Control Of Plasma Glucose Levels Research Articles

Treating Diabetes With Aerosolized Insulin

Because of the pain, inconvenience, and disruption of lifestyle associated with the injection of insulin, many patients with diabetes are noncompliant in terms of treatment regimens that require daily multiple injections. To eliminate the pain and to improve treatment outcome, there has been increasing interest in the development of aerosolized insulin to replace subcutaneously (SC) delivered formulations. Recent studies in human volunteers have shown that when aerosolized insulin is effectively delivered to the alveolar region of the lung, absorption rates and decreases in glucose levels are similar to those achieved with SC-delivered insulin during the fasting state. Other human trials have shown that inhaled insulin also effectively controls postprandial glucose levels. Aerosolized insulin is well-tolerated, and there is no evidence of irritation, hypoglycemia, or changes in pulmonary function when administered over short periods. At present, limitations in the delivery device result in less efficient administration of insulin aerosol compared to SC dosing. However, new devices and different formulations of insulin, which are currently under development, should improve the efficiency. It is likely that the treatment of diabetes with aerosolized insulin will provide an effective alternative means for controlling plasma glucose levels in diabetic individuals. Aerosolized insulin also will serve as a developmental model for this route of administration for a number of other therapeutic peptides that are currently administered by injection only.

Nateglinide: A structurally novel, short-acting, hypoglycemic agent.

Nateglinide is a short-acting, pancreatic, beta-cell-selective, K(ATP) potassium channel blocker that improves overall glycemic control in type 2 diabetes. Although nateglinide's mechanism of action is related to that of sulphonyl-ureas and repaglinide, important differences do exist. Nateglinide binds rapidly to the sulfonylurea SUR1 receptor with a relatively low affinity, and it dissociates from it extremely rapidly in a manner of seconds. This rapid association and dissociation gives nateglinide a unique "fast on-fast off" effect. Thus, nateglinide has a rapid onset and short duration of action stimulating insulin secretion in vivo and providing good control of postprandial hyperglycemia when taken immediately prior to meals. The rapid action of nateglinide on the beta cells stimulates and restores the normal physiological first and early phase of insulin secretion, consequently reducing postprandial hyperglycemia. This hypoglycemic effect of nateglinide leads to improved glycemic control, while the short duration avoids delayed hyperinsulinemia and hypoglycemia after meals. Nateglinide is not a sulfonylurea, but it shares the mechanism of action of commonly used oral hypoglycemic agents such as glibenclamide and glipizide. Like the recently introduced, short-acting agent, repaglinide, it does not incorporate a sulfonylurea moiety. However, nateglinide's effects on insulin secretion and glycemic control differ significantly from the sulfonylureas and repaglinide in that it preferentially stimulates acute phase insulin, better controls postprandial glucose excursions and spikes, and causes less hyperinsulinemia and hypoglycemia. Compounds with such a profile should not only achieve improved overall glucose control, but also reduce the risk of vascular complications which is the most important feature of nateglinide. Clinical studies with nateglinide have confirmed that it acts rapidly and both restores insulin release and attenuates the postprandial glucose spike. Nateglinide is both effective and well tolerated in the treatment of type 2 diabetes. The reported overall profile of adverse effects appears to be superior to that of other K(ATP) potassium channel blockers, the glucose modulator metformin and PPARgamma agonists such as troglitazone. Clinical comparisons of these agents have shown nateglinide to be more effective in attenuating postprandial glucose than any other oral hypoglycemic agent, and that treatment with both nateglinide and metformin provides additive effects that afford improved control of plasma glucose levels. The administration regimen for nateglinide, immediately prior to meals, also facilitates patient compliance. (c) 2001 Prous Science. All rights reserved.

Nanosphere based oral insulin delivery

Zinc insulin is successfully encapsulated in various polyester and polyanhydride nanosphere formulations using Phase Inversion Nanoencapsulation (PIN). The encapsulated insulin maintains its biological activity and is released from the nanospheres over a span of approximately 6 h. A specific formulation, 1.6% zinc insulin in poly(lactide-co-glycolide) (PLGA) with fumaric anhydride oligimer and iron oxide additives has been shown to be active orally. This formulation is shown to have 11.4% of the efficacy of intraperitoneally delivered zinc insulin and is able to control plasma glucose levels when faced with a simultaneously administered glucose challenge. A number of properties of this formulation, including size, release kinetics, bioadhesiveness and ability to traverse the gastrointestinal epithelium, are likely to contribute to its oral efficacy.

Insulin back into action with rosiglitazone

Rosiglitazone is an oral antihyperglycaemic agent that works by reducing insulin resistance - a problem that occurs when cells respond poorly to insulin, causing plasma glucose levels to rise. Studies presented at the 35th Annual Meeting of the European Association for the Study of Diabetes [Brussels, Belgium; September-October 1999] suggest that by reducing insulin resistance, rosiglitazone may provide long-term control of plasma glucose levels in patients with type 2 diabetes mellitus.

Effect of GIP and GLP-1 antagonists on insulin release in the rat.

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are potent insulinotropic peptides released from the small intestine. To examine their relative contribution to postprandial insulin release, a specific GIP antagonist (ANTGIP) and a GLP-1 antagonist, exendin-(9-39)-NH2, were infused into rats after an intragastric glucose meal. In control rats, plasma glucose and insulin levels rose gradually during the first 20 min and then decreased. Exendin-(9-39)-NH2 administration inhibited postprandial insulin secretion by 32% at 20 min and concomitantly increased plasma glucose concentrations. In contrast, ANTGIP treatment not only induced a 54% decrease in insulin secretion but also a 15% reduction in plasma glucose levels 20 min after the glucose meal. In vivo studies in rats demonstrated that glucose uptake in the upper small intestine was significantly inhibited by the ANTGIP, an effect that might account for the decrease in plasma glucose levels observed in ANTGIP-treated rats. When the two antagonists were administered to rats concomitantly, no potentiating effect on either insulin release or plasma glucose concentration was detected. Glucose meal-stimulated GLP-1 release was not affected by ANTGIP administration, whereas postprandial glucagon levels were diminished in rats receiving exendin-(9-39)-NH2. The results of these studies suggest that GIP and GLP-1 may share a common mechanism in stimulating pancreatic insulin release. Furthermore, the GIP receptor appears to play a role in facilitating glucose uptake in the small intestine.

Therapy for type 2 diabetes: where do we stand after the UK prospective diabetes study?

The Diabetes Control and Complications Trial (DCCT) in type 1 diabetes, published in 1993, demonstrated the beneficial effects of intensive insulin therapy on the onset and progression of diabetic retinopathy, nephropathy and neuropathy (1). Although many clinicians assumed that these results were also applicable to type 2 diabetic patients, this has not been demonstrated so far. In fact, a previous clinical trial in 1970, the University Group Diabetes Program (UGDP), compared five different treatments (diet and placebo, standard insulin doses according to body weight, variable insulin doses according to glycemia, and tolbutamide or phenformin) in type 2 diabetics (2). During the 5.5 years (range 3–8 years) that the 1000 patients were followed, the UGDP revealed no statistically significant differences in cardiovascular mortality or microvascular disease between the different treatment groups, except for the phenforminand tolbutamide-treated patients whose cardiovascular mortality was significantly higher compared with the placebo group. These results generated great controversy about the use of oral hypoglycemic agents, which was fueled by potential methodological deficiencies. For example, 46% of the patients included in the study already had signs of pre-existing cardiovascular disease and potentially due to non-homogeneous randomization, the pheneformine and tolbutamide group had a higher incidence of myocardial infarctions. Despite a reassessment by an international committee of the Biometric Society in 1976 the controversy over these results remains. Since then, in vitro studies have added to the fear that sulfonylureas may aggravate cardiovascular disease (3). In the study from Kumamoto, Japan in 1995 the effects of intensive and conventional insulin therapy on microvascular complications were compared in 100 lean (body mass index 2% difference in mean HbA1c levels (7% versus 9%) over the whole study period. Intensive glycemic control delayed the onset and the progression of diabetic retinopathy, nephropathy, and neuropathy. No major effect on macrovascular disease was seen. Despite the data showing a reduction in microvascular complications by insulin therapy, the effect of oral antidiabetic therapy on these complications remained to be elucidated. In the mid 1970s, the prospective and randomized United Kingdom Prospective Diabetes Study (UKPDS) was designed to try to clarify whether intensive therapy as compared with dietary therapy had a better longterm outcome in type 2 diabetes. An additional aim was to compare the advantages and disadvantages of insulin and sulfonylureas among patients in the intensive therapy group. In obese patients, an additional group was assigned to metformin. Later on, a hypertension study was added to examine the effects of tight blood pressure control on the risk of macroand microvascular complications. Three aggregate endpoints were used to assess differences between the conventional and intensive treatments: (i) diabetes-related endpoints (sudden death, death from hyperglycemia or hypoglycemia, myocardial infarction, angina, heart failure, stroke, renal failure, amputation, vitreous hemorrhage, retinopathy requiring photocoagulation, blindness in one eye, or cataract extraction); (ii) diabetes-related death (death from myocardial infarction, stroke, peripheral vascular disease, renal disease, hyperglycemia or hypoglycemia, and sudden death); and (iii) all-cause mortality. The most important results of the UKPDS have now been published in four different papers in September 1998 (5–8). Before examining the results of the UKPDS, it should be noted that, unavoidably, considerable therapeutic overlap among the different treatment groups occurred (9). If in the control or intensive therapy groups fasting plasma glucose (FPG) levels were above predefined limits (FPG>15 mmol/l or FPG>6 mmol/l respectively), a sulfonylurea was added. This therapy could be further supplemented with metformin, and eventually replaced by insulin if necessary. Thus, in each treatment group at least 30% of patients took at least one additional drug than they were initially assigned to. In the UKPDS 33 publication (5), intensive therapy with a sulfonylurea (chlorpropamide, glibenclamide, or glipizide) or with insulin aimed at obtaining a FPG of less than 6 mmol/l was compared with conventional therapy (diet only with drugs added only if hyperglycemia was symptomatic or if FPG>15 mmol/l) by randomizing patients with a FPG>6 mmol/l to either treatment group. On recruitment 93% of the patients had a FPG>7.0 mmol/l (novel American Diabetes Association (ADA) criteria for the diagnosis of diabetes) H IG H L IG H T European Journal of Endocrinology (1999) 140 4–6 ISSN 0804-4643

Acute Ethanol Effects on Focal Cerebral Ischemia in Nonfasted Rats

Focal cerebral ischemia was induced in a rat model of middle cerebral artery occlusion. Three groups of adult male Sprague-Dawley rats, given food and water ad libitum, were subjected to 4 hr of middle cerebral artery occlusion. All were given vehicle control and ethanol pretreatments intraperitoneally 1 hr before. Mean ipsilateral brain water content in the control, 2 g/kg ethanol, and 2 g/kg ethanol + insulin-treated groups showed: ischemia core: 81.1%, 82.5%, and 80.9%; intermediate zone: 81.0%, and 80.3%; and outer zone: 80.3%, 81.3%, and 80.1%, respectively. Brain Na+ and K4 content in these groups paralleled the water content. In addition to significantly (p < 0.05) more brain edema, the 2 g/kg ethanol-treated animal group also had significant hyperglycemia. In contrast, the 2 g/kg ethanol + insulin-treated animals were normoglycemic and had ischemic, intermediate, and outer zone Na+, K+, and Cl- levels comparable with the control group (p > 0.05). These results stress the importance of measuring and controlling plasma glucose levels in the in vivo studies of the neurotoxic effects of acute ethanol.

ACE Inhibitors as a Shield Against Diabetic Nephropathy

FEW READERS of theArchiveswould be surprised by the statistic that about one third of all cases of end-stage renal disease are caused by diabetes mellitus. Yet, despite the advances in the treatment of diabetes that have evolved over more than half a century since insulin became available as a therapeutic agent, little progress had been made toward the protection of the kidneys as a target for diabetic microvascular disease. Very tight control of plasma glucose levels appears to offer protection, but at a cost of increased risk for hypoglycemic reactions.¹The use of computer-based algorithms, insulin pumps, and islet cell transplantations may reduce the risk of tight control while retaining its benefits, but the cost will be high and not all diabetic patients will have access to these modalities.² The demonstration by Lewis et al³that the angiotensin-converting enzyme (ACE) inhibitor captopril could delay or

Alteration of oxide reductive and haemostatic factors in type 2 diabetics

To assess any pathogenic role of radical activity and haemostatic alteration in the early cardiovascular disease of microalbuminuric type 2 diabetics (non-insulin dependent). A selected cohort of type 2 diabetics was identified, divided according to urinary albumin excretion and compared with a healthy control group depending on some haemostatic factors and radical activity. All the subjects were studied as outpatients. Eighty diabetics and 84 healthy controls were interviewed and underwent blood tests to exclude standard cardiovascular risk factors before follow up. The subjects were males, age range 43-55 years, and divided according to albumin excretion (microalbuminuria > 30-200 mg L-1; normoalbuminuria < 15 mg L-1). The mean duration of diabetes referred by the patients was 9.3 years in albuminuric and 11.1 years in normoalbuminuric patients with a good control of plasma glucose level. Neither the diabetics nor the control group showed clinical evidence of renal and cardiovascular diseases. Microalbuminuric patients presented elevated malondialdehyde concentration, glutathione peroxidase activity, phospholipidic fatty acid levels, fibrinogen, plasminogen activator inhibitor, tissue plasminogen activator and von Willebrand factor compared with normoalbuminuric patients and controls. More collagen was required in microalbuminuric diabetics than in normoalbuminurics and controls. Our results confirm that both free radical activity and changes in haemostatic factors can be observed in type 2 diabetes and particularly in patients with albuminuria. Our very selected series with short duration, good control of diabetes and lack of clinical evidence of cardiovascular disease may suggest that these abnormalities develop earlier and may be associated with, and/or implicated in, the pathogenesis of microvascular complications which can be related to a higher and early cardiovascular morbidity and mortality rate in microalbuminuric diabetics.

Endocrine-Metabolic Function in Remission-Phase IDDM During Administration of Cyclosporine

We have studied the endocrine-metabolic status of patients in non-insulin-receiving (NIR) remission of insulin-dependent diabetes mellitus (IDDM) within 6-60 mo of diagnosis during administration of cyclosporine, in comparison with nondiabetic subjects. IDDM patients in NIR remission were recognized when target glycemic control (plasma glucose and mean capillary blood glucose levels less than 7.8 mM before meals) was maintained without administration of insulin for at least 2 wk. In so-called isoglycemic tests, 50 g glucose was administered orally, and the glycemic curve was simulated in a subsequent study by programmed intravenous infusion of glucose. Under these conditions, the subjects with diabetes exhibited obvious glucose intolerance: acute beta-cell responses to intravenous glucose were virtually absent but significant, although subnormal responses were present after oral glucose. The responses of plasma immunoreactive gastric inhibitory polypeptide to oral glucose were normal. After bolus intravenous injections of glucose, the patients with diabetes again exhibited glucose intolerance; acute responses of immunoreactive insulin (IRI) and C-peptide were present, although grossly obtunded. On intravenous infusion of arginine (30 g in 30 min), the patients with diabetes showed substantial but subnormal increases in plasma IRI and C-peptide. Intravenous infusion of arginine elicited increments of plasma immunoreactive glucagon (IRGI) in both groups, and this response was slightly exaggerated in the patients with diabetes. On ingestion of a standard mixed meal (Sustacal) delivering 600 cal, there was a modest but significantly greater increase in plasma glucose levels in the diabetic subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

A semiclosed-loop algorithm for the control of blood glucose levels in diabetics

In this paper, a theoretical analysis of the control of plasma glucose levels in diabetic individuals is undertaken using a simple mathematical model of the dynamics of glucose and insulin interaction in the blood system. Mathematical optimization techniques are applied to the mathematical model to derive insulin infusion programs for the control of blood levels in diabetic individuals. Based on the results of the mathematical optimization, a semiclosed-loop algorithm is proposed for continuous insulin delivery to diabetic patients. The algorithm is based on three hourly plasma glucose samples. A theoretical evaluation of the effectiveness of this algorithm shows that it is superior to two existing algorithms in controlling hyperglycemia. A glucose infusion term representing the effect of glucose intake resulting from a meal is then introduced into the model equations. Various insulin infusion programs for the control of plasma glucose levels following a meal are then assessed. The theoretical results suggest that the most effective short-term control is achieved by an insulin infusion program which incorporates an injection to coincide with the meal.

Fructosamine and glycated hemoglobin as indices of glycemic control in patients with liver cirrhosis

Glucose intolerance often occurs in liver cirrhosis; therefore a long-term control of plasma glucose levels appears to be important. For this purpose glycated hemoglobin A (HbA1c) determination is proposed as a suitable method, while no data are available on fructosamine test. In 98 cirrhotic patients serum fructosamine and HbA1c levels were compared with those of normal controls and among cirrhotic patients grouped in non glucose-intolerant and with non insulin-dependent (NIDDM) or insulin-dependent diabetes mellitus (IDDM). The mean HbA1c values of cirrhotic patients with normal glycemic control were significantly lower than normal, and only a few IDDM and NIDDM cirrhotic patients showed high values of HbA1c, indicating that HbA1c is often underestimated in these patients. On the contrary, serum fructosamine levels were on the average higher than normal in nondiabetic patients, but they were significantly higher in IDDM and NIDDM patients than in nondiabetics, and the 72% of NIDDM and 85% of IDDM patients had fructosamine levels higher than the upper normal value. In conclusion, in diabetic patients with liver cirrhosis fructosamine seems to be a more suitable test than HbA1c for monitoring blood glucose levels.

Pancreatic endocrine responses to nutrients and bombesin after segmental pancreas autotransplantation in dogs.

The capacity of autotransplanted (ATP) distal pancreas segments with systemic venous and peritoneal exocrine drainage to support physiologic control of plasma glucose levels was tested, and compared with the functions of "simulated autotransplants" (SATP) prepared with similar dissection and peritoneal exocrine drainage, but with hepatic portal venous drainage, in dogs. In ATP in the postabsorptive state, plasma levels of glucose, immunoreactive insulin (IRI) and immunoreactive glucagon (IRG1) were normal. Autotransplants resulted in impaired glucose tolerance after meals with impaired early insulin responses, and the normal brisk rise of IRG1 in the plasma was delayed and reduced through the first 30 min of feeding. In ATP, also, the response to bombesin was abnormal; the normal stimulation of release of both IRI and IRG1 was delayed in both cases. In studies of responses to oral and intravenous glucose in ATP and SATP dogs, similar mild degrees of glucose intolerance were found with both routes of administration; however, whereas in ATP dogs increases of IRI were highly exaggerated with both routes of administration of glucose, in SATP dogs plasma IRI rose from subnormal levels in the postabsorptive state through subnormal increments with both routes of administration. Further studies are necessary to determine the relative importance of denervation and reduction of the mass of the pancreas in these effects, and to assess the significance of the differences in blood insulin levels in the two preparations.

New alpha 2-adrenergic blocker (DG-5128) improves insulin secretion and in vivo glucose disposal in NIDDM patients.

Effects of oral administration of DG-5128, a new oral hypoglycemic agent, on glycemic control after a mixed meal and an in vivo glucose disposal were measured in subjects with nonobese non-insulin-dependent diabetes mellitus (NIDDM). Oral administration of DG-5128 significantly (P less than .05) enhanced insulin secretion both 30 and 60 min after a mixed meal (550 kcal), with a concomitant decrease in postprandial plasma glucose levels at 60 and 120 min. Glucose disposal rate between the 2nd and 4th h of a euglycemic insulin clamp, developed through a constant infusion of insulin (0.77 mU X kg-1 X min-1) together with somatostatin (80 ng X kg-1 X min-1), was 2.5-fold higher in a DG-5128-treated group (P less than .01) than in a control group. However, there was no difference between the two groups in either plasma glucose concentration or plasma insulin concentration at either the 2nd or the 4th h. These results indicate that DG-5128 is effective in controlling plasma glucose levels in subjects with NIDDM by stimulation of both insulin secretion and in vivo glucose disposal.

Nondetectable plasma glucose levels after insulin administration in the American bullfrog ( Rana catesbeiana)

The effect of a single intraarterial infusion of mammalian insulin on plasma glucose was determined in the American bullforg ( Rana catesbeiana). Insulin was administered, and blood samples were collected, from an indwelling cannula placed in the sciatic artery. Plasma glucose was estimated by the glucose oxidase method. Control plasma glucose levels were 8.7 ± 0.7 mg/dl at time zero immediately prior to the infusion of the hormone-free carrier solution and were 6.9 ± 1.0 mg/dl on Day 5 when sampling was terminated. The time-zero plasma glucose levels of the bullfrogs that received 15 IU/kg body weight insulin were 10.7 ± 1.0 mg/dl and declined to 0.4 ± 0.1 mg/dl by 12 hr after the infusion. The levels remained severely depressed at 24 hr and then returned to approximately the time-zero levels by Day 3. The initial plasma glucose levels of the animals that received 45 IU/kg body weight insulin were 8.7 ± 0.6 mg/dl. The levels declined to 0.5 ± 0.2 mg/dl by 12 hr, remained severely depressed at Day 2, and then returned to approximately the time-zero levels by Day 4. Convulsions occurred in all of the 45 IU insulin-treated animals and 40% of the bullfrogs died. In contrast, convulsions did not occur in any of the 15 IU insulin-treated bullfrogs and all of the animals survived, although plasma glucose was not detectable in one-half of the bullfrogs at one or more sampling periods between 6 and 24 hr after the infusion. The results support the hypothesis that glucose, in the absence of stress, may not be an essential source of energy in the bullfrog.

Improvement of insulin secretion but not insulin resistance after short term control of plasma glucose in obese type II diabetics.

Insulin secretion and insulin resistance were examined in seven obese type II diabetics before and after control of plasma glucose levels without weight loss. Control was achieved by regular insulin injection (60-205 U/day in four doses). After 10 days of therapy, plasma insulin and C-peptide responses to oral glucose were significantly improved. Insulin-induced glucose rates, estimated by the glucose clamp technique, averaged 1.08 +/- 0.30 mg/kg. min (mean +/- SEM; n = 7) before treatment and were unchanged (1.08 +/- 0.25) after treatment. These indicate that short term control of plasma glucose improved insulin secretion but not insulin sensitivity. The impaired insulin secretion and insulin sensitivity in type II diabetics appears to be, in part, secondary to metabolic abnormalities associated with hyperglycemia.

Prevention of insulin aggregation by dicarboxylic amino acids during prolonged infusion.

The dicarboxylic amino acids, aspartic and glutamic acid, at their isoelectric pH, reduced aggregation of insulin solutions in vitro for 16 days during continuous agitation at 37 degrees C. Unprotected insulin solutions, when infused via a 14-day implantable infusion device in diabetic Chinese hamsters, controlled plasma glucose levels for only 2 days, followed by escape coincident with insulin aggregation. However, when insulin solutions were protected with glutamic acid, euglycemia was maintained for the 14-day life of the device.

Severe insulin-induced hypoglycemia in the spiny dogfish shark ( Squalus acanthias)

The effect of a single intraaortic infusion of mammalian insulin on plasma glucose was studied in the spiny dogfish shark ( Squalus acanthias). Insulin was administered, and blood samples were collected, from an indwelling cannula placed in the dorsal aorta via the anterior mesenteric artery. Plasma glucose was estimated by the glucose oxidase method. Control plasma glucose levels were 37.4 ± 2.5 mg% at time-zero, increased gradually to 45.9 ± 4.4 mg% by 4 days after the infusion of the hormone-free carrier solution, and to 58.1 ± 5.5 mg% by Day 6 when sampling was terminated. The time-zero plasma glucose levels of the dogfish that received 0.5 IU/kg body wt insulin were 46.5 ± 3.2 mg%, declined to 10.2 ± 1.3 mg% by 24 hr after the infusion, and then returned to approximately the time-zero levels by Day 4. The initial plasma glycose levels of the animals that received 50 IU/kg body wt insulin were 38.6 ± 2.6 mg%. The levels fell to 2.1 ± 0.6 mg% by Day 3 and then increased slowly to approximately the time-zero levels between Days 13 and 14 after the treatment. The lowest plasma glucose levels in individual dogfish occurred either on Day 2 or 3 and averaged 1.4 ± 0.3 mg%. No convulsions or other symptoms were observed in the insulin-treated animals. The results indicate that both the magnitude and the duration of the hypoglycemia were dependent on the dose of insulin infused. In addition, the observations that the dogfish were able to tolerate the virutal absence of circulating glucose for extended periods suggest that glucose is not an essential source of energy in this species.

Elevation of plasma glucose levels by catecholamines in elasmobranch fish

The effects of a single intraaortic infusion of epinephrine on circulating glucose was studied in the nursehound shark ( Scyliorhinus stellaris) and the comparative effects of epinephrine and norepinephrine were studied in the spiny dogfish shark ( Squalus acanthias). The catecholamines were administered, and blood samples were collected, from an indwelling cannula placed in the dorsal aorta via the anterior mesenteric artery. Plasma glucose was estimated by the glucose oxidase method. Infusions of 25, 50, and 75 μg/kg body weight all elevated plasma glucose levels in the nursehound. The results indicate that the magnitude and duration of the hyperglycemia was dose dependent. On the basis of the data obtained, a dose of 75 μg/kg body weight and a 48-hr experimental period were used in the subsequent experiments on the dogfish. Control plasma glucose levels in the dogfish declined approximately 5% by 1 hr after the infusion of the hormone-free carrier solution and fluctuated about the time-zero levels for the remainder of the experimental period. The initial declines in plasma glucose levels observed at 15 min after norepinephrine treatment were followed by abrupt increases that were evident at 30 min and that attained maxima approximately 22% greater than the time-zero levels by 1 hr. The levels remained elevated through 3 hr and then declined to approximately the initial values by 12 hr. The infusion of epinephrine resulted in prompt increases in plasma glucose levels that were evident at 15 min and that attained maxima of approximately 72% greater than the initial levels by 3 hr. The level then declined gradually to approximately the time-zero levels by 24 hr after treatment. The results indicate that a catecholamine-induced increase in circulating glucose is an important aspect of the physiological mechanisms by which elasmobranch fish respond rapidly and adaptively to stressful environmental changes.

Elevation of plasma glucose levels by mammalian ACTH in the spiny dogfish shark ( Squalus acanthias)

The effect of a single intra-aortic administration of mammalian ACTH on plasma glucose levels was studied in the spiny dogfish shark ( Squalus acanthias). Blood was collected from an indwelling cannula placed in the dorsal aorta via the anterior mesenteric artery and plasma glucose was estimated by the glucose oxidase method. Plasma glucose levels of starved, untreated dogfish were 50.3 ± 4.9 mg % at the completion of the operation and ranged from 15.6 to 105.3 mg %. Plasma glucose levels were 39.7 ± 1.9 mg % on the third postoperative day and remained relatively stable from the third through the fifth day when this aspect of the study was terminated; the range in plasma glucose values between individual dogfish during this period was from 25.0 to 59.9 mg %. Experimental treatment began on postoperative day 3 to 5. The initial plasma glucose level on the morning of treatment was used as time-zero. Control plasma glucose levels declined approximately 7% within 45 min after the infusion of the hormone-free carrier solution. The levels returned to the time-zero levels at the 12- and 24-hour samples and to approximately 6% greater than the time-zero levels at 48 hr after the infusion. Plasma glucose levels showed a similar initial decline in the dogfish that received 40 units ACTH/kg body weight; however, the levels subsequently increased to approximately 19% greater than the time-zero levels at the 3-, 6-, and 12-hr samples. Plasma glucose levels then declined, but remained approximately 12% greater than the time-zero levels 48 hr after the infusion; the increases still evident at 48 hr were not significantly greater than the increases observed for the controls. The infusion of 20 units ACTH/kg body weight resulted in inconsistent and variable increases in plasma glucose levels. The data provide presumptive evidence for pituitary ACTH regulation of corticoid secretion in the dogfish and indicate that the pituitary-adrenocortical axis functions in relatively long-term physiological adjustments in carbohydrate metabolism.