UMLS:C0011860 - FACTA Search

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

Patients with type 2 diabetes (T2D) and their first-degree relatives (FDRs) are characterized by hypoadiponectinaema and insulin resistance. In T2D patients, plasma adiponectin and insulin sensitivity (SI) increase in response to thiazolidinediones (TZDs). These findings suggest a role for adiponectin in the regulation of SI. We studied the relationship between plasma adiponectin and glucose and lipid metabolism and the effect of troglitazone (200 mg/day) for 12 weeks in 19 normoglycaemic, obese FDR and 20 obese T2D patients, using euglycaemic-hyperinsulinaemic clamps, glycolytic flux calculations and indirect calorimetry. Plasma adiponectin was similar in both groups, despite higher glucose disposal (Rd), glucose oxidation and glycolytic flux and lower lipid oxidation during insulin stimulation in FDR compared with T2D patients. Plasma adiponectin correlated with insulin-stimulated Rd, non-oxidative glucose disposal (NOGD), glucose storage and SI in both groups after adjustment for sex and body fat. The troglitazone-mediated upregulation of plasma adiponectin was associated with increased insulin-stimulated Rd, NOGD and glucose storage in both groups. No effect on endogenous glucose production was observed. In FDR, plasma adiponectin correlated with insulin-stimulated glycogen synthase activity and the troglitazone-induced increase in plasma adiponectin correlated with the improvement in insulin-stimulated Rd and SI after adjustment for sex and body fat. In conclusion, plasma adiponectin in weight-matched FDR and T2D patients is comparably low and correlates with insulin-mediated glucose uptake and storage. Moreover, these data provide evidence for an adiponectin-dependent insulin-sensitizing effect of TZDs at an early stage before development of T2D and that this effect is exerted mainly on insulin-mediated glucose metabolism.
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PMID:Adiponectin and its response to thiazolidinediones are associated with insulin-mediated glucose metabolism in type 2 diabetic patients and their first-degree relatives. 1828 35

Dysregulation of the protein kinase glycogen synthase kinase 3 (GSK-3) has been implicated in the development of type 2 diabetes mellitus. GSK-3 protein expression and kinase activity are elevated in diabetes, while selective GSK-3 inhibitors have shown promise as modulators of glucose metabolism and insulin sensitivity. There are two GSK-3 isoforms in mammals, GSK-3alpha and GSK-3beta. Mice engineered to lack GSK-3beta die in late embryogenesis from liver apoptosis, whereas mice engineered to lack GSK-3alpha are viable and exhibit improved insulin sensitivity and hepatic glucose homeostasis. To assess the potential role of GSK-3beta in insulin function, a conditional gene-targeting approach whereby mice in which expression of GSK-3beta was specifically ablated within insulin-sensitive tissues were generated was undertaken. Liver-specific GSK-3beta knockout mice are viable and glucose and insulin tolerant and display "normal" metabolic characteristics and insulin signaling. Mice lacking expression of GSK-3beta in skeletal muscle are also viable but, in contrast to the liver-deleted animals, display improved glucose tolerance that is coupled with enhanced insulin-stimulated glycogen synthase regulation and glycogen deposition. These data indicate that there are not only distinct roles for GSK-3alpha and GSK-3beta within the adult but also tissue-specific phenotypes associated with each of these isoforms.
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PMID:Tissue-specific role of glycogen synthase kinase 3beta in glucose homeostasis and insulin action. 1869 57

The Spontaneously Diabetic Torii (SDT) rat has recently been established as a new model of non-obese type 2 diabetes. In this study, we examined changes in hepatic glucose metabolism in prediabetic and diabetic SDT rats compared with age-matched control rats. The prediabetic state was confirmed at 16 weeks of age, and the diabetic state was confirmed at 24 and 32 weeks of age. Decreases in glucokinase mRNA levels and activity were observed in the prediabetic state. In this state, glycogen synthase activity and glycogen content were also decreased in the SDT rat. In addition to the above changes, glycogen phosphorylase mRNA and activity were decreased and gluconeogenetic enzyme mRNA levels were significantly increased in the diabetic state. These results indicate there is a great potential that abnormalities in hepatic glucose metabolism play a role in the progression to onset of diabetes. We suggest that the SDT rat is a valuable diabetic model for investigations into mechanisms or causes of progression to diabetes.
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PMID:Characterization of hepatic glucose metabolism disorder with the progress of diabetes in male Spontaneously Diabetic Torii rats. 1905 44

The aim of this investigation was to review morphological and metabolic adaptations within skeletal muscle to exercise training in adults with type 2 diabetes mellitus (T2DM) or impaired glucose tolerance (IGT). A comprehensive, systematic database search for manuscripts was performed from 1966 to March 2008 using computerized databases, including Medline, Premedline, CINAHL, AMED, EMBASE and SportDiscus. Three reviewers independently assessed studies for potential inclusion (exposure to exercise training, T2DM or IGT, muscle biopsy performed). A total of 18 exercise training studies were reviewed. All morphological and metabolic outcomes from muscle biopsies were collected. The metabolic outcomes were divided into six domains: glycogen, glucose facilitated transporter 4 (GLUT4) and insulin signalling, enzymes, markers of inflammation, lipids metabolism and so on. Beneficial adaptations to exercise were seen primarily in muscle fiber area and capillary density, glycogen, glycogen synthase and GLUT4 protein expressions. Few randomized controlled trials including muscle biopsy data existed, with a small number of subjects involved. More trials, especially robustly designed exercise training studies, are needed in this field. Future research should focus on the insulin signalling pathway to better understand the mechanism of the improvements in insulin sensitivity and glucose homeostasis in response to various modalities and doses of exercise in this cohort.
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PMID:Adaptations to exercise training within skeletal muscle in adults with type 2 diabetes or impaired glucose tolerance: a systematic review. 1914 33

In mammals, excess carbohydrate is stored as glycogen and glycogen synthase is the enzyme that incorporates glucose units into the glycogen particle. Glycogen synthase activity is regulated by phosphorylation and allosterically activated by glucose 6-phosphate. Phosphorylation of nine serines by different kinases regulates glycogen synthase affinity for glucose 6-phosphate and its substrate UDP-glucose. Glucose 6-phosphate increases both enzyme activity and substrate affinity. Insulin and exercise increase glycogen synthase affinity for glucose 6-phosphate and activity whereas high glycogen content and adrenaline decrease affinity for glucose 6-phosphate and activity. However, insulin, exercise and adrenaline also regulate intracellular concentration of glucose 6-phosphate which will influence in vivo glycogen synthase activity. Importantly, type 2 diabetes is associated with reduced insulin-stimulated glycogen synthase activation. The nine phosphorylation sites theoretically allow 512 combinations of phosphorylation configurations of glycogen synthase with different kinetic properties. However, due to hierarchal phosphorylation, the number of configurations in vivo is most likely much lower. Unfortunately, many studies only report data on glycogen synthase activity measured with high concentration of UDP-glucose which holds back information about changes in substrate affinity. In this paper we discuss the physiological regulation of glycogen synthase phosphorylation and how the phosphorylation pattern regulates glycogen synthase kinetic properties.
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PMID:Regulation of muscle glycogen synthase phosphorylation and kinetic properties by insulin, exercise, adrenaline and role in insulin resistance. 1926 78

Insulin resistance is central to the pathogenesis of type 2 diabetes mellitus. Previous studies have demonstrated that compounds that cause adipogenesis and improve glucose uptake in 3T3-L1 cells are potential insulin sensitizers. Therefore, we evaluated one such compound, 18F9, for (1) adipogenesis in human subcutaneous preadipocyte (SQ) cells, (2) glucose uptake in human skeletal muscle myotubes and SQ cells, and (3) antidiabetic activity in db/db mice. We also investigated its effect on ex vivo glucose uptake in soleus muscle isolated from continuously treated db/db mice. Gene expression profiling in soleus muscle and epididymal fat of db/db mice was performed to understand its effect on glucose metabolism, lipid metabolism, and thermogenesis. 18F9 enhanced adipogenesis in SQ cells and increased glucose uptake in SQ and human skeletal muscle myotubes cells. In db/db mice, 18F9 exhibited dose-dependent reduction in plasma glucose and insulin level. Interestingly, 18F9 was as efficacious as rosiglitazone but did not cause body weight gain and hepatic adverse effects. In addition, 18F9 demonstrated no change in plasma volume in Wistar rats. Furthermore, it enhanced ex vivo glucose uptake in soleus muscles in these mice, which substantiates our in vitro findings. Human peroxisome proliferator activated receptor-gamma transactivation assay revealed a weak peroxisome proliferator activated receptor-gamma transactivation potential (44% of rosiglitazone at 10 mumol/L) of 18F9. Gene expression profiling indicated that 18F9 increased insulin sensitivity mainly through a phosphoinositide 3-kinase-dependent mechanism. 18F9 also up-regulated genes involved in lipid transport and synthesis at par with rosiglitazone. Unlike rosiglitazone, 18F9 elevated the expression of Pdk4. In addition, 18F9 elevated the expression of glycogen synthase and adiponectin significantly higher than rosiglitazone. Taken together, these observations suggest that 18F9 is a safer and potent insulin sensitizer that demonstrates promising antidiabetic activity and is worth further development.
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PMID:18F9 (4-(3,6-bis (ethoxycarbonyl)-4,5,6,7-tetrahydrothieno (2,3-c) pyridin-2-ylamino)-4-oxobutanoic acid) enhances insulin-mediated glucose uptake in vitro and exhibits antidiabetic activity in vivo in db/db mice. 1960 7

There is a substantial body of evidence suggesting that altered level of sex steroids in male is associated with insulin resistance and type 2 diabetes mellitus. However, the mechanism of this effect is not apparent. Our recent study indicated that testosterone deprivation decreases insulin receptor expression and glucose oxidation in insulin target tissues. The present study was designed to assess the impact of deficiency of testosterone and estradiol on Akt phosphorylation, glucose transporter expression, and glucose uptake in skeletal muscle, adipose tissue, and liver of adult male rat. Adult male albino rats of Wistar strain were orchidectomized and supplemented with testosterone (100 microg/100 g body weight per day), estradiol (5 microg/100 g body weight per day), and their combination (100 microg testosterone plus 5 microg estradiol per 100 g body weight per day) for 15 days from the 11th day postorchidectomy. On the day after the last treatment, animals were perfused; and blood was collected for the assay of plasma glucose, serum insulin, testosterone, and estradiol. Gastrocnemius muscle, adipose tissue, and liver were dissected out and used for the assay of various parameters such as Akt phosphorylation, glucose transporter (GLUT) 2 and 4 expression, glucose uptake, and glycogenic and glycogenolytic enzymes activity. Castration elevated the blood glucose level, which was accompanied by inhibitory effect on serum insulin, Akt phosphorylation, GLUT4 expression and its plasma membrane population, glucose uptake, glycogen and glycogen synthase activity, and stimulatory effect on GLUT2 expression and glycogen phosphorylase activity in tissues studied. After testosterone and its combination with estradiol supplementation to castrated rats, a normal pattern of all these parameters was restored. Estradiol administration to castrated rats increased the Akt phosphorylation without altering other parameters studied. It is concluded from the present study that sex steroids deficiency-induced defective glucose uptake in skeletal muscle and adipose tissue is mediated through defective Akt phosphorylation and GLUT4 expression in plasma membrane.
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PMID:Sex steroids deficiency impairs glucose transporter 4 expression and its translocation through defective Akt phosphorylation in target tissues of adult male rat. 1961 1

The protein complex AMP-activated protein kinase (AMPK) is believed to play an important role in the regulation of skeletal muscle glucose and lipid metabolism. Defects in the AMPK system might therefore be an important factor in the pathogenesis of type 2 diabetes. We aimed to identify genetic and environmental mechanisms involved in the regulation of AMPK expression and activity and to examine the association between AMPK protein levels and activity on the one hand, and glucose and fat metabolism on the other. We investigated skeletal muscle biopsies from 100 young and 82 older mono- and dizygotic nondiabetic twins excised during the basal and insulin-stimulated states of a physiological hyperinsulinemic-euglycemic clamp. AMPKalpha1, -alpha2, and -gamma3 mRNA expression was investigated using real-time PCR, and Western blotting was employed to measure protein levels. Multiple regression analyses indicated that skeletal muscle AMPK mRNA and protein expression as well as activity were regulated by sex, age, obesity, and aerobic capacity. Comparison of intraclass correlations on AMPK measurements from mono- and dizygotic twins suggested that skeletal muscle AMPK expression was under minor genetic influence. AMPKgamma3 protein expression and activity were negatively related to whole body glucose uptake through the nonoxidative metabolic pathway and positively related to phosphorylation of glycogen synthase. Our results suggest that skeletal muscle AMPK expression is under minor genetic control but regulated by age and sex and associated with obesity and aerobic capacity. Furthermore, our results indicate a role for gamma3-containing AMPK complexes in downregulation of insulin-stimulated nonoxidative glucose metabolism possibly through inhibition of glycogen synthase activity.
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PMID:Genetic and metabolic effects on skeletal muscle AMPK in young and older twins. 1967 40

The regulatory effects of insulin, insulin-like growth factor 1 (IGF-1), and relaxin on glucose-6-phosphate dehydrogenase (G6PDH) and glycogen synthase (GS) activities have been studied in myometrium of pregnant women of control group and with diabetes mellitus of different etiology. In patients with type 1 diabetes G6PDH activity did not differ from the control group, but the enzyme activity was sharply decreased in pregnant women with type 2 diabetes and gestational diabetes. In the control group maximal stimulation of G6PDH activity was observed at 10(-9) M of peptides and their stimulating effect decreased in the following order: insulin > relaxin > IGF-1. In pregnant women with types 1 diabetes insulin effect on the enzyme activity was lower than in the control, and the effects of IGF-1 and relaxin were absent. In the group of pregnant women with type 2 diabetes and gestational diabetes the effects of insulin and IGF-1 were decreased, but the effect of relaxin was somewhat higher thus giving the following order in their efficiency relaxin > IGF-1 = insulin. At 10(-9) M peptides exhibited similar stimulating effects on the active form of GS-I, but had no influence on the total enzyme activity in the control group of pregnant women. In patients with type 1 diabetes GS activity remained unchanged (versus control), and peptides did not stimulate the enzyme activity. In patients with type 2 diabetes a significant decrease in GS activity was accompanied by the decrease in the effect of peptides, giving the following order of their efficiency: insulin = IGF-1 > relaxin. In myometrium of pregnant women with gestational (treated and untreated) diabetes GS activity decreased, the effect of insulin was weaker, whereas the effects of relaxin and IGF-1 increased thus giving the following order of their efficiency: relaxin > IGF-1 > insulin. Insulin therapy of type 1 diabetes incompletely restored sensitivity of the enzymes to the peptide actions. At the same time, in women with gestational diabetes and subjected to insulin therapy the stimulating effect of relaxin on the enzyme activities increased. This fact suggests that relaxin exhibits replacement functions under conditions of attenuated insulin action.
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PMID:[The regulation of glucose-6-phosphate dehydrogenase and glycogen synthase activities by insulin superfamily peptides in myometrium of pregnant women and its impairments under different types of diabetes mellitus]. 2001 97

Although germ-line deletion of c-Jun NH(2)-terminal kinase (JNK) improves overall insulin sensitivity in mice, those studies could not reveal the underlying molecular mechanism and the tissue site(s) in which reduced JNK activity elicits the observed phenotype. Given its importance in nonesterified fatty acids (NEFA) and glucose utilization, we hypothesized that the insulin-sensitive phenotype associated with Jnk deletion originates from loss of JNK function in skeletal muscle. Short hairpin RNA (shRNA)-mediated gene silencing was used to identify the functions of JNK subtypes in regulating energy metabolism and metabolic responses to elevated concentrations of NEFA in C2C12 myotubes, a cellular model of skeletal muscle. We show for the first time that cellular JNK2- and JNK1/JNK2-deficiency divert glucose from oxidation to glycogenesis due to increased glycogen synthase (GS) activity and induction of Pdk4. We further show that JNK2- and JNK1/JNK2-deficiency profoundly increase cellular NEFA oxidation, and their conversion to phospholipids and triglyceride. The increased NEFA utilization was coupled to increased expressions of selective NEFA handling genes including Cd36, Acsl4, and Chka, and enhanced palmitic acid (PA)-dependent suppression of acetyl-CoA carboxylase (Acc). In JNK-intact cells, PA inhibited insulin signaling and glycogenesis. Although silencing Jnk1 and/or Jnk2 prevented PA-induced inhibition of insulin signaling, it did not completely block decreased insulin-mediated glycogenesis, thus indicating JNK-independent pathways in the suppression of glycogenesis by PA. Muscle-specific inhibition of JNK2 (or total JNK) improves the capacity of NEFA utilization and glycogenesis, and is a potential therapeutic target for improving systemic insulin sensitivity in type 2 diabetes (T2D).
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PMID:JNK deficiency enhances fatty acid utilization and diverts glucose from oxidation to glycogen storage in cultured myotubes. 2009 41

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