Pancreatic Cell Dysfunction Research Articles

A Review on Diabetes: Current and Future Perspectives

Diabetes Mellitus (DM) is a metabolic syndrome that gradually leads to chronic microvascular or macrovascular complications. There are 2 types of DM: Insulin-dependent diabetes, commonly called type I DM, is an organ-specific autoimmune disorder that destroys the body’s pancreatic β cells, causing insulin deficiency, and can be treated through insulin replacement therapy. Non-insulin-dependent diabetes mellitus, or type II DM, is caused by pancreatic cell dysfunction that affects a person’s ability to use insulin and can be treated with oral hypoglycaemics. Recent investigation confirms that combination therapy of metformin (biguanides), sodium-glucose co-transporter-2 (SGLT2) inhibitors, and Dipeptidyl Peptidase-4 (DPP-4) inhibitors not only reduces HbA1c glucose dependently but also provides better sustained glycaemic stability with good tolerability in comparison to monotherapy. Multi-particulate drug delivery provides targeted drug administration with high bioavailability and compressed dosage administration. In this review analysis, an effort has been made to explore the pathophysiology of type II DM and the importance of combination therapy using microspheres for the delivery of drugs for the management of type II DM.

The effects of Hibiscus sabdariffa Linn. on the levels of FGF21 and AMPK in the Heart of Diabetic Mice

Background : Diabetes Mellitus (DM) is a metabolic disorder characterized by pancreatic cell dysfunction and insulin resistance. Fibroblast Growth Factor 21 (FGF21) is thought to have a cardioprotective role. Through FGF21 signaling, AMP-activated protein kinase (AMPK) activity reduces apoptosis, inflammation, hypertrophy, and fibrosis in the heart. Hibiscus sabdariffa Linn. (HSL) contains flavonoids that have hypoglycemic effects and are anti-inflammatory and antioxidant-active. This study aims to assess the effect of HSL on FGF21 and AMPK levels in the heart of diabetic mice models. Methods : An experimental study using Deutschland Denken Yoken (DDY) mice aged eight weeks were divided into four groups: Control, DM Control, HSL 200, and HSL 400. In the DM control, HSL 200, and HSL 400 groups, diabetes was induced by giving a High Fat Diet(HFD) and STZ 40mg/kgbb. The HSL 200 group was given HSL 200mg/kgBB supplementation for three weeks, and the HSL 400 group was given HSL 400 mg/kgBB supplementation for three weeks. FGF21 and AMPK levels were measured using the enzyme-linked immunosorbent assay (ELISA) method. Results : There was no significant difference between FGF21 and AMPK levels between the control and DM control groups. FGF21 and AMPK levels in the HSL 400 group were higher than in the control, DM control, and HSL 200 groups. Conclusions : These findings suggest that HSL supplementation at specific doses can potentially increase the activation of FGF 21 and AMPK signaling in the heart of diabetic mice models.

Orange Peel Extract and Physical Exercise Synergistically Ameliorate Type 2 Diabetes Mellitus-Induced Dysmetabolism by Upregulating GLUT4 Concentration in Male Wistar Rats.

Diabetes mellitus (DM) is a chronic disease and one of the oldest known disorders. It is characterized by dysglycemia, dyslipidemia, insulin resistance (IR), and pancreatic cell dysfunction. Although different drugs, metformin (MET), glipizide, glimepiride, etc., have been introduced to treat type 2 DM (T2DM), these drugs are not without side effects. Scientists are now seeking natural treatments such as lifestyle modification and organic products known with limited side effects. Thirty-six male Wistar rats were randomized into six groups (n = 6 per group): control, DM untreated rats, DM+orange peel extract (OPE), DM+exercise (EX), DM+OPE +EX, and DM+MET. The administration was once daily through the oral route and lasted for 28 days. EX and OPE synergistically ameliorated the diabetic-induced increase in fasting blood sugar, homeostatic model assessment for insulin resistance (HOMA IR), total cholesterol (TC) and triglyceride (TG), TC/high-density lipoprotein (HDL), TG/HDL, triglyceride glucose (TyG) index, and hepatic lactate dehydrogenase, alanine transaminase, malondialdehyde, c-reactive protein, and tumour necrosis factor α when compared with the diabetic untreated group. Also, EX+OPE blunted DM-induced decrease in serum insulin, homeostasis model assessment of β-cell function (HOMA-B), homeostasis model assessment of insulin sensitivity (HOMA S), quantitative insulin-sensitivity check index (QUICK 1), HDL, total antioxidant capacity, superoxide dismutase, and hepatic glycogen. Furthermore, EX+OPE ameliorated the observed DM-induced decrease in glucose transporter type 4 (GLUT 4), expression. This study showed that OPE and EX synergistically ameliorate T2DM-induced dysglycaemia, dyslipidaemia, and down-regulation of GLUT4 expression.

Challenges in hyperglycemia management in critically ill patients with COVID-19.

Hyperglycemia is commonly associated with adverse outcomes especially in patients requiring intensive care unit stay. Data from the corona virus disease 2019 (COVID-19) pandemic indicates that individuals with diabetes appear to be at similar risk for COVID-19 infection to those without diabetes but are more likely to experience increased morbidity and mortality. The proposed hypothesis for hyperglycemia in COVID-19 include insulin resistance, critical illness hyperglycemia (stress- induced hyperglycemia) secondary to high levels of hormones like cortisol and catecholamines that counteract insulin action, acute cytokine storm and pancreatic cell dysfunction. Diabetic patients are more likely to have severe hyperglycemic complications including diabetic ketoacidosis and hyperosmolar hyperglycemic state. Management of hyperglycemia in COVID-19 is often complicated by use of steroids, prolonged total parenteral or enteral nutrition, frequent acute hyperglycemic events, and restrictions with fluid management due to acute respiratory distress syndrome. While managing hyperglycemia special attention should be paid to mode of insulin delivery, frequency of glucose monitoring based on patient and caregiver safety thereby minimizing exposure and conserving personal protective equipment. In this article we describe the pathophysiology of hyperglycemia, challenges encountered in managing hyperglycemia, and review some potential solutions to address them.

EFFECT OF TETRAHYDROCURCUMIN IN STREPTOZOTOCIN - NICOTINAMIDE INDUCED DIABETES

Diabetes is a major health problem affecting major populations worldwide. It is characterized by absolute or relative deficiencies in insulin secretion and/or insulin action associated with chronic hyperglycemia and disturbances of carbohydrate, lipid and protein metabolism. As a consequence of the metabolic derangements in diabetes, various complications develop including both macro and micro-vascular dysfunctions. Pancreatic cell dysfunction and insulin resistance are the two hallmarks of type 2 diabetes mellitus. Treatment of diabetes without any side effects is still a challenge to the medical system. There is an increasing demand by patients to use the natural products with antidiabetic activity, because insulin and oral hypoglycemic drugs are having so many side effects. Streptozotocin (STZ)-nicotinamide type 2 model shares a number of features with human type 2 diabetes and is characterized by moderate stable hyperglycemia, glucose intolerance, altered but significant glucose-stimulated insulin secretion, in vivo and in vitro. Tetrahydrocurcumin (THC) is one of the major colorless metabolite of curcumin. THC has been reported to exhibit the same physiological and pharmacological properties of curcumin. Curcumin is rapidly metabolized during absorption from the intestine, yielding THC, which has shown the strongest antioxidant activity among all curcuminoids. THC one of the active metabolites in curcumin on blood glucose and plasma insulin in streptozotocin induced diabetic rats. Different doses of THC (20, 40 and 80 mg\kg body weight) were orally administered to diabetic rats for 45 days, after which activities 6-weeks treatment with various doses of THC and curcumin on glucose levels were assayed

VITAMIN D DAN DISFUNGSI ENDOTEL PADA KAKI DIABETIK

Globally the prevalence of type 2 Diabetes Mellitus (DM) among adult remain increase, including in Indonesia. DM with complicated condition might be cause disability that’s call diabetic foot. Diabetic foot is a leg disorder caused by uncontrolled diabetes mellitus resulting in blood vessel disorders, nervous disorders and infection. There are three main problems with diabetic foot, namely ischemia, neuropathy, and infection. These three problems, if triggered by trauma, will cause diabetic foot ulcers. Diabetic foot process initiated by their state of chronic hyperglycemia that causes inflammation in the arterial endothelium, cause endothelial dysfunction. Many studies that suggest a relationship of vitamin D with this inflammatory process. Hipovitaminosis state D will give effect to the increasing activity of the RAAS include hypertension, increased insulin resistance and dysfunction of pancreatic cells which can lead to hyperglycemia, decreased HDL and increased triglycerides. Hypovitaminosis vitamin D can directly increase the proinflammatory cytokines that produce TNF-α. This inflammatory process would lead to decreased levels of Nitric Oxide (NO) and increased ROS. Vitamin D might be have a role in cotrolling inflammation in endothelial cells among people with diabetic foot. K eywords : endothelial dysfunction, diabetic foot, vitamin D

PPAR-α Agonist Improves Hyperglycemia-Induced Oxidative Stress in Pancreatic Cells by Potentiating Antioxidant Defense System

Diabetes-induced oxidative stress has an essential role in pancreatic cells dysfunction. The present study aimed to evaluate whether peroxisome proliferator activated receptor- alpha (PPAR-α) induction by fenofibrate counterbalances oxidative stress in pancreatic cells. In this in vivo study, male Wistar rats were randomly divided into four groups as normal, normal treated, diabetic and diabetic treated groups (n=6 in each group). Diabetes was induced by a single intravenous injection of streptozotocin (45 mg/kg). Treated animals received fenofibrate for 8 weeks (80 mg/kg/day) orally. At the end of the 8th week, rats were sacrificed and blood samples and pancreas tissues were collected. Then, the content of malondialdehyde (MDA), nitrate (Nox) and glutathione (GLT) and enzymatic activities of catalase (CAT) and superoxide dismutase (SOD) were assessed. D ata were analyzed using two-way ANOVA. Diabetes deteriorated anti-oxidant defense capacity in pancreatic cells by reducing SOD and CAT activities and induced oxidative stress as reflected by increased MDA content and free radicals production (Nox content). Treatment by fenofibrate increased SOD and CAT activities and improved oxidative stress by decreasing pancreatic MDA and Nox levels. Uncontrolled hyperglycemia weakens anti-oxidant defense capacity in pancreatic cells and contributes to oxidative stress. PPAR-α induction by fenofibrate can restore anti-oxidant defense systems and improve diabetes-induced oxidative stress.

Inhibition of TLR4 protects rat islets against lipopolysaccharide-induced dysfunction.

Oxidative stress leads to dysfunction in pancreatic cells, causing a reduction in insulin secretion following exposure to glucose. Toll-like receptor4 (TLR4) may be activated by exposure to lipopolysaccharide (LPS) stress. TLR4 may mediate the initiation of inflammatory and immune defense responses; however, the importance of the LPS/TLR4 interaction in apoptosis induced by oxidative stress in pancreatic βcells remains to be elucidated. The present study aimed to investigate the importance of TLR4 during LPS‑induced oxidative stress, apoptosis and dysfunction of insulin secretion in isolated islets of rats. LPS‑induced stimulation of TLR4 increased the production of reactive oxygen species and promoted apoptosis by upregulating the expression levels of caspase‑3, poly ADP ribose polymerase and altering the expression ratio of B‑cell lymphoma‑2 (Bcl‑2)/Bcl‑2 associated X protein. Additionally, the insulin secretion of islets cells was reduced. Anti‑TLR4 antibody and a knockdown of TLR4 by TLR4‑short hairpin RNA were used to inhibit TLR4 activity, which may reverse LPS‑induced events. The present study determined that in islets exposed to LPS oxidative stress, dysfunction may be partly mediated via the TLR4 pathway. Inhibition of TLR4 may prevent dysfunction of rat islets due to oxidative stress. The present study revealed that targeting the LPS/TLR4 signaling pathway and antioxidant therapy may be a novel treatment for the severely septic patients with hyperglycemia stress.

Drug-Induced Hyperglycaemia and Diabetes.

Drug-induced hyperglycaemia and diabetes is a global issue. It may be a serious problem, as it increases the risk of microvascular and macrovascular complications, infections, metabolic coma and even death. Drugs may induce hyperglycaemia through a variety of mechanisms, including alterations in insulin secretion and sensitivity, direct cytotoxic effects on pancreatic cells and increases in glucose production. Antihypertensive drugs are not equally implicated in increasing serum glucose levels. Glycaemic adverse events occur more frequently with thiazide diuretics and with certain beta-blocking agents than with calcium-channel blockers and inhibitors of the renin-angiotensin system. Lipid-modifying agents may also induce hyperglycaemia, and the diabetogenic effect seems to differ between the different types and daily doses of statins. Nicotinic acid may also alter glycaemic control. Among the anti-infectives, severe life-threatening events have been reported with fluoroquinolones, especially when high doses are used. Protease inhibitors and, to a lesser extent, nucleoside reverse transcriptase inhibitors have been reported to induce alterations in glucose metabolism. Pentamidine-induced hyperglycaemia seems to be related to direct dysfunction in pancreatic cells. Phenytoin and valproic acid may also induce hyperglycaemia. The mechanisms of second-generation antipsychotic-associated hyperglycaemia, diabetes mellitus and ketoacidosis are complex and are mainly due to insulin resistance. Antidepressant agents with high daily doses seem to be more frequently associated with an increased risk of diabetes. Ketoacidosis may occur in patients receiving beta-adrenergic stimulants, and theophylline may also induce hyperglycaemia. Steroid diabetes is more frequently associated with high doses of glucocorticoids. Some chemotherapeutic agents carry a higher risk of hyperglycaemia, and calcineurin inhibitor-induced hyperglycaemia is mainly due to a decrease in insulin secretion. Hyperglycaemia has been associated with oral contraceptives containing high doses of oestrogen. Growth hormone therapy and somatostatin analogues may also induce hyperglycaemia. Clinicians should be aware of medications that may alter glycaemia. Efforts should be made to identify and closely monitor patients receiving drugs that are known to induce hyperglycaemia.

Resveratrol protects against methylglyoxal-induced hyperglycemia and pancreatic damage in vivo.

Methylglyoxal (MG) has been found to cause inflammation and insulin resistance in vitro and in vivo in recent studies. Resveratrol has been proposed as an effective treatment that helps lower the risk of developing complications of diabetes. To study the significance of glycosylation-related stress on the pathology of diabetes, the effects of resveratrol were examined in a mouse model of diabetes induced by MG. Resveratrol was given via oral gavage in MG-treated mice, and diabetes-related tests and markers were assessed using biochemical and immunohistochemical analyses. Treatment with resveratrol markedly improved blood glucose level from the oral glucose tolerance test and promoted nuclear factor erythroid 2-related factor-2 (Nrf2) phosphorylation (p < 0.05) in the pancreas of MG-treated mice. However, these effects were abolished by retinoic acid, Nrf2 inhibitor, in resveratrol and retinoic acid-treated and MG-induced mice. These findings support that resveratrol may be useful in the treatment of type-2 diabetes by protecting against pancreatic cell dysfunction.

Alloxan에 의한 HIT-T15 세포 손상에 대한 쑥갓주정추출물의 세포보호효과

The objective of the present study was to evaluate the potential antidiabetic and antioxidant effect of the ethanol extract from Chrysanthemum cornarium L. var. spatiosum(CSE) against alloxan-induced oxidative stress in pancreatic <TEX>${\beta}$</TEX>-cells, HIT-T15. In this study, the antidiabetic effect of CSE was examined using the 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazoliu bromide(MTT) cell proliferation assay, lactate dehydrogenase(LDH) release assay, <TEX>$NAD^+$</TEX>/NADH ratio and insulin secretion. To further investigate whether CSE is involved in the antioxidant activity of alloxan-damaged HIT-T15 cells, its antioxidant effect against alloxan-induced oxidative stress was measured in HIT-T15 cells by determining the levels of antioxidant enzymes including superoxide dismutase(SOD), glutathione S-transferase(GST), glutathione reductase(GR) and glutathione peroxidase(GPx). The results of this analysis showed that alloxan significantly decreased cell viability, increased LDH leakage, and lowered <TEX>$NAD^+$</TEX>/NADH ratio and insulin secretion in HIT-T15 cells. However, CSE significantly increased the viability of alloxan-treated cells and lowered LDH leakage. The intracellular NAD+/NADH ratio and insulin secretion were also significantly increased by 1.7-fold and 1.3-fold, respectively, after treatment with 100 <TEX>${\mu}g/m{\ell}$</TEX> CSE. The HIT-T15 cells treated with alloxan showed significant decreases in the activities of antioxidant enzymes, while CSE significantly elevated the levels of antioxidant enzymes. These findings suggest that CSE could have a protective effect against cytotoxicity and dysfunction of pancreatic cells in the presence of alloxan-induced oxidative stress.

Role of CYP2E1 in ketone-stimulated insulin release in pancreatic B-cells

The role of CYP2E1 in ketone-stimulated insulin release was investigated using isolated pancreatic islets of Langerhans and two mammalian insulin secreting pancreatic beta-cell lines engineered to stably express human CYP2E1 (designated BRIN BD11h2E1 and INS-1h2E1). Isolated rat pancreatic islets were shown to express the CYP2E1 isoform which was inducible by pretreatment of animals with acetone. The cDNA encoded CYP2E1 was expressed and inducible in the engineered cells as shown by Western blotting. The transfected protein was enzymatically active in the heterologous cells as determined by p-nitrophenol hydroxylation rates (0.176 +/- 0.08 vs. 0.341 +/- 0.08 nmol/min/mg microsomal protein in BRIN BD11 control cells and BRIN BD11h2E1 cells respectively, P < 0.001; 0.204 +/- 0.03 vs. 0.633 +/- 0.102 nmol/min/mg microsomal protein in INS-1 and INS-1h2E1, respectively, P < 0.001). Cultivation of CYP2E1 expressing BRIN BD11h2E1 and INS-1h2E1 cells in 40 mM ethanol increased the rate of p-nitrophenol hydroxylation (0.968 +/- 0.09 nmol/min/mg microsomal protein, P < 0.001 and 0.846 +/- 0.103 nmol/min/mg microsomal protein, P < 0.001, respectively) providing further evidence that the heterologous protein is inducible. Cultivation of control cells with ethanol had no observable effect (0.186 +/- 0.05 and 0.195 +/- 0.03 in BRIN BD11 and INS-1, respectively). These cell lines also express NADPH-cytochrome P450 reductase protein which was enzymatically active (0.632 +/- 0.023 in parental BRIN BD11 vs. 0.657 +/- 0.066 without ethanol and 0.824 +/- 0.014 nmol/min/mg microsomal protein with ethanol in BRIN BD11h2E1, P < 0.05; and 1.568 +/- 0.118 in parental INS-1 vs. 1.607 +/- 0.093 without ethanol and 1.805 +/- 0.066 nmol/min/mg microsomal protein with ethanol in INS-1h2E1, P < 0.05) thereby providing a functional cytochrome P450 system. The insulin secretory response of control cell lines and islets was similar to cell lines and islets which had been chemically pretreated, to induce CYP2E1 expression, in response to known nutrient secretagogues. However, insulin output was significantly higher in pretreated islets (1.3-fold, P < 0.05) and CYP2E1 expressing cell lines (BRIN BD11h2E1 2.3-fold, P < 0.001; INS1-1h2E1 1.6-fold, P < 0.001) when stimulated with the ketone 3-hydroxybutyrate than control islets and parental cell lines respectively. Similar acute exposure to acetoacetate enhanced insulin secretion by 1.3-fold (P < 0.05) in pretreated islets, 2.6-fold (P < 0.001) in ethanol pretreated BRIN BD11h2E1 and 1.4-fold (P < 0.001) in ethanol pretreated INS-1h2E1 cells compared to the respective control islets or ethanol pretreated control parental cells. Therefore, these studies highlight a possible role for CYP2E1 in pancreatic cell dysfunction.