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Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. The hallmark of type 2 diabetes is pancreatic β-cell dysfunction and insulin resistance. The development of type 2 diabetes is usually associated with a combination of pancreatic β-cell dysfunction and insulin resistance.
Under diabetic conditions, reactive oxygen species (ROS) increase in various tissues and are involved in the development of diabetic complications [6-9]. The glycation reaction suppresses the insulin gene transcription in β-cells by provoking oxidative stress.
Because oxidative stress is produced under diabetic conditions and is likely to be involved in pancreatic β-cell dysfunction found in diabetes, we evaluated the potential usefulness of antioxidants in treatment for type 2 diabetes. Several signal transduction pathways including c-Jun N-terminal kinase (JNK) (also known as stress-activated protein kinase (SAPK)) [65-68], p38 mitogen-activated protein kinase (p38 MAPK), and protein kinase C (PKC) are activated by oxidative stress in several cell types including pancreatic β-cells. These results are correlated with changes in the binding of the major transcription factor PDX-1 to the insulin promoter; adenoviral over-expression of DN-JNK preserved PDX-1 DNA-binding activity in the presence of oxidative stress, while WT-JNK over-expression decreased PDX-1 DNA-binding activity. Toexamine whether DN-JNK can protect β-cells from the toxic effects of hyperglycemia and to explore the potential therapeutic application for islet transplantation, we performed islet transplantation into diabetic mice [69]. The JNK pathway is known to be activated under diabetic conditions and possibly to be involved in the progression of insulin resistance. It has been reported that serine phosphorylation of insulin receptor substrate-1 (IRS-1) inhibits insulin-stimulated tyrosine phosphorylation of IRS-1, leading to an increase in insulin resistance [83, 84]. It has been also reported recently that JNK activity is abnormally elevated in liver, muscle and adipose tissues in obese type 2 diabetic mice and that insulin resistance is substantially reduced in mice homozygous for a targeted mutation in the JNK1 gene (JNK-KO mice) [83]. Consequently, obese type 2 diabetes is associated with activation of the JNK pathway, and the absence of JNK results in substantial protection from obesity-induced insulin resistance.
Protein transduction domains (PTDs) such as the small PTD from the TAT protein of human immunodeficiency virus (HIV-1), the VP22 protein of Herpes simplex virus, and the third ?-helix of the homeodomain of Antennapedia, a Drosophila transcription factor, are known to allow various proteins and peptides to be efficiently delivered into cells through the plasma membrane, and thus there has been increasing interest in their potential usefulness for the delivery of bioactive proteins and peptides into cells [87-93]. We have recently evaluated the potential usefulness of a JNK inhibitory peptide in the treatment of type 2 diabetes and found that the cell-permeable JNK inhibitory peptide (amino acid sequence: GRKKRRQRRRPPRPKRPTTLNLFPQVPRSQDT) is very effective. To investigate the possible effects of the JNK inhibitory peptide on insulin action, we performed an insulin tolerance test. To further investigate the effect of the peptide on insulin resistance, we performed the euglycemic hyperinsulinemic clamp test.
To explore the molecular mechanism of how JIP-1-HIV-TAT-FITC treatment improves insulin sensitivity and ameliorates glucose tolerance, we evaluated IRS-1 serine 307 phosphorylation in various insulin target tissues (liver, fat, and muscle) of JIP-1-HIV-TAT-FITC-treated mice.
In conclusion, the cell-permeable JNK inhibitory peptide, JIP-1-HIV-TAT-FITC, improves insulin resistance and ameliorates glucose intolerance, indicating the critical involvement of the JNK pathway in diabetes and the usefulness of the cell-permeable JNK inhibitory peptide as a novel therapeutic agent for diabetes (Figure 4). Activation of the JNK pathway is involved in the progression of insulin resistance as well as deterioration of pancreatic β-cell function. Nishikawa T, Edelstein D, Du XL, Yamagishi S, Matsumura T, Kaneda Y, Yorek MA, Beebe D, Oates PJ, Hammes HP, Giardino I, Brownlee M.
Kaneto H, Fujii J, Myint T, Islam KN, Miyazawa N, Suzuki K, Kawasaki Y, Nakamura M, Tatsumi H, Yamasaki Y, Taniguchi N. Matsuoka T, Kajimoto Y, Watada H, Kaneto H, Kishimoto M, Umayahara Y, Fujitani Y, Kamada T, Kawamori R, Yamasaki Y.
Kaneto H, Kajimoto Y, Miyagawa J, Matsuoka T, Fujitani Y, Umayahara Y, Hanafusa T, Matsuzawa Y, Yamasaki Y, Hori M.
Kajimoto Y, Matsuoka T, Kaneto H, Watada H, Fujitani Y, Kishimoto M, Sakamoto K, Matsuhisa M, Kawamori R, Yamasaki Y, Hori M. Gorogawa S, Kajimoto Y, Umayahara Y, Kaneto H, Watada H, Kuroda A, Kawamori D, Yasuda T, Matsuhisa M, Yamasaki Y, Hori M. Sakai K, Matsumoto K, Nishikawa T, Suefuji M, Nakamura K, Hirashima Y, Kawashima J, Shirotani T, Ichinose K, Brownlee M, Araki E. Kaneto H, Miyagawa J, Kajimoto Y, Yamamoto K, Watada H, Umayahara Y, Hanafusa T, Matsuzawa Y, Yamasaki Y, Higashiyama S, Taniguchi N. Ferber S, Halkin A, Cohen H, Ber I, Einav Y, Goldberg I, Barshack I, Seijffers R, Kopolovic J, Kaiser N, Karasik A.
Kojima H, Nakamura T, Fujita Y, Kishi A, Fujimiya M, Yamada S, Kudo M, Nishio Y, Maegawa H, Haneda M, Yasuda H, Kojima I, Seno M, Wong NCW, Kikkawa R, Kashiwagi A. Yoshida S, Kajimoto Y, Yasuda T, Watada H, Fujitani Y, Kosaka H, Gotow T, Miyatsuka T, Umayahara Y, Yamasaki Y, Hori M.
Ber I, Shternhall K, Perl S, Ohanuna Z, Goldberg I, Barshack I, Benvenisti-Zarum L, Meivar-Levy I, Ferber S. Miyatsuka T, Kaneto H, Kajimoto Y, Hirota S, Arakawa Y, Fujitani Y, Umayahara Y, Watada H, Yamasaki Y, Magnuson MA, Miyazaki J, Hori M. Koizumi M, Doi R, Toyoda E, Tulachan SS, Kami K, Mori T, Ito D, Kawaguchi Y, Fujimoto K, Gittes GK, Imamura M.
Watada H, Kajimoto Y, Umayahara Y, Matsuoka T, Kaneto H, Fujitani Y, Kamada T, Kawamori R, Yamasaki Y.
Kawamori D, Kajimoto Y, Kaneto H, Umayahara Y, Fujitani Y, Miyatsuka T, Watada H, Leibiger IB, Yamasaki Y, Hori M. Eizirik DL, Sandler S, Welsh N, Cetkovic-Cvrlje M, Nieman A, Geller DA, Pipeleers DG, Bendtzen K, Hellerstrom C. Kaneto H, Fujii J, Seo HG, Suzuki K, Matsuoka T, Nakamura N, Tatsumi H, Yamasaki Y, Kamada T, Taniguchi N.
Ammendrup A, Maillard A, Nielsen K, Aabenhus Andersen N, Serup P, Dragsbaek Madsen O, Mandrup-Poulsen T, Bonny C. Dickens M, Rogers JS, Cavanagh J, Raitano A, Xia Z, Halpern JR, Greenberg ME, Sawyers CL, Davis RJ. Waeber G, Delplanque J, Bonny C, Mooser V, Steinmann M, Widmann C, Maillard A, Miklossy J, Dina C, Hani EH, Vionnet N, Nicod P, Boutin P, Froguel P. Nakatani Y, Kaneto H, Kawamori D, Hatazaki M, Miyatsuka T, Matsuoka T, Kajimoto Y, Matsuhisa M, Yamasaki Y, Hori M. Summer is perfect for many things, including staying current on the latest trends in dental hygiene. Dimensions of Dental Hygiene is committed to the highest standards of professionalism, accuracy and integrity in our mission of education supporting oral health care professionals and those allied with the dental industry.
Periodontology (EFP) on periodontitis and systemic diseases, which was held in Segovia, Spain, in November 2012. I hope you find this article a valuable resource in the management of patients with diabetes in your practice. Diabetes mellitus is a metabolic disease characterized by the loss of control of glucose homeostasis, along with changes affecting fat and protein metabolism.
AGEs are referred to as "long-lived molecules formed by the irreversible binding of glucose to protein and lipids in plasma, as well as the tissues during persisting hyperglycemia."12 These molecules form under normal conditions and accumulate during aging. In cell culture studies, monocytes from patients with diabetes, when stimulated with lipopolysaccharides found in the outer membrane of Gram-negative bacteria, produced greater amounts of tumor necrosis factor-alpha (TNF-alpha) compared to those without diabetes.18 TNF-alpha, an adipokine involved in systemic inflammation, is a potent inducer of apoptosis in fibroblasts and osteoblasts.
Obesity is a risk factor for the development of diabetes.1 Adipose tissue, by virtue of secreting adipokines, can activate the innate immune system and serve as a mediator of a low-grade chronic systemic inflammation. Severe periodontal diseases can cause insulin resistance.24 This interaction is likely due to stimulation of hepatocytes, leading to secretion of acute phase proteins that include C-reactive proteins along with TNF-alpha.
Oxidative stress refers to an imbalance between the production of free radicals and the ability of the body to counteract or detoxify their harmful effects through neutralization by antioxidants. Pharmacologic management of diabetes includes the use of glucophage, sulfonylureas, glinides, alpha-glucosidase inhibitors, thiazolidinediones, and insulin. Incretin hormones are involved in the regulation of blood glucose and, to a lesser extent, insulin and glucagon secretion.36,37 These hormones are released from endocrine cells in the small intestine in response to food.
Amylin, a neuroendocrine hormone, is secreted along with insulin in response to food intake.
Other treatments include the use of colesevelam and bromocriptine, which have been approved by the US Food and Drug Administration for the treatment of type 2 diabetes. Recently, Engebretson et al43 reported on findings from a RCT that was stopped early because nonsurgical periodontal therapy did not improve glycemic control in patients with type 2 diabetes and moderate to advanced chronic periodontitis.
In the consensus report of the joint European Federation of Periodontology and the AAP, several guidelines were suggested to support health care professionals in their treatment of patients with diabetes.
Diabetes and periodontitis are chronic disease conditions that have significant national and global implications. Glycemic Variability and Oxidative Stress: A Link between Diabetes and Cardiovascular Disease? Diabetes is associated with a two to three-fold increase in risk of cardiovascular disease. Correlation between postprandial C-peptide index (PCPRI) and glycated albumin (GA) to HbA1c ratio in patients with type 2 diabetes (A) and type 1 diabetes (B).
Correlation between age and (A) standard deviation (SD) or (B) mean amplitude of glycemic excursions (MAGE) assessed by CGM in patients with T2DM. Expanded Management by Hunter Carr Diabetes Childhood Obesity Macrovascular Glycemic Oxidative 2 Variability Mellitus Type Stress Complications and Scott Hepford is ining more patients to the Trina Health The success of Charlotte Miami and Memphis have caused Mr Insulin resistance like the name suggests is a developped immunity to the effects of insulin at the cellular level. Do you think that might be Infusion of inflammatory cytokines into healthy normal weight mice causes insulin resistance and people with other chronic inflammatory conditions Diabetes mellitus or simply diabetes is a chronic disease that occurs when the pancreas is no longer able to make insulin or when Type 2 diabetes used to be called non-insulin dependent diabetes or adult-onset diabetes and accounts for at least 90% of all cases of diabetes.
What were the most popular fatures patient handouts and This site features articles and resources on all aspects of the diagnosis and management of diabetes. If you’re diagnosed with type 2 diabetes you may be able to control your symptoms simply by eating a healthy diet exercising Read more about diabetic eye screening. Dogs which are off their food or need to be fasted as part of the management of vomiting or diarrhea need to continue to receive insulin since These arise when high glucose levels causes water in an individual’s body to soak into some tissues and out of the others in unusual ways.
Learn what foods you can eat as diabetic symptoms treatment The New Zealand Guidelines Group was an organisation set up to promote the use of evidence in the delivery of health and disability services.
Normal β-cells can compensate for insulin resistance by increasing insulin secretion, but insufficient compensation leads to the onset of glucose intolerance. Pancreatic β-cells have recently emerged as a target of oxidative stress-mediated tissue damage [10-25]. Immunostaining for oxidative stress markers such as 4-hydroxy-2-nonenal (HNE)-modified proteins and heme oxygenase-1 revealed that probucol treatment decreased reactive oxygen species (ROS) in pancreatic islets of diabetic animals. It has been shown recently that activation of JNK is involved in the reduction of insulin gene expression by oxidative stress and that suppression of the JNK pathway can protect β-cells from oxidative stress [69].
PDX-1 DNA-binding activity is decreased in association with a reduction of insulin gene transcription after chronic exposure to high glucose concentration. Wild-type-JNK over-expression decreases PDX-1 DNA-binding activity in association with a reduction of insulin gene transcription after chronic exposure to high glucose concentration leading to a decrease of insulin secretion. Addition of DN-JNK inhibited the oxidative stress-induced PDX-1 translocation, suggesting an essential role of JNK in mediating the phenomenon.
Isolated rat islets were infected with dominant-negative JNK expressing adenovirus (Ad-DN-JNK) or Ad-GFP and cultured for 2 days; then 500 islets were transplanted under kidney capsules of STZ-induced diabetic Swiss nude mice. Also, it has been reported that levels of 8-hydroxy-2'-deoxy-guanosine (8-OHdG), a marker for oxidative stress, are increased in the blood of type 2 diabetic patients as well as in islets of type 2 diabetic animal models [6, 13, 21] and that JNK activation by oxidative stress in islets actually reduces the PDX-1 DNA binding activity and insulin gene transcription [69]. We have recently examined the effects of a modulation of the JNK pathway in the liver on insulin resistance and glucose tolerance [82]. Under diabetic conditions, reactive oxygen species (ROS) are produced in various tissues and are involved in the development of insulin resistance as well as the progression of ?-cell deterioration. These results strongly suggest that JNK plays a crucial role in the progression of insulin resistance found in type 2 diabetes.
This peptide is derived from the JNK binding domain of JNK-interacting protein-1 (JIP-1), also known as islet-brain-1 (IB-1), and has been reported to function as a dominant inhibitor of the JNK pathway [76].
There was no difference in body weight and food intake between the JIP-1-HIV-TAT-FITC-treated and untreated mice. Oxidative stress mediated by chronic diabetic conditions activates JNK in several cells, such as liver-, fat-, muscle-, as well as ?-cells, leads to insulin resistance and ?-cell dysfunction. Reduction of blood glucose levels in response to injected insulin was much larger in JIP-HIV-TAT-FITC-treated mice than in untreated mice, indicating that the peptide treatment improves insulin sensitivity. IRS-1 serine 307 phosphorylation was decreased in JIP-1-HIV-TAT-FITC-treated mice compared to control mice.
Indeed, suppression of the JNK pathway in obese diabetic mice markedly improves insulin resistance and β-cell function, leading to amelioration of glucose tolerance. Minireview: Secondary beta-cell failure in type 2 diabetes - a convergence of glucotoxicity and lipotoxicity. The reduction of insulin gene transcription in HIT-T15beta-cells chronically exposed to high glucose concentration is associated with loss of RIPE3b1 and STF-1 transcription factor expression. Differentiation of glucose toxicity from beta cell exhaustion during the evolution of defective insulin gene expression in the pancreatic islet cell line, HIT-T15.
Chronic hyperglycemia triggers loss of pancreatic beta-cell differentiation in an animal model of diabetes. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Reducing sugars trigger oxidative modification and apoptosis in pancreatic beta-cells by provoking oxidative stress through the glycation reaction. Glycation-dependent, reactive oxygen species-mediated suppression of the insulin gene promoter activity in HIT cells.
Relation between antioxidant enzyme gene expression and antioxidative defense status of insulin-producing cells. Hyperglycemia causes oxidative stress in pancreatic beta-cells of GK rats, a model of type 2 diabetes. Beneficial effects of antioxidants for diabetes: possible protection of pancreatic beta-cells against glucose toxicity. Prevention of glucose toxicity in HIT-T15 cells and Zucker diabetic fatty rats by antioxidants. Oxidative stress induces p21 expression in pancreatic islet cells: possible implication in beta-cell dysfunction. Hydrogen peroxide alters mitochondrial activation and insulin secretion in pancreatic beta cells. Activation of the hexosamine pathway leads to deterioration of pancreatic beta-cell function by provoking oxidative stress. A role of glutathione peroxidase in protecting pancreatic beta-cells against oxidative stress in a model of glucose toxicity. Probucol preserves pancreatic beta-cell function through reduction of oxidative stress in type 2 diabetes. Glucose toxicity in beta-cells: type 2 diabetes, good radicals gone bad, and the glutathione connection. Are oxidative stress-activated signalling pathways mediators of insulin resistance and beta-cell dysfunction?
Characterization of somatostatin transactivating factor-1, a novel homeobox factor that stimulates somatostatin expression in pancreatic islet cells.
IDX-1: a new homeodomain transcription factor expressed in rat pancreatic islets and duodenum that transactivates the somatostatin gene. Expression of murine STF-1, a putative insulin gene transcription factor, in beta cells of pancreas, duodenal epithelium and pancreatic exocrine and endocrine progenitors during ontogeny. Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence.
Expression of heparin-binding epidermal growth factor-like growth factor during pancreas development: a potential role of PDX-1 in transcriptional activation.


Pancreatic and duodenal homeobox gene 1 induces expression of insulin genes in liver and ameliorates streptozotocin-induced hyperglycemia. Combined expression of pancreatic duodenal homeobox 1 and islet factor 1 induces immature enterocytes to produce insulin. PDX-1 induces differentiation of intestinal epithelioid IEC-6 into insulin-producing cells. Ectopically expressed PDX-1 in liver initiates endocrine and exocrine pancreas differentiation but causes dysmorphogenesis.
PDX-1 protein containing its own Antennapedia-like protein transduction domain can transduce pancreatic duct and islet cells. Analysis of insulin-producing cells during in vitro differentiation from feeder-free embryonic stem cells. Beta-cell neogenesis induced by adenovirus-mediated gene delivery of transcription factor pdx-1 into mouse pancreas. In vivo and in vitro characterization of insulin-producing cells obtained from murine bone marrow.
In vitro directed differentiation of mouse embryonic stem cells into insulin-producing cells.
Regulated expression of pdx-1 promotes in vitro differentiation of insulin-producing cells from embryonic stem cells. Hepatic regeneration and enforced PDX-1 expression accelerate transdifferentiation in liver. Insulin expression in pancreatic islet cells relies on cooperative interactions between the helix loop helix factor E47 and the homeobox factor STF-1. Pancreatic duodenal homeobox-1, PDX-1, a major regulator of beta cell identity and function.
Reduction in pancreatic transcription factor PDX-1 impairs glucose-stimulated insulin secretion.
Quantitative assessment of gene targeting in vitro and in vivo by the pancreatic transcription factor, pdx1: importance of chromatin structure in directing promoter binding. PDX-1 haploinsufficiency limits the compensatory islet hyperplasia that occurs in response to insulin resistance. Identification of an oncoprotein- and UV-responsive protein kinase that binds and potentiates the c-Jun activation domain. JNK1: a protein kianse stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain. Involvement of c-Jun N-terminal kinase in oxidative stress-mediated suppression of insulin gene expression.
Oxidative stress induces nucleo-cytoplasmic translocation of pancreatic transcription factor PDX-1 through activation of c-Jun N-terminal kinase. Interleukin 1 beta induces the formation of nitric oxide by beta-cells purified from rodent islets of Langerhans: evidence for the beta-cell as a source and site of action of nitric oxide. Cytokines suppress human islet function irrespective of their effects on nitric oxide generation. Interleukin-1beta-induced nitric oxide production activates apoptosis in pancreatic RINm5F cells. The c-Jun amino-terminal kinase pathway is preferentially activated by interleukin-1 and controls apoptosis in differentiating pancreatic beta-cells.
Answer the questions correctly and you will be placed in a drawing to WIN the ultimate Dimensions of Dental Hygiene gift basket. Our cover story, Preparing for the Zika Virus, offers two continuing education (CE) units and provides information on protection from this viral pandemic.
Through our print and digital media platforms, continuing education activities, and events, we strive to deliver relevant, cutting-edge information designed to support the highest level of oral health care. Discuss how the presence of advanced glycation end products, apoptosis, and impaired wound healing among people with diabetes affects their risk of periodontal diseases. Identify the negative effects that periodontal diseases exert on insulin resistance and kidney health. However, this process is enhanced during hyperglycemic conditions found in diabetes.12 AGEs interact with cell receptors, such as the receptor for advanced glycation end products (RAGE), which is a member of the immunoglobulin superfamily of cell surface molecules. AGEs can affect both connective tissue and bone by promoting the apoptosis of matrix-producing cells. Taylor et al12 noted that diabetes enhanced the inflammatory response to oral bacteria associated with periodontal diseases. Systemic bacteremia can result, increasing the presence of Gram-negative and obligate anaerobe bacteria in the blood stream. This occurs through the production of pro-inflammatory cytokines, including TNF-alpha, IL-1beta, and IL-6—which are also produced in periodontal tissues during the periodontal disease process. Recently, Bullon at al29 reviewed the role of oxidative stress and mitochondrial dysfunction as a common link between obesity, diabetes, atherosclerosis, and chronic periodontitis.
It is, therefore, the most accurate way to detect how well patients are maintaining their blood sugar levels.
However, new treatment regimens have emerged, such as incretin-based therapies and amylin agonists. Activation of G protein-coupled receptors on pancreatic beta-cells leads to stimulation of insulin secretion. This hormone causes inhibition of post-prandial glucagon secretion, slowing the rate of gastric emptying, enhancing satiety, and reducing food intake. Colesevelam, which sequesters bile acid, has been used for the treatment of hyperlipidemia.
The studies included those that had at least a 3-month follow up on the effects of periodontal treatment on patients with type 2 diabetes.
Accordingly, the authors concluded that findings from this RCT did not support the use of nonsurgical periodontal treatment in patients with diabetes for the purpose of lowering levels of HbA1c.
IL-6 levels in gingival crevicular fluid (GCF) from patients with non-insulin dependent diabetes mellitus (NIDDM), adult periodontitis and healthy subjects. Influence of high glucose concentrations on glycosaminoglycan and collagen synthesis in cultured human gingival fibroblasts. Tumor necrosis factor-alpha mediates diabetes-enhanced apoptosis of matrix producing cells and impairs diabetic healing.
Enhanced interaction of advanced glycation end products with their cellular receptor RAGE: implications for the pathogenesis of accelerated periodontal disease in diabetes. Diabetes causes decreased osteoclastogenesis, reduced bone formation and enhanced apoptosis of osteoblastic cells in bacteria stimulated bone loss.
Diabetic periodontitis: possible lipid-induced defect in tissue repair through alteration of macrophage phenotype and function. Effects of tumor necrosis factor-alpha on glucose metabolism in cultured human muscle cells from nondiabetic and type 2 diabetic subjects.
Prevalence of periodontal bacterial infection in non-obese Japanese type 2 diabetic patients: relationship with C-reactive protein and albuminuria. Obesity, diabetes mellitus, atherosclerosis and chronic periodontitis: a shared pathology via oxidative stress and mitochondrial dysfunction? The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complication in patients with type 2 diabetes (UKPDS 33). Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34).
The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes.
Management of type 2 diabetes: evolving strategies for the treatment of patients with type 2 diabetes. Evidence that periodontal treatment improves diabetes outcomes: a systematic review and meta-analysis.
The effect of nonsurgical periodontal therapy on hemoglobin A1c levels in persons with type 2 diabetes and chronic periodontitis: a randomized clinical trial.
However, intensive glucose-lowering therapy aiming at reducing HbA1c to a near-normal level failed to suppress cardiovascular events in recent randomized controlled trials.
IntroductionThe number of people with diabetes are continuously increasing all over the world. The central line is the mean, and the two outer lines represent the 5th and 95th percentiles (P5 and P95, respectively). Glycemic Variability and Vascular EventsIn DCCT, it was reported that the incidence of diabetic complications was lower in subjects with intensive therapy using basal-bolus therapy or continuous subcutaneous insulin infusion (CSII) compared with those with conventional therapy, even with the same HbA1c levels [22].
An inverse relationship between residual C-peptide level and GV has been reported in patients with T1DM [104,105,106]. Diabetes Childhood Obesity Macrovascular Glycemic Oxidative 2 Variability Mellitus Type Stress Complications this blood glucose Diabetes Childhood Obesity Macrovascular Glycemic Oxidative 2 Variability Mellitus Type Stress Complications monitoring system offers alternate site testing as well. Quick Links Educational Resources in multiple languages Blood glucose levels are normally regulated by the hormone insulin which is made by the pancreas. The American Heart Association explains the symptoms of high blood pressure Symptoms Diagnosis & Monitoring of Diabetes.
Once hyperglycemia becomes apparent, β-cell function gradually deteriorates and insulin resistance becomes aggravated. These were neutralized with aminoguanidine, an inhibitor of the glycation reaction, or N-acetyl-L-cysteine, an antioxidant, indicating that D-ribose suppresses insulin gene transcription by provoking oxidative stress through the glycation reaction.
During the development of the pancreas, PDX-1 expression is maintained in multipotential precursors that co-express several hormones and later it becomes restricted to β-cells. The antioxidant treatment retained glucose-stimulated insulin secretion and moderately decreased blood glucose levels.
Probucol treatment preserved β-cell mass, the insulin content, and glucose-stimulated insulin secretion, leading to the improvement of glucose tolerance [21].
When isolated rat islets were exposed to oxidative stress, JNK, p38 MAPK, and PKC pathways were activated, preceding the decrease of insulin gene expression. The impairment of PDX-1 activity and subsequent suppression of insulin gene transcription is mediated by the activation of the JNK pathway in the diabetic state. In addition, PDX-1 is translocated pathogenically from the nucleus to the cytoplasm by JNK activation. Whereas the nuclear localization signal (NLS) in PDX-1 was not affected by oxidative stress, leptomycin B, a specific inhibitor of the classical, leucine-rich nuclear export signal (NES), inhibited nucleo-cytoplasmic translocation of PDX-1 induced by oxidative stress.
Blood glucose levels were not sufficiently decreased by the transplantation of islets infected with Ad-GFP, which was probably due to toxic effects of hyperglycemia upon a marginal islet number, but were markedly decreased by Ad-DN-JNK.
In addition, the significance of JNK in the development of diabetes comes from the result of a genetic analysis in humans; while islet-brain-1 (IB1), the human and rat homologue of mouse JNK-interacting protein-1 (JIP-1) [79, 80], was known to selectively inhibit the JNK signaling [78], it was reported that a missense mutation within the IB1-encoding MAPKIP1 gene (S59N) is associated with a late onset type 2 diabetes [81]. Overexpression of dominant-negative type JNK in the liver of obese diabetic mice dramatically improved insulin resistance and markedly decreased blood glucose levels. Serine phosphorylation of insulin receptor substrate-1 (IRS-1) inhibits insulin-stimulated tyrosine phosphorylation of IRS-1 and leads to an increase in insulin resistance. We also found an increase in IRS-1 tyrosine phosphorylation in Ad-DN-JNK-treated mice compared to control mice. In contrast, blood glucose levels in obese JNK-KO mice were proven to be significantly lower than those in obese wild type mice.
Therefore, a selective interference with JNK activity is a potential therapeutic target for obesity, insulin resistance and type 2 diabetes [85, 86].
To convert the minimal JNK-binding domain into a bioactive cell-permeable compound, a 20-amino acid sequence derived from the JNK-binding domain of JIP-1 (RPK RPT TLN LFP QVP RSQ DT) was covalently linked to a 10-amino acid carrier peptide derived from the HIV-TAT sequence (GRK KRR QRR R); then to monitor peptide delivery, this JIP-1-HIV-TAT peptide was further conjugated with fluorescein isothiocyanate (FITC).
The non-fasting blood glucose levels in mice treated with JIP-1-HIV-TAT-FITC were significantly decreased compared to untreated mice or those treated with the scramble peptide.
In contrast, no such effect was observed when non-diabetic C57BL6 mice were treated with JIP-1-HIV-TAT-FITC.
Furthermore, we evaluated endogenous hepatic glucose production (HGP) and glucose disappearance rate (Rd) in the JNK inhibitory peptide-treated mice.
We also found an increase of IRS-1 tyrosine phosphorylation in the peptide-treated mice compared to control mice.
Taken together, the JNK pathway plays a crucial role in the progression of insulin resistance as well as β-cell dysfunction and thus could be a potential therapeutic target for the "glucose toxicity" found in diabetes.
In adults age 65 and older, 64% had either moderate or severe chronic periodontitis.2 Clearly, periodontitis is a significant health problem in the US, with disparities existing among different sociodemographic segments. Consequently, oral health professionals need to remain up to date on the association between periodontal diseases and diabetes. The AGE-RAGE interaction leads to the initiation of intracellular signaling pathways—which is partly mediated by enhanced cellular oxidant stress—thus encouraging the creation of a pro-inflammatory environment.13 The resulting inflammatory activity can lead to vascular alterations, development of vascular lesions, and impairment of normal reparative responses, all of which impede the healing process.
This programmed cell death can affect wound healing, which is hindered significantly in patients with uncontrolled diabetes. The increase in inflammation affected bone levels via increased bone resorption while inhibiting bone formation. Hyperlipidemia, often seen in patients with diabetes, affects the function of monocyte cell membrane-bound receptors and enzyme systems, leading to a slowing down of the wound healing process.20 Furthermore, AGEs affect the differentiation and maturation of monocytes. Additionally, bacterial components, such as lipopolysaccharides, are also evident in the blood stream.
Mitochondrial functions include generating cell energy, along with cell signaling, cell differentiation, cell-cycle control, and apoptosis.
They concluded that a consistent, moderate improvement was noted on HbA1c levels in response to periodontal treatment.
The American Academy of Periodontology (AAP) offered the following statement in response to Engebretson's report: "As a number of population studies suggest, there is indeed a relationship between diabetes and periodontal disease.
Severe periodontitis affects HbA1c levels in patients with diabetes, who are also more likely to experience moderate to severe chronic periodontitis. This finding raised the hypothesis that a reduction in GV by intensive therapy might contribute to reduce the incidence of diabetic complications. People with diabetes should learn how to examine their own feet and how to recognize the early signs and symptoms of diabetic We have been taught to cut back on the fat we eat to avoid getting fat and developing diabetes.
Accordingly, extracellular hyperglycemia causes intracellular hyperglycemia in β-cells, leading to the induction of ROS in pancreatic islets of diabetic animals. There is no pancreas in mice homozygous for a targeted mutation in the PDX-1 gene and the mice develop fatal perinatal hyperglycemia [29].
These data suggest the potential usefulness of antioxidants for treating diabetes and provide further evidence for the implication of oxidative stress in β-cell glucose toxicity found in diabetes (Figure 1).
Adenovirus-mediated over-expression of dominant-negative type (DN) JNK, but not the p38 MAPK inhibitor SB203580 nor the PKC inhibitor GF109203X, protected insulin gene expression and secretion from oxidative stress. Thus, it is likely that JNK-mediated suppression of PDX-1 DNA-binding activity accounts to some extent for the deterioration of the β-cell function (Figure 2). Four weeks after the transplantation of islets infected with Ad-GFP, insulin mRNA levels in islet grafts were clearly decreased compared with those before transplantation, but relatively preserved by DN-JNK overexpression [69]. Thus, we assume that JNK is involved in the deterioration of β-cell function in both type 2 diabetes and the early stage of type 1 diabetes. Thus, we assume that the improvement of insulin resistance by suppression of the JNK pathway is, at least in part, counterbalancing the deleterious effects of several factors such as oxidative stress, FFAs and TNF-α (Figure 3).
In addition, serum insulin levels in obese JNK-KO mice were significantly lower than those in obese wild type mice. Also, the glucose tolerance test showed that glucose tolerance in JIP-1-HIV-TAT-FITC-treated mice was significantly ameliorated in comparison to untreated or scramble peptide-treated mice [94].
Treatment with JIP-1 decreases non-fasting blood glucose levels and improves glucose tolerance in mice significantly. These results imply that the JNK pathway is activated under diabetic conditions and thus the JNK inhibitory peptide exerts beneficial effects on insulin action and glucose tolerance.
Concomitantly, an increase of Akt serine 473 and threonine 308 phosphorylation, both of which are known to be important for activation of the Akt pathway, was observed in JIP-1-HIV-TAT-FITC-treated mice. Maecenas ac tempor odio.Click here to view all articles in other categories not listed above. The pro-inflammatory cytokines—interleukin (IL)-1 beta and TNF-alpha—are stimulated, along with IL-6 and prostaglandin E2. Metabolic and oxidative stress seen in these conditions can lead to an inflammatory response and cell organelle dysfunction,30 and may serve as the common link between obesity, diabetes, atherosclerosis, and chronic periodontitis.


Incretin-based therapies include the use of glucagon-like peptide-1 receptor agonists (GLP-1) and dipeptidyl peptidase-4 inhibitors (DPP-4).
Taylor et al12 reviewed a heterogeneous set of 31 studies that included 10 randomized clinical trials (RCTs) and 21 nonRCTs. While this study specifically focuses on basic nonsurgical periodontal care, some cases of periodontal disease require more intensive treatment. In in vivo and in vitro studies, glycemic variability has been shown to be associated with greater reactive oxygen species production and vascular damage, compared to chronic hyperglycemia. On the other hand, recent clinical trials aiming at reducing HbA1c to a near-normal level in patients with T2DM have failed to show an additional benefit on CVD outcomes [5,6,7]. Thus, a lower serum 1,5-AG level reflects higher glycemic excursion, which usually occurs after meals [16]. However, the DCCT investigators recently reanalyzed the data and denied their previous conclusion [23]. Interestingly, the relationship between beta cell function assessed by serum C-peptide and GA to HbA1c ratio was comparable between patients with type 1 and type 2 diabetes [21] (Figure 3B), suggesting that the relationship between serum C-peptide and GV is independent of the type of diabetes. We have also reported that SD and MAGE assessed by CGM were significantly associated with age in patients with T2DM (Figure 4).
Diabetic Nephropathy childhood diabetes nutrition constipation diabetic neuropathy Diabetes Foot Diabetic Retinopathy Diabetes Cardiovascular Osteoarthritis Diabetes Dental Diabetic Neuropathy.
Find or Review a Drug; Find or Review a Vitamin or your mouth gets dry and uncomfortable Diabetes Mellitus blood glucose (BG) Essentially that is the mechanism by which those with T2 diabetes mellitus can become overweight and obese.
Under diabetic conditions, oxidative stress is induced and the JNK pathway is activated, which is involved in "glucose toxicity". Indeed, it was shown that the presence of oxidative stress markers 8-hydroxy-2'-deoxyguanosine (8-OHdG) and 4-hydroxy-2,3-nonenal (4-HNE) is increased in islets under diabetic conditions [13, 21].
Heterozygous PDX-1-deficient mice reveal impaired glucose tolerance [63], which also provides evidence for the crucial role of PDX-1 in pancreas development.
In contrast, wild type (WT) JNK over-expression suppressed both insulin gene expression and secretion. These results suggest that DN-JNK can protect ?-cells from some of the toxic effects of hyperglycemia during this transplant period, providing new insights into the mechanism through which oxidative stress suppresses insulin gene transcription in β-cells. Suppression of the JNK pathway by the treatment with Ad-DN-JNK enhances insulin signaling which leads to a decrease in gluconeogenesis and amelioration of glucose tolerance.
Therefore, an increase in IRS-1 serine phosphorylation may be closely associated with the development of insulin resistance induced by JNK overexpression.
Intraperitoneal insulin tolerance tests showed that hypoglycemic response to insulin in obese wild type mice is lower than that in obese JNK-KO mice. The FITC-conjugated peptide showed fluorescence signals in insulin target organs (liver, fat, muscle) and in insulin secreting tissue (pancreatic islets). These data indicate that the JNK pathway is involved in the exacerbation of diabetes and that suppression of the JNK pathway could be a therapeutic target for diabetes (Figure 4).
He et al17 suggested that the periodontal bone loss in patients with diabetes may be due to the reduction in matrix formation caused by increased apoptosis of the matrix-forming cells.
Therapeutic GLP-1 receptor agonists enhance insulin release and inhibit glucagon secretion.
Six of the 10 RCTs reported a beneficial effect of periodontal treatment on glycemic control. Research continues to be conducted on the relationship between these two chronic disease conditions. These findings suggest that management of glycemic variability may reduce cardiovascular disease in patients with diabetes; however, clinical studies have shown conflicting results.
In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, the trial was stopped because of a significant increase in all-cause mortality in patients with T2DM who were randomized to the intensive glycemic control group [5].A U-shaped association between HbA1c and CVD or all-cause mortality in patients with diabetes has been also reported by Currie et al.
Subsequent analyses of the DCCT data also found that there was no association between GV and micro- and macrovascular complications [24,25,26]. The progressive decline in beta cell function with duration of diabetes, impairment of multiple organs such as liver and kidney, reduction in lean mass, and autonomic neuropathy may be attributable to the relationship between age and GV. Activation of the JNK pathway suppresses insulin biosynthesis and interferes with insulin action. In addition, due to the relatively low expression of antioxidant enzymes such as catalase, and glutathione peroxidase [12], β-cells are rather vulnerable to oxidative stress.
ROS production in pancreatic ?-cells, therefore, leads to a decreased expression of PDX-1, which in turn causes the down-regulation of ?-cell genes, such as insulin, GLUT2, and glucokinase.
Clinically, mutations in PDX-1 are known to cause some cases of maturity-onset diabetes of the young (MODY) [64]. The amounts of insulin content and insulin mRNA were also retained by the antioxidant treatment. Also, the finding that this adverse outcome can be prevented by DN-JNK over-expression suggests that the JNK pathway in β-cells could become a new therapeutic target for diabetes.
To investigate this point further, we performed the euglycemic hyperinsulinemic clamp test. Next, we examined the expression levels of the key gluconeogenic enzymes, phosphoenolpyruvate carboxykinase (PEP CK) and glucose-6-phosphatase (G6Pase), both of which are known to be regulated by insulin signaling. Also, the intraperitoneal glucose tolerance test revealed a higher degree of hyperglycemia in obese wild type mice than in obese JNK-KO mice.
Next, we examined whether the JNK pathway is inhibited after treatment with JIP-1-HIV-TAT-FITC. In addition, Rd in JIP-1-HIV-TAT-FITC-treated mice was significantly higher than in untreated mice.
Health care professionals who treat patients with diabetes should remain up to date on advances in the understanding of diabetes, as well as guidelines and treatment recommendations. This review summarizes the current knowledge on glycemic variability and oxidative stress, and discusses the clinical implications. Also, since treatment with acarbose interferes with and decreases serum 1,5-AG level independent of the plasma glucose level, serum 1,5-AG level may not accurately reflect glycemic excursion in patients treated with acarbose [17,18].Glycated albumin (GA) is another marker of glycemic control. In DCCT, GV was assessed as SD and MAGE based on 7-point SMBG throughout the day.On the other hand, epidemiological studies have consistently shown a significant association between postprandial hyperglycemia, but not fasting hyperglycemia, and incidence of cardiovascular events and all-cause mortality in the general population [27,28,29].
Find the thousand of services and latest products on Streetdirectory Diabetes Specialist directory. Indeed, suppression of the JNK pathway in diabetic mice improves insulin resistance and ameliorates glucose tolerance.
Thus, it is likely that oxidative stress is involved in β-cell deterioration in type 2 diabetes.
As a possible cause of the reduction in the insulin gene promoter activity by oxidative stress, we found that the DNA-binding activity of PDX-1 is rather sensitive to oxidative stress; when HIT cells were exposed to D-ribose, PDX-1 binding to the insulin gene was markedly reduced, which was prevented by aminoguanidine or NAC [11]. Furthermore, PDX-1 expression was more clearly visible in the nuclei of islet cells after the antioxidant treatment [14].
These results indicate that the JNK-KO mice are protected from the development of dietary obesity-induced insulin resistance. In various tissues (liver, fat, and muscle), JNK activity was actually suppressed by JIP-1-HIV-TAT-FITC in a dose-dependent manner. These results indicate that JIP-1-HIV-TAT-FITC treatment reduces insulin resistance by decreasing HGP and increasing Rd. GA reflects average plasma glucose level over the past one to two weeks, while HbA1c reflects average plasma glucose level over the past one to two months [19]. Intensive insulin therapy for 4 weeks reduced GV assessed by 6-point SMBG, and the reduction in GV was significantly associated with improvement of beta cell function. A significant inverse association between MAGE and cognitive function has been reported in older patients with T2DM [113].
Consequently, the JNK pathway plays a crucial role in the progression of pancreatic β-cell dysfunction and insulin resistance and thus could be a potential therapeutic target for the "glucose toxicity" found in diabetes. In summary, chronic hyperglycemia suppresses insulin biosynthesis and secretion by provoking oxidative stress through various pathways, accompanied by the reduction of PDX-1 DNA-binding activity (Figure 1). Similar effects were observed with the Zucker diabetic fatty (ZDF) rat, another animal model for type 2 diabetes [15].
Furthermore, hepatic glucose production (HGP) was significantly lower in Ad-DN-JNK-treated mice. These results indicate that suppression of the JNK pathway enhances insulin signaling which leads to a decrease in gluconeogenesis and amelioration of glucose tolerance. The data provide strong evidence that JNK is indeed a crucial component of the biochemical pathway responsible for insulin resistance in vivo. This review summarizes current knowledge of GV and its association with oxidative stress and CVD, and discusses its clinical implication in the treatment of diabetes. Since albumin is more readily glycated compared with hemoglobin, GA also more sensitively reflects glycemic excursions and postprandial hyperglycemia compared with HbA1c [20]. Therefore, the increased risk of hypoglycemia in older patients with T2DM [114,115] is at least in part due to greater GV in this population.
In summary, these data indicate that antioxidant treatment can generate beneficial effects for diabetes with preservation of in vivo β-cell function. In contrast, there was no difference in the glucose disappearance rate (Rd) between these two groups.
We have reported that the ratio of GA to HbA1c was significantly correlated with postprandial plasma glucose level but not with fasting plasma glucose level, indicating that GA to HbA1c ratio reflects postprandial glucose excursion independently of fasting glucose level (Figure 2) [21].
In the San Luigi Gonzaga Diabetes Study, a 14-year follow-up of 505 patients with T2DM, HbA1c and 2 h postprandial blood glucose level after lunch were significantly associated with CVD events and mortality [32].Recently, using CGM, Torimoto et al.
These results indicate that the reduction of insulin resistance and the amelioration of glucose tolerance by DN-JNK overexpression are mainly effectuated by a suppression of hepatic glucose production (Figure 3).
Conversely, expression of wild type JNK in the liver of normal mice decreased insulin sensitivity. Thus, JNK deficiency can provide partial resistance against obesity, hyperglycemia and hyperinsulinemia in both genetic and dietary models of diabetes.
The insulin mRNA level and insulin content were significantly higher in the peptide-treated mice.
In summary, these findings suggest that suppression of the JNK pathway in liver exerts greatly beneficial effects on insulin resistance status and glucose tolerance in both genetic and dietary models of diabetes (Figure 3).
Thus, we assume that the JNK inhibitory peptide exerted some beneficial effects on the pancreatic islets. In diabetic animals, glycation can be observed in various tissues and organs, and various kinds of glycated proteins are produced in a non-enzymatical manner through the Maillard reaction.
During the reaction which in turn produces Schiff base, Amadori product and advanced glycosylation end products (AGE), ROS are also produced [10]. Thus, these observational studies indicated an association between GV or postprandial glycemic excursion and the development of atherosclerosis in patients with T2DM. Also, the electron transport chain in mitochondria is likely to be an important pathway triggering the production of ROS.
Indeed, it has been suggested that mitochondrial overwork, which causes the emergence of ROS, is a potential mechanism causing impaired first-phase glucose-stimulated insulin secretion found in the early stage of diabetes [22] as well as diabetic complications [8, 9]. A number of studies have reported that variability of fasting plasma glucose and HbA1c are associated with higher risk of development of retinopathy and nephropathy in patients with type 1 and type 2 diabetes [37,38,39,40,41,42].
They assessed visit-to-visit GV as the SD of five measurements of FPG or HbA1c during the first 3–24 months of the study.
As a result, visit-to-visit GV of FPG and HbA1c were significantly associated with micro- and macrovascular events and mortality: highest vs.
These results suggest that GV during a longer period is an important risk factor for vascular events and mortality, the impact of which may be equal to or even more than that of intraday GV. These changes with hyperglycemia were reversed by concomitant vitamin C infusion, suggesting that increased oxidative stress was the cause of endothelial dysfunction.In 2006, Monnier et al. This study was the first to use CGM to assess the relationship between GV and oxidative stress, and underpinned the important role of GV in increased oxidative stress in patients with diabetes.
They assessed GV with MAGE, MODD and CONGA-1 calculated from CGM data and oxidative stress with 24 h urinary excretion rate of 8-iso-PGF2?.
Although higher levels of 8-iso-PGF2? were observed in patients with T1DM compared with healthy controls, there was no correlation between GV and oxidative stress in these patients. In this study, a significant association between CONGA-2 and left ventricular mass index (LVMI) was also reported.
Glycated AlbuminGA has not only been shown to be a marker of GV, but GA itself has also been postulated to promote atherosclerosis [56].
Since glycation of albumin impairs the antioxidant activities of albumin, GA may contribute to increased oxidative stress in patients with diabetes [57].
GA or GA to HbA1c ratio, but not HbA1c, was associated with carotid IMT or plaque, and severity of coronary atherosclerosis [58,59,60,61].Recently, the predictive value of GA for vascular complications has been evaluated in two large prospective cohorts of DCCT and the Atherosclerosis Risk in Communities (ARIC) study [62,63]. Effects of Treatment of Glycemic Variability on Oxidative Stress and Cardiovascular OutcomesAs described above, in vitro and in vivo animal studies and observational and experimental human studies indicate that oxidative stress is a plausible link between GV and CVD. However, the results of intervention studies are more conflicting.The Hyperglycemia and its Effect after Acute myocardial infarction on cardiovascular outcomes in patients with Type 2 Diabetes mellitus (HEART2D) trial is to date the only study to directly compare the effects of postprandial vs.
A total of 1115 patients with T2DM who had had an acute myocardial infarction within 21 days were assigned to either a prandial strategy group or basal strategy group. The trial was stopped because of lack of efficacy, with a mean follow-up period of 963 days.
During the study, HbA1c was similarly reduced in both groups, and the prandial strategy group showed a lower daily mean postprandial blood glucose compared with the basal strategy group.
Improvement of the management of other coronary risk factors might also have affected the results. Nonetheless, it should be acknowledged that this study was designed to compare two different insulin regimens rather than to clarify the role of GV in CVD outcome.It has been reported that a similar reduction of oxidative stress was obtained by nine days of treatment with either inhaled mealtime insulin or basal insulin in patients with T2DM [79].
In the Study to Prevent Non-Insulin-Dependent Diabetes Mellitus (STOP-NIDDM) study, treatment with acarbose reduced the incidence of T2DM in patients with impaired glucose tolerance (IGT) [81]. In this study, a reduction in CVD in patients treated with acarbose was also reported [82].
A reduction in CVD by treatment with acarbose was also observed in patients with T2DM [83], suggesting the importance of reduction in postprandial excursion to prevent CVD in patients with IGT and T2DM.Glinides are rapid-acting insulin secretagogues, thereby reducing postprandial glucose excursion similarly to AGIs. Differences in patients’ characteristics and an insufficient dose of nateglinide used in the study might have affected these results. However, the different results between the STOP-NIDDM and NAVIGATOR trials may be associated with the different mechanisms of action of the two drugs. On the other hand, glinides suppress postprandial glucose excursion through increasing early phase insulin secretion after meal ingestion. In this study, a total of 104 patients with T2DM were randomly assigned to treatment with miglitol or nateglinide.
After 4 months of treatment, despite similar improvement of HbA1c and 1,5-AG in both groups, a reduction in oxidative stress assessed by diacron reactive oxygen metabolites (d-ROMs) and improvement of percent flow-mediated dilatation (%FMD) were observed only in the patients treated with miglitol, accompanied by improvement of insulin resistance and lipid profile, suggesting that treatment of postprandial glucose excursion without stimulating insulin secretion may be preferable to ameliorate endothelial dysfunction through a reduction in oxidative stress.
Whether endogenous and exogenous insulin have different effects on oxidative stress remains unknown.We have also recently reported the effects of mitiglinide on GV and oxidative stress markers in patients with T2DM [88].
Treatment with mitiglinide for 4 months significantly improved 1,5-AG and daily GV assessed by 7-point SMBG, but there was no change in plasma oxidized low-density lipoprotein (oxLDL), plasma pentosidine, urinary excretion of 8-hydroxydeoxy guanosine (8-OHdG) or 8-iso-PGF2? after treatment.
After 12 weeks of treatment, HbA1c was similarly improved in both groups; however, MAGE was significantly lower in patients treated with vildagliptin compared with those treated with sitagliptin.
Oxidative stress assessed by nitrotyrosine and inflammatory markers (interleukin (IL)-6 and IL-18) was significantly lower in the vildagliptin group, and there was a significant correlation between nitrotyrosine and change in MAGE but not HbA1c. The same researchers also reported that weight loss after bariatric surgery resulted in a reduction in MAGE and plasma nitrotyrosine levels accompanied by increased glucagon-like peptide 1 (GLP-1) level in patients with T2DM, although no change in MAGE and plasma nitrotyrosine levels was observed after weight loss by dieting [93].These favorable changes in GV without an excess risk of hypoglycemia by treatment with DPP-4 inhibitors are expected to result in improvement of CVD outcome. However, recently two randomized controlled trials failed to show a beneficial effect of DPP-4 inhibitors on CVD outcome [94,95].GLP-1 receptor agonists (GLP-1RA) also lead to a supraphysiological activation of GLP-1 receptor and improve GV.
They also reported additive beneficial effects of a combination of GLP-1 and insulin on hyperglycemia-induced oxidative stress and endothelial dysfunction in patients with T2DM [98]. However, this effect of GLP-1 was independent of GV since the same plasma glucose level was maintained during the study. Finally, it was reported that antioxidant vitamin supplementation did not improve CVD outcome and all-cause mortality in the general population and patients with diabetes [100,101].



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