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Biomedical subjects

H Rasmussen

Publications and source records attributed to H Rasmussen.

At least 109 records · Page 6Linked to original sources
PubMed1990

Energy expenditure and subsequent nutrient intakes in overfed young men.

We investigated the mechanisms of body weight regulation in young men of normal body weight leading unrestricted lives. Changes in total and resting energy expenditure, body composition, and subsequent voluntary nutrient intakes in response to overeating by 4,230 +/- 115 (SE) kJ/day (1,011 +/- 27 kcal/day) for 21 days were measured in seven subjects consuming a typical diet. On average, 85-90% of the excess energy intake was deposited (with 87% of this amount in fat and 13% in protein on average). There was no detectable difference between individuals in susceptibility to energy deposition. The resting metabolic rate, averaged for fasting and fed states, increased during overfeeding (mean +/- SE, 628 +/- 197 kJ/day, P less than 0.01), but at least some of this amount was obligatory expenditure associated with nutrient assimilation. No significant increase in energy expenditure for physical activity or thermoregulation resulted from overfeeding. Thus energy expenditure did not substantially adapt to increased energy intake. However, significant decreases in voluntary energy intake (1,991 +/- 824 kJ/day, P less than 0.05) and fat intake (48 +/- 11 g/day, P less than 0.01) followed overeating, indicating that adaptive changes in nutrient intakes can contribute significantly to body weight regulation after overeating.

Adult↗
PubMed1990

Atrial natriuretic peptide differentially modulates T- and L-type calcium channels.

Atrial natriuretic peptide (ANP) inhibits the secretion of aldosterone stimulated by any of these major physiological agonists: angiotensin II, adrenocorticotropic hormone, or K+. The stimulatory actions of each of these agonists depend on calcium influx through voltage-dependent calcium channels. Because two types of calcium channels have been previously described in bovine glomerulosa cells (T- and L-type), the patch-clamp technique was used to evaluate the effect of ANP on each voltage-dependent calcium channel type. ANP was found to differentially modulate these two channel types, stimulating L-current while inhibiting T-current. Inhibition of T-current resulted from a shift in the voltage dependence of inactivation to more negative potentials within the physiological range. These results indicate that the ANP-induced inhibition of aldosterone secretion may be partially mediated via a reduction of the calcium current through T-type channels.

Adrenal Glands↗
PubMed1990

A potential role for phospholipase-D in the angiotensin-II-induced stimulation of aldosterone secretion from bovine adrenal glomerulosa cells.

The mechanism by which angiotensin-II (Ang II) stimulates aldosterone secretion from adrenal glomerulosa cells involves a phospholipase-C-mediated increase in phosphoinositide turnover and diacylglycerol (DAG) production. Because agonist-induced activation of phospholipase-D (PLD) also contributes to elevations in DAG in other cell types, the ability of Ang II to stimulate PLD activity in cultured bovine adrenal glomerulosa cells was examined. Ang II elicited significant increases in the levels of phosphatidic acid and, in the presence of ethanol, of phosphatidylethanol, a more specific marker for PLD activation. The potential role of this increased PLD activity in the regulation of aldosterone secretion was examined by investigating the ability of exogenous PLD to alter secretory rates. PLD alone dose-dependently increased aldosterone secretion from 5.9 +/- 0.5 to 135 +/- 48 pg/min.mg protein. In the presence of the calcium channel agonist Bay K 8644, which by itself had only a modest effect on aldosterone production, the stimulatory action of PLD was enhanced, yielding a secretory rate (442 +/- 119 pg/min.mg protein) that was approximately 60% of that elicited by 10 nM Ang II (763 +/- 182 pg/min.mg protein). Exogenous PLD also induced a significant increase in DAG levels (from 0.76 +/- 0.03 to 1.10 +/- 0.1 nmol/mg protein), which was not altered by the addition of Bay K 8644. However, PLD did not stimulate inositol phosphate production. These data indicate that 1) Ang II activates PLD; 2) exogenous PLD can elevate aldosterone secretory rates and DAG levels without eliciting phosphoinositide hydrolysis; and 3) the stimulatory action of exogenous PLD on aldosterone secretion is enhanced in the presence of Bay K 8644. Thus, PLD-induced DAG production may play an important role in the Ang II-mediated stimulation of aldosterone secretion from the adrenal zona glomerulosa.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1990

Calcium ion as intracellular messenger and cellular toxin.

Ca2+ serves a nearly universal intracellular messenger function in cell activation, but excess Ca2+ is also a cellular toxin. The possibility of Ca2+ intoxication is minimized by an elaborate autoregulatory system in which changes in Ca2+ influx rate across the plasma membrane are rapidly compensated for by parallel changes in Ca2+ efflux rate. By this mean, cellular Ca2+ homestasis is maintained so that minimal changes in total cell calcium and cytosolic Ca2+ concentration occur during sustained Ca2(+)-mediated responses. Rather than a sustained increase in cytosolic Ca2+ concentration, it is the localized cycling of Ca2+ across the plasma membrane that is the critically important Ca2+ messenger during the sustained phase of cellular responses mediated via surface receptors linked to the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2). PIP2 hydrolysis gives rise to inositol(1,4,5)trisphosphate (IP3) and diacylglycerol (DAG). The IP3 acts to release Ca2+ from an intracellular pool, thereby causing a transient rise in cytosolic Ca2+ concentration. This transient Ca2+ signal activates calmodulin-dependent protein kinases transiently, and hence, causes the transient phosphorylation of a subset of cellular proteins that mediate the initial phase of the response. The DAG brings about the association of protein kinase C (PKC) with the plasma membrane where a receptor-mediated increase in Ca2+ cycling across the membrane regulates PKC activity. The sustained phosphorylation of a second subset of proteins by PKC mediates the sustained phase of the response. Hence, Ca2+ serves as a messenger during both phases of the cellular response, but its cellular sites of action, its mechanisms of generation, and its molecular targets differ during the initial and sustained phases of the response.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Physiology and pathophysiology of insulin secretion.

Mechanisms by which various classes of extracellular signals regulate insulin secretion are discussed regarding their cellular and molecular actions. Under physiological circumstances, the small postprandial changes in plasma glucose concentrations (approximately 4.4-6.6 mM) primarily serve as a conditioned modifier of insulin secretion and dramatically alter the responsiveness of islets to a combination of neurohormonal agonists. These agonists have two functions. Cholecystokinin (CCK) and acetylcholine activate the hydrolysis of polyphosphoinositides, and gastric inhibitory polypeptide (GIP) and glucagonlike peptide 1 activate adenylate cyclase. These two functional classes of neurohumoral agonists act synergistically to enhance insulin secretion when plasma glucose is greater than 6.0 mM but not when it is less than or equal to 4 mM. On the other hand, an increase in plasma glucose concentration to 8-10 mM induces an increase in insulin secretory rate in the absence of any of the neurohormonal agonists. Remarkably, high glucose leads to an increase in the same intracellular signals, as does a combination of acetylcholine and GIP. On the basis of these data, a model of how insulin secretion is regulated under physiological circumstances is proposed. This model emphasizes that the regulation of insulin secretion occurs in three stages: cephalic, early enteric, and later enteric. In this view, the crucial event occurring during the first two phases is the agonist-induced, translocation of protein kinase C (PKC) to the plasma membrane under conditions in which an increase in Ca2+ influx does not occur. PKC is now in a cellular location and a Ca2(+)-sensitive conformation such that an increase in Ca2+ influx rate occurring during the third phase leads to its immediate activation and an enhanced rate of insulin secretion. Furthermore, under physiological circumstances, an optimal insulin secretory response is dependent on a correct temporal pattern of signals arising from neural and enteric sources. If this pattern is deranged, an abnormal pattern of insulin secretion is observed. An important new insight is provided by the observation that agonists (e.g., CCK or acetylcholine) that act to stimulate the hydrolysis of phosphatidylinositides, when acting for a short period (10-20 min), induce an enhanced responsiveness of islets to glucose, i.e., proemial sensitization. However, when acting unopposed for several hours, these agonists will induce a time-dependent suppression of responsiveness to glucose and other agonists. The latter observation implies that optimal insulin secretion is dependent on periodic rather than a continuous exposure to the correct pattern of extracellular signals.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1989

Interactions between lithium, inositol and mono-oleoylglycerol in the regulation of insulin secretion from isolated perifused rat islets.

In response to stimulation by 20 mM-glucose, 15 mM-4-methyl-2-oxopentanoate or 10 mM-glyceraldehyde, isolated perifused rat islets respond with brisk biphasic insulin-secretory responses. The inclusion of 10 mM-LiCl significantly decreased second-phase insulin release in response to all agonists. Inositol, at a concentration (10 mM) which has no effect on secretion in the presence of 2.75 mM-glucose, restored significantly glucose-, 4-methyl-2-oxopentanoate- or glyceraldehyde-induced second-phase release from Li+-treated islets. The addition of the diacylglycerol kinase inhibitor mono-oleoylglycerol, at a concentration (25 microM) which has no stimulatory effect on insulin secretion in the presence of 2.75 mM-glucose, significantly amplified both the first- and second-phase insulin responses to 20 mM-glucose. This amplifying effect of mono-oleoylglycerol was readily reversible and dependent on Ca2+ influx into the beta-cell. Li+ decreased the amplified insulin response to 20 mM-glucose plus mono-oleoylglycerol. Inositol restored release under this condition. These findings suggest that Li+ inhibits release by sequestering inositol into biosynthetically ineffective inositol phosphates. By limiting phosphoinositide resynthesis, the continued hydrolysis of phosphoinositides is diminished. Our results with mono-oleoylglycerol suggest further that diacylglycerol content may play a critically important role in the regulation of both the first and second phases of insulin secretion.

Animals↗
PubMed1989

The conditions under which rat islets are labelled with [3H]inositol alter the subsequent responses of these islets to a high glucose concentration.

Isolated rat islets were incubated with myo-[2-3H]inositol for 2 h to label their phosphoinositide (PI) pools. Labelling was carried out under three separate conditions: in media containing low (2.75 mM) glucose, high (13.75 mM) glucose, or low (2.75 mM) glucose plus sulphated cholecystokinin (CCK-8S; 200 nM). After labelling, the islets were perifused and the insulin-secretory response to 20 mM-glucose was measured. PI hydrolysis in these same islets was assessed by measurements of both [3H]inositol efflux and the accumulation of labelled inositol phosphates. The following major observations were made. After prelabelling for 2 h in low glucose, perifusion with 20 mM-glucose resulted in a biphasic insulin-secretory response, an increase in [3H]inositol efflux and a parallel increase in the accumulation of labelled inositol phosphates. After prelabelling in high (13.75 mM) glucose, peak first-phase insulin secretion induced by 20 mM-glucose increased 2-2.5-fold, whereas the second phase of insulin release, as well as [3H]inositol efflux and inositol phosphate accumulation, were significantly decreased. The simultaneous infusion of the diacylglycerol kinase inhibitor 1-mono-oleoylglycerol (50 microM), along with 20 mM-glucose, restored the second-phase insulin-secretory response from these islets. After labelling in low (2.75 mM) glucose plus CCK-8S, the initial phases of the insulin-secretory and [3H]inositol-efflux responses to 20 mM-glucose were blunted and the sustained phases of both responses were markedly decreased. Inositol phosphate accumulation was also impaired. Labelling islets in high (13.75 mM) glucose or low (2.75 mM) glucose plus CCK-8S suppresses, in a parallel fashion, glucose-induced increases in PI hydrolysis and in second-phase insulin release. These findings suggest that desensitization of the insulin-secretory response is a consequence of impaired information flow in the inositol lipid cycle.

Animals↗
PubMed1989

The effect of monooleoylglycerol on insulin secretion from isolated perifused rat islets.

The effect of monooleoylglycerol on cholecystokinin- and tolbutamide-induced insulin secretion was examined in isolated perifused rat islets. In the presence of 5.5 mmol/l glucose, addition of 10 nmol/l cholecystokinin or 50 mumol/l tolbutamide had practically no effect on insulin secretion. Combined tolbutamide and cholecystokinin led to a biphasic insulin secretory response which was significantly enhanced by addition of 50 mumol/l monooleoylglycerol, an inhibitor of diacylglycerol kinase. Monooleoylglycerol (50 mumol/l) alone had a minimal stimulatory effect on insulin release in the presence of 5.5 mmol/l glucose. Perifusion of islets with 1 mumol/l forskolin had no significant effect on basal insulin secretion in the presence of 5.5 mmol/l glucose, but markedly enhanced the responses to both cholecystokinin plus tolbutamide, and to the combination of cholecystokinin, tolbutamide and monooleoylglycerol. Lowering the glucose level to 2.75 mmol/l abolished the profound stimulatory effect to these agonist combinations on insulin release. Finally, monooleoylglycerol also enhanced the first and second phase insulin secretory responses induced by 20 mmol/l glucose. These results are discussed in relationship to the possible role of protein kinase C in mediating insulin secretion.

Animals↗
PubMed1989

Studies of the mitogenic effect of serotonin in rat renal mesangial cells.

A vasoactive inflammatory amine, serotonin, stimulates DNA synthesis in rat glomerular mesangial cells in a dose-dependent manner and acts synergistically with either insulin or epidermal growth factor (EGF). The combined effects of 10(-6) M serotonin and these peptide hormones are nearly equal to those induced by 10% fetal bovine serum. Serotonin stimulates the turnover of polyphosphoinositols resulting in a transient rise in intracellular free Ca2+ concentration, as measured either with the photoprotein aequorin, or with fura-2. This is accompanied by a transient increase in 45Ca2+ efflux from prelabeled cells. Serotonin also induces a prompt and sustained threefold increase in Ca2+ influx rate across the plasma membrane and a rapid and sustained twofold increase in cellular 1,2-diacylglycerol content. In addition, there is an increase in the extent of phosphorylation of an acidic 80-kDa protein, a putative substrate for protein kinase C. Activators of protein kinase C (including phorbol 12-myristate 13-acetate or 1,2-dioctanoylglycerol) mimic the mitogenic effect of serotonin. The effect of serotonin on cell proliferation is partially inhibited in a reversible manner by LiCl. Treatment of mesangial cells with insulin plus EGF for 60 min leads to a small but consistent increase in the content of inositol phosphates and 1,2-diacylglycerol. Their effects are additive to those of serotonin. Moreover, insulin and EGF significantly stimulate the phosphorylation of the 80-kDa protein, and potentiate the serotonin-induced phosphorylation of this protein.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Interleukin-1 alpha exerts glucose-dependent stimulatory and inhibitory effects on islet cell phosphoinositide hydrolysis and insulin secretion.

Isolated rat islets were incubated with myo-[2-3H]inositol to label their phosphoinositides (PI). Labeling was carried out in the presence of various glucose levels (2.75-10 mM) with or without human recombinant interleukin-1 alpha (IL-1). After the labeling period, insulin release, [3H]inositol efflux, and the accumulation of labeled inositol phosphates in perfused islets were assessed under various conditions. The following major observations were made. 1) In islets labeled for 2 h with [3H]inositol in the presence of 2.75 mM glucose, subsequent perifusion with 5.0 nM IL-1 increased insulin output, [3H]inositol efflux, and [3H]inositol phosphate accumulation in the simultaneous presence of 7 mM, but not 2.75 mM, glucose. 2) Mannoheptulose, a competitive inhibitor of islet glucokinase, blocked the stimulatory effects of IL-1 noted in the presence of 7 mM glucose. In other experiments, the conditions used during the 2-h labeling period with myo-[2-3H]inositol were varied. The following major observations were made in islets subsequently stimulated during the perifusion with 20 mM glucose. 3) Islets labeled with [3H]inositol in the presence of 2.75 mM glucose with or without 5.0 nM IL-1 responded with similar increases in PI hydrolysis and insulin output. 4) Compared to that with 2.75 mM glucose alone, labeling in the presence of 7 mM glucose alone was without any adverse effect on the subsequent PI and insulin responses of perifused islets to 20 mM glucose. 5) Labeling in the presence of 7 mM glucose plus 5.0 nM IL-1 resulted in a significant reduction in the subsequent PI and insulin responses. 6) These inhibitory effects of IL-1 were abolished if mannoheptulose was included during the 2-h incubation with 7 mM glucose plus 5.0 nM IL-1. 7) The diacylglycerol kinase inhibitor 1-monooleoylglycerol (100 microM) significantly restored insulin output after IL-1 exposure (with 7 mM glucose). 8) Similar to the results obtained with 7 mM glucose plus IL-1, incubation of islets with 8-10 mM glucose alone produced dose-dependent impairments of [3H]inositol efflux patterns and inositol phosphate accumulation. Insulin secretion was also impaired. These results demonstrate that IL-1 has glucose-dependent stimulatory and inhibitory effects on beta-cell function. Both effects appear to involve alterations in islet PI hydrolysis.

Animals↗
PubMed1989

Cholinergic agonists prime the beta-cell to glucose stimulation.

The ability of the cholinergic agonists carbachol or acetylcholine to stimulate insulin release, activate phosphoinositide hydrolysis, and prime the beta-cell to the insulin stimulatory effect of 7.5 mM glucose was assessed. In the presence of 7 mM glucose, but not 2.75 mM glucose, 1 mM carbachol evoked a sustained insulin secretory response. At both glucose levels, carbachol stimulated phosphoinositide hydrolysis, an event monitored in myo-[2-3H]inositol-prelabeled islets by increases in [3H]inositol efflux and labeled inositol phosphate accumulation. Prior exposure to carbachol (0.1-1 mM) resulted in a dose-dependent increase in the subsequent insulin secretory response to 7.5 mM glucose. This sensitization developed within 2 min and lasted for at least 45 min after carbachol removal from the perifusion medium. Carbachol pretreatment also sensitized the islet to either 200 microM tolbutamide or 10 mM arginine. Prior exposure to 1 mM acetylcholine induced a similar proemial sensitization to a subsequent challenge with glucose. These results demonstrate that even though cholinergic stimulation increases phosphoinositide hydrolysis, this event is insufficient to initiate sustained insulin secretion from islets exposed to a low (2.75 mM) glucose concentration. However, this increase in phosphoinositide hydrolysis sensitizes islets to a subsequent challenge with one of several different stimuli, including glucose. Hence, this sensitization of islets to physiologically relevant glucose concentrations may represent the major contribution of vagal stimulation to the regulation of insulin secretion.

Animals↗