Basal Serum Insulin Levels Research Articles

Metabolic and skeletal homeostasis are maintained in full locus GPRC6A knockout mice

The G protein-coupled receptor class C, group 6, subtype A (GPRC6A) is suggested to have a physiological function in glucose and bone metabolism, although the precise role lacks consensus due to varying findings in different knockout (KO) mouse models and inconsistent findings on the role of osteocalcin, a proposed GPRC6A agonist. We have further characterized a full locus GPRC6A KO model with respect to energy metabolism, including a long-term high-dose glucocorticoid metabolic challenge. Additionally, we analyzed the microarchitecture of tibiae from young, middle-aged and aged GPRC6A KO mice and wildtype (WT) littermates. Compared to WT, vehicle-treated KO mice presented with normal body composition, unaltered insulin sensitivity and basal serum insulin and glucose levels. Corticosterone (CS) treatment resulted in insulin resistance, abnormal fat accrual, loss of lean mass and suppression of serum osteocalcin levels in both genotypes. Interestingly, serum osteocalcin and skeletal osteocalcin mRNA levels were significantly lower in vehicle-treated GPRC6A KO mice compared to WT animals. However, WT and KO age groups did not differ in long bone mass and structure assessed by micro-computed tomography. We conclude that GPRC6A is not involved in glucose metabolism under normal physiological conditions, nor does it mediate glucocorticoid-induced dysmetabolism in mice. Moreover, GPRC6A does not appear to possess a direct, non-compensable role in long bone microarchitecture under standard conditions.

Appropriate Insulin Level in Selecting Fortified Diet-Fed, Streptozotocin-Treated Rat Model of Type 2 Diabetes for Anti-Diabetic Studies.

BackgroundPathophysiological investigation of disease in a suitable animal model is a classical approach towards development of a credible therapeutic strategy. This study examined appropriate insulin level in selecting animal model for type 2 diabetes (T2D) studies.MethodAlbino Wistar rats (150-200g) were divided into two groups fed with commercially available normal-diet-feed (NDF) and water or fortified diet feed (FDF) (10g NDF per gram of margarine) with 20% fructose solution as drinking water. After 6 weeks of dietary regimen both groups were divided into 5 sub-groups and injected intraperitoneally with a graded dose of streptozotocin (STZ) (0, 25, 35, 45 & 55mg/kg bw.).ResultThe result showed that the FDF-fed rats increased significantly in body weight, basal serum insulin, total cholesterol, triglycerides and blood glucose levels as compared to NDF-fed rats. Ten days post STZ induction, the groups treated with STZ (45 & 55 mg/kg) developed frank hyperglycaemia with < 46.8% serum insulin, a severe deficiency typical of diabetes type 1. The NDF25 and NDF35 groups with 75.7% and 64.4% serum insulin respectively presented relative normoglycemia, whereas the FDF35 (85.8% serum insulin) were notably hyperglycaemia (>300 mg/dL) throughout the 6weeks post diabetes confirmation. These FDF35 rats were sensitive to glibenclamide, metformin and pioglitazone in lowering hyperglycaemia, hypertriglyceridemia and hypercholesterolemiaConclusionThe hyperglycaemia stability of the FDF35 rats (85.5% insulin) together with their sensitivity to 3 different hypoglycaemic drugs strongly suggests their suitability as a non-genetic model of T2D. Hence the study shows that circulating serum insulin ≥ 85.8% with overt hyperglycaemia may be utilized as the benchmark in selecting rat models for T2D studies.

Alterations of Pancreatic Islet Structure, Metabolism and Gene Expression in Diet-Induced Obese C57BL/6J Mice

The reduction of functional β cell mass is a key feature of type 2 diabetes. Here, we studied metabolic functions and islet gene expression profiles of C57BL/6J mice with naturally occurring nicotinamide nucleotide transhydrogenase (NNT) deletion mutation, a widely used model of diet-induced obesity and diabetes. On high fat diet (HF), the mice developed obesity and hyperinsulinemia, while blood glucose levels were only mildly elevated indicating a substantial capacity to compensate for insulin resistance. The basal serum insulin levels were elevated in HF mice, but insulin secretion in response to glucose load was significantly blunted. Hyperinsulinemia in HF fed mice was associated with an increase in islet mass and size along with higher BrdU incorporation to β cells. The temporal profiles of glucose-stimulated insulin secretion (GSIS) of isolated islets were comparable in HF and normal chow fed mice. Islets isolated from HF fed mice had elevated basal oxygen consumption per islet but failed to increase oxygen consumption further in response to glucose or carbonyl cyanide-4-trifluoromethoxyphenylhydrazone (FCCP). To obtain an unbiased assessment of metabolic pathways in islets, we performed microarray analysis comparing gene expression in islets from HF to normal chow-fed mice. A few genes, for example, those genes involved in the protection against oxidative stress (hypoxia upregulated protein 1) and Pgc1α were up-regulated in HF islets. In contrast, several genes in extracellular matrix and other pathways were suppressed in HF islets. These results indicate that islets from C57BL/6J mice with NNT deletion mutation develop structural, metabolic and gene expression features consistent with compensation and decompensation in response to HF diet.

Non‐obese early onset diabetes mellitus in mutant cryptochrome1 transgenic mice

An earlier report described that transgenic mice ubiquitously expressing cryptochrome1 (CRY1) with a mutation in cystein414 (CRY1-AP Tg mice) display diabetes mellitus in addition to anomalous circadian behaviours. This study examined characteristic aspects of symptoms to clarify the diabetes type and pathogenesis. The body weights and blood glucose levels of CRY1-AP Tg mice were measured for 7weeks starting at 3weeks after birth. Glucose tolerance test for the mice of various ages and insulin tolerance test at 6weeks of age were conducted. Immunohistochemical analysis of islets was carried out for the mice of 19 and 40weeks of age. Basal and glucose-stimulated serum insulin levels of mice at 27weeks were also measured. Three-week-old CRY1-AP Tg mice, which showed mild retardation in growth, already displayed glucose intolerance. Hyperglycaemia progressed with age, without accompanying insulin resistance. Insulin-stained areas in islets in CRY1-AP Tg mice were smaller than that in wild-type controls. Both basal and glucose-stimulated secretion of insulin decreased in CRY1-AP Tg mice. The symptoms of diabetes in CRY1-AP Tg mice turned out to be similar to those of maturity onset diabetes of the young (MODY) in humans in terms of early onset, non-obesity and primary dysfunction of beta cells. The CRY1-AP Tg mice might serve as an animal model of early onset insulin-secretory defect of diabetes.

Novel Role of Y1 Receptors in the Coordinated Regulation of Bone and Energy Homeostasis

The importance of neuropeptide Y (NPY) and Y2 receptors in the regulation of bone and energy homeostasis has recently been demonstrated. However, the contributions of the other Y receptors are less clear. Here we show that Y1 receptors are expressed on osteoblastic cells. Moreover, bone and adipose tissue mass are elevated in Y1(-/-) mice with a generalized increase in bone formation on cortical and cancellous surfaces. Importantly, the inhibitory effects of NPY on bone marrow stromal cells in vitro are absent in cells derived from Y1(-/-) mice, indicating a direct action of NPY on bone cells via this Y receptor. Interestingly, in contrast to Y2 receptor or germ line Y1 receptor deletion, conditional deletion of hypothalamic Y1 receptors in adult mice did not alter bone homeostasis, food intake, or adiposity. Furthermore, deletion of both Y1 and Y2 receptors did not produce additive effects in bone or adiposity. Thus Y1 receptor pathways act powerfully to inhibit bone production and adiposity by nonhypothalamic pathways, with potentially direct effects on bone tissue through a single pathway with Y2 receptors.

The Impact of Pegvisomant Treatment on Substrate Metabolism and Insulin Sensitivity in Patients with Acromegaly

Pegvisomant is a specific GH receptor antagonist that is able to normalize serum IGF-I concentrations in most patients with acromegaly. The impact of pegvisomant on insulin sensitivity and substrate metabolism is less well described. We assessed basal and insulin-stimulated (euglycemic clamp) substrate metabolism in seven patients with active acromegaly before and after 4-wk pegvisomant treatment (15 mg/d) in an open design. After pegvisomant, IGF-I decreased, whereas GH increased (IGF-I, 621 +/- 82 vs. 247 +/- 33 microg/liter, P = 0.02; GH, 5.3 +/- 1.5 vs. 10.8 +/- 3.3 microg/liter, P = 0.02). Basal serum insulin and plasma glucose levels decreased after treatment (insulin, 54 +/- 5.9 vs. 42 +/- 5.3 pmol/liter, P = 0.001; glucose, 5.7 +/- 0.1 vs. 5.3 +/- 0.0 mmol/liter, not significant), whereas palmitate kinetics were unaltered. During the clamp, the glucose infusion rate increased after pegvisomant (3.1 +/- 0.5 vs. 4.4 +/- 0.6 mg/kg.min, P = 0.02), whereas the suppression of endogenous glucose production tended to increase (0.7 +/- 0.0 vs. 0.5 +/- 0.1 mg/kg.min, not significant). Total resting energy expenditure decreased after pegvisomant treatment (1703 +/- 109 vs. 1563 +/- 101 kcal/24 h, P = 0.03), but the rate of lipid oxidation did not change significantly. 1) Pegvisomant treatment for 4 wk improves peripheral and hepatic insulin sensitivity in acromegaly. 2) This is associated with a decrease in resting energy expenditure, whereas free fatty acid metabolism is unaltered. 3) The data support the important direct effects of GH on glucose metabolism and add additional benefits to pegvisomant treatment for acromegaly.

Effect of experimental hypo- and hyperthyroidism on serum adiponectin

Adiponectin, an adipocyte-derived hormone, has been shown to decrease body weight by increasing thermogenesis and lipid oxidation. Thyroid hormones have similar effects. Here we investigated if experimental hypo- and hyperthyroidism in rats would induce changes in serum adiponectin concentration. Adult rats became hypothyroid by treatment with 0.03% methimazole in the drinking water for 28 days or hyperthyroid by subcutaneous thyroxine injections (50 μg/100g body weight) for 10 days. Serum adiponectin level of hyperthyroid rats was 3.2-fold higher than that of euthyroid ones ( P < .001), whereas that in hypothyroid rats tended to be lower (38%), but without statistical significance. Serum adiponectin had a positive correlation with serum thyroxine ( r = .81, P < .001) and triiodothyronine ( r = 0.68, P = .03) and a negative correlation with serum thyroid-stimulating hormone ( P = −.62, r = 0.015). In addition, there was a negative correlation between serum adiponectin level and total visceral white adipose mass (= sum of inguinal, epididymal, and retroperitoneal depots; r = −0.43; P = .032), which was reduced by 40.5% in hyperthyroid ( P < .01) but not in hypothyroid animals. A positive association between serum adiponectin level and brown adipose tissue mass was found ( r = 0.43, P = .03), but not with body weight, which was reduced in both hypo- and hyperthyroid groups. Adiponectin has been reported to have an insulin-sensitizing effect. However, in hyperthyroid rats, higher serum adiponectin level was not accompanied by statistically different changes in basal serum insulin levels, blood glucose concentrations, or glucose tolerance as compared with euthyroid rats, except for a slight increase in blood glucose level at 120 minutes after glucose intraperitoneal administration ( P < .05). Therefore, experimental hypothyroidism did not change serum adiponectin concentration, whereas hyperthyroidism induced an important elevation in the serum hormone concentration, with still unknown biological significance.

Body mass index and blood glucose: correlations with serum insulin, growth hormone, and insulin-like growth factor-1 levels in patients with diffuse idiopathic skeletal hyperostosis (DISH)

Obesity is a frequent co-morbid condition associated with diffuse idiopathic skeletal hyperostosis (DISH). Serum growth hormone (GH), insulin-like growth factor (IGF-1) and insulin are significantly elevated in patients with DISH. In this study, we examined the relationship between body mass index (BMI) and basal serum GH, IGF-1, and insulin concentration in a group of 36 DISH patients. Basal serum insulin levels were significantly elevated (P<0.001) in DISH patients with a BMI>28 kg m(-2), classified as obese, compared with DISH patients with BMI ranging from 23 to 28 kg m(-2). In addition, BMI strongly positively correlated with serum insulin concentration in DISH patients (adjusted r2 = 0.348, P<0.001). However, BMI did not correlate with either basal serum GH (adjusted r2 = -0.013) or IGF-1 levels (adjusted r2 = -0.010) in DISH. We conclude that BMI does not seem to contribute to elevated serum GH and IGF-1 levels in symptomatic DISH.

Serum growth hormone and insulin but not insulin-like growth factor-1 levels are elevated in patients with fibromyalgia syndrome

Standard radioimmunoassay (RIA) was employed to quantify basal serum growth hormone (GH), insulin-like growth factor-I (IGF-1), and insulin levels in 32 normoglycemic patients with clinically active fibromyalgia and in 29 normoglycemic control subjects. The GH concentration was significantly higher (P < 0.001) in female fibromyalgia patients than age-matched, normal female subjects. In contrast, basal serum IGF-1 concentrations did not differ between these groups. A scatter plot generated from two-stage, least-squares analysis showed that serum GH lacked correlation with the serum IGF-1 concentrations of normal female subjects (P = 0.73) and female fibromyalgia patients (P = 0.19). In addition to the results from serum GH and IGF-1 RIA, we also found significantly higher fasting serum insulin levels (P = 0.03) in male fibromyalgia patients and a trend toward elevated fasting serum insulin levels in the female fibromyalgia population ( P = 0.07), with the mean fasting level in the male fibromyalgia group (35.7 microU/ml(-1)) exceeding the upper limit of normal serum insulin levels (i.e., 27 microU/ml(-1)). Based on these results, basal serum GH and fasting serum insulin levels appear to be valuable surrogate markers in clinically active, normoglycemic fibromyalgia patients.

Hepatitis C virus infection and diabetes: direct involvement of the virus in the development of insulin resistance.

Epidemiological studies have suggested a linkage between type 2 diabetes and chronic hepatitis C virus (HCV) infection. However, the presence of additional factors such as obesity, aging, or cirrhosis prevents the establishment of a definite relationship between these 2 conditions. A mouse model transgenic for the HCV core gene was used. In the glucose tolerance test, plasma glucose levels were higher at all time points including in the fasting state in the core gene transgenic mice than in control mice, although the difference was not statistically significant. In contrast, the transgenic mice exhibited a marked insulin resistance as revealed by the insulin tolerance test, as well as significantly higher basal serum insulin levels. Feeding with a high-fat diet led to the development of overt diabetes in the transgenic mice but not in control mice. A high level of tumor necrosis factor-alpha, which has been also observed in human chronic hepatitis C patients, was considered to be one of the bases of insulin resistance in the transgenic mice, which acts by disturbing tyrosine phosphorylation of insulin receptor substrate-1. Moreover, administration of an anti-tumor necrosis factor-alpha antibody restored insulin sensitivity. The ability of insulin to lower the plasma glucose level in the HCV transgenic mice was impaired, as observed in chronic hepatitis C patients. These results provide a direct experimental evidence for the contribution of HCV in the development of insulin resistance in human HCV infection, which finally leads to the development of type 2 diabetes.

Peroxisome proliferator-activated receptor gamma coactivator-1-dependent uncoupling protein-2 expression in pancreatic islets of rats: a novel pathway for neural control of insulin secretion.

Sympathetic inputs inhibit insulin secretion through alpha2-adrenergic receptors coupled with Gi protein. High adrenergic tonus generated by exposure of homeothermic animals to cold reduces insulin secretion. In this study we evaluate the participation of UCP-2 in cold-induced regulation of insulin secretion. Static insulin secretion studies, western blotting and immunohistochemistry were used in this investigation. Exposure of rats to cold during 8 days promoted 60% ( n=15, p<0.05) reduction of basal serum insulin levels concentration accompanied by reduction of the area under insulin curve during i.p. GTT (50%, n=15, p<0.05). Isolated islets from cold-exposed rats secreted 57% ( n=6, p<0.05) less insulin following a glucose challenge. Previous sympathectomy, partially prevented the effect of cold exposure upon insulin secretion. Islets isolated from cold-exposed rats expressed 51% ( n=6, p<0.5) more UCP-2 than islets from control rats, while the inhibition of UCP-2 expression by antisense oligonucleotide treatment partially restored insulin secretion of islets obtained from cold-exposed rats. Cold exposure also induced an increase of 69% ( n=6, p<0.05) in PGC-1 protein content in pancreatic islets. Inhibition of islet PGC-1 expression by antisense oligonucleotide abrogated cold-induced UCP-2 expression and partially restored insulin secretion in islets exposed to cold. Our data indicate that sympathetic tonus generated by exposure of rats to cold induces the expression of PGC-1, which participates in the control of UCP-2 expression in pancreatic islets. Increased UCP-2 expression under these conditions could reduce the beta-cell ATP/ADP ratio and negatively regulate insulin secretion.

Should we consider performing oral glucose tolerance tests more frequently in postmenopausal women for optimal screening of impaired glucose tolerance?

To investigate an optimal screening protocol for impaired glucose tolerance (IGT) and type II or non-insulin-dependent diabetes mellitus (DM) by using fasting plasma glucose (FPG) and oral glucose tolerance test (OGTT) in postmenopausal women. One hundred consecutive postmenopausal women were screened with FPG determination, and then all underwent an OGTT. Basal serum lipid and insulin levels of these women were also determined. Insulin sensitivity was determined by using the homeostasis model assessment. Receiver operating characteristic analysis was performed to determine the efficacy of these variables in detecting women with IGT and DM, and optimal cutoff values were determined. FPG with a cutoff value of 98 mg/dL had the best combination of sensitivity (71%) and specificity (76%) for the detection of IGT and DM. Combined FPG and body mass index screening (with the optimal cutoff value of 26.5 kg/m2) improved the sensitivity to 96% but decreased the specificity to 47%. This combined screening protocol detected 94% of the women with IGT and all diabetic women. Given that IGT and DM are common among postmenopausal women and DM can be prevented by nonpharmacologic interventions in women with IGT, OGTT may be used more frequently among these women. Our data indicate that for optimal screening of non-insulin-dependent DM and IGT, OGTT should be considered in postmenopausal women, especially when risk factors in addition to age are present. This model may detect most of the women with IGT and almost all diabetic women.

Peripheral glucose metabolism in patients with essential hypertension.

The present study was designed to determine the effect of essential hypertension on peripheral glucose metabolism during the postabsorptive state and after an oral glucose challenge. Ten normal subjects and nine patients with essential hypertension were studied after an overnight fast (12-14 h) and for 3 h after the ingestion of 75 g of glucose. Peripheral glucose metabolism was analyzed by the forearm technique to estimate muscle exchange of substrate combined with indirect calorimetry. Decreased forearm glucose uptake was observed in hypertensive patients compared to normal subjects (4.9+/-0.6 vs. 8.6+/-0.5 mmol x 100 ml forearm(-1) x 3 h(-1)) with diminished nonoxidative glucose metabolism (2.7+/-0.5 vs. 6.9+/-0.6 mmol x 100 ml forearm(-1) x 3 h(-1)). Muscle glucose oxidation did not differ significantly between groups. Both serum free fatty acid levels and lipid oxidation rates were similar in the normal subjects and the hypertensive patients, and declined in a similar fashion after glucose ingestion. Basal serum insulin levels did not differ significantly between normal and hypertensive patients, whereas the insulinemic response to glucose load was greater among the patients with essential hypertension. These data show that insulin resistance occurring in patients with essential hypertension is accompanied by impaired muscle glucose uptake and nonoxidative metabolism.

LEPTIN IN OBESE CHILDREN

Obesity is a desorder of the energy balance. The knowledge of factors that are disregulated in obese humans should be of major importance in the prevention and treatment of obesity. Leptin, cholecistoquinin (CCK) and gastrin releasing peptide (GRP), have been related to the saciety-hunger cycle. The aims of this work were: a) to determine serum leptin, CCK and GRP plasma levels in obese children; and b) to investigate the relation between serum leptin concentration versus body weight, body mass fat, basal serum insulin levels(BSIL), CCK and GRP. Thirty six obese children were studied (18 boys and 18 girls; mean ± SD age was 10,7±3,2 years). The obesity was defined, aproximately, as 120% of ideal body weight. A blood sample was collected from each patient while fasting. Serum leptin and serum insulin were measured by RIA (Linco Research., S.Louis, Mo., and Peninsula Laboratories Inc., Belmont, Ca., respectively). CCK and GRP were also assessed by RIA (Peninsula Laboratories Inc., Belmont, Ca.). Body mass fat (BMF) was determined by impedance measurements (BIA) and anthropomorphic data were calculated from from skin fold (SK) density data. Serum leptin concetrations were 24.51±10 pg/ml (normal 1-7 pg/ml). The CCK levels were 0.54±0.5 pmol/L, and GRP levels were 5.54±1.39 pmol/L (normal 4.20±1.08 and 34.39±3.34 pmol/L, respectively). Serum leptin concentrations correlated well with children weight (r=0.52, p<0.02), Z weight (r=0.53, p<0.02), BMF (r=0.6, p<0.008), SK (r=0.7, p<0.004) and BSIL (r=0.6, p<0.02). We conclude that the simultaneous significant increase of serum leptin concentration and the low CCK an GRP levels found in these obese patients, suggest that the obesity is more likely to be due to central mechanisms regulating food intake than to the presence of defective signaling by adipocites.

Peptide YY does not inhibit glucose-stimulated insulin secretion in humans.

Peptide YY (PYY) is localized to gut and pancreatic endocrine cells. it may therefore be involved in the regulation of insulin secretion as a gut hormone as well as an islet local regulator. in laboratory animals, the peptide inhibits stimulated insulin secretion, but its effects in humans are not known. We therefore infused PYY intravenously at a low (1 pmol x kg(-1) x min(-1); N = 4); or a high rate (5 pmol x kg(-1) x min(-1); N = 5) for 120 min in healthy women aged 52 years. After 30 min of infusion, glucose (0.5 g/kg) was injected rapidly. In separate control experiments, saline was infused instead of PYY. We found that PYY did not inhibit the acute insulin response to glucose or affect the glucose elimination rate, and PYY was also without influence on the basal plasma glucose and serum insulin levels during the 30-min infusion before the challenge with glucose. We therefore conclude that intravenous infusion of PYY does not affect glucose-stimulated insulin secretion in man.

Effects of different energy levels, concentrate/forage ratios and lipid supplementation to the diet on the adaptation of the energy metabolism at calving in dairy cows.

A low level of energy (110 MJ ME) and a low concentrate/forage ratio (10/90) at calving resulted in low basal concentrations of glucose and insulin, but the cows had the capacity to increase the glucose level after glucagon injections. No signs of disturbances in the metabolic adaptation were observed. High intensity feeding (200 MJ ME and 50% concentrates) resulted in high basal serum insulin levels. The increase in the insulin concentrations after glucagon injections and the changes in insulin levels around calving varied widely between individual cows. The metabolic adaptation period was longer than in cows in the former group. An energy level of 170 MJ ME and variations of concentrate/forage ratios (5/95, 30/70 and 60/40) resulted in small differences in basal glucose and insulin concentrations and in response to glucagon injections. But the cows fed 60% concentrates showed signs of prolonged metabolic adaptation. Increased lipid concentrations in diets containing equal levels of energy and protein resulted in a fall in basal glucose and insulin levels and the metabolism seemed to be directed towards catabolism. Because of these metabolic effects, more needs to be known on fat supplementation if it is used in practical feeding. It is also necessary to take more interest in the effects of protein feeding on the periparturient metabolism.

Ovarian Stromal Hypertrophy in Hyperandrogenic Women

Dewailly, Didier; Robert, Yann; Helin, Isabelle; Ardaens, Yves; Thomas-Desrousseaux, Patricia; Lemaitre, Laurent; Fossati, PierreAuthor Information

Ovarian stromal hypertrophy in hyperandrogenic women

By using vaginal endosonography, ovarian stromal hypertrophy has been shown to be a strong diagnostic feature of polycystic ovarian syndrome and related states. However, this sign is difficult to quantify and to correlate with other findings because of its subjectivity. We have evaluated the use of computer assisted analysis of ultrasound scans to provide more objective measurements of ovarian structure and size. We used a computer assisted method for the reading of ultrasound scans. It allowed selective calculation of the stromal area by subtraction of the cyst area from the total ovarian area on a longitudinal ovarian section. A consecutive series of 57 patients with hyperandrogenism (group 1), 17 patients with hypothalamic anovulation (group 2) and 20 normal women (group 3). By computerized measure, 75% patients from group 1 had a bilateral stromal area above the mean +2 SD (700 mm2) of women from group 3. All patients from group 2 were below this threshold. Serum LH level was above the normal range in 45% patients from group 1. The stromal area correlated positively with the serum delta 4-androstenedione (r = 0.47, P < 0.005) and 17 alpha-hydroxyprogesterone (r = 0.39, P < 0.005) levels, exclusively in group 1. It did not correlate with the basal serum testosterone, LH or insulin levels. The cyst area did not correlate with any hormonal parameter. Ovarian stromal hypertrophy is a frequent and specific feature of hyperandrogenism. It correlates with the ovarian androgenic dysfunction. Its presence is not always linked with elevated serum immunoreactive LH levels. Further data are needed to elucidate the role of insulin and ovarian growth factors.

Aging exaggerates glucose intolerance following injury.

Hyperglycemia and glucose intolerance are characteristic of both the metabolic responses to injury and normal aging. To evaluate the interaction of such changes we conducted hyperglycemic glucose clamp studies (2-hour) in previously healthy young (20 +/- 4 years, Mean +/- SD) and older (73 +/- 9 years) trauma patients and volunteers (23 +/- 1 and 68 +/- 5 years), determining whole-body glucose disposal and insulin responses to hyperglycemia. Injury Severity Scores were similar in the young and older patient groups (range, 17-30). Plasma glucose levels were greater in patients than volunteers in both the basal and hyperglycemic periods. Basal serum insulin and C-peptide levels were similar among groups, but during hyperglycemia both were markedly higher in young patients than older (and both volunteer groups). Whole-body disposal of exogenous glucose was substantially lower in patients than volunteers and in the older groups. Aging has a major impact on postinjury metabolism, being associated with exaggerated glucose intolerance and diminished insulin responses to glucose infusion. These findings have important implications for the metabolic and nutritional care of older patients following trauma and during critical illness.

The effects of superphysiologic hyperinsulinemia on glucose and lipid metabolism in glucose-tolerant offspring of patients with non-insulin-dependent diabetes mellitus (NIDDM)

First-degree relatives of patients with NIDDM manifest severe insulin resistance despite normal glucose tolerance test. To examine the mechanisms underlying the normal glucose tolerance, we evaluated the serum glucose/C-peptide/insulin dynamics and free fatty acid (FFA) as well as substrate oxidation rates and energy expenditure (EE) (indirect calorimetry) in nine young offspring of NIDDM patients (mean ± SEM age 30 ± 2.3 years, body mass index 24.2 ± 1.2 kg/m 2). Nine age-, sex- and weight-matched, normal subjects with no family history of diabetes served as the controls. Metabolic parameters were measured before, during and after a two-step glucose infusion (2 and 4 mg/kg·min) for 120 min. Mean basal serum glucose, insulin and C-peptide levels were similar in both groups. During 2 mg/kg·min glucose infusion, mean serum insulin and C-peptide rose to significantly ( P < 0.05-0.02) greater levels in the offspring vs. controls, while serum glucose levels were similar. With the 4 mg/kg·min glucose infusion, mean serum glucose, insulin and C-peptide levels were significantly ( P < 0.02-0.001) greater in the offspring at 100–120 min. Isotopically-derived ( d[3- 3H]glucose), basal hepatic glucose output (HGO) was not significantly different between the offspring vs. controls (1.86 ± 0.30 vs. 1.78 ± 0.06 mg/kg·min). During glucose infusion, basal HGO was partially suppressed by 66% at 60 min and by 100% at 120 min in the offspring. In contrast, HGO was completely (100%) suppressed at both times in the controls. Following cessation of glucose infusion, HGO rose to 1.64 ± 0.12 mg/kg·min in the offspring and 1.46 ± 0.05 mg/kg·min in the controls ( P < 0.05) between 200 and 240 min. These were 88% and 82% of the respective basal HGO values. At low glucose infusion ( t = 0–60 min), the mean absolute, nonoxidative glucose disposal remained 1.5-fold greater in the offspring while at higher glucose infusion, nonoxidative glucose metabolism was not different in both groups. Throughout the study period, oxidative glucose disposal rate was not significantly different in both groups. The mean basal FFA was significantly greater in the offspring vs. controls (865 ± 57 vs. 642 ± 45 μEq/l). It was appropriately suppressed during glucose infusion to a similar nadir in both groups (395 ± 24 vs. 375 ± 33 μEq/l). The mean basal lipid oxidation was also significantly greater in the offspring than controls (1.06 ± 0.05 vs. 0.75 ± 0.04 mg/kg·min, P < 0.05). During glucose infusion, lipid oxidation was suppressed to a similar nadir in both groups (0.62 ± 0.07 vs. 0.63 ± 0.06 ng/kg·min). FFA did not correlate with the HGO or nonoxidative and oxidative glucose disposal in either group. We found insignificant correlations between lipid and glucose oxidation rates at basal ( r = −0.422) and during glucose infusion ( r = −0.402) in the offspring. In contrast, significant ( P < 0.001) negative relationships were found between both parameters at basal ( r = −0.850, P < 0.01) and during glucose infusion ( r = −0.825) in the healthy controls. There were no significant differences in resting energy expenditure (REE), post-glucose thermic effect in the offspring and controls, despite the higher insulin levels in the former. In summary, the present study demonstrates that nondiabetic offspring of NIDDM patients manifest impaired insulin-mediated glucose, energy and FFA/lipid metabolism. We found that beta-cell hormone secretion was extraordinarily sensitive to glucose infusion in the offspring. The resultant hyperinsulinemia could be an early compensation for the insulin resistance in the glucose-tolerant offspring. At low glucose load, the offspring appear to manifest normal glucose tolerance by maintaining greater nonoxidative glucose disposal, probably due to hyperinsulinemia. However, at higher glucose challenge, this compensatory mechanism is inadequate to achieve normal glucose concentrations, thus resulting in hyperglycemia.