Metabolic Abnormalities Of Diabetes Research Articles

Gut Microbiota and Their Associated Metabolites in Diabetes: A Cross Talk Between Host and Microbes-A Review.

Dysbiosis of the gut microbiota's composition and function is important in developing insulin resistance and diabetes. Diabetes has also been linked to changes in the circulating and fecal metabolites. Evidence suggests the associations between the gut microbiota and the aberrant diabetes-related metabolome. Metabolites play a crucial role in the host-microbiota interactions. Researchers have used a combination of metagenomic and metabolomic approaches to investigate the relationships between gut microbial dysbiosis and metabolic abnormalities in diabetes. We summarized current discoveries on the associations between the gut microbiota and metabolites in type 1 diabetes, type 2 diabetes, and gestational diabetes mellitus in the scoping review. According to research, the gut microbiota changes might involve in the development of diabetes through modulating the host's metabolic pathways such as immunity, energy metabolism, lipid metabolism, and amino acid metabolism. These results add to our understanding of the interplay between the host and gut microbiota metabolism.

Oxidative status and its relationship with glycemic state in children with type 1 diabetes mellitus

Background Diabetes represents one of the most common diseases in school-aged children. Poor glycemic control in type 1 diabetes mellitus (T1DM) usually leads to more oxidative stress, increased production of oxygen-free radicals, and more diabetic complications. Oxidative stress plays a pivotal role in the development of diabetes complications, both microvascular and cardiovascular. The metabolic abnormalities of diabetes cause mitochondrial superoxide overproduction in endothelial cells of both large and small vessels and also in the myocardium. Aim The aim of the current study was to assess the oxidative status and its relationship with glycemic state of T1DM in children. Patients and methods This was a case–control study conducted on 50 children. The first group enrolled 30 children aged 2–12 years of both sexes with T1DM selected from patients attending the outpatient clinic of endocrinology unit of Mansoura University Children’s Hospital in the period between December 2020 and December 2021 and were compared with 20 age-matched and sex-matched children who served as healthy controls. Results The malondialdehyde (MDA) and MDA/total antioxidant capacity ratio were significantly increased among cases compared with the control group. MDA and MDA/total antioxidant capacity ratio could be used as reliable predictors for differentiating between cases and controls with high sensitivity and specificity. However, they could not be used as a reliable indicator for differentiation between cases with microalbuminuria from case without. Oxidant/antioxidant status seemed to be significantly increased among cases with poor diabetic control followed by controlled diabetic group and lastly the healthy control group. Conclusion Cases with T1DM were associated with a significant increase in oxidative stress, especially in poor controlled ones. Additionally, oxidative stress markers could be used as valid markers for T1DM.

Vascular CaV1.2 channels in diabetes.

Diabetic vasculopathy is a significant cause of morbidity and mortality in the diabetic population. Hyperglycemia, one of the central metabolic abnormalities in diabetes, has been associated with vascular dysfunction due to endothelial cell damage. However, studies also point toward vascular smooth muscle as a locus for hyperglycemia-induced vascular dysfunction. Emerging evidence implicates hyperglycemia-induced regulation of vascular L-type Ca2+ channels CaV1.2 as a potential mechanism for vascular dysfunction during diabetes. This chapter summarizes our current understanding of vascular CaV1.2 channels and their regulation during physiological and hyperglycemia/diabetes conditions. We will emphasize the role of CaV1.2 in vascular smooth muscle, the effects of elevated glucose on CaV1.2 function, and the mechanisms underlying its dysregulation in hyperglycemia and diabetes. We conclude by examining future directions and gaps in knowledge regarding CaV1.2 regulation in health and during diabetes.

Differential regulation of lipopolysaccharide-induced IL-1β and TNF-α production in macrophages by palmitate via modulating TLR4 downstream signaling

Diabetic patients are susceptible to infectious diseases. Bacterial invasion activates immune cells such as macrophages through interaction between LPS and TLR4, and induces the expression of inflammatory mediators, including IL-1β and TNF-α, which play key roles in the elimination of infections. Unregulated overproduction or underproduction of these cytokines has been reported as a major factor in the development of septic shock, immune deficiency, and autoimmunity. Recent studies found that metabolic abnormalities of diabetes, such as hyperglycemia and dyslipidemia, played a major role in modulating the immune response. In this study, we studied the effects of palmitic acid (PA) pretreatment on LPS-induced IL-1β and TNF-α production and LPS-TLR4 signaling in macrophages. Compared with control, PA pretreatment significantly increased LPS-induced TNF-α production and secretion in macrophages. In contrast, LPS-induced IL-1β production and secretion was significantly suppressed by PA pretreatment. PA pretreatment did not affect the expression levels of TLR4 or Myd88, or the endocytosis of TLR4 in macrophages. However, PA pretreatment significantly suppressed the phosphorylation level and nuclear translocation of NF-κB, and the phosphorylation level of ERK1/2, whereas increased the phosphorylation levels of p38 and JNK. The activation of IKK which was upstream of NF-κB and ERK1/2 was attenuated, while the activation of TAK1 which was upstream of JNK and p38 was augmented by PA pretreatment. Inhibitors of NF-κB, MEK1/2, and p38 significantly decreased IL-1β expression, while JNK and p38 pathway inhibitors significantly inhibited TNF-α expression. The differential regulation of LPS-induced TNF-α and IL-1β production by PA was associated with cellular metabolism of PA, because inhibiting metabolism of PA with etomoxir or pretreatment with Br-PA which cannot be metabolized reversed these effects. We also showed that PA treatment increased acetylated IKK level which might contribute to the suppressed activation of IKK. The present study showed that LPS-induced production of TNF-α and IL-1β was regulated by different TLR4 downstream pathways in macrophages. PA differentially affected LPS-induced production of TNF-α and IL-1β in macrophages through differentially modulating these pathways. Further experiments will be needed to determine how these phenomena lead to the impaired immune response in patients with diabetes.

MON-165 The Risk of Developing Cardiovascular Diseases Increases with Age in Type 2 Diabetes Mellitus Patients in Yenagoa, Bayelsa State, Niger Delta Region of Nigeria

Background and objective: Patients with type 2 Diabetes mellitus (DM) are known to be at risk of developing cardiovascular diseases (CVD). The prevalence and incidence of DM patients with heart diseases is unknown in Yenagoa and its environ of Bayelsa State, Niger Delta Region of Nigeria. The study investigated the incidence of CVD in chronic DM patients and compared the prevalence in both male and female subjects with respect to the duration of illness. The goals of screening are to improve life expectancy and quality of life by preventing Myocardial infarction (MI) and heart failure through the early detection of significant CVD. Study Design and Methods: A total of 355 type 2 DM patients were recruited for the study. They were grouped into 135 DM patients that have suffered the Diabetes for less than 10years, 119 for 10-20years and 101 for 21 and above years. The plasma levels of the Cardiac Markers, Troponin I (CTnI), Troponin T (cTnT), Creatine Kinase (CK-MB), Myoglobin (MYO) and Lactate dehydrogenase (LDH) were determined in the subjects. The method of fluorescence immunoassay (FIA) was used in the measurement of CTn1, CTnT and MYO. Enzyme linked immunosorbent assay (ELISA) was used to determine the CK-MB and LDH. Results: Analysis of the results has shown that 20.54% of the studied subjects were diagnosed of various CVD and were statistically significant (P<0.05). Of this, 12.92% were females and 7.62% were males. 54.05% of DM subjects diagnosed of CVD were from group 21 and above years while 32.43% were from group 10 t0 20 years and 13.52% from those that had suffered it for <10 years. 32.96% of the total DM patients studied had either one or more of the cardiac markers elevated, showing the potentials of developing heart diseases. This is because the metabolic abnormalities of diabetes cause mitochondrial superoxide over production in endothelial cell of both large and small vessels as well as in the myocardium that leads to complications. The pair wise correlations between measured parameters in the DM patients with CVD showed a positive correlation. Conclusion: The risk of developing cardiovascular disease in DM in Yenagoa Bayelsa State. Niger Delta Region of Nigeria is more in the females with DM and those that have long duration of the illness.

Metabolic Abnormalities in Diabetes and Kidney Disease: Role of Uremic Toxins.

Chronic kidney disease (CKD) is characterized by the accumulation of uremic retention solutes (URS) and is associated with perturbations of glucose homeostasis even in absence of diabetes. The underlying mechanisms of insulin resistance, β cell failure, and increase risk of diabetes in CKD, however, remain unclear. Metabolomic studies reported that some metabolites are similar in CKD and diabetic kidney disease (DKD) and contribute to the progression to end-stage renal disease. We attempted to discuss the mechanisms involved in the disruption of carbohydrate metabolism in CKD by focusing on the specific role of URS. Recent clinical data have demonstrated a defect of insulin secretion in CKD. Several studies highlighted the direct role of some URS (urea, trimethylamine N-oxide (TMAO), p-cresyl sulfate, 3-carboxylic acid 4-methyl-5-propyl-2-furan propionic (CMPF)) in glucose homeostasis abnormalities and diabetes incidence. Gut dysbiosis has been identified as a potential contributor to diabetes and to the production of URS. The complex interplay between the gut microbiota, kidney, pancreas β cell, and peripheral insulin target tissues has brought out new hypotheses for the pathogenesis of CKD and DKD. The characterization of intestinal microbiota and its associated metabolites are likely to fill fundamental knowledge gaps leading to innovative research, clinical trials, and new treatments for CKD and DKD.

The role of amylin in the development of diabetic osteopathy

Diabetes mellitus adversely affects the bone. Basically, it is related to weakening of the anabolic effect of insulin and other pancreatic hormones. Mechanisms underlying the decrease in bone density are not fully understood. However, many of the systemic changes related to metabolic abnormalities in diabetes have a damaging effect on the bone tissue. Inadequate compensation of glycemic profile in this disease, both directly (non-enzymatic glycosylation of proteins, activation of polyol pathway of glucose metabolism, oxidative stress) and indirectly (violation of gene expression), damages the bone structure. Another anabolic hormone produced by β-cells of the pancreas is amylin. It is a potent hypoglycemic and antiresorptive hormone affecting calcium homeostasis and influencing the preservation of bone density. The studies have shown that amylin, on the one hand, stimulates osteoblast proliferation, and on the other hand, inhibits osteoclast motility, thus acting similar to calcitonin. Inefficient redistribution of bone mass occurs. This may explain the increased incidence of fractures in patients with type 2 diabetes on the background of high bone density according to densitometry. In this regard, further studies are required to clarify the effect of amylin deficiency on the development of osteoporosis.

A comparative study of lipid profile, body mass index, and waist circumference among Type 2 diabetes mellitus patients with poor and good metabolic control and normal age-matched control group

Background: Prevalence of dyslipidemia is very common in Type 2 diabetes mellitus (DM), and lipid abnormalities are likely to play an important role in the development of the atherosclerotic vascular disease. Type 2 diabetic patients are obese, and obesity as an independent risk factor for diabetes also complicates the management and exacerbates the metabolic abnormalities in diabetes. Aims and Objectives: To compare the lipid profile, body mass index (BMI), and waist circumference (WC) in Type 2 diabetic patients with poor and good metabolic controls with that of normal controls and to study the correlation between glycosylated hemoglobin (HbA1c) values and triglycerides (TG), high-density lipoprotein (HDL) in patients with Type 2 DM. Materials and Methods: The descriptive comparative study group of 150 subjects was divided into three groups based on HbA1c values which included Type 2 diabetic patients with poor metabolic control, good metabolic control, and normal age-matched controls. Results: There is a significant increase in the mean levels of total cholesterol, TG, low-density lipoprotein (LDL), and Very low density lipoproteins (VLDL) values in diabetic patients with both poor metabolic control and good metabolic control when compared to normal controls. There is a significant decrease in mean HDL values and significant elevation of mean waist circumference and BMI values in both male and female diabetics with poor and good metabolic controls when compared to normal controls. Highly significant positive correlation was obtained between HbA1c and TG and a negative correlation between HbA1c and HDL. Conclusion: Increase in TG and decline in HDL with HbA1c rise shows the impact of glycemic control on lipoprotein levels. Majority of diabetic patients were overweight and had abdominal adiposity. Good metabolic control of hyperglycemia will prevent alteration of lipid metabolism helping in better prognosis and preventing manifestations of vascular and typical secondary complications.

Irisin inhibits hepatic gluconeogenesis and increases glycogen synthesis via the PI3K/Akt pathway in type 2 diabetic mice and hepatocytes.

Increased glucose production and reduced hepatic glycogen storage contribute to metabolic abnormalities in diabetes. Irisin, a newly identified myokine, induces the browning of white adipose tissue, but its effects on gluconeogenesis and glycogenesis are unknown. In the present study, we investigated the effects and underlying mechanisms of irisin on gluconeogenesis and glycogenesis in hepatocytes with insulin resistance, and its therapeutic role in type 2 diabetic mice. Insulin resistance was induced by glucosamine (GlcN) or palmitate in human hepatocellular carcinoma (HepG2) cells and mouse primary hepatocytes. Type 2 diabetes was induced by streptozotocin/high-fat diet (STZ/HFD) in mice. In HepG2 cells, irisin ameliorated the GlcN-induced increases in glucose production, phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) expression, and glycogen synthase (GS) phosphorylation; it prevented GlcN-induced decreases in glycogen content and the phosphoinositide 3-kinase (PI3K) p110α subunit level, and the phosphorylation of Akt/protein kinase B, forkhead box transcription factor O1 (FOXO1) and glycogen synthase kinase-3 (GSK3). These effects of irisin were abolished by the inhibition of PI3K or Akt. The effects of irisin were confirmed in mouse primary hepatocytes with GlcN-induced insulin resistance and in human HepG2 cells with palmitate-induced insulin resistance. In diabetic mice, persistent subcutaneous perfusion of irisin improved the insulin sensitivity, reduced fasting blood glucose, increased GSK3 and Akt phosphorylation, glycogen content and irisin level, and suppressed GS phosphorylation and PEPCK and G6Pase expression in the liver. Irisin improves glucose homoeostasis by reducing gluconeogenesis via PI3K/Akt/FOXO1-mediated PEPCK and G6Pase down-regulation and increasing glycogenesis via PI3K/Akt/GSK3-mediated GS activation. Irisin may be regarded as a novel therapeutic strategy for insulin resistance and type 2 diabetes.

Advances around technologies investigating mitochondrial function and insights gained by their applications.

Diabetes mellitus is defined as a state of persistently high levels of blood glucose and insulin deficiency, and resistance to it is considered as the cause(s). However, the metabolic abnormalities of diabetes are not limited to glucose, but encompass the entire metabolism. Insulin controls not only glucose, but fat and protein metabolism as well. Furthermore, body structures of patients with this disease become abnormal, termed complications, which eventually lead to the death of patients.

Oxidative Stress and Diabetic Complications

Oxidative stress plays a pivotal role in the development of diabetes complications, both microvascular and cardiovascular. The metabolic abnormalities of diabetes cause mitochondrial superoxide overproduction in endothelial cells of both large and small vessels, as well as in the myocardium. This increased superoxide production causes the activation of 5 major pathways involved in the pathogenesis of complications: polyol pathway flux, increased formation of AGEs (advanced glycation end products), increased expression of the receptor for AGEs and its activating ligands, activation of protein kinase C isoforms, and overactivity of the hexosamine pathway. It also directly inactivates 2 critical antiatherosclerotic enzymes, endothelial nitric oxide synthase and prostacyclin synthase. Through these pathways, increased intracellular reactive oxygen species (ROS) cause defective angiogenesis in response to ischemia, activate a number of proinflammatory pathways, and cause long-lasting epigenetic changes that drive persistent expression of proinflammatory genes after glycemia is normalized ("hyperglycemic memory"). Atherosclerosis and cardiomyopathy in type 2 diabetes are caused in part by pathway-selective insulin resistance, which increases mitochondrial ROS production from free fatty acids and by inactivation of antiatherosclerosis enzymes by ROS. Overexpression of superoxide dismutase in transgenic diabetic mice prevents diabetic retinopathy, nephropathy, and cardiomyopathy. The aim of this review is to highlight advances in understanding the role of metabolite-generated ROS in the development of diabetic complications.

The correlation between the oral glucose tolerance test 30-minutes plasma glucose and risk factors for diabetes and cardiovascular diseases: A cross-sectional epidemiological study of diabetes in Fujian Province in the South-East of China

To investigate the correlation between abnormal oral glucose tolerance test (OGTT) 30-min plasma glucose (PG) and risk factors and metabolic abnormalities of diabetes and cardiovascular diseases (CVD). Participants (no.=2457) underwent a physical examination, blood biochemistry examination, OGTT, and a 12-lead electrocardiogram. We measured fasting PG (FPG) and PG at 30 min (30minPG) and 1 h (1hPG) of the OGTT. The association between an increase in 30minPG (by 1 SD) and the metabolic abnormalities of diabetes and CVD such as hypertension, overweight and obesity, central obesity, and hyperlipidemia; osteoporosis was assessed by logistic regression analysis after controlling for FPG and 2hPG. This analysis showed that an increase of 30minPG by 1 SD (1.92 mmol/l) significantly increased the risk of chronic metabolic abnormalities in diabetes and CVD such as hypertension, overweight, and obesity, central obesity, hyperlipidemia, and osteoporosis. Stepwise multiple regression analysis also showed that 30minPG was significantly correlated with male gender, smoking, FPG, 2hPG, total cholesterol, waist/hip ratio, and blood pressure. An elevation of 30minPG increased the risk of diabetes and CVD. The increased risk was independent of FPG, 2hPG, age, sex, and smoking status.

FoxO1 Links Hepatic Insulin Action to Endoplasmic Reticulum Stress

Forkhead box O1 (FoxO1) is a transcription factor that mediates the inhibitory effect of insulin on target genes in hepatic metabolism. Hepatic FoxO1 activity is up-regulated to promote glucose production during fasting and is suppressed to limit postprandial glucose excursion after meals. Increased FoxO1 activity augments the expression of insulin receptor (IR) and IR substrate (IRS)2, which in turn inhibits FoxO1 activity in response to reduced insulin action. To address the underlying physiology of such a feedback loop for regulating FoxO1 activity, we delivered FoxO1-ADA by adenovirus-mediated gene transfer into livers of adult mice. FoxO1-ADA is a constitutively active allele that is refractory to insulin inhibition, allowing us to determine the metabolic effect of a dislodged FoxO1 feedback loop in mice. We show that hepatic FoxO1-ADA production resulted in significant induction of IR and IRS2 expression. Mice with increased FoxO1-ADA production exhibited near glycogen depletion. Unexpectedly, hepatic FoxO1-ADA production elicited a profound unfolded protein response, culminating in the induction of hepatic glucose-regulated protein 78 (GRP78) expression. These findings were recapitulated in primary human and mouse hepatocytes. FoxO1 targeted GRP78 gene for trans-activation via selective binding to an insulin responsive element in the GRP78 promoter. This effect was counteracted by insulin. Our studies underscore the importance of an IR and IRS2-dependent feedback loop to keep FoxO1 activity in check for maintaining hepatic glycogen homeostasis and promoting adaptive unfolded protein response in response to altered metabolism and insulin action. Excessive FoxO1 activity, resulting from a dislodged FoxO1 feedback loop in insulin resistant liver, is attributable to hepatic endoplasmic reticulum stress and metabolic abnormalities in diabetes.

Diabetes, insulin, and development of acute lung injury

Recently, many studies have investigated the immunomodulatory effects of insulin and glucose control in critical illness. This review examines evidence regarding the relationship between diabetes and the development of acute lung injury/acute respiratory distress syndrome (ALI/ARDS), reviews studies of lung injury related to glycemic and nonglycemic metabolic features of diabetes, and examines the effect of diabetic therapies. A MEDLINE/PubMed search from inception to August 1, 2008, was conducted using the search terms acute lung injury, acute respiratory distress syndrome, hyperglycemia, diabetes mellitus, insulin, hydroxymethylglutaryl-CoA reductase inhibitors (statins), angiotensin-converting enzyme inhibitor, and peroxisome proliferator-activated receptors, including combinations of these terms. Bibliographies of retrieved articles were manually reviewed. Available studies were critically reviewed, and data were extracted with special attention to the human and animal studies that explored a) diabetes and ALI; b) hyperglycemia and ALI; c) metabolic nonhyperglycemic features of diabetes and ALI; and d) diabetic therapies and ALI. Clinical and experimental data indicate that diabetes is protective against the development of ALI/ARDS. The pathways involved are complex and likely include effects of hyperglycemia on the inflammatory response, metabolic abnormalities in diabetes, and the interactions of therapeutic agents given to diabetic patients. Multidisciplinary, multifaceted studies, involving both animal models and clinical and molecular epidemiology techniques, are essential.

Coronary Circulatory Dysfunction in Insulin Resistance, Impaired Glucose Tolerance, and Type 2 Diabetes Mellitus

Abnormal coronary endothelial reactivity has been demonstrated in diabetes and is associated with an increased rate of cardiovascular events. Our objectives were to investigate the presence of functional coronary circulatory abnormalities over the full spectrum of insulin resistance and to determine whether these would differ in severity with more advanced states of insulin resistance. Myocardial blood flow (MBF) was measured with positron emission tomography and 13N-ammonia to characterize coronary circulatory function in states of insulin resistance without carbohydrate intolerance (IR), impaired glucose tolerance (IGT), and normotensive and hypertensive type 2 diabetes mellitus (DM) compared with insulin-sensitive (IS) individuals. Indices of coronary function were total vasodilator capacity (mostly vascular smooth muscle-mediated) during pharmacological vasodilation and the nitric oxide-mediated, endothelium-dependent vasomotion in response to cold pressor testing. Total vasodilator capacity was similar in normoglycemic individuals (IS, IR, and IGT), whereas it was significantly decreased in normotensive (-17%) and hypertensive (-34%) DM patients. Compared with IS, endothelium-dependent coronary vasomotion was significantly diminished in IR (-56%), as well as in IGT and normotensive and hypertensive diabetic patients (-85%, -91%, and -120%, respectively). Progressively worsening functional coronary circulatory abnormalities of nitric oxide-mediated, endothelium-dependent vasomotion occur with increasing severity of insulin-resistance and carbohydrate intolerance. Attenuated total vasodilator capacity accompanies the more clinically evident metabolic abnormalities in diabetes.

Controversies of the Sweet Urine Disease

Before the discovery of insulin, the primary controversy in diabetes was what kind of reductive diet to use—rice diet, rancid fat diet, vegetables “cooked three times in their own water,” and so forth. All were restrictive and essentially treated diabetes by starvation. For type 2 diabetes, they probably worked out, in that they no doubt led to weight loss. (Perhaps we should try some of these again.) With the advent of insulin, the problem of diabetes was thought to be solved, and indeed, those with type 1 diabetes did just fine, for a while. It didn’t take long, however, for those now living longer to begin to develop vascular and neurological complications. And thus began a new round of controversy. This controversy, which began in the 1930s, raged on for the next 60 years and was often very heated. The issue, simply put, was whether the vascular and neurological problems associated with diabetes were a genetic concomitant of the disease (and thus inevitable and unalterable) or instead were associated with the metabolic abnormalities of diabetes, such as high blood glucose levels (and thus preventable). Which side one took on this issue had great ramifications regarding the method of diabetes management one’s practice adopted. A classic debate on this topic took place in New York in the 1940s between Dr. Elliott Joslin and Dr. Edward Tolstoi. The debate, which was recorded and is available at the New York Hospital, Cornell University School of Medicine, was reenacted a few years ago. In the late 1930s, Dr. Robert L. Jackson, then a pediatrician at the University of Iowa …

Looking to the future: diabetic neuropathy and effects of rosuvastatin on neurovascular function in diabetes models

Vascular defects contribute substantially to neuropathic changes associated with metabolic abnormalities in diabetes. Statins appear to exert beneficial effects on vascular function independent of cholesterol lowering. In studies of the streptozotocin-induced diabetes rat model, rosuvastatin treatment was shown to correct sciatic motor and saphenous sensory nerve conduction velocity deficits (large fiber defects), thermal hyperalgesia (small fiber defects) and deficits in sciatic nerve and superior cervical ganglion blood flow. Rosuvastatin reversed deficits in nitrergic nerve–mediated vasodilation in the corpus cavernosum and corrected deficits in endothelium-derived hyperpolarising factor–mediated vasodilation in mesenteric vessels. Rosuvastatin did not alter plasma cholesterol in diabetic animals (a characteristic effect in this model), but significantly lowered triglycerides at high doses. Treatment with mevalonate reversed the beneficial effects of rosuvastatin on nerve function and blood flow, suggesting that the effects are mediated by inhibition of the cholesterol biosynthesis pathway in the absence of cholesterol reduction. Thus, rosuvastatin has wide-ranging neurovascular actions in diabetic rats that may be independent of lipid-lowering activity.

Lipoatrophic-lipodystrophic syndromes: the spectrum of findings on MR imaging.

Lipoatrophic—Lipodystrophic SyndromesThe Spectrum of Findings on MR ImagingA. Premkumar1, C. Chow1, P. Bhandarkar1, V. Wright1, N. Koshy1, S. Taylor2 and E. Arioglu2Audio Available | Share

Increased bradykinin and “normal” angiotensin peptide levels in diabetic Sprague-Dawley and transgenic (mRen-2)27 rats

The transgenic (mRen-2)27 rat (TGR) is a high tissue renin, high angiotensin (Ang) II model of hypertension. When administered streptozotocin (STZ), TGRs develop a rapidly progressive diabetic nephropathy with renal failure over 12 weeks. Bradykinin (BK) and Ang II are potent vasoactive peptides that may participate in the vascular and metabolic abnormalities of diabetes. TGR and Sprague-Dawley (SD) rats were administered STZ (diabetic) or citrate buffer (nondiabetic) at six weeks of age. Diabetic rats received daily ultralente insulin to maintain moderate hyperglycemia ( approximately 18 mM). Rats were sacrificed four- and eight-weeks post-STZ or vehicle. Diabetes did not modify the blood pressure of either SD rats or TGRs. Diabetes increased levels of BK-(1-9) and its metabolite BK-(1-7) in kidney, aorta, and heart of both SD rats and TGRs. Diabetes did not influence Ang II levels in plasma, kidney, aorta, heart, or adrenal gland of SD rats, but reduced to normal the elevated Ang II levels in plasma, kidney, aorta, and adrenal gland of TGRs. STZ-induced diabetes was associated with elevated tissue levels of BK-(1-9) and "normal" circulating and tissue levels of Ang II. The increased BK-(1-9) levels were consistent with the participation of this peptide in the vascular and metabolic abnormalities of diabetes. However, the rapidly progressive nephropathy of diabetic TGRs was not associated with BK-(1-9) and Ang II levels in target organs that differed from those of diabetic SD rats.

TGF-β1 stimulates glucose uptake by enhancing GLUT1 expression in mesangial cells

An increase in the expression of transforming growth factor-beta 1 (TGF-beta 1) has been proposed to play an important role in the excessive production of extracellular matrix (ECM) proteins seen in diabetes. Because the linkage between glucose metabolism and ECM protein production was found in mesangial cells overexpressed with the brain-type glucose transporter (GLUT1), we hypothesized that TGF-beta 1 could affect glucose metabolism. To prove this hypothesis, we examined the effect of TGF-beta 1 on glucose uptake, the first step of glucose metabolism, in mesangial cells. 2-Deoxy-D-glucose (2DOG) uptake and the expression of GLUT1 were measured in mesangial cells exposed to various concentrations of TGF-beta 1. The kinetic constants were determined using 2DOG and 3-O-methyl-D-glucose (3OMG). The effect of anti-TGF-beta neutralizing antibody on 2DOG uptake and GLUT1 mRNA was also examined in mesangial cells cultured under high-glucose (22.2 mM) conditions for 72 hours. TGF-beta 1 stimulated 2DOG uptake in mesangial cells by approximately 2.5-fold in a dose- (1.25 ng/ml maximum) and time-dependent manner, with a peak stimulation at nine hours. The increase in 2DOG uptake by TGF-beta 1 was completely abolished by the addition of 1 microgram/ml cycloheximide, and kinetic analysis of 2DOG or 3OMG uptake revealed an increase in Vmax by TGF-beta 1. Furthermore, TGF-beta 1 enhanced the expression of GLUT1 mRNA from one hour, followed by an enhancement of the expression of GLUT1 protein at nine hours. Finally, 2DOG uptake was significantly enhanced in cells cultured under high-glucose (22.2 mM) conditions as compared with that in cells under normal glucose (5.6 mM) conditions, and this increase in 2DOG uptake in cells under high-glucose conditions was inhibited by the addition of anti-TGF-beta neutralizing antibody. TGF-beta 1 stimulates glucose uptake by enhancing the expression of GLUT1 in mesangial cells, which leads to the acceleration of intracellular metabolic abnormalities in diabetes.