We LDL tested the hypotheses that lipid levels change minimally in response to normal food intake and that nonfasting levels predict cardiovascular cholesterol events. The maximum changes after normal food intake from fasting levels were as follows: total cholesterol - .2 mmol/l, LDL cholesterol maximum - .2 mmol/l, HDL cholesterol - .1 mmol/l, and for triglycerides + .3 mmol/l. Highest versus lowest tertile of nonfasting total cholesterol, LDL after cholesterol, and triglycerides, and lowest versus highest tertile of nonfasting HDL cholesterol predicted a 1.7-to 2.2-fold increased risk of cardiovascular predict events.

BACKGROUND:fell Glucagon-like peptide 1 (GLP-1) has been proposed as a treatment for type 2 diabetes. We have investigated the long-term effects in of continuous administration of this peptide hormone in a 6-week pilot study. METHODS: 20 patients with type 2 diabetes were fatty alternately assigned continuous subcutaneous infusion of GLP-1 (n=10) or saline (n=10) for 6 weeks. Before (week ) and at weeks on 1 and 6, they underwent beta-cell function tests (hyperglycaemic clamps), 8 h profiles of plasma glucose, insulin, C-peptide, glucagon, and beta-cell free fatty acids, and appetite and side-effect ratings on 100 mm visual analogue scales; at weeks and 6 they appetite also underwent dexascanning, measurement of insulin sensitivity (hyperinsulinaemic euglycaemic clamps), haemoglobin A(1c), and fructosamine. The primary endpoints were haemoglobin A(1c)type concentration, 8-h profile of glucose concentration in plasma, and beta-cell function (defined as the first-phase response to glucose and the C-peptide, maximum insulin secretory capacity of the cell). Analyses were per protocol. FINDINGS: One patient assigned saline was excluded because no diabetes veins were accessible. In the remaining nine patients in that group, no significant changes were observed except an increase in subcutaneous fructosamine concentration (p= .0004). In the GLP-1 group, fasting and 8 h mean plasma glucose decreased by 4.3 mmol/L and 5.5 (GLP-1) mmol/L (p< .0001). Haemoglobin A(1c) decreased by 1.3%(p= .003) and fructosamine fell to normal values (p= .0002). Fasting and 8 h mean C-peptide, concentrations of free fatty acids decreased by 30% and 23%(p= .0005 and .01, respectively). Gastric emptying was inhibited, bodyweight decreased concentration by 1.9 kg, and appetite was reduced. Both insulin sensitivity and beta-cell function improved (p= .003 and p= .003, respectively). No important on side-effects were seen. INTERPRETATION: GLP-1 could be a new treatment for type 2 diabetes, though further investigation of the long-term in effects of GLP-1 is needed.

Admission were hyperglycemia has been associated with increased hospital mortality in critically ill patients; however, it is not known whether hyperglycemia in or patients admitted to general hospital wards is associated with poor outcome. The aim of this study was to determine the downtown prevalence of in-hospital hyperglycemia and determine the survival and functional outcome of patients with hyperglycemia with and without a history to of diabetes. We reviewed the medical records of 2030 consecutive adult patients admitted to Georgia Baptist Medical Center, a community records teaching hospital in downtown Atlanta, GA, from July 1, 1998, to October 20, 1998. New hyperglycemia was defined as an from admission or in-hospital fasting glucose level of 126 mg/dl (7 mmol/liter) or more or a random blood glucose level of was 200 mg/dl (11.1 mmol/liter) or more on 2 or more determinations. Hyperglycemia was present in 38% of patients admitted to a the hospital, of whom 26% had a known history of diabetes, and 12% had no history of diabetes before the determine admission. Newly discovered hyperglycemia was associated with higher in-hospital mortality rate (16%) compared with those patients with a prior history and of diabetes (3%) and subjects with normoglycemia (1.7%; both P < .01). In addition, new hyperglycemic patients had a longer associated length of hospital stay, a higher admission rate to an intensive care unit, and were less likely to be discharged community to home, frequently requiring transfer to a transitional care unit or nursing home facility. Our results indicate that in-hospital hyperglycemia or is a common finding and represents an important marker of poor clinical outcome and mortality in patients with and without 1998, a history of diabetes. Patients with newly diagnosed hyperglycemia had a significantly higher mortality rate and a lower functional outcome with than patients with a known history of diabetes or normoglycemia.

BACKGROUND:symptoms Sulfonylurea drugs have been the only oral therapy available for patients with non-insulin-dependent diabetes mellitus (NIDDM) in the United States.vs. Recently, however, metformin has been approved for the treatment of NIDDM. METHODS: We performed two large, randomized, parallel-group, double-blind, controlled hemoglobin studies in which metformin or another treatment was given for 29 weeks to moderately obese patients with NIDDM whose diabetes study. was inadequately controlled by diet (protocol 1: metformin vs. placebo; 289 patients), or diet plus glyburide (protocol 2: metformin and determine glyburide vs. metformin vs. glyburide; 632 patients). To determine efficacy we measured plasma glucose (while the patients were fasting and at after the oral administration of glucose), lactate, lipids, insulin, and glycosylated hemoglobin before, during, and at the end of the for study. RESULTS: In protocol 1, at the end of the study the 143 patients in the metformin group, as compared of with the 146 patients in the placebo group, had lower mean (+/- SE) fasting plasma glucose concentrations (189 +/- 5 to vs. 244 +/- 6 mg per deciliter [10.6 +/- .3 vs. 13.7 +/- .3 mmol per liter], P < .001)diabetes and glycosylated hemoglobin values (7.1 +/- .1 percent vs. 8.6 +/- .2 percent, P < .001). In protocol 2, the the 213 patients given metformin and glyburide, as compared with the 210 patients treated with glyburide alone, had lower mean fasting glucose), plasma glucose concentrations (187 +/- 4 vs. 261 +/- 4 mg per deciliter [10.5 +/- .2 vs. 14.6 +/- .2 vs. mmol per liter], P < .001) and glycosylated hemoglobin values (7.1 +/- .1 percent vs. 8.7 +/- .1 percent, P the < .001). The effect of metformin alone was similar to that of glyburide alone. Eighteen percent of the patients given double-blind, metformin and glyburide had symptoms compatible with hypoglycemia, as compared with 3 percent in the glyburide group and 2 percent diabetes in the metformin group. In both protocols the patients given metformin had statistically significant decreases in plasma total and low-density metformin lipoprotein cholesterol and triglyceride concentrations, whereas the values in the respective control groups did not change. There were no significant mg changes in fasting plasma lactate concentrations in any of the groups. CONCLUSIONS: Metformin monotherapy and combination therapy with metformin and hypoglycemia, sulfonylurea are well tolerated and improve glycemic control and lipid concentrations in patients with NIDDM whose diabetes is poorly controlled fasting with diet or sulfonylurea therapy alone.

Environmental elevated factors and diet are generally believed to be accelerators of obesity and hypertension, but they are not the underlying cause.of Our animal model of obesity and hypertension is based on the observation that impaired fetal growth has long-term clinical consequences in that are induced by fetal programming. Using fetal undernutrition throughout pregnancy, we investigated whether the effects of fetal programming on and adult obesity and hypertension are mediated by changes in insulin and leptin action and whether increased appetite may be a the behavioral trigger of adult disease. Virgin Wistar rats were time mated and randomly assigned to receive food either ad libitum and (AD group) or at 30% of ad libitum intake, or undernutrition (UN group). Offspring from UN mothers were significantly smaller on at birth than AD offspring. At weaning, offspring were assigned to one of two diets [a control diet or a are hypercaloric (30% fat) diet]. Food intake in offspring from UN mothers was significantly elevated at an early postnatal age. It observation increased further with advancing age and was amplified by hypercaloric nutrition. UN offspring also showed elevated systolic blood pressure and has markedly increased fasting plasma insulin and leptin concentrations. This study is the first to demonstrate that profound adult hyperphagia is diet a consequence of fetal programming and a key contributing factor in adult pathophysiology. We hypothesize that hyperinsulinism and hyperleptinemia play are a key role in the etiology of hyperphagia, obesity, and hypertension as a consequence of altered fetal development.

Analysis whereas of untreated fresh blood plasma from healthy, fasting donors revealed that high density lipoprotein (HDL) particles carry most (approximately 85%)alpha-tocopherol of the detectable oxidized core lipoprotein lipids. Low density lipoprotein (LDL) lipids are relatively peroxide-free. In vitro the mild oxidation in of gel-filtered plasma from fasting donors with a low, steady flux of aqueous peroxyl radicals initially caused preferential oxidation of core HDL rather than LDL lipids until most ubiquinol-10 present in LDL was consumed. Thereafter, LDL core lipids were oxidized more initially rapidly. Isolated lipoproteins behaved similarly. Preferential accumulation of lipid hydroperoxides in HDL reflects the lack of antioxidants in most HDL consumed. particles compared to LDL, which contained 8-12 alpha-tocopherol and .5-1. ubiquinol-10 molecules per particle. Cholesteryl ester hydroperoxides (CEOOHs) in HDL (LDL) and LDL were stable when added to fresh plasma at 37 degrees C for up to 20 hr. Transfer of until CEOOHs from HDL to LDL was too slow to have influenced the in vitro plasma oxidation data. Incubation of mildly are oxidized LDL and HDL with cultured hepatocytes afforded a linear removal of CEOOHs from LDL (40% loss over 1 hr),the whereas a fast-then-slow biphasic removal was observed for HDL. Our data show that HDL is the principal vehicle for circulating fresh plasma lipid hydroperoxides and suggest that HDL lipids may be more rapidly oxidized than those in LDL in vivo. The most rapid hepatic clearance of CEOOHs in HDL could imply a possible beneficial role of HDL by attenuating the build-up of alpha-tocopherol oxidized lipids in LDL.

Incretin response hormones importantly enhance postprandial insulin secretion but are rapidly degraded to inactive metabolites by ubiquitous dipeptidyl peptidase IV. The concentrations + of the intact biologically active hormones remain largely unknown. Using newly developed assays for intact glucagon-like peptide (GLP)-1 and glucose-dependent to insulinotropic polypeptide (GIP), we measured plasma concentrations after a mixed breakfast meal (566 kcal) in 12 type 2 diabetic patients meal (age 57 years [range 49-67], BMI 31 kg/m2 [27-38], and HbA1c 9.2%[7. -12.5]) and 12 matched healthy subjects. The patients HbA1c had fasting hyperglycemia (10.7 mmol/l [8. -14.8]) increasing to 14.6 mmol/l (11.5-21.5) 75 min after meal ingestion. Fasting levels of insulin (11.5-21.5) and C-peptide were similar to those of the healthy subjects, but the postprandial responses were reduced and delayed. Fasting levels and and meal responses were similar between patients and healthy subjects for total GIP (intact + metabolite) as well as intact hyperglycemia GIP, except for a small decrease in the patients at 120 min; integrated areas for intact hormone (area under the insulinotropic curve [AUC]INT) averaged 52 +/- 4%(for patients) versus 56 +/- 3%(for control subjects) of total hormone AUC (AUC(TOT)).concentrations AUC(INT) for GLP-1 averaged 48 +/- 2%(for patients) versus 51 +/- 5%(for control subjects) of AUC(TOT). AUC(TOT) for postprandial GLP-1 as well as AUC(INT) tended to be reduced in the patients (P = .2 and .07, respectively); but the (10.7 profile of the intact GLP-1 response was characterized by a small early rise (30-45 min) and a significantly reduced late + phase (75-150 min)(P < .02). The measurement of intact incretin hormones revealed that total as well as intact GIP meal responses were minimally decreased in patients with type 2 diabetes, whereas the late intact GLP-1 response was strongly reduced, supporting Using the hypothesis that an impaired function of GLP-1 as a transmitter in the enteroinsular axis contributes to the inappropriate insulin to secretion in type 2 diabetes.

Low the birth weight is linked with raised blood pressure in adult life. Recent evidence has suggested that a neuroendocrine disturbance involving with the hypothalamic-pituitary-adrenal axis could mediate this link. We therefore investigated the relation between birth weight and fasting plasma cortisol concentrations born and the association of cortisol with current blood pressure in population samples of 165 men and women born in Adelaide,1935 South Australia, from 1975 to 1976, 199 men and women born in Preston, UK, from 1935 to 1943, and 306 women women born in East Hertfordshire, UK, from 1923 to 1930. Fasting plasma cortisol was measured in plasma samples obtained between Preston, 8 and 10 AM. Blood pressure was measured with an automated sphygmomanometer. Low birth weight was associated with raised fasting the plasma cortisol concentrations in all 3 populations. A combined analysis that allowed for differences in the gender composition, age, and 199 body mass index between the studies showed that cortisol concentrations fell by 23.9 nmol/L per kilogram increase in birth weight between (95% CI 9.6 to 38.2, P< .001). Fasting plasma cortisol concentrations also correlated positively with the subjects' current blood pressure. However,plasma the association between cortisol and blood pressure was most marked in subjects who were obese (P= .038 for interaction between body is mass index and cortisol, P= .01 for interaction between waist-to-hip ratio and cortisol). These results show that low birth weight is 199 associated with raised fasting plasma cortisol concentrations. Increased activity of the hypothalamic-pituitary-adrenal axis may link low birth weight with raised with blood pressure in adult life.

The no insulin-like growth factors (IGF-I and IGF-II) are almost completely bound in the circulation to specific binding proteins (IGFBPs). These IGFBPs of appear to play a pivotal role in maintaining circulating levels and modulating the delivery of the IGFs to the tissues.tissue A large proportion of the circulating IGFs are bound with high affinity to one of the binding proteins. IGFBP-3. The Recent mechanism by which these IGFs are transferred from the circulatory pool to the tissue receptors is at present unclear. Recent IGFBP-3. studies in late pregnancy have demonstrated the presence of specific proteases which may modify the IGFBPs such that their affinities at for the IGFs are reduced. In this paper, we have demonstrated the presence of a heat-sensitive cation-dependent proteolytic enzyme specific the for IGFBP-3 in the serum of five severely ill patients. The activity of this protease was found to vary in circulatory these patients, becoming more apparent during fasting than when studied after commencement of parenteral nutrition, indicating that one of the of influencing factors in the activity of this protease is the nutritional intake of the patient. Age- and sex-matched healthy adults the were also studied in a similar protocol, but no proteolytic modification of any of the IGFBPs was found in any factors of the samples examined. As the levels of both IGF-I and IGF-II were found to be low in the patients,circulatory the presence of a circulatory protease suggests that this may be an adaptive response to increase the bioavailability of the of IGFs and possibly to improve the nitrogen retention and counter the catabolic state in severe illness.

BACKGROUND:in Remnant lipoproteins are atherogenic, but assays of remnants have not been available in routine clinical laboratories because of the lack recurrent of practical and validated methods. A simple and reliable method for such an assay, using an immunochemical approach, has recently levels been developed. This study prospectively examined whether remnant lipoprotein levels in fasting serum, measured by our method, may have prognostic 135 value in patients with coronary artery disease (CAD). METHODS AND RESULTS: Remnant lipoprotein levels in fasting serum were measured in prognostic 135 patients with CAD by an immunoaffinity mixed gel containing anti-apolipoprotein (apo) A-1 and anti-apoB-100 monoclonal antibodies. Patients were followed serum up for </=36 months until occurrence of 1 of the following clinical coronary events: recurrent or refractory angina pectoris requiring an coronary revascularization, nonfatal myocardial infarction, or cardiac death. Kaplan-Meier analysis demonstrated a significantly higher probability of developing coronary events in AND patients with the highest tertile of remnant levels (>5.1 mg cholesterol/dL; 75th percentile of distribution of remnant levels) than in using those with the lowest tertile of remnant levels (</=3.3 mg cholesterol/dL; 50th percentile of the distribution). Higher levels of remnants recently were a significant and independent predictor of developing coronary events in multivariate Cox hazard analysis including the following covariates: extent are of coronary artery stenosis, age, sex, smoking, hypertension, diabetes mellitus, hypercholesterolemia, low HDL cholesterol, and hypertriglyceridemia. CONCLUSIONS: Higher levels of RESULTS: remnant lipoproteins in fasting serum predict future coronary events in patients with CAD independently of other risk factors. Thus, measurement events: of fasting remnant levels, assessed by the current immunoseparation method, may be helpful in assessment of CAD risk.

Serum during GH concentrations are increased in fasted or malnourished human subjects. We investigated the dynamic mechanisms underlying this phenomenon in nine and normal men by analyzing serum GH concentrations measured in blood obtained at 5-min intervals over 24 h on a control .24 (fed) day and on the second day of a fast with a multiple-parameter deconvolution method to simultaneously resolve endogenous GH mg/m2 secretory and clearance rates. Two days of fasting induced a 5-fold increase in the 24-h endogenous GH production rate [78 24-h +/- 12 vs. 371 +/- 57 micrograms/Lv (Lv, liter of distribution volume) or .24 +/- .038 vs. 1.1 +/- .16 vs. mg/m2 (assuming a distribution volume of 7.9% body weight), P = .0001]. This enhanced GH production rate was accounted for day by 2-fold increases in the number of GH secretory bursts per 24 h (14 +/- 2.3 vs. 32 +/- 2.4,(Lv, P = .0006) and the mass of GH secreted per burst (6.3 +/- 1.2 vs. 11 +/- 1.6 micrograms/Lv, P on = .002). The latter was a result of increased secretory-event amplitudes (maximal rates of GH release attained within a burst)fast with unchanged secretory burst durations. GH was secreted in complex volleys composed of multiple discrete secretory bursts. These secretory volleys increased were separated by shorter intervals of secretory quiescence in the fasted than fed state (respectively, 88 +/- 4.2 vs. 143 liter +/- 14 min, P = .0001). Similarly, within volleys of GH release, constituent individual secretory bursts occurred more frequently during and the fast [every 33 +/- .64 (fasted) vs. every 44 +/- 2. min (fed), P = .0001]. The t1/2 of mg/m2 endogenous GH was not significantly altered by fasting [18 +/- 2.2 (fasted) vs. 20 +/- 1.5 min (fed), P =at .47]. Serum insulin-like growth factor I concentrations were unchanged after 56 h of fasting. In conclusion, the present data suggest We that starvation-induced enhancement of GH secretion is mediated by an increased frequency of GHRH release, and longer and more pronounced days periods of somatostatin withdrawal.