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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of the work described here was to improve our understanding of beta-cell function (BCF) and beta-cell mass (BCM) and their relationship in vivo using the minipig as a model for some of the aspects of human type 2 diabetes (T2DM). More specifically, the aim was to evaluate the following questions: How is BCF, especially high frequency pulsatile insulin secretion, affected by a primary reduction in BCM or by primary obesity or a combination of the two in the minipig? Can evaluation of BCF in vivo be used as a surrogate measure to predict BCM in minipigs over a range of BCM and body weight? We first developed a minipig model of reduced BCM and mild diabetes using administration of a combination of streptozotocin (STZ) and nicotinamide (NIA) as a tool to study effects of a primary reduction of BCM on BCF. The model was characterized using a mixed-meal oral glucose tolerance test and intravenous stimulation with glucose and arginine as well as by histology of the pancreas after euthanasia. It was shown that stable, moderate diabetes can be induced and that the model is characterized by fasting and postprandial hyperglycemia, reduced insulin secretion and reduced BCM. Several defects in insulin secretion are well documented in human T2DM; however, the role in the pathogenesis and the possible clinical relevance of high frequency (rapid) pulsatile insulin secretion is still debated. We therefore investigated this phenomenon in normal minipigs and found easily detectable pulses in peripheral vein plasma samples that were shown to be correlated with pulses found in portal vein plasma. Furthermore, the rapid kinetics of insulin in the minipig strongly facilitates pulse detection. These characteristics make the minipig particularly suitable for studying the occurrence of disturbed pulsatility in relation to T2DM. Disturbances of rapid pulsatile insulin secretion have been reported to be a very early event in the development of T2DM and include disorderliness of pulses and reduced ability to entrain pulses with glucose. However, the role of reduced BCM and/or obesity in the development of these defects in humans is unknown. Therefore, the investigations were extended to include lean NIA/STZ minipigs where it was shown that a primary reduction of BCM leads to reduced insulin pulse mass but does not change periodicity of the pulses or the ability of glucose to entrain pulses. In contrast, obesity was found to be associated with reduced pulsatile insulin secretion and improved orderliness of glucose entrained pulses in the minipig. Furthermore obesity was associated with pancreatic lipid accumulation and increased beta-cell volume, although BCM relative to body weight was not changed. Finally, a combination of obesity and reduced BCM resulted in severely disturbed insulin secretion and severe morphological changes. Thus, results from NIA/STZ minipigs suggest that not all of the defects of rapid pulsatile insulin secretion seen in human T2DM can be explained by a primary reduction of BCM mass or up to 2 weeks of mild hyperglycemia. Furthermore, based on the results from obese minipigs, obesity in itself induces small defects in rapid pulsatile insulin secretion and the combination of obesity and reduced BCM leads to further deterioration of BCF. Another major characteristic of human diabetes is thought to be reduction of BCM and the ability to follow this parameter over time would greatly improve our understanding of disease progression and allow evaluation of pharmacological methods to increase BCM. BCM cannot, at present, be measured in vivo in humans. We therefore set out to further validate data from smaller studies in lean non-human primates and minipigs showing a correlation between measures of BCF in vivo and BCM. In a large study in lean minipigs with a range of BCM, we found that a strong stimulation of insulin secretion with a combination of glucose and arginine resulted in the best correlation to BCM, as determined using stereology. A similar relationship was also shown in a group of both lean and obese animals, thereby supporting the application of similar methods to estimate BCM in humans over a range of body weights. Since changes in rapid pulsatile insulin secretion are detectable early in the development of diabetes and in obesity, we hypothesized that this parameter could also be highly correlated to BCM as it has been shown in smaller studies in lean minipigs. However, rapid pulsatile insulin secretion did not show a better correlation to BCM than combined stimulation with glucose and arginine, and thus analysis of pulses does not provide a better surrogate marker for BCM in the minipig. To evaluate the weaker correlation of glucose stimulation compared to combined glucose and arginine stimulation in vivo with BCM, we further investigated BCF in lean, beta-cell reduced minipigs by studying BCF in vitro after isolation and perfusion of their pancreases to investigate the ability of the remaining beta-cells to compensate for the loss of BCM by increasing insulin secretion per BCM. The perfused pancreas was chosen in order to allow direct measurement of the insulin secretion without the effects of peripheral tissues. During the perfusion, it was shown that the remaining beta-cells were indeed able to compensate for the loss of BCM to a large extent in response to stimulation with glucose and glucagon-like peptide-1 but not in response to arginine. This shows that the type of stimulus applied is important for the ability to compensate for reduced BCM from the remaining population of beta-cells, and further supports the use of combined stimulation with glucose and arginine for estimation of BCM in vivo. In conclusion, an animal model of reduced BCM and mild diabetes has been developed and characterized. The model has been used to evaluate effects of a primary reduction of BCM, showing a reduced rapid insulin pulse mass but normal periodicity and entrainability of the pulses, whereas obesity was associated with reduced rapid pulsatile insulin secretion. Thus, based on these data, the disturbed rapid pulsatile insulin secretion seen in T2DM humans may not directly be explained by the reduced BCM in diabetes, whereas obesity may be related to the reduced pulsatility. Furthermore, the model has been used to establish a correlation between extensive stimulation of insulin secretion in vivo and BCM obtained by stereology in both lean and obese animals. The ability to estimate BCM based on in vivo experiments in the minipig would allow longitudinal studies on changes in this parameter over time in the intact animal and support application of similar methods in humans. Such methods could be useful for the diagnosis and the measurement of the effectiveness of treatment of diabetes in humans in the future.
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PMID:Beta-cell function and mass in type 2 diabetes. 1972 71

Resveratrol is a natural polyphenolic compound that activates nicotinamide adenosine dinucleotide-dependent deacetylase SIRT1. Resveratrol has recently been shown to exert potent antidiabetic actions when orally delivered to animal models of type 2 diabetes. However, the tissue(s) mediating these beneficial effects is unknown. Because SIRT1 is expressed in central nervous system (CNS) neurons known to control glucose and insulin homeostasis, we hypothesized that resveratrol antidiabetic effects are mediated by the brain. Here, we report that long-term intracerebroventricular infusion of resveratrol normalizes hyperglycemia and greatly improves hyperinsulinemia in diet-induced obese and diabetic mice. It is noteworthy that these effects are independent of changes in body weight, food intake, and circulating leptin levels. In addition, CNS resveratrol delivery improves hypothalamic nuclear factor-kappaB inflammatory signaling by reducing acetylated-RelA/p65 and total RelA/p65 protein contents, and inhibitor of nuclear factor-kappaB alpha and IkappaB kinase beta mRNA levels. Furthermore, this treatment leads to reduced hepatic phosphoenolpyruvate carboxykinase 1 mRNA and protein levels and ameliorates pyruvate-induced hyperglycemia in this mouse model of type 2 diabetes. Collectively, our results unveiled a previously unrecognized key role for the CNS in mediating the antidiabetic actions of resveratrol.
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PMID:Central administration of resveratrol improves diet-induced diabetes. 1981 63

(2S,4S)-4-Fluoro-1-({[4-methyl-1-(methylsulfonyl)piperidin-4-yl]amino}acetyl)pyrrolidine-2-carbonitrile monofumarate (ASP8497) is a novel dipeptidyl peptidase (DPP)-IV inhibitor. In this study, we investigated the antidiabetic potency, mechanism, and duration of action of ASP8497 both in vitro and in vivo, and compared it with the DPP-IV inhibitors vildagliptin, sitagliptin, and saxagliptin. ASP8497 inhibited rat plasma DPP-IV activity in vitro with an IC(50) value of 2.96 nmol/l, while those for vildagliptin, sitagliptin, and saxagliptin were 2.12, 8.98, and 2.00 nmol/l, respectively. In rats that had streptozotocin-nicotinamide-induced, mildly diabetes, oral administration of ASP8497 dose-dependently and sustainably inhibited plasma DPP-IV activity. In addition, ASP8497 dose-dependently and significantly improved glucose tolerance with a concomitant increase in plasma glucagon-like peptide 1 (GLP-1) and insulin levels at both 0.5 h and 8 h after dosing. The order of both potency and duration of action for plasma DPP-IV inhibition and glucose tolerance improvement was as follows: saxagliptin > ASP8497 = vildagliptin = sitagliptin. These results suggest that ASP8497 exerts a potent and long-acting DPP-IV inhibitory effect and improves glucose tolerance through glucose-dependent insulinotropic action via elevation of the GLP-1 level in streptozotocin-nicotinamide-induced mildly diabetic rats. This compound is expected to be useful as a therapeutic agent for impaired glucose tolerance and type 2 diabetes.
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PMID:Antihyperglycemic effects of ASP8497 in streptozotocin-nicotinamide induced diabetic rats: comparison with other dipeptidyl peptidase-IV inhibitors. 1990 14

Type 2 diabetes is a major global health problem. It is generally accepted that type 2 diabetes is the result of gene-environmental interaction. However, the mechanism underlying the interaction is unclear. Diet change is known to play an important role in type 2 diabetes. The fact that the global high prevalence of type 2 diabetes has occurred following the spread of food fortification worldwide suggests a possible involvement of excess niacin intake. Our recent study found that nicotinamide overload and low nicotinamide detoxification may induce oxidative stress associated with insulin resistance. Based on the relevant facts, this review briefly summarized the relationship between the prevalence of type 2 diabetes and the nicotinamide metabolism changes induced by excess niacin intake, aldehyde oxidase inhibitors, liver diseases and functional defects of skin. We speculate that the gene-environmental interaction in type 2 diabetes may be a reflection of the outcome of the association of chronic nicotinamide overload-induced toxicity and the relatively low detoxification/excretion capacity of the body. Reducing the content of niacin in foods may be a promising strategy for the control of type 2 diabetes.
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PMID:[Chronic nicotinamide overload and type 2 diabetes]. 2017 94

Plant drug mixtures are widely used in the adjuvant therapy of type 2 diabetes mellitus for the prevention of complications. The drug mixtures generally contribute to the efficiency of the therapy and may also reduce undesirable side effects. Two herbal extracts (lyophilized aqueous extracts of plant drug mixtures 1: Myrtilli folium, Phaseoli fructus sine seminibus and 2: Myrtilli folium, Phaseoli fructus sine seminibus, Salviae folium) were investigated in in vitro rat models. The content of bioactive constituents (polyphenol, flavonoid and vitamin C) in plant drug mixtures and lyophilized samples was evaluated. The antioxidant activity of lyophilized extracts was determined by measuring the ferric reducing ability of the plant, Fe2+ induced lipid peroxidation (LPO) in rat brain homogenates and NADPH (beta-nicotinamide adenine dinucleotide phosphate reduced form) induced LPO in cerebral microsomes. The antioxidant activity of lyophilized extracts was compared to that of quercetin and rutin. Both teas of lyophilized extracts had significant reducing ability (2694 and 2771 micromol/l) and inhibited LPO (IC50 28.0 and 20.6 microl in NADPH induced LPO, 17.3 and 8.7 microl in Fe2+ induced LPO). The high concentration of polyphenol/flavonoid (12.38-13.00 and 1.45-5.22 g/100 g, respectively) and vitamin C (0.099-0.165 g/100 g) in the herbal extracts is related to their significant antioxidant properties. The tea mixtures have significant nutritional value, since the consumption of 2 or 3 cups of tea a day covers 50% of the daily requirement of vitamin C and it is also relevant polyphenol source. The high polyphenol/flavonoid content may restore the redox imbalance and contribute to the prevention of diabetic complications.
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PMID:Inhibition of lipid peroxidation of herbal extracts (obtained from plant drug mixtures of Myrtilli folium, Phaseoli fructus sine seminibus and Salviae folium) used in type 2 diabetes mellitus. 2019 98

Reduced nicotinamide adenine dinucleotide (NADPH) is a functionally important metabolite required to support numerous cellular processes. However, despite the identification of numerous NADPH-producing enzymes, the mechanisms underlying how the organellar pools of NADPH are maintained remain elusive. Here, we have identified glucose-6-phosphate dehydrogenase (G6PDH) as an important source of NADPH in mitochondria. Activity analysis, submitochondrial fractionation, fluorescence microscopy, and protease sensitivity assays revealed that G6PDH is localized to the mitochondrial matrix. 6-ANAM, a specific G6PDH inhibitor, depleted mitochondrial NADPH pools and increased oxidative stress revealing the importance of G6PDH in NADPH maintenance. We also show that glucose availability and differences in metabolic state modulate the enzymatic sources of NADPH in mitochondria. Indeed, cells cultured in high glucose (HG) not only adopted a glycolytic phenotype but also relied heavily on matrix-associated G6PDH as a source of NADPH. In contrast, cells exposed to low-glucose (LG) concentrations, which displayed increased oxygen consumption, mitochondrial metabolic efficiency, and decreased glycolysis, relied predominantly on isocitrate dehydrogenase (ICDH) as the principal NADPH-producing enzyme in the mitochondria. Culturing glycolytic cells in LG for 48 h decreased G6PDH and increased ICDH protein levels in the mitochondria, further pointing to the regulatory role of glucose. 2-Deoxyglucose treatment also prevented the increase of mitochondrial G6PDH in response to HG. The role of glucose in regulating enzymatic sources of mitochondrial NADPH pool maintenance was confirmed using human myotubes from obese adults with a history of type 2 diabetes mellitus (post-T2DM). Myotubes from post-T2DM participants failed to increase mitochondrial G6PDH in response to HG in contrast to mitochondria in myotubes from control participants (non-T2DM). Hence, we not only identified a matrix-associated G6PDH but also provide evidence that metabolic state/glucose availability modulate enzymatic sources of NADPH.
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PMID:Glucose regulates enzymatic sources of mitochondrial NADPH in skeletal muscle cells; a novel role for glucose-6-phosphate dehydrogenase. 2022 49

The present study evaluates the combined effect of tetrahydrocurcumin and chlorogenic acid on oxidative stress in streptozotocin-nicotinamide-induced diabetic rats. Rats were rendered diabetic by a single intraperitoneal injection (i.p) of streptozotocin (45 mg/kg BW), 15 min after an i.p injection of nicotinamide (110 mg/kg BW). The levels of fasting plasma glucose and insulin were estimated. As an index of oxidative stress, the levels of enzymic antioxidants and lipid peroxidation products were analyzed in liver and kidney. Diabetic rats showed an increase in the levels of fasting plasma glucose, lipid peroxidative products such as thiobarbituric acid reactive substances and lipid hydroperoxides and a decrease in plasma insulin, and enzymic antioxidants viz., superoxide dismutase, catalase, glutathione peroxidase and glutathione-S-transferase. Combined administration of tetrahydrocurcumin (80 mg/kg BW) and chlorogenic acid (5 mg/kg BW) to diabetic rats for 45 days, reversed the biochemical changes to near normal. The above findings were supported by histological observations of the liver and kidney. Together the present study clearly reflects that combined dosage of tetrahydrocurcumin and chlorogenic acid augments enzymic antioxidants with a concomitant decrease in lipid peroxidation and protects against streptozotocin-nicotinamide-induced type 2 diabetes in experimental rats.
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PMID:Comparative and combined effect of chlorogenic acid and tetrahydrocurcumin on antioxidant disparities in chemical induced experimental diabetes. 2033 5

Arginine (Arg) is known to possess numerous useful physiological properties and have immunomodulatory effects. In vitro studies reported that Arg inhibits advanced glycation endproduct (AGE) formation; however, the effects of Arg on the receptor of AGE (RAGE) expression in inflammatory conditions are not clear. The present study investigated the effects of dietary Arg supplementation on inflammatory mediator production and RAGE expression in type 2 diabetic rats. There were one normal control (NC) group and two diabetic groups in the present study. Rats in the NC group were fed with a regular chow diet. One diabetic group (DM) was fed a common semi-purified diet while the other diabetic group received a diet in which part of the casein was replaced by Arg (DM-Arg) for 8 weeks. Diabetes was induced by an intraperitoneal injection of nicotinamide followed by streptozotocin. Rats with blood glucose levels exceeding 1800 mg/l were considered diabetic. Blood samples and the liver and lungs of the animals were collected at the end of the study for further analysis. Results showed that plasma glucose and fructosamine contents were significantly higher in the diabetic groups than those in the NC group. The DM group had higher fructosamine and C-reactive protein than the DM-Arg group. Immunohistochemical staining showed that the expressions of RAGE in liver and lung tissues were significantly lower in the DM-Arg group than in the DM group. These results suggest that supplemental dietary Arg can decrease AGE-RAGE interactions and consequently reduce tissue damage in rats with type 2 diabetes.
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PMID:Effects of dietary arginine on inflammatory mediator and receptor of advanced glycation endproducts (RAGE) expression in rats with streptozotocin-induced type 2 diabetes. 2038 49

Diabetes mellitus is associated with dyslipidemia, which is a significant risk factor for cardiovascular complications. The present study was carried out to evaluate the effects of tetrahydrocurcumin (THC) and chlorogenic acid (CGA) alone and in combination on alterations in lipids, lipoproteins and enzymes involved in lipid metabolism in streptozotocin (STZ)-nicotinamide (NA)-induced type 2 diabetic rats. A significant (p<0.05) increase in the concentrations of plasma and tissue (liver and kidney) lipids (cholesterol, triglycerides (TGs), free fatty acids (FFAs) and phospholipids (PLs)) and low density and very low-density lipoproteins (LDL and VLDL), and a decrease in the concentration of high-density lipoproteins (HDL) were noticed in STZ administered diabetic rats. In addition, the activity of 3-hydroxy 3-methylglutaryl coenzyme A (HMG-CoA) reductase increased significantly (p<0.05) in the liver and kidney whereas the activities of lipoprotein lipase (LPL) and lecithin cholesterol acyl transferase (LCAT) were decreased significantly (p<0.05) in the plasma of diabetic rats. Combined administration of CGA (5mg/kg b.w.) and THC (80mg/kg b.w.) for 45 days remarkably reduced the STZ-induced changes in lipids, lipoproteins and lipid metabolising enzymes when compared to the effects of CGA or THC alone in diabetic rats. These results indicate that combination of THC and CGA can potentially ameliorate lipid abnormalities in experimental type 2 diabetes.
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PMID:Antihyperlipidemic effect of chlorogenic acid and tetrahydrocurcumin in rats subjected to diabetogenic agents. 2069 51

Retinopathy has been increasing in prevalence as a consequence of type 2 diabetes and a cluster of coexisting risk factors characterized as the metabolic syndrome. However, the combined effects of these conditions on the retina are poorly understood. Therefore, we focused on the spontaneously hypertensive corpulent rat (SHR/N-cp), a model with type 2 diabetes, obesity and features of the metabolic syndrome to characterize retinal changes at a structural and functional level. SHR/N-cp males at 4 and 8 months of age were used in this study. Metabolic parameters and blood pressure were measured by standard methods. Morphology was investigated by histological techniques supplemented by nicotinamide adenine dinucleotide phosphate-diaphorase staining of whole mounts and fluorescein angiography to analyze the retinal vasculature. The in vivo function of the retina was examined by electroretinography (ERG). Obese SHR/N-cp rats were hypertensive and showed significant increases in body weight, serum levels of glucose, triglycerides, total cholesterol and urinary glucose excretion compared with lean controls (P < 0.01 for each). Histology indicated an overall intact integrity of the retina and aspects of microangiopathy in obese SHR/N-cp rats. ERG revealed intact processing of light signals but significantly decreased amplitudes of b-waves for all (P < 0.01) and of a-waves for some examined light intensities (P < 0.05). Oscillatory potentials were significantly protracted (P < 0.01), whereas amplitudes were not reduced. Microangiopathy and electroretinographic deficits combine to produce an early non-proliferative retinopathy phenotype in the obese SHR/N-cp rats. Thus, this model represents a valuable experimental tool to obtain further insights into the mechanisms of retinopathy in the context of obesity, type 2 diabetes and metabolic syndrome.
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PMID:Microangiopathy and visual deficits characterize the retinopathy of a spontaneously hypertensive rat model with type 2 diabetes and metabolic syndrome. 2092 14


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