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PubMed2005

Identification of oral antidiabetics and their metabolites in human urine by liquid chromatography/tandem mass spectrometry--a matter for doping control analysis.

Since 1999, insulin belongs to the list of prohibited substances of the International Olympic Committee and the World Anti-Doping Agency. Except for patients suffering from insulin-dependent diabetes mellitus, the administration of insulin is not allowed. Therapeutics developed to treat non-insulin-dependent diabetes mellitus act as releasing factors of endogenously produced insulin or improve its efficiency mediating the glucose uptake into insulin-dependent tissues. Hence, these compounds are also relevant for sports drug testing, and a fast, robust, and sensitive assay was developed to identify 12 oral antidiabetic agents or respective hydroxylated metabolites in human urine. Urine specimens are enzymatically hydrolyzed; target analytes are extracted by liquid-liquid extraction and identified by means of liquid chromatography interfaced to tandem mass spectrometry by electrospray ionization. Detection limits of respective drugs ranged between 10 and 30 ng/mL, metabolites of therapeutics were characterized by diagnostic fragmentation pathways upon collisionally activated dissociation of protonated molecules, and general fragmentation routes were proposed.

Administration, Oral↗
PubMed2006

Liquid chromatography/tandem mass spectrometric study and analysis of xanthone and secoiridoid glycoside composition of Swertia chirata, a potent antidiabetic.

Swertia chirata is a bitter plant, used in the Indian system of medicine (Ayurveda) for various human ailments. The bioactive constituents include the xanthone and secoiridoid glycosides consisting of mangiferin, amarogentin, amaroswerin, sweroside and swertiamarin. Methanolic extracts of S. chirata possess constituents with antidiabetic activities, which was investigated by high-performance liquid chromatography/electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS). Preliminary HPLC analyses were performed on a reversed-phase C18 column using gradient elution. In the LC/ESI-MS spectra, predominant [M+H]+ and [M+Na]+ ions were observed in positive ion mode and provided molecular mass information. The five components of S. chirata were structurally correlated and confirmed based on the fragmentation characteristics and information available in the literature. The fragmentation behavior of [M+H]+/[M+Na]+ ions of these components were deduced from the collision-induced dissociation (CID) spectra obtained from the selective on-column information-dependant acquisition (IDA) approach. Xanthone-C-glycoside showed characteristic fragment ions due to fragmentation in the C-glycosidic unit while iridoid-O-glycosides showed characteristic fragment ions due to cleavage in the glycoside linkage and retro-Diels-Alder (RDA) cleavage within an iridoid aglycone. Furthermore, on the basis of this information, an analytical assay was developed and validated to determine relative concentrations of mangiferin, amarogentin, amaroswerin, sweroside and swertiamarin. The detection was carried out using multiple reaction monitoring (MRM) in positive ionization mode with a total analysis time of 3.5 min. The method was successfully applied to standardize four different batches of herbal preparation on the basis of relative concentration of five bioactive components.

Chromatography, Liquid↗
PubMed2000

Structural basis of the synergistic inhibition of glycogen phosphorylase a by caffeine and a potential antidiabetic drug.

Caffeine, an allosteric inhibitor of glycogen phosphorylase a (GPa), has been shown to act synergistically with the potential antidiabetic drug (-)(S)-3-isopropyl 4-(2-chlorophenyl)-1,4-dihydro-1-ethyl-2-methyl-pyridine-3,5,6-tricarboxylate (W1807). The structure of GPa complexed with caffeine and W1807 has been determined at 100K to 2.3 A resolution, and refined to a crystallographic R value of 0.210 (Rfree = 0.257). The complex structure provides a rationale to understand the structural basis of the synergistic inhibition between W1807 and caffeine. W1807 binds tightly at the allosteric site, and induces substantial conformational changes both in the vicinity of the allosteric site and the subunit interface which transform GPa to the T'-like state conformation already observed with GPa-glucose-W1807 complex. A disordering of the N-terminal tail occurs, while the loop of polypeptide chain containing residues 192-196 and residues 43'-49', from the symmetry related subunit, shift to accommodate W1807. Caffeine binds at the purine inhibitor site by intercalating between the two aromatic rings of Phe285 and Tyr613 and stabilises the location of the 280s loop in the T state conformation.

Allosteric Site↗
PubMed1997

The antidiabetic agent thiazolidinedione stimulates the interaction between PPAR gamma and CBP.

The peroxisome proliferator-activated receptor (PPAR) gamma is a member of the nuclear hormone receptor family, which is predominantly expressed on adipocytes and considered to be involved in the process of adipogenesis. The new thiazolidinedione (TZD) compound, T-174, developed as an antidiabetic drug, stimulated the transcription of PPAR gamma and the adipocyte differentiation of 3T3-L1 cells. Interestingly, T-174 induced the interaction between PPAR gamma and CBP (cAMP response element binding protein (CREB) binding protein), a co-factor of various transcription regulators. CBP mRNA was expressed in both preadipocytes and adipocytes. These results suggest that CBP plays a role in the PPAR gamma-mediated signaling pathway activated by TZD, including adipogenesis.

3T3 Cells↗
PubMed1985

Assessment of the antidiabetic activity of epicatechin in streptozotocin-diabetic and spontaneously diabetic BB/E rats.

(-)-Epicatechin has previously been suggested to rapidly reverse alloxan diabetes in rats. We have assessed the therapeutic value of the compound in two further animal models of insulin-dependent diabetes mellitus, namely streptozotocin-diabetic rats and the spontaneously diabetic BB/E rat. There was no indication of a reversal of established diabetes in either the streptozotocin-diabetic or the spontaneously diabetic BB/E rats. Moreover, epicatechin also failed to halt the progression of the disease in prediabetic BB/E rats. Earlier claims of the potential use of epicatechin as an antidiabetic agent must therefore be treated with some caution.

Administration, Oral↗
PubMed2004

Antidiabetic coumarin and cyclitol compounds from Peucedanum japonicum.

The antidiabetic activity-guided fractionation and isolation of the 80% EtOH extracts from Peucedani Radix (Peucedanum japonicum, Umbelliferae) led to the isolation and characterization of a coumarin and a cyclitol as active principles, that is, peucedanol 7-O-beta-D-glucopyranoside (1) and myo-inositol (2). Their structures were identified by spectroscopic methods. Compound 1 showed 39% inhibition of postprandial hyperglycemia at 5.8 mg/kg dose, and compound 2 also significantly inhibited postprandial hyperglycemia by 34% (P<0.05).

Animals↗
PubMed2005

Antidiabetic stilbene and anthraquinone derivatives from Rheum undulatum.

The antidiabetic-activity-guided fractionation and isolation of the 80% EtOH extracts obtained from cultivated Korean Rhubarb rhizomes (Rheum undulatum, Polygonaceae) led to the isolation and characterization of one stilbene, desoxyrhapontigenin (1) and two anthraquinones, emodin (2) and chrysophanol (3). Their structures were established by chemical and spectroscopic methods. Compounds 1, 2, and 3 inhibited postprandial hyperglycemia by 35.8, 29.5, 42.3%, respectively.

Animals↗
PubMed2006

Antidiabetic and hypolipidemic effects of Collybia confluens mycelia produced by submerged culture in streptozotocin-diabetic rats.

This investigation was undertaken to study the effects of oral administration (3 weeks) of Collybia confluens mycelial powder (CCMP) produced by a submerged culture on plasma glucose and other biochemical parameters in streptozotocin (STZ)-induced diabetic rats. Antidiabetic and hypolipidemic effects were proportionally increased with the increasing concentration of the CCMP for oral administration. The CCMP, at the dose of 400 mg/kg BW, substantially reduced the plasma glucose level by as much as 33.1% as compared to the STZ-induced diabetic rats group. It also lowered the plasma total cholesterol, triglyceride, and low density lipoprotein (LDL) cholesterol by 22.9%, 19.9%, and 37.3%, respectively. The levels of total cholesterol and triglyceride in liver were reduced to the extent of by 13.5% and 18.8%, and the activity of alanine transaminase (ALT) and aspartate transaminase (AST) was decreased by 48.8% and 37.2%, respectively, under the influence of CCMP. The general components of CCMP were found to contain 26.18% carbohydrate, 3.67% crude ash, 4.02% crude fat, 22.55% crude protein, and 43.58% dietary fiber. The amino acid composition of the CCMP was also analyzed in detail.

Agaricales↗
PubMed2005

Design and synthesis of novel antidiabetic agents.

The synthesis and structure-activity relationships of a novel series of substituted quercetins that activates peroxisome proliferator-activated receptor gamma (PPARgamma) are reported. The PPARgamma agonistic activity of the most potent compound in this series is comparable to that of the thiazolidinedione-based antidiabetic drugs currently in clinical use.

Animals↗
PubMed2001

Comparisons between white ginseng radix and rootlet for antidiabetic activity and mechanism in KKAy mice.

The mechanisms responsible for the antidiabetic activity of both the white ginseng radix (Ginseng Radix Alba, GRA) and the rootlet (Ginseng Radix Palva, GRP) were investigated. After a four week oral administration, the fasting blood glucose levels in the GRA- and GRP-treated groups were lower when compared to the control group. To elucidate the hypoglycemic mechanism(s) of the ginseng radices, glucose absorption from the small intestine, hepatic hexokinase and glucose-6-phosphatase activities, in addition to PPAR-gamma expression in adipose tissue were examined. The results strongly suggest that GRA can improve hyperglycemia in KKAy mice, possibly by blocking intestinal glucose absorption and inhibiting hepatic glucose-6-phosphatase, and GRP through the upregulation of adipocytic PPAR-y protein expression as well as inhibiting intestinal glucose absorption.

Animals↗
PubMed2003

[Glucocorticoid-induced insulin resistance and diabetes mellitus. Receptor-, postreceptor mechanisms, local cortisol action, and new aspects of antidiabetic therapy].

BACKGROUND: Glucocorticoids are frequently prescribed drugs. Nearly half of the patients treated with glucocorticoids over a longer period develop a deranged glucose metabolism. In about 50%, these disturbances persist despite reduction or even withdrawal of the drug. PATHOPHYSIOLOGY: Glucocorticoids antagonize the insulin-mediated inhibition of hepatic glucose release, decrease glucose utilisation in muscle, and reduce the binding affinity of insulin receptors. Therefore, glucocorticoid-induced diabetes mellitus is equivalent to unmasked type 2 diabetes. New studies presume that an increased endogenous production of glucocorticoids particularly in adipocytes could play a role in type 2 diabetes as well. THERAPY: Patients with glucocorticoid-induced diabetes bear, comparable to patients with other types of diabetes, a considerable risk of arteriosclerotic and cardiovascular diseases and should therefore receive an intensified treatment. Therapy of glucocorticoid-induced diabetes basically corresponds to that of type 2 diabetes. Applicable are oral antidiabetic drugs, particularly metformin and the glitazones as insulin sensitizers both requiring consideration of contraindications, or treatment with insulin.

Diabetes Mellitus, Type 2↗
PubMed2002

The role of oral antidiabetic agents: why and when to use an early-phase insulin secretion agent in Type II diabetes mellitus.

Evidence obtained in the 1990's strongly supports the notion that glycaemic control is important not only in Type I (insulin-dependent), but also in Type II (non-insulin-dependent) diabetes mellitus. Although measurement of HbA(1c) is the standard for assessing the effect of glucose control in the occurrence and prevention of diabetic sequelae, more recent evidence indicates that other glucose parameters are also important. Postchallenge and postprandial hyperglycaemic peaks seem to be prospective determinants of vascular damage in early Type II diabetes. Currently, there is no overall accepted standard approach for the pharmacological management of Type II diabetes. The United Kingdom Prospective Diabetes Study has shown that reaching a near-normal glycaemic target is critically important and the pharmacotherapy of this progressive disease is difficult. Loss of endogenous insulin secretion has been substantiated to cause the progression of Type II diabetes in the United Kingdom Prospective Diabetes Study. Early insulinization, however, was not advantageous over other forms of therapy. The advent of polypharmacy in recent years has greatly strengthened the treatment of this disease. This synergy has been extended of late with the development of early-phase insulin secretion agents. Two such agents, nateglinide and repaglinide, can be used to reduce mealtime glucose excursions and HbA(1c) as monotherapy, and in combination with metformin; their antidiabetic potential is similar to the combination treatment with glibenclamide and metformin. Additional substantiation of their long-term effect on improving life expectancy and reducing diabetic complications in Type II diabetic patients is now required.

Blood Glucose↗
PubMed2004

Antidiabetic effect of novel modulating peptides of G-protein-coupled kinase in experimental models of diabetes.

AIMS/HYPOTHESIS: G-protein-coupled receptor kinases (GRKs) play a key role in agonist-induced desensitisation of G-protein-coupled receptors (GPCRs) that are involved in metabolic regulation and glucose homeostasis. Our aim was to examine whether small peptides derived from the catalytic domain of GRK2 and -3 would ameliorate Type 2 diabetes in three separate animal models of diabetes. METHODS: Synthetic peptides derived from a kinase-substrate interaction site in GRK2/3 were initially screened for their effect on in vitro melanogenesis, a GRK-mediated process. The most effective peptides were administered intraperitoneally, utilising a variety of dosing regimens, to Psammomys obesus gerbils, Zucker diabetic fatty (ZDF) rats, or db/db mice. The metabolic effects of these peptides were assessed by measuring fasting and fed blood glucose levels and glucose tolerance. RESULTS: Two peptides, KRX-683(107) and KRX-683(124), significantly reduced fed-state blood glucose levels in the diabetic Psammomys obesus. In animals treated with KRX-683(124) at a dose of 12.5 mg/kg weekly for 7 weeks, ten of eleven treated animals responded with mean blood glucose significantly lower than controls (4.7+/-0.4 vs 16.8+/-0.8 mmol/l, p</=0.0001). Significant reductions in blood glucose compared with controls were also seen in ZDF rats administered KRX-683(124) and in db/db mice, which had significantly reduced fasting and 2-hour postprandial glucose levels after the treatment. CONCLUSIONS/INTERPRETATION: Sequence-based peptides derived from GRK2/3 have an antidiabetic effect demonstrated in three different animal models of Type 2 diabetes. By modulating GRK2/3 activity, these peptides enhance GPCR-initiated signal transduction, resulting in improved glucose homeostasis. Sequence-based peptide modulation of GRK could prove useful in the treatment of Type 2 diabetes.

Animals↗
PubMed2005

Relative fracture risk in patients with diabetes mellitus, and the impact of insulin and oral antidiabetic medication on relative fracture risk.

AIMS/HYPOTHESIS: We studied the association between fractures and type 1 and type 2 diabetes mellitus. METHODS: In this case-control study, all subjects diagnosed with a fracture (n=124,655) in Denmark served as cases, and for each case three control subjects (n=373,962) matched for sex and age were retrieved from the general population. RESULTS: Type 1 and type 2 diabetes were associated with an increased risk (1) of any fracture (odds ratio [OR]=1.3, 95% CI: 1.2-1.5 for type 1 diabetes and 1.2, 95% CI: 1.1-1.3 for type 2 diabetes after adjustment for confounders) and (2) of hip fractures (OR=1.7, 95% CI: 1.3-2.2 for type 1 diabetes, and 1.4, 95% CI: 1.2-1.6 for type 2 diabetes). Furthermore, type 2 diabetes was associated with a significant increase in forearm fractures (OR=1.2, 95% CI: 1.0-1.5), and type 1 diabetes was associated with an increased risk of spine fractures (OR=2.5, 95% CI: 1.3-4.6), whereas type 2 diabetes was not. Use of metformin and sulphonylureas was associated with a significantly decreased risk of any fracture, whereas a non-significant trend towards decreased risk of any fracture was associated with the use of insulin. Except for a decrease in hip fractures with use of sulphonylureas, no change in fracture risk in the hip, spine or forearm was associated with the use of insulin or oral antidiabetic drugs. CONCLUSIONS/INTERPRETATION: Type 1 and type 2 diabetes are associated with an increased risk of any fracture and hip fractures. The use of drugs to control diabetes may reduce the association between diabetes and fractures.

Administration, Oral↗
PubMed2006

Changes in patient weight and the impact of antidiabetic therapy during the first 5 years after diagnosis of diabetes mellitus.

AIMS/HYPOTHESIS: It is generally thought difficult for type 2 diabetic patients to lose weight. We monitored changes in patients' weight during the first 5 years after diabetes diagnosis in relation to initiation of antidiabetic treatment. SUBJECTS AND METHODS: Data from 711 newly diagnosed diabetic patients aged 40 or over were analysed with a random-effect linear-regression model. Patients were included consecutively from a well-defined patient list in general practice. RESULTS: In 245 patients whose only treatment was advice on diet, an initial weight loss of 6 to 7 kg was largely maintained over 5 years. Patients receiving metformin (n=86) or sulfonylureas (n=330) maintained an average weight loss of 2 to 4 kg that was dependent on age and sex. Patients' weight did not change on initiation of treatment with sulfonylureas or metformin. Over 5 years, median HbA(1c) increased from 7.0 to 7.8% (reference range 5.4-7.4%) in the diet-alone group. HbA(1c) was approximately 1 percentage point higher for most of the other treatment groups. CONCLUSIONS/INTERPRETATION: In newly diagnosed type 2 diabetic patients, long-term weight loss was common and weight loss was not affected by sulfonylurea treatment. The measurements in the study are taken from treatment results achieved in the general population of diabetic patients, who are rarely treated in secondary care and seldom the subject of research; the results thus indicate that weight reduction is a practicable treatment in diabetic patients.

Age Factors↗
PubMed1999

A new antidiabetic agent (JTT-501) rapidly stimulates glucose disposal rates by enhancing insulin signal transduction in skeletal muscle.

A newly synthesized antidiabetic agent, JTT-501 is an isoxazolidinedione rather than a thiazolidinedione. An oral dose of JTT-501 (100 mg x kg(-1) x day(-1)) given to 12-week-old male Zucker fatty rats for 7 days led to the amelioration of both hyperinsulinaemia (40% of non-treated) and hypertriglyceridaemia (23% of non-treated) as well as a 2.4-fold increased insulin sensitivity as determined by a euglycaemic insulin clamp. In our study, we further evaluated the acute effect of JTT-501 on both the glucose infusion rates (GIR) and insulin signalling in skeletal muscle. Male Sprague-Dawley (SD) rats aged 10 weeks were injected intravenously with JTT-501 (5 mg/kg) and then a euglycaemic insulin clamp was initiated and glucose infusion rates monitored for 150 min. We found that this treatment increased the glucose infusion rate by 33% during the last 30 min in SD rats. After the clamp had been initiated for 30 min, the insulin-stimulated phosphatidylinositol 3-kinase (PI3-kinase) activities co-immunoprecipitated with insulin receptor substrate 1 (IRS-1) were also enhanced, resulting in increased glycogen synthase activities in the soleus muscles. Treatment with JTT-501 also enhanced the phosphorylation of insulin receptors and insulin receptor-substrate 1 rapidly as well as the phosphatidylinositol 3-kinase activities, which were stimulated by a bolus injection of insulin. Similarly, JTT-501 stimulated the glucose infusion rate by 30% and enhanced insulin signalling in Zucker fatty rats. In conclusion, a newly developed isoxazolidinedione, JTT-501, rapidly potentiates the insulin sensitivity of skeletal muscle by enhancing insulin signalling and could be useful for the treatment of insulin-resistant diabetic subjects.

Animals↗
PubMed2005

Insulin glargine in combination with oral antidiabetic drugs as a cost-equivalent alternative to conventional insulin therapy in type 2 diabetes mellitus.

BACKGROUND AND RATIONALE: Recent data suggest that insulin glargine might be a cost-effective alternative to conventional insulin therapy in patients with type 2 diabetes mellitus (T2DM). The aim of this observational study was to evaluate the treatment costs of insulin glargine in combination with oral antidiabetic drugs (OADs) compared with conventional insulin therapy in T2DM in everyday clinical practice. PATIENTS AND METHODS: Data were obtained from a cohort of 678 patients with T2DM not adequately controlled by OADs alone (HbA1c mean 9.1 +/- 1.7%). Patients received either insulin glargine in addition to oral therapy or were switched to conventional insulin therapy. Treatment and dosing decisions were made at the physician's discretion, reflecting everyday practice. Patients were followed for 2-4 months. Primary outcome parameters were total treatment costs and clinical efficacy. RESULTS: The two therapeutic regimens were equally effective in decreasing HbA1c to 7.8% (p < 10(-9)). Patients in the insulin glargine plus OAD group controlled their blood glucose level at endpoint with a median of 60 test strips per month and those in the conventional insulin therapy group with a median of 80 strips per month (p = 0.000000739). Total daily costs of insulin, needles, glycemic control and OAD treatment per patient were similar in the two treatment groups (insulin glargine group 1.91 Euro vs conventional group 1.99 Euro). CONCLUSION: The two treatment regimens were equally effective in improving glycemic control. These results were achieved with significantly lower insulin doses and fewer blood glucose test strips in the insulin glargine group, which therefore led to cost equivalence when compared with conventional insulin therapy.

Administration, Oral↗