Biomedical subjects

Michael Roden

Publications and source records attributed to Michael Roden.

49 records · Page 3Linked to original sources

PubMed2003

Insulin-dependent modulation of plasma ghrelin and leptin concentrations is less pronounced in type 2 diabetic patients.

The gastric peptide ghrelin augments and the adipocyte-derived hormone leptin reduces appetite and food intake. In the central nervous system, insulin directly decreases hunger sensation but could also act indirectly by modulating ghrelin and leptin secretion. This study examines dose-dependent effects of insulin on plasma ghrelin and leptin concentrations during hyperinsulinemic (1, 2, and 4 mU x kg(-1) x min(-1))-euglycemic clamp tests in six nondiabetic (control subjects) and six type 2 diabetic patients. Type 2 diabetic patients were studied before and after prolonged (12-h and 67-h) variable intravenous insulin treatment aiming at near-normoglycemia (115 +/- 4 mg/dl). Nondiabetic subjects were also studied during saline infusion, which did not affect ghrelin but decreased leptin by 19 +/- 6% (P < 0.03). In control subjects, plasma ghrelin decreased at all clamp steps (-17 +/- 1, -27 +/- 6, and -33 +/- 4%, respectively; P < 0.006 vs. baseline), whereas leptin increased by 35 +/- 11% (P < 0.05). In type 2 diabetic patients without insulin treatment, ghrelin decreased by 18 +/- 7% (P < 0.05) only after 4 mU x kg(-1) x min(-1) insulin infusion and leptin increased by 19 +/- 6% (P < 0.05). After prolonged insulin treatment and near-normoglycemia, ghrelin and leptin remained unchanged in type 2 diabetic patients during the clamps. In conclusion, insulin reduces plasma ghrelin in nondiabetic patients and, to a lesser extent, in type 2 diabetic patients before insulin therapy. These findings indicate an indirect effect of insulin via ghrelin on the suppression of hunger sensation and appetite.

Aged↗

PubMed2002

How to detect pheochromocytomas?--the diagnostic relevance of plasma free metanephrines.

Pheochromocytomas are chromaffin cell tumors, mostly originating from the adrenal medulla, and represent a rare cause of hypertensiondue to excessive production of catecholamines (norepinephrine and/or epinephrine). More than 10% occur in families with multiple endocrine neoplasia type II, von Hippel-Lindau disease, neurofibromatosis type I, and familial carotid body tumors. Since approximately half of the afflicted patients present without or with only episodic hypertension, detailed clinical evaluation and sensitive biochemical tests are mandatory for the diagnosis, which relies on the detection of increased catecholamine production. Commonly employed tests such as the measurement of free catecholamines in plasma and urine or of their metabolites, vanillylmandelic acid and total metanephrines (= free + conjugated normetanephrine and metanephrine) in urine, suffer from interference from external factors and sometimes low clinical sensitivity and/or specificity. Recent technical advances now allow us to measure plasma free (unconjugated) metanephrines, thus increasing clinical sensitivity and specificity to close to 100%. Plasma free metanephrines offer the following advantages for the detection of pheochromocytomas: (i) independence of short-term changes in catecholamine secretion which may result from change of posture, exercise or intraoperative stress, (ii) information on long-term increase of catecholamine production, (iii) tight correlation with tumor mass, and (iv) only minor interference from drugs. This method does not need time-consuming standardized procedures for blood sampling, which are a prerequisite for the determination of free catecholamines. In conclusion, it is therefore recommended to use plasma free metanephrines--after meticulous clinical screening--as the first-line biochemical test for detecting pheochromocytomas.

Adrenal Gland Neoplasms↗

PubMed2002

Effect of pravastatin on responsiveness to N-monomethyl-L-arginine in patients with hypercholesterolaemia.

Improvement of endothelial function in hypercholesterolaemia is attributed to lipid lowering and to pleiotropic effects of statin therapy. We investigated whether responsiveness to inhibition of constitutive NO formation with N-monomethyl-L-arginine (L-NMMA) is improved after 7 and 28 days of pravastatin. Twelve female and four male subjects with mild or moderate primary hypercholesterolaemia were randomized to pravastatin (20 mg per oral (p.o.) n=8) or placebo (n=8) in a double blind parallel group design. Vascular responsiveness was studied by intravenous bolus infusions of L-NMMA (cumulative doses of 3 and 6 mg/kg). Mean arterial blood pressure (MAP) and pulse rate (PR) were measured noninvasively, pulsatile choroidal blood flow was assessed with laser interferometric measurement of fundus pulsation amplitudes (FPA) and renal plasma flow (RPF) was measured by the PAH clearance method. Pravastatin lowered plasma cholesterol levels by 16 and 24% after 7 and 28 days of treatment, respectively (P<0.01). L-NMMA caused comparable changes in MAP, PR and RPF between groups. L-NMMA reduced FPA to a similar extent in both groups before and after 7 days of treatment, but the response to L-NMMA was significantly enhanced after 28 days of pravastatin (21%; P<0.001 vs baseline) and greater than after placebo (15%; P<0.01 vs pravastatin). Pravastatin enhances responsiveness to L-NMMA in the ocular microvasculature. Improved responsiveness is associated with changes in total cholesterol levels.

Australia↗

PubMed2002

Inhibition of glucose production and stimulation of bile flow by R (+)-alpha-lipoic acid enantiomer in rat liver.

AIMS/BACKGROUND: R (+)-alpha-lipoic acid (RLA) has been suggested for the treatment of liver diseases, but has also been shown to improve glucose utilization in diabetic patients. Because detailed information of RLA action on carbohydrate metabolism in intact liver is lacking, we examined concentration-dependent effects of RLA on hepatic glucose production. METHODS: RLA (10(-6-)10(-3) mol L(-1)) or buffer (control) was infused in isolated livers of fasted rats during recirculating perfusion for 90 min (n = 4-6/group). Hepatic glucose and lactate fluxes and bile secretion were continuously monitored. RESULTS: RLA reduced lactate (10 mmol L(-1))-dependent glucose production in concentration-dependent fashion (R = - 0.780, P < 0.001) by up to 67% compared with control (0.36 +/- 0.02 micromol min(-1) g(-1)). In parallel, RLA dose dependently decreased lactate uptake (R = - 0.592, P < 0.001) also by up to 67% (control: 0.58 +/- 0.08 micromol min(-1) g(-1)). RLA (10(-4) mol L(-1) and 10(-3) mol L(-1)) stimulated bile flow by approximately 20 and approximately 50%, respectively (P < 0.02 vs. control). After 10(-3) mol L(-1) RLA infusion, liver glycogen was approximately 3 fold higher (5.2 +/- 1.1 vs. control: 1.8 +/- 0.2 micromol g(-1), P < 0.002). Also at low lactate concentrations (1 mmol L(-1)), 10(-3) mol L(-1) RLA reduced glucose production by approximately 53% and lactate uptake by approximately 60%, but stimulated bile secretion by approximately 50% (P < 0.05). CONCLUSION: RLA reduces hepatic glucose release by inhibiting lactate-dependent glucose production in a concentration-dependent fashion.

Animals↗

PubMed2002

Reduction of plasma leptin concentrations by arginine but not lipid infusion in humans.

OBJECTIVE: We examined short-term effects of arginine infusion on plasma leptin in diabetic and healthy subjects. RESEARCH METHODS AND PROCEDURES: Arginine stimulation tests were performed in C-peptide negative type 1 [DM1; hemoglobin A(1c); 7.3 +/- 0.3%], hyperinsulinemic type 2 diabetic (DM2; 7.6 +/- 0.7%), and nondiabetic subjects (CON; 5.4 +/- 0.1%). RESULTS: Fasting plasma leptin correlated linearly with body mass index among all groups (r = 0.61, p = 0.001). During arginine infusion, peak plasma insulin was lower in DM1 than in DM2 (p < 0.05) and CON (p < 0.01). Plasma leptin decreased within 30 minutes by approximately 11% in DM1 (p < 0.001), DM2 (p < 0.01), and CON (p < 0.005), slowly returning to baseline thereafter. Plasma free fatty acids (FFAs) were higher in DM1 (0.6 +/- 0.1 mM) and DM2 (0.6 +/- 0.1 mM) than in CON (0.4 +/- 0.1 mM, p < 0.05) and transiently declined by approximately 50% (p < 0.05) at 45 minutes in all groups before rebounding toward baseline. To examine the direct effects of FFAs on plasma leptin, we infused healthy subjects with lipid/heparin and glycerol during fasting, and somatostatin-insulin ( approximately 35 pM) -glucagon ( approximately 90 ng/mL) clamps were performed. In both protocols, plasma leptin continuously declined by approximately 25% (p < 0.05) during 540 minutes without any difference between the high and low FFA conditions. DISCUSSION: Arginine infusion transiently decreased plasma leptin concentrations both in insulin-deficient and hyperinsulinemic diabetic patients, indicating a direct inhibitory effect of the amino acid but not of insulin or FFAs.

Adult↗

PubMed2002

Renal hemodynamic effects of somatostatin are not related to inhibition of endogenous insulin release.

BACKGROUND: Somatostatin inhibits endocrine and exocrine secretions and exerts renal vasoconstriction. The mechanism underlying somatostatin's vascular effects is unknown. Since insulin can cause vasodilation, we hypothesized that removal of basal insulin release by somatostatin may contribute to somatostatin-induced renal vasoconstriction. METHODS: The study was conducted in different protocols comprising forty-six healthy male volunteers. Randomized studies were performed to compare the effects of somatostatin alone (0.1 microg/kg/min) to the effects of somatostatin + low dose insulin (0.1 mU/kg/min), the effects of somatostatin + low dose insulin to the effects of somatostatin + high dose insulin (1.5 mU/kg/min), and the effects of insulin (1.5 mU/kg/min) + somatostatin. Renal plasma flow (RPF) and glomerular filtration rate (GFR) were measured with the para-aminohippurate (PAH) and the inulin clearance technique, respectively. Blood pressure and pulse rate were measured non-invasively. RESULTS: Somatostatin alone decreased GFR (-14 +/- 6%, P < 0.001) and RPF (-16 +/- 7%, P < 0.001) whereas systemic hemodynamics were unchanged. Preceding or concomitant infusion of insulin at high doses (insulin plasma concentration of 127 +/- 25 or 144 +/- 17 microU/mL) but not co-infusion with low dose insulin (insulin plasma concentration of 11 +/- 3 microU/mL) mitigated or reversed the vasoconstrictive actions of somatostatin on GFR and RPF. CONCLUSIONS: Somatostatin induces marked renal vasoconstriction and exogenous restoration of fasting insulin concentrations does not influence the renal vascular effects. Therefore, it is unlikely that somatostatin-induced vasoconstriction is due to removal of basal insulin. Plasma insulin concentrations in the high postprandial range can reverse somatostatin-induced renal vasoconstriction, suggesting functional antagonism.

Adult↗

PubMed2002

Thiazolidinediones influence plasma steroids of male obese Zucker rats.

Insulin sensitizing thiazolidinediones (TZDs) inhibit steroidogenic enzyme activities in vitro and affect plasma steroids in women with polycystic ovary syndrome. This study was to examine TZD action on circulating steroids in male genetically obese Zucker rats (fa/fa), which were treated with troglitazone or rosiglitazone (0.3% and 0.01% food admixture, respectively) and were compared to untreated obese and lean littermates. After 36 days of TZD administration, obesity- associated derangement of carbohydrate metabolism was ameliorated (e.g., insulin-stimulated glucose oxidation by isolated soleus muscle, nmol/g/h: lean controls, 1049 +/- 100; obese controls, 518 +/- 30; troglitazone-treated obese, 672 +/- 43; rosiglitazone-treated obese, 761 +/- 77; p < 0.01 each vs. obese controls). While plasma pregnenolone and testosterone were neither affected by obesity nor by TZDs, a marked reduction of 17-hydroxyprogesterone in obese vs. lean controls (27 +/- 3 vs. 58 +/- 10 ng/dl; p < 0.01) was partially reversed by TZD treatment (46 +/- 5 and 48 +/- 9 ng/dl for troglitazone and rosiglitazone, respectively; p < 0.02 each vs. untreated obese). Plasma 5-alpha-dihydrotestosterone, in contrast, was not reduced by obesity (76 +/- 9 vs. 59 +/- 7 ng/dl in obese vs. lean controls; n.s.) but blunted by TZD treatment of obese rats (38 +/- 4 and 44 +/- 3 ng/dl for troglitazone and rosiglitazone, respectively; p < 0.05 each vs. untreated obese). We conclude that (i) oral TZD treatment influences circulating steroid concentrations of male obese Zucker rats, and (ii) these effects are at least in part mediated via mechanisms other than those underlying TZD-induced insulin sensitization.

Animals↗

PubMed2002

Reduction of hepatic glycogen synthesis and breakdown in patients with agenesis of the dorsal pancreas.

In a family with agenesis of the dorsal pancreas only the mother presents with insulin-dependent diabetes mellitus, whereas her sons are glucose tolerant. We examined whether metabolic defects can be detected early in this disease. Plasma glucose profiles were obtained from patients with dorsal pancreas agenesis and from matched healthy subjects. Hepatic glycogen synthesis and breakdown were determined from the time course of glycogen concentrations using noninvasive (13)C nuclear magnetic resonance spectroscopy. Gluconeogenesis was calculated from the difference between glucose production (measured with D-[6,6-(2)H(2)]glucose) and glycogen breakdown. Frequently sampled iv glucose tolerance tests were performed to assess insulin secretion and sensitivity. The mean plasma glucose level was higher (12.9 +/- 0.4 vs. 5.9 +/- 0.1 mmol/liter), whereas the peak plasma insulin level was lower (236 vs. 397 +/- 23 pmol/liter) in the diabetic mother than in her nondiabetic sons and healthy subjects. In all patients, however, glycogen synthesis and breakdown were reduced by approximately 55% (P < 0.05) and 40% (P < 0.02), respectively. Gluconeogenesis (6.8 +/- 0.8 vs. 4.2 +/- 0.3 micro mol/kg.min; P < 0.05) and hepatic insulin clearance (6.8 +/- 1.3 vs. 2.8 +/- 1.0 ml/kg.min) were increased in all patients. In conclusion, patients with complete agenesis of the dorsal pancreas exhibit marked defects in hepatic glycogen metabolism, which are present even in the nondiabetic offspring.

Blood Glucose↗

PubMed2002

FFA-induced endothelial dysfunction can be corrected by vitamin C.

Insulin resistance is associated with an inappropriate elevation of plasma FFA and endothelial dysfunction. FFA could stimulate formation of reactive oxygen species, which could be responsible for vascular impairment. In this randomized, double-blind, cross-over study in 10 healthy volunteers (24 +/- 3 yr old), forearm blood flow (FBF) responses to intraarterial acetylcholine (ACh) and glyceryl trinitrate were assessed with coadministration of vitamin C (24 mg/ml) or placebo, respectively, in the presence of increased plasma FFA induced by Intralipid/heparin infusion. The rise in plasma FFA from 320 +/- 64 to 1852 +/- 232 micromol/liter was associated with a reduced response of FBF to ACh by 55% (P < 0.01). During coadministration of vitamin C, the impaired responsiveness of FBF to ACh was completely reversed and not different from that observed under baseline conditions. Vitamin C did not affect plasma FFA concentrations. Glyceryl trinitrate responsiveness was unchanged during FFA elevation, with or without vitamin C. These data suggest that FFA-induced vascular oxidative stress could contribute to endothelial dysfunction in insulin-resistant patients. High concentrations of antioxidants are able to reverse the local effects of FFA on endothelium-dependent vasodilation.

Acetylcholine↗

PubMed2002

Short-term leptin-dependent inhibition of hepatic gluconeogenesis is mediated by insulin receptor substrate-2.

Leptin has both insulin-like and insulin-antagonistic effects on glucose metabolism. To test whether leptin interferes directly with insulin signaling, we perfused isolated rat livers with leptin (0.1, 0.5, 5, and 25 nmol/liter), leptin + insulin (5 nmol/liter + 10 nmol/liter), insulin (10 nmol/liter), or vehicle (control). Leptin reduced L-lactate-(10 mmol/liter)-stimulated glucose production by 39-66% (P < 0.006 vs. control) and phosphoenolpyruvate carboxykinase (PEPCK) activity by 22-52% (P < 0.001). Physiological leptin concentrations (0.1-5 nmol/liter) stimulated the tyrosine phosphorylation (pY) of insulin receptor substrate-2 (IRS-2) (280-954%; P < 0.05) and its associated phosphatidylinositol-3 kinase activity (122-621%; P < 0.003). Leptin (0.5-25 nmol/liter) inhibited IRS-1 pY and its associated phosphatidylinositol-3 kinase activity (20-89%; P < 0.03) but stimulated janus kinase-2 pY (272-342%; P < 0.001). Leptin also down-regulated its short receptor isoform in a time- and concentration-dependent manner (28-54%; P < 0.05). Exposure to leptin + insulin additively reduced glucose production and PEPCK activity (approximately 50%; P < 0.001 vs. control) and doubled IRS-2 pY (P < 0.01 vs. insulin). However, leptin + insulin decreased IRS-1 pY by 57% (P < 0.01 vs. insulin). Insulin alone (P < 0.01), but not leptin, increased autophosphorylation of nonreceptor tyrosine kinases (pp59(Lyn) + pp125(Fak)). In conclusion, leptin both alone and in combination with insulin reduces hepatic glucose production by decreasing the synthesis of the key enzyme of gluconeogenesis, PEPCK, which results mainly from the stimulation of the IRS-2 pathway.

Animals↗

PubMed2002

Hepatic glycogen metabolism in type 1 diabetes after long-term near normoglycemia.

We tested the impact of long-term near normoglycemia (HbA(1c) <7% for >1 year) on glycogen metabolism in seven type 1 diabetic and seven matched nondiabetic subjects after a mixed meal. Glycemic profiles (6.2 +/- 0.10 vs. 5.9 +/- 0.07 mmol/l; P < 0.05) of diabetic patients were approximated to that of nondiabetic subjects by variable insulin infusion. Rates of hepatic glycogen synthesis and breakdown were calculated from the glycogen concentration time curves between 7:30 P.M. and 8:00 A.M. using in vivo (13)C nuclear magnetic resonance spectroscopy. Glucose production was determined with D-[6,6-(2)H(2)]glucose, and the hepatic uridine-diphosphate glucose pool was sampled with acetaminophen. Glycogen synthesis and breakdown as well as glucose production were identical in diabetic and healthy subjects: 7.3 +/- 0.9 vs. 7.1 +/- 0.7, 4.2 +/- 0.5 vs. 3.8 +/- 0.3, and 8.7 +/- 0.5 vs. 8.4 +/- 0.7 micromol x kg(-1) x min(-1), respectively. Although portal vein insulin concentrations were doubled, the flux through the indirect pathway of glycogen synthesis remained higher in type 1 diabetic subjects: approximately 70 vs. approximately 50%; P < 0.05. In conclusion, combined long- and short-term intensified insulin substitution normalizes rates of hepatic glycogen synthesis but not the contribution of gluconeogenesis to glycogen synthesis in type 1 diabetes.

Adult↗

PubMed2002

Effects of insulin treatment in type 2 diabetic patients on intracellular lipid content in liver and skeletal muscle.

Insulin resistance is frequently associated with increased lipid content in muscle and liver. Insulin excess stimulates tissue lipid accumulation. To examine the effects of insulin and improved glycemia on insulin sensitivity and intracellular lipids, we performed stepped (1, 2, and 4 mU x min(-1) x kg(-1)) hyperinsulinemic-euglycemic clamps in eight type 2 diabetic and six nondiabetic control subjects at baseline and after 12 and 67 h of insulin-mediated near-normoglycemia (118 +/- 7 mg/dl). Intrahepatocellular lipids (IHCLs) and intramyocellular lipids (IMCLs) of soleus (IMCL-S) and tibialis anterior muscle (IMCL-TA) were measured with (1)H nuclear magnetic resonance spectroscopy. At baseline, nondiabetic subjects had an approximate twofold higher insulin sensitivity (P < 0.02) and lower IHCLs than diabetic patients (5.8 +/- 1.2 vs. 18.3 +/- 4.2%, P < 0.03), in whom IMCL-TA negatively correlated with insulin sensitivity (r = -0.969, P < 0.001). After a 67-h insulin infusion in diabetic patients, IMCL-S and IHCLs were increased (P < 0.05) by approximately 36 and approximately 18%, respectively, and correlated positively with insulin sensitivity (IMCL-S: r = 0.982, P < 0.0005; IHCL: r = 0.865, P < 0.03), whereas fasting glucose production, measured with D-[6,6-(2)H(2)]glucose, decreased by approximately 10% (P < 0.04). In conclusion, these results indicate that IMCLs relate to insulin resistance in type 2 diabetic patients at baseline and that insulin-mediated near-normoglycemia for approximately 3 days reduces fasting glucose production but stimulates lipid accumulation in liver and muscle without affecting insulin sensitivity.

Aged↗

PubMed2002

Mechanism of amino acid-induced skeletal muscle insulin resistance in humans.

Plasma concentrations of amino acids are frequently elevated in insulin-resistant states, and a protein-enriched diet can impair glucose metabolism. This study examined effects of short-term plasma amino acid (AA) elevation on whole-body glucose disposal and cellular insulin action in skeletal muscle. Seven healthy men were studied for 5.5 h during euglycemic (5.5 mmol/l), hyperinsulinemic (430 pmol/l), fasting glucagon (65 ng/l), and growth hormone (0.4 microg/l) somatostatin clamp tests in the presence of low (approximately 1.6 mmol/l) and increased (approximately 4.6 mmol/l) plasma AA concentrations. Glucose turnover was measured with D-[6,6-(2)H(2)]glucose. Intramuscular concentrations of glycogen and glucose-6-phosphate (G6P) were monitored using (13)C and (31)P nuclear magnetic resonance spectroscopy, respectively. A approximately 2.1-fold elevation of plasma AAs reduced whole-body glucose disposal by 25% (P < 0.01). Rates of muscle glycogen synthesis decreased by 64% (180--315 min, 24 plus minus 3; control, 67 plus minus 10 micromol center dot l(-1) center dot min(-1); P < 0.01), which was accompanied by a reduction in G6P starting at 130 min (DeltaG6P(260--300 min), 18 plus minus 19; control, 103 plus minus 33 micromol/l; P < 0.05). In conclusion, plasma amino acid elevation induces skeletal muscle insulin resistance in humans by inhibition of glucose transport/phosphorylation, resulting in marked reduction of glycogen synthesis.

Adenosine Diphosphate↗