Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Twenty-one naturally occurring flavonoids were tested for inhibitory activities against alpha-glucosidase (EC 3.2.1.20) and alpha-amylase (EC 3.2.1.1). Luteolin, amentoflavone, luteolin 7-O-glucoside, and daidzein were the strongest inhibitors among the compounds tested. Luteolin inhibited alpha-glucosidase by 36% at the concentration of 0.5 mg/ml and was stronger than acarbose, the most widely prescribed drug, in inhibitory potency, suggesting that it has the possibility to effectively suppress postprandial hyperglycemia in patients with non-insulin dependent diabetes mellitus. Luteolin also inhibited alpha-amylase effectively although it was less potent than acarbose. The clinical value of luteolin needs to be further evaluated.
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PMID:Inhibition of alpha-glucosidase and amylase by luteolin, a flavonoid. 1119 16

Insulin resistance, an important feature of type 2 diabetes, is manifested as attenuated insulin receptor (IR) signaling in response to insulin binding. A drug that promotes the initiation of IR signaling by enhancing IR autophosphorylation should, therefore, be useful for treating type 2 diabetes. This report describes the effect of a small molecule IR sensitizer, TLK16998, on IR signaling. This compound activated the tyrosine kinase domain of the IR beta-subunit at concentrations of 1 micromol/l or less but had no effect on insulin binding to the IR alpha-subunit even at much higher concentrations. TLK16998 alone had no effect on IR signaling in mouse 3T3-L1 adipocytes but, at concentrations as low as 3.2 micromol/l, enhanced the effects of insulin on the phosphorylation of the IR beta-subunit and IR substrate 1, and on the amount of phosphatidylinositol 3-kinase that coimmunoprecipitated with IRS-1. Phosphopeptide mapping revealed that the effect of TLK16998 on the IR was associated with increased tyrosine phosphorylation of the activation loop of the beta-subunit tyrosine kinase domain. TLK16998 also increased the potency of insulin in stimulating 2-deoxy-D-glucose uptake in 3T3-L1 adipocytes, with a detectable effect at 8 micromol/l and a 10-fold increase at 40 micromol/l. In contrast, only small effects were observed on IGF-1-stimulated 2-deoxy-D-glucose uptake. In diabetic mice, TLK16998, at a dose of 10 mg/kg, lowered blood glucose levels for up to 6 h. These results suggest, therefore, that small nonpeptide molecules that directly sensitize the IR may be useful for treating type 2 diabetes.
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PMID:A novel small molecule that directly sensitizes the insulin receptor in vitro and in vivo. 1128 48

Activation of AMP-activated protein kinase (AMPK) with 5-aminoimidazole-4-carboxamide-1-beta-D-ribofurano-side (AICAR) increases glucose transport in skeletal muscle via an insulin-independent pathway. To examine the effects of AMPK activation on skeletal muscle glucose transport activity and whole-body carbohydrate and lipid metabolism in an insulin-resistant rat model, awake obese Zuckerfa/fa rats (n = 26) and their lean (n = 23) littermates were infused for 90 min with AICAR, insulin, or saline. The insulin infusion rate (4 mU.kg(-1).min(-1)) was selected to match the glucose requirements during AICAR (bolus, 100 mg/kg; constant, 10 mg.kg(-1).min(-1)) isoglycemic clamps in the lean rats. The effects of these identical AICAR and insulin infusion rates were then examined in the obese Zucker rats. AICAR infusion increased muscle AMPK activity more than fivefold (P < 0.01 vs. control and insulin) in both lean and obese rats. Plasma triglycerides, fatty acid concentrations, and glycerol turnover, as assessed by [2-13C]glycerol, were all decreased in both lean and obese rats infused with AICAR (P < 0.05 vs. basal), whereas insulin had no effect on these parameters in the obese rats. Endogenous glucose production rates, measured by [U-13C]glucose, were suppressed by >50% during AICAR and insulin infusions in both lean and obese rats (P < 0.05 vs. basal). In lean rats, rates of whole-body glucose disposal increased by more than two-fold (P < 0.05 vs. basal) during both AICAR and insulin infusion; [3H]2-deoxy-D-glucose transport activity increased to a similar extent, by >2.2-fold (both P < 0.05 vs. control), in both soleus and red gastrocnemius muscles of lean rats infused with either AICAR or insulin. In the obese Zucker rats, neither AICAR nor insulin stimulated whole-body glucose disposal or soleus muscle glucose transport activity. However, AICAR increased glucose transport activity by approximately 2.4-fold (P < 0.05 vs. control) in the red gastrocnemius from obese rats, whereas insulin had no effect. In summary, acute infusion of AICAR in an insulin-resistant rat model activates skeletal muscle AMPK and increases glucose transport activity in red gastrocnemius muscle while suppressing endogenous glucose production and lipolysis. Because type 2 diabetes is characterized by diminished rates of insulin-stimulated glucose uptake as well as increased basal rates of endogenous glucose production and lipolysis, these results suggest that AICAR-related compounds may represent a new class of antidiabetic agents.
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PMID:Effect of 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside infusion on in vivo glucose and lipid metabolism in lean and obese Zucker rats. 1133 11

A number of studies have demonstrated that insulin resistance in the skeletal muscle plays a pivotal role in the insulin resistance associated with obesity and type 2 diabetes. A decrease in GLUT4 translocation from the intracellular pool to the plasma membranes in skeletal muscles has been implicated as a possible cause of insulin resistance. Herein, we examined the effects of an insulin-sensitizing drug, troglitazone (TGZ), on glucose uptake and the translocation of GLUT4 in L6 myotubes. The prolonged exposure (24 h) of L6 myotubes to TGZ (10(-5) mol/l) caused a substantial increase in the 2-deoxy-[3H]D-glucose (2-DG) uptake without changing the total amount of the glucose transporters GLUT4, GLUT1, and GLUT3. The TGZ-induced 2-DG uptake was completely abolished by cytochalasin-B (10 micromol/l). The ability of TGZ to translocate GLUT4 from light microsomes to the crude plasma membranes was greater than that of insulin. Both cycloheximide treatment (3.5 x 10(-6) mol/l) and the removal of TGZ by washing reversed the 2-DG uptake to the basal level. Moreover, insulin did not enhance the TGZ-induced 2-DG uptake additively. The TGZ-induced 2-DG uptake was only partially reversed by wortmannin to 80%, and TGZ did not change the expression and the phosphorylation of protein kinase B; the expression of protein kinase C (PKC)-lambda, PKC-beta2, and PKC-zeta; or 5'AMP-activated protein kinase activity. a-Tocopherol, which has a molecular structure similar to that of TGZ, did not increase 2-DG uptake. We conclude that the glucose transport in L6 myotubes exposed to TGZ for 24 h is the result of an increased translocation of GLUT4. The present results imply that the effects of troglitazone on GLUT4 translocation may include a new mechanism for improving glucose transport in skeletal muscle.
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PMID:Troglitazone induces GLUT4 translocation in L6 myotubes. 1133 13

The aim of this study was to ascertain whether the presence of hypertension conveys a more severe degree of insulin resistance in type 2 diabetes mellitus and, if so, which biochemical pathways are involved. We quantitated the rates of total glucose disposal, glycogen synthesis (GS), glycolysis, glucose oxidation, endogenous glucose production, and LOX in the basal state and during a 4-h euglycemic ( approximately 5 mM) hyperinsulinemic ( approximately 300 pM) clamp carried out in combination with a dual-tracer infusion ([(3)H]-3- and [(14)C]-U-D-glucose) and indirect calorimetry in 42 nonobese noninsulin-treated type 2 diabetic subjects (22 hypertensive and 20 normotensive) and 23 nonobese nondiabetic subjects (9 without and 14 with essential hypertension). Compared with normotensive controls, both groups of diabetic subjects were markedly insulin resistant. In the basal state, all glucose fluxes were similar in diabetic subjects with or without hypertension. During insulin infusion, total glucose disposal was significantly reduced in hypertensive diabetic subjects, compared with their normotensive counterparts (18.7 +/- 1.0 vs. 28.6 +/- 3.0 micromol/min.kg lean body mass; P < 0.01). This difference was almost entirely explained by a marked reduction in GS (4.5 +/- 2.0 vs. 12.5 +/- 3.3 micromol/min.kg lean body mass; P < 0.01). Endogenous glucose production was not different in the two diabetic groups during insulin infusion and was significantly higher than in normotensive controls. Lipid oxidation was less suppressed by hyperinsulinemia in hypertensive than in normotensive diabetic subjects (1.46 +/- 0.1 vs. 0.91 +/- 0.1 micromol/min.kg lean body mass; P < 0.01). Glucose fluxes were not significantly different in nondiabetic subjects with essential hypertension and in normotensive diabetic individuals. These results indicate that hypertension markedly aggravates insulin resistance featuring type 2 diabetes mellitus. The molecular defects underlying this phenomenon involve primarily GS.
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PMID:Intracellular partition of plasma glucose disposal in hypertensive and normotensive subjects with type 2 diabetes mellitus. 1134 9

It has been postulated that glucose transport is the principal site of skeletal muscle insulin resistance in obesity and type 2 diabetes, though a distribution of control between glucose transport and phosphorylation has also been proposed. The current study examined whether the respective contributions of transport and phosphorylation to insulin resistance are modulated across a dose range of insulin stimulation. Rate constants for transport and phosphorylation in skeletal muscle were estimated using dynamic positron emission tomography (PET) imaging of 2-deoxy-2[18F]fluoro-D-glucose ([18F]FDG) during insulin infusions at three rates (0, 40, and 120 mU/m2 per min) in lean glucose-tolerant, obese glucose-tolerant, and obese type 2 diabetic subjects. Parallel studies of arteriovenous fractional extraction across the leg of [18F]FDG and [2-3H] glucose were performed to measure the "lumped constant" (LC) (i.e., the analog effect) for [18F]FDG to determine whether this value is affected by insulin dose or insulin resistance. The value of the LC was similar across insulin doses and groups. Leg glucose uptake (LGU) also provided a measure of skeletal muscle glucose metabolism independent of PET. [18F]FDG uptake determined by PET imaging strongly correlated with LGU across groups and across insulin doses (r = 0.81, P < 0.001). Likewise, LGU correlated with PET parameters of glucose transport (r = 0.67, P < 0.001) and glucose phosphorylation (r = 0.86, P < 0.001). Glucose transport increased in response to insulin in the lean and obese groups (P < 0.05), but did not increase significantly in the type 2 diabetic group. A dose-responsive pattern of stimulation of glucose phosphorylation was observed in all groups of subjects (P < 0.05); however, glucose phosphorylation was lower in both the obese and type 2 diabetic groups compared with the lean group at the moderate insulin dose (P < 0.05). These findings indicate an important interaction between transport and phosphorylation in the insulin resistance of obesity and type 2 diabetes.
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PMID:Interactions of impaired glucose transport and phosphorylation in skeletal muscle insulin resistance: a dose-response assessment using positron emission tomography. 1152 73

The antidiabetic activity of the rhizoma of Anemarrhena asphodeloides was investigated in KK-Ay mice, an animal model of genetic type 2 diabetes. The water extract of the rhizoma (AA) (90 mg/kg) reduced blood glucose levels from 570 +/- 29 to 401 +/- 59 mg/dl 7 h after oral administration (p<0.05) and also tended to reduce serum insulin levels in KK-Ay mice. AA-treated KK-Ay mice had significantly reduced blood glucose levels in an insulin tolerance test. Based on these results, the antidiabetic mechanism of AA may be due to decreased insulin resistance. In addition, the active components of AA were confirmed to be mangiferin and its glucoside.
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PMID:Antidiabetic activity of the rhizoma of Anemarrhena asphodeloides and active components, mangiferin and its glucoside. 1155 59

Noninsulin-dependent diabetes mellitus (NIDDM) is an increasingly common disease, which brings a number of life-threatening complications. In rats with experimentally induced diabetes, there is an increase in the capacity of the intestine to absorb monosaccharides. We have examined the activity and the expression of monosaccharide transporters in the intestine of patients suffering from NIDDM. Na(+)-dependent D-glucose transport was 3.3-fold higher in brush-border membrane (BBM) vesicles isolated from duodenal biopsies of NIDDM patients compared with healthy controls. Western analysis indicated that SGLT1 and GLUT5 protein levels were also 4.3- and 4.1-fold higher in diabetic patients. This was associated with threefold increases in SGLT1 and GLUT5 mRNA measured by Northern blotting. GLUT2 mRNA levels were also increased threefold in the intestine of diabetic patients. Analysis of other BBM proteins indicated that the activity and abundance of sucrase and lactase were increased by 1.5- to 2-fold and the level of the structural proteins villin and beta-actin was enhanced 2-fold in diabetic patients compared with controls. The increase in the capacity of the intestine to absorb monosaccharides in human NIDDM is due to a combination of intestinal structural change with a specific increase in the expression of the monosaccharide transporters SGLT1, GLUT5, and GLUT2.
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PMID:Expression of monosaccharide transporters in intestine of diabetic humans. 1180 45

Increased major histocompatibility complex (MHC) class I gene expression in target tissues may be relevant to the pathogenesis of autoimmune diseases. In this study, we questioned whether high glucose levels might increase MHC class I levels and thereby contribute to autoimmune complications. We used thyrocytes in continuous culture, because there is an increased incidence of autoimmune thyroiditis in type 2 diabetics and because transcriptional regulation of MHC class I is well studied in these cells. Northern analysis and flow cytometry showed that 20 and 30 mM D-glucose up-regulated MHC class I expression and that the glucose effect was additive to and independent of interferon-gamma. The effect was specific, because L-glucose did not modify class I expression. The glucose acted transcriptionally, requiring both enhancer A and a cAMP-response element-like element located in the hormone-sensitive region of the MHC class I 5'flanking region. These elements are different from those activated by interferon-gamma. High glucose levels increase formation of the MOD-1 complex with enhancer A; MOD-1 is a heterodimer of fra-2 and the p50 subunit of NF-kappaB. Both TSH and insulin are required for full expression of the glucose activity in thyrocytes. The glucose effect is partially blocked by wortmannin, suggesting involvement of the PI3K signal system. The data support the possibility that high serum glucose levels in type 2 diabetic patients may increase MHC class I levels in target tissues and contribute to autoimmune complications of the disease.
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PMID:High glucose levels increase major histocompatibility complex class I gene expression in thyroid cells and amplify interferon-gamma action. 1186 26

The ability of hyperglycemia per se to suppress endogenous glucose production (GP) is blunted in type 2 diabetes. This could be due in part to decreased glucose-induced flux through glucokinase (GK). Because fructose activates hepatic GK, we examined whether catalytic amounts of fructose could restore inhibition of GP by hyperglycemia in humans with type 2 diabetes. Glucose fluxes ([3-(3)H]glucose) were measured during euglycemia (5 mmol/l) and after abrupt onset of hyperglycemia (10 mmol/l; variable dextrose infusion) under fixed hormonal conditions (somatostatin infusion for 6 h with basal insulin/glucagon/growth hormone replacement). A total of 10 subjects with moderately controlled type 2 diabetes and 7 age- and BMI-matched nondiabetic subjects were studied on up to three separate occasions under the following conditions: without fructose (F(-)) or with infusion of fructose at two dosages: 0.6 mg/kg center dot min (low F) and 1.8 mg/kg center dot min (high F). Although GP failed to decrease in response to hyperglycemia in type 2 diabetes, the coinfusion of both doses of fructose was associated with comparable decreases in GP in response to hyperglycemia (low F = -27%, high F = -33%; P < 0.01 vs. F(-) at both dosages), which approached the 44% decline in GP observed without fructose in the nondiabetic subjects. GP responses to hyperglycemia were not altered by the addition of fructose in the nondiabetic group (low F = -47%, high F = -42%; P > 0.05 vs. F(-)). Thus, the administration of small amounts of fructose to type 2 diabetic subjects partially corrected the regulation of GP by hyperglycemia per se, yet did not affect this regulation in the nondiabetic subjects. This suggests that the liver's inability to respond to hyperglycemia in type 2 diabetes, likely caused by impaired GK activity, contributes substantially to the increased GP in these individuals.
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PMID:Fructose improves the ability of hyperglycemia per se to regulate glucose production in type 2 diabetes. 1187 57


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