Generation Sulfonylurea Research Articles

Efficacy of glimepiride in type 2 diabetic patients treated with glibenclamide

Multicentric study was conducted to evaluate the efficacy of glimepiride in the oral hypoglycemic agents therapy of type 2 diabetic patients treated with glibenclamide so far, and to claim an adequate use of this new generation sulfonylurea. In 66 diabetic outpatients, glibenclamide was switched to glimepiride. After 6 months’ therapy, a significant reduction in fasting plasma IRI was observed in relatively hyperinsulinemic patients. In addition, weight reduction was achieved in patients with insulin resistance during this study. These findings suggest that glimepiride improves insulin resistance in hyperinsulinemic patients treated with glibenclamide. Also, glimepiride is favored especially for overweight, insulin-resistant patients inadequately controlled by glibenclamide.

Effect of glimepiride on insulin-stimulated glycogen synthesis in cultured human skeletal muscle cells: a comparison to glibenclamide.

To examine the effect of glimepiride on insulin-stimulated glycogen synthesis in cultured human skeletal muscle cells in comparison with glibenclamide. Myotubes derived from glucose-tolerant subjects were incubated with glimepiride or glibenclamide (0-100 micro mol/l) for 4 h and with or without insulin (100 nmol/l) for 2 h, and subsequently glycogen synthesis was determined. Glimepiride had no significant effect on basal glycogen synthesis; in contrast, glimepiride caused a dose-dependent increase of insulin-stimulated glycogen synthesis, with a maximal effect of 39.97 +/- 8.4% (mean +/- SEM, n = 4, P < 0,02). The time course of this glimepiride effect on insulin-stimulated glycogen synthesis showed a peak after 12 h incubation with a half maximal effect after 4 h. Preincubation of the myotubes with wortmannin (100 nmol/l), an inhibitor of phosphatidylinositol (PI)- 3 kinase, caused an inhibition of this glimepiride effect on insulin-stimulated glycogen synthesis. In contrast to glimepiride, incubation of myotubes with glibenclamide (0-100nmol/l), a second generation sulfonylurea, had no significant effect on basal or insulin-stimulated glycogen synthesis. Incubation of cultured human skeletal muscle cells derived from glucose-tolerant subjects with glimepiride caused a dose-dependent increase of insulin-stimulated glycogen synthesis using therapeutic glimepiride concentrations. This glimepiride effect seems to be mediated via the PI3 kinase pathway. In contrast to glimepiride, glibenclamide had no significant effect on basal or insulin-stimulated glycogen synthesis. These results suggest that glimepiride, beside its well-known effect to stimulate insulin secretion, possess an insulin-sensitizing action in cultured human skeletal muscle cells in support of the concept of an extrapancreatic action of glimepiride.

Oral hypoglycemic agents: insulin secretagogues, alpha-glucosidase inhibitors and insulin sensitizers.

In this review we present the agents that are in use in the treatment of type 2 diabetes. Sulfonylureas of the 1st and 2nd generation increase insulin secretion but can induce hyperinsulinemia and sometimes prolonged hypoglycemia. Glimepiride is a new 3rd generation sulfonylurea with some advantages over the other members of this group, such as a lower risk of hypoglycemia, no interaction with cardiovascular KATP-channels and a possibility that it may increase insulin sensitivity. There are also newer insulin secretagogues (such as neteglinide and repaglinide) with a rapid onset of action on the beta-cell, therefore inducing a more physiological profile of insulin secretion during meals. The category of insulin sensitizers includes metformin and thiazolidinediones. Metformin effectively reduces hyperglycemia, hyperlipidemia and macroangiopathy in patients with type 2 diabetes. This agent increases the sensitivity of the liver and peripheral tissues to insulin and, therefore, it could be considered as a drug of choice for the prevention of type 2 diabetes. Thiazolidinediones (rosiglitazone and pioglitazone) increase the sensitivity of the tissues to insulin. This mechanism of action makes them powerful therapeutic tools for the treatment of type 2 diabetes (and possibly other insulin resistant states) either alone or in combination with other oral agents. The category of agents that interfere with the absorption of glucose and lipids includes alpha-glucosidase inhibitors (acarbose and miglitol) and lipase inhibitors (or-listat). alpha-Glucocidase inhibitors improve the time relationship between plasma insulin and glucose increases after a meal. Therefore, these agents may be used in the treatment of patients with type 2 diabetes, either alone at a very early stage of this disease (when insulin secretion is still adequate), or in combination with insulin secretagogues. alpha-Glucosidase inhibition may also prove useful as a supplement to insulin therapy in patients with type 1 diabetes mellitus. The inhibitor of gastrointestinal lipase orlistat may prove a useful adjunct to hypocaloric diets in patients with type 2 diabetes and obesity.

Pharmacokinetics of chlorpheniramine, phenytoin, glipizide and nifedipine in an individual homozygous for the CYP2C9*3 allele.

Genetic polymorphisms in the cytochrome P450 (CYP) family are widely known to contribute to interindividual differences in the pharmacokinetics of many drugs. Several alleles for the CYP2C9 gene have been reported. Individuals homozygous for the Leu359 variant (CYP2C9*3) have been shown to have significantly lower drug clearances compared with Ile359 (CYP2C9*1) homozygous individuals. A male Caucasian who participated in six bioavailability studies in our laboratory over a period of several years showed extremely low clearance of two drugs: phenytoin and glipizide (both substrates of CYP2C9), but not for nifedipine (a CYP3A4 substrate) and chlorpheniramine (a CYP2D6 substrate). His oral clearance of phenytoin was 21% of the mean of the other 11 individuals participating in the study, and his oral clearance of glipizide, a second generation sulfonylurea structurally similar to tolbutamide, was only 188% of the mean of the other 10 individuals. However, his oral clearance of nifedipine and chlorpheniramine did not differ from individuals in other studies performed at our laboratories. An additional blood sample was obtained from this individual to determine if he possessed any of the known CYP2C9 or CYP2C19 allelic variants that would account for his poor clearance of the CYP2C9 substrates (phenytoin and glipizide) compared with the CYP3A4 (nifedipine) and CYP2D6 (chlorpheniramine) substrates. The results of the genotype testing showed that this individual was homozygous for the CYP2C9*3 allele and did not possess any of the known defective CYP2C19 alleles. This study establishes that the Leu359 mutation is responsible for the phenytoin and glipizide/tolbutamide poor metabolizer phenotype.

Utility of a Short-Term 25% Carbohydrate Diet on Improving Glycemic Control in Type 2 Diabetes Mellitus

Objective: To determine if introduction of a low carbohydrate diet might be a useful option for type 2 diabetic patients who do not achieve glucose target levels despite conventional treatment.Methods: Subjects with type 2 diabetes, either treated with diet alone (n=9) or second generation sulfonylurea agents (n=19), which were discontinued, were placed on a diet based on ideal body weight and comprised of 25% carbohydrate. After a mean of 8 weeks, they were then switched to a caloricly equivalent diet, but composed of 55% carbohydrate.Results: Compared to baseline diet, after 8 weeks of a 25% diet, subjects showed significantly improved glycemia as evidenced by fasting blood glucose values (p<0.005) and hemoglobin A1c levels (p<0.05). Those previously treated with oral hypoglycemic agents showed, in addition, a significant decrease in weight and diastolic blood pressure despite the discontinuation of the oral agent. When then placed on a 55% carbohydrate diet, the hemoglobin A1c rose significantly over the ensuing next 12 weeks (p<0.05).Conclusion: A low carbohydrate, caloricly-restricted diet has beneficial short-term effects in subjects with type 2 who have failed either diet or sulfonylurea therapy and may obviate the necessity for insulin. Our study also affirms the need for reassessing the role of diet whenever type 2 diabetic patients manifests hyperglycemia, despite conventional oral treatment or diet management.

Capillary electrophoretic detection of metabolites in the urine of patients receiving hypoglycemic drug therapy.

Micellar electrokinetic chromatography (MEKC) in tandem with diode array detection (DAD) has been exploited as an analytical method for the separation and detection of sulfonylurea drugs. The ultimate goal is the development of an assay to detect these drugs or their metabolites in urine as a means of diagnosing sulfonylurea drug abuse. Using a separation buffer consisting of 5 mM borate/5 mM phosphate/75 mM sodium cholate, separation of both the second and third generation sulfonylurea drugs can be achieved. The characteristic absorbance spectra associated with each of the third generation drugs, glipizide and glyburide, allow for their identification in mixtures. Coinjection of glyburide, its primary metabolite, hydroxy glyburide, and glipizide demonstrated that the metabolite was resolved from the parent drug but shared its absorbance spectral properties. MEKC analysis of a series of solid phase-extracted urine samples from patients prescribed glipizide or glyburide, as well as from control patients not ingesting the drug, showed that the parent compounds were difficult to detect in the urine. However, the use of DAD allowed for detection of metabolites in the urine of these patients. With glyburide patients, only primary metabolites were detected, while urine from patients on glipizide showed a series of peaks whose absorbance spectra was consistent with the presence of both primary and secondary metabolites. In addition, the intensity of the metabolite peaks corresponded reasonably well with the respective dose and in vivo time interval associated with the urine collection. This study shows that MEKC with DAD has potential for further exploration as a clinical assay for detecting surreptitious abuse of sulfonylurea drugs.

Individual Sulfonylureas and Serious Hypoglycemia in Older People

To compare the risk of serious hypoglycemia associated with the use of individual sulfonylureas in older people. A retrospective cohort study. The Tennessee Medicaid Program. A total of 13,963 Medicaid enrollees, aged 65 years or older, who were prescribed one of six sulfonylureas from 1985 to 1989. Hospitalization, emergency room admission, or death associated with neuroglycopenic or autonomic symptoms, myocardial infarction, stroke, or injury, with a concomitant blood glucose determination of less than 2.8 mmol/L (50 mg/dL). We identified 255 persons with a first episode of serious hypoglycemia during 20,715 person-years of sulfonylurea use. The crude rate (per 1000 person-years) of serious hypoglycemia was highest in glyburide users, 16.6 (95% confidence interval [CI], 13.2 to 19.9 and lowest among users of tolbutamide, 3.5 (95% CI, 1.2 to 5.9). Users of tolbutamide, tolazamide, and glipizide had lower risks of serious hypoglycemia than users of chlorpropamide, whereas the risk of serious hypoglycemia among glyburide users did not differ from that of chlorpropamide users. Among second generation sulfonylureas, the adjusted relative risk of severe hypoglycemia among glyburide users, compared with glipizide users, was 1.9 (95% CI, 1.2 to 2.9). An increased risk of serious hypoglycemia associated with use of glyburide compared with glipizide occurred in all strata, including those defined by gender, race, nursing home residence, dose, and duration of use. Significant differences in risk of serious hypoglycemia were observed among users of individual agents. This may be explained by duration, timing, or potency of hypoglycemic action. These data confirm previous findings that chlorpropamide use is associated with high risk of hypoglycemia and indicate that among second generation sulfonylureas, glipizide is less associated with hypoglycemia than is glyburide. More information comparing the effectiveness of glycemic control among individual sulfonylureas is needed to assist prescribers in selecting a specific agent for use in clinical practice.

The use of second generation sulfonylurea agents and the role of glurenorm in the therapy of non-insulin-dependent diabetes mellitus

Sulfonylurea drugs stimulate the 1st phase of insulin secretion, activate adenylate cyclase, inhibit phosphodiesterase or cause prolonged depolarization of the beta cell membrane. The peripheral effect of the hypoglycemic action of sulfonylurea drugs is mediated through the effect on insulin receptors. It is clearly shown that sulfonylureas lead to an increase in the number of receptors on target cells (hepatocytes, muscle and adipose tissue, lymphocytes and other cells). It is known that patients with type II diabetes mellitus have a decrease in both the number of receptors and their affinity. The increase in the number of receptors on the membrane of target cells is not due to their de novo synthesis, but by improving the return of the receptor to the membrane from the cytosol, where they are translocated as an insulin-receptor complex after the interaction of insulin with the corresponding receptor.&#x0D; One of the sulfonylurea drugs of the second generation is Gliquidone (glurenorm). This drug has one advantage, distinguishing it from other sulfonylurea drugs. About 95% of the drug is excreted from the body through the gastrointestinal tract, and only 5% is extracted by the kidneys. Therefore, it is the drug of choice in the treatment of diabetic patients with nephropathy, given the fact that the drug is metabolized in the liver and eliminated through the bile ducts into the intestine. Naturally, the question arises of the possibility of its influence on the liver function of patients who have been receiving long-term treatment with glurenorm.

Hemobiological properties of gliclazide

Non-insulin-dependent diabetes mellitus (NIDDM) is associated with an increased risk of macro- and microvascular degenerative complications. Gliclazide is a second generation sulfonylurea that is widely used in the treatment of type II diabetes mellitus. Its hypoglycemic activity is well documented. In addition to its metabolic effects, gliclazide has beneficial effects on the hemobiological abnormalities of NIDDM. These effects are mediated by the azabicyclo-octyl ring grafted on to its aulfonylurea core. Numerous studies have demonstrated that gliclazide reduces platelet hyperadhesion and platelet hyperaggregability. These actions have been extensively confirmed in diabetic patients over periods of up to 3 years. With regard to platelet functions, several groups have demonstrated a significant reduction in serum and intraplatelet β thromboglobulin and thromboxane B 2. In animal models, in-vitro and in-vivo gliclazide stimulates endothelial prostacyclin synthesis. The beneficial effects of the compound on thromboxane/prostacyclin balance have been recently confirmed in type II diabetic patients after a 3-month treatment period. Concerning fibrinolysis, gliclazide restores low plasminogen activity to normal in NIDDM patients previously treated with first-generation sulfonyl-ureas. Gliclazide increases fibrinolytic potential by increasing endothelial cell tissue plasminogen activator and pre-kallikrein activity. More recent studies suggest that gliclazide may have effects on fibrin network structure, rendering the fibrin more amenable to fibrinolysis. Finally, it has been shown that gliclazide has a potent free-radical-scavenging activity in vitro. This property has been recently confirmed in vivo in type II diabetic patients and may suggest that platelet reactivity and oxidative stress are related in these patients. It is worth noting that the hemobiological properties of gliclazide are largely independent of its hypoglycemic activity. In addition, these properties are not shared with other first or second generation sulfonylureas.

Dosing schedule of second generation sulfonylureas in the treatment of non-insulin dependent diabetes should be revised (A commentary)

Dosing schedule of second generation sulfonylureas in the treatment of non-insulin dependent diabetes should be revised (A commentary)

ATP-dependent K+ channels of pancreatic ß-cells under the effects of some sulfonylurea drugs

The authors analyze the relationships between electrophysiologic processes taking place on (J-cell membranes under the effects of some second generation sulfonylurea drugs: glycaside, glybenclamide, and glypizine and their secretogenic effects on insulin secretion. All the tested drugs induced complete blocking of K+-ATP-dependent channels when administered in concentrations from 1 to 20 pM (physiologic doses). Glucose had a similar effect. The canal is closed very soon, within 30 sec, and is closed for approximately 10 min, rapidly opening after the drug is washed away. Reduced activity of the channels up to their closure is conducive to the onset of insulin secretion. Glybenclamide proved to be the most potent suppressor of individual channel activity, this being confirmed by its more potent hypoglycemic effect as compared to glyclaside or glypizine.

Effect of a sulfonylurea (gliclazide) treatment on insulin sensitivity and glucose-mediated glucose disposal in patients with non-insulin-dependent diabetes mellitus (NIDDM)

Five male non-obese newly diagnosed NIDDM and 5 age-, sex- and body mass index (BMI) matched healthy controls without a family history of diabetes were submitted to a frequently sampled intravenous (i.v.) glucose tolerance test modified by exogenous insulin administration for estimation of insulin sensitivity (S I) and glucose-mediated glucose disposal (S G) with Bergman's minimal model computer analysis of glucose kinetics. The tests were repeated after 3 months treatment with a second generation sulfonylurea, gliclazide, in the diabetics subjects. S I and S G were markedly reduced before gliclazide therapy in the diabetics in comparison to the paired controls. After gliclazide, despite significantly lower (almost normal) plasma glucose, normalization of glycosylated hemoglobin and increased fasting insulin levels, there was a slight but significant increase in S I while S G showed a further reduction, the improvement in glucose control being also associated to the significant increased first and 2nd phase insulin release for the first 20 min after glucose infusion.

Glibenclamide partly reverses monensin inhibition of insulin secretion, in vivo

Glibenclamide, a second generation sulfonylurea, is an oral hypoglycemic drug. It seems to act mainly on the ATP-driven K + - channels of the β-cells of pancreas determining insulin secretion. Because monensin, a Na +/H + antiport, is able when administered to rats in vivo to inhibit insulin secretion, the action of glibenclamide is studied on glycemia and insulinemia to verify if it can antagonize the action of monensin. The results show that glibenclamide is able to partly reverse ionophore induced hyperglycemia and the inhibition of insulin secretion. These results might be interpreted as if glibenclamide only reverses the ATP-driven K + - channel dependent insulin secretion. Moreover the antagonist action of glibenclamide is slightly delayed when both drugs are administered together. The role of Na +/H + antiport in basal insulin secretion is discussed.

Specificity of photolabeling of beta-cell membrane proteins with an 125I-labeled glyburide analog.

The interaction between sulfonylureas and membrane proteins from a hamster insulin-secreting tumor (HIT) cell line has been examined. Four HIT cell membrane proteins were covalently linked to an 125I-labeled glyburide analog by photolabeling. Three photolabeled polypeptides of M(r) 65,000, 55,000, and 30,000 were identified as low affinity "glyburide receptors." These proteins appear to be of similar abundance, when quantitated by photolabeling, with half-maximal displacements (Ki values) by glyburide, glipizide, and tolbutamide in the low micromolar range. The glyburide analog is more tightly bound to a M(r) 140,000 protein with dissociation constants, determined by filtration binding assays and by photolabeling, of 7 and 9.0 nM, respectively. The labeled analog was displaced from the M(r) 140,000 protein by glyburide, glipizide and tolbutamide with Ki values of 3.3 nM, 103 nM, and 25 microM, respectively, as estimated by photolabeling. Optimal conditions established for visualizing the M(r) 140,000 band on autoradiograms prepared after UV cross-linking and sodium dodecyl sulfate-polyacrylamide gel electrophoresis include irradiating the radioligand-receptor complex at 1.5 J/cm2 at 312 nm, followed by heating samples in pH 9.0 sodium dodecyl sulfate-gel sample buffer. With receptor sites partially occupied (5 nM radioligand), approximately 0.75% of the protein is photocoupled to the radioligand and visualized by autoradiography. Our results confirm that the M(r) 140,000 polypeptide contains the beta-cell high affinity glyburide binding site and show that the second generation sulfonylurea antidiabetic drugs have a selective increase in affinity for this receptor.

Comparative study of the therapeutic effects of glibenclamide or the fixed combination of glibenclamide-phenformin with those of gliclazide or chlorpropamide

This study was designed to compare the therapeutic effects of glibenclamide or the fixed combination of glibenclamide-phenformin with those of gliclazide, chlorpropamide or biguanides in non-insulin-dependent diabetes. It is divided into two parts: a) in the retrospective study (473 subjects), glucose control of patients who were transferred from chlorpropamide, gliclazide, glibenclamide, glibenclamide + biguanide or metformin to the fixed combination glibenclamide-phenformin in the same tablet (2.5 mg and 25 mg, respectively) was monitored. A statistically significant decrease of blood glucose and glycosylated hemoglobin values was found under the combination of glibenclamide-phenformin contained in the same tablet in contrast to the values obtained with the treatment with glibenclamide, gliclazide, chlorpropamide, combination of glibenclamide and biguanides, metformin, and insulin. b) In the prospective study (57 subjects), the patients were transferred from chlorpropamide or gliclazide to glibenclamide for 3 months and then reallocated to the previous treatment for 3 additional months. It was found that under glibenclamide, glucose control was significantly better than under chlorpropamide or gliclazide. In conclusion, glibenclamide, a second generation sulfonylurea, and the fixed combination glibenclamide-phenformin in the same tablet are more effective compared to the other antidiabetic agents here studied and lead to a better control of type II diabetic patients. There was no increase in plasma lactic acid concentration in all patients studied before and after having received the fixed combination of glibenclamide-phenformin in the single tablet form.

Divergent cardiac effects of the first and second generation hypoglycemic sulfonylurea compounds

The effects of first and second generation hypoglycemic sulfonylureas on the incidence of ventricular ectopic beats and on the duration of transitional ventricular fibrillation in the ischemic rat heart were investigated. First generation sulfonylurea compounds (tolbutamide, carbutamide and gliclazide) in 105 preparations increased, while second generation sulfonylurea compounds (glibenclamide and glipizide) in 50 preparations decreased in a dose-dependent manner both the number of ventricular ectopic beats and the duration of transitional ventricular fibrillation during the first 30 min after ligation of the left anterior descending coronary artery. Therefore, second generation sulfonylureas should be preferred in the treatment of type 2 diabetics with ischemic heart diseases, if satisfactory metabolic control cannot be achieved by a treatment regimen and diet alone.

Glyburide but not ciglitazone enhances insulin action in the liver independent of insulin receptor kinase activation

To test the hypothesis that sulfonylureas enhance insulin action by activating the insulin receptor tyrosine kinase, the effects of glyburide, a second generation sulfonylurea, and ciglitazone, a nonsulfonylurea hypoglycemic agent, were determined in primary cultures of rat hepatocytes on insulin action and insulin receptor structure and function. Twenty hours of preincubation with glyburide (1 μg/mL) resulted in increased insulin (1 × 10 −7 mol/L) stimulation of [ 14C] acetate incorporation into lipids and [ 14C] α-aminoisobutyric acid uptake without any change in basal activity. Ciglitazone (1 μg/mL) was without any effect. Glyburide's actions were mediated without altering the following: (1) 125I-insulin binding; (2) the electrophoretic mobility of the affinity labeled α-subunit or the autophosphorylated β-subunit of the insulin receptor; and (3) the insulin-stimulated insulin receptor kinase activity using histone or the β-subunit of the insulin receptor as phosphoacceptors. These data suggest that the action of sulfonylureas is distal to the insulin receptor tyrosine kinase. Ciglitazone in vitro is ineffective in the liver, which suggests the peripheral tissues as the possible site of action.

Linogliride fumarate, an oral hypoglycemic agent, improves oral glucose tolerance in a rat model of non‐insulin‐dependent diabetes mellitus (NIDDM)

AbstractLinogliride fumarate, a structurally novel oral hypoglycemic compound, was tested in the neonatal streptozotocin‐induced rat model of non‐insulin‐dependent diabetes mellitus (NIDDM) [Weir et al.: Diabetes 30:590–595, 1981], and its antihyperglycemic effects were compared to those of representative first and second generation sulfonylureas. Two‐day‐old male Sprague‐Dawley rats (STZ) were injected with the beta cell toxin, streptozotocin (90 mg/kg i.p.); male littermates injected with citrate buffer served as controls (CTL). By 8 weeks of age, blood glucose of fed STZ rats was significantly elevated compared to that of CTL animals (&gt;300 mg/dl vs.&lt;110 mg/dl, respectively) and, in response to an oral glucose (1 g/kg) challenge, 18 hr fasted STZ rats exhibited marked glucose intolerance. Linogliride fumarate (10–100 mg/kg p.o.) significantly lowered blood glucose in 18 hr fasted STZ rats and produced a dose‐dependent improvement of oral glucose tolerance. Linogliride fumarate (ED30 = 12.5 mg/kg) was approximately six times as potent as tolbutamide (ED30 = 72.1 mg/kg) in improving oral glucose tolerance in STZ rats, while glyburide (0.5–2.5 mg/kg p.o.) and glipizide (2.5 mg/kg) were ineffective. This rat model of NIDDM may be useful for evaluating new hypoglycemic compounds.

Glipentide and glucose metabolism in isolated rat hepatocytes

Glipentide, a second generation sulfonylurea, raised the cellular concentration of fructose 2,6-bisphosphate in isolated rat hepatocytes. Parallel to accumulating this regulatory metabolite, glipentide inhibited basal gluconeogenesis and increased the rate of l-lactate production, as well as the metabolic flux through the 6-phosphofructo 1-kinase reaction. Tolbutamide elicited similar metabolic effects to those reported for glipentide, although the latter sulfonylurea was about 10 times more potent. The biochemical mechanism by which sulfonylureas promote the accumulation of fructose 2,6-bisphosphate in hepatocytes seems to be related to a significant increase of the hexose 6-phosphate pool (glucose 6-phosphate plus fructose 6-phosphate), together with the activation of 6-phosphofructo 2-kinase and inactivation of fructose 2,6-bisphosphatase, enzyme activities responsible, respectively, for the synthesis and degradation of fructose 2,6-bisphosphate.

Kidney disease in KK mice: effect of glyburide.

We previously demonstrated that glomerulosclerosis and proteinuria can be prevented by control of blood glucose levels either by insulin or glyburide in genetically diabetic KK mice (1,2). Also, we demonstrated that poor control of glucose despite treatment with glyburide did not prevent glomerulosclerosis in a subset of KK mice (2). This reinforces the impact of glycemic control in the prevention of diabetic nephropathy. The purpose of the present study is two-fold: 1) to evaluate the efficacy of another second generation sulfonylurea compound, glipizide, in controlling blood glucose levels in KK mice; and 2) to investigate the relationship between glucose control and structural, biochemical and functional characteristics of kidney disease in KK mice.