabetics .This review describes the therapeutic arsenal of conventional oral antidiabetic drugs and emphasizes on innovative therapeutic option introducing herbal medicine and nutrition to the management of diabetic patients. Recent studies showed interesting potential in the reduction of blood sugar for many herbal for example Cinnamon, also berberine has been linked to the reduction of blood glucose levels, insulin levels and showed to be as effective as metformin, the most commonly prescribed drug for diabetics, at controlling blood sugar levels in diabetics. Moreover, a medicinal plant or herbal mixture can provide multi-targeted therapeutic action due to its complex chemical composition with hundreds of active ingredients such as oligosaccharides, alkaloids, polyphenols, flavonoids, tannins and at the same time ensure safety for the patients. We conclude by the fact that herbal and nutritional supplementation can bring major and promising progress in order to improve the patient care, by slowing the progression of type 2 diabetes and limiting its complications.

Download Full-text

Circulating Levels of IL-1B+IL-6 Cause ER Stress and Dysfunction in Islets From Prediabetic Male Mice

Endocrinology ◽

10.1210/en.2012-2138 ◽

2013 ◽

Vol 154 (9) ◽

pp. 3077-3088 ◽

Cited By ~ 65

Author(s):

Christina M. O'Neill ◽

Christine Lu ◽

Kathryn L. Corbin ◽

Poonam R. Sharma ◽

Stacey B. Dula ◽

...

Keyword(s):

Type 2 Diabetes ◽

Insulin Secretion ◽

Er Stress ◽

Systemic Inflammation ◽

Proinflammatory Cytokines ◽

Serum Levels ◽

Low Grade ◽

Increased Risk ◽

Islet Dysfunction

Elevated levels of circulating proinflammatory cytokines are associated with obesity and increased risk of type 2 diabetes, but the mechanism is unknown. We tested whether proinflammatory cytokines IL-1B+IL-6 at low picogram per milliliter concentrations (consistent with serum levels) could directly trigger pancreatic islet dysfunction. Overnight exposure to IL-1B+IL-6 in islets isolated from normal mice and humans disrupted glucose-stimulated intracellular calcium responses; cytokine-induced effects were more severe among islets from prediabetic db/db mice that otherwise showed no signs of dysfunction. IL-1B+IL-6 exposure reduced endoplasmic reticulum (ER) calcium storage, activated ER stress responses (Nos2, Bip, Atf4, and Ddit3 [CHOP]), impaired glucose-stimulated insulin secretion, and increased cell death only in islets from prediabetic db/db mice. Furthermore, we found increased serum levels of IL-1B and IL-6 in diabetes-prone mice at an age before hyperglycemia was exhibited, suggesting that low-grade systemic inflammation develops early in the disease process. In addition, we implanted normal outbred and inbred mice with subcutaneous osmotic mini-pumps containing IL-1B+IL-6 to mimic the serum increases found in prediabetic db/db mice. Both IL-1B and IL-6 were elevated in serum from cytokine-pump mice, but glucose tolerance and blood glucose levels did not differ from controls. However, when compared with controls, isolated islets from cytokine-pump mice showed deficiencies in calcium handling and insulin secretion that were similar to observations with islets exposed to cytokines in vitro. These findings provide proof of principle that low-grade systemic inflammation is present early in the development of type 2 diabetes and can trigger ER stress-mediated islet dysfunction that can lead to islet failure.

Download Full-text

The Inflammatory Marker HSCRP as a Predictor of Increased Insulin Resistance in Type 2 Diabetics without Atherosclerotic Manifestations

Revista de Chimie ◽

10.37358/rc.19.5.7216 ◽

2019 ◽

Vol 70 (5) ◽

pp. 1791-1794

Author(s):

Elena-Daniela Grigorescu ◽

Victorita Sorodoc ◽

Mariana Floria ◽

Ecaterina Anisie ◽

Alina Delia Popa ◽

...

Keyword(s):

Diabetes Mellitus ◽

Insulin Resistance ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Inflammatory Marker ◽

Diabetic Patients ◽

Low Grade ◽

Type 2 Diabetic Patients ◽

Care Plans

Low-grade inflammation is not only a specific feature in type 2 diabetes mellitus, but also a contributor to cardiovascular risk. Together with insulin resistance as the main characteristic of type 2 diabetes mellitus, subclinical imflammation maintains a vicious cycle of health-damaging processes. Our study assessed the inflammatory marker hsCRP in relation to the metabolic profiles of type 2 diabetic patients without clinical atherosclerotic manifestations. The results confirmed the hypothesized connection, which should be taken into consideration when designing and recommending diabetes care plans.

Download Full-text

Association of Major Dietary Patterns with General and Abdominal Obesity in Iranian Patients with Type 2 Diabetes Mellitus

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831/a000233 ◽

2015 ◽

Vol 85 (3-4) ◽

pp. 145-155 ◽

Cited By ~ 9

Author(s):

Marjan Ghane Basiri ◽

Gity Sotoudeh ◽

Mahmood Djalali ◽

Mohammad Reza Eshraghian ◽

Neda Noorshahi ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Abdominal Obesity ◽

Dietary Patterns ◽

Dietary Pattern ◽

Diabetic Patients ◽

General Obesity ◽

Healthy Dietary Pattern

Abstract. Background: The aim of this study was to identify dietary patterns associated with general and abdominal obesity in type 2 diabetic patients. Methods: We included 728 patients (35 - 65 years) with type 2 diabetes mellitus in this cross-sectional study. The usual dietary intake of individuals over 1 year was collected using a validated semi-quantitative food frequency questionnaire. Weight, height, and waist circumference were measured according to standard protocol. Results: The two major dietary patterns identified by factor analysis were healthy and unhealthy dietary patterns. After adjustment for potential confounders, subjects in the highest quintile of the healthy dietary pattern scores had a lower odds ratio for the general obesity when compared to the lowest quintile (OR = 0.45, 95 % CI = 0.26 - 0.79, P for trend = 0.02), while patients in the highest quintile of the unhealthy dietary pattern scores had greater odds for the general obesity (OR = 3.2, 95 % CI = 1.8 - 5.9, P for trend < 0.001). There were no significant associations between major dietary patterns and abdominal obesity, even after adjusting for confounding factors. Conclusion: This study shows that in patients with type 2 diabetes mellitus, a healthy dietary pattern is inversely associated and an unhealthy dietary pattern is directly associated with general obesity.

Download Full-text

ESTIMATION OF SERUM FERRITIN LEVELS IN TYPE 2 DIABETIC PATIENTS AND ITS RELATION WITH HbA1C LEVEL.

International Journal of Medical and Biomedical Studies ◽

10.32553/ijmbs.v3i8.456 ◽

2019 ◽

Vol 3 (8) ◽

Author(s):

Shah Namrata Vinubhai ◽

Pardeep Agarwal ◽

Bushra Fiza ◽

Ramkishan Jat

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Blood Sugar ◽

Serum Ferritin ◽

Inflammatory Marker ◽

Control Group ◽

Diabetic Patients ◽

Positive Correlation

Background: Serum ferritin is known as an index for body iron stores also as an inflammatory marker and it is influenced by several disease. We were looking for a correlation between HbA1c and S. Ferritin in type 2 DM. Methodology: The present study a total of 150 participants were enrolled of which 100 were confirmed cases of Type 2 Diabetes Mellitus and rest 50 age and sex matched healthy subjects constituted the control group. All were screened for HbA1c, Fasting blood sugar, Post prandial blood sugar and S.Ferritin. Results: A highly significant variation and positive correlation was observed with respect to S.Ferritin and HbA1c levels. Mean S.Ferritin was high in the subgroup with poor glycemic control. Conclusion: The fasting, post prandial sugar levels, HbA1c and S.Ferritin were significantly higher in the diabetic subjects. This study shows a positive correlation between HbA1c and S. Ferritin levels. So we can conclude that in diabetic patients S. Ferritin may serve as an independent marker of poor glycemic and metabolic control. Keywords: Serum ferritin, Type 2 Diabetes Mellitus, HbA1c.

Download Full-text