Relative Hypoglycemia Research Articles

Moderate hypoglycemia aggravates effects of hypoxia in hippocampal slices from diabetic rats

We recorded the effects of hypoxia combined with relative hypoglycemia on pre- and post-synaptic potentials in the CA1 area of slices from 4-month-old control and diabetic (streptozotocin-treated) Wistar rats. In experiments on slices kept in 10 or 4 mM glucose (at 33°C), hypoxia was applied until the pre-synaptic afferent volley disappeared – after 12–13 min in most slices, but much earlier (5±0.8 min) in diabetic slices kept in 4 mM glucose. When oxygenation was resumed, the afferent volley returned in all slices, for an overall mean recovery of 86.5% (±8.8%). Field post-synaptic potentials were fully blocked within 2–3 min of the onset of hypoxia. After the end of hypoxia, they failed to reappear in some slices: overall, their recovery varied between 62 and 68% in control slices, as well as in diabetic slices kept in 10 mM glucose; but recovery was very poor in diabetic slices kept in 4 mM glucose (only 15±0.94%). In the latter, hypoxic injury discharges occurred earlier (4.2±0.68 min vs. 6.5–8 min for other groups). We conclude that diabetes appears to make hippocampal slices more prone to irreversible loss of synaptic function and early block of axonal conduction when temporary hypoxia is combined with moderate hypoglycemia.

Blood flows and nutrient uptakes in growth-restricted pregnancies induced by overnourishing adolescent sheep.

To establish physiological mechanisms for fetal growth restriction in pregnant adolescent ewes we studied uterine, fetal, and uteroplacental metabolism in ewes offered a high (n = 12) or moderate (n = 10) dietary intake. High intakes decreased placental (226 vs. 414 g, P < 0.001) and fetal weight (3,323 vs. 4,626 g, P < 0.01). Uterine blood flow was reduced absolutely (-36%) but proportional to conceptus weight; umbilical blood flow was reduced absolutely (-37%) and per fetal weight (-15%). Uterine oxygen uptake was decreased per conceptus weight (-14%); there was no change in fetal weight oxygen consumption. Uteroplacental oxygen consumption and clearance were reduced proportional to weight. Similar changes were measured for glucose fluxes and fetal glucose concentration; fetal insulin concentration was reduced. In this model of fetal growth restriction, therefore, maintenance of fetal weight-specific glucose and oxygen consumption rates are producing relative hypoglycemia and hypoxemia. This indicates that increased fetal glucose clearance and/or insulin sensitivity may be operating as compensatory mechanisms to preserve normal fetal metabolism while fetal growth is sacrificed.

Secretion of bioactive human insulin following plasmid-mediated gene transfer to non-neuroendocrine cell lines, primary cultures and rat skeletal muscle in vivo.

The objective of these studies was to evaluate human insulin gene expression following intramuscular plasmid injection in non-diabetic rats as a potential approach to gene therapy for diabetes mellitus avoiding the need for immunosuppression. A wild-type human preproinsulin construct and a mutant construct in which PC2/PC3 sites were engineered to form furin consensus sites were evaluated in in vitro transfections of hepatocyte (HepG2) and myoblast (C2C12/L6) cell lines, primary rat myoblasts, and dermal fibroblasts. In vivo gene transfer by percutaneous plasmid injection of soleus muscle +/- prior notexin-induced myolysis was assessed in rats. In vitro transfection of non-neuroendocrine cell lines and primary cultures with wild-type human preproinsulin resulted in secretion of predominantly unprocessed proinsulin. Employing the mutant construct, there was significant processing to mature insulin (HepG2, 95%; C2C12, 75%; L6, 65%; primary myoblasts, 48%; neonatal fibroblasts, 56%; adult fibroblasts, 87%). In rats aged 5 weeks, circulating human (pro)insulin was detected from 1 to 37 days following plasmid injection and the potential of augmenting transfection efficiency by prior notexin injection was demonstrated (wild-type processing, 87%; mutant, 90%). Relative hypoglycaemia was confirmed by HbA1C (saline, 5.5%; wild type, 5.1%; mutant, 5.1% (P<0.05)). Human (pro)insulin levels and processing (wild-type, 8%; mutant, 53%) were lower in rats aged 9 months but relative hypoglycaemia was confirmed by serum glucose at 10 days (saline, 6.4 mmol/l; wild-type, 6.0 mmol/l; mutant, 5.4 mmol/l). In conclusion, prolonged constitutive systemic secretion of bioactive human (pro)insulin has been attained in non-neuroendocrine cells in vitro and in growing and mature rats following intramuscular plasmid injection.

Oral delivery of insulin from enteric-coated capsules containing sodium salicylate: effect on relative hypoglycemia of diabetic beagle dogs

The hypoglycemic effect of Eudragit S100 enteric-coated capsules containing sodium salicylate as an absorption promoter formulated with insulin in various ways: as physical mixture, by wet granulation or in suppository bases (polyethylene glycol 4000 or Witepsol W35) was studied in hyperglycemic beagle dogs. The capsules containing insulin formulated with sodium salicylate (50 mg) and prepared by either physical mixing or wet granulation using 10% polyvinyl pyrollidone gave almost the same results producing a maximum reduction in plasma glucose level ( C max) of 81.53±8.21 and 79.59±5.75%, T max of 6 and 5 h, area under the curve (AUC) of 69.37±48.64 and 57.98±23.15% reduction hour (% red. h) and resulting in relative hypoglycemia (RH) of 8.73±6.12 and 7.29±2.91%, respectively. Formulation of insulin with sodium salicylate in PEG 4000 produced a lower AUC of 37.30±10.36% red. h and RH of 4.69±1.3%. While, formulation in Witepsol W35 (0.5, 1.0 and 2.0 g) that was sieved to produce particle size of 180–315 μm and filled in enteric-coated capsules showed that formulating insulin and sodium salicylate in 1 g base is the best formulation. It produced 25% reduction in plasma glucose levels of the hyperglycemic beagle dogs at T max of 4 h and the largest AUC of 100.10±25.72% red. h, resulting in the highest RH of 12.59±3.23%. In conclusion, 25–30% reduction in plasma glucose levels and RH of about 12.5% relative to subcutaneous injection of regular soluble insulin can be achieved by formulating insulin in Witepsol W35 (1 g) with sodium salicylate (50 mg) as an absorption promoter, reducing the resulting mass into particle size 180–315 μm, packing into hard gelatin capsules and coating with Eudragit S100.

Effect of Bioadhesive Polymers, Sodium Salicylate, Polyoxyethylene-9-lauryl Ether, and Method of Preparation on the Relative Hypoglycemia Produced by Insulin Enteric-Coated Capsules in Diabetic Beagle Dogs

ABSTRACTThe hypoglycemic effect of oral insulin capsules coated with pH-dependent Eudragit® S100 and containing various absorption promoters was studied in hyperglycemic beagle dogs. The absorption enhancers used were bioadhesive polymers, sodium salicylate, and non-ionic surfactants. A comparative study of the bioadhesive polymers, polycarbophil (PC), hydroxypropyl methylcellulose (HPMC), and carbopol 934 in insulin-coated capsules revealed no significant difference between the insulin capsules containing these polymers, giving relative hypoglycemia (RH) values ranging from 4.3±2.3% to 6.5±5.1%. It was also found that the method of preparation of the mixture of the bioadhesive polymer with insulin either by physical mixing or freeze-drying did not affect the RH values obtained. Sodium salicylate, when used in insulin enteric-coated capsules (50 mg) mixed with insulin as a physical mixture, or prepared by wet granulation using 10% polyvinyl pyrollidone (PVP), or by freeze-drying, produced RH values ranging from 7.3±2.9% to 9.4±3.7%. When sodium salicylate (100 mg) was used with insulin in freeze-dried granules an RH value of 10±2.6% was produced. As the dose of insulin increased from 6 to 9 U/kg, the area under curve (AUC) of the enteric-coated capsules containing 50 mg sodium salicylate increased from 73.2±27.8% to 121.4±102.7% reduction, but the RH did not change significantly. Insulin capsules containing polyoxyethylene-9-lauryl ether (POELE) used in its optimum concentration (2%), found in these experiments, produced RH of 9.5±6.8% when prepared as granules by wetting with a few drops of absolute alcohol in the presence of PC (50 mg). Insulin capsules containing lower (1%) or higher (3%) concentrations of POELE and prepared with PC, 50 mg by wet granulation produced lower RH of about 6%. The enteric-coated oral insulin capsules containing insulin (6 or 9 U/kg) and sodium salicylate (50 mg) as an absorption promoter, together with the bioadhesive polymer polycarbophil (50 mg), and prepared either by wet granulation using ethanol or by freeze-drying, are the best formulations to be used. They achieved a reduction in plasma glucose levels of about 25–30% and RH of about 10%. Also insulin (9 U/kg) capsules containing 2% POELE produced a 28% reduction in plasma glucose levels and RH of 9.6±6.8%.

Foxa3 (hepatocyte nuclear factor 3gamma ) is required for the regulation of hepatic GLUT2 expression and the maintenance of glucose homeostasis during a prolonged fast.

The winged helix transcription factors, hepatocyte nuclear factors 3alpha, -beta, and -gamma (HNF-3, encoded by the Foxa1, -a2, and -a3 genes, respectively), are expressed early in embryonic endoderm and play important roles in the regulation of gene expression in liver and pancreas. Foxa1 has been shown to be required for glucagon secretion in the pancreas, whereas Foxa2 is critical for the regulation of insulin secretion in pancreatic beta-cells. Here we address the role of Foxa3 in the maintenance of glucose homeostasis. Mice homozygous for a null mutation in Foxa3 appear normal under fed conditions. However, when fasted, Foxa3(-/-) mice have a significantly lower blood glucose compared with control mice. The fasting hypoglycemia in Foxa3(-/-) mice could not be attributed to defects in pancreatic hormone secretion, ketone production, or hepatic glycogen breakdown. Surprisingly, mRNA levels for several gluconeogenic enzymes were up-regulated appropriately in fasted Foxa3(-/-) mice, despite the fact that the corresponding genes had been shown to be activated by FOXA proteins in vitro. However, the mRNA for the plasma membrane glucose transporter GLUT2 was decreased by 64% in the fasted and 93% in the fed state, suggesting that efflux of newly synthesized glucose is limiting in Foxa3(-/-) hepatocytes. Thus, Foxa3 is the dominating transcriptional regulator of GLUT2 expression in hepatocytes in vivo. In addition, we investigated the hepatic transcription factor network in Foxa3(-/-) mice and found that the normal activation of HNF-4alpha, HNF-1alpha, and PGC-1 induced by fasting is attenuated in mice lacking Foxa3.

Factors Influencing Fetal Growth

After completing this article, readers should be able to: 1. Describe the roles of insulin-like growth factor on fetal growth and development. 2. Delineate components of “maternal constraint.” 3. Explain the role of the placenta in regulating fetal growth. 4. Describe the effects of fetal glucose, amino acid, and fat supply on fetal growth. The principal determinants of fetal growth are fetal genotype and in utero environment. Environmental factors include maternal and paternal genetics, maternal size, and the capacity of the placenta to provide nutrients to the fetus. These environmental factors interact with the intrinsic growth pattern of the fetus, yielding a particular rate and composition of fetal growth. Most of the variation in fetal growth in a population is due to variations in environmental factors, not the fetal genome, although a genetically abnormal fetus clearly might not grow as well as a normal fetus if affected genes include those that are important for growth. Many genes contribute to fetal growth and birthweight. Techniques in which specific genes can either be deleted (“knockouts”) or overexpressed have led to greater understanding of how some of these genes regulate fetal growth. Such studies have shown that both maternal and paternal influences are present during fetal development and are passed on to the developing fetus by spermatozoa or oogonia by a mechanism called imprinting. Although the maternal genetic composition exerts greater influence than fetal genotype in the overall regulation of fetal growth, both maternal and paternal genomes are important in fetal growth and development (1)(2). For example, gynogenetic zygotes (two maternal genome copies) lead to underdeveloped extraembryonic tissues but well-developed embryos. The more modest regulation offered by the paternal genotype is essential for trophoblast development. For example, zygote nuclear transfer experiments have shown that androgenetic zygotes (two paternal genome copies) develop extensive trophoblast tissues but …

Differential effects of short and long duration insulinotropic agents on meal-related glucose excursions.

Abnormal beta-cell function, characterized as the inability of the beta-cell to mount a rapid secretory response to glucose, is a well-established pathology of type 2 diabetes mellitus. These studies were designed to demonstrate the importance of early insulin release on the control of meal-induced glucose excursions by capitalizing on the significant pharmacodynamic differences between several oral insulin secreting agents. Male Sprague Dawley fitted with indwelling jugular cannulas were used to compare the pharmacodynamic profiles of nateglinide (Nateg), glipizide (Glip) and repaglinide (Repag) through frequent blood samples following the administration of these compounds via oral gavage. In similar animals which were pretrained to consume their daily food intake in two discrete 45-min meals, the effects of compound induced changes in pre-meal, meal and post-meal insulin profiles on glycaemic control were assessed through frequent blood sampling following the administration of these compounds 10 min prior to a 30-min meal. There were significant pharmacodynamics differences between the three oral agents tested and the time to elicit peak insulin secretory responses increased from Nateg (4 min) to Repag (10 min) to Glip (45 min). During the meal tolerance test, glibenclamide did not increase pre-meal insulin levels and glucose excursions paralleled those in the control. Conversely, the other three agents, at doses that produced hypoglycaemic responses of similar magnitude, all increased early insulin release (Delta AUC(-15 to 3 min) = 0.5 +/- 0.01, 1.6 +/- 0.4, 3.6 +/- 0.0, 1.2 +/- 0.1 and 1.73 +/- 0.4 nmol/min, for control, Nateg at 60 and 120 mg/kg, Glip and Repag, respectively) and curbed glucose excursions during the meal at varying rates and degrees (Delta AUC(0--30 min) = 39 +/- 6, 8 +/- 7, 5 +/- 7, - 1 +/- 8 and - 3 +/- 8 mmol/min for control, Nateg at 60 and 120 mg/kg, Glip and Repag, respectively). However, unlike Nateg, the longer duration of action of Repag and Glip elicited sustained post-meal relative hypoglycaemia. These data support the impact of early and rapid insulin release in the control of prandial and post-meal glycaemia and demonstrate that a short anticipatory burst of insulin, restricted to the beginning of a meal, provides a clear metabolic advantage and prevents post-meal hypoglycaemic episodes when compared to a greater but reactive insulin exposure that follows a meal-induced increase in glucose excursion.

Effect of Different Bile Salts on the Relative Hypoglycemia of Witepsol W35 Suppositories Containing Insulin in Diabetic Beagle Dogs

Insulin suppositories were formulated using Witepsol W35 as a base to investigate the effect of various bile salts/acids on the plasma glucose concentration of diabetic beagle dogs. Comparison of the effect of these formulations was made with that produced by insulin subcutaneous injections. Of the bile salts/acids studied, incorporation of 100 mg of deoxycholic acid (DCA), sodium cholate (NaC), or sodium deoxycholate (NaDC) with insulin (10 U/Kg) showed that suppositories containing NaDC produced the highest area under the curve (AUC) and relative hypoglycemia (RH) of 290 ± 83 mg%h and 28% ± 8.1%, respectively. To study the optimum amount of NaDC in insulin suppositories to produce the highest RH, 50–200 mg/suppository were used, and we found that 150 mg NaDC produced 35% ± 13% RH. We also studied the influence of different doses of insulin (5–20 U/kg) in the presence of NaDC (100 mg). It was found that increase of the insulin dose was accompanied by an increase in AUC and maximum reduction in plasma glucose level Cmax. A combination of NaDC (100 mg) and NaC (50 mg) produced an AUC of 252 ± 13 mg% h and an RH of 49% ± 2.6%, which were higher than produced by either of its individual components (NaC 50 mg or NaDC 100 mg) when used alone or when compared with an equivalent amount of NaDC (150 mg). When the effect of sodium taurocholate (NaTC) and sodium taurodeoxycholate (NaTDC) was studied, it was found that an insulin suppository containing 100 mg of either NaTC or NaTDC produced an RH equivalent to that produced previously with a mixture of NaDC (100 mg) and NaC (50 mg). On the other hand, NaC (50 mg) did not improve the hypoglycemic effect of NaTC any further. In conclusion, a relative hypoglycemia of about 50% can be reached using insulin suppositories containing Witepsol W35 as a base and NaDC plus NaC (100 mg plus 50 mg, respectively), NaTDC (100 mg), or NaTC (100 mg) as rectal absorption enhancers of insulin. A desirable hypoglycemia, expressed as Cmax, and/or AUC can be reached by adjusting the insulin dose in the formulation according to the degree of hyperglycemia.

Relative Hypoglycemia of Rectal Insulin Suppositories Containing Deoxycholic Acid, Sodium Taurocholate, Polycarbophil, and Their Combinations in Diabetic Rabbits

In this study, insulin suppositories containing 50 U insulin incorporated with 50 mg of deoxycholic acid, sodium taurocholate, or both were placed in the rectum of alloxan-induced hyperglycemic rabbits. A large decrease in plasma glucose concentrations was observed, and the relative hypoglycemias were calculated to be 38.0%, 34.9%, and 44.4%, respectively, compared with insulin subcutaneous (s.c.) injection (40 U). Insulin suppositories containing 50 mg polycarbophil alone or mixed with 50 mg deoxycholic acid produced relative hypoglycemia of 43.1% and 42.2%, respectively. The most pronounced effect was observed with the addition of polycarbophil to the suppository formulation containing a combination of deoxycholic acid and sodium taurocholate, which produced a 56% relative hypoglycemia compared with subcutaneous injection. These suppository formulations could be very promising alternatives to the current insulin injections, being roughly half as efficacious as subcutaneous injection.

Risk factors of severe hypoglycaemia in adult patients with Type I diabetes--a prospective population based study.

The objective of this study was to identify possible risk factors of severe hypoglycaemia (SH) in a prospective population based study of adult Type I (insulin-dependent) diabetic patients. A representative sample of 684 patients (41% women, mean +/- SD age 36 +/- 11, diabetes duration 18 +/- 11 years), living in the district of Northrhine (9.5 million inhabitants), Germany, were examined in their homes using a mobile ambulance. A comprehensive baseline assessment of possible predictors of SH included sociodemographic and disease related variables, hypoglycaemia awareness, diabetes management, and attitudes and behavioural aspects as expressed by the patients. After a mean of 19 +/- 6 months 669 (98%) patients were interviewed about events of SH since the baseline examination. Using the multiple Cox proportional hazards model, five risk factors of SH were identified: SH during the preceding year [hazard ratio (HR) 2.7, 95% confidence intervals (CI) 1.8-4.2], any history of SH (HR 1.9, CI 1.1-3.4), C-peptide negativity (HR 4.0, CI 1.2-12.7), social status (HR 0.8 for a difference of 5 units for a value range of 0-24, CI 0.6-0.9), and patients' determination to reach normoglycaemia (HR 0.7 for a difference of 1 unit for a value range of 1-6, CI 0.5-0.9), indicating that the lower the social status and the higher the patients' determination to reach normoglycaemia, the higher the risk of SH. After eliminating the history of hypoglycaemia from the model, impaired hypoglycaemia awareness and patients' inappropriate denial of SH as their particular problem became additional significant risk factors of SH. In conclusion, in this population based study of adult Type I diabetic patients, C-peptide negativity, a previous event of SH, patients' determination to reach normoglycaemia and social class were risk factors of SH.

Hypoglycemic Effect of Oral Insulin in Diabetic Rabbits Using pH-Dependent Coated Capsules Containing Sodium Salicylate Without and with Sodium Cholate

The hypoglycemic effect of oral insulin (20 U and 40 U) capsules coated with a pH-dependent soluble polymer (Eudragit S100) and containing sodium salicylate (50 mg) without and with sodium cholate (50 mg) was studied in alloxan-hyperglycemic rabbits and compared with that of s.c. insulin injection (20 U). The capsules containing 20 U insulin + sodium salicylate (50 mg) produced a significant reduction in plasma glucose level to 82 and 73% of initial values at 2 and 3 hr after administration, respectively. The blood glucose level slowly returned to normal values at 5 hr. The AUC0–5 hr was 73.7 ± 43.5 mg. hr/dl compared to 242 ± 70.5 mg. hr/dl for insulin (20 U, s.c.) with a relative hypoglycemia of 30.4%. A higher dose of oral insulin (40 U) + sodium salicylate (50 mg) was more effective in reducing plasma glucose level which steadily decreased and reached 56% of the initial value by 5 hr (AUC0–5 hr = 132 ± 41.5 mg. hr/dl and relative hypoglycemia = 27.3%). Sodium cholate (50 mg), however, slightly improved sodium salicylate effect producing an AUC0–5 hr of 139 ± 37.3 mg. hr/dl with relative hypoglycemia of 28.7%. The relative hypoglycemia of pH-dependent coated capsules reached in the present experiment is the highest found so far.

Exercise in transgenic mice overexpressing GLUT4 glucose transporters: Effects on substrate metabolism and glycogen regulation

We assessed the effects of GLUT4 glucose transporter expression on substrate metabolism and glycogen regulation during exercise. Transgenic mice overexpressing human (h)GLUT4 in muscle and fat (TG) and their wild-type littermates (WT) were studied by indirect calorimetry at rest and during acute treadmill exercise (30 minutes) and recovery (30 minutes). The rate of carbon dioxide production (V co 2) increased to a greater degree in TG during exercise, whereas resting V co 2, resting oxygen production (V o 2), and exercise-induced increments in V o 2 were similar in TG and WT. As a result, the respiratory quotient (RQ) was increased by .03 to .05 in TG during exercise, due to greater consumption of carbohydrate (up to ∼64% more) and less consumption of lipid (up to ∼40% less) compared with WT, without differences in overall energy expenditure. These differences in substrate metabolism were observed despite relative hypoglycemia and elevated free fatty acids (FFAs) in TG that persisted throughout resting, exercise, and recovery periods. To further assess substrate availability, glycogen content and glycogen synthase activity were measured in skeletal muscle and liver. At rest, muscle glycogen content was 50% higher and glycogen synthase I was 40% lower in TG compared with WT. During exercise and recovery, muscle glycogen was more profoundly depleted in TG than in WT, and glycogen synthase I increased to levels observed in WT, with no change in total glycogen synthase. In the liver, glycogen content and total glycogen synthase were similar in TG and WT under resting conditions, while glycogen synthase I was reduced by 48%. Exercise and recovery induced a more profound depletion of liver glycogen (76% v 30%) and greater increments in both I-form and total glycogen synthase in TG. In conclusion, (1) TG overexpressing GLUT4 exhibit greater muscle glycogen content at rest than WT; (2) during exercise, TG metabolize more carbohydrate, made possible by increased glycogenolysis in muscle and liver, and this predominates as a fuel source despite hypoglycemia and increased availability of FFA; (3) increased carbohydrate metabolism is linked to a decrease in lipid metabolism such that there is no change in overall energy expenditure; and (4) glycogen synthase I activity is inversely proportional to tissue glycogen content despite differences in circulating glucose, insulin, and FFA concentrations, indicating that glycogen content has an overriding regulatory influence on glycogen synthase.

Promotion of oral insulin absorption in diabetic rabbits using pH-dependent coated capsules containing sodium cholate

The hypoglycemic effect of oral insulin (40 U) capsules coated with a pH-dependent soluble polymer (Eudragit S100) and containing various doses of sodium cholate (20, 50, 100 mg) was studied in alloxan-hyperglycemic rabbits and compared with that of s.c. insulin injection (20 U). Sodium cholate (20 and 50 mg/capsule) produced a dose-related enhancement of an insulin-induced decrease in the blood glucose level. Insulin capsules containing sodium cholate (50 mg/capsule) produced a steady reduction of the blood glucose level reaching 69% of the initial values (P < 0.01) by 3 h and 48% (P < 0.001) by 5 h after administration. This capsule produced an AUC0–5h of 125 ± 14.8 mg · hdl with relative hypoglycemia (R.H.) of 25.8% compared with insulin s.c. The capsules containing sodium cholate (100 mg), however, did not significantly (P > 0.05) improve the hypoglycemic effect of insulin more than the smaller dose (50 mg/capsule) producing an AUC and R.H. of 135 ± 12.3 mg · hdl and 27.9%, respectively. The capsule coated with Eudragit S100 and containing insulin mixed with sodium cholate seems to be a promising formulation to overcome the unavailability of oral insulin.

Treatment of non-resectable pelvic malignancies by isolated pelvic perfusion. a preliminary study

Management of non-resectable pelvic tumours by intra-arterial local chemotherapy was shown to be beneficial but systemic toxicity limits its use. To overcome this problem isolated pelvic perfusion (IPP) was introduced as an alternative. This study summarizes our preliminary experience with IPP in the treatment of 18 non-resectable pelvic tumours [recurrent rectal adenocarcinoma (six), soft tissue sarcoma (STS) (five), bone tumour (three), epidermoid carcinoma (two), prostatic adenocarcinoma (one), malignant melanoma (one)]. Results of IPP were regarded as complete remission (CR), partial remission (PR), stable disease (SD) and disease progression (DP) according to the changes in three parameters including; scoring in pain, tumour marker and tumour size measurements. Complete and partial remission were established in five (27%) and seven (39%) patients respectively indicating a benefit ratio of 66%. Objective pain relief was encountered in 53% of the cases. All patients with STS had undergone further surgical treatment after IPP with successful curative resections in four. No residual tumour was found at the laparotomy of the fifth patient. Presenting symptom of the prostatic adenocarcinoma patient was symptomatic hypoglycaemia which resolved completely after IPP. To our knowledge, this represents the first case reported in the English literature in whom tumour related hypoglycaemia was successfully managed by IPP. In conclusion; management of non-resectable pelvic tumours by IPP seems to offer serious palliation and increase in the quality of life without any systemic toxicity. Our preliminary experience suggests even resectability may be achieved in a number of patients especially in those with STS.

Weanling and adult rats differ in fatty acid and carnitine metabolism during sepsis

Increased oxidation of fat is an important host response to sepsis, and carnitine is essential for long-chain fatty acid oxidation. Because neonates have low levels of carnitine, their ability to respond to a septic insult may be impaired. The purpose of this study was to compare fatty acid and carnitine metabolism in septic weanling (60 to 85 g) and septic adult (285 to 310 g) rats. Sepsis was induced in weanling and adult male Sprague-Dawley rats by cecal ligation and puncture (CLP). The rats were killed 16 hours after CLP or sham operation, and serum glucose, lactate, β-hydroxybutyrate, fatty acid, carnitine, liver fatty acid, and tissue carnitine levels were measured. The data suggest that during sepsis weanling rats may be more dependent on fatty acid oxidation than adult rats are, as evidenced by their elevated serum fatty acid and acylcarnitine levels, and relative hypoglycemia and hyperketonemia. In addition, although total serum carnitine levels were increased in both adult and weanling septic rats, tissue carnitine levels of weanling rats became significantly depleted during sepsis, unlike in adult rats. This study supports further investigation regarding the role of exogenous carnitine in newborn sepsis.

Fasting glucose homeostasis in the adaptation to chronic nutritional deprivation in rats.

The hormonal basis for the metabolic paradox of relative hypoglycemia despite insulinopenia and insulin resistance in chronic nutritional deprivation was studied in weanling rats restricted to 60% of ad libitum intake over 8 wk (n = 12 each). Lower insulin and glucagon levels were observed in both peripheral and portal blood (P = 0.0016) in the malnourished rats on multivariate analysis of variance, indicating decreased islet secretion. Peripheral and portal hormone levels were proportionately similar, indicating that hepatic extraction was not altered. Despite relative hypoglycemia, glucose turnover rate, total glucose mass, and volume of distribution of glucose were not altered. This indicates that the sum total of the effects of malnutrition on the various hormonal influences controlling glucose turnover had resulted in the establishment of a new dynamic equilibrium associated with lower plasma glucose levels. It is concluded that fasting glucose levels are sustained at a lower level in chronic malnutrition by an adaptive process that includes insulin resistance and insulinopenia, counterbalanced not only by glucagon resistance, as shown earlier, but also by decreased glucagon secretion.

Hypoglycaemia in pregnancy

Normally there is a very close relationship between maternal and fetal glucose concentrations during both early and late gestation. Maternal hypoglycaemia during pregnancy will therefore not only affect the mother herself but also the conceptus. As can be judged from the literature, acute hypoglycaemic episodes are only rarely seen in non-diabetic pregnancies. In recent years it has become increasingly evident that insulin-dependent diabetic patients, whether pregnant or not, run a much increased risk of having severe hypoglycaemia (SH) attacks (i.e. the patient needs the assistance of another person to relieve the attack) whenever attempts are made to introduce tight blood glucose control. Very high incidence rates of SH between 19% and 44% have been reported in diabetic pregnancy. Episodes of SH could have serious consequences; neuroglycopenia seems especially hazardous for the mother particularly during the performance of a critical task like driving a car. While hypoglycaemia has embryopathic effects in rodents, there are no data in the human to support a teratogenic effect. Insulin-induced hypoglycaemia in the last trimester of diabetic pregnancy may increase fetal body movement and decrease the fetal heart rate variability. A number of very rare conditions such as insulinoma, severe malaria, HELLP syndrome (haemolysis, elevated liver enzymes, low platelet count), severe fulminating liver disease, and ACTH and/or growth hormone deficiency have been reported to be associated with SH. Relative hypoglycaemia--i.e. low fasting blood glucose and 'flat' glucose tolerance test--is frequently seen in normotensive pregnant women with intrauterine fetal growth retardation. This pattern of maternal carbohydrate metabolism could lead to fetal hypoglycaemia and hypoinsulinaemia and contribute to poor fetal growth.

High Fat Feeding Causes Insulin Resistance and a Marked Decrease in the Expression of Glucose Transporters (Glut 4) in Fat Cells of Rats*

With the identification of two different glucose transporter species in adipose cells it is crucial to determine the role of these transporters in the alterations in glucose transport activity associated with different metabolic and nutritional states. In the present study we assess levels of expression of Glut 1 and Glut 4 transporters and basal and insulin-stimulated glucose transport activity in adipocytes from Sprague-Dawley rats fed standard chow (control), combined liquid diet and standard chow (overfed), high fat diet, or energy-restricted diet for 7 weeks. High fat feeding was associated with relative postprandial hypoglycemia (P less than 0.05) and hypoinsulinemia (P less than 0.05). Although the high fat fed animals had lower body weights (P less than 0.05) than control rats, their body compositions showed obesity, with 36% heavier epididymal fat pads (P less than 0.05) and a 47% increase in adipocyte volume (P less than 0.05). Fat feeding caused a 78% reduction in insulin-stimulated glucose transport per adipocyte (P less than 0.05). In parallel we found 92% and 94% reductions in Glut 4 protein and mRNA per adipocyte, respectively, (P less than 0.01) in fat-fed rats. Substantial reductions were also seen in Glut 1 protein and mRNA per fat cell in the same rats (62% and 76%, respectively; P less than 0.05). However, the changes in Glut 1 expression were of the same magnitude as changes in the cytoskeletal protein beta-actin, reflecting a decreased expression of several proteins in this nutritional state. Even though overfeeding and energy restriction brought about opposite changes in adiposity, no significant alterations were demonstrated in glucose transport rate or glucose transporter expression. The impaired insulin-stimulated glucose transport in adipose cells from high fat-fed rats occurs in the presence of a dramatic decrease in the expression of the major insulin-responsive glucose transporter (Glut 4). The reduced gene expression may be caused by chronic hypoinsulinemia and may contribute to the insulin resistance observed in this state.

1 Carbohydrate Ingestion During Prolonged Exercise

It is well recognized that energy from CHO oxidation is required to perform prolonged strenuous (greater than 60% VO2 max) exercise. During the past 25 years, the concept has developed that muscle glycogen is the predominant source of CHO energy for strenuous exercise; as a result, the potential energy contribution of blood glucose has been somewhat overlooked. Although during the first hour of exercise at 70-75% VO2max, most of the CHO energy is derived from muscle glycogen, it is clear that the contribution of muscle glycogen decreases over time as muscle glycogen stores become depleted, and that blood glucose uptake and oxidation increase progressively to maintain CHO oxidation (Fig. 1.7). We theorize that over the course of several hours of strenuous exercise (i.e., 3-4 h), blood glucose and muscle glycogen contribute equal amounts of CHO energy, making blood glucose at least as important as muscle glycogen as a CHO source. During the latter stages of exercise, blood glucose can potentially provide all of the CHO energy needed to support exercise at 70-75% VO2max if blood glucose availability is maintained. During prolonged exercise in the fasted state, however, blood glucose concentration often decreases owing to depletion of liver glycogen stores. This relative hypoglycemia, although only occasionally severe enough to result in fatigue from neuroglucopenia, causes fatigue by limiting blood glucose (and therefore total CHO) oxidation. The primary purpose of CHO ingestion during continuous strenuous exercise is to maintain blood glucose concentration and thus CHO oxidation and exercise tolerance during the latter stages of prolonged exercise. CHO feeding throughout continuous exercise does not alter muscle glycogen use. It appears that blood glucose must be supplemented at a rate of approximately 1 g/min late in exercise. Feeding sufficient amounts of CHO 30 minutes before fatigue is as effective as ingesting CHO throughout exercise in maintaining blood glucose availability and CHO oxidation late in exercise. Most persons should not wait, however, until they are fatigued before ingesting CHO, because it appears that glucose entry into the blood does not occur rapidly enough at this time. It also may be advantageous to ingest CHO throughout intermittent or low-intensity exercise rather than toward the end of exercise because of the potential for glycogen synthesis in resting muscle fibers. Finally, CHO ingestion during prolonged strenuous exercise delays by approximately 45 minutes but does not prevent fatigue, suggesting that factors other than CHO availability eventually cause fatigue.