Plasma Immunoreactive Insulin Research Articles

Effect of broth from meat of linseed-fed cattle on glucose-stimulated insulin release in healthy male volunteers.

Polyunsaturated fatty acid consumption has been shown to improve insulin sensitivity. We studied if administration of broth with beef meat enriched with polyunsaturated fatty acids influenced glucose-stimulated insulin release in healthy male volunteers. Broth was made either from cattles undergone dietary supplementation with lightly bruised whole linseed in addition to feeding ad libitum on grass silage (test meal) or from those fed grass silage alone (control meal). Oral glucose tolerance tests (OGTT) were performed in patients after a 6-day period of eating 300ml broth containing 100g meat once a day in addition to their otherwise normal mixed nourishment. During OGTT, blood samples were taken for blood glucose level and plasma insulin immunoreactivity before and 15, 30, 60, 90, 120, and 180min after the glucose load. Glucose-stimulated maximum increase in plasma insulin immunoreactivity was 42±6.6 and 81±7.4mU/ml (p<0.05) after the test and the control meals, respectively. However, both fasting and postload blood glucose levels were the same after either meal period. The results suggest an insulin-sensitizing effect of food produced from beef cattle maintained on linseed diet in healthy human volunteers.

MICROCIRCULATORY DISORDERS IN WOMEN WITH POLYCYSTIC OVARY SYNDROME

: It is believed that microvascular dysfunction plays a major role in the development of insulin resistance (IR). Performing nailfold capillaroscopy wit­h evaluation of microvascular parameters in women with polycystic ovary syndrome (PCOS) would undoubtedly be helpful for the investigation of novel pathophysiological mechanisms in IR occurrence. The aim of the present study was to compare the values of microvascular parameters between PCOS patients and clinically healthy women and to assess its relationship with clinical and metabolic parameters in the PCOS women. Our study included 21 PCOS patients and 22 clinically healthy women (controls). Nailfold capillaroscopy was conducted and the following parameters were assessed: arterial limb diameter (d art), venous limb diameter (d ven), top diameter of loops (top d), length of loops, d art/d ven ratio, d ven/d art ratio, number of capillary loops (n cap), number of abnormal loops (% abn cap) and a presence of perivascular diapedesis. Weight, height, fasting plasma glucose (FPG), immunoreactive insulin (IRI), lipid parameters, total testosterone, systolic (SBP) and diastolic blood pressure (DBP) were measured in the PCOS women. Body mass index (BMI) and homeostasis model of insulin resistance index (HOMA-IR) were calculated. We found significantly higher values of age, BMI and % abn cap in the women with PCOS as compared to the controls. Interestingly, % abn cap showed a negative correlation with age. Furthermore, an inverse association between top d and the values of SBP and DBP was established. We determined a positive correlation between the presence of perivascular diapedesis and the values of FPG, HOMA-IR and testosterone. As a conclusion, the higher % abn cap in the PCOS women might be an early pathophysiological sign of microvascular dysfunction. The positive correlation between perivascular diapedesis and the degree of IR, hyperglycemia, and hyperandrogenemia shows the existence of a chronic low-grade inflammatory process in PCOS.

Association between Perinatal Status and Insulin Resistance in Neonates during the Birth Period

The aim of this study was to assess the association between perinatal status and insulin resistance in neonates during the birth period. The subjects were 49 neonates (27 boys, 22 girls) who had been admitted to the neonatal intensive care unit at Nihon University Itabashi Hospital within 2 h after birth. We retrospectively analyzed the associations between perinatal status (Apgar score, sex, gestational age, birth weight, etc.) and insulin resistance (assessed by plasma immunoreactive insulin (IRI), plasma cortisol, homeostatic model analysis ratio (HOMA-R), quantitative insulin sensitivity check index (QUICKI), plasma glucose/IRI ratio, and plasma IRI/cortisol ratio) based on the medical records. The preterm neonates had significantly lower plasma cortisol levels (P = 0.02) and significantly higher plasma IRI/cortisol ratios (P = 0.04) compared with the full-term neonates. No significant differences were found in any of the parameters between neonates with asphyxia and those without. In cases with hyperinsulinemia, male predominance was significant (P < 0.01) in neonates with hypoglycemia; furthermore, birth weight, HOMA-R, and plasma glucose/IRI ratio tended to be lower (P = 0.07, P = 0.01 and P < 0.01, respectively), while QUICKI and plasma IRI/cortisol ratio tended to be higher (P = 0.02 and P = 0.09, respectively) in neonates with hypoglycemia compared with those without. One possible reason for these findings could be the immaturity of the hypothalamic-pituitary-adrenal axis in preterm infants. There was no significant correlation between perinatal status and the indices of insulin resistance in neonates during the birth period.

Effects of ezetimibe on atherogenic lipoproteins and glucose metabolism in patients with diabetes and glucose intolerance

AimTo evaluate the effects of ezetimibe on atherogenic lipoproteins and glucose metabolism in patients with diabetes and glucose intolerance. MethodsSeventy-six patients with diabetes and glucose intolerance were enrolled in this study. At baseline and 12 weeks after treatment with ezetimibe 10mg/day, we measured the levels of lipid and glucose parameters. ResultsEzetimibe reduced the mean levels of low-density lipoprotein cholesterol (LDL-C) (−20%, P<0.001), remnant-like particle cholesterol (−22%, P<0.001), small dense-LDL (−19%, P<0.001), apolipoprotein B-48 (−2%, P<0.01), malondialdehyde modified-LDL (−15%, P<0.001), and serum immunoreactive insulin (IRI) (−4%, P<0.01). In the insulin resistance subgroup, ezetimibe reduced the abdominal circumference (−1%, P<0.05) and mean levels of fasting plasma glucose (−7%, P<0.05), IRI (−36%, P<0.01), s-CPR (−27%, P<0.01), HOMA-IR (−39%, P<0.01) and HbA1c tended to decrease (−2%, P=0.06). ConclusionsEzetimibe reduced atherogenic lipoproteins in patients with diabetes and glucose intolerance; besides, it improved glucose metabolism in patients with insulin resistance.

Insulin resistance at diagnosis in Japanese children with type 2 diabetes mellitus

Insulin resistance at diagnosis was investigated in Japanese children with type 2 diabetes mellitus (T2DM). A total of 160 children with T2DM were divided into groups on the basis of percent overweight at time of diagnosis: group A (n = 28), <20%; group B (n = 55), 20-39%; group C (n = 37), 40-59%; group D (n = 40), ≥ 60%. Indicators of insulin resistance at diagnosis were compared among the four patient groups, and also between the children with T2DM and the 201 age-matched normal Japanese children. There were no significant differences in plasma glucose (PG) levels among the four patient groups. The mean concentration of fasting plasma immunoreactive insulin (IRI) was significantly higher in group D than in groups A and B (39.2 µU/mL vs 16.2 µU/mL and 24.1 µU/mL, P < 0.05, respectively). The mean homeostasis model assessment (HOMA-R) was significantly higher in group D than in all the other three groups (17.6 vs 7.8, 10.8 and 12.7, P < 0.05, respectively). The indicators HOMA-R and fasting IRI were significantly higher in each diabetes group, even in non-obese group A, than in normal children (P < 0.01, respectively). Japanese children with T2DM had insulin resistance at diagnosis regardless of percent overweight, and the degree of insulin resistance gradually increased with rise in percent overweight.

Abstract 2986: Bilateral Thalamic Lesions in Subcortical Vascular Dementia

Subcortical vascular dementia (SVaD) is categorized to the group of dementia due to the small-vessel disease which consists of lacunar infarcts, microbleeds and leuko-araiosis. However, the causative lesions and their relationship have not been clarified yet in SVaD. In order to elucidate the pathophysiology underlying SVaD, MR findings and vascular risk factors were analyzed in 31 patients (25 men and 6 women) who were diagnosed as having SVaD based on the NINDS-AIREN criteria. Their mean age was 75.7 years. Thirty-six non-demented patients with asymptomatic cerebral infarction (ACI) and 49 non-demented patients with symptomatic lacunar infarcts (SCI) served as disease controls. All subjects underwent 1.5 Tesla MRI including T1WI, T2WI, T2*WI, FLAIR and MR angiography. Numbers of lacunar infarcts and old microbleeds were counted in all MR slices, and the degree of leuko-araiosis was evaluated according the Fazekas’ categories. Laboratory studies included fibrinogen, d-dimer, serum lipid profile, glucose, plasma immunoreactive insulin (IRI) and brain natriuretic peptide (BNP). In the neuropsychological evaluation, MMSE, clock drawing test (CDT) and Benton’s visual retention test (BVRT) were carried out. In the results, the mean MMSE score was 13.0, and the mean CDT was 2.7/5.0. In the MR findings, the mean number of lacunar infarcts was 11.4, 15.2 and 17.2 for ACI, SCI and SVaD group, respectively. Thalamic lesions were detected in 30 (96.8%) of 31 SVaD patients, and 86.6% were lacunar infarcts whereas 13.3% were microbleeds on T2*WI. Bilateral thalamic lesions were detected in 66.7%, and the right-side and left-side lesions were seen in 16.6%, respectively. Antero-medial thalamic lesion was detected in 23.3%. No bilateral thalamic lesions were found in ACI or SCI group. Microbleeds were detected in 90% of SVaD patients. The mean number of microbleeds was 1.3, 2.1 and 5.8 for ACI, SCI and SVaD group, respectively. In the laboratory studies, the mean fibrinogen was significantly greater in SVaD group than in ACI or SCI group. The mean insulin was significantly greater in SVaD group than in ACI and SCI group. Advanced leuko-araiosis (Grade II and III) was seen in 87.1% of SVaD patients, whereas 52.8% of ACI patients and 34.7% of SCI patients. In the laboratory studies, the mean fibrinogen, IRI and BNP were significantly greater in SVaD group than in ACI or SCI group (p&lt;0.05). The mean ratio of LDL-cholesterol to HDL-cholesterol was significantly greater in SVaD and SCI groups than in ACI group (p&lt;0.05). In the present results, thalamic lesions, especially bilateral thalamic lesions, were detected frequently in SVaD patients. As thalamus plays an important role in both medial limbic and basolateral limbic systems which mediate cognitive information processing including memory and emotion, thalamic lesions may redound to the formation of SVaD.

Comparison of vildagliptin twice daily vs. sitagliptin once daily using continuous glucose monitoring (CGM): Crossover pilot study (J-VICTORIA study)

BackgroundNo previous studies have compared the DPP-4 inhibitors vildagliptin and sitagliptin in terms of blood glucose levels using continuous glucose monitoring (CGM) and cardiovascular parameters.MethodsTwenty patients with type 2 diabetes mellitus were randomly allocated to groups who received vildagliptin then sitagliptin, or vice versa. Patients were hospitalized at 1 month after starting each drug, and CGM was used to determine: 1) mean (± standard deviation) 24-hour blood glucose level, 2) mean amplitude of glycemic excursions (MAGE), 3) fasting blood glucose level, 4) highest postprandial blood glucose level and time, 5) increase in blood glucose level after each meal, 6) area under the curve (AUC) for blood glucose level ≥180 mg/dL within 3 hours after each meal, and 7) area over the curve (AOC) for daily blood glucose level <70 mg/dL. Plasma glycosylated hemoglobin (HbA1c), glycoalbumin (GA), 1,5-anhydroglucitol (1,5AG), immunoreactive insulin (IRI), C-peptide immunoreactivity (CPR), brain natriuretic peptide (BNP), and plasminogen activator inhibitor-1 (PAI-1) levels, and urinary CPR levels, were measured.ResultsThe mean 24-hour blood glucose level was significantly lower in patients taking vildagliptin than sitagliptin (142.1 ± 35.5 vs. 153.2 ± 37.0 mg/dL; p = 0.012). In patients taking vildagliptin, MAGE was significantly lower (110.5 ± 33.5 vs. 129.4 ± 45.1 mg/dL; p = 0.040), the highest blood glucose level after supper was significantly lower (206.1 ± 40.2 vs. 223.2 ± 43.5 mg/dL; p = 0.015), the AUC (≥180 mg/dL) within 3 h was significantly lower after breakfast (484.3 vs. 897.9 mg/min/dL; p = 0.025), and urinary CPR level was significantly higher (97.0 ± 41.6 vs. 85.2 ± 39.9 μg/day; p = 0.008) than in patients taking sitagliptin. There were no significant differences in plasma HbA1c, GA, 1,5AG, IRI, CPR, BNP, or PAI-1 levels between patients taking vildagliptin and sitagliptin.ConclusionsCGM showed that mean 24-h blood glucose, MAGE, highest blood glucose level after supper, and hyperglycemia after breakfast were significantly lower in patients with type 2 diabetes mellitus taking vildagliptin than those taking sitagliptin. There were no significant differences in BNP and PAI-1 levels between patients taking vildagliptin and sitagliptin.Trial registrationUMIN000007687

202: The association between maternal insulin resistance in mid pregnancy and neonatal birth weight in uncomplicated pregnancies

resistance in mid pregnancy and neonatal birth weight in uncomplicated pregnancies Hiroshi Yamashita, Masashi Fukuda, Yukari Kugishima, Yuki Yamauchi, Akiko Kuzume, Takashi Hashimoto, So Sugimi, Naoko Yatsunami, Sachie Suga, Nobuko Kusuda, Ichiro Yasuhi Nagasaki Medical Center, Obstetrics and Gynecology, Omura-city, Japan OBJECTIVE: The purpose of this study was to determine whether maternal insulin resistance measured by homeostasis model assessmentinsulin resistance (HOMA-IR) in mid pregnancy is associated with neonatal birth weight in uncomplicated pregnancies. STUDY DESIGN: We included singleton pregnant women who had a 75g oral glucose tolerance test (OGTT) during mid pregnancy because of a positive gestational diabetes (GDM) screen. We measured HOMA-IR derived from fasting plasma glucose and immuno-reactive insulin concentration at OGTT. Women with GDM, hypertension, or fetal malformation were excluded. Using multiple and logistic regression analysis to adjust for confounding variables including maternal age, prepregnancy body mass index (BMI), plasma glucose levels at OGTT, and gestational age (GA) at delivery, we tested the relation of mid pregnancy maternal HOMA-IR to neonatal birth weight and large for GA (LGA) infants. RESULTS: We included 557 Japanese pregnant women. The mean maternal age, prepregnancy BMI, GA at OGTT, and HOMA-IR, GA at delivery, and birth weight were 31.8 / 5.0 years, 22.0 / 3.7 kg/ m2, 30.5 / 4.0 weeks, and 1.46 / 0.8, 39.0 / 1.7 weeks, and 3,030 / 470 g, respectively. HOMA-IR was positively associated with birth weight after controlling confounding variables (p .05). Higher HOMA-IR was significantly associated with an increased incidence of LGA infants (n 38) with the adjusted odds ratio of 1.71 per one unit of HOMA-IR (95% confidence interval, 1.11-2.66). CONCLUSION: Our findings suggest that the degree of maternal insulin resistance measured by HOMA-IR during mid pregnancy is associated with birth weight in uncomplicated pregnancies. Mid pregnancy HOMA-IR could be a predictor of fetal overgrowth, independent of maternal glucose levels and obesity.

Diagnosis and Treatment of Diabetic Patients Requiring Insulin Who Repeatedly Manifest Hyperglycemia and Hypoglycemia Due to Anti-Insulin Antibodies

A lthough anti-insulin antibodies (IAs) are often observed in patients treated with general regimens of insulin, their existence is not thought to be related to hypoglycemia.1 However, IA-positive patients treated with human insulin may manifest unexplainable hypoglycemia.2–5 The IAs of these patients have a lower affinity and a higher binding capacity than those from patients with insulin autoimmune syndrome (IAS)6 or those who do not develop hypoglycemia when treated with insulin. Ceasing insulin administration2 and switching to insulin analogs,3 steroid therapy,4 or double filtration plasmapheresis (DFPP)5 are all therapies that have been advocated to treat such patients. Recently, we described analog insulin-receiving patients who developed severe daytime hyperglycemia and morning hypoglycemia associated with IA formation.7 Such cases seem to be augmenting with the spread of insulin analog treatment, and, unfortunately, they did not appear to respond well to the aforementioned therapies. Thus, we set out to define the clinical characteristics of these patients who generated IAs and manifested unexplainable fluctuations in blood glucose levels while receiving insulin analogs and to determine how best to treat them. The characteristics of six insulin-treated patients with IAs who repeatedly manifested unexplainable hyperglycemia and hypoglycemia (Group D) were investigated. They were compared with the same features in six patients seen to have IAs when a cohort of 100 insulin-treated patients without unexplainable hyperglycemia or hypoglycemia were screened randomly (Group B), three patients with IAS (Group A), and three insulin-treated patients with IAs who did not manifest hyperglycemia but occasionally developed inexplicable hypoglycemia (Group C). The binding capacity and affinity of the IAs were compared between the groups using Scatchard plots. Plasma immunoreactive insulin (IRI) and plasma free insulin were measured at the time of hyperglycemia or hypoglycemia. In addition, the clinical course of …

Lack of effect of BW755c on glucose-induced insulin secretion in the rat in-vivo.

Glucose-induced elevations in plasma immunoreactive insulin (IRI) were examined in anaesthetized rats pretreated with BW755c, sodium meclofenamate or vehicle. Neither drug influenced the glucose-induced hyperinsulinaemia or the glucose disappearance rate. The results do not support a physiological role for arachidonic acid metabolites in the regulation of glucose-induced insulin secretion.

Rectal absorption of insulin suppositories in rabbits.

When insulin solutions (100 U kg-1) at various pH values were placed in the rectum of rabbits, a large decrease in blood glucose concentration was observed except at the pH close to the iso-electric point of insulin. The effect of surface-active agents on the rectal absorption of insulin was examined by measuring the blood glucose concentration after the administration of 2 or 5 U kg-1. Non-ionic ether type, anionic, cationic and amphoteric surfactants as well as bile acids increased the absorption. The optimal effect with suppositories was reached with the addition of 1% polyoxyethylene (9) lauryl alcohol ether. Insulin suppositories containing agents enhancing rectal absorption were compared with the insulin for intravenous, intramuscular and subcutaneous injection. The changes of blood glucose and plasma immuno-reactive insulin concentration after rectal administration of insulin were similar to those after intravenous injection.

Effect of addition of hyaluronic acid to highly concentrated insulin on absorption from the conjunctiva in conscious diabetic dogs.

Insulin absorption from the conjunctiva was investigated in five pancreatectomized diabetic mongrel dogs, with the nasolacrimal ducts occluded by micro plugs to prevent insulin absorption from nasolacrimal membrane. In the anaesthetized state, highly concentrated porcine insulin (1000 units mL-1, pH 7.4) was absorbed rapidly and significantly from the conjunctiva. Plasma immunoreactive insulin concentrations increased significantly up to 3 h after insulin administration to conjunctival membranes. Plasma glucose concentration decreased significantly compared with saline control experiments after insulin administration (10 units kg-1) at 3 h (8.3 +/- 0.1 vs 15.6 +/- 0.6 mmol, P < 0.01). However, in the conscious state, there was no significant increase in the plasma insulin levels after topical insulin administration. To improve insulin absorption in the conscious state, we examined the effect of increasing viscosity of insulin preparation with hyaluronic acid. In anaesthetized experiments, there were no significant changes in the bioavailability of insulin after addition of hyaluronate (0.84 +/- 0.11 vs 0.87 +/- 0.05%). In the conscious state, with addition of hyaluronic acid, the area under the curve of plasma insulin concentration was significantly increased (1842 +/- 383 vs 75 +/- 24 m units min L-1, P < 0.01). The bioavailability of insulin absorption was significantly increased after addition of hyaluronate (0.68 +/- 0.14 vs 0.03 +/- 0.01%, P < 0.01). From this study we could demonstrate that the conjunctiva is a potential route for insulin administration, and increased viscosity by the addition of hyaluronate was found effective in increasing the bioavailability of insulin absorption from conjunctival membrane in the conscious state.

Angiotensin II type 1 receptor blockers improve insulin sensitivity in patients with schizophrenia being treated with olanzapine

Olanzapine (OLZ) is known to cause weight gain and metabolic disturbances, which may have serious implications with respect to medical comorbidities such as metabolic syndrome and insulin resistance. The aim of this study was to evaluate the effects of two angiotensin II type 1 receptor blockers (ARBs) which are widely used as antihypertensive agents, valsartan (VAL) and telmisartan (TEL), on insulin resistance in patients with schizophrenia treated with OLZ. Thirty inpatients with schizophrenia with OLZ monotherapy over 8 weeks participated in this study. To assess insulin resistance, the homeostasis model assessment of insulin resistance (HOMA-IR), fasting plasma glucose (PG) levels and immunoreactive insulin (IRI) levels were measured [HOMA-IR = fasting PG level (mmol/L) x fasting IRI level (μU/ml)/22.5]. VAL add-on treatment was performed in insulin-resistant patients (HOMA-IR > 1.6) for 12 weeks. After a 12-week VAL washout period, TEL add-on treatment was carried out for 12 weeks. The effects of ARBs on insulin resistance and other metabolic variables were assessed. In all 30 patients, both body mass index and abdominal circumference were strongly correlated with HOMA-IR. Twelve patients showed high HOMA-IR and were deemed to be insulin resistant. Add-on therapy of VAL and TEL resulted in a significant decrease in fasting IRI levels and HOMA-IR. No differences in any effects were observed between VAL and TEL. No adverse effects of either ARBs were observed in this study. ARBs for patients treated with OLZ improved insulin sensitivity and attenuated insulin resistance.

Involvement of cholecystokinin in baseline and post-prandial whole body insulin sensitivity in rats

The objective of the study was to investigate the role of cholecystokinin (CCK) on the food-induced insulin sensitization phenomenon in healthy Long Evans Tokushima Otsuka (LETO) and Otsuka Long Evans Tokushima Fatty (OLETF) rats. Whole body insulin sensitivity determined by hyperinsulinaemic euglycaemic glucose clamping and the rapid insulin sensitivity test served as endpoints. Determinations were done in both fasted and re-fed animals. The involvement of CCK in post-prandial insulin sensitization was assessed by using proglumide, a CCK receptor blocker, by assessment of hypothalamic CCK-1/CCK-2 receptor expression by rt-PCR technique and by plasma insulin immunoreactivity determinations by means of radioimmunoassay as pharmacological, genetic and analytical approaches, respectively. The body weight of the OLETF rats and the amount of food consumed much exceeded those seen with LETO rats. The post-prandial increase in insulin sensitivity was marked in LETO, but not in OLETF rats. Intravenous proglumide attenuated post-prandial insulin sensitivity in LETO rats, with no effect in OLETF rats. Nevertheless, baseline insulin sensitivity was much lower in OLETF than in LETO rats. Treatment with rosiglitazone increased baseline insulin sensitivity of OLETF rats and evoked an increase in CCK-1 receptor gene expression in LETO rats. The results provide evidence for the involvement of CCK receptors in adjustment of both fasting and post-prandial insulin sensitivity. The data obtained with OLETF rats strongly suggest the predominant role of CCK-1 receptors.

Improvement of subcutaneous bioavailability of insulin by sulphobutyl ether beta-cyclodextrin in rats.

The objective of this study was to examine and compare how hydrophilic beta-cyclodextrin derivatives (beta-CyDs) improve the bioavailability of insulin following subcutaneous injection of insulin solution in rats. When insulin solutions in the absence of beta-CyDs were injected into the dorsal subcutaneous tissues of rats, the absolute bioavailability of insulin calculated from plasma immunoreactive insulin (IRI) levels was approximately 50%. When maltosyl-beta-cyclodextrin was added to the solutions, there was no change in the plasma IRI levels and hypoglycaemia compared with those of the insulin-alone solution. Dimethyl-beta-cyclodextrin decreased the bioavailability of insulin, although it increased the maximal concentration of IRI in plasma and the capillary permeability of the fluorescein isothiocyanatedextran 40, a non-degraded permeation marker. When insulin solutions containing sulphobutyl ether-beta-cyclodextrin with a degree of substitution of the sulphobutyl group of 3.9 (SBE4-beta-CyD) were injected, the IRI level rapidly increased and maintained higher IRI levels for at least 8 h. The bioavailability of the insulin/SBE4-beta-CyD system was about twice that of insulin alone and approached 96%. The enhancing effects of SBE4-beta-CyD may be in part due to the inhibitory effects of SBE4-beta-CyDs on the enzymatic degradation and/or the adsorption of insulin onto the subcutaneous tissue at the injection site, although this does not apparently facilitate capillary permeability. These results suggest that SBE4-beta-CyD in aqueous insulin injection for subcutaneous administration is useful for improving the bioavailability and the hence the pharmacological effects of insulin.

Pharmacokinetic-pharmacodynamic modelling of human insulin: validity of pharmacological availability as a substitute for extent of bioavailability.

A method for assessing the extent of bioavailability (EBA) of human insulin from pharmacological data was determined. The time course governing increases in the plasma concentration of immuno-reactive insulin (IRI), as well as its pharmacological effects (glucodynamics), was determined after the intravascular administration of varying doses of human insulin. Pharmacokinetic (PK), pharmacodynamic (PD), and link models were constructed to elucidate the quantitative relationship between plasma IRI levels and pharmacological effects. After extravascular administration of the test formulation, only the time course governing the observed pharmacological effects was determined. The pharmacological data was translated into theoretical plasma concentration data, using the PK-PD model. Following this, the area under the theoretical plasma concentration-time curve (AUC) of the test formulation was calculated. The EBA was then estimated against a reference (intravascular) formulation, using a conventional equation. Since the pharmacological effects of insulin were observed to be highly dosing-rate-dependent, the PD model used in this study was modified to apply over a wide range of infusion rates. The results of the PK-PD analysis indicate that the doses administered can be accurately predicted from pharmacological data. To validate this method, the EBAs of controlled release formulations (the Osmotic Mini Pumps) of insulin, subcutaneously administered to the rat, were estimated. The EBA values obtained (92-96%) fell within a reasonable range. The area under the effect-time curves (AUE) obtained following subcutaneous applications of the Osmotic Mini Pump were calculated in a model-independent manner, in addition to pharmacological availabilities (PA), which were estimated against the reference (intravascular) formulations. The estimated PA values varied from 312% to 78%, in accordance with the intravascular input rates of the reference formulations. This indicates that PA should not be used as a substitute for EBA, unless data involving similar intravascular dosing rates to that of the reference formulations is available.

Association of gene polymorphism of the fat-mass and obesity-associated gene with insulin resistance in Japanese

It was reported that gene polymorphisms in the fat-mass and obesity-associated gene (FTO) were associated with obesity and diabetes in several genome-wide association studies. A recent report indicated that FTO-knockout mice exhibited phenotypes of skinny body shape and normal metabolic profiles. Thus, FTO could be important in metabolic disorders. The aim of this study was to clarify the role of single nucleotide polymorphisms (SNPs) in FTO in metabolic disorders such as hypertension, obesity, diabetes, dyslipidemia, insulin resistance and metabolic syndrome in the Japanese general population using data from a cohort study in Hokkaido, namely the Tanno-Sobetsu study. Written informed consent for the genetic analysis was obtained from each subject participating in the study. A total of 1514 subjects were genotyped by TaqMan PCR methods for three SNPs, rs9939609, rs1121980 and rs1558902, in FTO. Association analyses between the SNPs and metabolic parameters were performed. Although two SNPs, rs9939609 and rs1558902, were not significantly associated with hypertension, obesity, metabolic syndrome or any metabolic parameters, additive and recessive models of rs1121980 were strongly associated with plasma immunoreactive insulin (IRI) level and homeostasis model assessment insulin resistance (HOMA-IR), even after adjusting for confounding factors such as age, gender and body mass index. A haplotype of three SNPs was also significantly associated with IRI and HOMA-IR. One SNP, rs1121980, and a haplotype of three SNPs in FTO that contains this SNP, might be important in the progression of insulin resistance in Japanese subjects.

Perinatal Hyperinsulinism and Perinatal Obesity as Risk Factors for Hyperinsulinaemia in Later Life

In the offspring of gestational or long-term diabetic mothers the following findings were obtained: (1) Immunoreactive plasma insulin levels on the first day of life were weakly correlated to the thickness of the skin-fold at the neck on the third day of life (n = 82; r = 0.27; P less than 0.05). (2) A significant correlation was found between the plasma insulin levels at birth and the basal as well as the maximal plasma insulin values after glucose loading (1.75 g/kg b. wt.) at 2 years of age (for basal values: n = 25; r = 0.53; P less than 0.01; and for maximal values: n = 21; r = 0.63; P less than 0.01). (3) A highly significant correlation was even observed between the thickness of the neck-fold at 3 days of age and the fasting plasma insulin levels at 3-8 years of age (n = 26; r = 0.61; P less than 0.001). These findings suggest that perinatal hyperinsulinism and perinatal obesity, induced by maternal hyperglycaemia and/or overnutrition during pregnancy, are risk factors for persistent hyperinsulinaemia predisposing to diabetes mellitus and cardiovascular disease in later life.

Glucose tolerance in amyotrophic lateral sclerosis.

Blood glucose and plasma insulin during an oral glucose tolerance test were determined in 21 patients with amyotrophic lateral sclerosis and in 10 control patients matched for age, obesity and physical activity. In addition, 125I-insulin binding to circulating erythrocytes were studied in a subgroup of 4 ALS patients and 8 controls. Both impaired glucose tolerance and diabetes mellitus were evenly distributed between the study groups, and no difference in mean blood glucose levels during the OGTT was found between ALS and control patients. Fasting plasma immunoreactive insulin concentration was significantly higher in ALS patients as compared to controls, but plasma IRI increments to the glycemic stimulus were similar in the 2 groups. The number of insulin binding sites per cell appeared lower in patients with ALS, but the difference in receptor concentration was not statistically significant. In addition, the specific bound fraction of 125I-insulin showed no difference between ALS and control patients. In conclusion, we were unable to demonstrate any marked deterioration of glucose tolerance or increase in insulin resistance in patients with ALS.

Effect of diazoxide on golden hamsters with chronic hypoglycemia due to a transplantable islet-cell tumor.

The development of the transplantable islet-cell tumor in the golden hamster induces, within six to eight weeks, a severe fasting hypoglycemia and a significant increase in the circulating levels of plasma insulin. The chronic oral administration of diazoxide (250 mg/kg/day) induces a significant increase in blood sugar in fed animals. The elevation of blood sugar is not significant in overnight-fasted animals. The diazoxide-induced hyperglycemia is not accompanied by any reduction in plasma insulin level. The acute intraperitoneal infection of diazoxide (100 mg/kg) markedly increases blood glucose in normal overnight-fasted hamsters; concomitantly, circulating plasma insulin levels are significantly reduced. In the overnight-fasted tumor-bearing animals, the acute injection of diazoxide induces a rise in blood sugar usually accompanied by a paradoxical rise in plasma immunoreactive insulin. Neither depletion of the catecholamine stores by previous administration of reserpine nor β-receptor blockade by propranolol administration can suppress the hyperglycemic response to the acute injection of diazoxide. These data clearly indicate that, in hamster bearing the transplantable islet-cell tumor, the hyperglycemic action of diazoxide does not result from an inhibition of insulin secretion and strongly suggest that this effect is independent of catecholamine release. This conclusion is supported by the lack of effect of diazoxide on both tumor and adrenal catecholamine content.