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Spontaneously Diabetic Torii (SDT) rat is a model of severe type 2 diabetes and its complications. These characteristics of SDT rat are very useful to research diseases; however, the slow onset of diabetes may limit the usefulness of this animal model. To solve this problem, we performed bilateral midbrain transection on SDT rats and evaluated whether hyperphagia accelerates the onset of diabetes. By severing ascending fibers from the nucleus tractus solitarius to limbic regions through ventral and dorsal tegmental regions, food consumption was significantly increased in SDT rats and the onset of diabetes was accelerated. Cumulative incidence of diabetes in midbrain transected SDT rats was 88.9% at 7 weeks after surgery (14 weeks of age), while sham operated rats was 20.0%. Increased food consumption was correlated to body weight, plasma glucose level, plasma triglyceride level, and plasma insulin level. In conclusion, the overeating caused by blocking anorexigenic signal in brain significantly accelerates the onset of diabetes in SDT rats. The early development of type 2 diabetes may accelerate microvascular complications and is considered useful in the study of the disease in SDT rats.

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.

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.

Male patients with idiopathic hypogonadotropic hypogonadism (IHH) characterized with low serum testosterone(T) might have higher risks of diabetes and coronary heart disease partly due to the high level of plasma insulin. Low serum T might also affect the body fat mass(BFM) in patients with IHH. However, the relationship between BFM and plasma insulin level in IHH patients has not been clearly clarified. A total of 22 patients who were admitted to our hospital with IHH and normal glucose tolerance(NGT) confirmed by oral glucose tolerance test and 10 healthy subjects as controls were enrolled into our study. Glucose, insulin, serum T levels, HOMA-IR, HOMA-B and percentage of BFM were determined. When compared with controls subjects, patients with IHH had significantly lower T concentrations(1.80nmol/L vs. 19.82nmol/L, P BFM was an independent factor of plasma insulin level in IHH patients with NGT. Disclosure X. Yang: None. Q. Lin: None. X. Hu: None. W. Xu: None. H.R. Deng: None.

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 ...

The aim of this study was to investigate serum chemerin and insulin sensitivity alterations due to exercise training below and above lactate thresholds in streptozocin-induced diabetic rats. Twenty-four rats (190 ± 14 g) were randomly assigned to three groups of control (CON), above lactate thresholds (ALT) and below lactate thresholds (BLT) (n = 8). Then after induction of diabetes, BLT and ALT performed an 8-week exercise program on treadmill running (15 and 27 m/min, respectively) at 0° slope, 1 h/day, and 5 days/week. SPSS version 16 was used for data analysis. The findings showed that, BLT serum chemerin decreased −27 % compared to CON that was statistically significant (p = 0.042), fasting Glucose level of ALT was significantly decreased 19 % compared to CON after 8-week training protocol (p = 0.02). Also 24 % significant reduction was observed in BLT in comparison to CON (p = 0.005). Insulin sensitivity of BLT and ALT improved 7 and 5 %, respectively, compared to CON and both were not significant. Also, positive correlationship was observed between fasting plasma glucose and serum chemerin but it was not significant statistically. Negative correlationship was seen between plasma insulin level and chemerin concentrations and it was not significant too. Compared with CON, BLT weight was significantly reduced 12 % (p = 0.012). Also 9 % weight loss was observed in ALT due to 8-week exercise training which was not statistically significant (p = 0.058). In summary, 8-week exercise training below lactate thresholds may reduce serum chemerin and improve fasting glucose levels.

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.

This study was performed to clarify the influence of liraglutide on gastric emptying in Japanese patients with type 2 diabetes. In 16 patients, the [ 13 C]-acetate breath test was performed to compare gastric emptying before and after liraglutide treatment. We found two patterns of response, with gastric emptying being delayed by liraglutide in seven patients (delayers) and not delayed in nine patients (non-delayers). The mean increase of the maximum gastric emptying time was 31 ± 4m in (p< 0.01 vs. baseline) in the delayers, while it was only 2 ± 3m in (p= 0.60 vs. baseline) in the non-delayers. The delayers showed a greater early decrease of AUC-PG from 0 to 60 min, despite no increase of the plasma insulin level compared with non-delayers. In conclusion, the effect of liraglutide treatment on gastric emptying shows heterogeneity, and patients can be classified as delayers or non-delayers.

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 clinical aspects and the plasma insulin response patterns in young subjects with mild diabetes are described. Young subjects with mild diabetes have no or very few symptoms and can be controlled by diet or oral antidiabetic drugs. The mild diabetics are divided into two groups according to the fasting blood glucose concentration. Subjects having a normal fasting blood glucose concentration but a diabetic glucose tolerance test are called juvenile glucose tolerance test diabetics and those with elevated fasting blood glucose concentration and a diabetic glucose tolerance test are designated mild juvenile diabetics. It is demonstrated that juvenile glucose tolerance test diabetics have a normal plasma insulin response after i.v. glucose and tolbutamide. The plasma insulin response to oral glucose, however, is weak and slow in comparison to non-diabetics. In contradistinction, mild juvenile diabetics exhibit a weak and delayed plasma insulin response both to i.v. and oral glucose and to i.v. tolbutamide. In comparison with classic juvenile diabetics, juvenile glucose tolerance test diabetics and mild juvenile diabetics have a much higher plasma insulin level during the tests.

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.

BACKGROUND High altitude illness (HAI) is a cluster of syndromes which develops due to the injury of the central nervous system produced by the reduction of the partial pressure of O2 in the atmosphere which disappears on decent. The HAI also results in a prothrombotic condition leading to acute coronary syndrome (ACS), which cannot be controlled on descent to the ground level. There is no diagnosis in HAI to forewarn of the impending ACS. A protein identified to be dermcidin isoform 2 (dermcidin), produced in the system due to environmental stresses, has been reported to be a potent diabetogenic agent. Investigation was carried out to determine the systemic stimulation of dermcidin synthesis at different levels of altitudes in normal adult male volunteers to assess the feasibility of developing a diagnosis for ACS in HAI due to dermcidin synthesis. METHODS Normal, nondiabetic, normotensive male volunteers (25 - 35 years old, n = 16) participated in the study. The plasma dermcidin level was determined by enzyme linked immunosorbent assay (ELISA) and by in vitro translation of dermcidin mRNA. The plasma insulin level was determined by ELISA and blood glucose level was determined in a glucometer (Behringer). RESULTS The plasma dermcidin level in the volunteers at ground level was 10 +/- 2.10 nM and increased to 80 +/- 4.62 nM at 15000 feet altitude. For each 1000 feet increase of altitude, the dermcidin level increased by 5.83 +/- 0.21 nM with a Coefficient of Correlation "r" = +0.9405. The increase of plasma dermcidin level was found to be inversely related to the decrease of plasma insulin level from 23 microunit/mL to 5 microunit/mL from sea level to 15000 feet height ("r" = -0.9951) with concomitant increase of blood sugar level from 80 +/- 3.6 mg/dL to 135 +/- 2.01 mg/dL. CONCLUSIONS These results suggest the feasibility of a diagnosis of a prediabetic condition by determining the plasma dermcidin level in HAI by simple ELISA which may also be useful to forewarn of the possibility of developing an impending prothrombotic condition in HAI.

The antidiabetic activity of Thea sinensis was investigated in KK-Ay mice, an animal model of genetically type 2 diabetes with hyperinsulinemia. The water extract of Thea sinensis (green tea cold ext) (100 mg/kg body weight) reduced the blood glucose of KK-Ay mice 4 and 8 weeks after repeated administration and tended to decrease the plasma insulin level of KK-Ay mice under similar conditions. However, green tea cold ext did not affect blood glucose levels in normal mice. Green tea cold ext decreased blood glucose levels in an insulin tolerance test. These results suggest that the antidiabetic activity of green tea cold ext is derived, at least in part, from a decrease in plasma insulin, due to decreased insulin resistance.

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

Introduction: During late pregnancy, hypertriglyceridemia develops. The hepatic expression of genes related to lipid metabolism is modulated through the activation of the peroxisome proliferator-activated alpha receptor (PPAR alpha). Since fatty acids have been demonstrated to activate PPAR, we studied the effects of diets with different fatty acids compositions in pregnant rats on maternal triglyceridemia and the expression of PPAR related genes.

Insulin lispro has a more rapid onset and a shorter duration of hypoglycaemic action than regular insulin. We report a 39-year-old woman, with no previous medical history, who injected 300 U of the insulin lispro (Humalog) in an attempted suicide. Half an hour later, she was found comatose and brought to our emergency department. On arrival, she was comatose, with capillary glucose of 0.4 mmol/L. She awoke after a 50 ml intravenous bolus of 50% glucose. A continuous infusion of 10% glucose was started. Intermittent hypoglycaemia with neurological signs requiring treatment with 50% glucose was recorded three times during subsequent hospitalization, the last episode being 11 h after insulin injection. The plasma insulin level 4 h after injection was 1465 mU/L, and 18 h after injection was 11 mU/L. Hypoglycaemia after an insulin lispro overdose may last for more than 11 h. Repeated hypoglycaemia after an insulin overdose could be avoided with a glucose infusion rate equivalent to the maximal glucose disposal rate.

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

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.

Effects of l-methyl-2-(β-naphthyl)-aziridine (250059-S), which possesses characteristic tranquilizing actions, on levels of blood glucose and liver glycogen, and on adrenaline release from the adrenal gland were studied in rats. While there was no elevation of blood glucose, a decrease of liver glycogen was detected after an s.c. injection of 250059-S (5 or 25 mg/kg). Marked decrease of adrenaline content in adrenal glands was observed 2 hours after subcutaneous administration of 50 mg/kg of this compound. This result is consistent with the marked adrenaline secretion from the adrenal gland into adrenal-venous blood after injection of 25 mg/kg or more of 250059-S. In splanchnicotomized rats, however, 250059-S-induced adrenaline release was not clearly observed. Pretreatment with 250059-S prevented adrenaline-induced hyperglycemia. 250059-S, at doses of 10 and 25 mg/kg, elevated the plasma insulin level to about twice that of the control. The 250059-S-induced depletion of liver glycogen was not completely blocked by adrenal demedullation, although it completely disappeared with pretreatment with 10 mg/kg of propranolol. In conclusion, 250059-S causes hypersecretion of adrenaline from the adrenal glands through excitation of the splanchnic nerves, though it causes no elevation of blood glucose, mainly because of its direct or indirect blocking action on adrenaline hyperglycemia.

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.

Under certain circumstances exercise and deficient calorie intake can cause hypoglycemia. Hypoglycemia results when hepatic glucose output from glycogen breakdown and glu- coneogenesis is inadequate to support essential glucose utilization, which is increased in muscles during exercise and decreased in all tissues during starvation. In both exercise and starvation the plasma insulin level falls and glucagon and growth hormone levels increase. The symp toms of exhaustion during exercise are not due to hypoglycemia, and the usual symptoms of hypoglycemia are absent during severe caloric restriction. In some patients with hypoglycemia and starvation, low plasma glucose persisted despite administration of very large amounts of glucose.

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.

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.

The effect of physiological dose of purified secretin on glucose-stimulated insulin secretion was studied in healthy volunteers during a continuous infusion of glucose. The intravenous injection of ten unit of secretin during the infusion of glucose caused a greater rise in plasma insulin level and a more marked decrease in blood glucose concentration than either the infusion of glucose or secretin alone did, resulting in a significant increase in the insulinogenic index. One unit of secretin has no effect on plasma insulin and glucose concentrations in the fasting or hyperglycemic state.The physiological role of secretin in regulating insulin secretion after ingestion of food was discussed.

Extract: A steady-state radioglyucose dilution technique was used to determine new glucose production in six newborn (1–4 days) and two adult dogs in the postabsorptive state, and during a 90-min glucagon infusion. Basal new glucose production rates were 2.0 and 2.2 mg/kg body weight per minute in the adults. In contrast, basal rates in the newborn were 2–4 times (4.1–7.9 mg/kg/min) the values for the adults. During glucagon-induced hyperglycemia in the adult, glucose production increased to 2.5 times the basal level, while plasma glucose concentration rose to a peak at 30 min. The newborn dog responded with only a 40% increment above basal production while glucose concentation rose continuously. The adult responded with a rise in plasma insulin level but no change was observed in the newborn. The fractional rate of glucose utilization during the glucagon-induced hyperglycemia was observed to decline in newborn dogs; no decline was observed in the adults. Glucose metabolism in the newborn differs from that in the adult dog as follows: 1) basal glucose production and utilization per unit body weight are rathter in the newborn; and 2) during glucagon-stimulated hyperglycemia the newborn adaps with less acceleration of both the production and the utilization of glucose. Speculation: If the human newborn responds similarly to the puppy, then hepatic glucose output appears to be near maximum in order to meet basal requirements for glucose. Conditions that accelerate peripheral tissue glucose uptake will, therefore, rapidly result in hypoglycemia. Conversely, a reduction in hepatic output may result in low blood glucose concentration.

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.

In recent years estrogens, either alone or with progestins in a sequential dosage schedule, have been introduced in the hormonal substitution treatment of post-menopausal women. Synthetic estrogen-progestin combinations given for contraceptive purposes are known to cause certain metabolic alterations (for a recent review see, e.g. Spellacy1). These include an increase in the fasting plasma insulin level and an increase in the plasma insulin response after glucose load. An increase in the serum triglyceride level is found almost without exception in women taking oral contraceptives. Alterations in serum cholesterol levels are less consistent.

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.

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)

During 1979 sufficient amounts of ‘semi-synthetic’ human insulin produced by enzymatic conversion of porcine insulin (Markussen, 1980) became available for pre-clinical toxicity and general pharmacological studies in animals. No real difference was found between the effects of human and porcine insulin (Gamst-Andersen et al, 1983; Jorgensen et al, 1983). Following the satisfactory completion of these studies, human insulin prepared to monocomponent specifications (Schlichtkrull et al, 1970, 1974) became available for clinical evaluation during August 1980.

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.

Gestational diabetes mellitus is a heterogenous clinical entity with substantial phenotypic and genotypic diversity in the mother (Freinkel etal., 1985). It is most common in obese women and in those over 30 years old. Typically, the insulin response to glucose intake is delayed, while the basal plasma insulin level is normal or even elevated (Kuhl etal., 1985; Persson and Lunell, 1975). The increase of maternal plasma insulin response to an increase in blood glucose, however, is diminished (Freinkel etal., 1985), leading to a relative insulin deficiency in the gravida and consequently to fetopathy. HLA antigens DR 3 and DR 4 are often associated with gestational diabetes mellitus as are cytoplasmic islet-cell antibodies (Freinkel etal., 1985).

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.

It already has been reported that marked hypoglycemia with a significant increase of plasma insulin level was observed in normal dogs following intravenous administration of xylitol. These characteristic responses of blood sugar and plasma insulin to xylitol were not found in diabetic dogs in our previous experiment [1].

The plasma insulin level and glucose tolerance were studied In five patients with homocystinuria. Two of them showed a marked hyperinsulinemia and a concomitant pathologic glucose tolerance, while the remaining three showed a normal glucose tolerance, two of them, however, had plasma insulin values in the upper level of the normal range. These preliminary results support the earlier hypothesis that the pancreatic islets β-cells are particularly sensitive to an imbalance in the sulfhydryl levels of the organism since homocystinurics have an increased plasma methionine level due to an inborn error of the methionine metabolism.