Study on the relationship between onset age and ketosis in newly diagnosed type 2 diabetes patients / 公共卫生与预防医学

Objective To explore the relationship between the age of onset and ketosis in patients with newly diagnosed type 2 diabetes mellitus (T2DM), and to provide reference for clinical early intervention and treatment of ketosis according to the characteristics of age. Methods A single center cross-sectional study was conducted to study newly diagnosed T2DM patients who were hospitalized in the Endocrinology Department of Zhongnan Hospital of Wuhan University from January 2016 to December 2019. According to the age of onset, they were divided into young group, middle-aged group and old group. The general clinical data were analyzed and compared. Spearman correlation analysis and multivariate logistic regression were used to analyze the correlation between age and ketosis. Results The proportion of ketosis, males, overweight/obesity, MS, TyG, BMI, β-HB, and TG levels in the young group were significantly higher than those in the middle-aged and old groups, and HbA1c, HOMA-IR, MBS, and OGTT0h were significantly higher than those in the old group. HDL-C in the young group was significantly lower than that in the middle-aged group and old group, and AUGinsulin and IRT2h were significantly lower than those in the old group (P＜0.05). Spearman correlation analysis showed that age was positively correlated with HDL-C and AUGinsulin, and negatively correlated with BMI, TG, HbA1c, β-HB, HOMA-IR, and TyG (P<0.05). Multivariate logistic regression analysis showed that compared with the old group, the OR values of ketosis in the middle-aged group and the young group were 2.584 and 3.870, respectively (P<0.05). Conclusion Early onset age can increase the risk of ketosis in newly diagnosed T2DM patients, and it is necessary to strengthen early intervention and comprehensive treatment for young patients with disease onset.

Obestatin attenuates apoptosis induced by high glucose in INS 1 cells / 基础医学与临床

Objective To investigate the effect of obestatin on the apoptosis of rat pancreatic islet cell line INS1 induced by high glucose .Methods INS1 cells were cultured in different concentrations of glucose .The survival rate and proliferation of INS1 cells were detected by MTT method;Hoechst33258 nuclear staining was used to de-tect nuclear morphology.caspase-3 method was used to study the relationship between the protective effect of obestatin and the PI3K pathway;Finally,using real-time PCR detection of FOXO1 and SREBP1c, Bax, PDX-1 expression, to further clarify the protective effect of obestatin on cells.Results In high glucose condition,obesta-tin promoted the proliferation of INS1 cells at 100 nmol/L,and promoted the proliferation of INS 1 cells significantly ( P<0.01 , compared with the control group and high glucose group ) .Obestatin can reduce high glucose-induced apoptosis(P<0.01).The expressions of FOXO1,SREBP1c,Bax and PDX-1 decreased,while the expression of FOXO1,SREBP1c,Bax and PDX-1 increased in high glucose group .Conclusions OB can attenuate the injury of INS1 cells induced by high glucose in rats .

Sobrevida de los islotes β pancreáticos y uso de hipoglucemiantes orales: un gran reto para el médico actual / Survival of pancreatic islet β and use of oral hypoglycemic agents: a challenge for the current doctor

La célula β no sólo es capaz de fabricar y secretar la insulina, sino además, hace que dicha secreción sea en el momento justo y en la cantidad adecuada. Las elevaciones postprandiales de glucosa generan una respuesta secretora aguda en la célula β, pero en ciertas patologías como la diabética, el escenario cambia radicalmente, resultando en una disfunción caracterizada por un proceso secretor alterado y múltiples cambios fenotípicos. En estos, los nutrientes, glucosa y ácidos grasos, están elevados de forma crónica, convirtiéndose en sustancias tóxicas que pueden llevar a la muerte de la propia célula β. Por lo tanto, cualquier aproximación terapéutica a la cura de esta enfermedad debe afrontar la necesidad de reemplazar o evitar esta disminución celular, siendo imperativo mencionar el papel de los hipoglucemiantes orales como los inhibidores de la DPP-4 y los análogos de la GLP-1 en la protección contra el fracaso de la masa de células β.

The beta cell is not only able to produce and secrete insulin, but also makes this secretion is at the right time and in the right amount. Postprandial glucose elevations produce an acute secretory response in the beta cell, but in certain diseases such as diabetes mellitus, the scene changes dramatically, resulting in dysfunction, characterized by an altered secretion process and multiple phenotypic changes. In these, nutrients like glucose and fatty acids are chronically elevated, becoming toxic substances that can lead to death of the beta cell itself. Therefore, any therapeutic approach to cure this disease must face the need to replace or avoid this cell decline, it is imperative to mention the role of oral hypoglycemic agents as inhibitors of DPP-4 and analogs of the GLP-1 in protection against failure of the β cell mass.

Aloe-Emodin Protects RIN-5F (Pancreatic beta-cell) Cell from Glucotoxicity via Regulation of Pro-Inflammatory Cytokine and Downregulation of Bax and Caspase 3

To determine the protective effect of aloe-emodin (AE) from high glucose induced toxicity in RIN-5F (pancreatic beta-cell) cell and restoration of its function was analyzed. RIN-5F cells have been cultured in high glucose (25 mM glucose) condition, with and without AE treatment. RIN-5F cells cultured in high glucose decreased cell viability and increased ROS levels after 48 hr compared with standard medium (5.5 mM glucose). Glucotoxicity was confirmed by significantly increased ROS production, increased pro-inflammatory (IFN-gamma, IL-1beta,) & decreased anti-inflammatory (IL-6&IL-10) cytokine levels, increased DNA fragmentation. In addition, we found increased Bax, caspase 3, Fadd, and Fas and significantly reduced Bcl-2 expression after 48 hr. RIN-5F treated with both high glucose and AE (20 muM) decreased ROS generation and prevent RIN-5F cell from glucotoxicity. In addition, AE treated cells cultured in high glucose were transferred to standard medium, normal responsiveness to glucose was restored within 8hr and normal basal insulin release within 24 hr was achieved when compared to high glucose.

The Glucotoxicity Protecting Effect of Ezetimibe in Pancreatic Beta Cells via Inhibition of CD36

Inhibition of CD36, a fatty acid transporter, has been reported to prevent glucotoxicity and ameliorate high glucose induced beta cell dysfunction. Ezetimibe is a selective cholesterol absorption inhibitor that blocks Niemann Pick C1-like 1 protein, but may exert its effect through suppression of CD36. We attempted to clarify the beneficial effect of ezetimibe on insulin secreting cells and to determine whether this effect is related to change of CD36 expression. mRNA expression of insulin and CD36, intracellular peroxide level and glucose stimulated insulin secretion (GSIS) under normal (5.6 mM) or high glucose (30 mM) condition in INS-1 cells and primary rat islet cells were compared. Changes of the aforementioned factors with treatment with ezetimibe (20 μM) under normal or high glucose condition were also assessed. mRNA expression of insulin was decreased with high glucose, which was reversed by ezetimibe in both INS-1 cells and primary rat islets. CD36 mRNA expression was increased with high glucose, but decreased by ezetimibe in INS-1 cells and primary rat islets. Three-day treatment with high glucose resulted in an increase in intracellular peroxide level; however, it was decreased by treatment with ezetimibe. Decrease in GSIS by three-day treatment with high glucose was reversed by ezetimibe. Palmitate uptake following exposure to high glucose conditions for three days was significantly elevated, which was reversed by ezetimibe in INS-1 cells. Ezetimibe may prevent glucotoxicity in pancreatic β-cells through a decrease in fatty acid influx via inhibition of CD36.

Hexane Extract of Orthosiphon stamineus Induces Insulin Expression and Prevents Glucotoxicity in INS-1 Cells

BACKGROUND: Hyperglycemia, a characteristic feature of diabetes, induces glucotoxicity in pancreatic beta-cells, resulting in further impairment of insulin secretion and worsening glycemic control. Thus, preservation of insulin secretory capacity is essential for the management of type 2 diabetes. In this study, we evaluated the ability of an Orthosiphon stamineus (OS) extract to prevent glucotoxicity in insulin-producing cells. METHODS: We measured insulin mRNA expression and glucose-stimulated insulin secretion (GSIS) in OS-treated INS-1 cells after exposure to a high glucose (HG; 30 mM) concentration. RESULTS: The hexane extract of OS elevated mRNA expression of insulin as well as pancreatic and duodenal homeobox-1 of INS-1 cells in a dose-dependent manner. The hexane OS extract also increased the levels of phosphorylated phosphatidylinositol 3-kinase (PI3K) in a concentration-dependent manner. Additionally, Akt phosphorylation was elevated by treatment with 100 and 200 micromol of the hexane OS extract. Three days of HG exposure suppressed insulin mRNA expression and GSIS; these expressions were restored by treatment with the hexane OS extract. HG elevated peroxide levels in the INS-1 cells. These levels were unaffected by OS treatment under both normal and hyperglycemic conditions. CONCLUSION: Our results suggested that the hexane extract of OS elevates insulin mRNA expression and prevents glucotoxicity induced by a 3-day treatment with HG. This was associated with the activation of PI-3K and Akt.

Low glibenclamide concentrations affect endoplasmic reticulum stress in INS-1 cells under glucotoxic or glucolipotoxic conditions

BACKGROUND/AIMS: beta-Cell apoptosis caused by increased endoplasmic reticulum (ER) stress is an important pathogenic component of type 2 diabetes mellitus. In theory, sulfonylureas, used for the treatment of diabetes, can contribute to ER stress. We assessed changes in ER stress in pancreatic beta-cells under glucotoxic or glucolipotoxic conditions using low concentrations of the sulfonylurea, glibenclamide (GB). METHODS: Low concentrations of GB (10 or 100 nM) were added to INS-1 cells cultured under glucotoxic or glucolipotoxic conditions. The degree of viability, level of apoptosis and levels of markers associated with ER stress were measured. RESULTS: Apoptosis decreased in response to low concentrations of GB under glucolipotoxic but not glucotoxic conditions. Most ER stress markers decreased upon the addition of GB. Under glucotoxic conditions, changes in the levels of ER stress markers were not consistent. However, all decreased significantly under glucolipotoxic conditions. CONCLUSIONS: Low concentrations of GB exerted antiapoptotic effects through the attenuation of ER stress under glucolipotoxic conditions.

Glucolipotoxicity in Pancreatic beta-Cells

The recent epidemic of type 2 diabetes in Asia differs from that reported in other regions of the world in several key areas: it has evolved over a much shorter time, in an earlier stage of life, and in people with lower body mass indices. These phenotypic characteristics of patients strongly suggest that insulin secretory defects may perform a more important function in the development and progression of diabetes. A genetic element clearly underlies beta-cell dysfunction and insufficient beta-cell mass; however, a number of modifiable factors are also linked to beta-cell deterioration, most notably chronic hyperglycemia and elevated free fatty acid (FFA) levels. Neither glucose nor FFAs alone cause clinically meaningful beta-cell toxicity, especially in patients with normal or impaired glucose tolerance. Thus the term "glucolipotoxicity" is perhaps more appropriate in describing the phenomenon. Several mechanisms have been proposed to explain glucolipotoxicity-induced beta-cell dysfunction and death, but its major factors appear to be depression of key transcription factor gene expression by altered intracellular energy metabolism and oxidative stress. Therefore, stabilization of metabolic changes induced by glucolipotoxicity in beta-cells represents a new avenue for the treatment of type 2 diabetes mellitus.

Protective Effect of Heme Oxygenase-1 on High Glucose-Induced Pancreatic beta-Cell Injury

BACKGROUND: Glucose toxicity that is caused by chronic exposure to a high glucose concentration leads to islet dysfunction and induces apoptosis in pancreatic beta-cells. Heme oxygenase-1 (HO-1) has been identified as an anti-apoptotic and cytoprotective gene. The purpose of this study is to investigate whether HO-1 up-regulation when using metalloprotophyrin (cobalt protoporphyrin, CoPP) could protect pancreatic beta-cells from high glucose-induced apoptosis. METHODS: Reverse transcription-polymerase chain reaction was performed to analyze the CoPP-induced mRNA expression of HO-1. Cell viability of INS-1 cells cultured in the presence of CoPP was examined by acridine orange/propidium iodide staining. The generation of intracellular reactive oxygen species (ROS) was measured using flow cytometry. Glucose stimulated insulin secretion (GSIS) was determined following incubation with CoPP in different glucose concentrations. RESULTS: CoPP increased HO-1 mRNA expression in both a dose- and time-dependent manner. Overexpression of HO-1 inhibited caspase-3, and the number of dead cells in the presence of CoPP was significantly decreased when exposed to high glucose conditions (HG). CoPP also decreased the generation of intracellular ROS by 50% during 72 hours of culture with HG. However, decreased GSIS was not recovered even in the presence of CoPP. CONCLUSION: Our data suggest that CoPP-induced HO-1 up-regulation results in protection from high glucose-induced apoptosis in INS-1 cells; however, glucose stimulated insulin secretion is not restored.

Effects of "glucotoxicity", "lipotoxicity" and "glucolipotoxicity" on islet β-cells / 中华内分泌代谢杂志

Glucotoxicity, lipotoxicity and glucolipotoxieity are secondary phenomena following the primary pathogenesis, including the effects of genetic and environmental factors of type 2 diabetes. However, there exist two theories: (1) Lipotoxicity, presents before blood glucose rising, may trigger off a chain reaction which results in hyperglycemia. Hence the term " diabetes mellipidus" was proposed. (2) Hyperglycemia is a prerequisite for lipotoxicity. It seems more appropriate to state that (1) the glucotoxieity and iipotoxicity may present separately or concurrently in type 2 diabetes; (2) The combined glucolipotoxicity should describe the deleterious actions by higher levels of both glucose and free fatty acids on β-cell function, which finally causes progressive deterioration of insulin secretion.

Combination of glucotoxicity and lipitoxicity impairs pancreatic β-cell function / 中华内分泌代谢杂志

The effects of elevated levels of glucose and (or) free fatty acids on insulin secretion were studied in obese rats by intravenous glucose tolerance test and isolated pancreas perfusinn. The results showed that both glucose- and arginine-stimulated insulin secretions were severely impaired by glucolipotoxicity and the production of ketone was increased dramatically.

Diabetes associated cognitive impairment: a problem should not be ignored / 中华内分泌代谢杂志

Diabetes can affect structure and function of brain in several aspects, but diabetic cognitive impairment is often ignored. The pathogenesis of diabetes associated cognitive impairment is complicated. Factors such as glucotoxicity, lipotoxicity, insulin resistance, hypoglycaemia and disturbance of Ca2 homeostasis may play important roles. Besides conventional diabetes therapy, new methods still need to be explored.