Hypoglycaemic Effect Of Exogenous Insulin Research Articles

Increasing glucagon secretion could antagonize the action of exogenous insulin for glycemic control in streptozocin-induced diabetic rhesus monkeys

Although intraislet insulin signaling is known to play a critical role in regulating glucagon secretion, it is unknown whether abnormal glucagon secretion influences the hypoglycemic effect of exogenous insulin with intraislet insulin deletion. We performed a longitudinal study using 16 streptozocin (STZ)-induced diabetic rhesus monkeys to explore α-cell function under the absence β-cells and to assess whether increasing glucagon secretion antagonizes the action of exogenous insulin for glycemic control. We found that although the α-cells were impaired and the basal secretion levels of glucagon decreased rapidly after STZ (80-90 mg/kg) administration, as based on long-term observation post-STZ injection, glucagon secretion and the number of α-cells were increased. Glycemic control was increasingly difficult, the insulin resistance (HOMA-IR) index was significantly higher, and the triglycerides (TG) levels were gradually decreased. Moreover, a significant correlation between the levels of glucagon and HOMA-IR was found. Under the long-term absence of β-cells, the inhibitory effect on α-cell activity is profoundly attenuated, leading to an increase in glucagon secretion and the amount of α-cells and even α-cell dysfunction. Increased glucagon levels have a serious impact on the insulin sensitivity in vivo and result in an antagonization of the hypoglycemic effect of exogenous insulin.

Electroacupuncture-Induced Cholinergic Nerve Activation Enhances the Hypoglycemic Effect of Exogenous Insulin in a Rat Model of Streptozotocin-Induced Diabetes

The aim of this study is to explore the mechanisms by which electroacupuncture (EA) enhances the hypoglycemic effect of exogenous insulin in a streptozotocin- (STZ-) diabetic rats. Animals in the EA group were anesthetized and subjected to the insulin challenge test (ICT) and EA for 60 minutes. In the control group, rats were subjected to the same treatment with the exception of EA stimulation. Blood samples were drawn to measure changes in plasma glucose, free fatty acids (FFA), and insulin levels. Western blot was used to assay proteins involved in insulin signaling. Furthermore, atropine, hemicholinium-3 (HC-3), and Eserine were used to explore the relationship between EA and cholinergic nerve activation during ICT. EA augmented the blood glucose-lowering effects of EA by activating the cholinergic nerves in STZ rats that had been exposed to exogenous insulin. This phenomenon may be related to enhancement of insulin signaling rather than to changes in FFA concentration.

Insulin–glucose interactions characterised in newly hatched broiler chicks

1. A study was conducted to identify the specificity of insulin–glucose interactions in newly hatched broiler chicks. 2. Plasma insulin concentrations in fed chicks at one day post-hatch were lower than those at later ages and tended to increase up to d 7, while the concentrations from 1 to 7 d of age were lower than those in chickens of 10 to 28 d of age. 3. Plasma glucose concentrations were lowered for 60 min by injection of insulin at 10 and 40 µg/kg body weight (BW) in both 1- and 21-d-old chicks, showing that the hypoglycaemic effect of exogenous insulin is of larger magnitude but shorter duration in 1-d-old chicks. 4. The decrease in plasma glucose concentration at 60 min after insulin injection (10 and 40 µg/kg BW) was larger in 1- to 7-d-old chicks than in 14- to 21-d-old chickens. 5. These results indicate that newly hatched broiler chicks are under the control of specific insulin–glucose interactions characterised by low plasma insulin concentrations with high sensitivity to insulin.

Control mechanisms of the oscillations of insulin secretion in vitro and in vivo.

The mechanisms driving the pulsatility of insulin secretion in vivo and in vitro are still unclear. Because glucose metabolism and changes in cytosolic free Ca(2+) ([Ca(2+)](c)) in beta-cells play a key role in the control of insulin secretion, and because oscillations of these two factors have been observed in single isolated islets and beta-cells, pulsatile insulin secretion could theoretically result from [Ca(2+)](c) or metabolism oscillations. We could not detect metabolic oscillations independent from [Ca(2+)](c) changes in beta-cells, and imposed metabolic oscillations were poorly effective in inducing oscillations of secretion when [Ca(2+)](c) was kept stable, which suggests that metabolic oscillations are not the direct regulator of the oscillations of secretion. By contrast, tight temporal and quantitative correlations between the changes in [Ca(2+)](c) and insulin release strongly suggest that [Ca(2+)](c) oscillations are the direct drivers of insulin secretion oscillations. Metabolism may play a dual role, inducing [Ca(2+)](c) oscillations (via changes in ATP-sensitive K(+) channel activity and membrane potential) and amplifying the secretory response by increasing the efficiency of Ca(2+) on exocytosis. The mechanisms underlying the oscillations of insulin secretion by the isolated pancreas and those observed in vivo remain elusive. It is not known how the functioning of distinct islets is synchronized, and the possible role of intrapancreatic ganglia in this synchronization requires confirmation. That pulsatile insulin secretion is beneficial in vivo, by preventing insulin resistance, is suggested by the greater hypoglycemic effect of exogenous insulin when it is infused in a pulsatile rather than continuous manner. The observation that type 2 diabetic patients have impaired pulsatile insulin secretion has prompted the suggestion that such dysregulation contributes to the disease and justifies the efforts toward understanding of the mechanism underlying the pulsatility of insulin secretion both in vitro and in vivo.

Actions of novel antidiabetic thiazolidinedione, T-174, in animal models of non-insulin-dependent diabetes mellitus (NIDDM) and in cultured muscle cells.

1. The antihyperglycaemic effect and the possible mechanism of action of T-174, a novel thiazolidinedione derivative, was determined in vivo and in vitro. 2. Oral administration of T-174 markedly improved hyperglycaemia, hyperinsulinaemia, hyperlipidaemia, and glucose intolerance in genetically obese and diabetic yellow KK (KK-Ay) mice (0.2-15.5 mg kg(-1) day(-1), for 7 days) and Zucker fatty rats (1.4-11.4 mg kg(-1) day(-1), for 6 days). The ED50 values for the glucose lowering action of T-174 and pioglitazone, another thiazolidinedione antidiabetic, were 1.8 and 29 mg kg(-1) day(-1), respectively in KK-Ay mice; T-174 was about 16 times more potent than pioglitazone. 3. The hypoglycaemic effect of exogenous insulin in KK-Ay mice was enhanced after the administration of T-174. A hyperinsulinaemic euglycaemic clamp study in Zucker fatty rats showed an amelioration of whole-body insulin resistance by the T-174 treatment. 4. Insulin-stimulated glucose metabolism was enhanced in adipocytes from KK-Ay mice treated with T-174. The insulin receptor number of the adipocytes was increased without a change in the affinity of the receptor. 5. The hypomagnesaemia in KK-Ay mice was completely restored by T-174. 6. In cultured L6 myotubes, glucose consumption and [3H]-2-deoxy-glucose transport were enhanced by T-174 (EC50; 6 and 4 microM, respectively). Combination of insulin with T-174 was additive to stimulate glucose disposal. 7. These results suggest that the antihyperglycaemic effect of T-174 was mediated by enhanced insulin action. This was associated with amelioration of the hypomagnesaemia and T-174 directly increased basal and insulin-stimulated glucose utilization by cultured muscle cells.

Antihyperglycaemic effect of saccharin in diabetic ob/ob mice.

1. The effect of chronic saccharin (benzosulphimide) consumption on glucose homeostasis was examined in normal lean +/+ mice and genetically obese hyperglycaemic insulin-resistant ob/ob mice. 2. Consumption of a 5% (w/v) sodium saccharin solution for 7 weeks prevented the development of hyperglycaemia, improved glucose tolerance (area under curve decreased by 51%), reduced the extent of hyperinsulinaemia (by 21%), and reduced excessive weight gain (by 18%) in ob/ob mice. 3. Consumption of 5% (w/v) sodium saccharin temporarily decreased hyperphagia at the beginning of treatment, decreased hepatic glycogen content (by 47%), increased abdominal muscle glycogen content (by 82%), but did not significantly alter the hypoglycaemic response to exogenous insulin in ob/ob mice. 4. Consumption of a 1% (w/v) sodium saccharin solution did not prevent the development of hyperglycaemia in ob/ob mice. 5. Normal lean +/+ mice consuming 5% (w/v) sodium saccharin solution showed a marginal decrease (by 8%) in glycaemia, and glucose tolerance was improved (area under curve decreased by 30%) without a significant change in the insulin response to glucose or the hypoglycaemic effect of exogenous insulin. 6. These results suggest that chronic consumption of saccharin can defer the development of hyperglycaemia and improve glucose homeostasis in insulin-resistant ob/ob mice through a mechanism that is independent of insulin.

Corticosterone-Induced Insulin Resistance Is Not Associated with Alterations of Insulin Receptor Number and Kinase Activity in Chicken Kidney

Chicken renal insulin receptors have been recently characterized; their number and kinase activities vary in response to altered nutritional status. In the present study, the effect of chronic corticosterone treatment was examined in 5-week-old chickens. The development of an insulin resistance following corticosterone was suggested after 1 and 2 weeks of treatment by a significant decrease in the hypoglycemic effect of exogenous insulin and after 2 weeks by significant increases in plasma insulin levels (1.63 ± 0.13 vs 0.56 ± 0.14 ng insulin/ml in controls) and in renal cytosolic phosphoenolpyruvate carboxykinase activity (17.2 ± 0.8 vs 13.7 ± 0.7 nm/mn/mg tissue in controls). No significant changes were present at the level of insulin receptor number and kinase activity. Therefore, in kidney and, as previously observed, in muscles, corticosterone can induce insulin resistance at postreceptor steps in the cascade of events leading to insulin action.

Corticosterone Effect on Insulin Receptor Number and Kinase Activity in Chicken Muscle and Liver

The effects of chronic corticosterone treatment (6 mg/kg/day) on insulin sensitivity and on liver and muscle insulin receptors were examined in 5-week-old chickens. The hypoglycemic effect of exogenous insulin was completely abolished within 2 weeks of treatment, suggesting a corticosterone-induced insulin resistance. Hepatic insulin receptor numbers were slightly reduced (P < 0.001) after 2 weeks of treatment. After 1 or 2 weeks, corticosterone treatment significantly reduced liver insulin receptor kinase activity toward the artificial substrate poly(Glu4,Tyr1). Muscle insulin receptor kinase activity was also significantly decreased after 1 week of treatment but this effect was accounted for by a decrease in basal activity. Therefore the corticosterone-induced insulin resistance is accounted for, at least in part, by altered hepatic receptor numbers and kinase activity. The impairment of muscle development involves postreceptor defects.

Glucoregulatory hormone response to insulin-induced hypoglycaemia following long-term calcium antagonism with felodipine in patients with essential hypertension.

The effect of 8 weeks' treatment with the dihydropyridine calcium antagonist felodipine on glucoregulatory hormone response following insulin-induced hypoglycaemia was evaluated in 7 patients with essential hypertension, WHO grade I-II. After an iv insulin injection (0.1 IU/kg), blood glucose decrement and nadir were similar before and during felodipine treatment. Basal glucagon, noradrenaline, adrenaline, GH and cortisol levels were unchanged, and the response to insulin-induced hypoglycaemia was similar before and during felodipine treatment. Basal plasma dopamine levels were similar and did not change during insulin-induced hypoglycaemia before and during felodipine treatment. Basal serum levels of TSH, T3 and T4 were unaltered following felodipine. In conclusion, long-term treatment with felodipine did not alter the hypoglycaemic effect of exogenous insulin, or the recovery from hypoglycaemia or the glucoregulatory hormone response to insulin-induced hypoglycaemia in patients with essential hypertension.

Decreased insulin sensitivity and glucose tolerance in spontaneous canine hyperadrenocorticism

Alterations in carbohydrate metabolism were evaluated in 60 dogs with untreated hyperadrenocorticism by measuring basal concentrations of plasma glucose and insulin and performing glucose and insulin tolerance tests. The 60 dogs could be divided into four groups based on paired glucose and insulin concentrations. Eight dogs had normal concentrations of both glucose and insulin. Twenty-four dogs (40 per cent) were euglycaemic with mild to moderate hyperinsulinaemia whereas 23 (38 per cent) had moderate hyperglycaemia with moderate to severe hyperinsulinaemia. The five dogs (8 per cent) with overt ketoacidotic diabetes mellitus had relative insulin deficiency. Of eight dogs tested, six had intravenous glucose intolerance; all of the dogs had increased total insulin secretion during glucose tolerance testing. Resistance to the hypoglycaemic effect of exogenous insulin was demonstrated in six of the seven dogs tested. In 20 dogs that had basal glucose and insulin again determined after correction of hyperadrenocorticism, mean concentrations of both glucose and insulin decreased into the normal range.

Hormonal control of glucose homeostasis during development and ageing in mice

Age-related changes in the hormonal control of glucose homeostasis were examined in immature (5-wk-old), young adult (10-wk-old) and older adult (30 and 60-wk-old mice). In immature mice, basal plasma glucose and insulin concentrations were higher than young adult mice. Glucose tolerance was impaired in immature mice, although the plasma insulin response to glucose and other secretagogues (arginine and glucagon) was well developed, and the hypoglycaemic effect of exogenous insulin was not impaired. Glucagon and epinephrine evoked a greater acute hyperglycaemia in immmature mice, suggesting that these hormones exert a stronger rapid glucose-raising effect in preadult life. Basal plasma glucose and insulin concentrations were lowest in young adult mice, and increased with advancing adult age. Glucose tolerance was best in young adult mice and deteriorated with age, while plasma insulin concentrations after administration of glucose, arginine and glucagon were lowest in young adult mice and increased with age. However, in response to these secretagogues, the percentage increase in plasma insulin above basal was reduced in older adult mice. This indicates a defect of stimulus-recognition-secretion-coupling in the B-cells of older adult mice. The raised plasma glucose concentrations of older adult mice could not be attributed to an increase in the acute hyperglycaemic action of glucagon or epinephrine. The hypoglycaemic response to exogenous insulin decreased with age, suggesting that tissue sensitivity to insulin was impaired. Treatment with growth hormone and cortisone for 5 days produced a greater antagonism of insulin in older mice than young adult or immature mice. Growth hormone imparied glucose tolerance at each age, but only produced a marked hyperinsulinaemia in older adult mice. In contrast, cortisone produced a marked hyperinsulinaemia at each age, but only impaired glucose tolerance in older adult mice.

Diurnal variations in insulin secretion and insulin sensitivity in aged subjects.

Glucose tolerance tends to decrease in healthy aged subjects without family history of diabetes. Either reduced insulin secretion or insulin resistance may be responsible. Insulin secretion and insulin sensitivity were studied in 7 aged subjects (68-75 years) and 8 young controls (21-27 years). A 1-mg i.v. glucagon and a 5-U/m2 body area i.v. insulin test were run in each subject at 07(00) and at 19(00) on two different days to detect diurnal variations. An arginine test was also performed to evaluate pancreatic glucagon behavior. In the evening, young subjects presented a glucose tolerance impairment with significantly decreased plasma insulin levels, and a reduced hypoglycemic effect of exogenous insulin. Resistance to both endogenous and exogenous insulin in the aged was observed in the morning without significant morning/evening variations. Since the response to contra-insular hormones (GH in the insulin test, glucagon in the arginine test) was the same in both age groups, their role in the phenomenon could be ruled out. It is suggested that in the aged a stable reduction in number and/or a change in affinity of insulin receptors may occur. In addition, since aging is seen to be associated with the disappearance of diurnal variations in glucose tolerance and insulin secretion and sensitivity, and since a reduction in the receptor level of young healthy subjects in the evening has been reported by some authors, it is suggested that aged subjects may be less able to modulate the binding of insulin to its peripheral receptors in the course of the day.

Diabetes, obesity and heat production — possible links

Animal models have proved useful in the study of obesity and diabetes, and the genetically obese (ob/ob) mouse has been suggested as the counterpart of maturity onset diabetes in humans [ 11. The adult obese mouse is hyperglycaemic, hyperinsulinaemic and is grossly obese [2]. Ketosis is not present, and obese mice are resistant to the hypoglycaemic effect of exogenous insulin [3]. When subjected to restricted food intake, obese mice show a reduction in blood glucose to the level observed in lean controls and a significant fall in plasma insulin levels [4], but remain obese (since the percentage of body weight accounted for by lipid is above that of lean controls, despite weight loss), indicating that hyperglycaemia and hyperinsulinaemia are secondary to the genetic lesion. insulinaemia, hyperglycaemia and insulin resistance are usually observed the total profile in fact closely resembles that seen in the obese hyperglycaemic mouse. This contrasts with the lowered or nonexistent insulin production in juvenile onset diabetes where ketosis is present if exogenous insulin is not supplied.

Effects of insulin on lipolysis and lipogenesis in adipocytes from genetically obese (ob/ob) mice.

A method for the preparation of isolated adipocytes from obese mice is described. Similar yields of adipocytes (50--60%), as judged by several criteria, are obtained from obese mice and lean controls. Few fat-globules and no free nuclei were observed in cell preparations, which are metabolically active, respond to hormonal control and appear to be representative of intact adipose tissue. Noradrenaline-stimulated lipolysis was inhibited by insulin, equally in adipocytes from lean and obese mice. Inhibition in obese cells required exogenous glucose, and the insulin dose--response curve was shifted to the right. Basal lipogenesis from glucose was higher in adipocytes from obese mice, and the stimulatory effect of insulin was greater in cells from obese mice compared with lean controls. A rightward shift in the insulin dose--response curve was again observed with cells from obese animals. This suggests that adipose tissue from obese mice is insulin-sensitive at the high blood insulin concentrations found in vivo. The resistance of obese mice to the hypoglycaemic effect of exogenous insulin and their impaired tolerance to glucose loading appear to be associated with an impaired insulin response by muscle rather than by adipose tissue.

Longitudinal Study on the Establishment of Insulin Resistance in Hypothalamic Obese Mice*

A longitudinal in vivo and in vitro analysis of the genesis of insulin resistance has been carried out in mice made obese by chemical made obese by chemical lesion (goldthioglucose, GTG) of the hypothalamus. Six weeks after GTG administration, glycemia and glucose disposal were normal but associated with increased insulin concentration, suggesting incipient insulin resistance. The in vitro counterpart of the latter in obese mice was observed in soleus muscle that was somewhat less responsive to insulin than controls, in liver that had increased basal lipogenesis but was uninfluenced by insulin, and in hepatic plasma membranes in which a slight decrease of insulin binding was measured. At this stage of obesity, basal adipose tissue lipogenesis was increased but the tissue responded in a normal fashion to insulin. These relatively discrete early metabolic changes were corroborated in vivo by a normal hypoglycemic effect of exogenous insulin. Sixteen weeks after GTG administration, hyperglycemia and gross hyperinsulinemia were recorded. This insulin resistance was evidenced in vivo by the lack of hypoglycemic effect of exogenous insulin unless considerable amounts of the hormone were administered. It coincided in vitro with a poor response of soleus muscle to insulin, an absence of a stimulatory effect of the hormone upon both adipose tissue and liver tissue, and a marked decrease in insulin binding to liver plasma membranes. It appears that insulin resistance is a multifactorial and progressive abnormality that might involve both insulin receptor and intracellular metabolic alterations.

Reversal of progesterone-enhanced insulin production by human chorionic somatommammotropin.

The interactions between human chorionic somatomammotropin (HCS) and progesterone in their effect on glucose and insulin metabolism were assessed in 10 female rhesus monkeys. Treatment with HCS alone (50 mg im twice daily for 7 days) produced decreased sensitivity to the hypoglycemic effect of exogenous insulin, but no significant change in glucose tolerance or the mean total serum insulin responses (ΣI40) to iv glucose (1 g⁄kg). By contrast, progesterone administration (5 mg daily in olive oil sc×3 weeks) led to significantly increased mean SI40 and mean initial rate of insulin release (Δl⁄ΔG10) in association with significantly slower mean glucose disappearance rate after iv glucose. Combined HCS-progesterone treatment blocked the augmented insulin responses (ΣI40 and Δl⁄ ΔG10) produced by progesterone alone, while glucose tolerance remained deteriorated. These results indicate that HCS affects carbohydrate metabolism through at least 2 mechanisms: a) by increasing peripheral resistance to insulin, and ...

Enhanced hypoglycaemic effect of exogenous insulin associated with an increased response of adipose tissue and a diminished response of the diaphragm in ‘meal fed’ rats

Intraperitoneale Verabreichung von Insulin führte bei Ratten, die täglich 2 h gefüttert wurden, im Vergleich mit ad libitum gefütterten Kontrolltieren, zu einer grösseren Herabsetzung des Blutzuckerspiegels, einer höheren Fett- und Glykogensynthese im Fettgewebe, jedoch zu einer verminderten Glykogensynthese im Zwerchfell.

A diabetogenic polypeptide from bovine adenohypophysis similar to that excreted in lipoatrophic diabetes

A polypeptide has been isolated from bovine adenohypophysis which antagonizes the hypoglycemic effect of exogenous insulin and which, per se, induces loss of carbohydrate tolerance in men and dogs. Mild acid hydrolysis of the active polypeptide yields a compound which retains the same biological properties. Characteristics of the active principle and its hydrolytic product is the long duration of their activities, the greatest intensity of the effects being observed between 34 and 60 hours after a single intramuscular injection. Both substances are devoid of ACTH activity. The active polypeptide resembles closely the insulin antagonist isolated from the urine of patients with lipoatrophic diabetes previously reported from this laboratory. Details of the isolation and physiologic effects of the active substance and its hydrolytic product are described.