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The objective of this paper was to determine the effect of tamsulosin use on plasma insulin status in benign prostatic hyperplasia (BPH) patients in Sokoto, Nigeria. Standard methods and procedures were used. At 2nd and 3rd months of tamsulosin use, there was a significant increase (P0.05). Plasma insulin at 4th months of the study in BPH patients (45-54 years) treated with tamsulosin revealed a significant increase (P0.05). BPH patients (aged 55-64 years) at 3rd month showed a significant increase (P0.05). In BPH patients aged 65 and above, there was no significant difference (P>0.05) in plasma insulin values from 1st through 4th month compared to baseline and other inter mean values comparisons. Plasma insulin at 0th , 1st , 2nd , 3rd and 4th months of BPH patients of different age groups treated with tamsulosin revealed no significant differences (P>0.05). This study revealed that tamsulosin use in the patients lead to significant increase in plasma insulin level (hyperinsulinemia). Careful and routine monitoring of BPH patients should be done. Patients need enough exercise activities and some drugs can be administered to alleviate elevated glucose or insulin. Keywords: Tamsulosin, hyperinsulinemia, benign prostatic hyperplasia patients, insulin resistance

Objective: to detect the changes induced by STZ induced diabetes on uterine contractility and expression of connexin 43 in pregnant rat and the possible role of L carnitine to detect the role of L Carnitine in a model of diabetic pregnant rat. Method:40 female Sprague Dawley rats were subdivided into four groups; G I (NC): normal pregnant rats, G II (DI): in which rats received single i.p injection of 40 mg/kg b.wt STZ at day 1 of pregnancy, G III (DI+CAR): in which rats received STZ as above, and then at day 3 of pregnancy, diabetic pregnant rats received daily i.p L carnitine injection at a dose of 100 mg/kg b.wt till end of pregnancy, and G IV (DI+INS): in which rats received STZ as above, and then at day 3 of pregnancy, diabetic pregnant rats received daily i.p insulin injection at a dose of 1 IU/100 g b.wt (till end of pregnancy. Plasma glucose and insulin level, uterine contractility, pathological changes were assessed at the end of the experiment and scarifying of rats. Results: STZ induced DM caused significant increase in plasma glucose level, decreased plasma insulin level, impaired uterine contractility, pathological changes in diabetic group compared to normal control group. L Carnitine caused significant improvement in the studied parameters.

The diet schedule and food intake effect on body glucose is the key problem of the diabetic patient. For type 1 diabetic patients, it is necessary to optimize the diet schedule and insulin regimen to control the body glucose level in the postprandial state. Hence, a closed-loop system containing insulin delivery and diet schedule is required for type 1 diabetic patients. In the current paper, a mathematical model of glucose-insulin is proposed to investigate the glucose profile along with plasma insulin level for type 1 diabetic patients. Four different and most common cases have been considered with the scheduled plan of diet and insulin regimen to simulate the glucose profile along with plasma insulin level. The glucose-insulin model was simulated using MATLAB to investigate the artificial pancreas system. The analysis includes glucose absorption parameters and net hepatic glucose balance (NHGB). The results represent that the proposed mathematical model may be useful to predict the glycaemic status of diabetic patients and personalise it as per their historical data. Index Terms—Glycemic control, Type 1 diabetes, Glucose-insulin modeling, Closed loop control system, Artificial pancreas system, Continuous glucose measurement, Insulin secretion

The objective of this study was to develop a thermoresponsive injectable hydrogel for the sustained release of drugs by taking advantage of host-guest interactions between a hydrophobically modified hydroxypropylmethyl cellulose (HM-HPMC) and cyclodextrin (CD). A thermoresponsive injectable hydrogel was prepared by simply adding CDs to HM-HPMC hydrogel. The HM-HPMC hydrogel was converted into a sol with a low viscosity through host-guest interactions with CDs. The HM-HPMC/β-CD hydrogel became a gel near body temperature where the host dissociated from the hydrophobic moieties of the polymer in response to the temperature. The yield stress of the HM-HPMC became progressively lower on the addition of β-CD which was desirable in the case of developing an injectable formulation. When the HM-HPMC/β-CD hydrogel containing indocyanine green (ICG) was subcutaneously administered to mice, the fluorescence of the ICG remained relatively constant for 24 h after the administration, which was substantially longer than that for ICG alone or an HPMC formulation. The plasma insulin level was maintained for a longer period of time when the HM-HPMC/β-CD containing insulin was administered and the MRT value was increased by 1.6 times compared to a solution of insulin alone. In addition, the HM-HPMC/β-CD hydrogel formulation showed a prolonged hypoglycemic effect in response to the insulin which was slowly released from the hydrogel. A thermoresponsive injectable hydrogel was successfully constructed from the highly viscous HM-HPMC and β-CD, and the resulting formulation functioned as a sustained release carrier for drugs.

Background: Ascertaining Kraft dynamic insulin response patterns following a 3-h 100 g oral glucose tolerance test seems to be the most reliable method for diagnosing hyperinsulinaemia. However, this test may be too resource-intensive for standard clinical use. Aim: This study aims to see if Kraft patterns can be accurately predicted using fewer blood samples with sensitivity and specificity analyses. Setting: St Joseph Hospital, Chicago, Illinois, United States and Human Potential Centre, Auckland University of technology, Auckland, New Zealand. Method: We analysed the results of 4185 men and women with a normal glucose tolerance, who had a 100 g oral glucose tolerance test with Kraft pattern analysis. Participants were dichotomised into normal–low insulin tolerance (Kraft I or V patterns) or hyperinsulinaemia (Kraft IIA–IV patterns). Sensitivity and specificity analysis was applied to available variables (including age, body mass index, fasting insulin or glucose) both individually and in combination. Results: Out of a maximal combined sensitivity and specificity score of 2.0, 2-h insulin level > 45 µU/mL attained the highest score (1.80). Two-hour insulin also attained the highest sensitivity (> 30 µU/mL, 0.98) and the highest specificity (> 50 µU/mL, 0.99) scores. Combining the 2-h insulin with other variables reduced the sensitivity and/or specificity. Dynamic measures had a better combined sensitivity and specificity compared to fasting or anthropological measures. Conclusion: People with a 2-h plasma insulin level < 30 µU/mL are unlikely to be hyperinsulinaemic. Given that first-line treatment is lifestyle modification, we recommend that a 2-h plasma insulin level > 30 µU/mL following a 100 g oral glucose tolerance test be used to identify the hyperinsulinaemic individual.

Objective: To determine the effects of supervised structured aerobic exercise training (SSAET) program on fasting blood glucose level (FBGL), plasma insulin level (PIL), glycemic control (GC), and insulin resistance (IR) in type 2 diabetes mellitus (T2DM). Methods: Riphah Rehabilitation and Research Centre (RRRC) was the clinical setting for this randomized controlled trial, located at Pakistan Railways General Hospital (PRGH), Rawalpindi, Pakistan. Study duration was 18 months from January 1, 2015 to June 30, 2016. Patients of both genders ranging 40-70 years of age with at least one year of history of T2DM were considered eligible according to WHO criteria, while patients with other chronic diseases, history of smoking, regular exercise and diet plan were excluded. Cohorts of 195 patients were screened out of whom 120 fulfilled the inclusion criteria. Amongst them 102 agreed to participate and were assigned to experimental (n=51) and control (n=51) groups. Experimental group underwent SSAET program, routine medication and dietary plan, whereas the control group received routine medication and dietary plan, while both group received treatment for 25 weeks. The blood samples were taken at baseline and on the completion of 25 weeks. The investigation of fasting blood glucose level, plasma insulin level, and glycemic control was conducted to calculate IR. Results: Patients with T2DM in experimental group (n=51) treated with SSAET program, routine medication and dietary plan significantly improved FBGL (pre-mean= 276.41±25.31, post-mean=250.07±28.23), PIL (pre-mean=13.66±5.31, post-mean=8.91±3.83), GC (pre-mean=8.31±1.79, post-mean 7.28±1.43), and IR (pre-mean=64.95±27.26, post-mean 37.97±15.58), as compared with patients in control group treated with routine medication and dietary plan in whom deteriorations were noted in FBGL (pre-mean=268.19±22.48, post-mean=281.41±31.30), PIL(pre-mean=14.14±5.48, post-mean=14.85±5.27) GC (pre-mean=8.15±1.74, post-mean=8.20±1.44, and IR (pre-mean=64.49±23.63. post-mean=70.79 ±23.30). Statistically at the baseline the results were not significant (p>0.05), but at the completion of 25 weeks intervention all the variable showed significant results (p

Background: Oxidative stress induced by hyperglycaemia plays a crucial role in the development of diabetic complications and metformin is commonly used in treating diabetes mellitus (DM). The aim of this study was to investigate whether metformin at the dose of 100 mg/kg/day could ameliorate oxidative stress and improve plasma insulin level in streptozotocin-induced diabetic rats.Methods: Twenty one rats (8-10 week old; weighing 190-220 g) were assigned into three groups (n=7 rats per group) i.e. non-DM, DM and DM+metformin (100 mg/kg/day metformin) groups. DM was induced using streptozotocin (60 mg/kg) intraperitoneally and treatments were given daily by oral gavage for four weeks. The levels of plasma biomarkers such as fasting blood glucose, oxidant-antioxidant markers and insulin levels were analysed.Results: Fasting blood glucose, malonyldehyde and protein carbonyls levels were significantly higher while insulin, total antioxidant capacity, catalase and glutathione peroxidase levels were significantly lower in DM group compared to non-DM group. The levels of fasting blood glucose, malonyldehyde and protein carbonyls were significantly lower while levels of total antioxidant capacity, catalase and insulin were significantly higher in DM+metformin group compared to DM group.Conclusion: This study may suggest that metformin at the dose of 100 mg/kg/day for 4 weeks reduces oxidative stress status and improves plasma insulin level in streptozotocin-induced diabetic rats possibly through its antihyperglycaemic action.

The long-term administration of insulin requires the development of new delivery routes. Using a base developed in-house, called HAMIN®, an insulin suppository containing 100 units (U) of insulin was formulated. The suppository was subjected to stability testing at various temperatures and the assay value was monitored. Other physical factors such as hardness, disintegration time, thermal analysis and dissolution were also tested. The suppository released more than 80% of its drug content in 30 min, and was stable for up to 11 months at −20°C. The suppository effect was studied on 11 New Zealand white rabbits, with body weight ranging from 1.6 to 2.1 kg. The results show that there was a marked reduction in glucose content when the suppository was inserted. The average drop in glucose content was 2.7 mmol/L in 15 min from the time of insertion. The maximum drop in glucose content reached 3.9 mmol/L in 2 h. Plasma insulin level, quantified using an enzyme-linked immunosorbent assay, showed a value of more ...

Objective To identify potential correlations between baseline plasma insulin level and shifts in metabolic status in psychiatric inpatients. Methods A population of 75 patients was identified for this single-center, retrospective study conducted at a state psychiatric hospital in Kansas City, Missouri. Patients were selected on the basis of presence of a baseline fasting plasma insulin level drawn at admission; duration of stay ≥ 12 weeks between August 1, 2013, and December 31, 2015; and presence of metabolic laboratory and weight measurements at baseline and 3 months. Total initial plasma insulin level (≥ 19 µIU/mL or < 19 µIU/mL) was compared to shifts in metabolic laboratory measurements and weight. A secondary analysis was performed to detect association between the numerical values of assessed parameters and the numerical values for plasma insulin measurements. Results The primary analysis found no correlation between plasma insulin level and changes in any metabolic parameter category at 3 (n = 75) or 6 months (n = 30) after admission. Secondary analysis found significant correlations between the numerical values of baseline total plasma insulin level and fasting plasma glucose level at baseline (r = 0.492, P < .001), 3 months (r = 0.247, P = .035), and 6 months (r = 0.723, P < .001). Secondary analysis demonstrated a significant correlation between baseline total plasma insulin level and hemoglobin A1c values at baseline (r = 0.329, P = .004), 3 months (r = 0.455, P < .001), and 6 months (r = 0.517, P = .003). Conclusions Baseline total plasma insulin levels were strongly correlated with parameters affected directly by alterations in glucose up to 6 months after admission but were weakly correlated or not correlated with other metabolic parameters. The results do not support routine use of plasma insulin as a predictor for shifts in metabolic parameters in patients receiving antipsychotic medications.

The present study investigated the effect of parity on plasma insulin level around parturition in Saanen goats. On d -14, -7, 0, 3, 7, 10, and 14 from parturition, plasma glucose, NEFA, free AA, cortisol, and insulin concentrations were analyzed in 10 primiparous and 10 multiparous goats. At parturition, BW of primiparous goats was about 75% of that of multiparous ones (P < 0.001) and then their milk production was lower than that of multiparous ones (P < 0.001). At parturition, glucose increased (P < 0.01) in both primiparous and multiparous goats and then decreased (P < 0.01) on d 3 of lactation, remaining higher (P < 0.01) in primiparous than multiparous goats until the end of the study period. In both groups, free AA decreased (P < 0.01) at parturition, returning to prepartum levels (P < 0.01) on d 3 of lactation without difference between groups. Only in multiparous goats, plasma NEFA increased at parturition (P < 0.01), returning to prepartum levels on d 14 (P < 0.01). Changes in glucose and AA could have been caused by cortisol, which increased (P < 0.01) at parturition in both primiparous and multiparous goats, returning to prepartum levels (P < 0.01) on d 7 of lactation, without difference between the parity groups. In multiparous goats, insulin decreased soon after parturition (P < 0.05), remaining at low levels until the end of the study period, whereas in primiparous goats, insulin did not vary until d 14 of lactation, when it decreased (P < 0.05) also in this group. Therefore, between d 3 and 14 of lactation, insulin was higher in primiparous than multiparous goats (P < 0.05). Only in primiparous goats, at kidding, insulin was negatively correlated to BW (P < 0.01), and after parturition it was negatively correlated with milk yield (P < 0.05) and plasma NEFA (P < 0.05). We hypothesize that higher insulin levels in primiparous Saanen goats, which are still immature at their first breeding season, acted to limit both the mobilization of bodily reserves and the capture of nutrients by the lactating mammary gland, thus providing nutrients for their own physical and physiological development.

Plant-based remedies have been used to treat numerous diseases for thousands of years in various parts of the world. Azadirachta excelsa or sentang traditionally used by Malay as an agent for lowering blood glucose. The study was designed to evaluate the antidiabetic properties of this plant by measuring the plasma blood glucose level, the percentage of HbA1c and the plasma insulin level. Thirty two Sprague dawley rats were divided into four groups which received different treatments. The first and second groups served as positive and negative control were treated with saline respectively while the rats in the third group were received metformin. The fourth group was treated with ethanolic extract of A. excelsa. After 14 days of treatment, the plant extract was significantly reduced the fasting blood glucose and the concentration of HbA1c in diabetic rats by 72.89% and 6.58% respectively. The plasma insulin in diabetic rats was also significantly increased after treated with plant extract. These results suggest that the ethanolic extract of A. excelsa possess antidiabetic activity by improving the insulin secretion, with consequent decrease in the level of plasma blood glucose and HbA1c.

The plasma insulin responses of newly diagnosed, untreated, non-obese, middle-aged and old diabetics constitute a wide spectrum of responses varying with the metabolic state. The insulin response pattern after oral glucose in the mildest degree of glucose intolerance is characterized by a sustained rise in the plasma insulin concentration and a delayed decline towards the fasting level with a plasma insulin level higher than normal during the later part of the oral tests. The initial plasma insulin release in the mildest degree of glucose intolerance is, however, quite normal. In patients with more pronounced glucose intolerance the initial insulin response is proportionally more sluggish, and in severe glucose intolerance an overall diminishing of the insulin response obtains. After i.v. glucose and tolbutamide largely the same pattern is seen. The initial plasma insulin release in the mildest degree of glucose intolerance is normal. In patients with more pronounced glucose intolerance the initial insulin response is delayed, while only small changes occur during the later part of the insulin response. In the diabetics a significant positive correlation is found between the fasting plasma insulin and the fasting blood glucose concentration. A significant negative correlation is found in the diabetics between the fasting blood glucose and the increment from fasting to 15-min and 2-hour plasma insulin concentration in the oral tests and the increment from fasting to the 10-min insulin value in the i.v. tests. There is, however, no correlation between the fasting plasma insulin and the 2-hour plasma insulin concentrations in the oral tests in the diabetics. In the i.v. glucose tolerance test a significant inverse correlation exists in the diabetics between the fasting plasma insulin concentration and the increment from fasting to the 10-min plasma insulin value, while such a correlation between the same parameters does not exist in the i.v. tolbutamide test.

The effect of insulin on the ascorbate recycling system in the chicken liver was examined. First, insulin was injected subcutaneously into the chicken, and liver glutathione-dependent dehydroascorbate reductase (GSH-DHAR) activity was determined. Insulin increased liver GSH-DHAR activity, but did not affect plasma and liver ascorbate concentration. Dehydroascorbate increased plasma and liver ascorbate levels, and liver GSH-DHAR activity. However, distinct changes in plasma insulin level were not observed by dehydroascorbate injection. In addition, reduction of external dehydroascorbate in cultured chicken hepatocytes could not be observed in an insulin-deprived culture, although the cells reduced external dehydroascorbate in a serum-free culture with insulin. We concluded that insulin affects the ascorbate recycling system as an essential factor in the chicken liver.

The objective of the current work was to develop and evaluate thermoreversible subcutaneous drug delivery system for Insulin. Thermoreversible in-situ gel system was developed and evaluated both in-vitro and in-vivo comprising of pluronic F-127 alone or in combination with methylcellulose in different ratios. The drug release kinetics and mechanism was predicted by applying various mathematical models to the in-vitro dissolution data. Rabbits were used as animal model following subcutaneous injection to predict various pharmacokinetic parameters by applying Pk-Summit® software. The in-vitro and in-vivo data revealed that the formulation IPM 15/3 consisting of the pluronic F-127 (15% w/v) and methylcellulose (3% w/v) was the most robust and capable formulation for extending the drug release and maintaining basal plasma insulin level between 10 and 40 µU/ml for 240 h (10 d).

The purpose of the present study was to examine the responses of plasma growth hormone (GH) and insulin-like growth factor-I (IGF-I) levels to intravenous injection of xylazine in female dairy calves. Xylazine (0.05, 0.15 and 0.30 mg/kg body wt., i.v.) injections induced a significant dose-dependent increase in plasma GH level within 30 min. After plasma GH levels reached peaks, GH concentrations began to decrease immediately and they returned to control levels 1 h after xylazine injection. Plasma IGF-I concentration tended to be suppressed by xylazine treatment. Xylazine induced a significant dose-dependent increase in plasma glucose for 3.5 to 5.5 h after the treatments. Xylazine also induced a significant decrease in plasma insulin level within 30 min after treatments. The present data suggested that xylazine stimulates GH release in cattle.

10 M comparable to 10 M WY14,643. Therefore, PPARα-mediated mechanism is a possible relevant pathway for FE anti-diabetic activity. We also evaluated the effects of a low-fat diet (LFD), high-fat diet (HFD), and high fat diet + 0.5% FE (FED) on C57BL/6J mice during 16-weeks. FED decreased fasting blood glucose (33.2%, P

Like many poecilotherms, salmonids exhibit seasonal variations of growth rate in relation with seasonal temperatures and plasma GH level. However, temperature alters other parameters like food intake, which may directly modify the level of plasma GH. In order to determine whether temperature regulates plasma GH levels independently of nutritional status, fish were reared at 8, 12, or 16 degrees C and either fed ad libitum (fish with different food intake) to determine the global effect of temperature, or with the same ration (1.2%/body weight) to observe the temperature effect in fish with the same growth rate. Plasma insulin level was inversely proportional to the temperature (8, 12, and 16 degrees C) in fish fed ad libitum (12.1+/-0.3 ng/ml, 10.9+/-0.3 ng/ml, 9.5+/-0.4 ng/ml; P0.001) and in restricted fish (14.0+/-0.3 ng/ml, 11.3+/-0.3 ng/ml, 10.0+/-0.2 ng/ml; P0.0001), probably due to a prolonged nutrient absorption, and delayed recovery of basal insulin level at low temperature. Conversely, temperature did not affect plasma T3 level of fish fed ad libitum (2.5+/-0.2 ng/ml, 2.4+/-0.1 ng/ml, 2.5+/-0.1 ng/ml at 8, 12, and 16 degrees C) while fish fed with the same ration present less T3 at 16 degrees C than at 8 degrees C (1.83+/-0.1 ng/ml versus 1.2+/-0.1 ng/ml; P0.001) throughout the experiment; these observations indicate that different plasma T3 levels reflect the different nutritional status of the fish. The levels of GH1 and GH2 mRNA, and GH1/GH2 ratio were not different for whatever the temperature or the nutritional status. Pituitary GH content, of fish fed ad libitum did not exhibit obvious differences at 8, 12, or 16 degrees C (254+/-9 ng/g bw, 237+/-18 ng/g bw, 236+/-18 ng/g bw), while fish fed with the same ration have higher pituitary GH contents at 16 degrees C than at 8 degrees C (401+/-30 ng/g bw versus 285+/-25 ng/g bw; P0.0001). Interestingly, high temperature strongly increases plasma GH levels (2.5+/-0.3 ng/ml at 8 degrees C versus 4.8+/-0.6 ng/ml at 16 degrees C; P0.0001) to the same extent in both experiments, since at a given temperature average plasma GH was similar between fish fed ad libitum or a restricted diet. Our results, demonstrate that temperature regulates plasma GH levels specifically but not pituitary GH content, nor the levels of GH1 and GH2 mRNA. In addition no differential regulation of both GH genes was evidenced whatever the temperature.

Sulfonylureas are widely used as an antidiabetic drug. In the present study, the effects of sulfonylurea administered supraspinally on immobilization stress-induced blood glucose level were studied in ICR mice. Mice were once enforced into immobilization stress for 30 min and returned to the cage. The blood glucose level was measured 30, 60, and 120 min after immobilization stress initiation. We found that intracerebroventricular (i.c.v.) injection with 30 µg of glyburide, glipizide, glimepiride or tolazamide attenuated the increased blood glucose level induced by immobilization stress. Immobilization stress causes an elevation of the blood corticosterone and insulin levels. Sulfonylureas pretreated i.c.v. caused a further elevation of the blood corticosterone level when mice were forced into the stress. In addition, sulfonylureas pretreated i.c.v. alone caused an elevation of the plasma insulin level. Furthermore, immobilization stress-induced insulin level was reduced by i.c.v. pretreated sulfonylureas. Our results suggest that lowering effect of sulfonylureas administered supraspinally against immobilization stress-induced increase of the blood glucose level appears to be primarily mediated via elevation of the plasma insulin level.

Diabetes mellitus therapy, in which the treatment must maintain a moment-to-moment glycaemic balance, is a major domain in which the principles of chronopharmacology must be included in the therapeutic regime. The therapeutic action, via insulin treatment in the case of insulin-dependent diabetes, or oral sulfamides or biguanides in the case of non-insulin-dependent diabetes, must take into account the physiological variations in induced blood glucose levels in order to avoid hyper or hypoglycaemia.

To elucidate the effect of aging and blood pressure on glucose tolerance, we examined the subjects who received 75g OGTT annually for 10 years. They were classified into 2 groups by blood pressure, and into 4 groups by age. The study group consisted of 34 cases (mean 62 years old), including 11 hypertensive (HT) and 23 normotensive (NT) control. All cases had their body weight fluctuate in less than 4 kgs. After blood pressure was measured, blood was drawn for determination of plasma glucose and insulin concentrations in each subject before 75g OGTT and 30, 60, 90, 120 minutes afterward. sigma BS and sigma IRI were defined as the sum of 5 points in BS and IRI, respectively. Insulinogenic index (I.I) was defined as deltaIRI/deltaBS in 30 min. sigma IRI/sigma BS and I.I of each year were calculated serially. They were compared between HT and NT group, and among 4 groups of age; 40s, 50s, 60s and 70s. sigma IRI/sigma BS was significantly decreased in both HT and NT groups (0.52 +/- 0.05 (mean +/- SE) to 0.29 +/- 0.04; p

Clearance rates of unlabelled insulin were studied in 45 unanaesthetized non-diabetic humans. The clearance rate, as well as the pancreatic secretion rate, of endogenous insulin was estimated from steady-state concentrations in portal and arterial blood. The clearance rate of exogenous insulin was determined after brief intraportal infusion. In the basal fasting state, the endogenous plasma insulin level varied as closely with the clearance of endogenous insulin as with the rate of pancreatic secretion. During elevation of insulin by glucose infusion, it varied predominantly with the rate of insulin secretion. Clearance of exogenous insulin did not vary with the pre-test endogenous insulin level. The clearance of endogenous insulin increased from 11 ml · min−1 · kg−1 in the basal fasting state to 17 ml · min−1 · kg−1 during glucose infusion. Clearance of exogenous insulin fell progressively with increasing dose, from 35 (8 mU/kg) to 14 (43 mU/kg) ml · min−1 · kg−1 at normoglycaemia and from 23 (8 mU/kg) to 17 (34 mU/kg) ml · min−1 · kg−1 at hyperglycaemia. The clearance of endogenous insulin was lower than that of exogenous insulin at normoglycaemia, but of similar size during glucose infusion. It is concluded that variation in clearance rate is partly responsible for variation in plasma insulin concentration, particularly in the basal fasting state, and that the clearance rate is lower in the basal state than otherwise. To some extent, the low clearance values for endogenous insulin in the basal state may reflect poor specificity of the insulin radioimmunoassay.

It is known that the effectiveness of a physiologic increment in glucagon to stimulate glucose production wanes with time even when counterregulatory insulin secretion is prevented. The aim of the present study was to establish whether the converse is true: does glucagon become a more effective stimulus of glucose production following a period of acute hypoglu-cagonemia? To determine this, somatostatin was infused along with basal replacement amounts of glucagon (0.65 ng/kg - min) and insulin (228 μU/kg · min) into five postabsorptive conscious dogs. After 1.5 h of basal hormone replacement, the glucagon infusion was terminated and a selective fall in the plasma glucagon level (75 ± 6 to 30 ± 4 pg/ml) occurred. This resulted in a drop in tracer (3H-glucose)-determined glucose production from 3.0 ± 0.4 to 1.5 ± 0.3 mg/kg min. The plasma insulin level remained unchanged at 10 ± 1 μU/ml throughout the experiment. Euglycemia (110 ± 4 mg/dl) was maintained by exogenous glucose infusion. After 3 h of glucagon lack, restoration of the glucagon infusion returned the IRG level to control values (78 ± 6 pg/ml) but restored glucose output only partially (42 ± 9%), necessitating continued glucose infusion to preserve euglycemia. Repetition of the experiment in dogs whose pancreatic glucoregulatory feedback loops were broken surgically (two-stage pancreatectomy) rather than pharmacologically resulted in similar findings. It is concluded that glucagon deficiency of 3-h duration leads to a decrease, rather than an increase, in hepatic sensitivity to glucagon.

Repeatedly supplementing glucose after birth abolishes postnatal increase in ornithine transcarbamylase activity and increases the plasma insulin level. A single administration of actinomycin D does not affect this activity. When glucose and actinomycin D are administered in association at birth or 13 hours after birth, actinomycin D overcomes the inhibitory effect of glucose on ornithine transcarbamylase activity and decreases insulinemia at the level found in normal neonate. Insulin supply 20 hours after birth to neonates, which previously received glucose and actinomycin D, decreases the enzyme activity and increases plasma insulin level. It is concluded that the postnatal increase in ornithine transcarbamylase activity is bound to the normal postnatal decrease in insulinemia. Furthermore, the paradoxical effect of actinomycin D on enzyme activity might be due to an inhibition of insulin synthesis or a decrease in insulin release.

Oral glucose (75 g) tolerance tests were performed on 189 urbanized Micronesians with an age range of 15 to 70 years. The subjects were divided into 6 groups on the basis of the 2 h plasma glucose and the pattern of insulin response examined. Fasting plasma insulin levels were not significantly different over the entire range of glucose tolerance. The 2 h plasma insulin levels were highest in the group with 2 h plasma glucose value of 140–199 mg/100 ml. There was a progressive fall in 2 h plasma insulin with increasing glucose intolerance, so that in the group with a 2 h plasma glucose ⩾ 400 mg/100 ml, the 2 h plasma insulin level was significantly less than that in all the other groups. Obesity was the most important factor influencing both fasting and 2 h insulin levels and no effect of corresponding plasma glucose level was demonstrated. In maturity-onset diabetes, a wide range of insulin responses may be seen and the earlier controversy regarding patterns of insulin response has arisen from equating groups of diabetic subjects with varying degrees of glucose intolerance.

UNLABELLED Insulin binding to isolated adipocytes from 16 normal and 14 obese patients was studied. The data indicated that, as a group, adipocytes from the obese patients bound significantly less insulin than normal. However, of the 14 obese patients, 5 were not hyperinsulinemic and 4 of these 5 subjects had normal insulin binding. These subjects were also younger, and had the onset of obesity in childhood. When these five patients were separated from the original 14 obese patients, enhanced differences in insulin binding to adipocytes were observed when normals and the remaining 9 obese subjects were compared. Similar findings were obtained with isolated circulating mononuclear cells from these same patients. Presumably the five normoinsulinemic obese patients were not insulin-resistant, and, thus, the data indicate that insulin binding to adipocytes was decreased only in insulin-resistant obese patients. This conclusion was strengthened by finding a highly significant correlation (r=-0.71, p less than 0.001) between insulin binding to adipocytes and fasting plasma insulin level, while a weaker correlation (r=-0.49,p less than 0.01) existed between insulin binding and degree of obesity. Finally, when insulin binding to adipocytes and mononuclear cells from the same individual was compared, a significant positive correlation was found (r=0.53,p less than 0.01). IN CONCLUSION (a) insulin binding to adipocytes and mononuclear cells is decreased in cells from insulin-resistant obese patients; (b) a significant inverse relationship exists between fasting plasma insulin level and insulin binding to adipocytes; and (c) in obesity, events that affect insulin receptors on adipocytes similarly affect insulin receptors on mononuclear cells.

The studies were carried out in 45 patients with extensive burns. Plasma insulin level rose and the rise persisted for weeks; glucose tolerance decreased and resistance to insulin was increased. The STH response to hypoglycaemia provoked by insulin was greatly reduced or abolished during the first two weeks after burning but was increased at a later period. Fasting STH levels were somewhat increased, especially during the second month. High plasma renin and angiotensin II levels persisted for weeks and their response was increased during walking. High ACTH levels were found and they persisted for a few weeks, sometimes reaching values found in some subjects with Cushing's syndrome (central form). The increased ACTH values were temporarily reduced by the neuroplegic M2 mixture. LH levels were temporarily raised. The therapeutic administration of insulin and glucose is advocated, and there may also be a place for STH administration during the first weeks after burning. The levels of renin, angiotensin II and ACTH could be used to test the efficacy of certain new drugs for burned subjects.

Glucose and amino acid-stimulated insulin release was studied in vivo in cannulated European silver eels ( Anguilla anguilla ). Glucose-stimulated insulin release was dose dependent over a range of glucose loads (10–100 mg/kg) while higher doses (300 and 500 mg/kg) produced no greater increments than 100 mg/kg. Arginine and lysine injections of 10, 25 and 100 mg/kg caused greater significant increases in plasma insulin levels than glucose at the same dose levels. Histidine (10 and 25 mg/kg) caused a small but significant reduction in the plasma insulin level. Simultaneous injection of arginine (100 mg/kg) and glucose (100 mg/kg) caused an increase in plasma insulin which was sustained for 60 min and remained significantly above the controls over the 360 min sampling period. Total insulin secretion appeared to be significantly greater over the entire sampling period than when arginine and glucose were injected alone.

The effects of insulin-treatment on induction of liver lipogenic enzymes by a fat-free diet were investigated in 1-, 2- and 9-month-old rats. The magnitudes of the induction of the enzymes were very high in 1-month-old rats and decreased with aging (Iritani, N., Fukuda, H. and Fukuda, E. (1981) Biochim. Biophys. Acta 665, 636). The induction of lipogenic enzymes was not affected by insulin injection in young rats. In 9-month-old rats, however, although the maximal magnitudes of the induction were not affected by the insulin injection, the lag periods of the induction were shortened. The lipogenic enzyme induction in 9-month-olds did not correlate with plasma insulin level but paralleled changes in the insulin binding capacities to liver plasma membranes and adipocytes. The results suggest that insulin binding is implicated in age-dependent decrease of lipogenic enzyme induction, and support our previous report (Iritani, N., Fukuda, H., Tashiro, S. and Ikeda, Y. (1982) J. Biochem. 92, 569).

Oral glucose tolerance tests were performed in 16 patients with chronic renal failure undergoing hemodialysis. In ten patients, studies were performed before and after one dialysis, while six patients were studied immediately prior to the start of chronic hemodialysis and just after the fifteenth dialysis. Hemodialysis did not lead to improvement in either the plasma glucose or growth hormone response to the oral glucose challenge. There was, however, a modest increase noted in the plasma insulin level 2 hr after the oral glucose challenge following dialysis. On the other hand, there was not any change in the overall relationship between the plasma glucose and insulin response to the oral glucose load as a result of dialysis. These results indicate that chronic hemodialysis as it is routinely conducted in the treatment of patients with chronic renal failure has, at best, a relatively modest effect on the plasma glucose, growth hormone, and insulin responses to an oral glucose challenge.

Phentolamine, yohimbine or dihydroergotamine markedly increased plasma immunoreactive insulin (IRI) and inhibited epinephrine-induced hyperglycemia in fasted mice. On the other hand, phenoxybenzamine or prazosin only slightly increased plasma IRI and enhanced epinephrine-induced hyperglycemia. These results indicate that there is a distinct difference in the effects of alpha-adrenergic blockers on the plasma IRI and glucose levels, and that alpha-adrenergic receptors responsible for the plasma IRI level resemble alpha 2-adrenergic receptors more closely.

Pregnant Wistar rats received four high-dose intramuscular injections of ritodrine per day during the last 6 days of pregnancy. The injections provoked an immediate but transient increase in plasma insulin level, without affecting the plasma glucose concentration. At the end of the treatment, the morphology of the endocrine pancreas and the ultrastructure of the B cells of the ritodrine-treated mothers were similar to those of the control mothers. No lasting influence of the treatment was seen in the fetuses of these rats: body weights, blood glucose and insulin levels, morphology of the endocrine pancreas and ultrastructure of the B cells were all normal.

Measurement of endogenous insulin in monkey plasma by an imunoassay technic is described. The procedure is a modification of that used by Yalow and Berson 1 for measurement of insulin in human plasma. This method exploits the ability of endogenous monkey insulin to inhibit competitively the binding of I 131 -labeled pork insulin to beef insulin antibodies. A critical evaluation of the method with respect to precision, reproducibility, and recovery supports the reliability of its application to the assay of monkey insulin levels. The plasma insulin level of the fasting adult male monkey was found to be in the range of

The plasma insulin was measured by a radioimmunoassay method in 48 non-pregnant or pregnant women during glucose tolerance test (100 g glucose by mouth). Each of these 2 groups included non-obese, non-diabetic women, obese females and potential diabetic patients. The non-obese, non-diabetic, non-pregnant subjects showed mean plasma insulin levels of 25.2, 77.2, 57.0, 57.8 and 44.7μU/ml respectively 0, 45, 90, 135 and 180 minutes after glucose loading. The obese normoglycemic non pregnant females presented a normal fasting plasma insulin level which reaches 184.7,μU/ml 45 minutes after glucose intake. The late pregnancy (7th to 9th month) did not change the plasma insulin observed in the non-obese, non-diabetic and obese women. The non-pregnant females with potential diabetes showed a normal fasting plasma insulin with a maximum of 96.9μU/ml 90 minutes after the beginning of the test. In these patients between the 4th to the 9th month of the pregnancy, the maximum of 68.2μU/ml was only obtained 3 hours after the glucose loading.-The physio-pathological significance of these results is discussed.

Most preparations of cholecystokinin reported to release insulin have been impure. When highly purified preparations of extracted cholecystokinin and also the synthetic C-terminal octapeptide of the hormone became available for use in humans, we investigated their insulinotropic activity in comparison with a cruder preparation of cholecystokinin in 10 fasting non-diabetic subjects. The doses employed were 75 Ivy dog units, except for the synthetic C-terminal octapeptide of cholecystokinin that was given in a dose of 200 Ivy dog units to compensate for a shorter half-life. Blood samples for determination of insulin and glucose were drawn every minute during 10 min after each injection, thereafter at intervals of 5 min. The mean plasma insulin level increased significantly, reaching a peak 4–5 min after i. v. injection of the cruder cholecystokinin preparation, but after the other two preparations the plasma insulin level was not significantly changed. The blood glucose level was not significantly changed by any of the preparations used. It is concluded that the plasma insulin peak seen in man after i.v. injection of the less highly purified preparation was due not to cholecystokinin but to some other agent present in this less pure preparation. The identity of this factor is discussed.

Electrolytic lesions of the ventromedial hypothalamus including nucl. hypothalamicus inferior caused the cockerels to become hyperphagic. The plasma insulin level of the control birds was low before feeding and it increased after feeding, while that of the hyperphagic birds was higher before feeding and increased even more after feeding. Under the fasting condition on the 19th day, the insulin secretion of the hyperphagic birds remained at a high level, and there was a high correlation between the insulin value and the food consumption. Hyperactivity of insulin secretion in the hypothalamic hyperphagic birds was inhibited by administration of diazoxide and their insulin levels declined to a level similar to that of the controls. As a result the hyperphagia was interrupted and the daily food consumption declined to the same level as the controls. Therefore, the hyperinsulinemia seemed to be necessary for maintaining the hypothalamic hyperphagia in chickens. The role of glucagon in this phenomenon is also discussed.

Secretory responses of plasma insulin, glucagon, cortical and glucose to heat exposure (33°C, 60% RH) were investigated using Holstein calves. Plasma gluagon concentration had a significant increase, but plasma insulin, cortisol and glucose had significant decreases within 24 h following heat exposure. Concerning subsequent responses to heat exposure, plasma glucagon level maintained increased concentrations for 8 days of heat exposure. Plasma insulin level increased on and after day 4 of heat exposure. However, plasma cortisol and glucose levels maintained declined levels throughout the heat days.

Paraquat dichloride was administered (45 mg/kg i.p.) to male Sprague-Dawley rats. The rats were sacrificed at different times after treatment. Blood was collected and plasma was used for various biochemical measurements. A significant increase in creatine phosphokinase activity was obtained at 12, 24, and 48 hr after paraquat treatment. The activities of glutamic oxaloacetic transaminase (GOT) and sorbitol dehydrogenase were also consistently elevated in paraquat-treated animals but a statistically significant increase was obtained only at 48 hr for GOT. Paraquat had no effect on glutamic pyruvic transaminase activity. Paraquat caused a marked increase in blood glucose and a marked depletion of liver glycogen that lasted for at least a period of 48 hr. The plasma insulin level in paraquat-treated animals was markedly depressed as compared to saline control. Various possibilities have been discussed for the hyperglycemic and liver glycogen-depleting effects of paraquat in the rat.

After heterotopic pancreatic allotransplantation in dogs and in the absence of rejection there was a fasting normoglycemia with a marked hyperinsulinemia. On intravenous glucose tolerance testing and intravenous glucagon testing, the blood sugar response of dogs receiving no immunosuppression was normal but the response in dogs receiving immunosuppressive therapy was exaggerated. There was a marked increase in the insulin response compared with normal animals whether or not immunosuppressive therapy was administered. The first endocrine even during allograft rejection seemed to be a drop in the pancreatic insulin reserve as demonstrated by plasma insulin results during a glucagon test; occurring 2 to 3 days before clinically overt rejection. This was also found on glucose tolerance testing. A rise in the fasting plasma insulin occurred next, 1 to 2 days before a rise in the fasting blood sugar. As the rejection process progressed, the plasma insulin levels subsequently dropped until the death of the animal. If, during a rejection process, the blood sugar did not rise above 150 mg/100 ml and the plasma insulin level did not drop below the lower limit of normal the rejection was usually reversible with intravenous methylprednisolone.

Insulin resistance was studied by comparing insulin response and insulin binding in four groups of rats. Glucose metabolism in isolated fat cells from male Wistar rats weighing 340 g was less responsive to a supramaximal dose of insulin than glucose metabolism in fat cells from rats weighing 200 g. Induction of streptozotocin-diabetes in rats weighing 200 g resulted in a marked decrease in the insulin responsiveness of fat cells. Ventromedial hypothalamic lesions of 340 g rats had the opposite effect and restored the insulin responsiveness of fat cells. The responsiveness in the four groups was correlated to the rate of glucose conversion to fatty acids in fat cells. The binding of 125I-insulin was the same in both 340 and 200 g rats. The ventromedial hypothalamic lesioned rats and the diabetic rats showed, in spite of their great difference in insulin responsiveness, the highest binding of 125I-insulin to fat cells. Insulin binding was not correlated to the plasma insulin level which however was reflected in the lipoprotein lipase activity in the adipose tissue. In conclusion, these results indicate that variations in insulin responsiveness in fat cells are due to alterations in cellular metabolism rather than in insulin binding.

The effect of mazindol on insulin and glucagon secretion was studied in ventromedial hypothalamic lesioned (VMH) obese rats with hyperinsulinemia and VMH sham rats. Three weeks after the VMH or sham operation, VMH and sham rats were divided into two groups: one was fed diet containing mazindol (50 mg/kg) and the other was fed diet without mazindol. They were housed three more weeks before the experiment. Mazindol reduced significantly body weight increase and calorie intake in VMH rats, but not in sham rats. In addition, the fasting plasma insulin level and the arginine-induced insulin secretion in VMH rats treated with mazindol were significantly lower than those in the VMH rats without treatment of mazindol. On the other hand, in both in vivo and in vitro experiments, mazindol produced no significant change in the insulin secretion of sham-operated rats. These results suggest that mazindol suppresses hypersecretion of insulin in VMH rats probably through an anorectic effect and/or suppression of vagal hyperactivity.

• On two occasions, a 3½-year-old black girl had severe hypoglycemia associated with transient hepatomegaly. The plasma insulin level during the second hypoglycemic episode was excessive and led to a diagnosis of malicious insulin administration. We suggest that plasma be obtained for insulin determination in children with hypoglycemia, and that transient hepatomegaly may be a helpful sign in cases of insulin overdose. ( Am J Dis Child 130:998-999, 1976)

Four cases of suicidal insulin overdose in insulin-requiring diabetics presented to one hospital in three years. In three cases there was a history of depression; but despite huge doses of insulin (3,000 and 1,500 units) in two, no patient died and only one had residual signs of clinical brain damage. The estimated plasma insulin level was not well correlated with the severity of the hypoglycaemia. It is probable that suicidal insulin overdose is more common than reports in the literature suggest, and may often be unrecognized. The dissociation between huge doses of insulin and the severity of the subsequent hypoglycaemia in diabetics is unexplained.

The effect of hyperglycemia on insulin-induced glucose metabolism (M) was investigated in healthy subjects using sequential clamp protocols at constant insulin + somatostatin infusions and varying plasma glucose. During euglycemia (4.8 mmol/l) M increased from 5.6 to 12.5 mg·kg−1·min−1 with increasing plasma insulin (0.34-3.00 nmol/l). At increasing glucose (6.7 mmol/l), M further increased (9.7 to 19.2 mg·kg−1·min−1) with the plasma insulin level (0.41 to 2.99 nmol/l). At a plasma glucose level of 9.8 mmol/l insulin (0.42 to 3.17 nmol/l) was still effective to increase M (13.7 to 25.2 mg·kg−1·min−1). Regression analysis showed that hyperglycemia does not only increase the maximal insulin-stimulated M, but also decreases the insulin concentration causing a half maximum effect. During prolonged clamp studies M increased by about 10% per h, independent by the plasma glucose level. We conclude that hyperglycemia increases M by increasing insulin responsiveness as well as insulin sensitivity. Data derived from euglycemic clamp studies alone are of limited value with respect to the assessment of insulin action.

In dogs acutely immersed in cold water (8--13 degrees C), oxygen uptake increased approximately sevenfold and colonic temperature rapidly began to decrease. Fifteen minutes after the start of immersion a high level of hyperglycemia was found but no increase in immunoreactive plasma insulin level was observed. Under these conditions exogenous insulin (0.3 U.kg-1) induced a further increase in oxygen uptake and in shivering intensity whereas a decrease in the fall of colonic temperature was observed. It can be concluded that insulin may have a calorigenic effect and improve the resistance to cold of dogs exposed to an acute cold stress.

Changes in plasma glucose and insulin concentration in response to palatinose ingestion were compared with those to sucrose in eight normal volunteers. When 50 g of palatinose was administered, the plasma glucose gradually increased to its peak of 110.9 +/- 4.9 mg/dl at 60 min after administration and maintained a plateau during the 120 min of the experiment. The peak value of plasma glucose to 50 g sucrose in the same group was 143.3 +/- 8.8 mg/dl at 30 min after administration and then the value sharply decreased to the fasting level. The cumulative increase in plasma glucose (sigma delta PG) to palatinose was significantly smaller than that to sucrose. The changes in the plasma insulin level almost paralleled those in the plasma glucose level. These results indicate that palatinose is more slowly absorbed than sucrose and therefore useful as a sweetener for diabetic patients.

We have previously shown that a significant inverse correlation exists between the height of the plasma insulin concentration and the efficiency of glucose uptake in the fasting state. Subsequently, we devised an infusion technic that provides a more specific measure of cellular resistance to insulin mediated glucose uptake. We have used this technic to study the relationship between fasting plasma insulin level and resistance to insulin mediated glucose uptake in twenty-two patients with normal oral glucose tolerance, fourteen patients with impaired glucose tolerance, and fourteen patients classified as having chemical diabetes mellitus. The results indicate a highly significant positive correlation between the degree of insulin resistance and fasting plasma insulin concentration (r = .69, p < .0001). A positive correlation (r = .43, p < .005) was also found between the degree of insulin resistance and the two hour plasma glucose level during an oral glucose tolerance test. However, no significant correlation was found between per cent adiposity and fasting insulin level, and the relationship between insulin resistance and fasting insulin level appeared to be independent of obesity or any other known cause of decreased insulin responsiveness. These studies indicate that: (1) increases in fasting insulin levels and increase in resistance to insulin mediated glucose uptake are closely related, and that these changes can occur in the absence of any of the “known” causes of decreased insulin responsiveness; (2) in the types of subjects we have studied, deterioration of glucose tolerance is closely related to increases in insulin resistance; and (3) the increases in fasting insulin levels which we have observed appear to be compensatory attempts to overcome the resistance to glucose uptake.

The clinical observation that diabetic patients who exercise recquire less insulin therapy than those who do not, led to interest in the behaviour of circulating insulin concentrations during exercise. An increase in insulin concentration should result in increased glucose transport, and thus a decrease in blood glucose concentration. Studies of diabetic patients have shown (Sanders et al l961) that blood glucose concentration does, in fact, decrease as a result of exercise. However, since the same effect can be elicited in pancreatectomized animals (Ingle et al 1950, Goldstein et al 1953, Dulin and Clark 1961), it seems impossible that an increase in plasma insulin concentrations could be the only cause of the increased glucose transport. Thus a decrease in plasma insulin concentrations was also a possibility, and because of the necessity of preserving the blood and liver glucose for utilization by the central nervous system, this latter possibility seemed logical. A few studies of the effect of various types of exercise on plasma immunoreactive insulin (IRI) concentrations have demonstrated a decrease (Cochrane et al 1966, Rasio et al 1966, Hunter and Sukkar 1968). A study of insulin secretion in both normal and diabetic patients showed no increase as a result of exercise (Nikkila et al 1969). Studies of exercising animals have shown that insulin concentrations could be decreased during exercise even when glucose was infused (Issekutz et al 1967, Wright and Malaisse 1968).

The diurnal change in plasma immunoreactive insulin level of seventeen diabetic patients was studied before and after the treatment with sulfonylurea. The insulin area was calculated as an index to represent the diurnal summation of plasma insulin. The insulin area of the mild diabetic group and that of the moderately severe group were within a normal range before and after the treatment. The area decreased significantly in the mild diabetic group by the treatment, with a concomitant decrease in the blood glucose. However, the insulin area was unchanged in the moderately severe group. This result may be attributed to an increase of the sensitivity to insulin of the tissues by the treatment in mild diabetic group. In moderately severe group, the plasma free fatty acids (FFA) remained high still after the treatment and this high FFA is thought to be one of the reasons for unchanged plasma insulin level in this group.

The literature on the estimation of plasma insulin level by the rat diaphragm technique is surveyed briefly with particular reference to discrepancies in data on normal levels in human plasma. The difficulty of determining absolute plasma insulin levels by this technique is discussed. The method seems useful in estimating insulin activity by means of relative values.