Translation of nutritional sciences into medical education: the Nutrition Academic Award Program.

For the past 40 y the scientific community has decried the inadequacy of the training of physicians and other health professionals in the subject of human nutrition. In 1997 the National Heart, Lung, and Blood Institute developed the Nutrition Academic Award (NAA) Program, an initiative to improve nutrition training across a network of US medical schools. The purpose of this funding, which began in 1998, is to support the development and enhancement of nutrition curricula for medical students, residents, and practicing physicians to learn principles and practice skills in nutrition. The NAA recipients developed the Nutrition Curricular Guide for Training Physicians, a plan to incorporate clinical guidelines into physician practice skills, create educational and assessment practice tools, and evaluate curricula, materials, and teaching tools. Dissemination of NAA activities and materials will be facilitated by a national website, presentations and publications, and consultants and advisors from the NAA nutrition education programs. The NAA Program constitutes a major new effort to enhance nutrition knowledge and skills among health care providers and to effectively apply the science of human nutrition to clinical medicine. This article describes the purpose and aims of the NAA Program, the organizational structure of the network of recipients, a profile of the recipients and individual programs at 21 medical schools, the various strategies to overcome barriers in training physicians in human nutrition, and collaborative and dissemination efforts.

Altered TNF-alpha, glucose, insulin, and amino acids in islets of Langerhans cultured in a microgravity model system.

The present studies were designed to determine effects of a microgravity model system upon lipopolysaccharide (LPS)-stimulated tumor necrosis factor-alpha (TNF-alpha) activity and indexes of insulin and fuel homeostasis of pancreatic islets of Langerhans. Islets (1,726 +/- 117, 150 islet equivalent units) from Wistar-Furth rats were treated as 1) high aspect ratio vessel (HARV) cell culture, 2) HARV plus LPS, 3) static culture, and 4) static culture plus LPS. TNF-alpha (L929 cytotoxicity assay) was significantly increased in LPS-induced HARV and static cultures; yet the increase was more pronounced in the static culture group (P < 0.05). A decrease in insulin concentration was demonstrated in the LPS-stimulated HARV culture (P < 0.05). We observed a greater glucose concentration and increased disappearance of arginine in islets cultured in HARVs. Although nitrogenous compound analysis indicated a ubiquitous reliance on glutamine in all experimental groups, arginine was converted to ornithine at a twofold greater rate in the islets cultured in the HARV microgravity model system (P < 0.05). These studies demonstrate alterations in LPS-induced TNF-alpha production of pancreatic islets of Langerhans, favoring a lesser TNF activity in the HARV. These alterations in fuel homeostasis may be promulgated by gravity-averaged cell culture methods or by three-dimensional cell assembly.

Increased body fat in streptozotocin diabetic rats treated with intensive subcutaneous insulin therapy vs. islet transplantation.

The continued development of novel insulin treatment is predicated on the hypothesis that strict glycemic control is necessary to prevent the secondary complications of diabetes. Although dramatically successful in reducing selected secondary complications, intensive insulin therapy has consequences. These include hypoglycemia, weight gain, and body fat accumulation. In the present studies we compared a model of intensive insulin therapy in diabetic rats and contrasted weight gain and body fat accumulation with pancreatic islet transplantation. Female Wistar Furth rats (173 g) administered streptozotocin (55 mg x kg(-1), iv) remained diabetic (DB) for four or nine weeks. At week three, a third group was transplanted (TRAN) with islets of Langerhans (3519 +/- 838 150 microm islets); one week later group four began intensive subcutaneous insulin therapy (ISIT; 4 x 0.5-1.0 U regular insulin x day(-1)). Within one week ISIT rats had normalized plasma glucose; levels were not different from age matched controls (CN) or TRAN animals (ISIT 10.6 +/- 1.7, CN 7.2 +/- 0.4, TRAN 7.7 +/- 0.8 mmol x L(-1), P > 0.05). The cumulative occurrence of one episode of hypoglycemia (< 2.8 mmol x L(-1)) occurred in 50% of ISIT rats. At study termination, body weight of ISIT and CN rats did not differ (199 +/- 4 vs. 207 +/- 3, P > 0.05). While carcass protein content was similar for TRAN, ISIT, and CN animals, the body fat of ISIT animals was 24% greater than in CN rats and 21% greater than in TRAN rats (P < 0.05). Correlation of body fat vs. plasma glucose illustrated hypoglycemia contributed to the body fat gain of ISIT rats (n = 8, r = -0.70, P = 0.0535). These studies illustrate a disproportionate gain of body fat from ISIT, an effect not observed with islet transplantation. Thus, the metabolic benefit ascribed to islet transplantation appears related to the absence of hypoglycemia.

Pancreatic islet transplantation, but not intensive insulin therapy, corrects the pulmonary vascular complications of streptozotocin diabetes.

We examined the effects of long-term streptozotocin (STZ) diabetes and its treatment by intensive insulin therapy (IIT) or pancreatic islet transplantation on pulmonary pressor and depressor responses and segmental resistance profiles in female Wistar-Furth rats. Pulmonary vascular reactivity was examined using isolated, salt-perfused lungs at a constant flow rate of 30 mL.min-1.kg-1 body weight. Baseline perfusion pressure was significantly (p < 0.05) lower in lungs obtained from IIT animals compared with all other treatment groups. Following STZ administration, pressor responsiveness to 1.0 microgram of U-46619 (9,11-dideoxy-9 alpha, 11 alpha-methanoepoxy prostaglandin F2 alpha) was decreased in diabetic compared with IIT animals (9.33 +/- 0.54 vs. 11.94 +/- 0.29 mmHg (1 mmHg = 133.3 Pa)). Diabetes caused a similar decrease in the vasodilatory response to arginine vasopressin when compared with IIT animals (39.25 +/- 7.54 vs. 68.24 +/- 4.75%). Diabetes was also associated with a shift in the primary site of resistance from the pulmonary arterial to the pulmonary venous bed. This shift was restored to normal following pancreatic islet transplantation, but not IIT. IIT was also associated with significant alterations in the pattern of constrictor and dilator responses to U-46619 and arginine vasopressin. Pulmonary venous vasoconstrictor responses to U-46619 were augmented when compared with either control or diabetic animals, but not transplant. In addition, pulmonary venous vasoconstrictor responses in IIT animals were significantly greater than pulmonary arterial responses in the same group, a finding that was unique to IIT animals. Finally, IIT significantly augmented the pulmonary venous vasodilatory response to arginine vasopressin when compared with all other treatment groups. These data demonstrate significant alterations in pulmonary hemodynamic status of STZ diabetic female animals and suggest that pancreatic islet transplantation may be more beneficial than intensive insulin therapy in ameliorating these changes.

Differential pulmonary vascular effects of streptozotocin diabetes in male and female rats.

We examined the effect of streptozotocin (STZ) diabetes on pulmonary pressor responses and segmental pulmonary vascular resistance in male and female Wistar-Furth rats. Pulmonary vascular reactivity was studied using isolated, salt-perfused lungs at a constant flow rate of 30 ml/min/kg body weight. Following STZ administration, pressor responsiveness to 1.0 microg of U-46619 (9,11 dideoxy-9alpha, 11alpha-methanoepoxy Prostaglandin F2alpha) was diminished (p < 0.05) in lungs obtained from male diabetic rats when compared to sham treated controls (7.87 +/- 1.67 vs. 13.59 +/- 1.67 mmHg). In contrast, diabetes failed to affect pressor responsiveness in lungs from female animals. In another set of animals, segmental pulmonary vascular resistance was determined in lungs isolated from male and female diabetic or sham-treated (STZ carrier vehicle) animals. Total pulmonary vascular resistance was significantly elevated in male diabetic animals as compared to controls. This elevation was attributable to significant increases in resistance at the level of small pulmonary veins. In addition, diabetes was associated with a shift in the primary site of resistance from small arteries to small veins in male animals. We were unable to detect any effect of short-term diabetes on the segmental resistance profile in lungs obtained from female animals. These data indicate that both the pulmonary segmental resistance profile and pulmonary vascular reactivity are altered by short-term diabetes in male rats. Additionally, these studies demonstrate gender-related effects of short-term diabetes, which may suggest a more favorable pulmonary response to diabetes in female animals.

Tumor necrosis factor activity of pancreatic islets.

Tumor necrosis factor (TNF) is involved in the pathogenesis of acute sepsis-induced organ injury and has been implicated as a mediator of metabolic alterations observed during sepsis. Pancreatic islet cell function may be significantly compromised during sepsis or endotoxemia, and sepsis also increases plasma levels of epinephrine, a modifier of islet insulin secretion. We proposed that islets exposed to bacterial lipopolysaccharide (LPS) produce TNF and that epinephrine attenuates islet secretory activity. We monitored the effects of LPS and epinephrine on TNF and insulin activity of isolated Wistar-Furth rat islets (pancreas digested with collagenase, islets isolated using Ficoll gradients; n = 4 islet populations, each with 632 +/- 11 islets/2.5 ml culture medium). Islets were incubated (37 degrees C, 5% CO2) 3 days. LPS (Escherichia coli, 1 microgram/ml) and epinephrine (14 micrograms/ml) were added to the islets, and incubations were continued for 1-4 h. Glucose (Beckman Glucose Analyzer), insulin (radioimmunoassay), and TNF (L929 cytotoxicity assay) were measured in the islet medium samples at 1- to 4-h time points. In the conditioned medium, glucose decreased (P < 0.05), insulin increased (P < 0.05), and exposure to LPS did not alter these levels [P = not significant (NS)] but did increase TNF activity by 400% (P < 0.05). Epinephrine reduced insulin by 38-43% (P < 0.05) and TNF by 20-25% (P < 0.05) but had no effect on glucose levels (P = NS). We conclude that insulin is secreted from isolated islets and that exposure to LPS acutely increases islet-derived TNF activity, whereas epinephrine modifies TNF and insulin secretion of rat pancreatic islets.

Pancreatic islet transplantation improves body composition, decreases energy intake and normalizes energy efficiency in previously diabetic female rats.

We investigated the weight gain, body composition, and feed efficiency of female Wistar Furth rats (170 +/- 1 g) made diabetic with streptozotocin (55 mg/kg intravenously), then infused intraportally with 3519 +/- 838 (150 mu equivalent units) syngeneic pancreatic islets of Langerhans. After islet transplants (5-6 wk), nutritional energetics were evaluated in transplanted rats (Transplant), and also in 3- and 9-wk diabetic (Diab-3, 9) and control rats treated with sham infusions and similar surgical manipulations (Sham-3, 9). Diabetic rats demonstrated marked hyperphagia, which was corrected by islet transplantation (577 +/- 53 vs. 266 +/- 19 kJ/d; P < 0.0001) and was not different than sham control rats (285 +/- 24 kJ/d; P > 0.05). Three weeks of diabetes resulted in a lower protein (Diab-3, 24.8 +/- 2.6 g vs. Sham-3, 30.9 +/- 1.0 g) and fat content (1.9 +/- 0.8 g vs. 11.6 +/- 1.7 g) in the rats' carcasses. However, 6 wk after islet transplantation, rats receiving islets (Transplant) were not different than control rats (Sham-9) (31.9 +/- 1.7 g vs. 33.3 +/- 1.9 g protein and 15.4 +/- 3.0 g vs. 15.1 +/- 3.2 g fat). Three weeks of diabetes resulted in a lesser energy efficiency compared with Sham rats (2.7 +/- 2.0 vs. 7.1 +/- 1.9 kJ gained/100 kJ ingested); islet-transplanted rats were not different than Sham-9 rats (4.9 +/- 2.3 vs. 4.7 +/- 1.4 kJ gained/100 kJ ingested). These data illustrate that islet transplantation in previously diabetic female rats improves growth with proportional gains in body protein and fat mass. This is modulated in part by a reduced food intake and an energy efficiency that is improved relative to controls. These studies offer an optimistic outlook for the continued development of more physiological insulin delivery strategies that preclude the nutritional complications associated with exogenous insulin administration.

Alteration of segmental vascular resistance in the pulmonary circulation of diabetic rats.

Numerous studies have shown that altered plasma glucose and (or) insulin have profound effects on the pulmonary circulation. Recently, we documented diminished pressor responses to the synthetic thromboxane analogue U-46619 (9,11-dideoxy-9 alpha, 11 alpha-methanoepoxy prostaglandin F2 alpha) following short-term streptozotocin-induced diabetes in rats. However, these earlier studies examined the effects of diabetes on resistance changes across the entire pulmonary vasculature and made no effort to localize the site(s) of any abnormalities. Thus, in the present study we examined segmental pulmonary vascular resistances using the double-occlusion method in isolated, perfused rat lungs 2 weeks after streptozotocin-induced diabetes. Under baseline conditions, total pulmonary vascular resistance (TPVR) did not differ in lungs isolated from control and diabetic animals (0.66 +/- 0.03 vs. 0.85 +/- 0.05 mmHg.mL-1.min-1, respectively (1 mmHg = 133.3 Pa)). However, control animals demonstrated greater arterial (Ra) than venous (Rv) contribution to TPVR (0.43 +/- 0.02 vs. 0.23 +/- 0.02 mmHg.mL-1.min-1, respectively). This relationship was reversed in diabetic animals (Ra = 0.30 +/- 0.02 mmHg.mL-1.min-1; Rv = 0.54 +/- 0.04 mmHg.mL-1.min-1). Following constriction with U-46619 this pattern persisted, although the absolute vasoconstrictor response to the agent was similar in each segment. Likewise, this pattern of resistance was unaffected following dilation of the pulmonary vascular bed with arginine vasopressin. These findings illustrate that pulmonary segmental vascular resistances are altered and, more specifically, that pulmonary venous resistance is selectively increased, 2 weeks following the induction of diabetes.

Islet transplantation reverses carcass protein loss in diabetic rats without inducing disproportionate fat accumulation.

The Diabetes Control and Complications Trial demonstrated that intensive insulin therapy (IIT) improves many secondary complications of insulin-dependent diabetes mellitus. However, weight gain in IIT is associated with increased body fat, and no improvement in lean body mass. In the present study we investigated the effects of experimental diabetes on changes in body composition and probed the benefit of glycaemic control achieved through islet transplantation. Male Wistar Furth rats (weight 273 +/- 9 g) made diabetic for 2 weeks with streptozotocin (55 mg/kg) were infused intraportally with 3265 +/- 692 (150 microns islet equivalent units) syngeneic islets of Langerhans. Body composition was evaluated by proximate analysis in carcasses of transplant rats (Trans), and also in rats made diabetic for 2 or 7 weeks (Db-2, Db-7) and in 2- and 7-week sham controls (Sham-2, Sham-7). Fed plasma glucose levels were 7.3 +/- 1.1, 28.2 +/- 2.4, 26.8 +/- 3.9, 7.5 +/- 1.0 and 7.0 +/- 0.1 mm/l, respectively, and neither glucose tolerance nor fasting plasma insulin differed between control vs transplant rats (p > 0.05). Two weeks of diabetes resulted in a body weight 82% of that of controls (240 +/- 5 vs 292 +/- 8 g, p < 0.05) and 5 subsequent weeks of diabetes further suppressed growth by an additional 12% (p < 0.05). Five weeks following islet transplantation, islet-transplant rats had regained lost weight and were not significantly different from control animals (274 +/- 19 vs 291 +/- 21 g, p > 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Estimation of rat body composition by means of electromagnetic scanning is altered by duration of anesthesia.

We determined the effect of anesthesia on estimation of fat-free mass and body fat in rats using electromagnetic scanning (EMS). Male Wistar Furth rats (n = 7, approximately 226 g) were injected with 66 mg/kg ketamine hydrochloride and 6.6 mg/kg xylazine intramuscular anesthesia. EMS measures were repeated every 4 min, up to 80 min post-anesthesia injection. From 4 to 44 min post-injection, the EMS signal and consequently the estimation of fat-free mass decreased from 198 +/- 5 to 180 +/- 5 g (mean +/- SD, P < 0.05). Conversely, the estimation of body fat increased by 63% during this period of anesthesia (12.9 +/- 2.9 vs. 21.1 +/- 2.6 g/100 g body wt, P < 0.05). In cohort animals (n = 6), body temperature and respiration rate declined following anesthesia (P < 0.05), and may have correspondingly suppressed EMS signal via reduced ion flux and/or muscular activity. In another study the effects of food deprivation, tail position, and anesthesia duration were demonstrated to alter estimation of fat-free mass (P = 0.0001), but these effects were not interactive (P > 0.05). Proximate analysis of body composition in cohort rats indicated that EMS predicted fat-free mass with a 3.5% error when estimated at 4 min post-anesthesia injection. Taken together, these data suggest that standardized EMS protocols should be adopted to account for effects of anesthesia, animal position and food deprivation. When manufacturer's equations are used, body composition should be measured immediately after induction of anesthesia. However, laboratories that choose to internally generate EMS regression equations with proximate analysis should determine and utilize the period of minimal variability in EMS measures.(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin action in previously diabetic rats receiving graded numbers of islets of Langerhans.

We characterized insulin sensitivity in islet transplanted rats receiving from 500 to 3000 islets. Male Wistar Furth rats made previously diabetic with streptozotocin (55 mg/kg) were infused intraportally with islets of Langerhans (500 islets: n = 8; 1000: n = 6; 2000: n = 6; 3000: n = 5) from syngeneic donors and compared with sham-operated controls (n = 7). At four weeks after islet transplantation, fasting blood glucose was not significantly different between groups (500: 5.1 +/- 0.3; 1000: 4.8 +/- 0.3; 2000: 5.1 +/- 0.3; 3000: 4.6 +/- 0.1; control: 4.7 +/- 0.2 mM; P = 0.6146), and fasting plasma insulin was also not different (P = 0.28). The acute insulin response to glucose (0.3 g/kg i.v.) was correlated with islet equivalent mass (r = 0.63, P = 0.004; transplant rats only); islet transplant animals presented a range of acute insulin secretion from 3 to 90% of control values. Insulin action was measured in vivo in fasted, conscious animals during a hyperinsulinemic-euglycemic glucose clamp with insulin infused at 29 and 72 nmol/kg/min. Despite a wide range of islet mass and insulin secretory capacity, there was no significant difference in the glucose infusion rate between islet groups at either insulin level (P = 0.8211, P = 0.8021). There was also no difference in the glucose infusion rate normalized to the prevailing insulin level (P = 0.1638, P = 0.2302). Thus, our results demonstrate that the islet transplanted rat is consistent with other animal studies and human studies illustrating that a diminished insulin secretion does not necessarily precipitate insulin resistance.

A new model for the study of mild diabetes during pregnancy. Syngeneic islet-transplanted STZ-induced diabetic rats.

Diabetes during pregnancy carries short- and long-term consequences for the offspring. Improved obstetrical and diabetic care has resulted in decreased morbidity and mortality in the neonate of the diabetic mother. Mild hyperglycemia is still found in both IDDM pregnant women and women with GDM. The long-term consequences of exposure to mild hyperglycemia in utero remain to be determined. In an effort to develop an appropriate animal model of mild diabetes during pregnancy, we mated female STZ-induced diabetic rats previously transplanted with specific numbers of islets of Langerhans (2500, 1000, 700, or 500 islets). Diabetic and nondiabetic sham-transplanted control groups also were studied. During pregnancy, the plasma glucose levels in the diabetic rats and the group receiving 500 islets (26.5 +/- 1.1 and 10.0 +/- 0.8 mM, respectively) were significantly greater than in control animals (5.4 +/- 0.5 mM, P < 0.0001). The mean glucose levels in rats receiving 700 or 1000 transplanted islets (6.8 +/- 0.2 and 6.5 +/- 0.2 mM) also were significantly greater than in control animals (P < 0.001). No difference was evident between control rats and the group receiving 2500 islets (5.8 +/- 0.2 mM). No gross congenital abnormalities were apparent in the offspring. The pup plasma glucose was significantly greater in the offspring of dams receiving either none (diabetic) or 500 islets (10.6 +/- 0.7 and 11.1 +/- 1.1 mM, respectively) compared with the offspring of nondiabetic control dams (4.4 +/- 0.3 mM, P < 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Exercise training alters feed efficiency and body composition in iron deficient rats.

Studies of body composition and feed efficiency were conducted on 80 male Sprague-Dawley rats to determine how exercise training alters growth and development in iron deficient animals. Animals were assigned to iron deficient (ID) or control (CN) diets (AIN-76, w/o cellulose), and sedentary (SD) or exercised groups [EX, treadmill running, 4 d.wk-1, 90 min.d-1, 65% maximal oxygen consumption (VO2max), maintained for 6 or 12 wk. The ID diet caused a sustained moderate iron deficiency (Hb 7.2 +/- 0.2 g.dl-1). Iron deficient animals failed to increase maximal oxygen consumption despite the rigorous training program, through training resulted in 25% or 35% higher VO2max in 6- or 12-wk CN rats. At 6 wk, IDEX animals had significantly (33%) lower growth rates than did IDSD animals, which in turn were 22% less than CNs. Overall, exercise did not alter relative amounts of protein in the carcass (% total mass); however, a significant interaction between diet and treatment duration was evident in IDEX animals at 12 wk, who had lower % protein than CNEX-12 or IDSD-6 rats. Training decreased fat 11% in CN at 6 wk but not 12 wk, and 20% in IDs at 12 wk but not 6 wk. Feed efficiency and energy intake were 28% and 12% lower in IDEX animals than CNEX at 6 wk. Training increased caloric intake in CNEX animals but not IDEX animals at 6 and 12 wk. Thus, exercise training exacerbates the poor growth associated with ID through alterations in both food intake and feed efficiency in early phases of training, but adaptation is apparent.

Insulin secretory function in relation to transplanted islet mass in STZ-induced diabetic rats.

In vivo insulin secretion was quantified as the AIRg or AIRa in islet-transplanted rats. Male Wistar-Furth rats previously made diabetic by STZ administration (55 mg/kg) were transplanted with 500, 1000, 2000, or 3000 islets infused into the portal vein (n = 12-14 per group) and were compared with sham-treated controls (CN, n = 16). At 4-5 wk posttransplantation, no significant differences were noted in the FPG or fasting plasma insulin of the experimental groups (P > 0.05). Body weight, however, was 10% less (P < 0.05) in rats receiving 500 islets than in controls, indicating an effect of beta-cell deficiency on growth rates. To determine the relationship between islet mass and insulin secretion, we measured AIRg after a 0.3 g/kg glucose bolus in fasted conscious animals. A significant correlation was observed between the AIRg and islet number (r = 0.61, P = 0.0001), and both 500- and 1000-islet groups could be differentiated from controls by ANOVA (500: 8%; 1000: 12% of controls; P < 0.05). During a glycemic potentiation protocol, AIRa was measured at basal and elevated blood glucose (approximately 16 mM). At neither basal nor elevated blood glucose was AIRa correlated with islet number (basal r = 0.0622, P = 0.7834; elevated r = 0.3133, P = 0.1667). None of the groups could be differentiated by ANOVA (elevated 500: 37%; 1000, 68% of controls; P > 0.05). Although this study illustrates that AIRa may be better preserved in islet-transplanted rats, AIRg is the better correlate of islet number.(ABSTRACT TRUNCATED AT 250 WORDS)

Markedly reduced beta-cell function does not result in insulin resistance in islet autografted dogs.

Autotransplantation of islets of Langerhans has resulted in long-term normoglycemia in pancreatectomized dogs. This canine model is useful in evaluating both the progress of islet transplantation and the effect of a reduced islet mass upon the determinants of glucose tolerance: i.e., insulin secretion, insulin sensitivity, and glucose effectiveness. To determine the effect of a reduced islet mass on these factors, we measured the acute insulin response to arginine (AIRa) and glucose (AIRg), the slope of glycemic potentiation of AIRa (SP), insulin sensitivity (Sl), and glucose effectiveness (SG) in control (CN), diabetic (DM), and pancreatectomized dogs rendered normoglycemic with transplanted autografts of islets of Langerhans (TX). Normal fasting plasma glucose (FPG) (TX 4.7 +/- 0.2 mM; CN 4.9 +/- 0.1 mM; P greater than 0.05) was maintained despite a markedly reduced insulin secretion in TX (AIRa 24%, AIRg 15%, and SP 11% of CN). All measures of insulin secretion were significantly correlated (SP vs. AIRg, r = 0.80, P less than 0.0001; AIRa vs. AIRg, r = 0.92, P less than 0.0001) across all animals, but none of the measures of secretion were significantly correlated with either the number of islets transplanted or time posttransplant (P greater than 0.10). Insulin sensitivity was normal in islet autografted dogs (TX: 136 +/- 12 min-1/(nmol/ml); CN: 101 +/- 11 min-1/(nmol/ml), P greater than 0.05) but SG was reduced (TX: 1.93 +/- 0.28 x 100 min-1; CN: 3.53 +/- 0.35 x 100 min-1, P less than 0.05), as determined by the minimal-model method. In diabetic animals (FPG = 16.1 +/- 1.3 mM), insulin secretion was negligible by all measures (P greater than 0.05), and was associated with insulin resistance (Sl = 28 +/- 8 min-1/(nmol/ml)) and reduced SG (1.72 +/- 0.11 x 100 min-1). These studies indicate that across a range of insulin secretion in dogs, the secretagogues arginine and glucose provide similar estimates of beta-cell function. This markedly reduced beta-cell function does not result in insulin resistance when fasting normoglycemia is maintained, but is associated with a decrease in glucose action at basal insulin.

Dynamics of glycemic normalization following transplantation of incremental islet masses in streptozotocin-diabetic rats.

We examined the dynamics of glycemic normalization following intraportal infusion of an incremental number of islets of Langerhans in male Wistar-Furth rats. Non-fasted plasma glucose, 24-hr urine volume, and body weight were determined weekly during three weeks of streptozotocin-induced diabetes and for 5 weeks following transplantation of 250-3000 freshly isolated islets. At one week following transplantation, urine volume was inversely proportional to the mass of islets transplanted, but by 5 weeks posttransplantation urine volume was near-normal except in rats receiving only 250 islets. On the basis of the mean data, the nonfasted plasma glucose fell linearly at a rate of 66 mg/dl per week in rats receiving 500-1000 islets, with normoglycemia (147 +/- 9 mg/dl) being obtained 5 weeks posttransplantation. Examination of the individual time courses for nonfasted plasma glucose revealed a different pattern of glycemic normalization, which consisted of sustained hyperglycemia followed by a rapid fall in the plasma glucose level. During the week prior to normalization glucose fell at a rate of 170 mg/dl per week and normoglycemia was obtained from 1 to 5 weeks following transplantation. Examination of the frequency distribution of nonfasted glucose levels suggested a threshold of 300 mg/dl for glycemic normalization. We conclude that the dynamics of glycemic normalization following transplantation of a suboptimal islet mass include sustained hyperglycemia of variable duration, followed by a rapid fall in the nonfasted plasma glucose level. The contributions of changes in insulin secretion and insulin action underlying this dynamic behavior remain to be determined.

Interactions of iron deficiency and exercise training relative to tissue norepinephrine turnover, triiodothyronine production and metabolic rate in rats.

The interactions of iron deficiency and exercise training relative to resting metabolic rate (RMR), tissue norepinephrine (NE) turnover and triiodothyronine (T3) production were examined in male Sprague-Dawley rats. Animals were assigned to iron-deficient (ID) or control (CN) diets and to sedentary (SD) or treadmill-exercise (EX) groups for 6 or 12 wk. Iron-deficient animals (hemoglobin 7.2 +/- 0.2 g 100 mL-1) had a 17% higher RMR and had slower growth rates than CN animals. Exercise training affected growth but not RMR in iron deficiency. Oxygen consumption (Vo2) following pharmacologic injection of norepinephrine was similar in both iron-deficient and exercised groups despite a 35% lower maximal exercise Vo2 in trained iron-deficient rats. NE turnover was lower in heart (55%) and liver (80%) of iron-deficient animals relative to controls. Trained iron-deficient animals had lower NE turnover in interscapular brown adipose tissue (IBAT) than sedentary iron-deficient animals; however, training did not alter NE turnover in control animals. In vitro liver and IBAT T3 production was similar in all groups except for lower activities (40%) in 6-wk iron-deficient, exercised animals. The significant effect of exercise on the growth attenuation of iron-deficient, exercised animals is thus not explained by increased IBAT metabolic activity or a generalized sympathetic nervous system activation. Decreased T3 production during periods of rapid growth and lean body mass development, however, may be important in exercised, iron-deficient animals.

Effects of iron repletion and correction of anemia on norepinephrine turnover and thyroid metabolism in iron deficiency.

The reversibility of the alterations in norepinephrine (NE) content and turnover in interscapular brown adipose tissue and heart of iron-deficient rats has not been demonstrated. We therefore examined NE metabolism in age-matched male Sprague-Dawley rats depleted of iron by dietary means and after repletion with iron dextran. Heart NE content was 58, 61, and 85% of controls at 0, 3, and 7 days after repletion, whereas interscapular brown adipose tissue-NE content was 87, 103, and 104% of controls. Fractional heart NE turnover was 225% greater in iron-deficient anemics than controls but normalized within 3 days. Interscapular brown adipose tissue NE turnover was 58%, 46%, and 20% above controls in iron-deficient rats after 0, 3, or 7 days of iron repletion. Hematocrit returned to 80% of normal in 7 days. Liver triiodothyronine production also increased to 80% of control in this period. A second experiment used isovolemic exchange transfusion to examine the influence of anemia per se on these alterations in organ NE turnover. Acute correction of anemia in iron deficiency did not alter brown fat NE turnover. Heart NE turnover was significantly lower in anemic animals regardless of iron status. Defects in heart and brown fat NE metabolism are reversible within 7 days of iron treatment as are alterations in triiodothyronine production. Anemia per se has little effect on brown fat NE metabolism but does dramatically decrease heart NE content.

Interactions of iron deficiency and exercise training in male Sprague-Dawley rats: ferrokinetics and hematology.

Ferrokinetic and hematologic studies were performed using adult male Sprague-Dawley rats to determine if 12 wk of exercise training alters the delivery of iron to the red blood cell (RBC) mass, the severity of the anemia or the maximal exercise performance of moderately iron-deficient animals. Forty rats were assigned to either iron-deficient (ID) or control (CN) diets, and further subdivided into sedentary (SD) and exercised (EX) groups. Exercised groups were trained on a treadmill, at a 15% grade, 65% VO2max, for 90 min/d, 4 d/wk. After 12 wk of exercise training and dietary iron deficiency, the final body weight of IDEX rats was 90.5% that of IDSD rats. Fractional plasma iron clearance in IDEX rats was 86% of that in IDSD rats (3.32 vs. 2.85%/min). Exercise training failed to increase absolute VO2max (ml/min) or change hemoglobin concentration in iron-deficient rats. Resting oxygen consumption in IDEX rats was 116% that in IDSD rats (42.8 vs. 32.5 ml.kg-1.min-1, P less than 0.05). We conclude that exercise training and iron deficiency interact to alter iron physiology in exercised, iron-deficient animals. This interaction affects the kinetic behavior of plasma iron, growth and basal oxygen consumption.