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)

Severe and resistant hypoglycemia occurred in two patients with diabetes mellitus who were receiving concomitant gatifloxacin and glyburide. An 84-year-old woman treated with glyburide for type 2 diabetes mellitus experienced, for the first time, a severe episode of hypoglycemia after 2 days of gatifloxacin 400 mg/day for nonproductive cough. Her blood glucose level on hospital admission was 28 mg/dl. Gatifloxacin and glyburide were discontinued, and the patient was treated with intravenous dextrose infused over 36 hours. Glyburide was restarted before her discharge, with no recurrence of hypoglycemia. A 79-year-old man with type 2 diabetes mellitus treated with glyburide was prescribed gatifloxacin 400 mg/day for pneumonia. After 1 day of therapy, the patient was admitted to the emergency department in a coma. His blood glucose level was 18 mg/dl. Despite discontinuation of gatifloxacin and oral hypoglycemic therapy, hypoglycemia was reversed only after administration of multiple boluses of intravenous dextrose, followed by intravenous dextrose infused over 48 hours. On hospital day 7, gliclazide and levofloxacin were started; the patient experienced no recurrence of hypoglycemia and was discharged on day 10. Several cases of severe and resistant hypoglycemia associated with gatifloxacin therapy have been reported in the recent literature. Although the exact mechanism is not fully understood, it may be linked to a gatifloxacin-induced closing of the adenosine 5'-triphosphate-sensitive potassium channels in the pancreatic beta cells, leading to insulin secretion. The onset of hypoglycemia in relation to the start of gatifloxacin suggests that the drug precipitated this adverse event. Patients receiving oral hypoglycemic agents are at greater risk of experiencing gatifloxacin-induced hypoglycemia than patients not receiving these agents. Clinicians should be aware of this potentially life-threatening adverse event and monitor blood glucose levels in all patients receiving concomitant oral hypoglycemic agents and gatifloxacin.
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PMID:Severe and resistant hypoglycemia associated with concomitant gatifloxacin and glyburide therapy. 1530 56

We hypothesized that sepsis during hyperglycemia would activate left ventricular (LV) mitogen activated protein kinase (MAPK) signaling mechanisms and modulate generation of endothelin-1 (ET-1) and nitric oxide (NO) that can contribute to the progression of LV dysfunction. A single injection of streptozotocin (STZ, 60 mg/kg, via tail vein) was used to produce type 2 diabetes in male SD rats. Polymicrobial sepsis and sham-sepsis were induced using single i.p. injection of cecal inoculum and sterile 5% dextrose water, respectively, on the 13th and 27th day following STZ injection. Both 2-week (2-wk) and 4-wk diabetes groups were associated with hyperglycemia and weight loss. LV end diastolic pressure (LVEDP) was significantly increased in 4-wk diabetes but not in 2-wk diabetes group. Plasma concentration of tumor necrosis factor-alpha (TNF-alpha) was significantly increased in 4-wk diabetes+sepsis group as compared to sham, 2-wk diabetes+sepsis and sepsis groups. Elevated plasma and LV ET-1 and NO byproducts (NOx) along with LV preproET-1 and inducible nitric oxide synthase (iNOS) protein expression were observed in 4-wk but not in 2-wk diabetes group. Sepsis further elevated LV iNOS and preproET-1 in 4-wk diabetes group. Up-regulated phosphorylation of LV p38-MAPK, extracellular signal-regulated kinase 1/2 (ERK1/2) and heat shock protein-27 (Hsp27) was observed in 4-wk diabetes group. Sepsis caused a factorial increase in LV p38-MAPK and Hsp27 phosphorylation and iNOS up-regulation but not ERK1/2 following progression from 2-wk to 4-wk diabetes. The study provides evidence that sepsis up-regulated LV iNOS, p38-MAPK phosphorylation and elevated LVEDP during 4-wk diabetes. We concluded that sepsis contributes in the development of LVEDP dysfunction and alteration in signaling mechanisms depending upon the progression from 2-wk to 4-wk diabetes in the rat.
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PMID:Left ventricular mitogen activated protein kinase signaling following polymicrobial sepsis during streptozotocin-induced hyperglycemia. 1533 69

The minute-to-minute effect on blood glucose levels of high-dextrose peritoneal dialysate is not known. We arranged for 7 patients with diabetes, treated by peritoneal dialysis (PD), to wear a continuous glucose monitoring system (CGMS: Medtronic MiniMed, Northridge, CA, U.S.A.). A sensor was inserted subcutaneously into the skin of the patient's abdomen or back to measure glucose in the interstitial fluid. Readings were recorded every 5 minutes for up to 72 hours. The portion of the day during which the patient's blood glucose levels were greater than 180 mg/dL (calculated as a percentage of time) was recorded. Most of the patients participating in the study had elevated levels of glycohemoglobin and hemoglobin A1c, and, for a large percentage of the day, showed blood glucose tracings well above the recommended standards of control. Representative CGMS tracings from patients with type 1 and type 2 diabetes are shown.
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PMID:Assessing 24-hour blood glucose patterns in diabetic paitents treated by peritoneal dialysis. 1538 29

D-mannose is an essential monosaccharide constituent of glycoproteins and glycolipids. However, it is unknown how plasma mannose is supplied. The aim of this study was to explore the source of plasma mannose. Oral administration of glucose resulted in a significant decrease of plasma mannose concentration after 20 min in fasted normal rats. However, in fasted type 2 diabetes model rats, plasma mannose concentrations that were higher compared with normal rats did not change after the administration of glucose. When insulin was administered intravenously to fed rats, it took longer for plasma mannose concentrations to decrease significantly in diabetic rats than in normal rats (20 and 5 min, respectively). Intravenous administration of epinephrine to fed normal rats increased the plasma mannose concentration, but this effect was negated by fasting or by administration of a glycogen phosphorylase inhibitor. Epinephrine increased mannose output from the perfused liver of fed rats, but this effect was negated in the presence of a glucose-6-phosphatase inhibitor. Epinephrine also increased the hepatic levels of hexose 6-phosphates, including mannose 6-phosphate. When either lactate alone or lactate plus alanine were administered as gluconeogenic substrates to fasted rats, the concentration of plasma mannose did not increase. When lactate was used to perfuse the liver of fasted rats, a decrease, rather than an increase, in mannose output was observed. These findings indicate that hepatic glycogen is a source of plasma mannose.
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PMID:Hepatic glycogen breakdown is implicated in the maintenance of plasma mannose concentration. 1553 4

In an attempt to identify leads that would enable the design of inhibitors with enhanced affinity for glycogen phosphorylase (GP), that might control hyperglycaemia in type 2 diabetes, three new analogs of beta-D-glucopyranose, 2-(beta-D-glucopyranosyl)-5-methyl-1, 3, 4-oxadiazole, -benzothiazole, and -benzimidazole were assessed for their potency to inhibit GPb activity. The compounds showed competitive inhibition (with respect to substrate Glc-1-P) with K(i) values of 145.2 (+/-11.6), 76 (+/-4.8), and 8.6 (+/-0.7) muM, respectively. In order to establish the mechanism of this inhibition, crystallographic studies were carried out and the structures of GPb in complex with the three analogs were determined at high resolution (GPb-methyl-oxadiazole complex, 1.92 A; GPb-benzothiazole, 2.10 A; GPb-benzimidazole, 1.93 A). The complex structures revealed that the inhibitors can be accommodated in the catalytic site of T-state GPb with very little change of the tertiary structure, and provide a rationalization for understanding variations in potency of the inhibitors. In addition, benzimidazole bound at the new allosteric inhibitor or indole binding site, located at the subunit interface, in the region of the central cavity, and also at a novel binding site, located at the protein surface, far removed (approximately 32 A) from the other binding sites, that is mostly dominated by the nonpolar groups of Phe202, Tyr203, Val221, and Phe252.
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PMID:Kinetic and crystallographic studies on 2-(beta-D-glucopyranosyl)-5-methyl-1, 3, 4-oxadiazole, -benzothiazole, and -benzimidazole, inhibitors of muscle glycogen phosphorylase b. Evidence for a new binding site. 1574 40

The expression meglitinide analogs was introduced in 1995 to cover new molecules proposed as non-sulfonylurea insulinotropic agents and displaying structural analogy with meglitinide, such as repaglinide, nateglinide, and mitiglinide. Meglitinide analogs display, as judged by conformation analysis, a U-shaped configuration similar to that of antihyperglycemic sulfonylureas such as glibenclamide (glyburide) and glimepiride. In rat pancreatic islets incubated in the presence of 7.0 mmol/L D-glucose, repaglinide and mitiglinide demonstrate comparable concentration-response relationships for stimulation of insulin release, with a threshold value < 10 nmol/L and a maximal secretory response at about 10 nmol/L. Several findings indicate that meglitinide analogs provoke the closing of adenosine triphosphate-sensitive potassium channels, with subsequent gating of voltage-sensitive calcium channels. The effects of meglitinide analogs upon the binding of [3H]glibenclamide to islet cells membranes reinforces this concept. At variance, however, with other meglitinide analogs, the ionic and secretory response to repaglinide (10 micromol/L) is not rapidly reversible in perifused rat islets. In experiments conducted in vivo in control and diabetic rats, repaglinide provokes a greater and more rapid increase in plasma insulin concentration and an earlier fall in glycemia than glibenclamide or glimepiride. Onset of effect is also more rapid and duration of effect shorter with nateglinide versus glibenclamide. In clinical studies, single or repeated daily administration of repaglinide increased plasma insulin concentration in a dose-dependent manner, with an incremental peak reached about 2 hours after repaglinide intake. Plasma concentrations of repaglinide are about 5.0 microg/L 2-2.5 hours after oral intake of the drug. Despite the slow reversibility of repaglinide action in vitro, this drug offers advantages over glibenclamide in terms of the possible occurrence of hypoglycemia if a meal is missed. In volunteers receiving a single oral dose of nateglinide (120mg) 10 minutes before a standardized 800 Kcal breakfast, the plasma insulin concentration was higher 5, 10, and 20 minutes after meal intake than when they received a single dose of repaglinide (0.5 or 2.0mg) or placebo 10 minutes before breakfast. Peak plasma concentrations of nateglinide were reached within 2 hours in most volunteers. Peak plasma concentrations of mitiglinide were reached 30 minutes after a single oral dose in a representative volunteer. Mitiglinide significantly suppressed meal-induced elevations in blood glucose concentrations in a study of patients with type 2 diabetes. In conclusion, two obvious differences among these meglitinide analogs should be underlined. First, on a molar basis, nateglinide is somewhat less potent than repaglinide or mitiglinide, as an insulinotropic agent. The maximal secretory responses evoked by these three meglitinide analogs are, however, identical to one another. Secondly, and as already mentioned, the functional effects of nateglinide and mitiglinide are more rapidly reversible than those of repaglinide, for instance in perifused rat islets. The meglitinide analogs offer the advantage over the long-acting antihyperglycemic sulfonylurea glibenclamide of minimizing the risk of undesirable hypoglycemia.
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PMID:Pharmacology of the meglitinide analogs: new treatment options for type 2 diabetes mellitus. 1598 44

High glucose concentrations are involved in the development of diabetic-associated vascular complications. We have previously reported that acute high glucose challenge, corresponding to post-prandial glycemia levels observed in patients with type 2 diabetes, blunts ACh-induced endothelium-dependent relaxation of the renal circulation of non-diabetic rabbits. Isolated perfused kidneys from non-diabetic rabbits were acutely exposed (3 h) to normal (5.5 mM--control group) or high (15 mM) D-glucose concentrations in the presence or absence of a continuous infusion of metformin (20 or 100 microM). Renal vascular reactivity was evaluated with endothelium-dependent (acetylcholine, ACh) and -independent (sodium nitroprusside, SNP) vasodilating agents. ACh-induced maximal renal vasodilation was reduced by high glucose infusion (15 mM) in comparison to the control group (25+/-3% and 41+/-3% respectively; P<0.01), being restored to 41+/-4% and 43+/-2% by a simultaneous 3-h infusion of 20 or 100 microM of metformin respectively (P>0.05). Perfusion of the kidneys with the angiotensin II-converting enzyme inhibitor captopril (10 microM) also significantly prevented the deleterious effects of high glucose challenge in the renal circulation. The use of a continuous infusion of N(omega)-nitro-L-arginine methyl ester (L-NAME, 100 microM) did not affect the protective effect of metformin in the renal circulation (39+/-4%; P>0.05), while tetraethylammonium (TEA, 10 mM) partially blunted this effect (33+/-4, P<0.01). Renal vasodilation induced by SNP was not modified by simultaneous infusion of high glucose and/or metformin. It is concluded that the impairment of ACh-induced endothelium-dependent renal vasodilation observed after acute exposure to high glucose concentrations is abolished by metformin administration. These alterations of renal vascular reactivity can be accounted for, at least in part, by the activation of the renal renin-angiotensin system during hyperglycemia. The protective effects of metformin present some EDHF-dependent component and are not related to metabolic pathways dependent on nitric oxide.
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PMID:Metformin prevents the impairment of endothelium-dependent vascular relaxation induced by high glucose challenge in rabbit isolated perfused kidneys. 1613 90

Puerarin and daidzin are the major isoflavone glucosides found in kudzu dietary supplements. In this study, we demonstrated that puerarin significantly improves glucose tolerance in C57BL/6J-ob/ob mice, an animal model of type 2 diabetes mellitus, blunting the rise in blood glucose levels after i.p. administration of glucose. In contrast, daidzin, the O-glucoside, had a significant but opposite effect, impairing glucose tolerance as compared to saline-treated controls. When they were administered i.p. with (14)C-glucose to C57BL/6J lean mice, puerarin inhibited glucose uptake into tissues and incorporation into glycogen, while daidzin stimulated glucose uptake, showing an opposite effect to puerarin. Puerarin also antagonized the stimulatory effect of decyl-beta-D-thiomaltoside, an artificial primer of glycogen synthesis, which increases (14)C-glucose uptake and incorporation into glycogen in mouse liver and heart. A liquid chromatography-tandem mass spectrometry procedure was used to investigate the metabolism and bioavailability of puerarin and daidzin. The blood puerarin concentration-time curve by i.p. and oral administration indicated that puerarin was four times more bioavailable via i.p. injection than via the oral route of administration. This may account for the increased hypoglycemic effect seen in the i.p. glucose tolerance test vs that seen orally. Our results suggest that puerarin is rapidly absorbed from the intestine without metabolism, while daidzin is hydrolyzed to the aglycone daidzein. The opposing effects of puerarin and daidzin on glucose homeostasis may have implications for the activity of dietary supplements that contain both of these isoflavonoids.
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PMID:Contrasting effects of puerarin and daidzin on glucose homeostasis in mice. 1624 82

Hyperglycemic hyperosmolar nonketotic syndrome (HHNS) was infrequently diagnosed till recently. Now it is being diagnosed with increasing frequency in obese children with type 2 diabetes mellitus (T2 DM) and its incidence is likely to go up, given global increase in incidence of childhood obesity, increased insulin resistance, and T2 DM. The syndrome is characterized by severe hyperglycemia, a marked increase in serum osmolality and dehydration without accumulation of beta -hydroxybutyric or acetoacetic ketoacids. Significant ketogenesis is restrained by the ability of the pancreas to secrete small amount of insulin. Prolonged phase of osmotic diuresis leads to severe depletion of body water, which excees that of sodium, resulting in hypertonic dehydration. These children, usually obese adolescents with T2 DM, present with signs of severe dehydration and depressed mental status but continue to have increased rather than decreased urine output and are at increased risk of developing rhabdomyolysis and malignant hyperthermia. Emergency treatment is directed at restoration of the intravascular volume, followed by correction of deficits of fluid and electrolyte (Na+, K+, Ca++, Mg++, PO4++), hyperglycemia and serum hyperosmolarity, and a thorough search for conditions that may lead to this metabolic decompensation and their treatment. Use of iso-osomolar isotonic fluid (0.9% saline) until hemodynamic stabilization initially, followed by 0.45% saline with insulin infusion at the rate of 0.1 units/kg/hour, addition of 5% dextrose in fluids and reduction of insulin infusion once the blood glucose is 250 to 300 mg/dl is generally recommended. However, evidence-based guidelines about composition and tonicity of fluids and electrolyte solutions for early resuscitation and rehydration, the rate of infusion-rapid vs slow, and insulin dose-low vs normal, in treatment of HHNS in children are awaited. Careful monitoring of glucose levels and ensuring adequate hydration in patients 'at risk' of HHNS, including those receiving medications that interfere with the secretion or effectiveness of insulin should decrease the risk of HHNS.
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PMID:Hyperglycemic hyperosmolar nonketotic syndrome. 1644 62

Nonalcoholic fatty liver (NAFL) is a common comorbidity in patients with type 2 diabetes and links to the risk of coronary syndromes. The aim was to determine the manifestations of metabolic syndrome in different organs in patients with liver steatosis. We studied 55 type 2 diabetic patients with coronary artery disease using positron emission tomography. Myocardial perfusion was measured with [15O]H2O and myocardial and skeletal muscle glucose uptake with 2-deoxy-2-[18F]fluoro-D-glucose during hyperinsulinemic euglycemia. Liver fat content was determined by magnetic resonance proton spectroscopy. Patients were divided on the basis of their median (8%) into two groups with low (4.6 +/- 2.0%) and high (17.4 +/- 8.0%) liver fat content. The groups were well matched for age, BMI, and fasting plasma glucose. In addition to insulin resistance at the whole body level (P = 0.012) and muscle (P = 0.002), the high liver fat group had lower insulin-stimulated myocardial glucose uptake (P = 0.040) and glucose extraction rate (P = 0.0006) compared with the low liver fat group. In multiple regression analysis, liver fat content was the most significant explanatory variable for myocardial insulin resistance. In addition, the high liver fat group had increased concentrations of high sensitivity C-reactive protein, soluble forms of E-selectin, vascular adhesion protein-1, and intercellular adhesion molecule-1 (P < 0.05) and lower coronary flow reserve (P = 0.02) compared with the low liver fat group. In conclusion, in patients with type 2 diabetes and coronary artery disease, liver fat content is a novel independent indicator of myocardial insulin resistance and reduced coronary functional capacity. Further studies will reveal the effect of hepatic fat reduction on myocardial metabolism and coronary function.
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PMID:Liver steatosis coexists with myocardial insulin resistance and coronary dysfunction in patients with type 2 diabetes. 1647 72


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