Eicosanoids, β-cell function, and diabetes

Arachidonic acid (AA) is metabolized by cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP) enzymes into eicosanoids, which are involved in diverse diseases, including type 1 and type 2 diabetes. During the last 30 years, evidence has been accumulated that suggests important functions for eicosanoids in the control of pancreatic β-cell function and destruction. AA metabolites of the COX pathway, especially prostaglandin E(2) (PGE(2)), appear to be significant factors to β-cell dysfunction and destruction, participating in the pathogenesis of diabetes and its complications. Several elegant studies have contributed to the sorting out of the importance of 12-LOX eicosanoids in cytokine-mediated inflammation in pancreatic β cells. The role of CYP eicosanoids in diabetes is yet to be explored. A recent publication has demonstrated that stabilizing the levels of epoxyeicosatrienoic acids (EETs), CYP eicosanoids, by inhibiting or deleting soluble epoxide hydrolase (sEH) improves β-cell function and reduces β-cell apoptosis in diabetes. In this review we summarize recent findings implicating these eicosanoid pathways in diabetes and its complications. We also discuss the development of animal models with targeted gene deletion and specific enzymatic inhibitors in each pathway to identify potential targets for the treatment of diabetes and its complications.     

Of fat, β cells, and diabetes

The molecular mechanisms linking diet, obesity, and type 2 diabetes are still poorly understood. In a recent paper, Ohtsubo et?al. (2011) show that high lipid levels induce nuclear exclusion of Foxa2 and HNF1α in β cells, leading to impaired expression and glycosylation of proteins controlling glucose-stimulated insulin secretion.     

Cholesterol metabolism,pancreatic β-cell function and diabetes

Cholesterol plays an essential role in determining cell membrane physico-chemical characteristics and functions. A proper membrane structure is critical in pancreatic β-cells for glucose-mediated insulin secretion, and alterations in cellular cholesterol content may negatively affect this process, leading to β-cell dysfunction. The low density lipoprotein receptor (LDL-R) appears to play a relevant role in ß-cell dysfunction due to cholesterol accumulation. This observation raised the question of whether hypocholesterolemic drugs which increase LDL-R expression might bear diabetogenic properties, thus increasing the risk of new-onset diabetes or worsen glycaemic parameters in diabetic patients.Being at higher cardiovascular risk, diabetic patients are usually treated with hypolipidemic drugs to correct the atherogenic dyslipidemia characteristic of this pathological condition. Statin therapy has been associated with an increased incidence of new-onset diabetes (NOD), being the diabetogenic effect depending on the type and dose of statin. However, it is worth noting that the benefits on cardiovascular mortality largely exceed the increased risk associated with the development of diabetes. Although genetic variants associated with lower levels of LDL-C are also associated with an increased NOD risk, clinical trials with lipid-lowering drugs other than statins, namely ezetimibe or monoclonal antibodies against PCSK9, did not observe an increase of developing diabetes.In summary, molecular evidence clearly points to a key role for cholesterol homeostasis in pancreatic β-cell function which, in humans, is negatively affected by statins. Available data exclude that this could be the case for other hypocholesterolemic approaches, but long-term studies are warranted to explore this critical aspect.     

Global diabetes landscape—type 2 diabetes mellitus in South Asia: Epidemiology,risk factors,and control

Background: Type 2 diabetes mellitus (DM) is a new epidemic in South Asia and is the result of societal influences and changing lifestyles. Epidemiologic studies suggest that the prevalence of DM has increased exponentially in urban and rural populations.Objective: This study was conducted to determine trends in the prevalence of DM in various countries in South Asia.Methods: We performed an extensive, systematic MEDLINE search for primary articles that reported on the epidemiology of DM in South Asia. Additional articles were obtained from personal collections and references cited in the primary articles. No formal meta-analysis was performed because of differing methodologies and diagnostic criteria.Results: Epidemiologic studies conducted in India during the 1960s and 1970s, using random and postload blood glucose estimations, reported DM in 1% to 4% of urban populations and 1% to 2% of rural populations. More standardized epidemiologic studies in adults since the late 1980s reported DM in 5% to 15% of urban populations, 4% to 6% of semiurban populations, and 2% to 5% of rural populations. A significantly increasing trend has been observed in urban populations (exponential trend R² = 0.74), whereas the increase is slower (R² = 0.29) in rural populations. The diabetes scenario is similar in other South Asian countries. Current prevalence rates are 5% to 16% in urban areas and 2% to 8% in rural areas. Risk factors for DM in this region are increasing sedentariness, dietary excess, obesity (especially high waist-to-hip ratio), low birth weight, and genetic influences.Conclusions: DM is a major public health problem in South Asia. The prevalence is higher in urban areas than in rural areas and is increasing. Population-based measures to control the epidemic of DM include avoidance of adiposity through enhanced physical activity and regulated calorie intake. A comprehensive national chronic care program is needed.     

Experimental diabetes treated with trigonelline: effect on key enzymes related to diabetes and hypertension, β-cell and liver function

Type 2 diabetes is quite diverse, including the improvement of insulin sensitivity by dipeptidylpeptidase-4 (DPP-4) inhibitor, α-glucosidase inhibitors, and the protection of β-cells islet. The aim of this study was to search the effect of trigonelline (Trig) on DPP-4, α-glucosidase and angiotensin converting enzyme (ACE) activities as well as β-cells architecture, and starch and glucose tolerance test. In surviving diabetic rats, the supplement of Trig potentially inhibited DPP-4 and α-glucosidase activities in both plasma and small intestine. The pancreas islet and less β-cells damage were observed after the administration of trig to diabetic rats. The increase of GLP-1 in surviving diabetic rats suppressed the increase of blood glucose level and improved results in the oral glucose and starch tolerance test. Trig also normalized key enzyme related to hypertension as ACE and improved the hemoglobin A1c and lipid profiles (plasma triglyceride, HDL-cholesterol, LDL-cholesterol, and total cholesterol), and liver indices toxicity. Therefore, these results revealed that Trig was successful in improving glycemic control, metabolic parameters, and liver function in diabetic rats. It is therefore suggested that Trig may be a potential agent for the treatment of type 2 diabetes.     

Zinc and diabetes — clinical links and molecular mechanisms

Zinc is an essential trace element crucial for the function of more than 300 enzymes and it is important for cellular processes like cell division and apoptosis. Hence, the concentration of zinc in the human body is tightly regulated and disturbances of zinc homeostasis have been associated with several diseases including diabetes mellitus, a disease characterized by high blood glucose concentrations as a consequence of decreased secretion or action of insulin. Zinc supplementation of animals and humans has been shown to ameliorate glycemic control in type 1 and 2 diabetes, the two major forms of diabetes mellitus, but the underlying molecular mechanisms have only slowly been elucidated. Zinc seems to exert insulin-like effects by supporting the signal transduction of insulin and by reducing the production of cytokines, which lead to beta-cell death during the inflammatory process in the pancreas in the course of the disease. Furthermore, zinc might play a role in the development of diabetes, since genetic polymorphisms in the gene of zinc transporter 8 and in metallothionein (MT)-encoding genes could be demonstrated to be associated with type 2 diabetes mellitus. The fact that antibodies against this zinc transporter have been detected in type 1 diabetic patients offers new diagnostic possibilities. This article reviews the influence of zinc on the diabetic state including the molecular mechanisms, the role of the zinc transporter 8 and MT for diabetes development and the resulting diagnostic and therapeutic options.     

Selenium and diabetes: an enigma?

In recent years diabetes has become one of the most common metabolic diseases in developed countries and it is closely related to supernutrition and obesity. Since untreated diabetes produces oxidative stress responsible for secondary complications of the disease, antioxidant supplements were considered as being favourable for the therapy of diabetes. However, the situation has changed recently, since large cross-sectional and interventional trials revealed a positive correlation between a high Se status and diabetes incidence in humans. Thus, currently available data on the role of Se in diabetes are inconsistent and an enigma appears to exist for the relation between selenium and diabetes. This review summarizes selected human and animal studies, pointing to beneficial and critical virtues of Se in diabetes. Moreover, the review discusses possible underlying mechanisms how Se may influence diabetes in both directions. From the current literature, the following information can be extracted: (1) In populations with a high Se status, with the single exception of pregnant women, Se supplements cannot be recommended for the prevention of diabetes; (2) Anti-diabetic effects of Se seem to be restricted to high and nearly toxic doses which cannot be used in humans; and (3) Future investigations should consider the stage of the disease.     

Serum γ-glutamyltransferase: independent predictor of risk of diabetes, hypertension, metabolic syndrome, and coronary disease

Serum γ-glutamyltransferase (GGT) is associated with oxidative stress and hepatic steatosis. The extent to which its value in determining incident cardiometabolic risk (coronary heart disease (CHD), metabolic syndrome (MetS), hypertension and type 2 diabetes) is independent of obesity needs to be further explored in ethnicities. After appropriate exclusions, a cohort of 1,667 adults of a general population (age 52 ±11 years) was evaluated prospectively at 4 year's follow-up using partly Cox proportional hazard regressions. GGT activity was measured kinetically, and values were log-transformed for analyses. MetS was identified by Adult Treatment Panel-III criteria modified for male abdominal obesity. Median (interquartile range) GGT activity was 24.9 (17.0; 35.05) U/l in men, 17.0 (12.3; 24.0) U/l in women. In linear regression analysis, while smoking status was not associated, (male) sex, sex-dependent age, alcohol usage, BMI, fasting triglycerides and C-reactive protein (CRP) were significant independent determinants of circulating GGT. Each 1-s.d. increment in (= 0.53 ln GGT) GGT activity significantly predicted in each sex incident hypertension (hazard ratio (HR) 1.20 (95% confidence interval (CI) 1.10; 1.31)), and similarly MetS, after adjustment for age, alcohol usage, smoking status, BMI and menopause. Strongest independent association existed with diabetes (HR 1.3 (95% CI 1.1; 1.5)) whereas GGT activity tended to marginally predict CHD independent of total bilirubin but not of BMI. Higher serum total bilirubin levels were protective against CHD risk in women. We conclude that elevated serum GGT confers, additively to BMI, risk of hypertension, MetS, and type 2 diabetes but only mediates adiposity against CHD risk.     

Crocus cancellatus subsp. damascenus stigmas: chemical profile,and inhibition of α-amylase, α-glucosidase and lipase,key enzymes related to type 2 diabetes and obesity

Spices are appreciated for their medicinal properties besides their use as food adjuncts to enhance the sensory quality of food. In this study, Crocus cancellatus subsp. damascenus was investigated for its antioxidant activities employing different in vitro systems. Stigma extract demonstrated a radical scavenging activity against both 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) radicals with IC₅₀ values of 34.6 and 21.6?µg/mL and a good ferric reducing ability (53.9?µM Fe(II)/g). In order to clarify the potential functional properties of this spice, the carbohydrate-hydrolysing enzymes and pancreatic lipase inhibitory properties were investigated. Crocus cancellatus subsp. damascenus extract inhibited α-amylase and α-glucosidase with IC₅₀ values of 57.1 and 68.6?µg/mL, respectively. The bioactivity was discussed in terms of phytochemicals content. The obtained results may be of interest from a functional point of view or as food additive and to promote the revalorization of this species.     

Vanadium and diabetes. What about vanadium toxicity?

Molecular and Cellular Biochemistry -     

Birth weight and non-insulin dependent diabetes: thrifty genotype,thrifty phenotype,or surviving small baby genotype?

OBJECTIVE--To determine the prevalence of diabetes in relation to birth weight in Pima Indians. DESIGN--Follow up study of infants born during 1940-72 who had undergone a glucose tolerance test at ages 20-39 years. SETTING--Gila River Indian community, Arizona. SUBJECTS--1179 American Indians. MAIN OUTCOME MEASURE--Prevalence of non-insulin dependent diabetes mellitus (plasma glucose concentration > or = 11.1 mmol/l two hours after ingestion of carbohydrate). RESULTS--The prevalence was greatest in those with the lowest and highest birth weights. The age adjusted prevalences for birth weights < 2500 g, 2500-4499 g, and > or = 4500 g were 30%, 17%, and 32%, respectively. When age, sex, body mass index, maternal diabetes during pregnancy, and birth year were controlled for, subjects with birth weights < 2500 g had a higher rate than those with weights 2500-4499 g (odds ratio 3.81; 95% confidence interval 1.70 to 8.52). The risk for subsequent diabetes among higher birthweight infants (> or = 4500 g) was associated with maternal diabetes during pregnancy. Most diabetes, however, occurred in subjects with intermediate birth weights (2500-4500 g). CONCLUSIONS--The relation of the prevalence of diabetes to birth weight in the Pima Indians is U shaped and is related to parental diabetes. Low birth weight is associated with non-insulin dependent diabetes. Given the high mortality of low birthweight infants selective survival in infancy of those genetically predisposed to insulin resistance and diabetes provides an explanation for the observed relation between low birth weight and diabetes and the high prevalence of diabetes in many populations.     

Enhanced NTPDase and 5′-nucleotidase activities in diabetes mellitus and iron-overload model

The activity of the enzymes NTPDase and 5′-nucleotidase was studied in both diabetes mellitus and an associated model of iron-overload. Rats were divided in five groups: citrate (CC), saline (S), diabetic (D), iron-overload (IO), and diabetic iron-overload (DIO). Diabetes was induced with alloxan (150 mg/kg), and iron-overload was induced with iron-dextran (10 intramuscular applications of ±80 mg/kg). The enzymatic activities were evaluated in the platelets. The results demonstrated an increase in the activity of NTPDase with substrates ATP and ADP (60% and 120%, respectively; P < 0.001), and 5′-nucleotidase (60%, P < 0.001). This increase was more intense in the IO and DIO groups. The results obtained in vitro showed an activation in ATP, ADP, and AMP hydrolysis between 1 μM and 1,000 μM ferric nitrate concentrations, being more pronounced at 100 μM and decreasing at 1,000 μM. We concluded that diabetes mellitus in association with iron-overload increased the hydrolysis of adenine nucleotides in platelets, contributing to the abnormalities found in these pathological conditions.     

Is the endogenous digitalis-like factor the link between hypertension and metabolic disorders as diabetes mellitus, obesity and acromegaly?

Endogenous factors cross-reacting with antidigoxin antibodies have been found in several tissues and body fluids of animals and humans, using commercially available digoxin radioimmunoassay or enzyme immunoassay methods. The chemical characteristics of these endogenous factors are, at present, unknown, although it has been suggested that they could be substances with low molecular weight. Experimental studies and theoretical considerations indicate that endogenous digitalis-like factors (DDLFs), in addition to the ability to react with antibodies, might also bind to the specific cellular receptor of the cardiac glycosides and thus inhibit the membrane Na+/K(+)-ATPase (sodium pump). Therefore, EDLF can be an endogenous modulator of the membrane sodium-potassium pump and several authors have suggested that EDLF could play a role in the regulation of fluids and electrolytes, muscular tone of myocardial and also in the pathogenesis of arterial hypertension. In this review, the authors discuss the hypothesis that, in metabolic diseases such as diabetes mellitus, obesity and acromegaly, the sodium retention and volume expansion, possibly due to exaggerated sodium intake, and/or exogenously induced peripheral hyperinsulinemia and high levels of growth hormone, could trigger a sustained release of EDLF, which in turn increases the blood pressure.     

Aleglitazar,a new,potent, and balanced dual PPARα/γ agonist for the treatment of type II diabetes

Design, synthesis, and SAR of novel α-alkoxy-β-arylpropionic acids as potent and balanced PPARαγ coagonists are described. One representative thereof, Aleglitazar ((S)-2Aa), was chosen for clinical development. Its X-ray structure in complex with both receptors as well as its high efficacy in animal models of T2D and dyslipidemia are also presented.     

Zinc and diabetes mellitus: is there a need of zinc supplementation in diabetes mellitus patients?

Diabetes mellitus is a group of metabolic disorders, the incidence of which varies widely throughout the world. The treatment of diabetes mellitus includes insulin, oral antidiabetic agents, and dietary regimens. Although the emphasis is on macronutrients intakes, there is strong evidence that there is an abnormal metabolism of several micronutrients in diabetic individuals. Zinc is one of the essential micronutrients of which status and metabolism is altered in this condition. This work is a short review about the close relation among zinc, glucose metabolism, and insulin physiology, as well as about the few experimental data about zinc absorption and zinc supplementation in diabetes mellitus patients.     

Honey and diabetes mellitus: Obstacles and challenges – Road to be repaired

Background and objectiveSince ancient times, honey has been used due to its nutritional and therapeutic value. The role of honey has been acknowledged in the scientific literature however, its use has been controversially discussed and has not been well accepted in modern medicine especially for diabetic patients. This study aimed to investigate the role of honey in diabetic patients.MethodsIn this study, we identified 107 research articles from data based search engines including “PubMed”, “ISI-Web of Science”, “Embase” and “Google Scholar”. The research papers were selected by using the primary key-terms including “Honey”, “Honey bee” and “Diabetes Mellitus”. The research documents in which “Honey” and “Diabetes Mellitus” were debated are included. After screening, we reviewed 66 papers and finally we selected 35 studies which met the inclusion criteria and the remaining documents were excluded.ResultsThis study investigated the preclinical, clinical, human and animal model studies on honey and diabetes mellitus and found that honey decreases the fasting serum glucose, increases the sting C-peptide and 2-h postprandial C-peptide. Although, there is a dearth of data and literature also contrary discussed the use of honey in diabetic patients.ConclusionHoney decreases the fasting serum glucose, increases fasting C-peptide and 2-h postprandial C-peptide. Honey had low glycemic index and peak incremental index in diabetic patients. The use of honey in diabetic patients still has obstacles and challenges and needs more large sample sized, multi-center clinical controlled studies to reach better conclusions.     

The role of autophagy in pancreatic β-cell and diabetes

Pancreatic β-cells play a key role in glucose homeostasis in mammals. Although large-scale protein synthesis and degradation occur in pancreatic β-cells, the mechanism underlying dynamic protein turnover in β-cells remains largely unknown. We found low-level constitutive autophagy in β-cells of C57BL/6 mice fed a standard diet; however, autophagy was markedly upregulated in mice fed a high-fat diet. β-cells of diabetic db/db mice contained large numbers of autophagosomes, compared with non-diabetic db/misty controls. The functional importance of autophagy was analyzed using β-cell-specific Atg7 knockout mice. Autophagy-deficient mice showed degeneration of β-cells and impaired glucose tolerance with reduced insulin secretion. While a high-fat diet stimulated β-cell autophagy in control mice, it induced a profound deterioration of glucose intolerance in β-cell autophagy-deficient mutants, partly because of the lack of a compensatory increase in β-cell mass. These results suggest that the degradation of unnecessary cellular components by autophagy is essential for maintenance of the architecture and function of β-cells. Autophagy also serves as a crucial element of stress responses to protect β-cells under insulin resistant states. Impairment of autophagic machinery could thus predispose individuals to type 2 diabetes.