Biomedical subjects

J E Foley

Publications and source records attributed to J E Foley.

At least 19 recordsLinked to original sources

PubMed2007

Characterization of Anaplasma phagocytophilum major surface protein 5 and the extent of its cross-reactivity with A. marginale.

Major surface protein 5 (Msp5) of Anaplasma marginale is highly conserved in the genus Anaplasma and the antigen used in a commercially available competitive enzyme-linked immunosorbent assay (cELISA) for serologic identification of cattle with anaplasmosis. This study analyzes the degrees of conservation of Msp5 among various isolates of Anaplasma phagocytophilum and the extent of serologic cross-reactivity between recombinant Msp5 (rMsp5) of Anaplasma marginale and A. phagocytophilum. The msp5 genes from various isolates of A. phagocytophilum were sequenced and compared. rMsp5 proteins of A. phagocytophilum and A. marginale were used separately in an indirect ELISA to detect cross-reactivity in serum samples from humans and dogs infected with A. phagocytophilum and cattle infected with A. marginale. Serum samples were also tested with a commercially available competitive ELISA that uses monoclonal antibody ANAF16C1. There were 100% sequence identities in the msp5 genes among all of the A. phagocytophilum isolates from the United States and a horse isolate from Sweden. Sheep isolates from Norway and dog isolates from Sweden were 99% identical to one another but differed in 17 base pairs from the United States isolates and the horse isolate. Serologic cross-reactivity was identified when serum samples from cattle infected with A. marginale were reacted with rMsp5 of A. phagocytophilum and when serum samples from humans and dogs infected with A. phagocytophilum were reacted with rMsp5 of A. marginale in an indirect-ELISA format. Serum samples from dogs or humans infected with A. phagocytophilum did not cross-react with rMsp5 of A. marginale when tested with the commercially available cELISA. These results suggest that rMsp5 of A. phagocytophilum is highly conserved among United States and European isolates and that serologic distinction between A. phagocytophilum and A. marginale infections cannot be accomplished if rMsp5 from either organism is used in an indirect ELISA.

Anaplasma marginale↗

PubMed2006

Vildagliptin therapy reduces postprandial intestinal triglyceride-rich lipoprotein particles in patients with type 2 diabetes.

AIMS/HYPOTHESIS: We assessed the effects of vildagliptin, a novel dipeptidyl peptidase IV inhibitor, on postprandial lipid and lipoprotein metabolism in patients with type 2 diabetes. SUBJECTS, MATERIALS AND METHODS: This was a single-centre, randomised, double-blind study in drug-naive patients with type 2 diabetes. Patients received vildagliptin (50 mg twice daily, n=15) or placebo (n=16) for 4 weeks. Triglyceride, cholesterol, lipoprotein, glucose, insulin, glucagon and glucagon-like peptide-1 (GLP-1) responses to a fat-rich mixed meal were determined for 8 h postprandially before and after 4 weeks of treatment. RESULTS: Relative to placebo, 4 weeks of treatment with vildagliptin decreased the AUC(0-8h) for total trigyceride by 22+/-11% (p=0.037), the incremental AUC(0-8h) (IAUC(0-8h)) for total triglyceride by 85+/-47% (p=0.065), the AUC(0-8h) for chylomicron triglyceride by 65+/-19% (p=0.001) and the IAUC(0-8h) for chylomicron triglyceride by 91+/-28% (p=0.002). This was associated with a decrease in chylomicron apolipoprotein B-48 (AUC(0-8h), -1.0+/-0.5 mg l(-1) h, p=0.037) and chylomicron cholesterol (AUC(0-8h), -0.14+/-0.07 mmol l(-1) h, p=0.046). Consistent with previous studies, 4 weeks of treatment with vildagliptin also increased intact GLP-1, suppressed inappropriate glucagon secretion, decreased fasting and postprandial glucose, and decreased HbA(1c) from a baseline of 6.7% (change, -0.4+/-0.1%, p<0.001), all relative to placebo. CONCLUSIONS/INTERPRETATION: Treatment with vildagliptin for 4 weeks improves postprandial plasma triglyceride and apolipoprotein B-48-containing triglyceride-rich lipoprotein particle metabolism after a fat-rich meal. The mechanisms underlying the effects of this dipeptidyl peptidase IV inhibitor on postprandial lipid metabolism remain to be explored.

Adamantane↗

PubMed2005

Alpha cell function in health and disease: influence of glucagon-like peptide-1.

Although there is abundant evidence that hyperglucagonaemia plays a key role in the development of hyperglycaemia in type 2 diabetes, efforts to understand and correct this abnormality have been overshadowed by the emphasis on insulin secretion and action. However, recognition that the incretin hormone glucagon-like peptide-1 (GLP-1) exerts opposing effects on glucagon and insulin secretion has revived interest in glucagon, the neglected partner of insulin, in the bihormonal hypothesis. In healthy subjects, glucagon secretion is regulated by a variety of nutrient, neural and hormonal factors, the most important of which is glucose. The defect in alpha cell function that occurs in type 2 diabetes reflects impaired glucose sensing. GLP-1 inhibits glucagon secretion in vitro and in vivo in experimental animals, and suppresses glucagon release in a glucose-dependent manner in healthy subjects. This effect is also evident in diabetic patients, but GLP-1 does not inhibit glucagon release in response to hypoglycaemia, and may even enhance it. Early clinical studies with agents acting through GLP-1 signalling mechanisms (e.g. exenatide, liraglutide and vildagliptin) suggest that GLP-1 can improve alpha cell glucose sensing in patients with type 2 diabetes. Therapeutic approaches based around GLP-1 have the potential to improve both alpha cell and beta cell function, and could be of benefit in patients with a broad range of metabolic disorders.

Blood Glucose↗

PubMed2005

Vildagliptin, a dipeptidyl peptidase-IV inhibitor, improves model-assessed beta-cell function in patients with type 2 diabetes.

AIMS/HYPOTHESIS: The dipeptidyl peptidase IV inhibitor, vildagliptin, increases levels of intact glucagon-like peptide-1 (GLP-1) and improves glycemic control in patients with type 2 diabetes. Although GLP-1 is known to stimulate insulin secretion, vildagliptin does not affect plasma insulin levels in diabetic patients, suggesting that more sophisticated measures are necessary to ascertain the influence of vildagliptin on beta-cell function. METHODS: This study examined the effects of 28-d treatment with vildagliptin (100 mg, twice daily; n = 9) vs. placebo (n = 11) on beta-cell function in diabetic patients using a mathematical model that describes the insulin secretory rate as a function of glucose levels (beta-cell dose response), the change in glucose with time (derivative component), and a potentiation factor, which is a function of time and may reflect the actions of nonglucose secretagogues and other factors. RESULTS: Vildagliptin significantly increased the insulin secretory rate at 7 mmol/liter glucose (secretory tone), calculated from the dose response; the difference in least squares mean (deltaLSM) was 101 +/- 51 pmol.min(-1).m(-2) (P = 0.002). The slope of the beta-cell dose response, the derivative component, and the potentiation factor were not affected. Vildagliptin also significantly decreased mean prandial glucose (deltaLSM, -1.2 +/- 0.4 mmol/liter; P = 0.01) and glucagon (deltaLSM, -10.7 +/- 4.8 ng/liter; P = 0.03) levels and increased plasma levels of intact GLP-1 (deltaLSM, +10.8 +/- 1.6 pmol/liter; P < 0.0001) and gastric inhibitory polypeptide (deltaLSM, +43.4 +/- 9.4 pmol/liter; P < 0.0001) relative to placebo. CONCLUSION: Vildagliptin is an incretin degradation inhibitor that improves beta-cell function in diabetic patients by increasing the insulin secretory tone.

Adamantane↗

PubMed2005

Environmental factors associated with Bartonella vinsonii subsp. berkhoffii seropositivity in free-ranging coyotes from northern California.

Bartonella vinsonii subsp. berkhoffii is a newly recognized pathogen of domestic dogs and humans. Coyotes (Canis latrans) are considered an important reservoir of this bacterium in the western United States, but its vectors are still unknown. Our objective was to identify environmental factors associated with Bartonella antibody prevalence in 239 coyotes from northern California, using an enzyme-linked immunosorbent assay. In addition, associations were evaluated between B. v. berkhoffii and two pathogens with known vectors and habitat requirements, Dirofilaria immitis and Anaplasma phagocytophilum. Overall, B. v. berkhoffii seroprevalence was 28% (95% confidence interval [CI], 22.3%, 33.7%) and Bartonella seropositive coyotes were more likely than seronegative coyotes to be positive for Anaplasma phagocytophilum (Odds ratio = 3.3; 95% CI = 1.8, 5.9) and Dirofilaria immitis (Odds ratio = 2.1; 95% CI = 1.2, 3.8). The most likely geographic clusters of Bartonella and Dirofilaria overlapped. Bartonella seropositivity was associated with higher precipitation (p = 0.003) and proximity to the coast (p = 0.007) in univariate analysis. The association with precipitation varied with season, based on a logistic regression model.

Anaplasma phagocytophilum↗

PubMed2004

Common virus infections in cats, before and after being placed in shelters, with emphasis on feline enteric coronavirus.

The purpose of this study was to determine the origin and subsequent spread of feline calicivirus (FCV), feline herpesvirus (FHV), and feline enteric coronavirus (FECV) in cats relinquished to shelters. FCV was isolated from the oral fauces of 11% of healthy cats upon entry, and isolation rates were highest for kittens (33%). FHV shedding was very low (4%) at the time of entry and occurred mainly in juveniles. FECV shedding was also common among newly relinquished cats (33%), especially older kittens and juveniles (90%). The subsequent spread of all three viruses was rapid and efficient in the shelter environment. Fifteen percent of cats were shedding FCV, 52% FHV, and 60% FECV after 1 week. More detailed studies were done with FECV shedding, which could be accurately quantitated. The amounts of FECV shed by infected cats ranged from 10(2)to 10(16)particles/swab of feces. FECV shedding was several logs higher in young kittens with primary infection than adult cats with primary infections. The mean levels of FECV shedding among adults were the same for primary and chronic infections. Although shelters were not the primary source of these viruses for many relinquished cats, factors intrinsic to the shelter environment were critical in amplifying shedding and spread to susceptible individuals. Extrinsic factors were especially important for the spread of FHV and FECV. FHV shedding rates increased from 4% to 50% in 1 week's time. The speed and magnitude of the increase in FHV shedding suggested that there was reactivation of latent infections as well as acquisition of new infections. FECV shedding increased 10 to 1,000,000 fold in 1 week among cats that were already infected at entry, and more than one-half of initially negative cats were shedding FECV a week later. Feline calicivirus infection was the least likely to spread in the shelter. The infection rate only increased from 11 to 15% in 1 week.

Animal Husbandry↗

PubMed2003

Evidence for modulated immune response to Anaplasma phagocytophila sensu lato in cats with FIV-induced immunosuppression.

Human granulocytic ehrlichiosis (HGE) is an emerging infectious disease in which some patients experience unusual opportunistic infections. In this study, cats infected with the HGE agent, Anaplasma phagocytophila s.l., had clinical granulocytic ehrlichiosis (GE), anti-nuclear antibodies and increased IFN-gamma mRNA. In FIV-immunosuppressed cats with GE, there was upregulated IL-10 transcription but not IFN-gamma. Cats with FIV had poor response to vaccines, regardless of GE status. This preliminary report demonstrates that cats with FIV-infection make a good model of ehrlichiosis in an immunocompromised host, and that viral immunosuppression may not increase the severity of ehrlichiosis but may attenuate immune responses to the pathogen.

Anaplasma phagocytophilum↗

PubMed2003

Inflammation and changes in cytokine levels in neurological feline infectious peritonitis.

Feline infectious peritonitis (FIP) is a progressive, fatal, predominantly Arthus-type immune-mediated disease that is triggered when cats are infected with a mutant enteric coronavirus. The disease presents variably with multiple organ failure, seizures, generalized effusion, or shock. Neurological FIP is clinically and pathologically more homogeneous than systemic 'wet' or 'dry' FIP; thus, comparison of cytokine profiles from cats with neurological FIP, wet FIP, and non-FIP neurological disease may provide insight into some baseline characteristics relating to the immunopathogenesis of neurological FIP. This study characterizes inflammation and changes in cytokines in the brain tissue of FIP-affected cats. Cellular infiltrates in cats with FIP included lymphocytes, plasma cells, neutrophils, macrophages, and eosinophils. IL-1 beta, IL-6, IL-12, IL-18, TNF-alpha, macrophage inhibitory protein (MIP)-1 alpha, and RANTES showed no upregulation in the brains of control cats, moderate upregulation in neurological FIP cats, and very high upregulation in generalized FIP cats. Transcription of IFN-gamma appeared upregulated in cats with systemic FIP and slightly downregulated in neurological FIP. In most cytokines tested, variance was extremely high in generalized FIP and much less in neurological FIP. Principal components analysis was performed in order to find the least number of 'components' that would summarize the cytokine profiles in cats with neurological FIP. A large component of the variance (91.7%) was accounted for by levels of IL-6, MIP-1 alpha, and RANTES. These findings provide new insight into the immunopathogenesis of FIP and suggest targets for immune therapy of this disease.

Animals↗

PubMed2002

Pharmacologic restoration of the early insulin response in pre-diabetic monkeys controls mealtime glucose excursions without peripheral hyperinsulinaemia.

AIMS/HYPOTHESIS: This study sought first to compare the pharmacodynamics and pharmocokinetics of two rapid-onset, rapidly-reversible insulinotropic agents, nateglinide and repaglinide, in pre-diabetic Cynomolgus monkeys and second to use these agents to assess the metabolic effects of early insulin secretion on prandial glucose control. METHODS: First, equipotent doses of nateglinide (20 mg/kg) and repaglinide (0.1 mg/kg) or vehicle were given intragastrically to overnight-fasted ketamine-anesthetized pre-diabetic Cynomolgus monkeys and samples were obtained for measurement of plasma glucose, insulin, glucagon, NEFA and drug concentrations. Second, nateglinide, repaglinide or vehicle were administered 10 min before a glucose-supplemented liquid meal and prandial glucose and insulin profiles were compared. RESULTS: Although oral administration of nateglinide and repaglinide elicited similar maximum increments of plasma insulin (+403 and +448 pmol/l, respectively), the effects of nateglinide were more rapidly manifest and less prolonged. With nateglinide, insulin increased within 10 min and returned to baseline within 50 min. After repaglinide, the first increase occurred at 30 min and insulin concentrations remained increased for 3.5 h post-dose. When given 10 min before a meal, nateglinide increased early, but not total insulin release (AUC(0-210)=108 vs 150 nmol/l min for nateglinide and vehicle, respectively) and reduced prandial glucose excursions by 78%. Repaglinide increased total insulin release (AUC(0-210)=298 nmol/l min) and reduced glucose excursions by 53%. CONCLUSION/INTERPRETATION: Nateglinide is more rapid-acting and rapidly-reversible than is repaglinide. By restoring a more physiologic insulin profile, nateglinide is more effective than repaglinide in controlling prandial glucose excursions with less hyperinsulinaemia.

Animals↗

PubMed2002

Feline inflammatory polyps: historical, clinical, and PCR findings for feline calici virus and feline herpes virus-1 in 28 cases.

Inflammatory polyps are associated with significant aural or nasopharyngeal disease in cats. It has been proposed that chronic viral infection may induce the masses. Ventral bulla osteotomy (VBO) is usually recommended for definitive therapy but removal of masses from the nasopharynx or external ear canal by traction/avulsion is also used. A retrospective study of 28 cats with inflammatory polyps was conducted to correlate recurrence with mode of therapy. Tissues from 41 polyps were assayed for feline calicivirus and feline herpesvirus-1 by RT-PCR and PCR, respectively. Of the 14 cats initially treated by traction/avulsion, recurrence was detected in five of nine cats with radiographic evidence of bulla disease but none of the cats with normal bullae. Traction/avulsion is a reasonable treatment for inflammatory polyps if the bullae are radiographically normal. Failure to detect feline calicivirus and feline herpesvirus-1 suggests that tissue persistence of these viruses is not associated with the development of inflammatory polyps.

Animals↗

PubMed2002

Clinical, microscopic, and molecular aspects of canine leproid granuloma in the United States.

Leproid granulomas from seven dogs in the United States were evaluated. Gross characteristics included nodular and ulcerated dermal and subcutaneous lesions primarily on the caudal aspects of the pinnae and to a lesser extent on the muzzle, face, and forelimbs. In all except one dog, there was complete regression of the lesions within 6 months, either with no therapy or after surgical resection. Cytology or histopathology revealed pyogranulomatous inflammation with few to many acid-fast mycobacterial bacilli within macrophages. The organisms could not be cultivated in vitro. DNA sequencing of part of the 16S ribosomal RNA gene region revealed 99-100% homology among fragments from five of these dogs and fragments from dogs in the south Pacific. This syndrome occurs in dogs in North America and the prognosis is excellent, in contrast to the prognosis for rapid-growing or tuberculous mycobacteriosis.

Animals↗

PubMed2001

alpha 1(Xx) collagen, a new member of the collagen subfamily, fibril-associated collagens with interrupted triple helices.

Chick cDNA clones for a new member of the FACIT (fibril-associated collagens with interrupted triple helices) subfamily have been isolated and sequenced. The collagen chain encoded by these cDNAs was assigned the next consecutive number, making it the alpha1(XX) collagen chain. Assignment of type XX collagen to the FACIT family was based on sequence similarities to types XII and XIV collagen. Type XX collagen mRNA is not abundant in the chick embryo. It is most prevalent in corneal epithelium. It is also detectable by reverse transcription polymerase chain reaction in embryonic skin, sternal cartilage, and tendon, but is barely detectable in calvaria, notochord, or neural retina at select stages of development, suggesting that it is not expressed in these tissues. The cDNA predicts that the alpha1(XX) collagen polypeptide is smaller than the short forms of collagen XII and XIV. A polyclonal antibody against a synthetic alpha1(XX) peptide reacts with polypeptide bands of 185, 170, and 135 kDa by Western blot analysis. From its similarity to types XII and XIV collagen, type XX is expected to bind to collagen fibrils, projecting the amino-terminal domains away from the fibrillar surface. The projecting NC 3 domains are predicted to be about half the length of those of collagen XIV.

Amino Acid Sequence↗

PubMed2001

Subcutaneous abdominal adipocyte size, a predictor of type 2 diabetes, is linked to chromosome 1q21--q23 and is associated with a common polymorphism in LMNA in Pima Indians.

Large subcutaneous abdominal adipocyte size (s.c. abd. AS) is associated with insulin resistance and predicts type 2 diabetes in Pima Indians. Because type 2 diabetes is familial, we aimed to determine whether mean s.c. abd. AS is also familial and if so, to identify chromosomal regions linked to this measure. Body composition (hydrodensitometry) and mean s.c. abd. AS (fat biopsy) were measured in 295 Pima Indians (179 with normal, 80 with impaired, and 36 with diabetic glucose tolerance) representing 164 nuclear families. Mean s.c. abd. AS, adjusted for age, sex, and percentage body fat was a familial trait (heritability h(2) = 0.48, P < 0.0001). A genome-wide autosomal scan revealed suggestive evidence for linkage (LOD 1.73) of adjusted mean s.c. abd. AS to chromosome 1q21--q23, a region containing LMNA, the gene encoding for the nuclear envelope proteins lamin A/C. Rare mutations in LMNA were recently shown to underlie familial partial lipodystrophy (FPLD), a syndrome characterized by regional loss of adipose tissue, insulin resistance, and glucose intolerance. A common (allelic frequency 0.43) single nucleotide polymorphism (silent 1908C --> T substitution) in exon 10 of LMNA (GenBank X03444) was associated with reduced age-, sex- and percentage body fat-adjusted mean s.c. abd. AS [0.80 +/- 0.17 (CC), 0.76 +/- 0.15 (CT), 0.73 +/- 0.16 (TT) microg lipid/cell, P < 0.05 for CC vs TT]. These findings indicate that approximately half of the variance in mean s.c. abd. AS can be attributed to familial factors and that genetic variation in LMNA might not only underlie rare cases of FPLD, but may also contribute to variation in adipocyte size in the general population.

Adipocytes↗

PubMed2001

Acarologic risk of exposure to emerging tick-borne bacterial pathogens in a semirural community in northern California.

An acarologic study was conducted in a semirural community in northern California to determine the relative abundance of, and the prevalence of infection with, three emerging bacterial pathogens in the western black-legged tick (Ixodes pacificus). These included the agents causing Lyme disease (Borrelia burgdorferi), human granulocytic ehrlichiosis [Ehrlichia phagocytophila (formerly Ehrlichia equi)], and human monocytic ehrlichiosis (Ehrlichia chaffeensis). The study area in Sonoma County consisted of two properties each with four residents and an uninhabited adjacent comparison area. Six of the eight residents had been either physician-diagnosed or serodiagnosed previously with Lyme disease, and, of these, one also had been serodiagnosed with human monocytic ehrlichiosis. Direct immunofluorescent/culture assays and bacterial species-specific polymerase chain reaction assays were used to test whole ticks individually for presence of B. burgdorferi and Ehrlichia spp., respectively. Overall, 6.5% of the nymphal (n = 589) and 1.6% of the adult ticks (n = 318) from the same generational cohort were found to contain B. burgdorferi. In contrast, none of 465 nymphs and 9.9% of 202 adults were infected with E. phagocytophila. Excised tissues from another 95 adult ticks yielded a comparable E. phagocytophila infection prevalence of 13.7%. E. chaffeensis was not detected in either nymphal or adult ticks. Using a combination of culture and polymerase chain reaction assays, coinfection of I. pacificus adults with B. burgdorferi and E. phagocytophila was demonstrated for the first time. The marked disparity in the infection prevalence of these pathogens in nymphal and adult ticks suggests that their maintenance cycles are inherently different.

Anaplasma phagocytophilum↗

PubMed2001

'Candidatus Mycoplasma haemominutum', a low-virulence epierythrocytic parasite of cats.

The phylogenetic position and some taxonomically relevant characteristics of a small, low-virulence bacterial parasite of cats are described. A 16S rDNA analysis revealed that the organism was in the Mycoplasma clade and was most closely related to a parasite of pigs previously designated Eperythrozoon suis. As the organism has not been cultured in vitro and is maintained in serial passage in cats in vivo, Candidatus status is proposed for this novel taxon as 'Candidatus Mycoplasma haemominutum'.

Animals↗

PubMed2001

Aortic valve endocarditis in a dog due to Bartonella clarridgeiae.

We report the first documented case of endocarditis associated with Bartonella clarridgeiae in any species. B. clarridgeiae was identified as a possible etiological agent of human cat scratch disease. Infective vegetative valvular aortic endocarditis was diagnosed in a 2.5-year-old male neutered boxer. Historically, the dog had been diagnosed with a systolic murmur at 16 months of age and underwent balloon valvuloplasty for severe valvular aortic stenosis. Six months later, the dog was brought to a veterinary hospital with an acute third-degree atrioventricular block and was diagnosed with infective endocarditis. The dog died of cardiopulmonary arrest prior to pacemaker implantation. Necropsy confirmed severe aortic vegetative endocarditis. Blood culture grew a fastidious, gram-negative organism 8 days after being plated. Phenotypic and genotypic characterization of the isolate, including partial sequencing of the citrate synthase (gltA) and 16S rRNA genes indicated that this organism was B. clarridgeiae. DNA extraction from the deformed aortic valve and the healthy pulmonic valve revealed the presence of B. clarridgeiae DNA only from the diseased valve. No Borrelia burgdorferi or Ehrlichia sp. DNA could be identified. Using indirect immunofluorescence tests, the dog was seropositive for B. clarridgeiae and had antibodies against Ehrlichia phagocytophila but not against Ehrlichia canis, Ehrlichia ewingii, B. burgdorferi, or Coxiella burnetii.

Animals↗

PubMed2001

Importance of early phase insulin secretion to intravenous glucose tolerance in subjects with type 2 diabetes mellitus.

Insulin secretion is impaired in type 2 diabetes with the early response being essentially absent. The loss of this early insulin secretion is hypothesized to be important in the deterioration of glucose tolerance. To determine whether enhancement of the early-phase insulin response can enhance glucose tolerance, we administered 1) 120 mg nateglinide, an insulinotropic agent that enhances early insulin secretion; 2) 10 mg glyburide, which enhances the later phases of insulin secretion; or 3) placebo in random order to 21 subjects with type 2 diabetes (14 males and 7 females; aged 59.2 +/- 2.1 yr, x +/- SEM; body mass index 29.7 +/- 1.0 kg/m(2); fasting plasma glucose 8.1 +/- 0.1 mM). beta-Cell function was quantified as the incremental area under the curve for different time periods for the 5 h following iv glucose administration and glucose tolerance as the glucose disappearance constant (Kg) from 10 to 60 min. Insulin release commenced immediately after nateglinide administration, even before glucose injection, but this was not observed with glyburide. Both nateglinide and glyburide enhanced glucose-induced insulin release, compared with placebo (area under the curve -15-300 min: nateglinide 23,595 +/- 11,212 pM/min, glyburide 54,556 +/- 15,253 pM/min, placebo 10,242 +/- 2,414 pM/min). The profiles of insulin release demonstrated significant enhancement of release between -15 and 30 min for nateglinide, compared with glyburide and between 60 and 300 min for glyburide over nateglinide. Kg increased by 15% with nateglinide (0.87 +/- 0.04%/min), but it did not increase significantly with glyburide (0.79 +/- 0.04%/min), compared with placebo (0.76 +/- 0.04%/min). The enhancement of insulin release by glyburide resulted in a lower minimal glucose concentration with glyburide (3.8 +/- 0.2 mM), compared with nateglinide (5.0 +/- 0.2 mM) and placebo (5.9 +/- 0.2 mM). Thus, enhancement of the early phase of insulin secretion improves iv glucose tolerance, whereas delaying it by 30 min results in a slower rate of glucose disappearance for the first 2 h after iv glucose administration. Further, the differences in the kinetics of nateglinide and glyburide action results in continued insulin release with glyburide despite the fact that glucose levels have returned to basal, thus resulting in a further reduction in glucose levels and a lower nadir.

Aged↗

PubMed2001

Rapid acting insulinotropic agents: restoration of early insulin secretion as a physiologic approach to improve glucose control.

The loss of early insulin secretion appears to be a critical event in the deterioration in glucose tolerance during the development of type 2 diabetes. There is therefore a strong rationale for developing new antidiabetic agents aimed at restoring or replacing early prandial insulin secretion and thereby curbing mealtime glucose excursions in patients with type 2 diabetes. Four such new agents are either now available (repaglinide and nateglinide) or in clinical development (KAD-1229 and BTS 67 582). Preclinical studies suggest that each of these new insulinotropic agents share a common receptor/effector mechanism with the sulfonylureas (SUs) but that each may have distinct characteristics that differentiate them from the SUs and from each other. Nateglinide and KAD-1229 clearly stimulate biphasic insulin secretion in vitro and in vivo and their effects are rapidly reversible, whereas the effects of repaglinide and BTS 67 582 are prolonged well beyond their removal from perfusion media in vitro or their clearance in vivo. Available data from human studies indicate that the pharmacokinetics of repaglinide and nateglinide are similar, i.e., they are both rapidly absorbed and eliminated, but consistent with findings from animal studies, the insulinotropic and glucose-lowering effects of repaglinide are slower in onset and more prolonged than those of nateglinide. Repaglinide and nateglinide have been shown to be safe and well-tolerated in patients with type 2 diabetes and to produce clinically-meaningful reductions of HbA1c, both alone and in combination with agents with complementary modes of action (e.g., metformin and thiazolidinediones). Because these new agents can potentially bring patients to near normoglycemia without an undue risk of hypoglycemia, they are important additions to the therapeutic armamentarium.

Animals↗