Serum Immunoreactive Insulin Research Articles

A Non-Obese Hyperglycemic Mouse Model that Develops after Birth with Low Birthweight.

The number of low birthweight (LBW) infants weighing below 2500 g has not decreased in Japan. This study aimed to develop an adult non-obese hyperglycemic mouse model born with LBW to study the pathogenesis. At 16.5 days of gestation, transient intrauterine ischemia (blocked blood flow in both uterine arteries for 15 min) was performed in a subgroup of pregnant mice (group I). Non-occluded dams were used as sham controls (group C). After birth, female pups in each group were weaned at 4 weeks of age and reared on the normal diet until 8 weeks of age (n = 7). Fasting blood glucose levels, serum immunoreactive insulin (IRI), and body composition were then measured. Metabolite analyses was performed on the liver tissues. Birthweight was significantly lower in group I compared with group C. Pups from group I remained underweight with low fat-free mass and showed hyperglycemia with high serum IRI and homeostasis model assessment of insulin resistance levels, indicating insulin resistance. Metabolite analyses showed significantly reduced adenosine triphosphate and nicotinamide adenine dinucleotide production and increased lactic acid in group I. The pathogenesis of our non-obese hyperglycemic mouse model may be due to increased myogenic insulin resistance based on mitochondrial dysfunction and reduced lean body mass.

Association of Flow Parameters and Diameter in the Common Carotid Artery with Impaired Glucose Metabolism.

Aim: Diameter, intima–media thickness (IMT), and flow parameters, including resistance index (RI) and pulsatility index (PI), in the common carotid artery (CCA) are markers of arterial remodeling, atherosclerosis, and vascular resistance, respectively. We investigated the differences among these markers in association with plasma glucose level, serum insulin level, and insulin resistance in participants without cardiovascular disease. Methods: CCA parameters (including the CCA interadventitial diameter and mean IMT at the time of 75-g oral glucose tolerance testing) were assessed in 4218 participants. RI and PI were assessed in 3380 of these participants. To assess plasma glucose and serum immunoreactive insulin profiles during oral glucose tolerance testing, we used the total areas under the curves (AUCglu and AUCins, respectively). We used the homeostasis model assessment of insulin resistance (HOMA-IR) and the Matsuda index to assess insulin resistance. Insulin secretion was assessed with the HOMA-β. Results: AUCglu was significantly associated with CCA interadventitial diameter (β=0.048,P＜0.001), RI (β=0.144,P＜0.001), and PI (β=0.103,P＜0.001) but not with mean IMT. AUCins (β=−0.064,P＜0.001) and HOMA-β (β=−0.054,P＜0.001) were significantly and negatively associated with CCA interadventitial diameter, but not with mean IMT. Both HOMA-IR and Matsuda index were significantly associated with RI and PI. Conclusions: These findings indicate that all CCA parameters except IMT are associated with impaired glucose metabolism in patients without cardiovascular disease.

Вплив гіпоандрогенемії на складові метаболічного синдрому в підлітків із затримкою статевого розвитку

Мета — дослідити вплив гіпоандрогенемії (ГА) на формування компонентів метаболічного синдрому (МС) у хлопців із затримкою статевого розвитку. Матеріал і методи. Комплексне дослідження проведено у 55 хлопців 14-18 років із клінічними ознаками затримки статевого розвитку та лабораторно підтвердженим зниженим рівнем тестостерону (<12,0 нмоль/л) (основна група). Групу порівняння становили 44 практично здорових однолітки із нормальним рівнем статевого дозрівання. Оцінювали статевий та фізичний розвиток хлопців. Визначали рівні загального тестостерону (ЗТ) та естрадіолу (Е 2), сексстероїдзв’язуючого глобуліну (СЗГ), загального холестерину (ЗХС), тригліцеридів (ТГ), холестерину ліпопротеїдів високої щільності (ХС ЛПВЩ), рівень натще глюкози та імунореактивного інсуліну в сироватці крові. Розраховували співвідношення (Т/Е 2), індекс вільного андрогена (ІВА); показники холестерину ліпопротеїдів низької щільності (ХС ЛПНЩ) та коефіцієнту атерогенності (КА), індекс інсулінорезистентності НОМА. Статистичний аналіз виконано в програмі SPSS17.00. Результати. У підлітків із ГА зниження рівня ЗТ поєднувалось із достовірними зменшеннями співвідношення Т/Е 2 (40,35±28,02 ум.од., р<0,05) та ІВА (22,08±6,05 ум. од., р<0,05) на тлі зниження рівня СЗГ (28,11±3,64 нмоль/л, р<0,05). За індивідуального аналізу у 23,6% хворих із ГА діагностовано ознаки інсулінорезистентності (ІР). Встановлено, що хлопці з ГА мали вірогідно більші показники ЗХС (4,91±0,17 нмоль/л, р<0,05), ТГ(1,15±0,12 нмоль/л, р<0,05) та ХС ЛПНЩ (2,65±0,19 нмоль/л, р<0,05) порівняно зі здоровими однолітками. Доведено наявність негативних зв’язків рівнів ЗТ, СЗГ із вмістом ЗХС та позитивного зв’язку Е 2 із ЗХС, які не залежали від віку та індексу маси тіла (ІМТ). Висновки. Низькі рівні ЗТ у хлопців вже в підлітковому віці асоціюються з порушеннями ліпідного профілю, які можуть бути предиктором формування МС. Підлітки з ГА потребують динамічного спостереження та комплексного лікування, спрямованого на покращення репродуктивного потенціалу та попередження прогресування метаболічних порушень.

Non-Alcoholic Fatty Liver Disease Markers Associated with Fasting Serum Insulin and Urinary Albumin Excretion Independent of Fasting Plasma Glucose.

Objective: We examined the association between non-alcoholic fatty liver disease (NAFLD) markers and fasting serum immunoreactive insulin (FIRI) and urinary albumin excretion (UAE). Subjects and methods: This study comprised Periods I and II from January 2007 to May 2009, and from June 2009 to December 2011, respectively. After excluding people with ethanol intake ≥210 g/week in men and ≥140 g/week in women, 961 people (613 men, 348 women; mean age: 44 years) were included. We evaluated the fatty liver using ultrasonography score (FLUS) and measured liver enzymes. Results: The mean observation period was 25 ± 9 months. We stratified people into two groups by fasting plasma glucose (FPG) in Period I. The cutoff point between the lower FPG and higher FPG was 100 mg/dL. In regression analysis, serum alanine aminotransferase (ALT) (p < 0.001), FLUS (p < 0.001) and γ-glutamyl transpeptidase (GGTP) (p = 0.022) in Period I were independently associated with FIRI in Period II, whereas in all participants FPG was not. ALT (p < 0.001) and GGTP (p = 0.001) were also independently associated with UAE in people with FPG < 100 mg/dL in Period II. Conclusions: Some NAFLD markers were associated with FIRI and UAE independently of fasting plasma glucose.

Role of serum myostatin in the association between hyperinsulinemia and muscle atrophy in Japanese obese patients

AimsThe protein myostatin is a member of the transforming growth factor β superfamily. This is mainly expressed in skeletal muscle and negatively regulates skeletal muscle growth. The present study aimed to elucidate the associations among circulating myostatin level, skeletal muscle mass, and metabolic profiles in Japanese obese patients. MethodsJapanese obese outpatients (n = 74) were enrolled. We measured clinical parameters, quantified serum myostatin levels, and examined their associations in a cross-sectional manner. ResultsBoth total skeletal muscle mass and serum myostatin level were higher in males than in females. Among 74 patients, serum myostatin level was positively correlated with skeletal muscle mass and serum immunoreactive insulin (IRI) level [correlation coefficient (r) = 0.294, P = 0.011; r = 0.262, P = 0.024, respectively]. Furthermore, multivariate linear regression analysis revealed that serum myostatin level was positively correlated with IRI after adjusting for gender and skeletal muscle mass (β-coefficient = 0.230, P = 0.029, R2 = 0.236). ConclusionsIn obese patients, serum myostatin level was elevated in conjunction with an increase in IRI level independent of skeletal muscle mass. This may imply possible novel pathological implications of serum myostatin in muscle mass and metabolism in obese patients with hyperinsulinemia.

Peripheral arterial endothelial dysfunction of neurodegenerative diseases

This study evaluates endothelial functions of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), progressive supranuclear palsy (PSP), multiple system atrophy (MSA) and spinocerebellar ataxia (SCA).The reactive hyperemia index (RHI) of peripheral arterial tonometry and serological data were compared between age- and gender-matched normal controls (n=302) and five disease groups (ALS; n=75, PD; n=180, PSP; n=30, MSA; n=35, SCA; n=53). Correlation analyses were performed in ALS with functional rating scale-revised (FRS-R), and in PD with the Hehn-Yahr scale (H-Y) and a heart to mediastinum ratio using 123I-MIBG scintigraphy (MIBG).The RHI of ALS and PD, but not of PSP, MSA or SCA, were significantly lower than normal controls (p<0.01). ALS showed a negative correlation of RHI with serum triglycerides (TG) and immunoreactive insulin (IRI) levels, but not with disease severity (FRS-R) or rates of disease progression (∆FRS-R). On the other hand, PD showed a negative correlation of RHI with a progressive disease severity (H-Y) and a positive correlation of RHI with early/delayed MIBG scintigraphy, but not with serological data.The present study demonstrated significant declines of peripheral arterial endothelial functions in ALS and PD. The RHI of ALS was more correlated with disease duration and serum parameters while the RHI of PD was more correlated with disease severity and MIBG, suggesting different mechanisms of endothelial dysfunction.

Cвязь Т455С полиморфизма гена аполипопротеина С-III с инсулинорезистентностью и компонентами метаболического синдрома

to study an association between T455C apolipoprotein C-III (apo C-III) gene polymorphism, insulin resistance (IR), metabolic syndrome (MS) and its components in a Kyrgyz ethnic group.259 persons: 162 patients with MS and 97 sex and age matched controls without MS, diabetes mellitus and cardiovascular diseases were included in the study. Clinical examination with arterial blood pressure, anthropometric data measurement and laboratory tests for blood glucose and lipid parameters were performed in all included persons. In 140 patients test for immunoreactive serum insulin was done. DNA was extracted from blood cells and T455C polymorphism of apo C-III gene was determined by PCR method.In examined persons the most frequent was TC genotype as in group with MS as in controls. The difference on genotype's frequency between group was close to significant level (χ2 =5.48; p = 0.06) and odd ratio (OR) for MS between CC and TT carriers was 2.57 (95% CI 1.15-5.72); p = 0.019). Frequency of 455C allele in control group was--0.44 and in group with MS--0.54 (χ2 = 4.55; p = 0.036). In carriers of CC genotype there was noted that the frequency of IR (61.8% vs 23.1% vs 36.3%; p < 0.005), insulin level (11.9 [7.04-16.3] vs 5.73 [3.34-10.3] vs 7.54 [4.59-12.2] µIU/ml; p < 0.01) and HOMA index (3.14 [1.66-4.79] vs 1.46 [0.8-2.6] vs 2.05 [1.12-3.6]; p < 0.01) were significantly higher compared with TT and TC genotypes groups respectively. OR for IR between CC and TT carriers was 5.39 (95% CI 1.7-16.9; p = 0.0028). There also was an association between CC genotype and other MS components such as abdominal obesity (χ2--6.24; p--0.044, OR (95% CI--2.21 [1.03-4.82]) and high level of blood triglycerides (χ2--7.57; p--0.022, OR (95% CI) 2.5 [1.14-5.5]).In examined Kyrgyz ethnic population the most frequent was heterozygous TC genotype of T455C polymorphism of apo C-III. An association of 455C allele and CC genotype with MS, IR, abdominal obesity and high level of triglycerides was revealed. Key words: apolipoprotein C-III; T455C gene polymorphism; metabolic syndrome, insulin resistance.

Primary insulin autoimmune syndrome in an Italian woman: a case report

Insulin autoimmune syndrome (IAS) is a rare syndrome characterized by fasting or postprandial hypoglycemia, high levels of anti-insulin antibodies and high concentration of total serum immunoreactive insulin. It is relatively known in Japan, rare in remaining Asia and it is extremely uncommon in Western countries, being characterized by a different race-related incidence and associated with HLADR4 alleles. Usually IAS is related to particular drugs, or to autoimmune, rheumatologic or hematological diseases, while it is very rare as a primary form. Here we described a case of an Italian woman affected by a primary form of Hirata syndrome.

Immunological hypoglycemia associated with insulin antibodies induced by exogenous insulin in 11 Chinese patients with diabetes.

Aims. To investigate the characteristics of immunological hypoglycemia associated with insulin antibodies (IAbs) induced by exogenous insulin in Chinese patients with diabetes. Methods. The clinical data of patients with immunological hypoglycemia due to IAbs were retrospectively analyzed by screening patients with diabetes discharged from West China Hospital from 2007 to 2013. Results. A total of 11 patients (eight men and three women) were identified. Insulin-C-peptide separation was found in all patients via insulin and C-peptide release test. Previous insulin use was ceased after admission and was switched to oral hypoglycemic agents (OHAs) (8/11), lifestyle modification only (2/11), or regular human insulin (1/11). Hypoglycemia was ameliorated after a median of 20 days (interquartile range [IQR], 11–40), while IAbs turned negative after a median of 17 months (IQR, 4–19), and serum immunoreactive insulin (IRI) levels dropped substantially after a median of 22 months (IQR, 9–32) in these cases. Conclusions. In insulin-treated patients with unexpected and refractory hypoglycemia even after insulin therapy was gradually reduced or even withdrawn, IAbs induced by exogenous insulin should be considered, and insulin withdrawal might be promptly needed. The course of immunological hypoglycemia was benign and self-limited.

Effects of short-term intensive glycemic control on insulin, glucagon, and glucagon-like peptide-1 secretion in patients with Type 2 diabetes.

Short-term intensive insulin therapy (IIT) in patients with Type 2 diabetes mellitus (T2DM) has beneficial effects on insulin secretion. However, IIT effect on glucagon and glucagon-like peptide-1 (GLP-1) secretion is unknown. We evaluated short-term intensive glycemic control effects on insulin, glucagon, and GLP-1 secretory dynamics in T2DM. Twenty-six patients with T2DM were hospitalized and treated with IIT for 10-14 days. A meal tolerance test was performed before and after IIT and the differences in serum immunoreactive insulin (IRI) and C-peptide immunoreactivity (CPR) as well as plasma glucagon and active GLP-1 levels were evaluated. Glycoalbumin levels decreased significantly from 23.0% before to 19.6% after IIT (p<0.001). However, pre- and post-IIT, IRI and CPR levels were not significantly different; post-IIT glucose levels were significantly decreased. The post-IIT glucagon levels at 0 and 60 min were lower than pre-IIT levels. Moreover, post- IIT area under the curve (AUC) of glucagon significantly reduced from 6755 ± 996 pg/dl · 60 min to 5796 ± 1074 pg/dl · 60 min (p<0.001). Furthermore, post-IIT GLP-1 levels and AUC were significantly higher than pre-IIT values. Our results suggest that patients with T2DM who received shortterm IIT demonstrated decreased postprandial glucagon levels and increased GLP-1 levels following a meal tolerance test.

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.

Repeated Hypoglycemia Caused by the Overproduction of Anti-insulin Antibodies and Isolated ACTH Deficiency in a Type 2 Diabetic Patient Receiving Insulin Therapy

A 46-year-old man with untreated type 2 diabetes visited our hospital. His plasma glucose and HbA1c levels were 429 mg/dL and 11.5%, respectively. He had no renal dysfunction. Insulin therapy (18 units aspart and 22 units biphasic insulin aspart 30/70) was initiated, and the HbA1c level improved (5.7–6.4%). One year later, he started experiencing frequent hypoglycemic attacks, which persisted despite significantly reducing his insulin dosage (total 9 units). Fasting plasma glucose, serum immunoreactive insulin (IRI), C-peptide, and HbA1c levels were 75 mg/dL, 420 μU/mL (reference, 1.7–10.4), 1.2 ng/mL (reference, 0.6–1.8), and 5.4%, respectively. His anti-insulin immunoglobulin G antibody (IA) titer (125I-insulin binding rate) was 95.5% (reference, 0–7.0); free and total IRI levels were 11.0 and >240 μU/mL, respectively. After insulin cessation, …

Insulin Autoimmune Syndrome in a Health Supplement User: The Effectiveness of Cornstarch Therapy for Treating Hypoglycemia

A 70-year-old woman with no history of diabetes was admitted to the hospital for the management of hypoglycemia. Her fasting plasma glucose level was 54 mg/dL with an extremely high serum immunoreactive insulin level (1210 μU/mL). She had high titers of anti-insulin antibodies and exhibited the DRB1*0406 genotype for HLA-DR4, leading to a diagnosis of insulin autoimmune syndrome. She had been taking several health preparations for approximately 10 years; however, all were thiol group-free. Due to frequent episodes of nocturnal hypoglycemia, the health preparations were discontinued and the patient was treated with cornstarch. This protocol successfully ameliorated the hypoglycemic episodes and normalized the patient's laboratory and serological test results.

Effects of Moxifloxacin on Serum Glucose Concentrations in Rats

Moxifloxacin, a fluoroquinolone antimicrobial agent, has been reported to cause serum glucose abnormalities such as hyper- and hypoglycemia. The purpose of the present study was to investigate the effect of moxifloxacin on serum glucose concentrations in rats. Rats were intravenously injected with moxifloxacin and samples of their arterial blood were collected periodically. Serum glucose concentrations increased with moxifloxacin at 100 mg/kg, and temporal elevations were observed in serum epinephrine and histamine concentrations. On the other hand, intravenous injection of moxifloxacin at 75 mg/kg did not affect serum glucose, epinephrine, or histamine concentrations. Serum immunoreactive insulin concentrations remained unchanged by moxifloxacin both at 75 and 100 mg/kg. In conclusion, moxifloxacin can induce histamine release, leading to an increase in serum epinephrine concentrations and hyperglycemia.

Relationship between proinsulin and beta cell function in different states of glucose tolerance

To measure proinsulin concentrations in different states of glucose tolerance and examine the relationship between proinsulin and beta cell function. Serum true insulin (TI), proinsulin (PI), immunoreactive insulin (IRI), C peptide (CP) and blood glucose (BG) levels were measured in the fasting state and during an oral glucose tolerance test (OGTT) in 32 individuals with normal glucose tolerance (NGT), 42 individuals with impaired glucose tolerance (IGT), and 54 individuals with newly diagnosed type 2 diabetes mellitus. All participants were also subdivided into nonobese [body mass index (BMI) <25 kg/m2] and obese (BMI ≥25 kg/m2) subgroups. The levels of TI, PI, IRI and CP were higher in obese patients compared with the corresponding NGT subgroup, whereas there was no difference in PI/TI. The levels of IRI, PI and PI/TI were higher in nonobese patients with type 2 diabetes mellitus than in the corresponding NGT subgroup. The levels of PI and TI increased in obese patients with NGT and IGT, whereas PI/TI did not change. In contrast, PI increased but TI did not in subjects with newly diagnosed diabetes mellitus, which led to an increase in PI/TI, and a decrease in beta cell function. Therefore, PI and the PI/TI ratio could offer markers for beta cell dysfunction in DM.

Circulating insulin-like growth factors may contribute substantially to insulin receptor isoform A and insulin receptor isoform B signalling

BackgroundOnly a fraction of circulating insulin-like activity is due to insulin itself. The aim of this study was to determine total serum insulin-like activity mediated via the insulin receptor isoform A (IR-A) and isoform B (IR-B) by using kinase receptor activation (KIRA) assays specific for the IR-A and IR-B. MethodsThe IR-A and IR-B KIRA assays use human embryonic kidney cells which have been transfected with the human IR-A or IR-B gene and quantify serum-mediated phosphorylation of the IR. ResultsBoth IR KIRA assays were sensitive (detection limit 32pmol/L) and precise (intra- and inter assay CV: <12% and <15%). The EC50s of insulin, IGF-I and IGF-II were 1.4, 11.2 and 6.7nmol/L for the IR-A KIRA assay, and 1.3, 31.0 and 15.7nmol/L for the IR-B KIRA assay.The operational range of both assays allowed for determination of total insulin-like activity in human serum. Analysis of serum samples showed that there was a significant positive correlation between serum insulin-like and immunoreactive insulin concentrations (IR-A: r=0.56, p=0.01, IR-B: r=0.68, p=0.001). Importantly, addition of IGF-I or IGF-II antibodies to human serum samples could substantially decrease the endpoint signal in both KIRA assays. ConclusionsWe showed that serum IGF-I and IGF-II may substantially contribute to IR signalling. Since IR isoform specific KIRA assays also take into account the contribution of IGFs present in serum on IR signalling, they may help to gain more insight into the roles of IGF mediated IR-A and IR-B activation in health and disease.

Predictive values of serum insulin kinetics for reversion of impaired glucose tolerance to normal glucose tolerance and the effects of voglibose treatment: a retrospective post hoc analysis of a Japanese phase III study

In a phase III study, voglibose was shown to reduce the risk of development of type 2 diabetes mellitus (T2DM) by 40.5 % in Japanese individuals with impaired glucose tolerance (IGT), and appeared to promote reversion of IGT to normal glucose tolerance (NGT). In a retrospective, post hoc analysis, data from this study, plus follow-up findings from subjects who achieved NGT during the study and who were off-treatment, were analyzed to investigate serum insulin kinetic parameters which might be predictors of IGT reversion to NGT, and maintenance of NGT once achieved. The effects of voglibose on serum insulin kinetics in individuals with IGT were also assessed. Subjects with IGT (n = 1778) were randomized to receive voglibose (0.6 mg/day) or placebo for a mean of 48.1 weeks. During treatment, 1053 subjects achieved NGT, 569 continued to have IGT, and 156 developed T2DM. Analysis of baseline characteristics in each outcome group showed that subjects with higher 30-min serum immunoreactive insulin (IRI) levels in a 75 g oral glucose tolerance test (OGTT) or higher insulinogenic indexes at baseline were more likely to achieve NGT, whether they received voglibose or placebo. Among subjects who achieved NGT, the mean increase in OGTT 30-min IRI level from baseline to endpoint was significantly greater after treatment with voglibose than with placebo. Individuals who had higher OGTT 30-min IRI levels when achieving NGT seemed more likely to sustain this state. Thus, insulin secretion kinetics appeared to predict reversion of IGT to NGT and maintenance of NGT once achieved.

Suicide attempt by an overdose of sitagliptin, an oral hypoglycemic agent: A case report and a review of the literature

Dipeptidyl peptidase-4 (DPP-4) inhibitors are a newer class of oral hypoglycemic agents for the management of diabetes that elevate the plasma concentration of active glucagon-like peptide-1 via inhibition of DPP-4. They effectively lower not only glycosylated hemoglobin levels, but also fasting and postprandial plasma glucose levels. Patients with diabetes occasionally consume an overdose of oral hypoglycemic agents in suicide attempts: the prevalence of depression is high in patients with diabetes, and depression is a strong risk factor for suicide. We encountered an 86-year-old woman with type 2 diabetes and depression, who was transferred to the emergency room 4h after ingestion of 1,700 mg of the DPP-4 inhibitor sitagliptin (1,700 mg is 17 times greater than the approved maximum dose). Upon arrival, she was fully conscious, plasma glucose was 124 mg/dL, and serum immunoreactive insulin level was 5.81 µU/mL. Thereafter, the plasma concentration of sitagliptin rose to 3,793 nM, which is 4.5 times higher than the value found under regular treatment with the maximum dose. The patient did not suffer from hypoglycemia, suggesting that a single oral overdose of sitagliptin is unlikely to cause hypoglycemia. A literature review of oral anti-diabetic agents revealed that overdose of biguanides is occasionally fatal when immediate intensive care is not provided. In summary, sitagliptin is a good treatment option for diabetic elderly patients or patients with psychiatric disorders who are suicidal and do not require insulin.

Effect of Troglitazone on Serum γ-Glutamyltransferase Activity and Plasma t-PA/PAI-1 Complex in Type 2 Diabetic Patients

This study was conducted to determine whether troglitazone (CAS 97322-87-7, Noscal), a thiazolidinedione with alpha-tocopherol in the side chain, had an antioxidant effect in patients with Type 2 diabetes. In 46 Type 2 diabetic outpatients aged 64 +/- 7 years (male/female: 33/13), with a body mass index of 23.4 +/-2.8 kg/m2, a 2-year prospective study was performed. Patients were given troglitazone tablet (200 mg) twice a day. After treatment for 4 months, troglitazone was withheld for one month (washout period). Then troglitazone was resumed for a further 19 months. The study was completed in 28 patients. In 18 patients, it was not completed because of side effects in 4 female patients and because of withdrawal of troglitazone from the Japanese market in 14 patients. Fasting plasma glucose was decreased by troglitazone treatment from 170.2 +/- 38.2 mg/dl to 151.6 +/- 34.5 mg/dl (ANOVA: F = 8.054, p < 0.001). Washout caused it to return to the pre-treatment level (170.9 +/- 38.0 mg/dl), but it decreased again to 145.4 +/- 33.4 mg/dl with the resumption of treatment (F = 3.845, p < 0.001). Glycated hemoglobin was decreased by treatment from 8.2 +/- 1.6 % to 7.9 +/- 1.6 % (F = 7.558, D < 0.001). Washout caused it to return to the pre-treatment level (8.0 +/- 1.6 %), but it decreased again to 7.6 +/- 1.2 % with the resumption of treatment (F = 1.985, p = 0.041). Fasting serum immunoreactive insulin was decreased by treatment from 5.5 +/- 3.4 pU/ml to 4.0 +/- 2.2 pU/ml (F = 9.098, p < 0.001). Washout caused it to return to near the pre-treatment level (4.6 +/- 2.4 pU/ml). After resumption of treatment, it remained unchanged. Serum n-glutamyltransferase (gamma-GT) activity was decreased by treatment from 37.5 +/- 25.7 U/I to 25.6 +/- 12.3 U/I (F = 19.406, p < 0.001). Washout caused it to return to the pre-treatment level (36.5 +/- 25.1 U/I), but it decreased again to 24.2 +/- 10.1 U/l with the resumption of treatment (F = 7.931, p < 0.001). Plasma tissue plasminogen activator(t-PA)/plasminogen activator inhibitor-1 (PAI-1) complex was decreased by treatment from 21.7 + 8.6 ng/ml to 19.0 +/- 6.6 ng/ml (F = 8.784, p < 0.001). Washout caused it to return to the pretreatment level (21.9 +/- 7.4 ng/ml), but it decreased again to 14.3 +/- 4.3 ng/ml after the resumption of treatment (F = 12.341, p < 0.001). Decreases in serum gamma-GT activity and plasma t-PA/PAI-1 complex were closely related with antioxidant action of troglitazone.

Reduction in Intrasubject Variability in the Pharmacokinetic Response to Insulin After Subcutaneous Co-Administration with Recombinant Human Hyaluronidase in Healthy Volunteers

This study was designed to test the hypothesis that co-administration of recombinant human hyaluronidase (rHuPH20) with regular insulin or insulin lispro will reduce intrasubject variability in pharmacokinetic end points compared with lispro alone. Healthy adult volunteers (18-55 years old) were enrolled in this phase 1, randomized, double-blind, crossover study. Subjects were administered two injections, each on a separate occasion, of three treatments during six euglycemic clamps. Treatments were 0.15 U/kg insulin lispro, 0.15 U/kg insulin lispro with 5 μg/mL rHuPH20, and 0.15 IU/kg regular insulin with 5 μg/mL rHuPH20. Insulin formulations were administered at a concentration of 40 U/mL. Serum immunoreactive insulin levels, blood glucose concentration, and glucose infusion rate determinations were made at baseline and for approximately 8 h after study drug administration. Intrasubject variability was assessed using a general linear mixed model with a fixed effect for treatment using a compound symmetric covariance matrix. Co-injection of rHuPH20 with lispro significantly reduced intrasubject root mean square differences in time to peak serum insulin, time to early 50% peak serum insulin (t(50%)), and time to late t(50%) levels compared with lispro alone. Also, the intrasubject coefficient of variation for percentage of total area under the plasma concentration-versus-time curve for early time intervals compared with lispro alone was reduced. Intrasubject variability for regular insulin with rHuPH20 for most pharmacokinetic parameters was similar to the variability of lispro alone, although variability in early exposure was significantly reduced. Co-administration of rHuPH20 with lispro significantly reduced the variability of insulin pharmacokinetics relative to insulin lispro alone.