Continuous Glucose Infusion Research Articles

Differential regulation of insulin action and tumor necrosis factor α system activity by metformin

Background Tumor necrosis factor α has a key role in insulin resistance. We study the effects of metformin on glucose tolerance, insulin resistance, beta cell function, and soluble tumor necrosis factor receptor (sTNFR) levels. Methods We performed a double-blind, randomized metformin-placebo study. Twenty-three subjects with impaired glucose tolerance or impaired fasting glucose were studied. Oral glucose tolerance, homeostasis model assessment, and continuous infusion of glucose with model assessment tests were used to evaluate glucose tolerance, insulin sensitivity, and beta cell function, respectively. Soluble tumor necrosis factor receptor levels were measured before and after therapy. Repeated measures analysis of variance was used for statistical analysis. Results After 12-week treatment, fasting glucose (110.1 ± 9.9 to 98.9 ± 15.7 mg/dl, P < .001), fasting insulin (11.6 ± 5.4 to 8.8 ± 3.5 mU/L, P = .05), fasting C-peptide (2.5 ± 0.7 to 1.8 ± 0.5 ng/mL, P < .05), and achieved C-peptide (5.2 ± 1.2 to 4.2 ± 1 ng/mL, P < .05) levels decreased in the metformin group. In addition, there was an improvement in insulin sensitivity (37.4% ± 15.2% to 50.4% ± 23.2%, P < .05) with unchanged sTNFR1 (2.0 ± 0.8 to 2.3 ± 1.2 μg/L, P = NS) and sTNFR2 (4.8 ± 1.7 to 4.4 ± 1.2 μg/L, P = NS) levels. Conclusions Metformin is able to reverse insulin resistance and hyperglycemia in high-risk subjects for type 2 diabetes mellitus independently of the effects on tumor necrosis factor α system activity.

Adiponectin is independently associated with insulin sensitivity in women with polycystic ovary syndrome

The polycystic ovary syndrome (PCOS) is associated with obesity and insulin resistance predisposing to diabetes mellitus type 2 and atherosclerosis. Adiponectin is a recently discovered adipocytokine with insulin-sensitizing and putative antiatherosclerotic properties. The aim of the study was to elucidate determinants of circulating adiponectin levels and to investigate the potential role of adiponectin in insulin resistance in PCOS women. Plasma adiponectin and parameters of obesity, insulin resistance and hyperandrogenism were measured In 62 women with PCOS and in 35 healthy female controls. Both in PCOS and controls, adiponectin levels were lower in overweight or obese women than in normal-weight women, without any difference between PCOS and controls after adjustment for body mass index (BMI). In PCOS and in controls there was a significant correlation of adiponectin with BMI (r = -0.516, P < 0.001), fasting insulin (r = -0.404, P < 0.001), homeostasis model sensitivity (HOMA %S) (r = -0.424, P < 0.001) and testosterone (r = -0.279, P < 0.01), but no correlation with androstenedione (r = -0.112, P = 0.325), 17-OH-progesterone (r =-0.031, P = 0.784) or the LH/FSH ratio (r =-0.033, P = 0.753). Multiple linear regression analysis revealed that BMI and HOMA %S but not testosterone were independently associated with adiponectin plasma levels, explaining 16% (BMI) and 13% (HOMA %S) of the variability of adiponectin, respectively. In PCOS patients insulin sensitivity, as indicated by continuous infusion of glucose with model assessment (CIGMA %S) was significantly correlated with adiponectin (r = 0.55; P < 0.001), BMI (r =-0.575; P < 0.001), waist-to-hip ratio (WHR) (r =-0.48; P = 0.001), body fat mass assessed by dual-energy X-ray-absorptiometry (DEXA) [Dexa-fat (total) (r = -0.61; P < 0.001) and Dexa-fat (trunk) (r = -0.59; P < 0.001)] and with testosterone (r = -0.42; P = 0.001). Multiple linear regression analysis demonstrated that markers of obesity such as BMI, total or truncal fat mass, age and adiponectin were independently associated with CIGMA %S, and that circulating adiponectin accounted for about 18% of the degree of insulin resistance in PCOS. By contrast, testosterone was not a significant factor, suggesting that PCOS per se did not affect insulin sensitivity independent from obesity, age and adiponectin. Metformin treatment for 6 months in insulin-resistant PCOS women (n = 9) had no effect on plasma adiponectin (P = 0.59) despite significant loss of weight and fat mass and improvement in hyperandrogenaemia. PCOS per se is not associated with decreased levels of plasma adiponectin. However, circulating adiponectin is independently associated with the degree of insulin resistance in PCOS women and may contribute to the development and/or maintenance of insulin resistance independent from adiposity.

My Love Affair with Insulin: JBC Centennial 1905-2005 100 Years of Biochemistry and Molecular Biology

My Love Affair with Insulin: JBC Centennial 1905-2005 100 Years of Biochemistry and Molecular Biology

Physiological Measurement of Insulin Action across a Range of Insulin Sensitivities

2265 Resistance to insulin action, i.e. decreased uptake of glucose from the blood at a given plasma insulin concentration, is a large public health problem in the U.S. Insulin action is quantifiable using 2 broad classes of methods. Open-loop techniques in which endogenous insulin production is replaced by exogenous infusion, e.g. the hyperinsulinemic clamp, allow quantitative assessment of peripheral glucose uptake (PGU) but do not closely approximate physiological conditions. Closed-loop techniques based on endogenous insulin secretion, e.g. the oral glucose tolerance test (OGTT), better simulate physiological conditions but do not allow calculation of PGU. The CIGMA technique (Continuous Infusion of Glucose with Model Assessment) is a closed-loop system developed and validated to quantitatively measure glucose uptake under “physiological” conditions. CIGMA is useful to characterize insulin resistance in a population but not to assess changes before and after an intervention. Purpose: To compare insulin action measured with by CIGMA, modified by scaling the infusion rate to fat free mass and including a glucose stable isotope to quantify glucose (m- CIGMA), to the Composite Insulin Sensitivity Index (C-ISI) derived from the glucose and insulin responses to a standard OGTT. Methods: On 2 separate mornings, in balanced order, insulin action was measured by m-CIGMA or C-ISI in 18 individuals (8 F, 9 M) who were expected to encompass a wide range of insulin actions. In the m-CIGMA test, [6,62H]glucose was infused for 90' in the fasted state followed by infusion of 20% dextrose (2% enriched with [6,62H]glucose) at 8.45 mg/kg FFM for 60'. During the steady-state period (last 10 minutes of the infusion) glucose (SSPG) and insulin (SSPI) concentrations were used to calculate insulin action (SSPG/SSPI). Insulin action was calculated from Glucose and insulin concentrations measured every 30' during the OGTT were incorporated into a mathematical model to derive C-ISI. Measures of whole-body insulin action generated by the 2 methods were compared with Pearson's correlation analysis. Results: There was a statistically significant relationship (r=.707, p =.003) between insulin action measured by M-CIGMA and C-ISI. Conclusion: These results suggest that for individuals with a range of insulin sensitivities, steady-state plasma glucose and insulin responses to the m-CIGMA infusion simulate the responses to a typical mixed meal. Insulin action measured by the m-CIGMA method is in good agreement with estimates based on the OGTT and can be used in conjunction with stable isotope dilution to assess peripheral and hepatic insulin action under physiological conditions

Both relative insulin resistance and defective islet beta-cell processing of proinsulin are responsible for transient hyperglycemia in extremely preterm infants.

Many extremely preterm infants develop hyperglycemia in the first week of life during continuous glucose infusion. The objective of this study was to determine whether defective insulin secretion or resistance to insulin was the primary factor involved in transient hyperglycemia of extremely preterm infants. A prospective comparative study was conducted in appropriate-for-gestational-age preterm infants <30 weeks of gestational age with the aim specifically to evaluate the serum levels of proinsulin, insulin, and C-peptide secreted during transient hyperglycemia by specific immunoassays. Three groups of infants were investigated hyperglycemic (n = 15) and normoglycemic preterm neonates (n = 12) and normal, term neonates (n = 21). In addition, the changes in beta-cell peptide levels were analyzed during and after intravenous insulin infusion in the hyperglycemic group. Data were analyzed using analysis of variance and analysis of variance for repeated measures. At inclusion, insulin and C-peptide levels did not differ in hyperglycemic subjects and in preterm controls. Proinsulin concentration was significantly higher in the hyperglycemic group (36.5 +/- 3.9 vs 23.2 +/- 0.9 pmol/L). Compared with term neonates, proinsulin and C-peptide levels were higher in normoglycemic preterm infants (23.2 +/- 0.9 vs 18.9 +/- 2.71 pmol/L and 1.67 +/- 0.3 vs 0.62 +/- 0.12 nmol/L, respectively). During and after insulin infusion in hyperglycemic neonates, plasma glucose concentration fell and proinsulin and C-peptide levels were lowered (18.4 +/- 7.6 and 20.7 +/- 4.5 pmol/L, respectively). These data suggest that 1) preterm neonates are sensitive to changes in plasma glucose concentration, but proinsulin processing to insulin is partially defective in hyperglycemic preterm neonates; 2) hyperglycemic neonates are relatively resistant to insulin because higher insulin levels are needed to achieve euglycemia in this group compared with normoglycemic neonates. These results also show that insulin infusion is beneficial in extremely preterm infants with transient hyperglycemia.

The 1st World Congress on the Insulin Resistance Syndrome.

This is the first of two articles covering the 1st World Congress on the Insulin Resistance Syndrome (IRS), which was held in Los Angeles, 21–22 November 2003. Yehuda Handlesman (Tarzana, CA), the conference organizer, noted that it reflects an endeavor to bring an understanding of basic science into the clinical practice of medicine. Contributory causes of insulin resistance include obesity, sedentary lifestyle, and many other characteristics and conditions. Handlesman noted that the syndrome has been assigned International Classification of Disease (ICD)-9 code 277.7 as the dysmetabolic syndrome. Many aspects of the IRS are pharmacologically treatable when lifestyle modification is ineffective, and we need tools to determine which approaches are appropriate for particular individuals. Gerald Reaven (Stanford, CA) reviewed the six- to eightfold variation in steady-state plasma glucose (SSPG) with continuous octreotide, insulin, and glucose infusion among apparently healthy persons. He attributed the lack of glycemic abnormality of persons with insulin resistance to compensatory hyperinsulinemia, although noting that there is great variation in insulin levels for a given level of insulin sensitivity. Similarly, there is variation in the correlations between obesity and insulin resistance, as well as between maximal aerobic capacity, a measure of physical fitness, and insulin sensitivity. Reaven suggested that adiposity and physical fitness each account for ∼25% of the variability in insulin sensitivity, with genetic factors, which he illustrated with the differences in insulin sensitivity between persons of European and persons of South Asian or Mexican ancestry and with the similarity in insulin sensitivity of related persons in a family, responsible for an additional 50% of this variation. Syndrome X, as Reaven originally termed it, included insulin resistance, hyperinsulinemia, dyslipidemia, hypertension, and increased risk of both diabetes and coronary heart disease. Other abnormalities associated with the IRS include glucose intolerance, small LDL particle size, postprandial accumulation of triglyceride-rich …

The impact of insulin resistance on the outcome of laparoscopic ovarian electrocautery in infertile women with the polycystic ovary syndrome

In this study we assessed how insulin resistance affects pregnancy rates in infertile women with the polycystic ovary syndrome (PCOS) treated with laparoscopic ovarian electrocautery. Sixty-four PCOS women were included in the study in a consecutive fashion. Following the CIGMA (continuous infusion of glucose with model assessment) test, 28 women were classified as insulin resistant and 36 women as non-insulin resistant. After the ovarian electrocautery patients were observed for 12-18 months. If pregnancy did not ensue, they were referred for one or more cycles of in vitro fertilization (IVF). Following ovarian electrocautery the non-insulin-resistant women more frequently achieved a regular menstrual cycle and ovulation than the insulin-resistant PCOS women. Consequently 18 (50%) of the non-insulin-resistant PCOS women achieved a pregnancy versus only five (18%) of women in the insulin-resistant PCOS group. Following treatment with both ovarian electrocautery and IVF, 27 (75%) of the non-insulin resistant PCOS women achieved a successful pregnancy, while 13 (46%) of the insulin-resistant PCOS group achieved this. In conclusion, insulin resistance may be an important marker of a poor outcome of treatment in PCOS infertility. Further studies are needed to evaluate the possible effect of treatment alternatives to alleviate the unfavorable influences of insulin resistance and hyperinsulinemia on ovulation induction in PCOS women.

Evaluation of insulin sensitivity in clinical practice and in research settings.

Insulin resistance is the core metabolic abnormality in type 2 diabetes. Its high prevalence and its association with dyslipidemia, hypertension, hyperinsulinemia, and high coronary and cerebrovascular mortality put it in the forefront as the plausible target for aggressive intervention. Measurements of insulin sensitivity provide clinicians and clinical researchers with invaluable instruments to objectively evaluate the efficiency of both current and potentially useful interventional tools. Although several methods had been developed and validated to evaluate insulin sensitivity, none of these methods can be universally used in all patients. Nonetheless, a method suitable for use in clinical or basic research may not necessarily be a practical method for use in clinical practice or for epidemiologic research. We reviewed the currently used methods for assessment of insulin sensitivity. For each method, we summarized its procedure, normal value, cut-off value for defining insulin resistance, advantages and limitations, validity, accuracy for each patient population, and suitability for use in clinical practice and in research settings. The methods reviewed include fasting plasma insulin, homeostatic model assessment, quantitative insulin sensitivity check index, glucose-to-insulin ratio, continuous infusion of glucose with model assessment, indices based on oral glucose tolerance test, insulin tolerance test, and the so called "gold standard" methods, the hyperinsulinemic euglycemic clamp and the frequently sampled-intravenous glucose tolerance test.

Effects of Casein and Glucose on Responses of Cows Fed Diets Based on Restrictively Fermented Grass Silage

This study was conducted to investigate whether well fed dairy cows given restrictively fermented grass silage diet will respond to incremental glucose and amino acid supply at early stage of lactation. Four rumen-cannulated Finnish Ayrshire cows were used in a 4×4 Latin square experiment with 14-d periods. The cows were fed good quality restrictively fermented grass silage ensiled with a formic acid additive for ad libitum intake. A concentrate mixture consisting of barley (85%) and solvent extracted rapeseed meal (11.4%) was given at a rate of 9 kg/d. The four treatments were continuous abomasal infusions of water (control), casein 300g/d, glucose 300g/d, and casein 300g/d + glucose 300g/d. The infusions had only minor effects on feed intake, diet digestibility, or rumen fermentation pattern. Both casein and glucose infusions increased milk, protein and lactose yields the effects being partly additive on the combined infusion. Infused casein increased milk protein and urea as well as plasma urea concentrations. Both casein and glucose tended to increase plasma glucose concentration. Casein increased arterial plasma concentrations of essential amino acids (EAA), branched-chain AA (BCAA), and total AA (TAA). Both casein and glucose, although glucose usually less than casein, increased arteriovenous differences of EAA, nonessential AA, BCAA, and TAA. Extraction efficiencies of AA were higher for glucose than for casein. Mammary plasma flow was at highest on the control diet, but reduced owing to infused nutrients, the reduction being less with combined rather than separate infusions of casein and glucose. Based on the partly additive increases in milk production parameters and changes in plasma metabolites, it is suggested that glucose alone increased milk protein yield by sparing AA from hepatic utilization, while casein increased both supply of AA and glucose. It was concluded that cows at early stage of lactation fed diets comprising of restrictively fermented grass silage and a cereal-based concentrate suffer from both limited AA and glucose supplies.

Methods for quantifying insulin resistance in human immunodeficiency virus-positive patients

Various indirect indices have been used in human immunodeficiency virus (HIV)-infected individuals to assess insulin resistance, but the validity of these measures has not been rigorously assessed by comparison with physiologic methods of quantifying insulin-mediated glucose uptake (IMGU). We directly measured IMGU in 50 nondiabetic HIV-positive subjects by determining the steady-state plasma glucose (SSPG) concentration in response to a 3-hour continuous infusion of insulin, glucose, and somatostatin. Because steady-state plasma insulin concentrations were similar (∼60 μU/mL) in all subjects, the SSPG concentrations provided direct assessments of insulin action. Relationships between SSPG levels and various surrogate measures of IMGU derived from the 75-g oral glucose tolerance test (OGTT) were determined. The indirect measure of IMGU most closely related to SSPG concentrations was the total integrated insulin response to a 75-g glucose load ( r = 0.78, P < .01), accounting for approximately two thirds of the variability in SSPG ( r 2 = 0.61). Other indirect measures of IMGU, including the homeostasis assessment for insulin resistance (HOMA-IR), were also significantly related to SSPG values, but had lower magnitudes of correlation ( r = 0.43 to 0.61), thereby possessing limited ability to predict SSPG variability ( r 2 = 0.18 to 0.37). In conclusion, indirect measures of IMGU need to be applied with caution when evaluating insulin action in HIV-infected patients.

Glucose oversupply increases Delta9-desaturase expression and its metabolites in rat skeletal muscle.

Previous studies have shown that prolonged glucose infusion causes insulin resistance and triglyceride accumulation in rat skeletal muscle. In this study, we investigated a possible relationship between insulin resistance and the composition of different accumulated lipid fractions in rat skeletal muscle. Continuous glucose infusion was carried out in rats for 7 days. Lipids were extracted from skeletal muscle, separated by thin layer chromatography and fatty acid composition of phospholipids, triglycerides, diglycerides, free fatty acids and cholesterol esters fractions was analysed by gas chromatography. Delta9-Desaturase mRNA was measured by real time polymerase chain reaction. The enzyme activity was measured in the microsomal fractions. Prolonged glucose infusion (5 days) increased the relative content of palmitoleic acid (16:1 N7) several-fold (2.3- to 5.8-fold) in four out of five lipid fractions and enhanced oleic acid (18:1 N9) two-fold in three lipid fractions suggesting increased Delta9-desaturase activity while the content of several polyunsaturated fatty acids was reduced. In parallel, Delta9-Desaturase mRNA contents and enzyme activities in skeletal muscle were increased 10-fold, 75-fold, 2.6-fold and 7.7-fold after 2 and 5 days of glucose infusion, respectively. Our results suggest that long-term glucose oversupply induces a rapid increase in Delta9-desaturase expression and enzyme activity in skeletal muscle which leads to fast and specific changes in fatty acid metabolism possibly contributing to the insulin resistance in this animal model.

Impact of Insulin Resistance on Pregnancy Complications and Outcome in Women with Polycystic Ovary Syndrome

The aim of the study was to determine the risk of developing gestational diabetes mellitus (GDM) and pregnancy-induced hypertension (PIH)/pre-eclampsia in a cohort of pregnant women with the polycystic ovary syndrome (PCOS) and known insulin sensitivity status. Pregnancies and neonatal outcome were recorded in a prospective cohort study comprising 29 non-insulin-resistant PCOS women, 23 insulin-resistant PCOS women and a control group of 355 women who had conceived after assisted reproduction. Hypertension, pre-eclampsia and GDM were recorded as well as pregnancy duration, method of delivery and birth weight. The frequency of hypertension was significantly elevated in PCOS women (11.5%) compared to controls (0.3%), p < 0.01. However, the frequency of pre-eclampsia was significantly elevated only in the insulin resistant PCOS women (13.5%) compared to controls (7.0%), p < 0.02. GDM was significantly more frequent in PCOS women (7.7%) than controls (0.6%), p < 0.01. Insulin resistance prior to pregnancy, determined by continuous infusion of glucose with model assessment (CIGMA) test, did not further increase the frequency of GDM. Newborns from PCOS pregnancies were significantly more often delivered by Caesarean section than controls (40.3 vs. 27.3%, p < 0.05) and transferred to neonatal intensive care unit more often than controls (19.2 vs. 9.0%, p < 0.01). Thus we show that the frequencies of pre-eclampsia and GDM are increased in PCOS pregnancies.

Insulin secretion and insulin sensitivity in normal pregnancy and gestational diabetes mellitus

The purpose of this study was to evaluate insulin sensitivity ,β-cell function and islet-cell-directed autoimmunity in pregnant women with normal glucose tolerance and gestational diabetes mellitus(GDM). A total of 21 women with normal glucose tolerance and 21 women with GDM were evaluated at 24-36 weeks' gestation. Insulin resistance and β-cell function were evaluated using the continuous infusionof glucose with model assessment (CIGMA) method ,which aims to give a near-physiological stimulus and to evaluate the endogenous insulin and glucose response. Islet-cell autoantibody was positive in onewoman with GDM ,and glutamic acid decarboxylase autoantibodies were negative in both groups. The calculated CIGMA insulin resistance (CIGMA IR) was 2.04 ± 1.74 and 1.08 ± 1.22 in patientswith GDM and in control subjects ,respectively (p < 0.05). CIGMA percentage β-cell values were 64.04 ± 44.55% and 87.07 ± 52.77% in patients with GDM and control subjects ,respectively(p > 0.05). Decreased insulin sensitivity in late pregnancy was more evident in lean GDM subjects with mild hyperglycemia who did not require insulin therapy ,and β-cell function was partially preservedin this group of patients.

Circulating ghrelin levels in patients with polycystic ovary syndrome.

The syndrome of polycystic ovaries (PCOS) is associated with adiposity and metabolic changes predisposing to insulin resistance and diabetes mellitus. Because the recently discovered GH secretagogue, ghrelin, is intimately involved in the control of appetite and weight regulation, we studied ghrelin levels in a group of 26 otherwise healthy women with PCOS. They were compared with 61 healthy female control subjects and 5 gastrectomized women. Insulin sensitivity was assessed by homeostasis model assessment (HOMA) and continuous infusion of glucose with model assessment (CIGMA) in all patients. In PCOS women, serum ghrelin levels were significantly lower than in healthy lean or obese controls (P < 0.001). In insulin-sensitive PCOS women, ghrelin concentrations compared well with the healthy controls, whereas in insulin-resistant PCOS ghrelin levels were significantly lower and indistinguishable from the low levels found in the gastrectomized women. There was a close correlation of ghrelin to insulin sensitivity (HOMA, r(2) = 0.330, P < 0.002; CIGMA, r(2) = 0.568, P < 0.0001). Treatment of 10 insulin-resistant PCOS women with metformin significantly increased circulating fasting ghrelin concentrations (P < 0.02). Ghrelin levels did not correlate to any of the parameters of hyperandrogenemia, to the LH/FSH ratio, to body mass index, or to fasting insulin and glucose concentrations. In summary, ghrelin levels are decreased in PCOS women and are highly correlated to the degree of insulin resistance. This suggests that ghrelin could be linked to insulin resistance in PCOS women. However, whether low ghrelin in PCOS is a cause or the consequence of insulin resistance awaits further investigations.

Prolonged glucose infusion into conscious rats inhibits early steps in insulin signalling and induces translocation of GLUT4 and protein kinase C in skeletal muscle.

Previous studies on diabetic patients have shown that hyperglycaemia increases glucose uptake in an apparently insulin-independent manner. However, the molecular mechanism has not been clarified. We studied rats receiving continuous glucose infusion to address this question. In this animal model, rats accommodate systemic glucose oversupply and rapidly develop insulin resistance. Glucose infusion increased both plasma glucose and insulin concentrations to peak after one day. In spite of continuous glucose infusion normoglycaemia was reached after 5 days while insulin concentrations remained higher. Focusing our studies in day 2 (hyperglycaemia/hyperinsulinaemia) and day 5 (normoglycaemia/hyperinsulinaemia) we found, particularly in day 5, that the early steps of the insulin signalling cascade in skeletal muscle of glucose-infused rats were not more activated when compared to control animals as assessed by a comparable phosphorylation of the insulin receptor, IRS-1 and PKB and by an unaltered IRS-1-associated Ptd(Ins) 3' kinase activity. Continuous glucose infusion induced GLUT4 protein expression and translocation to the plasma membrane while neither expression nor translocation of GLUT1 was affected. Translocation of PKC- betaI, - betaII (> threefold) and -alpha, -theta (to a lesser extent) to the plasma membrane was significantly induced after 2 days but not after 5 days of glucose infusion when normoglycaemia was reached. Our data support the hypothesis that continuous glucose infusion induces translocation of GLUT4 while the early steps of the insulin signalling cascade were not increased. These effects could be mediated by activation of PKC.

Nutritional Management of Neonatal and Infant Liver Disease

After completing this article, readers should be able to: 1. Describe the caloric requirements of a neonate who has chronic liver disease. 2. Identify the vitamin and mineral deficiencies associated with cholestasis and the methods used to correct these deficits. 3. Describe the relationship between total parenteral nutrition and the development of chronic liver disease. 4. Delineate the relationship between malnutrition at the time of liver transplantation and subsequent morbidity and mortality. 5. List the best measurements of nutrition assessment in infants who have chronic liver disease. The liver is involved in many of the body’s metabolic processes, including: regulation of protein, fat, and carbohydrate metabolism; vitamin storage and activation; and detoxification and excretion of waste products. The healthy liver synthesizes and excretes bile salts. With cholestatic liver diseases, poor bile flow results in fat malabsorption because micelles, which solubilize long-chain fatty acids, cannot form without bile salts. Fat malabsorption results in enteric losses of the fat-soluble vitamins A, D, E, and K. Impaired liver function can lead to nutrient deficiencies and eventually protein-energy malnutrition. All of these factors, combined with the common symptoms of anorexia and poor dietary intake, make malnutrition common in chronic liver disease, particularly if it occurs in infants, who are more vulnerable to the debilitating effects of malnutrition because of their higher energy and growth requirements. A wide range of deficits occurs in most chronic liver diseases of children (Table 1⇓ ). Malnutrition itself may induce further derangements of liver function because the liver requires energy for a number of synthetic, storage, and detoxification functions. View this table: Table 1. Nutritional Risk Factors in Acute and Chronic Liver Disease The need for aggressive, early nutrition support in neonates has been well established and discussed extensively. Some centers routinely use a “standardized” approach to nutrition support; we use a “tailored” approach that entails parenteral or …

The impact of obesity and insulin resistance on the outcome of IVF or ICSI in women with polycystic ovarian syndrome.

The impact of insulin resistance on the outcome of IVF or intracytoplasmic sperm injection (ICSI) in women with polycystic ovarian syndrome (PCOS) was examined. Insulin sensitivity was measured by the continuous infusion of glucose with model assessment (CIGMA) test. Insulin-resistant (n = 26) and non-insulin-resistant women (n = 30) with PCOS underwent a total of 100 cycles of long-term down-regulation with buserelin acetate, stimulation with human recombinant FSH, and IVF or ICSI. Blood samples were taken throughout ovarian stimulation for hormone assays. Insulin-resistant and non-insulin-resistant women had similar concentrations of FSH, LH, testosterone and androstenedione throughout stimulation, but insulin-resistant women had hyperinsulinaemia and lower sex hormone binding globulin concentrations. Insulin-resistant women also had lower oestradiol concentrations during stimulation and required higher FSH doses, but these differences disappeared after controlling for the higher body weight in the group of insulin-resistant women. Groups had similar number of oocytes collected, similar implantation and pregnancy rates, and the incidence of ovarian hyperstimulation syndrome was also similar. Obesity, independent of hyperinsulinaemia, was related to a lower oocyte count and increased FSH requirement. It is concluded that in PCOS women receiving long-term down-regulation and stimulation with recombinant FSH, insulin resistance is neither related to hormone levels nor to IVF outcome. Obesity, independent of insulin resistance, is associated with relative gonadotrophin resistance.

Simplification of continuous infusion of glucose with model assessment in the evaluation of insulin resistance in women with PCOS

Ninety-seven women with polycystic ovary syndrome (PCOS) were tested for insulin resistance and glucose tolerance by means of the continuous infusion of glucose with model assessment (CIGMA) test. The mean concentrations of glucose and insulin at 50 ,55 and 60 min of glucose infusion were interpreted using a mathematical model of glucose and insulin homeostasis ,and an insulin resistance index (IR1) was obtained. Using insulin and glucose values at 60 min only ,a new insulin resistance index (IR2) was obtained using the same mathematical method. In addition ,fasting insulin ,fasting C-peptide, fasting glucose ,fasting insulin : glucose ratio and fasting C-peptide : glucose ratio were also used to assess insulin resistance. There were significant correlations between IR1 and IR2, fasting glucose ,fasting insulin ,fasting insulin : glucose ratio ,fasting C-peptide : glucose ratio. IR2 had the highest correlation with IR1 (r =0.97 ,p < 0.001) and provided the best combination of sensitivity (82.9%) ,specificity (93.9%) ,positive predictive value (91.9%) and negative predictive value (86.8%). In conclusion ,the simplified CIGMA test ,using insulin and glucose concentration at 60 min of glucose infusion only ,is a highly sensitive and specific measure of insulin sensitivity in women with PCOS.

Simplification of continuous infusion of glucose with model assessment in the evaluation of insulin resistance in women with PCOS

Ninety-seven women with polycystic ovary syndrome (PCOS) were tested for insulin resistance and glucose tolerance by means of the continuous infusion of glucose with model assessment (CIGMA) test. The meanconcentrations of glucose and insulin at 50 ,55 and 60 min of glucose infusion were interpreted using a mathematical model of glucose and insulin homeostasis ,and an insulin resistance index (IR1)was obtained. Using insulin and glucose values at 60 min only ,a new insulin resistance index (IR2) was obtained using the same mathematical method. In addition ,fasting insulin ,fasting C-peptide,fasting glucose ,fasting insulin : glucose ratio and fasting C-peptide : glucose ratio were also used to assess insulin resistance. There were significant correlations between IR1 and IR2,fasting glucose ,fasting insulin ,fasting insulin : glucose ratio ,fasting C-peptide : glucose ratio. IR2 had the highest correlation with IR1 (r =0.97 ,p < 0.001)and provided the best combination of sensitivity (82.9%) ,specificity (93.9%) ,positive predictive value (91.9%) and negative predictive value (86.8%). In conclusion ,the simplified CIGMA test ,using insulinand glucose concentration at 60 min of glucose infusion only ,is a highly sensitive and specific measure of insulin sensitivity in women with PCOS.

Hepatic glucose metabolism during intraduodenal glucose infusion: impact of infection.

We previously reported that infection decreases hepatic glucose uptake when glucose is given as a constant peripheral glucose infusion (8 mg. kg(-1) x min(-1)). This impairment persisted despite greater hyperinsulinemia in the infected group. In a normal setting, hepatic glucose uptake can be further enhanced if glucose is given gastrointestinally. Thus the aim of this study was to determine whether hepatic glucose uptake is impaired during an infection when glucose is given gastrointestinally. Thirty-six hours before study, a sham (SH, n = 7) or Escherichia coli-containing (2 x 10(9) organisms/kg; INF; n = 7) fibrin clot was placed in the peritoneal cavity of chronically catheterized dogs. After the 36 h, a glucose bolus (150 mg/kg) followed by a continuous infusion (8 mg. kg(-1). min(-1)) of glucose was given intraduodenally to conscious dogs for 240 min. Tracer ([3-(3)H]glucose and [U-(14)C]glucose) and arterial-venous difference techniques were used to assess hepatic and intestinal glucose metabolism. Infection increased hepatic blood flow (35 +/- 5 vs. 47+/-3 ml x g(-1) x min(-1); SH vs. INF) and basal glucose rate of appearance (2.1+/-0.2 vs. 3.3+/-0.1 mg x kg(-1) x min(-1)). Arterial insulin concentrations increased similarly in SH and INF during the last hour of glucose infusion (38+/-8 vs. 46+/-20 microU/ml), and arterial glucagon concentrations fell (62+/-14 to 30+/-3 vs. 624+/-191 to 208+/-97 pg/ml). Net intestinal glucose absorption was decreased in INF, attenuating the increase in blood glucose caused by the glucose load. Despite this, net hepatic glucose uptake (1.6+/-0.8 vs. 2.4+/- 0.9 mg x kg(-1) x min(-1); SH vs. INF) and consequently tracer-determined glycogen synthesis (1.3+/-0.3 vs. 1.0+/-0.3 mg. kg(-1) x min(-1)) were similar between groups. In summary, infection impairs net glucose absorption, but not net hepatic glucose uptake or glycogen deposition, when glucose is given intraduodenally.