Showing papers in "Experimental Diabetes Research in 2011"

Maternal Diabetes in Pregnancy: Early and Long-Term Outcomes on the Offspring and the Concept of “Metabolic Memory”

Abstract: The adverse outcomes on the offspring from maternal diabetes in pregnancy are substantially documented. In this paper, we report main knowledge on impacts of maternal diabetes on early and long-term health of the offspring, with specific comments on maternal obesity. The main adverse outcome on progenies from pregnancy complicated with maternal diabetes appears to be macrosomia, as it is commonly known that intrauterine exposure to hyperglycemia increases the risk and programs the offspring to develop diabetes and/or obesity at adulthood. This “fetal programming”, due to intrauterine diabetic milieu, is termed as “metabolic memory”. In gestational diabetes as well as in macrosomia, the complications include metabolic abnormalities, degraded antioxidant status, disrupted immune system and potential metabolic syndrome in adult offspring. Furthermore, there is evidence that maternal obesity may also increase the risk of obesity and diabetes in offspring. However, women with GDM possibly exhibit greater macrosomia than obese women. Obesity and diabetes in pregnancy have independent and additive effects on obstetric complications, and both require proper management. Management of gestational diabetes mellitus and maternal obesity is essential for maternal and offspring's good health. Increasing physical activity, preventing gestational weight gain, and having some qualitative nutritional habits may be beneficial during both the pregnancy and offspring's future life.

Dietary Restriction Ameliorates Diabetic Nephropathy through Anti-Inflammatory Effects and Regulation of the Autophagy via Restoration of Sirt1 in Diabetic Wistar Fatty (fa/fa) Rats: A Model of Type 2 Diabetes

Abstract: Aim. Despite the beneficial effects of dietary restriction (DR) on lifespan, age-related diseases, including diabetes and cardiovascular diseases, its effects on type 2 diabetic nephropathy remain unknown. This study examined the renoprotective effects of DR in Wistar fatty (fa/fa) rats (WFRs). Methods. WFRs were treated with DR (40% restriction) for 24 weeks. Urinary albumin excretion, creatinine clearance, renal histologies, acetylated-NF-κB (p65), Sirt1 protein expression, and p62/Sqstm 1 accumulation in the renal cortex, as well as electron microscopic observation of mitochondrial morphology and autophagosomes in proximal tubular cells were estimated. Results. DR ameliorated renal abnormalities including inflammation in WFRs. The decrease in Sirt1 levels, increase in acetylated-NF-κB, and impaired autophagy in WFRs were improved by DR. Conclusions. DR exerted anti-inflammatory effects and improved the dysregulation of autophagy through the restoration of Sirt1 in the kidneys of WFRs, which resulted in the amelioration of renal injuries in type 2 diabetes.

Maternal Obesity and Developmental Programming of Metabolic Disorders in Offspring: Evidence from Animal Models

Abstract: The incidence of obesity and overweight has reached epidemic proportions in the developed world as well as in those countries transitioning to first world economies, and this represents a major global health problem. Concern is rising over the rapid increases in childhood obesity and metabolic disease that will translate into later adult obesity. Although an obesogenic nutritional environment and increasingly sedentary lifestyle contribute to our risk of developing obesity, a growing body of evidence links early life nutritional adversity to the development of long-term metabolic disorders. In particular, the increasing prevalence of maternal obesity and excess maternal weight gain has been associated with a heightened risk of obesity development in offspring in addition to an increased risk of pregnancy-related complications. The mechanisms that link maternal obesity to obesity in offspring and the level of gene-environment interactions are not well understood, but the early life environment may represent a critical window for which intervention strategies could be developed to curb the current obesity epidemic. This paper will discuss the various animal models of maternal overnutrition and their importance in our understanding of the mechanisms underlying altered obesity risk in offspring.

Gestational Diabetes Mellitus and Risk of Childhood Overweight and Obesity in Offspring: A Systematic Review

Abstract: We systematically reviewed research examining the association between gestational diabetes (GDM) and childhood overweight and obesity We identified studies from three sources: (1) a PubMed search of articles published between January 1990–January 2011, (2) reference lists of publications from the PubMed search, and (3) reference lists of review articles We included studies that examined GDM separately from pregestational diabetes and childhood overweight or obesity defined as BMI > 85th or 95th percentile A total of 12 studies were included in the systematic review Crude odds ratios for the relationship between GDM and childhood overweight or obesity ranged from 07 to 63; in 8 studies, the associations were not statistically significant In only 3 studies were results adjusted for any confounders; in the 2 that adjusted for prepregnancy obesity, the GDM and childhood overweight or obesity associations were attenuated and not statistically significant after adjustment This paper demonstrates inconsistent evidence of an association between GDM and offspring overweight and obesity due to the methodological limitations of existing studies Recommendations for future research are presented, which address methodological challenges

Diabetic nephropathy amelioration by a low-dose sitagliptin in an animal model of type 2 diabetes (Zucker diabetic fatty rat).

Abstract: This study was performed to assess the effect of chronic low-dose sitagliptin, a dipeptidyl peptidase 4 inhibitor, on metabolic profile and on renal lesions aggravation in a rat model of type-2 diabetic nephropathy, the Zucker diabetic fatty (ZDF) rat. Diabetic and obese ZDF (fa/fa) rats and their controls ZDF (+/+) were treated for 6 weeks with vehicle (control) or sitagliptin (10 mg/kg/bw). Blood/serum glucose, HbA1c, insulin, Total-c, TGs, urea, and creatinine were assessed, as well as kidney glomerular and tubulointerstitial lesions (interstitial fibrosis/tubular atrophy), using a semiquantitative rating from 0 (absent/normal) to 3 (severe and extensive damage). Vascular lesions were scored from 0–2. Sitagliptin in the diabetic rats promoted an amelioration of glycemia, HbA1c, Total-c, and TGs, accompanied by a partial prevention of insulinopenia. Furthermore, together with urea increment prevention, renal lesions were ameliorated in the diabetic rats, including glomerular, tubulointerstitial, and vascular lesions, accompanied by reduced lipid peroxidation. In conclusion, chronic low-dose sitagliptin treatment was able to ameliorate diabetic nephropathy, which might represent a key step forward in the management of T2DM and this serious complication.

Glucagon-Like Peptide-1 Receptor Agonists and Cardiovascular Events: A Meta-Analysis of Randomized Clinical Trials

Abstract: Objective. Data from randomized clinical trials with metabolic outcomes can be used to address concerns about potential issues of cardiovascular safety for newer drugs for type 2 diabetes. This meta-analysis was designed to assess cardiovascular safety of GLP-1 receptor agonists. Design and Methods. MEDLINE, Embase, and Cochrane databases were searched for randomized trials of GLP-1 receptor agonists (versus placebo or other comparators) with a duration ≥12 weeks, performed in type 2 diabetic patients. Mantel-Haenszel odds ratio with 95% confidence interval (MH-OR) was calculated for major cardiovascular events (MACE), on an intention-to-treat basis, excluding trials with zero events. Results. Out of 36 trials, 20 reported at least one MACE. The MH-OR for all GLP-1 receptor agonists was 0.74 (0.50–1.08), P = .12 (0.85 (0.50–1.45), P = .55, and 0.69 (0.40–1.22), P = .20, for exenatide and liraglutide, resp.). Corresponding figures for placebo-controlled and active comparator studies were 0.46 (0.25–0.83), P = .009, and 1.05 (0.63–1.76), P = .84, respectively. Conclusions. To date, results of randomized trials do not suggest any detrimental effect of GLP-1 receptor agonists on cardiovascular events. Specifically designed longer-term trials are needed to verify the possibility of a beneficial effect.

Development of a nongenetic mouse model of type 2 diabetes.

Abstract: Insulin resistance and loss of β-cell mass cause Type 2 diabetes (T2D). The objective of this study was to generate a nongenetic mouse model of T2D. Ninety-six 6-month-old C57BL/6N males were assigned to 1 of 12 groups including (1) low-fat diet (LFD; low-fat control; LFC), (2) LFD with 1 i.p. 40 mg/kg BW streptozotocin (STZ) injection, (3), (4), (5), (6) LFD with 2, 3, 4, or 5 STZ injections on consecutive days, respectively, (7) high-fat diet (HFD), (8) HFD with 1 STZ injection, (9), (10), (11), (12) HFD with 2, 3, 4, or 5 STZ injections on consecutive days, respectively. After 4 weeks, serum insulin levels were reduced in HFD mice administered at least 2 STZ injections as compared with HFC. Glucose tolerance was impaired in mice that consumed HFD and received 2, 3, or 4 injections of STZ. Insulin sensitivity in HFD mice was lower than that of LFD mice, regardless of STZ treatment. Islet mass was not affected by diet but was reduced by 50% in mice that received 3 STZ injections. The combination of HFD and three 40 mg/kg STZ injections induced a model with metabolic characteristics of T2D, including peripheral insulin resistance and reduced β-cell mass.

Early-life origins of type 2 diabetes: fetal programming of the beta-cell mass.

Abstract: A substantial body of evidence suggests that an abnormal intrauterine milieu elicited by maternal metabolic disturbances as diverse as undernutrition, placental insufficiency, diabetes or obesity, may program susceptibility in the fetus to later develop chronic degenerative diseases, such as obesity, hypertension, cardiovascular diseases and diabetes. This paper examines the developmental programming of glucose intolerance/diabetes by disturbed intrauterine metabolic condition experimentally obtained in various rodent models of maternal protein restriction, caloric restriction, overnutrition or diabetes, with a focus on the alteration of the developing beta-cell mass. In most of the cases, whatever the type of initial maternal metabolic stress, the beta-cell adaptive growth which normally occurs during gestation, does not take place in the pregnant offspring and this results in the development of gestational diabetes. Therefore gestational diabetes turns to be the ultimate insult targeting the offspring beta-cell mass and propagates diabetes risk to the next generation again. The aetiology and the transmission of spontaneous diabetes as encountered in the GK/Par rat model of type 2 diabetes, are discussed in such a perspective. This review also discusses the non-genomic mechanisms involved in the installation of the programmed effect as well as in its intergenerational transmission.

Exocrine pancreatic insufficiency in diabetes mellitus: a complication of diabetic neuropathy or a different type of diabetes?

Abstract: Pancreatic exocrine insufficiency is a frequently observed phenomenon in type 1 and type 2 diabetes mellitus. Alterations of exocrine pancreatic morphology can also be found frequently in diabetic patients. Several hypotheses try to explain these findings, including lack of insulin as a trophic factor for exocrine tissue, changes in secretion and/or action of other islet hormones, and autoimmunity against common endocrine and exocrine antigens. Another explanation might be that diabetes mellitus could also be a consequence of underlying pancreatic diseases (e.g., chronic pancreatitis). Another pathophysiological concept proposes the functional and morphological alterations as a consequence of diabetic neuropathy. This paper discusses the currently available studies on this subject and tries to provide an overview of the current concepts of exocrine pancreatic insufficiency in diabetes mellitus.

TGR5: A Novel Target for Weight Maintenance and Glucose Metabolism

Abstract: TGR5, an emerging G protein-coupled receptor, was identified as a membrane receptor for bile acids. The expression of TGR5 and its function are distinct from the previously identified nuclear bile acid receptor, farnesoid X receptor (FXR). These two bile acid receptors complement with each other for maintaining bile acid homeostasis and mediating bile acid signaling. Both receptors are also shown to play roles in regulating inflammation and glucose metabolism. An interesting finding for TGR5 is its role in energy metabolism. The discovery of TGR5 expression in brown adipocyte tissues (BATs) and the recent demonstration of BAT in adult human body suggest a potential approach to combat obesity by targeting TGR5 to increase thermogenesis. We summarize here the latest finding of TGR5 research, especially its role in energy metabolism and glucose homeostasis.

Effects of GLP-1 and Incretin-Based Therapies on Gastrointestinal Motor Function

Abstract: Glucagon-like peptide 1 (GLP-1) is a hormone secreted predominantly by the distal small intestine and colon and released in response to enteral nutrient exposure. GLP-1-based therapies are now used widely in the management of type 2 diabetes and have the potential to be effective antiobesity agents. Although widely known as an incretin hormone, there is a growing body of evidence that GLP-1 also acts as an enterogastrone, with profound effects on the gastrointestinal motor system. Moreover, the effects of GLP-1 on gastrointestinal motility appear to be pivotal to its effect of reducing postprandial glycaemic excursions and may, potentially, represent the dominant mechanism. This review summarizes current knowledge of the enterogastrone properties of GLP-1, focusing on its effects on gut motility at physiological and pharmacological concentrations, and the motor actions of incretin-based therapies. While of potential importance, the inhibitory action of GLP-1 on gastric acid secretion is beyond the scope of this paper.

Exercise increases insulin content and basal secretion in pancreatic islets in type 1 diabetic mice.

Abstract: Exercise appears to improve glycemic control for people with type 1 diabetes (T1D). However, the mechanism responsible for this improvement is unknown. We hypothesized that exercise has a direct effect on the insulin-producing islets. Eight-week-old mice were divided into four groups: sedentary diabetic, exercised diabetic, sedentary control, and exercised control. The exercised groups participated in voluntary wheel running for 6 weeks. When compared to the control groups, the islet density, islet diameter, and β-cell proportion per islet were significantly lower in both sedentary and exercised diabetic groups and these alterations were not improved with exercise. The total insulin content and insulin secretion were significantly lower in sedentary diabetics compared to controls. Exercise significantly improved insulin content and insulin secretion in islets in basal conditions. Thus, some improvements in exercise-induced glycemic control in T1D mice may be due to enhancement of insulin content and secretion in islets.

Neural Degeneration in the Retina of the Streptozotocin-Induced Type 1 Diabetes Model

Abstract: Diabetic retinopathy, a vision-threatening disease, has been regarded as a vascular disorder. However, impaired oscillatory potentials (OPs) in the electroretinogram (ERG) and visual dysfunction are recorded before severe vascular lesions appear. Here, we review the molecular mechanisms underlying the retinal neural degeneration observed in the streptozotocin-(STZ-) induced type 1 diabetes model. The renin-angiotensin system (RAS) and reactive oxygen species (ROS) both cause OP impairment and reduced levels of synaptophysin, a synaptic vesicle protein for neurotransmitter release, most likely through excessive protein degradation by the ubiquitin-proteasome system. ROS also decrease brain-derived neurotrophic factor (BDNF) and inner retinal neuronal cells. The influence of both RAS and ROS on synaptophysin suggests that RAS-ROS crosstalk occurs in the diabetic retina. Therefore, suppressors of RAS or ROS, such as angiotensin II type 1 receptor blockers or the antioxidant lutein, respectively, are potential candidates for neuroprotective and preventive therapies to improve the visual prognosis.

Exogenous superoxide dismutase: action on liver oxidative stress in animals with streptozotocin-induced diabetes.

Abstract: Aim. To investigate the effects of exogenous antioxidant copper zinc superoxide dismutase (Cu/Zn SOD) on oxidative stress in the experimental model of diabetes mellitus (DM). Methods. Twenty eight male Wistar rats divided in four groups were used: control (CO), controls treated with SOD (CO

Role of T Cells in Type 2 Diabetic Nephropathy

Abstract: Type 2 diabetic nephropathy (DN) is the most common cause of end-stage renal disease and is increasingly considered as an inflammatory disease characterized by leukocyte infiltration at every stage of renal involvement Inflammation and activation of the immune system are closely involved in the pathogenesis of diabetes and its microvascular complications Macrophage has been well recognized to play an important role in type 2 DN, leukocyte infiltration, and participated in process of DN, as was proposed recently Th1, Th2, Th17, T reg, and cytotoxic T cells are involved in the development and progression of DN The purpose of this review is to assemble current information concerning the role of T cells in the development and progression of type 2 DN Specific emphasis is placed on the potential interaction and contribution of the T cells to renal damage The therapeutic strategies involving T cells in the treatment of type 2 DN are also reviewed Improving knowledge of the recognition of T cells as significant pathogenic mediators in DN reinforces the possibility of new potential therapeutic targets translated into future clinical treatments

Fetoplacental Vascular Endothelial Dysfunction as an Early Phenomenon in the Programming of Human Adult Diseases in Subjects Born from Gestational Diabetes Mellitus or Obesity in Pregnancy

Abstract: Gestational diabetes mellitus (GDM) and obesity in pregnancy (OP) are pathological conditions associated with placenta vascular dysfunction coursing with metabolic changes at the fetoplacental microvascular and macrovascular endothelium. These alterations are seen as abnormal expression and activity of the cationic amino acid transporters and endothelial nitric oxide synthase isoform, that is, the “endothelial L-arginine/nitric oxide signalling pathway.” Several studies suggest that the endogenous nucleoside adenosine along with insulin, and potentially arginases, are factors involved in GDM-, but much less information regards their role in OP-associated placental vascular alterations. There is convincing evidence that GDM and OP prone placental endothelium to an “altered metabolic state” leading to fetal programming evidenced at birth, a phenomenon associated with future development of chronic diseases. In this paper it is suggested that this pathological state could be considered as a metabolic marker that could predict occurrence of diseases in adulthood, such as cardiovascular disease, obesity, diabetes mellitus (including gestational diabetes), and metabolic syndrome.

Activation of the GLP-1 Receptor Signalling Pathway: A Relevant Strategy to Repair a Deficient Beta-Cell Mass

Abstract: Recent preclinical studies in rodent models of diabetes suggest that exogenous GLP-1R agonists and DPP-4 inhibitors have the ability to increase islet mass and preserve beta-cell function, by immediate reactivation of beta-cell glucose competence, as well as enhanced beta-cell proliferation and neogenesis and promotion of beta-cell survival. These effects have tremendous implication in the treatment of T2D because they directly address one of the basic defects in T2D, that is, beta-cell failure. In human diabetes, however, evidence that the GLP-1-based drugs alter the course of beta-cell function remains to be found. Several questions surrounding the risks and benefits of GLP-1-based therapy for the diabetic beta-cell mass are discussed in this review and require further investigation.

Maternal Obesity and the Early Origins of Childhood Obesity: Weighing Up the Benefits and Costs of Maternal Weight Loss in the Periconceptional Period for the Offspring

Abstract: There is a need to understand the separate or interdependent contributions of maternal prepregnancy BMI, gestational weight gain, glycaemic control, and macronutrient intake on the metabolic outcomes for the offspring. Experimental studies highlight that there may be separate influences of maternal obesity during the periconceptional period and late gestation on the adiposity of the offspring. While a period of dietary restriction in obese mothers may ablate the programming of obesity, it is associated with an activation of the stress axis in the offspring. Thus, maternal obesity may result in epigenetic changes which predict the need for efficient fat storage in postnatal life, while maternal weight loss may lead to epigenetic changes which predict later adversity. Thus, development of dietary interventions for obese mothers during the periconceptional period requires a greater evidence base which allows the effective weighing up of the metabolic benefits and costs for the offspring.

Maternal behaviors during pregnancy impact offspring obesity risk.

Abstract: This study investigated the effects of maternal changes during pregnancy in diet, exercise, and psychosocial factors on offspring weight parameters at birth and 6 months. In overweight/obese (OW/OB; n = 132 ) mothers, greater % kcal from sweets early in pregnancy was the strongest, independent predictor of higher weight for age (WFA) (beta = 0 . 19 ; P = 0 . 004 ), higher odds of macrosomia (OR = 1.1 (1.0–1.2); P = 0 . 004 ) andWFA >90th percentile at birth (OR = 1.2 (1.1–1.3); P = 0 . 002 ) and higher WFA at 6 months (beta = 0 . 30 ; P = 0 . 002 ). In normal weight ( n = 153 ) mothers, higher intake of soft drinks was the strongest predictor of higher offspring WFA at birth (beta = 0.16; P = 0 . 04 ) but not at 6 months. Prenatal physical activity, depressive symptoms, and sleep-related variables did not significantly predict offspring weight outcomes. Mothers’ eating behaviors during pregnancy, especially intake of sweets in OW/OB mothers, may have a lasting effect on child weight.

Angiotensin II Type II Receptor Deficiency Accelerates the Development of Nephropathy in Type I Diabetes via Oxidative Stress and ACE2

Abstract: Since the functional role(s) of angiotensin II (Ang II) type II receptor (AT2R) in type I diabetes is unknown, we hypothesized that AT2R is involved in decreasing the effects of type I diabetes on the kidneys. We induced diabetes with low-dose streptozotocin (STZ) in both AT2R knockout (AT2RKO) and wild-type (WT) male mice aged 12 weeks and followed them for 4 weeks. Three subgroups nondiabetic, diabetic, and insulin-treated diabetic (Rx insulin implant) were studied. Systolic blood pressure (SBP), physiological parameters, glomerular filtration rate (GFR), renal morphology, gene expression, and apoptosis were assessed. After 4 weeks of diabetes, compared to WT controls, AT2RKO mice clearly developed features of early diabetic nephropathy (DN), such as renal hypertrophy, tubular apoptosis, and progressive extracellular matrix (ECM) protein accumulation as well as increased GFR. AT2RKO mice presented hypertension unaffected by diabetes. Renal oxidative stress (measured as heme oxygenase 1 (HO-1) gene expression and reactive oxygen species (ROS) generation) and intrarenal renin angiotensin system components, such as angiotensinogen (Agt), AT1R, and angiotensin-converting enzyme (ACE) gene expression, were augmented whereas angiotensin-converting enzyme2 (ACE2) gene expression was decreased in renal proximal tubules (RPTs) of AT2RKO mice. The renal changes noted above were significantly enhanced in diabetic AT2RKO mice but partially attenuated in insulin-treated diabetic WT and AT2RKO mice. In conclusion, AT2R deficiency accelerates the development of DN, which appears to be mediated, at least in part, via heightened oxidative stress and ACE/ACE2 ratio in RPTs.

Phenotypic changes in diabetic neuropathy induced by a high-fat diet in diabetic C57BL/6 mice

Abstract: Emerging evidence suggests that dyslipidemia is an independent risk factor for diabetic neuropathy (DN) (reviewed by Vincent et al. 2009). To experimentally determine how dyslipidemia alters DN, we quantified neuropathic symptoms in diabetic mice fed a high-fat diet. Streptozotocin-induced diabetic C57BL/6 mice fed a high-fat diet developed dyslipidemia and a painful neuropathy (mechanical allodynia) instead of the insensate neuropathy (mechanical insensitivity) that normally develops in this strain. Nondiabetic mice fed a high-fat diet also developed dyslipidemia and mechanical allodynia. Thermal sensitivity was significantly reduced in diabetic compared to nondiabetic mice, but was not worsened by the high-fat diet. Moreover, diabetic mice fed a high-fat diet had significantly slower sensory and motor nerve conduction velocities compared to nondiabetic mice. Overall, dyslipidemia resulting from a high-fat diet may modify DN phenotypes and/or increase risk for developing DN. These results provide new insight as to how dyslipidemia may alter the development and phenotype of diabetic neuropathy.

Insulin receptor substrate 2 expression and involvement in neuronal insulin resistance in diabetic neuropathy.

Abstract: Insulin signaling depends on tyrosine phosphorylation of insulin receptor substrates (IRSs) to mediate downstream effects; however, elevated serine phosphorylation of IRS impairs insulin signaling. Here, we investigated IRS protein expression patterns in dorsal root ganglia (DRG) of mice and whether their signaling was affected by diabetes. Both IRS1 and IRS2 are expressed in DRG; however, IRS2 appears to be the prevalent isoform and is expressed by many DRG neuronal subtypes. Phosphorylation of Ser(731)IRS2 was significantly elevated in DRG neurons from type 1 and type 2 diabetic mice. Additionally, Akt activation and neurite outgrowth in response to insulin were significantly decreased in DRG cultures from diabetic ob/ob mice. These results suggest that DRG neurons express IRS proteins that are altered by diabetes similar to other peripheral tissues, and insulin signaling downstream of the insulin receptor may be impaired in sensory neurons and contribute to the pathogenesis of diabetic neuropathy.

Intergenerational Cycle of Obesity and Diabetes: How Can We Reduce the Burdens of These Conditions on the Health of Future Generations?

Abstract: Prepregnancy overweight or obesity and excessive gestational weight gain have been associated with increased risk of maternal and neonatal complications. Moreover, offspring from obese women are more likely to develop obesity, diabetes mellitus, and cardiovascular diseases in their lifetime. Gestational diabetes mellitus (GDM) is one of the most common complications associated with obesity and appears to have a direct impact on the future metabolic health of the child. Fetal programming of metabolic function induced by obesity and GDM may have intergenerational effect and thus perpetuate the epidemic of cardiometabolic conditions. The present paper thus aims at discussing the impact of maternal obesity and GDM on the developmental programming of obesity and metabolic disorders in the offspring. The main interventions designed to reduce maternal obesity and GDM and their ability to break the vicious circle that perpetuates the transmission of obesity and metabolic conditions to the next generations are also addressed.

Blood Sugar Lowering Effect of Coccinia grandis (L.) J. Voigt: Path for a New Drug for Diabetes Mellitus

Abstract: Background. Role of herbs in the management and control of diabetes has emerged fast over the years. We assessed the efficacy of Coccinia grandis (locally known as Ken, Kovakka) leaves as a hypoglycemic agent. Methods. Double-blind phase I clinical trial was conducted at the general hospital and a private hospital in Matara in August 2009. All the participants were given a common meal for dinner, and they maintained a 10-hour fasting period. Sixty-one healthy volunteers were given a meal containing 20 g of leaves of Coccinia grandis which was mixed with a measured amount of scraped coconut and table salt for breakfast, and other 61 were given the placebo meal which also contained scraped coconut and salt. Glucose tolerance test was performed blindly for the two groups. Mixed factorial design analysis of variance and student's t-test were applied. Results. Overall blood sugar levels of the experimental group were also significantly lower than those of the control group (F(1,117) 5.56, 𝑃 0 . 0 5 ). Increase in the blood sugar levels from fasting to one hour (F(1,117) 6.77, 𝑃 0 . 0 5 ) and two hours (F(1,117) 5.28, 𝑃 0 . 0 5 ) postprandially was statistically significant for participants who were in the control group than those of in the experimental group. The mean difference of postprandial blood sugar levels (mg/dL) after one hour (20.2, 95% confidence interval, 4.81 to 35.5) and two hours (11.46, 95% confidence interval; 1.03 to 21.9) was statistically significant between the two groups. Conclusions. Coccinia grandis has a blood sugar lowering effect. However further studies are needed to validate our findings.

The Effect of Metformin on the Myocardial Tolerance to Ischemia-Reperfusion Injury in the Rat Model of Diabetes Mellitus Type II

Abstract: In recent years, evidence has been accumulated that metformin, an antidiabetic drug in the biguanide class, in addition to its well-recognized glucose-lowering effect, can also reduce cardiovascular mortality in the patients with type 2 diabetes mellitus (T2DM). Besides, there are a few experimental studies on the possibility of the direct anti-ischemic effect of the drug in both type 1 diabetes mellitus and T2DM. In our study, myocardial tolerance to ischemia in rats with neonatal streptozotocin T2DM was investigated using the model of global ischemia-reperfusion of the isolated perfused heart. Metformin was administered i.p. at a dose of 200 mg/kg/day for 3 days prior to isolated heart perfusion. The results showed that both the infarct size and postischemic recovery of left ventricular function were not different between controls and metformin-treated animals. At the same time, the infarct size in the T2DM animals was significantly lower than that in the controls (24.4 ± 7.6% versus 45.0 ± 10.4%, resp., ), indicative of the metabolic preconditioning in T2DM. It follows that the protocol of metformin administration used in this study had not elicited cardioprotective effect in animals with T2DM so that the different mechanism(s) may underlie the beneficial effect of metformin on cardiovascular complications in patients with T2DM which, however, would need further investigation.

Neurovascular Interaction and the Pathophysiology of Diabetic Retinopathy

Abstract: Diabetic retinopathy (DR) is the most severe of the several ocular complications of diabetes, and in the United States it is the leading cause of blindness among adults 20 to 74 years of age. Despite recent advances in our understanding of the pathogenesis of DR, there is a pressing need to develop novel therapeutic treatments that are both safe and efficacious. In the present paper, we identify a key mechanism involved in the development of the disease, namely, the interaction between neuronal and vascular activities. Numerous pathological conditions in the CNS have been linked to abnormalities in the relationship between these systems. We suggest that a similar situation arises in the diabetic retina, and we propose a logical strategy aimed at therapeutic intervention.

Obesity and Blood Pressure in 17-Year-Old Offspring of Mothers with Gestational Diabetes: Insights from the Jerusalem Perinatal Study

Abstract: Objective. Gestational diabetes mellitus (GDM) influences fetal development and offspring's metabolic risk. We evaluated this association in 17-year-old offspring adjusting for birth weight (BW) and prepregnancy maternal BMI (mBMI). Study Design. The JPS birth cohort contains extensive data on 92,408 births from 1964 to 1976. Offspring's BMI and blood pressure (BP) were obtained from military records. For a subcohort born between 1974 and 1976, prepregnancy mBMI was available. Offspring were classified as born to mothers with GDM (n = 293) or born to mothers without recorded GDM (n = 59,499). Results. GDM offspring had higher mean BMI and systolic and diastolic BP compared to no-recorded-GDM offspring. After adjusting for BW, GDM remained significantly associated with offspring BMI and diastolic BP (β = 1.169 and 1.520, resp.). In the subcohort, when prepregnancy mBMI was entered to the models, it markedly attenuated the associations with GDM. Conclusions. Maternal characteristics have long-term effects on cardiometabolic outcomes of their offspring aged 17 years.

Extrinsic factors involved in the differentiation of stem cells into insulin-producing cells: an overview

Abstract: Diabetes mellitus is a chronic disease with many debilitating complications. Treatment of diabetes mellitus mainly revolves around conventional oral hypoglycaemic agents and insulin replacement therapy. Recently, scientists have turned their attention to the generation of insulin-producing cells (IPCs) from stem cells of various sources. To date, many types of stem cells of human and animal origins have been successfully turned into IPCs in vitro and have been shown to exert glucose-lowering effect in vivo. However, scientists are still faced with the challenge of producing a sufficient number of IPCs that can in turn produce sufficient insulin for clinical use. A careful choice of stem cells, methods, and extrinsic factors for induction may all be contributing factors to successful production of functional beta-islet like IPCs. It is also important that the mechanism of differentiation and mechanism by which IPCs correct hyperglycaemia are carefully studied before they are used in human subjects.

Dysregulation of the Intrarenal Vitamin D Endocytic Pathway in a Nephropathy-Prone Mouse Model of Type 1 Diabetes

Abstract: Microalbuminuria in humans with Type 1 diabetes (T1D) is associated with increased urinary excretion of megalin, as well as many megalin ligands, including vitamin-D-binding protein (VDBP). We examined the DBA/2J diabetic mouse, nephropathy prone model, to determine if megalin and VDBP excretion coincide with the development of diabetic nephropathy. Megalin, VDBP, and 25-hydroxy-vitamin D (25-OHD) were measured in urine, and genes involved in vitamin D metabolism were assessed in renal tissues from diabetic and control mice at 10, 15, and 18 weeks following the onset of diabetes. Megalin, VDBP, and 25-OHD were increased in the urine of diabetic mice. 1-α hydroxylase (CYP27B1) mRNA in the kidney was persistently increased in diabetic mice, as were several vitamin D-target genes. These studies show that intrarenal vitamin D handling is altered in the diabetic kidney, and they suggest that in T1D, urinary losses of VDBP may portend risk for intrarenal and extrarenal vitamin D deficiencies.

Glucagon-Like Peptide-1, Diabetes, and Cognitive Decline: Possible Pathophysiological Links and Therapeutic Opportunities

Abstract: Metabolic and neurodegenerative disorders have a growing prevalence in Western countries. Available epidemiologic and neurobiological evidences support the existence of a pathophysiological link between these conditions. Glucagon-like peptide 1 (GLP-1), whose activity is reduced in insulin resistance, has been implicated in central nervous system function, including cognition, synaptic plasticity, and neurogenesis. We review the experimental researches suggesting that GLP-1 dysfunction might be a mediating factor between Type 2 diabetes mellitus (T2DM) and neurodegeneration. Drug treatments enhancing GLP-1 activity hold out hope for treatment and prevention of Alzheimer's disease (AD) and cognitive decline.