Transient glucose intolerance during attacks of thyrotoxic periodic paralysis

In a 19-year-old Japanese male (case 1) with thyrotoxic periodic paralysis (TPP), an increase of plasma glucose concentration together with abnormally high levels of serum immunoreactive insulin (IRI) was observed preceding a spontaneous attack of paralysis. Therefore, the plasma glucose, glucagon, epinephrine, norepinephrine, serum IRI, growth hormone and cortisol levels, and the erythrocyte insulin receptors were measured in case 1 and a 40-year-old Japanese male (case 2) with TPP during attacks of paralysis induced by prolonged glucose loading. In case 1, the serum IRI concentration was elevated to the extraordinarily high level of 655.0 microU/ml at the beginning of paralysis, and at that time, the plasma glucose concentration was 147 mg/dl. However, when paralysis was not induced by a similar glucose loading during methimazole treatment, the serum IRI and plasma glucose levels at the corresponding time after glucose loading were 20.9 microU/ml and 87 mg/dl, respectively. Furthermore, the affinity of the erythrocyte insulin receptors was decreased during the attack. In case 2, plasma glucose and serum IRI concentrations were increased in accordance with the initiation of paralysis although the blood levels of hormones counteracting insulin were not significantly changed. These findings suggest that there is something interacting with the normal action of the insulin in the early phase of paralysis.     

A case of insulin autoimmune syndrome associated with small insulinomas and rheumatoid arthritis

Twenty five cases of insulin autoimmune syndrome including this case has been reported so far without having the pathogenesis clarified. This paper describes a case which suggests one aspect of pathogenesis. The patient, a housewife concurrently had insulinoma and severe rheumatoid arthritis, complaining of hypoglycemic syncope attacks. During the attacks her blood sugar levels ranged from 19 to 22 mg%. Her serum extractable immunoreactive insulin (IRI) and insulin binding antibody levels were 557 microunits/ml and 0.390 mU/ml, respectively. gamma-Globulin-bound insulin was also measured electrophoretically. Bio-Gel P 10 column chromatography eluted almost all IRI at the void volume at pH 7.4 and a smaller but significant IRI peak also at pH 3.0. Selective angiography revealed a tumor-like staining in the pancreas body. Pancreatectomy relieved her of hypoglycemic attacks. Histology disclosed two small insulinomas. Insulinoma, rheumatoid arthritis and insulin autoimmune syndrome coexisted in this case, suggesting some causal relationship among them.     

Effect of doxazosin on insulin resistance in hypertensive patients with obesity.

We determined the effect of alpha-adrenergic blocking agent doxazosin on insulin resistance in 19 hypertensive patients (blood pressure [BP] >160/90 mmHg) with obesity (mean body mass index [BMI]: 26.7 +/- 1.9 kg/m (2)). Patients received doxazosin 4 mg/day for 12 months. Systolic and diastolic BP decreased from 169 +/- 10.8 mmHg to 147 +/- 11.9 mmHg (p < 0.0001) and from 102 +/- 8.1 mmHg to 87 +/- 5.0 mmHg (p < 0.0001), respectively. Insulin resistance and fasting immunoreactive insulin (IRI) were lower at study end vs. baseline (HOMA-R = 1.29 +/- 0.38 vs. 3.58 +/- 2.23 [p = 0.022]; IRI = 6.00 +/- 1.88 microU/ml vs 13.74 +/- 8.51 microU/ml [p = 0.046]). Total cholesterol was significantly reduced following treatment. Circulating TNF-alpha and leptin levels decreased significantly within 3 months of treatment; leptin was independently associated with insulin resistance when adjusted for BMI. We conclude that doxazosin improves insulin resistance and improves dyslipidemia in obese hypertensive patients, and has a beneficial effect on adipose endocrine activity.     

Changes in plasma glucagon, pancreatic polypeptide and insulin during development of alloxan diabetes mellitus in dog

Changes in canine plasma glucose, immunoreactive glucagon (IRG), pancreatic polypeptide (PP) and insulin (IRI) were studied during the acute development of diabetes mellitus after iv alloxan injection. 100 mg or 75 mg/kg body weight of alloxan was injected iv and blood was taken successively till one or two days later. Plasma glucose showed four phases: first immediate and moderate decrease appeared 30 min after injection, second initial hyperglycemic phase, third hypoglycemic and fourth diabetic ones. Plasma IRI had already increased to 182 +/- 60 microU/ml 10 min after injection and again began to increase after about 6 h, peaking to 134 +/- 49 microU/ml at 18 h. Plasma IRG began increasing gradually soon after alloxan injection. The initial value was 196 +/- 26 pg/ml and it increased to 534 +/- 144 pg/ml at 4 h during the initial hyperglycemic phase, then reached a higher level through the hypoglycemic and diabetic phases. The change in plasma PP was similar to that in IRG. The initial value was 256 +/- 95 pg/ml at 12 h after injection, peaking to 840 +/- 100 pg/ml in the hypoglycemic phase. Similar blunted values were obtained following 75 mg/kg alloxan injection. Thus not only plasma IRI but also plasma IRG and PP varied greatly during the acute development of alloxan diabetes and some contribution of IRG to the initial hyperglycemic phase was suggested.     

Important role of glucagon during exercise in diabetic dogs

To define the role of immunoreactive glucagon (IRG) during exercise in diabetes, 12 insulin-deprived alloxan-diabetic (A-D) dogs were run for 90 min (100 m/min, 12 degrees) with or without somatostatin (St 0.5 microgram . kg-1 . min-1). Compared with normal dogs, A-D dogs were characterized by similar hepatic glucose production (Ra), lower glucose metabolic clearance, and higher plasma glucose and free fatty acid levels during rest and exercise. In A-D dogs IRG was greater at rest and exhibited a threefold greater exercise increment than controls, whereas immunoreactive insulin (IRI) was reduced by 68% at rest but had similar values to controls during exercise. Basal norepinephrine, epinephrine, cortisol, and lactate levels were similar in normal and A-D dogs. However, exercise increments in norepinephrine, cortisol, and lactate were higher in A-D dogs. When St was infused during exercise in the A-D dogs, IRG was suppressed by 432 +/- 146 pg/ml below basal and far below the exercise response in A-D controls (delta = 645 +/- 153 pg/ml). IRI was reduced by 1.8 +/- 0.2 microU/ml with St. With IRG suppression the increase in Ra seen in exercising A-D controls (delta = 4.8 +/- 1.6 mg . kg-1 . min-1) was virtually abolished, and glycemia fell by 104 to 133 +/- 37 mg/dl. Owing to this decrease in glycemia, the increase in glucose disappearance was attenuated. Despite the large fall in glucose during IRG suppression, counterregulatory increases were not excessive compared with A-D controls. In fact, as glucose levels approached euglycemia, the increments in norepinephrine and cortisol were reduced to levels similar to those seen in normal exercising dogs. In conclusion, IRG suppression during exercise in A-D dogs almost completely obviated the increase in Ra, resulting in a large decrease in plasma glucose. Despite this large fall in glucose, there was no excess counterregulation, since glucose concentrations never reached the hypoglycemic range.     

Glucagon and insulin relationships in genetically diabetic (db/db) and in streptozotocin-induced diabetic mice.

An inappropriate molar ratio of circulating insulin to glucagon is frequently associated with the metabolic alterations accompanying diabetes mellitus. Plasma immunoreactive insulin (IRI) and immunoreactive glucagon (IRG) levels were determined and the IRG:IRI ratio calculated at various intervals in overt diabetes in genetically diabetic (db/db) and in streptozotocin-treated mice. Plasma IRI levels in genetic mutants are elevated at nine weeks of age, but are comparable to values found in lean littermates by 21 weeks. The presence of a prevailing hyperglucagonemia is established for the first time in the intact db/db mice. Streptozotocin diabetics are found to have characteristically low plasma IRI and high plasma IRG values. The hormonal imbalance present in these two experimental animal models is accentuated when the data are expressed as the IRG:IRI ratio, which is seen to increase with the progression of diabetes.     

The relationship between plasma concentration and disappearance rate of immunoreactive insulin in the conscious dog

The relationship between plasma concentration and disappearance (infusion) rate of insulin was determined during infusion of insulin via the portal circulation of 14 normal euglycaemic dogs when somatostatin was infused to block endogenous insulin secretion. The relationship could be represented by one straight line over the plasma immunoreactive insulin range 0 to 110 microU/ml (r = 0.99) but above 110 microU/ml the fractional insulin disappearance rate declined. The results indicate the existence in the dog of a saturable pathway of insulin degradation that could conceivably be located in liver and which may become saturated only at insulin concentrations in the portal vein exceeding approximately 330 microU/ml.     

Liver glycogen and plasma insulin and glucagon levels in food- and water-deprived black-tailed prairie dogs (Cynomys ludovicianus)

1. Liver glycogen levels and plasma levels of insulin and glucagon were measured in fed and in food- and water-deprived prairie dogs. 2. Liver glycogen values decreased from 45.5 to 12.4 mg/g (73%) after 21 days of food and water deprivation, while a 24-hr fast resulted in a liver glycogen value of 47.5 mg/g. 3. Rat liver glycogen values decreased from 45.6 to 2.3 mg/g (95%) after a 24-hr fast. 4. Prairie dog plasma insulin values were 69.2, 15.8 and 25.4 microU/ml in fed, and in 24-hr and 32-day food- and water-deprived animals, respectively. 5. Prairie dog plasma glucagon levels were 57.0 and 38.4 microU/ml in fed and in 32-day food- and water-deprived animals. 6. Plasma values for glucose, urea nitrogen, acetone and triglyceride agreed with previously published results. 7. We conclude that it is possible that the maintenance of liver glycogen levels in food- and water-deprived prairie dogs may be correlated with a smaller decrease in plasma insulin levels, relative to other species, and with a decrease in plasma glucagon levels.     

Regulation of insulin synthesis in an insulin-producing cell line (RINm5F): Long-term experiments

Summary The insulin-producing cell line RINm5F, has been used in short-term experiments to evaluate insulin secretion. We sought to maintain the responsiveness of these cells to stimuli for up to 2 days. We examined the course of new insulin synthesis over this period by measuring at intervals immunoreactive insulin (IRI) in two parts: IRI in the medium (M) and IRI extracted from the cells (C). Control cells were incubated in RPMI 1640/2.8 mM glucose/10% fetal bovine serum/200 μg/ml bacitracin (to prevent insulin degradation). The addition of dibutyryl cAMP 10 mM to the experimental dishes significantly increased total (M+C) IRI at 48 hr to 37% above the insulin content of the control dishes (p<0.01). Theophylline 10 mM increased total (M+C) IRI by 24% over control (p<0.05) after 24 hrs. Glucose, glyceraldehyde, leucine, arginine, glucagon and tolbutamide, other stimulants of insulin production, had no effect. Under the experimental conditions reported here, including the use of bacitracin, IRI synthesis can be studied for up to 48 hr. Portions of this study have been published in abstract form for the 47th Annual Meeting of the American Diabetes Association, Indianapolis, Indiana, 1987. Supported in part by the American Diabetic Association, Maryland Affiliate.     

Interleukin 1 pretreatment reduces the insulin response to glucose in chronic sucrose-fed rats.

The present studies were undertaken to determine whether interleukin 1 beta ([IL-1] 1.0 micrograms/kg, ip) pretreatment for 3 days impairs the adaptive response to sucrose feeding in rats. One week after the last IL-1 injection, when no differences in plasma glucose and serum immunoreactive insulin (IRI) levels were observed, sucrose feeding was started. Sucrose feeding for 4 weeks did not affect basal glucose levels, whereas basal IRI levels were increased in sucrose-fed rats without IL-1 pretreatment. Eight weeks later, plasma glucose levels were increased before and at 15 min after intravenous bolus of 0.5 g/kg of glucose in sucrose-fed rats with IL-1 pretreatment. Only in IL-1-treated sucrose-fed rats were basal and glucose-stimulated IRI levels significantly reduced, compared with those levels in sucrose-fed vehicle-treated rats. IL-1 decreased pancreatic IRI contents at 1 and 9 weeks after the injection. These data suggest that pancreatic damage by IL-1 attenuated insulin response to glucose stimulation after long-term sucrose feeding.     

消炎痛对四氧嘧啶引起的大鼠糖尿病的保护作用

本工作观察了预先给予消炎痛对四氧嘧啶引起的糖尿病大鼠血糖、血清胰岛素和胰高血糖素浓度的影响。结果表明:预先皮下注射消炎痛能使糖尿病大鼠血糖浓度明显降低,并且具有明显的量效关系。在消炎痛剂量5,10,15mg/kg时,注射四氧嘧啶48h后血糖浓度由对照组的591.5±38.2mg％分别降低到559.1±53.2,463.2±16.6和266.6±29.9mg％。在注射消炎痛10mg/kg的实验组,血清胰岛素浓度由对照组的10.5±2.7μU/ml增加到31.9±7.0μU/ml,胰高血糖素由对照组的550.0±27.0pg/ml降低到303.1±22.9pg/ml。组织学观察结果表明,消炎痛对四氧嘧啶引起的大鼠胰岛β细胞的损伤具有显著的保护作用。     

Behavior of C-peptide and immunoreactive insulin in essential obesity]

The levels of glucose, immunoreactive insulin and C-peptide were studied in 13 obese patients and 10 control subjects, in basal conditions and after an oral glucose load (OGTT). The IRI and C-peptide levels were higher in the obese patients than in the controls either during fasting or during the OGTT. The C-peptide/IRI ratio decreased after the oral glucose load in both groups studied. However in the obese subjects the values for the C-peptide/IRI ratio were lower than those found in the controls during the same observation period. These results suggest the hypothesis that in the obese patients the high IRI levels which reflect an increased insulin secretion, are, at least in part, due to an early saturation of the hepatic degradation of insulin and/or to a decrease in the specific receptor sites normally present in the cell membranes.     

The effect of magnesium deficiency on glucose stimulated insulin secretion in rats

Weanling Sherman rats were pair-fed for 8 days on a control or a magnesium deficient diet containing 70.5% sucrose. After a 12-hour fast, the rats were injected intraperitoneally with glucose (250 mg/100 g body weight) and arterial blood was drawn at 0, 15, 30, 60, 90 minutes after injection. Before glucose loading, in magnesium deficient rats, plasma magnesium levels were significantly increased. The plasma triglyceride concentration was significantly higher in magnesium deficient rats compared to controls. After glucose loading, in the control group, the plasma insulin concentrations increased to 67.9 +/- 5.8 microU/ml at 15 minutes and returned to pretreatment levels by 30 minutes; in the magnesium-deficient rats, the plasma insulin levels were significantly lower at 15 minutes 32.9 +/- 5.6 microU/ml (P less than 0.01) and returned more slowly to the pre-challenge level. No significant differences were observed in plasma glucose levels between the two groups of rats.     

The effect of long-distance running on plasma immunoreactive glucagon levels

Twelve highly conditioned long-distance runners were studied to determine the effects of marathon (42 km) and 10,000 m running on plasma immunoreactive glucagon (IRG), serum immunoreactive insulin (IRI), and serum glucose (G) levels. Blood samples were drawn just prior to and immediately upon completion of the run. Marathon running resulted in no significant change in G, IRI, or IRG levels. After running 10,000 m, plasma IRG levels did not change significantly, while IRI and G increased significantly. In evaluating the pooled data from both runs, a significant inverse correlation was observed between delta G and delta IRG. This relationship between delta G and delta IRG suggests that glucagon plays a role in maintaining normal blood glucose levels during strenuous exercise.     

Inhibitory effect of anaesthesia with 2-phenoxyethanol as compared to MS222 on glucose release in isolated hepatocytes from rainbow trout (Salmo gairdneri)

1. Glucose production by freshly isolated hepatocytes from rainbow trout was studied after anaesthesia of the animals with 2-phenoxy ethanol (2PE) or tricaine methanesulphonate (MS222). 2. At the end of the procedure, hepatic contents of glycogen, glucose, lactate, ATP, ADP, AMP, were not significantly different between the two treatments. 3. Glucose production was considerably lower for 2PE than for MS222 anaesthetized trouts. This discrepancy results probably from an inhibition of glycogenolysis, suggesting that 2PE anaesthetized animals were less stressed than MS222 anaesthetized ones.     

Dexamethasone-induced catabolism and insulin resistance in L6 myoblasts are reversed by the removal of serum.

1. One hundred nanomolar dexamethasone reduced protein synthesis by 16% and also decreased the accretion of protein and RNA in L6 myoblasts when foetal calf serum was present; these effects were reversed when serum was omitted from the medium. 2. Insulin (100 microU/ml) increased protein synthesis, protein accretion and RNA accretion both in the presence and the absence of serum. 3. Dexamethasone inhibited the effects of 100 microU insulin/ml in the presence of serum and induced insulin resistance; in the presence of 25 or 100 nM dexamethasone insulin was ineffective at concentrations below 250 microU and 1 mU/ml respectively.     

Differences in insulin-induced glucose uptake and enzyme activity in running rats

To evaluate the relationship between enhanced insulin action and level of exercise training, in vivo glucose uptake was assessed in the absence of added insulin and during insulin-stimulated conditions for three activity levels of voluntarily trained rats (low 2-5 km/day, medium 6-9 km/day, high 11-16 km/day). After rats rested for 24 h and fasted overnight, glucose uptake was estimated by comparing steady-state serum glucose (SSSG) levels at low insulin (SSSI) concentrations achieved during an insulin suppression test. In the absence of added insulin, SSSI averaged approximately 20 microU/ml and glucose uptake was similar for high runners and younger weight-matched controls. However, with insulin added to sustain SSSI at approximately 35 microU/ml, SSSG was significantly reduced in all runners (P less than 0.02), with the lowest value attained in high runners. Fasting serum triglycerides were also reduced in all runners (P less than 0.05), with the lowest values seen in medium and high runners. The concentration of glycogen in liver and select skeletal muscles at the start of the study was not different between trained and control rats, suggesting that enhanced insulin-stimulated glucose uptake was not the result of lower glycogen levels. In addition, glycogen synthase and succinate dehydrogenase activities in biceps femoris muscle were only elevated for high runners, but glycogen synthase activity was not enhanced in plantaris muscle and was decreased in soleus muscle. These findings indicate that enhanced insulin-stimulated glucose uptake and reduced serum triglyceride concentrations induced in exercise-trained rats at varying activity levels are dissociated from changes in glycogen synthase and oxidative enzyme activity for skeletal muscle.     

Role of 5-hydroxytryptamine in the regulation of brain neuropeptides in normal and diabetic rat

The effect of 5-hydroxytryptamine (5-HT) alteration on brain dopamine (DA), norepinephrine (NE), beta-endorphin (beta E) and immunoreactive insulin (IRI) was studied in Sprague-Dawley diabetic and control rats. Diabetes was induced using alloxan (45 mg/kg), 15 days prior to sacrificing. Both control and diabetic animals were treated with either p-chlorophenylalanine (PCPA, 300 mg/kg) 3 days prior to sacrificing or fluoxetine (10 mg/kg) twice daily for 3 days. PCPA treatment significantly decreased brain content of 5-HT and 5-hydroxyindole acetic acid (5-HIAA) while it caused significant increase and decrease in brain beta E and insulin levels, respectively, in both normal and diabetic rat. Meanwhile, the administration of fluoxetine resulted in significant increase in brain content of 5-HT, DA, NE and insulin but significant decline of beta E in diabetic and saline control rats. The results of this experiment indicate that 5-HT may be regulating both beta E and insulin regardless of the availability of pancreatic insulin.     

Association between serum insulin, serum somatomedin and liver receptors for human growth hormone in streptozotocin diabetes

Streptozotocin-induced diabetes in the female rat caused a decrease in the serum level of somatomedin (Sm), measured by radioreceptor assay. The decrease was reversed by insulin therapy. In diabetes of varying severity, serum insulin and Sm levels showed highly significant association up to the insulin concentration (18 microU/ml) corresponding to normal serum Sm (1 U/ml). Similarly, the hepatic binding of human growth hormone (hGH) showed highly significant association with serum Sm levels up to the degree of binding (7% of tracer) corresponding to normal serum Sm. Binding of hGH to normal liver was about 12% of tracer. These results suggest that insulin might regulate serum Sm via its effect on liver lactogenic receptors, and that about half of these receptors are "spare", or in excess of those required to maintain normal serum Sm levels.     

A case of autoimmune insulin antibody syndrome associated with polymyositis, empty sella and apparent high urinary output of immunoreactive insulin.

Patients with autoimmune insulin antibody are characterized by hypoglycemic attacks and antibodies to insulin in serum without prior insulin administration. In the present report, a patient with hypoglycemia due to autoimmune insulin antibody associated with primary empty sella syndrome and polymyositis appeared to have high urinary immunoreactive insulin (IRI) in the face of normal urinary C peptide. Consequently, the urinary IRI/C peptide ratio was apparently high. The amelioration of hypoglycemic attacks and polymyositis by prednisolone treatment was accompanied by the disappearance of the antibodies and complete normalization of the urinary IRI and IRI/C peptide ratio. No comparable rise in the urinary IRI and IRI/C peptide ratio was observed in the patients with other disorders studied. Glucose clamp and glucose tolerance study showed decreased sensitivity to exogenous or newly secreted insulin, prolonged half disappearance time of serum insulin, and normal disappearance of blood glucose. These results were consistent with the idea that autoantibodies buffered the effect of exogenous or newly secreted insulin and maintained a relatively constant level of serum free insulin which was not high enough when a large amount of glucose was loaded, but was too high after prolonged fasting, which eventually caused hypoglycemic attacks.