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PubMed2006

Comparison of once-daily insulin detemir with NPH insulin added to a regimen of oral antidiabetic drugs in poorly controlled type 2 diabetes.

BACKGROUND: Many patients with poorly controlled type 2 diabetes mellitus (DM) receive, as initial insulin treatment, the addition of a basal formulation to an existing regimen of oral antidiabetic drug (OAD) therapy. Used this way, the insulin analogue detemir has been associated with improved glycemic control of a magnitude similar to neutral protamine Hagedorn (NPH), with lower rates of hypoglycemia and weight gain. Initial studies investigated detemir administered BID, but pharmacologic data suggest that detemir might be effective with QD administration. OBJECTIVES: The aims of this study were to compare the effectiveness and tolerability of detemir versus NPH administered QD together with > or =1 OAD in poorly controlled type 2 DM, and to compare different administration times of detemir. METHODS: This 20-week, multicenter, randomized, open-label, 3-arm, parallel-group trial was conducted at 91 centers across Europe and the United States. Men and women were eligible for participation if they were aged > or =18 years, had a body mass index (BMI) < or =40 kg/m(2), had a diagnosis of type 2 DM of at least 12 months' duration, and were insulin naive. Eligible patients also had a glycosylated hemoglobin (HbA(1c)) concentration value not outside the range of 7.5% to 11.0% following at least 3 months' treatment with > or =10 AD. Patients were randomly assigned to receive an evening SC injection of detemir, a prebreakfast injection of detemir, or an evening injection of NPH insulin (1:1:1), administered at initial doses of 10 IU (U). RESULTS: A total of 504 patients were enrolled 5 men, 219 women; mean [SD] age, 59 [11] years; mean [SD] BMI, 30 [5] kg/m2; insulin detemir before breakfast, 168; insulin detemir evening, 170; NPH insulin evening, 166). The intent-to-treat population comprised 498 patients. Morning and evening detemir were associated with reductions in HbA(1c) similar to those with evening NPH (raw mean decreases, -1.58%, -1.48%, and -1.74%, respectively). Nine-point profile and fasting and predinner plasma glucose data found morning detemir to be associated with a different diurnal glycemic profile compared with the evening regimens. Compared with evening NPH, 24-hour and nocturnal hypoglycemia were reduced by 53% (P = 0.019) and 65% (P = 0.031), respectively, with evening detemir. Incidences of hypoglycemia did not differ significantly between groups that received morning and evening detemir, but nocturnal hypoglycemia was reduced further, by 87%, with morning detemir compared with evening NPH (P < 0.001). Weight gain was 1.2, 0.7, and 1.6 kg with morning detemir, evening detemir, and NPH, respectively (P = 0.005 for evening detemir vs NPH). No between-treatment differences were seen in other tolerability end points. CONCLUSIONS: The results of this study in patients whose type 2 DM was poorly controlled with > or =1 OAD suggest that insulin detemir QD in the morning or evening can be used to improve glycemic control. Compared with NPH, insulin detemir may offer some tolerability advantages in this role.

Administration, Oral↗
PubMed2005

Pathophysiology of type 2 diabetes: rationale for different oral antidiabetic treatment strategies.

Type 2 diabetes mellitus is a chronic metabolic disorder that results from defects in both insulin secretion and insulin action. Both insulin resistance and beta-cell failure are genetically determined to some extent; however, environmental factors contribute to exacerbate both abnormalities. Type 2 diabetic individuals are also characterised by reduced beta-cell mass likely due to increased cellular apoptosis. The early use of insulin therapy in type 2 diabetes may prove beneficial to prevent further beta-cell loss and need for exogenous insulin. Treatment options with oral agents are quite diverse, including insulin sensitizers, alpha-glucosidase inhibitors, and beta-cell secretagogues. Although in recent years the emphasis on initial therapy has been shifting from insulin secretagogues to insulin sensitizers such as metformin and thiazolidinediones, questions remain as to genetic and/or phenotypic factors may dictate a different choice of the first antidiabetic drug to be used. It is not totally clear whether monotherapy should be pursued until the maximally effective dose of a given drug or combination therapy should be used to target distinct pathogenic defects in a single patient. Individual phenotypic and genetic characterisation of the patients may help to solve this conundrum, eventually providing tailored treatment algorithms.

Administration, Oral↗
PubMed2006

Inhibition of dipeptidyl peptidase-IV activity by metformin enhances the antidiabetic effects of glucagon-like peptide-1.

GLP-1 and GIP are insulin-releasing 'incretin' hormones inactivated following degradation by dipeptidyl peptidase IV. Incretin hormone analogues resistant to degradation by DPP IV, as well as, inhibitors of DPP IV are in development as novel treatments for type 2 diabetes. The biguanide metformin is an oral agent commonly prescribed to treat type 2 diabetes. Antidiabetic actions of metformin involve the reduction of hepatic glucose production and/or insulin resistance. Recent reports indicate that metformin may have the additional property of inhibiting DPP IV activity. Here we examine the effects of metformin on plasma DPP IV activity of normal and ob/ob diabetic mice. DPP IV activity present in mouse plasma was concentration-dependently inhibited by metformin generating IC(50) values of 38 microM for normal mice and 29 microM for ob/ob mice. In vivo metformin lowered plasma DPP IV activity in ob/ob mice, and improved glucose-lowering and insulin-releasing effects of exogenous GLP-1 administration. This was associated with increased circulating concentrations of active GLP-1(7-36)amide. In contrast metformin had minor effects on in vitro GLP-1-stimulated insulin release from clonal beta cells. Long-term (12 day) oral metformin administration to ob/ob mice resulted in lower DPP IV activity but had no effect on basal glucose and insulin levels. These findings indicate that metformin decreases the plasma DPP IV activity, limiting the inactivation of exogenously administered GLP-1 and improving glycaemic control.

Analysis of Variance↗
PubMed2004

Antidiabetic activity of Boerhaavia diffusa L.: effect on hepatic key enzymes in experimental diabetes.

The purpose of this study was to investigate the effects of daily oral administration of aqueous solution of Boerhaavia diffusa L. leaf extract (BLEt) (200 mg/kg) for 4 weeks on blood glucose concentration and hepatic enzymes in normal and alloxan induced diabetic rats. A significant decrease in blood glucose and significant increase in plasma insulin levels were observed in normal and diabetic rats treated with BLEt. Treatment with BLEt resulted in a significant reduction of glycosylated haemoglobin and an increase in total haemoglobin level. The activities of the hepatic enzymes such as hexokinase was significantly increased and glucose-6-phosphatase, fructose-1,6-bisphosphatase were significantly decreased by the administration of BLEt in normal and diabetic rats. An oral glucose tolerance test (OGTT) was also performed in the same groups, in which there was a significant improvement in glucose tolerance in rats treated with BLEt. A comparison was made between the action of BLEt and antidiabetic drug-glibenclamide (600 microg/kg). The effect of BLEt was more prominent when compared to glibenclamide.

Alloxan↗
PubMed2004

The antidiabetic activity of the herbal preparation ADD-199 in mice: a comparative study with two oral hypoglycaemic drugs.

The antidiabetic and antioxidant effects of the herbal preparation ADD-199 were investigated in STZ-induced diabetic C(3)H mice and results were compared with two allopathic hypoglycaemic drugs, glibenclamide and metformin. Plasma glucose, insulin and lipids as well as liver glycogen, lipids and lipid peroxidation were measured following treatment for 8 weeks. The results indicated that plasma insulin levels in normal controls at termination were about 76 micromol/L compared to trace levels in untreated diabetic mice. Glibenclamide and ADD-199 increased insulin levels in diabetic mice up to 70% of levels in untreated non-diabetic mice whilst metformin had no effect. Basal plasma glucose levels in diabetic controls (18.8 mM) were reduced to 14.0 mM by 100 mg/kg ADD-199 in <2 weeks compared to 4 and 6 weeks for glibenclamide and metformin, respectively. This hypoglycaemic effect of ADD-199 appeared to be associated with the alkaloidal content of the extract. Treatment with ADD-199 or the hypoglycaemic agents reversed the observed elevation in plasma lipids but increased hepatic glycogen, triacylglycerol and cholesterol levels. Treatment also increased glucose uptake by isolated diaphragms and attenuated hepatic lipid peroxidation. These antihyperglycaemic and antioxidant actions of ADD-199 at a dose of 100mg/kg/day are comparable to those of the maximum daily therapeutic doses of glibenclamide (0.25 mg/kg) and metformin (50 mg/kg). These could explain the basis for use of this plant extract to manage diabetes mellitus (DM).

Administration, Oral↗
PubMed2005

Subchronic toxicity studies of the antidiabetic herbal preparation ADD-199 in the rat: absence of organ toxicity and modulation of cytochrome P450.

The subchronic toxicity of the aqueous antidiabetic herbal extract ADD-199, prepared from Maytenus senegalensis, Annona senegalensis, Kigelia africana and Lanneawelwitschii, and administered at a daily dose of 100 or 500 mg/kg body weight over 30 days, was investigated in male Wistar albino rats. Certain haematological, urine and plasma biochemical parameters, and modulation of some hepatic cytochrome P450 (CYP) isozymes were measured as indices of organ specific toxicity or potential for drug interactions. ADD-199 did not affect plasma aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and albumin or creatinine kinase (CK) levels. It also did not affect plasma creatinine and urea levels. Furthermore, ADD-199 neither affected PCV nor blood Hb, RBC, reticulocytes, platelets, lymphocytes and granulocyte levels. It, however, caused significant dose-dependent reductions in WBC counts at day 15 with varying degrees of recovery by day 30. It also reduced the rate of body weight increases after week 3. However, no changes were observed in organ weights at termination. ADD-199 did not significantly affect zoxazolamine-induced paralysis and pentobarbital-induced sleeping times as well as certain CYP isozyme activities in rats. These findings suggest that ADD-199 had no overt organ specific toxicity and did not demonstrate a potential for drug interactions via CYP-mediated metabolism in the rat on subchronic administration.

Animals↗
PubMed2005

Antidiabetic activity of alcoholic stem extract of Coscinium fenestratum in streptozotocin-nicotinamide induced type 2 diabetic rats.

The antidiabetic potential of the alcoholic stem extract of Coscinium fenestratum Colebr. (Menispermaceae), a medicinal plant widely used in the traditional Ayurveda and Siddha systems of medicine for the treatment of diabetes mellitus was evaluated in the STZ-nicotinamide induced type 2 diabetic model. Graded doses of the alcoholic stem extract were administered to normal and experimental diabetic rats for 12 days. Significant (p < 0.05) reduction in fasting blood glucose levels were observed in the normal as well as in the treated diabetic animals. Serum insulin levels were not stimulated in the animals treated with the extract. In addition, changes in body weight, serum lipid profiles, thiobarbituric acid reactive substance levels, glycosylated hemoglobin and liver glycogen levels assessed in the extract treated diabetic rats were compared with diabetic control and normal animals. Significant results were observed in the estimated parameters, thereby justifying the use of the plant in the indigenous system of medicine.

Animals↗
PubMed2005

Antidiabetic plants used by Sikkim and Darjeeling Himalayan tribes, India.

Sikkim and Darjeeling Himalayan region is characterized by a rich floral diversity and an equally rich ethnomedicinal tradition. Herbal medicine is the dominant system of medicine practiced by the local tribes of this region for the treatment of diabetes. During the course of the present studies it was found that 37 species of plants belonging to 28 families are used as antidiabetic agents in the folk medicinal practices in the region and 81% of these plants are hitherto unreported as hypoglycemic agents. This finding may lead to serious research towards developing new and efficient drugs for diabetes.

Diabetes Mellitus, Type 1↗
PubMed2006

Antidiabetic effects of dietary administration of Aloe arborescens Miller components on multiple low-dose streptozotocin-induced diabetes in mice: investigation on hypoglycemic action and systemic absorption dynamics of aloe components.

We carried out three experimental trials to determine antidiabetic effects of Aloe arborescens Miller components. Firstly, ICR mice which received frequent injections of streptozotocin (Sz) in small doses (low-dose Sz-induced diabetes mice) were fed ad libitum with basal diets supplemented with components of Aloe arborescens Miller var. natalensis Berger (Kidachi aloe) and Aloe vera Linne from 31 days before to 73 days after the Sz injections. Variation in blood glucose levels, incidence rates of insulitis and blood insulin levels were examined during the trial. As a result, groups receiving diets supplemented at the rate of 2% with whole leaf of Kidachi aloe and 10 KDa fraction powder (a fraction with less than 10 KDa molecular weight derived from Kidachi aloe leaf skin juice by ultra filtration) significantly suppressed the elevation of blood sugar as compared to a control group receiving basal diet. In contrast, there was no significant effect with Aloe vera leaf pulp powder. Insulitis emerged at the rate of 87% in the basal diet group. On the contrary, the whole aloe leaf and 10 KDa fraction groups significantly decreased the incidence of insulitis and incidence rates of whole aloe leaf and 10 KDa fraction powder were 51 and 38%, respectively. While insulin levels in the basal diet group averaged at 0.05 ng, more than four times the insulin level was observed in the 10 KDa group relative to the basal diet group. Secondary, the inhibitory effects of test materials on intestinal glucose absorption were observed using the jejunum of rats. A strong inhibitory action on intestinal glucose absorption was observed in the 10 KDa fraction powder group. Thirdly, phenol compounds derived from aloe in the blood serum and organs were quantitatively measured by a HPLC following forced administration of aloe components to rats to determine absorption kinetics of aloe components inside the body. The primary component of aloe phenol compounds is the same component of the 10 KDa fraction powder and it was found in the pancreas and liver in addition to in the blood serum. The above results indicate that fore and aft when Sz injections could cause selective toxicity to B cells of islets, the dietary administration of 10 KDa fraction powder to mice would lead to the persistence of aloe phenol compound having an antioxidant activity in the pancreas and blood, which could protect islets of Langerhans from the destruction caused by methyl radical derived from Sz. The results also suggested the possibility of the 10 KDa fraction powder to alleviate the burden of insulin secretion as it has an inhibitory action on glucose absorption in the jejunum of rats.

Aloe↗
PubMed2006

Drugs share antidiabetic and antiatherosclerotic actions through "the common soil".

There have been increasing evidences that atherosclerosis is not the result of diabetes mellitus, but that both type 2 diabetes mellitus and atherosclerosis may share common pathogenesis, as Stern proposed as 'common soil' hypothesis in 1995. There are several candidates for 'common soil', such as insulin resistance, vascular inflammation and endothelial dysfunction. Recently many of clinical studies have indicated that some drugs can prevent or delay the development of cardiovascular diseases (CVD). Furthermore, many studies have suggested that some classes of drugs may prevent the development of type 2 diabetes. It is to be noted that most of the drugs may have both actions, i.e., to prevent development of new diabetes and to prevent CVD. Furthermore, they are reported to inhibit inflammation or endothelial dysfunction. Taken together, it is hypothesized that the drug which may have antiatherogenetic action may also have antidiabetic action, and vice versa. This hypothesis may provide the new insights into perspectives of drug development both to prevent type 2 diabetes and to prevent CVD.

Atherosclerosis↗
PubMed2004

Effect of antidiabetic medications on microalbuminuria in patients with type 2 diabetes.

The progression of diabetes and hypertension complications is associated with microalbuminuria. Intensive glycemic control prevents or retards microalbuminuria in patients with type 2 diabetes, but little is known about the respective benefits of different antidiabetic drugs. We studied the effect of gliclazide and pioglitazone on microalbuminuria in patients with type 2 diabetes. We excluded patients with very poor glycemic control (glycated hemoglobin [HbA(1c)] >10%), impaired liver function, nondiabetic renal diseases, and those whose urine contained red blood cells, hemoglobin, or casts. Each patient received the designated drug for 12 weeks and their body weight, blood pressure (BP), fasting plasma glucose (FPG), HbA(1c), lipids (triglycerides [TG], total, and high-density lipoprotein-cholesterol [HDL-C]), 1,5 anhidroglucitol (1,5-AG), immunoreactive insulin (IRI), and urinary albumin to creatinine ratio (UACR) were measured every month. The effects of the drugs were analyzed using 2-way repeated measures analysis of variance (ANOVA). The 2 groups of patients were well matched for age, duration of diabetes, retinal status, blood pressure, body mass index (BMI), IRI, FPG, HBA(1c), 1,5-AG, lipids, and UACR, as well as the use of antihypertensive drugs. After treatment, no significant differences were seen in drug efficacy between the 2 groups. Gliclazide and pioglitazone significantly reduced FPG (F = 26.0, P <.0001), HBA(1c) (F = 48.1, P <.0001), and total cholesterol (TC) levels (F = 3.5, P <.05). Decrements in these metabolic parameters were comparable between the groups. 1,5-AG increased in both groups (F = 27.5, P <.0001), and the increment was comparable in both groups. Gliclazide and pioglitazone significantly reduced UACR (F = 15.7, P <.0001) with a comparable decrement in both groups. No other variables changed significantly throughout the 12-week treatment. These results suggest that 12 weeks of treatment with gliclazide or pioglitazone are equally effective in reducing microalbuminuria with similar improvements in blood glucose and cholesterol levels, independent of their mechanisms of actions.

Adult↗
PubMed2005

Self-monitoring of blood glucose--psychological aspects relevant to changes in HbA1c in type 2 diabetic patients treated with diet or diet plus oral antidiabetic medication.

OBJECTIVE: To investigate the influence of psychological aspects on glycemic control in type 2 diabetic patients treated with diet alone or diet plus oral antidiabetic medication using meal-related self-monitoring of blood glucose (SMBG). These psychological aspects refer to the process of self-management including the tendency to structure situations and activate resources (self-perception), to accept options for action (self-reflection) and to believe in self-efficacy (self-regulation). METHODS: In a randomized controlled 6-month group comparison study, one group (n = 113; mean age 58.7 years) used a blood glucose monitoring device, kept a blood glucose/eating diary and received standardized counseling focusing on self-perception, self-reflection and self-regulation. A control group (n = 110; mean age 60.5 years) received non-standardized counseling on diet and lifestyle. RESULTS: Statistically significant endpoint differences between the SMBG and the control group were seen in glycemic control (p = 0.0086) and the well-being item 'depression' (p = 0.032). All aspects of counseling were influenced by SMBG with the extent of self-perception and self-reflection gradually increasing over time. Three HbA1c response types were identified among SMBG patients: continuous-achievers, late-achievers and non-achievers. CONCLUSION: This study identified processes (structuring the situation and activating resources, accepting options for action and believing in self-efficacy) which lead to a change in the metabolic profile. SMBG coupled with structured counseling provided patients with a tool for taking on more self-control and resulted in an improved outlook on life. PRACTICE IMPLICATIONS: This short-term intervention involved a structured counseling algorithm which requires 5-10 min of physician-patient contact and a structured documentation of metabolic control by the patient and can be taught by a diabetes training team within 4 h. The identification of the different response types might be of importance in clinical practice as it enables the physician to determine the right counseling option.

Administration, Oral↗
PubMed2006

Cinnamaldehyde--a potential antidiabetic agent.

Cinnamonum zeylanicum (cinnamon) is widely used in traditional system of medicine to treat diabetes in India. The present study was carried out to isolate and identify the putative antidiabetic compounds based on bioassay-guided fractionation; the compound identified decreased the plasma glucose levels. The active compound was purified by repeat column and structure of cinnamaldehyde was determined on the basis of chemical and physiochemical evidence. The LD(50) value of cinnamaldehyde was determined as 1850+/-37 mg/kg bw. Cinnamaldehyde was administered at different doses (5, 10 and 20 mg/kg bw) for 45 days to streptozotocin (STZ) (60 mg/kg bw)-induced male diabetic wistar rats. It was found that plasma glucose concentration was significantly (p<0.05) decreased in a dose-dependent manner (63.29%) compared to the control. In addition, oral administration of cinnamaldehyde (20 mg/kg bw) significantly decreased glycosylated hemoglobin (HbA(1C)), serum total cholesterol, triglyceride levels and at the same time markedly increased plasma insulin, hepatic glycogen and high-density lipoprotein-cholesterol levels. Also cinnamaldehyde restored the altered plasma enzyme (aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, alkaline phosphatase and acid phosphatase) levels to near normal. Administration of glibenclamide, a reference drug (0.6 mg/kg bw) also produced a significant (p<0.05) reduction in blood glucose concentration in STZ-induced diabetic rats. The results of this experimental study indicate that cinnamaldehyde possesses hypoglycemic and hypolipidemic effects in STZ-induced diabetic rats.

Acrolein↗
PubMed2006

Biological activity and antidiabetic potential of synthetic fragment peptides of glucose-dependent insulinotropic polypeptide, GIP(1-16) and (Pro3)GIP(1-16).

Glucose-dependent insulinotropic polypeptide (GIP) is a key physiological insulin releasing peptide and potential antidiabetic agent. The present study was undertaken in an attempt to develop small molecular weight GIP agonist and antagonist molecules. The bioactivity of two modified C-terminally truncated fragment GIP peptides, GIP(1-16) and (Pro3)GIP(1-16), was examined in terms of insulin secretion and glucose homeostasis using BRIN-BD11 cells and type 2 diabetic mice. In vitro insulin release studies demonstrated that GIP(1-16) and (Pro3)GIP(1-16) possessed weak GIP-receptor agonist and antagonistic properties, respectively. Intraperitoneal administration of GIP(1-16) in combination with glucose to obese diabetic (ob/ob) mice did not effect the glycaemic excursion and had a marginal effect on insulin release. GIP(1-16) was substantially less effective than the native GIP(1-42). (Pro3)GIP(1-16) administration significantly curtailed (P < 0.05) the insulinotropic and glucose lowering effects of native GIP, but was significantly less effective than (Pro3)GIP. Based on the established concept of a therapeutic benefit of GIP receptor antagonism in obesity-diabetes, ob/ob mice received once daily injection of (Pro3)GIP(1-16) for 14 days. No significant effects were observed on food intake, body weight, HbA1c, glucose tolerance, metabolic response to feeding and either insulin secretion or insulin sensitivity following prolonged (Pro3)GIP(1-16) treatment. These data demonstrate that C-terminal truncation of GIP or (Pro3)GIP yields small molecular weight GIP molecules with significantly reduced biological activity that precludes therapeutic utility.

Animals↗
PubMed2006

Mitochondrial permeability transition as a potential determinant of hepatotoxicity of antidiabetic thiazolidinediones.

Troglitazone, a thiazolidinedione class of antidiabetic agent, causes serious idiosyncratic hepatotoxicity. Troglitazone is metabolized to a reactive metabolite that covalently binds to cellular macromolecules, but the role of the covalent adduct in the hepatotoxicity is controversial. Because troglitazone has been found to cause cytotoxicity to hepatocytes along with mitochondrial dysfunction, we investigated the effects of troglitazone and other thiazolidinediones on mitochondrial function by using liver mitochondria fraction isolated from male CD-1 mice. Incubation of energized mitochondria with succinate in the presence of Ca2+ and troglitazone induced mitochondrial swelling, and the swelling was partially inhibited by cyclosporin A. Troglitazone also induced decreases in mitochondrial membrane potential and mitochondrial Ca2+ accumulation. These results demonstrate that troglitazone induces mitochondrial permeability transition (MPT). Similar results were obtained for ciglitazone, whereas rosiglitazone and pioglitazone, which are less hepatotoxic than troglitazone, had little effect on these mitochondria functions. It is therefore possible that the troglitazone-induced opening of MPT pore, which is not induced by rosiglitazone or pioglitazone, may contribute to the hepatotoxicity induced specifically by troglitazone.

Animals↗
PubMed1998

Stimulation of the intracellular portion of the human insulin receptor by the antidiabetic drug metformin.

Our prior work suggested that the antidiabetic metformin must enter the cell to act and that the drug stimulates tyrosine kinase activity. We now report that therapeutic concentrations (approximately 1 microg/mL) of metformin stimulated the tyrosine kinase activity of the intracellular portion of the beta-subunit of the human insulin receptor (IPbetaIRK), the intracellular portion of the epidermal growth factor receptor and pp60-src, but not cAMP-dependent protein kinase. A derivative of metformin unable to lower glucose was ineffective in stimulating IPbetaIRK. Two derivatives more effective than metformin in patients were also more effective than metformin in stimulating IPbetaIRK. Higher levels (10-100 microg/mL) of metformin or methylglyoxyl bis(guanylhydrazone) inhibited the tyrosine kinases, and this inhibition may be responsible for the ability of these two drugs to block cell proliferation.

Buformin↗
PubMed2000

Antidiabetic effect of T-1095, an inhibitor of Na(+)-glucose cotransporter, in neonatally streptozotocin-treated rats.

3-(Benzo[b]furan-5-yl)-2', 6'-dihydroxy-4'-methylpropiophenone-2'-O-(6-O-methoxycarbonyl)-bet a-D -glucopyranoside (T-1095) is a derivative of phlorizin, a potent inhibitor of Na(+)-glucose cotransporters. We determined the antidiabetic effect of T-1095 in neonatally streptozotocin-treated diabetic rats. Orally administered T-1095 is metabolized to an active form, 3-(benzo[b]furan-5-yl)-2', 6'-dihydroxy-4'-methylpropiophenone-2'-O-beta-D-glucopyranoside (T-1095A), which inhibits renal Na(+)-glucose cotransporters as potently as phlorizin in vitro. A single oral administration of T-1095 (30 and 100 mg/kg, p.o.) markedly lowered blood glucose levels with a concomitant increase in urinary glucose excretion; whereas the effect on blood glucose levels in non-diabetic rats was minimal. Continuous administration of T-1095 to diabetic rats for 6 weeks (0.1% in diet) improved not only hyperglycemia, but also the elevation of plasma free fatty acid and plasma ketone body levels. In addition, oral glucose tolerance testing clearly illustrated the improvement of glucose tolerance and insulin secretion with T-1095. In fact, amelioration of impaired insulin sensitivity in diabetic rats was demonstrated by the increase of whole-body and skeletal-muscle insulin-mediated glucose utilization with normalization of muscle glucose transporter (GLUT)4 content, and decrease of the hepatic glucose production rate. Consequently, polyuria and glucosuria were also improved in the T-1095-treated group. Therefore, T-1095 has a therapeutic potential as a means of ameliorating abnormal glucose metabolism via diminished glucose toxicity.

Animals↗
PubMed2002

Inhibition of recombinant K(ATP) channels by the antidiabetic agents midaglizole, LY397364 and LY389382.

Most imidazolines inhibit ATP-sensitive K(+) (K(ATP)) channels. Since these drugs are potentially clinically relevant insulin secretagogues, it is important to know whether extrapancreatic K(ATP) channels are targeted. We examined the effects of three imidazoline-derived antidiabetic drugs on the cloned K(ATP) channel, expressed in Xenopus laevis oocytes, and their specificity for interaction with the pore-forming Kir6.2 or the sulphonylurea receptor (SUR) 1 subunit. Midaglizole, LY397364 and LY389382 blocked Kir6.2deltaC currents with IC(50) of 3.8, 6.1 and 0.7 microM, respectively. The block of Kir6.2/SUR1 currents by LY397364 and LY389382 was best fit by a two-site model, suggesting that these drugs also interact with SUR1. However, since all three drugs interact with the Kir6.2 subunit, and Kir6.2 forms the pore of extrapancreatic K(ATP) channels, these drugs are unlikely to be specific for the beta-cell.

ATP-Binding Cassette Transporters↗