Lower Plasma Insulin Concentrations Research Articles

Metabolic and Secretory Response to [formula omitted]-Fructose in Pancreatic Islets from Adult Rats Injected with Streptozotocin during the Neonatal Period

The metabolic and secretory responses to d-glucose and/or d-fructose were measured in pancreatic islets prepared from either control rats or animals that had been injected with streptozotocin during the neonatal period (STZ rats). The STZ rats displayed higher plasma d-glucose concentrations, but lower plasma insulin concentrations, islet insulin content, as well as basal and nutrient-stimulated insulin release. This coincided with lower rates of d-[U-14C]hexose oxidation and d-[5-3H]hexose utilization. In both control and STZ rats, d-fructose failed to affect significantly the metabolism of d-glucose, while the aldohexose increased the ratio between d-[U-14C]fructose oxidation and d-[5-3H]fructose conversion to 3HOH. Such a ratio was higher than that found with radioactive d-glucose in islets exposed to both hexoses, whether in control or STZ rats, indicating a far-from-negligible contribution of fructokinase to the phosphorylation of d-fructose. Despite these analogies between both the respective fate of d-glucose and d-fructose and the reciprocal metabolic effects of the two hexoses in islets from control and STZ rats, the secretory response to the ketohexose in islets from STZ rats was preferentially suppressed, relative to that evoked by the aldohexose. This gives support to the idea that the insulinotropic action of d-fructose may not be entirely accounted for by its nutritional value in islet cells.

The activation of fatty acid metabolism by Vespa amino acid mixture (VAAM) and related nutrients during endurance exercise in mice

Advances in Exercise and Sports Physiology Volume 3, No. 1:35-44, 1997 Abstract: The action of Vespa amino acid mixture (VAAM) on fatty acid metabolism was analyzed as changed in blood biochemical indices during endurance exercise in swimming mice. In response to the oral ingestion of VAAM, but not other nutrients, the concentrations of serum NEFA, blood ketone bodies, and plasma noradrenaline (NA) increased significantly during endurance exercise. The same mice showed the suppression of increase in blood lactate and decrease in blood glucose. Under similar exercise conditions, a relatively low plasma insulin concentration and an increase in the pyruvate/lactate ratio were observed simultaneously compared with other nutrients. A strong correlation (r = 0.794) was found between the blood glucose and lactate concentration in mice ingesting various nutrients other than VAAM. The minimal compositional requirement for the induction of serum NEFA during endurance exercise was an amino acid mixture containing proline, alanine, valine, lysine, and isoleucine or leucine in the same compositional ratio as in VAAM, but the effect was not the same as with VAAM. Compositional analyses suggest that the excretion of plasma NA and adrenaline (A) are stimulated by different amino acid compositions, but a constant ratio of both catecholamines was secreted following feeding with either VAAM or VAAM 8. We also showed a high correlation (r = 0.746) between the induction of serum NEFA and the secretion of plasma NA by various nutrients. These results suggest that VAAM suppresses glucose oxidation, increases fatty acid oxidation, and also enhances the aerobic metabolism through the hormonal activation of NA during endurance exercise

Anomalies of fetal development in GK rats.

Fetal development was investigated in Goto-Kakizaki (GK) rats. Between days 15 and 20 after identification of a positive sperm plug, the GK rats gained less weight than control animals. The number of conceptuses in each litter was not significantly different in control and GK rats. The incidence of abortive fetal development, however, averaged 39.7% +/- 9.1% in GK rats, compared with only 5.6% +/- 0.2% in control animals. The placental weight in living fetuses was slightly lower in GK rats than control rats. The crown-rump length was identical in the fetuses of control and diabetic mothers. The number of ossification points in the lumbosacral spine, pelvic girdle and anterior and posterior limbs was significantly lower in fetuses of GK rats than control animals. These anomalies could not be blamed on a lower plasma insulin concentration in GK than control animals, whether before or during (days 15-20) pregnancy. Moreover, in both control and GK rats, the insulinogenic index was raised during pregnancy. These findings indicate that GK rats represent a new model for the study of diabetes-related fetal anomalies, their pathogenesis and prevention.

Serum leptin concentrations correlate to plasma insulin concentrations independent of body fat content in chronic renal failure.

The ob gene product leptin is secreted by fat cells and reflects the content of fat in the body. Leptin and insulin concentrations as well as body weight are interrelated and a direct correlation has been found between these concentrations in humans with normal renal function. Markedly elevated serum leptin concentrations have recently been reported in patients with chronic renal failure (CRF). The aim of the present study was to investigate the relation between serum leptin and plasma insulin in patients with advanced CRF. Serum leptin, plasma insulin, as well as body fat content (determined with dual-energy X-ray absorptiometry) were determined in a cohort of 46 patients (mean age 54 +/- 2 years) with advanced CRF (creatinine clearance 8 +/- 1 ml/min). In 23 CRF patients with plasma insulin below the median value (14 mU/l), serum leptin concentrations were no higher than in healthy controls (8.0 +/- 1.2 vs 8.4 +/- 0.9 ng/ml). However, in CRF patients with plasma insulin > 14 mU/l (n = 23) the serum leptin concentrations were much higher (38.2 +/- 11.0 ng/ml; P < 0.0001). In CRF patients, serum leptin (normalized for the per cent body fat content) correlated significantly (r = 0.64; P < 0.0001) with plasma insulin concentrations. However, the increase in plasma insulin was blunted in patients with very high serum leptin concentrations in relation to the per cent body fat content. The present results demonstrate that serum leptin concentrations are markedly elevated in CRF patients with higher plasma insulin than in those with lower plasma insulin concentrations. This suggests that insulin resistance and hyperinsulinaemia contribute to elevated serum leptin concentrations in CRF. The present results also demonstrate that, when circulating serum leptin concentrations are much higher in relation to the per cent body fat content, no additional increase in plasma insulin occurs. This latter observation suggests that the secretion of insulin by the pancreas is lower in hyperleptinaemic patients. Consequently, extremely elevated serum leptin may play a role in reducing glucose-stimulated insulin secretion and glucose intolerance in CRF.

Low protein diet in uremia: Effects on glucose metabolism and energy production rate

Low-protein diets (LPD) increase insulin-mediated glucose disposal in chronic renal failure (CRF), but the fate of the better utilized glucose and the effect on energy production rate are unknown. Using a two-step (1 and 5 mU x kg(-1) x min(-1)) euglycemic hyperinsulinemic clamp combined with indirect calorimetry, we studied the effects of a LPD (0.3 g x kg(-1) x day(-1), supplemented with essential amino acids and ketoanalogs) in six patients suffering from chronic renal failure. After three months of diet, no significant change was observed concerning glomerular filtration rate, body wt, or arterial pH. In the postabsorptive state, plasma glucose and insulin levels were significantly lower, and energy production rose from 15.72 +/- 0.48 to 17.16 +/- 0.67 Cal x kg(-1) x min(-1) (P < 0.05). Insulin-stimulated glucose oxidation (2.36 +/- 0.29 vs. 3.37 +/- 0.35 mg x kg(-1) x min(-1); P < 0.05 at first clamp step) and nonoxidative disposal (P < 0.05 at both clamp steps) increased after LPD. This confirms that LPD ameliorates insulin sensitivity in CRF, even for low plasma insulin concentrations. Since energy production rate is increased by LPD, the caloric intake should be increased when protein intake is restricted.

Intracellular Glucose and Fat Metabolism in Identical Twins Discordant for Non-insulin-dependent Diabetes Mellitus (NIDDM): Acquired Versus Genetic Metabolic Defects?

Intracellular glucose and lipid metabolism was studied in 12 identical twin pairs discordant for non-insulin-dependent (Type 2) diabetes mellitus (NIDDM) and 13 control subjects without family history of diabetes during low (baseline) and high plasma insulin concentrations, using the hyperinsulinaemic clamp technique combined with indirect calorimetry, tritiated water glycolytic flux rates and biopsy skeletal muscle glycogen synthase activity determinations. Baseline and insulin stimulated rates of lipid oxidation were elevated--and glucose oxidation decreased--in the NIDDM twins compared with the non-diabetic co-twins and controls (all p < 0.05). Baseline and insulin stimulated rates of glucose and lipid oxidation were similar in non-diabetic twins and controls. Exogenous glycolytic flux was decreased in NIDDM twins compared with both their non-diabetic co-twins and controls during clamp insulin measurements (p < 0.02), but similar in all study groups during baseline measurements. Insulin stimulated glucose disposal, exogenous glucose storage (glucose disposal-exogenous glycolytic flux) and skeletal muscle glycogen synthase activity were all significantly decreased in NIDDM twins compared with both their non-diabetic co-twins and controls. Furthermore, glucose disposal and glucose storage were decreased in the non-diabetic twins (n = 12) compared with controls (p < 0.05 both). However, insulin stimulated fractional skeletal muscle glycogen synthase activity was not significantly decreased in non-diabetic twins compared with controls. (1) the glucose fatty acid cycle plays a major role in the secondary--but not the primary--abnormalities of glucose metabolism in NIDDM; (2) insulin resistance in non-diabetic identical co-twins of NIDDM patients is restricted exclusively to the pathway of exogenous glucose storage; (3) however, the decreased glucose storage is not explained solely by an impairment of insulin stimulated skeletal muscle glycogen synthase activity; and finally (4) the impairment of skeletal muscle glycogen synthase activity in NIDDM has an apparent non-genetic component and can be escaped (or postponed) in individuals (twins) with a 100% genetic predisposition to NIDDM.

Effects of Acute and Chronic Exercise on Fat Metabolism

Fatty acids are an important source of energy for skeletal muscle contraction, particularly during exercise of mild-moderate intensity, prolonged duration, and in the fasting state. Plasma FFA transported from remote adipose tissue stores and triglycerides contained within skeletal muscle fibers are the major sources of these fatty acids. The relative contribution of each source is dependent on the mode, intensity, and duration of exercise and on training status. Plasma FFA oxidation is directly related to the rate of lipolysis in adiopose tissue. The most potent stimulants of the latter are the catecholamines, but a lower plasma insulin concentration during exercise also plays a contributory role. In contrast, intramuscular triglyceride hydrolysis appears to be mediated entirely by beta 2-adrenergic stimulation. Endurance training substantially enhances fatty acid oxidative capacity in skeletal muscle and increases the proportion of energy derived from fatty acid oxidation during exercise. In addition, the sympathoadrenal response to exercise is markedly blunted in the trained state. Studies conducted in our laboratory indicate that plasma FFA and glycerol concentrations and whole body FFA uptake and oxidation are all decreased during moderate-intensity exercise at the same absolute work rate after physical conditioning, probably because of the reduction of sympathoadrenal activity. However, the lipolytic response to catecholamines also is enhanced in trained subjects. Perhaps as a consequence, the magnitude of the decrease in lipolysis and plasma FFA oxidation is less than the decrement in sympathoadrenal activity in the same individuals during exercise in the trained state. Other investigations were conducted in our laboratory to determine the source of the additional fatty acids oxidized in physically conditioned subjects. These studies demonstrated that during moderate-intensity exercise at the same absolute work rate, depletion of triglycerides from within skeletal muscle fibers was twice as great after, as opposed to, before training. Regardless of training status, intramuscular triglyceride use accounted for about 90% of the oxidized fatty acids that were not supplied from adipose tissue via the plasma. Intramuscular triglycerides were the source of virtually all of the additional fatty acids oxidized in the trained state. Both before and after physical conditioning they explained the discrepancy between the rates of plasma FFA and total fat oxidation during moderate-intensity exercise of up to 2 hr in duration.

Types of carbohydrate in an ordinary diet affect insulin action and muscle substrates in humans

The influence of dietary carbohydrate types on insulin action and muscle substrates was investigated. Seven healthy young men ingested two isoenergetic diets with 46-47% of energy as carbohydrates, 41% as fat, and 13-14% as protein, in which the carbohydrates either had a high glycemic index (HGI) or a low glycemic index (LGI) for 30 d, two times in a randomized crossover design. A euglycemic hyperinsulinemic clamp procedure was performed at the end of each dietary period. Whole-body glucose uptake was similar with both diets at a low plasma insulin concentration (370 pmol/L) but decreased (P < 0.05) at a high insulin concentration (2.4 nmol/L) with the LGI diet compared with the HGI diet. Higher plasma fatty acid concentrations during part of the day were found with the LGI diet compared with the HGI diet (P < 0.05). Initially, blood glucose and plasma insulin concentrations were lower (P < 0.05) during part of the day with the LGI than with the HGI diet, but after 30 d of the diet this difference diminished. Muscle glycogen and triacylglycerol concentrations were increased (P < 0.05) by 14% and 22%, respectively, with the HGI diet compared with the LGI diet, and muscle triacylglycerol concentrations did not correlate with insulin action. It is concluded that when ingesting a diet with an energy composition common in Western countries, switching the carbohydrates from high to low GI sources decreases insulin action on whole-body glucose disposal at a high but not at a physiologic plasma insulin concentration. Furthermore, adaptation in terms of carbohydrate digestion and/or absorption to a diet rich in LGI carbohydrates may take place over 4 wk.

An educational tool for understanding the cardiovascular changes associated with diabetes.

Diabetes, a syndrome characterized by high plasma glucose and low plasma insulin concentrations, is associated with somatic and autonomic neuropadiabetes as well as cardiac and vascular disorders. These consequences of diabetes significantly affect the organism's ability to maintain homeostasis. To understand the changes associated with diabetes, we developed a laboratory exercise that compares and contrasts the cardiovascular responses to exercise in an individual with diabetes and in an individual without diabetes. This exercise provides a unique opportunity to analyze, integrate, and interpret the changes associated with diabetes, since more is learned about how a system operated when the system is forced to perform than when it is idle. In this laboratory, anatomical and physiological data concerning diabetes are provided. Subsequently, a figure that illustrates the response of a specific cardiovascular variable during exercise (e.g., heart rate, cardiac output, blood pressure) is presented. Students are challenged to analyze and assimilate information from figures, answer questions, make calculations, fill in tables, and plot graphs. The laboratory does not require equipment or software, only rulers and pencils. The answers to the questions and tables are provided in the APPENDIX. Students obtain experience in evaluating and understanding diabetes as well as applying basic cardiovascular concepts. The emphasis is on the application of basic cardiovascular principles, interpretation of pictorial or tabular material, and problem-solving skills.

Impaired activity of rat pancreatic islet mitochondrial glycerophosphate dehydrogenase in protein malnutrition.

In rats that received a low protein isocaloric diet (protein content of the diet: 8 instead of 20%) during fetal life and thereafter up to the time of sacrifice at 12-13 weeks of age, a low plasma insulin concentration, a decreased insulin content of isolated pancreatic islets, and an impaired secretory response of the islets to either D-glucose or the association of L-leucine and L-glutamine coincided, in islet homogenates, with a low activity of the mitochondrial glycerophosphate dehydrogenase and an abnormally high ratio between glutamate-alanine and glutamate-aspartate transaminase activities. Opposite enzymatic changes were found in liver extracts of the same rats. No obvious change in these hormonal, secretory, and enzymatic variables were observed when the period of protein deficiency was restricted to fetal life. These findings support the view that, in protein malnutrition, an impaired activity of pancreatic B-cell mitochondrial glycerophosphate dehydrogenase contributes, possibly in association with other enzymatic anomalies, to the perturbation of islet function.

Impaired activity of rat pancreatic islet mitochondrial glycerophosphate dehydrogenase in protein malnutrition

In rats that received a low protein isocaloric diet (protein content of the diet: 8 instead of 20%) during fetal life and thereafter up to the time of sacrifice at 12-13 weeks of age, a low plasma insulin concentration, a decreased insulin content of isolated pancreatic islets, and an impaired secretory response of the islets to either D-glucose or the association of L-leucine and L-glutamine coincided, in islet homogenates, with a low activity of the mitochondrial glycerophosphate dehydrogenase and an abnormally high ratio between glutamate-alanine and glutamate-aspartate transaminase activities. Opposite enzymatic changes were found in liver extracts of the same rats. No obvious change in these hormonal, secretory, and enzymatic variables were observed when the period of protein deficiency was restricted to fetal life. These findings support the view that, in protein malnutrition, an impaired activity of pancreatic B-cell mitochondrial glycerophosphate dehydrogenase contributes, possibly in association with other enzymatic anomalies, to the perturbation of islet function.

Seasonal changes in systemic hormone profiles and their relationship to patterns of fibre growth and moulting in goats of contrasting genotypes

In a 2 x 2 factorial experiment, seasonal changes in hormone and insulin-like growth factor-1 (IGF-1) profiles were compared in goats of two genotypes (Siberian (S) and Icelandic x Scottish feral (IF); n = 20 per genotype) with differing patterns of secondary fibre growth. Half of the goats of each genotype were fed rations containing either 100 or 180 g crude protein (CP)/kg dry matter. The period of secondary fibre growth was longer and the rate of growth greater in S than IF goats, but there were no effects of dietary protein concentration. Mean plasma concentrations of insulin, cortisol, T3 and T4 were higher in winter and those of prolactin, GH and IGF-1 concentrations were higher in summer. Growth of secondary fibre in S goats between January and March was associated with higher plasma prolactin and lower plasma insulin concentrations at this time than in IF goats in which there was no secondary fibre growth. The observed genotypic differences in times of onset and cessation of fibre growth were not associated with differences in the times of seasonal changes in any of the other hormones measured, and there was no effect of dietary protein level on hormone profiles. The higher mean growth rate and greater diameter of secondary fibre in S goats was associated with higher mean concentrations of T4 than in IF goats, throughout the study. Four S goats which exhibited secondary fibre growth during the summer had higher (P &lt; 0.05) mean plasma insulin concentrations than other animals of that genotype. It is suggested that genotypic differences in prolactin concentrations in late winter/spring may affect the time of onset of secondary fibre growth and that the cessation of growth may be influenced by differences in the timing of the seasonal decline of circulating prolactin concentrations to basal levels. However, the maintenance of relatively high plasma insulin concentrations may prolong growth in some circumstances. The higher concentrations of T4 in S than IF goats may have a role in the enhancement of the rate of fibre growth in these animals. The onset of moult in both genotypes was associated with the spring increase in plasma prolactin concentrations.

Regulation of rat insulin receptor tyrosine kinase by hypoglycemia.

To investigate the effect of hypoglycemia on the regulation of muscle-derived insulin receptor tyrosine kinase activity, four groups of Sprague-Dawley rats were studied: two groups in which either insulin (4 mU/kg.min) or phloridzin (3 mg/kg.min) was infused to acutely reach hypoglycemia (mean, 3.2-3.5 mM); and two control groups in which either saline or phloridzin (3 mg/kg.min) was infused, while maintaining euglycemia. Plasma glucose was maintained constant for 40 min in the hypoglycemic group and for 60 min in the phloridzin-infused euglycemic groups by a variable glucose infusion. Insulin receptors were isolated under conditions designed to preserve their in vivo phosphorylation state, and their tyrosine kinase activity toward poly(Glu-Tyr) was measured in the absence and presence of in vitro exposure to insulin. Insulin infusion resulted in an enhanced in vivo tyrosine kinase activity. Surprising was the finding of a slight increase of the in vivo tyrosine kinase activity in the phloridzin-infused hypoglycemic rats. The in vitro insulin dose-response curves of tyrosine kinase activity showed no significant differences between insulin-infused and control rats. In contrast, there was a marked increase of the insulin-stimulated kinase activity in phloridzin-infused hypoglycemic rats; at 100 nM insulin, tyrosine kinase activity was 1.8-fold more responsive when compared with either insulin-infused rats or control groups. Moreover, in phloridzin-infused hypoglycemic rats, the half-maximal stimulation of tyrosine kinase activity was greater than 10-fold (0.36 +/- 0.01 nM) more sensitive to insulin than both insulin-infused (3.8 +/- 0.03 nM, mean +/- SE) and control groups (4.2 +/- 0.05 and 4.1 +/- 0.04 nM in saline- and phloridzin-infused euglycemic rats, respectively, mean +/- SE). In conclusion, hypoglycemia associated with low plasma insulin concentrations determines a hypersensitization of the intrinsic tyrosine kinase of the insulin receptor.

Glucose-fatty acid cycle operates in humans at the levels of both whole body and skeletal muscle during low and high physiological plasma insulin concentrations.

Plasma non-esterified fatty acid concentrations were elevated acutely (Intralipid+heparin infusion) in 14 normal humans in order to study the effects of fatty acids on whole-body basal and insulin-stimulated glucose metabolism, and on activities of skeletal muscle key enzymes. Whole-body glucose metabolism was assessed using [3-3H]glucose and indirect calorimetry. Biopsies were taken from the vastus lateralis muscle during basal and insulin-stimulated (3 h, 40 mU.m-2.min-1) steady-state periods. Total peripheral glucose uptake was unaffected by Intralipid infusion in the basal state, whereas it decreased during Intralipid infusion in the hyperinsulinemic state (10.7 +/- 0.7 vs 8.7 +/- 0.8 mg.kg-1 fat-free mass.min-1, p < 0.02). Intralipid infusion decreased whole-body glucose oxidation in the basal state (1.3 +/- 0.2 vs 0.8 +/- 0.1 mg.kg-1 fat-free mass.min-1, p < 0.001) and during hyperinsulinemia (3.6 +/- 0.2 vs 1.7 +/- 0.2 mg.kg-1 fat-free mass.min-1 p < 0.001). Whole-body nonoxidative glucose uptake increased during Intralipid infusion in the basal state and was unaffected in the hyperinsulinemic state. The skeletal muscle pyruvate dehydrogenase activity ratio decreased in the basal state during Intralipid infusion (55 +/- 6 vs 43 +/- 5%, p < 0.05), whereas no statistical significant decrease in the pyruvate dehydrogenase activity ratio was observed during insulin infusion (57 +/- 8 vs 47 +/- 5%, NS). Insulin increased the activity of the active form of pyruvate dehydrogenase on the control day, but not during Intralipid infusion. Activities of phosphofructokinase and glycogen synthase were unaffected by Intralipid infusion. Plasma glucose concentrations were similar during Intralipid infusion and on the control day, whereas Intralipid infusion increased the muscle glucose content in the basal state (1.36 +/- 0.09 vs 1.77 +/- 0.12 mmol/kg dry wt, p < 0.05) and in the hyperinsulinemic state (1.23 +/- 0.09 vs 1.82 +/- 0.16 mmol/kg dry wt, p < 0.05). Insulin increased the muscle lactate content on the control day (6.50 +/- 0.95 vs 8.65 +/- 0.77 mmol/kg dry wt, p < 0.05), but not during Intralipid infusion. In conclusion, the glucose-fatty acid cycle operates in humans in vivo at the levels of both whole body and skeletal muscle during both low and high physiological insulin concentrations.

Ontogeny of Insulin Effect in Fetal Sheep

Compared with fetuses near term, midgestation fetal sheep at about 75 d of gestation have higher weight-specific glucose uptake rates, higher plasma glucose concentrations, lower plasma insulin concentrations, higher red blood cell insulin receptor concentrations and affinity, and a lower proportion of body weight accounted for by potentially insulin-sensitive skeletal muscle. Based on these observations, we measured the net rate of glucose uptake by the fetus from the uteroplacenta under basal and hyperinsulinemic conditions in eight fetal sheep at 76 d of gestation and eight fetal sheep at 132 d of gestation (term approximately 150 d). Hyperinsulinemia (414 +/- 90 pM) in the 76-d fetal sheep decreased plasma glucose concentration by 0.20 +/- 0.03 mM (-13%, p < 0.01) and increased the net rate of glucose uptake (8.4 +/- 2.2 mumol/min/kg, +21.3%, p < 0.05) and glucose clearance (11.4 +/- 2.6 mL/min/kg, +39%, p < 0.01). In the 132-d fetuses, a comparable hyperinsulinemia (306 +/- 36 pM) decreased plasma glucose concentration (-0.31 +/- 0.02 mM, -26%, p < 0.05) and increased glucose clearance (16.7 +/- 1.8 mL/min/kg, +73.6%, p < 0.05) to a greater extent than in the 76-d fetuses (p < 0.05 and p < 0.01, respectively). Net glucose uptake rate increased significantly in the 132-d fetuses (6.7 +/- 1.1 mumol/min/kg, +27.5%, p < 0.05), but not differently from the 76-d fetuses (p = 0.21). These data define brisk and significant effects of insulin on glucose metabolism in fetal sheep, even as early as approximately 50% of gestation. The midgestation fetal sheep, particularly in relation to its larger fractional content of body water and smaller fractional content of insulin-sensitive tissues, demonstrates glucose metabolic responses to insulin at least as great as those that occur near term.

Acute continuous hemofiltration with dialysis

To quantitate insulin losses and glucose absorption during acute continuous hemofiltration with dialysis and to assess the clinical importance of these changes. Prospective collection of serum and ultradiafiltrate fluid in patients receiving acute continuous hemofiltration with dialysis. Measurements of serum and ultradiafiltrate insulin and glucose concentrations. Calculations of insulin excretion and glucose absorption. Correlation of findings with patient outcome. University medical center. Sixteen ICU patients with acute renal failure. The mean serum glucose concentration before acute continuous hemofiltration with dialysis was 178 mg/dL (9.9 mmol/L) (95% confidence interval 112 to 244 mg/dL [6.2 to 13.6 mmol/L]), increasing to 257 mg/dL (14.3 mmol/L) (95% confidence interval 167 to 347 mg/dL [9.3 to 19.3 mmol/L]) after 4 hrs of acute continuous hemofiltration with dialysis, and stabilizing at 207 mg/dL (11.5 mmol/L) (95% confidence interval 160 to 254 mg/dL [8.9 to 14.1 mmol/L]) at 24 hrs. Mean plasma insulin concentration before acute continuous hemofiltration with dialysis was 34.4 mU/L (95% confidence interval 8.6 to 60.2 mU/L), increasing to 54.4 mU/L at 4 hrs (95% confidence interval 25 to 83.8 mU/L; NS). There was no significant decrease in mean insulin concentration across the filter (51.8 mU/L before filtration vs. 51.9 mU/L after filtration). Insulin was detected in the ultradiafiltrate but its overall mean clearance rate was only 6.2 mL/min, with mean daily losses of 689 mU/day (95% confidence interval 325 to 1053 mU/day). During acute continuous hemofiltration with dialysis, glucose absorption through the filter averaged 134 g/day (95% confidence interval 96.2 to 171.8 g/day). Plasma insulin concentrations were significantly (p < .05) lower in survivors than nonsurvivors (51.7 vs. 123.6 mU/L). Significant glucose absorption occurs during acute continuous hemofiltration with dialysis and is coupled with minor insulin losses (< 1 U/day) through the filter. These events do not appear to have major clinical impact. A low plasma insulin concentration is associated with diminished mortality rates in this group of patients.

Insulin receptor function is preserved in a physiological state of hypoinsulinemia and insulin resistance.

The suckling period in the rat is characterized by a continuously low plasma insulin concentration and a physiological insulin resistance, particularly in the adipose tissue. This insulin resistance disappears after weaning on the high-carbohydrate adult diet. We have studied the number, structure, and function of adipose tissue insulin receptors during the suckling-weaning transition. The insulin receptor number determined either on intact adipocytes or after partial purification was higher during suckling (15 days), whereas the affinity was similar when compared with weaned rats (30 days). The molecular weight of the alpha- and beta-subunits were identical in both groups and, when analyzed in nonreducing conditions, the alpha 2 beta 2-form was the unique detectable form of the receptor. Neither the basal and insulin-stimulated autophosphorylation of the insulin receptor beta-subunit nor the tyrosine kinase activity toward a synthetic substrate was decreased during the suckling period. Thus, in the adipose tissue of the suckling rat, a marked insulin resistance is concomitant with a normal insulin receptor number and function.

Impact of associated conditions on glycemic control of NIDDM patients.

To assess the impact of associated conditions (obesity, dyslipidemia, and hypertension) on the glycemic control of non-insulin-dependent diabetes mellitus (NIDDM) patients under home-life conditions. We analyzed the metabolic data of 271 NIDDM patients (89% Mexican American) screened in a population-based survey (the San Antonio Heart Study). Obesity was present in 77% of the patients, hypertension in 23%, hypertriglyceridemia (serum triglycerides greater than 2.9 mM) in 23%, and hypercholesterolemia (serum total cholesterol greater than 6.5 mM) in 14%. Forty percent of the patients had two or more comorbid conditions. With the use of a multiple linear regression model, which was adjusted for age, sex, ethnicity, distribution of body fat (waist-hip ratio), plasma insulin, and treatment (of both diabetes and hypertension), we found that the presence of higher serum triglyceride concentrations was associated with significantly higher plasma glucose levels both in the fasting state (1.4 mM, P less than 0.001) and 2 h after an oral glucose load (1.2 mM, P = 0.003). The presence of obesity, hypertension, or high serum cholesterol levels was not associated with significant changes in glycemic control. When the entire group was stratified by diabetes treatment (untreated n = 89, diet n = 75, oral agents n = 82, insulin n = 25) and after adjusting for age, sex, ethnicity, and waist-hip ratio, only fasting and 2-h plasma glucose and insulin concentrations were significantly different across treatment groups, with diet and oral agents being associated with higher fasting (P less than 0.001) and postglucose (P less than 0.005) plasma glucose levels and lower plasma insulin concentrations (P less than 0.005) compared with newly diagnosed patients. Neither serum lipids nor blood pressure differed across treatment. In NIDDM patients under home-life conditions, higher serum triglycerides are associated with higher fasting and postglucose hyperglycemia regardless of antidiabetic treatment. The presence of obesity, hypertension, or high serum cholesterol levels is not associated with significant changes in glycemic control.

Exercise in the Treatment of NIDDM: Applications for GDM?

Physical training is associated with lower plasma insulin concentrations and increased sensitivity to insulin in skeletal muscle and adipose tissue of individuals with non-insulin-dependent diabetes mellitus (NIDDM). The benefits of exercise to individuals with NIDDM in terms of increased insulin sensitivity could be applied to reversing the insulin resistance associated with gestational diabetes mellitus (GDM). Exercise may also benefit women with GDM by acting as an adjunct to diet in preventing excessive weight gain and preventing or decreasing the severity of hypertension and/or hyperlipidemia during pregnancy. Regular physical exercise should be considered as a potential approach to the prevention and treatment of GDM.

Comparison of effects of platelet-activating factor and tumour necrosis factor-α on lipid metabolism in adrenalectomized rats in vivo

The acute metabolic effects of platelet-activating factor (PAF) and tumour necrosis factor-alpha (TNF-alpha) were compared in sham-operated and adrenalectomized rats. PAF caused hyperglycaemia in sham-operated rats, whereas with TNF-alpha there was a slight decrease in blood glucose. Both PAF and TNF-alpha resulted in marked hypoglycaemia in the adrenalectomized rats. Plasma insulin was depressed (about 50%) by PAF and TNF-alpha in sham-operated rats, whereas in the adrenalectomized rats the already low plasma insulin concentration was not significantly altered. Liver glycogen content was the same in control and treated sham-operated rats, but was considerably decreased (about 50%) in the adrenalectomized rats. In sham-operated rats, PAF and TNF-alpha increased plasma non-esterified fatty acids and triacylglycerols, suggesting increased lipolysis, whereas in adrenalectomized rats there was no significant increase in non-esterified fatty acids with PAF, although it still occurred with TNF-alpha. This suggests that the lipolytic effect of TNF-alpha may be direct, whereas that of PAF is indirect, possibly via increased catecholamines in the sham-operated rats. The stimulation (about 3-fold) of hepatic fatty acid synthesis in vivo by PAF and TNF-alpha in sham-operated rats was still evident in the adrenalectomized rats, although the absolute increase was smaller. PAF, but not TNF-alpha increased (100%) sterol synthesis in adrenalectomized rats. It is concluded that PAF and TNF-alpha can increase hepatic lipogenesis in vivo in the absence of adrenal hormones and in the presence of a low plasma insulin.