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Biomedical subjects

E Cerasi

Publications and source records attributed to E Cerasi.

At least 73 records · Page 4Linked to original sources
PubMed1991

The ubiquitous glucose transporter GLUT-1 belongs to the glucose-regulated protein family of stress-inducible proteins.

In mammals, glucose transport is mediated by five structurally related glucose transporters that show a characteristic cell-specific expression. However, the rat brain/HepG2/erythrocyte-type glucose transporter GLUT-1 is expressed at low levels in most cells. The reason for this coexpression is not clear. GLUT-1 is negatively regulated by glucose. Another family of proteins, glucose-regulated proteins (GRPs), is also ubiquitously expressed and stimulated by glucose deprivation and other cellular stresses. We therefore hypothesized that GLUT-1 may be a glucose-regulated stress protein. This was tested by subjecting L8 myocytes and NIH 3T3 fibroblasts to glucose starvation or exposure to the calcium ionophore A23187, 2-mercaptoethanol, or tunicamycin, all known to increase GRP levels. The mRNA for GLUT-1 was augmented by 50-300% in a time-dependent manner, similarly to the changes in GRP-78 mRNA. Ex vivo incubation of rat soleus muscles induced a marked and concomitant rise in the mRNA levels of GLUT-1 and GRP-78. Finally, calcium ionophore A23187 and 2-mercaptoethanol induced a 2- to 3-fold increase in the levels of the GLUT-1 protein and hexose uptake. In all instances in which GRP-78 and GLUT-1 responded to stress, the transcription of the cell-specific muscle/adipocyte-type insulin-responsive glucose transporter (GLUT-4) did not change. Thus, despite the lack of structural similarity, GLUT-1 and GRP-78 expression is regulated similarly, whereas the regulation of GLUT-4, which is structurally related to GLUT-1, is different. We propose that GLUT-1 belongs to the GRP family of stress proteins and that its ubiquitous expression may serve a specific purpose during cellular stress.

Animals↗
PubMed1991

Insulin resistance, insulin deficiency, and non-insulin-dependent diabetes mellitus.

Recent information suggests that type 2 diabetes mellitus (NIDDM) is associated with severe insulin resistance, but other information suggests that there is a hypoinsulinemic state. To investigate the nature of the insulin resistance, 10 newly diagnosed, mildly obese type 2 diabetics and 11 long-standing type 2 diabetics with secondary failure to sulfonylureas were studied. Insulin was given by continuous subcutaneous infusion (CSII) for two weeks. CSII produced near-normoglycemia after 1-4 days in all patients with modest amounts of insulin (0.5-0.9 U/kg/24 h). These results demonstrate that whatever insulin resistance prevails in NIDDM, it does not prevent induction of normoglycemia by insulin. This suggests that either the insulin resistance is a secondary event caused by hyperglycaemia, or that NIDDM patients are hypoinsulinemic. In further studies in vitro, the effect of glucose on the rate of glycolytic glucose utilization by isolated rat soleus muscle and on hexose transport in rat skeletal myocyte line L8 were assessed. In the first case, an increase in glucose concentration led to a decrease in muscle glycolysis, and in the second case a hyperglycemic concentration of glucose led to a marked reduction in hexose transport, which was fully reversible within two hours. The clinical and in vitro results plus literature data suggest that insulin resistance can be overcome by insulin in NIDDM, and that beta-cell responsiveness to glucose is greatly reduced in NIDDM, but the defect is restricted to the acute stimulatory phase of glucose induction of insulin release. If this defect can be corrected, acute insulin release will occur so that NIDDM would be cured notwithstanding the existence of insulin resistance.

Animals↗
PubMed1991

Effect of 6 months' gliclazide treatment on insulin release and sensitivity to endogenous insulin in NIDDM: role of initial CSII-induced normoglycemia.

In 10 obese, newly diagnosed non-insulin-dependent diabetes mellitus (NIDDM) patients (group A) continuous subcutaneous insulin infusion (CSII) was used to induce normoglycemia over a period of 14 days. Fasting blood glucose was 4.61 +/- 0.22 mmol/l and mean daily blood glucose 5.83 +/- 0.27 mmol/l at the end of the CSII period. This excellent glycemic control was obtained with 35 +/- 4.8 U insulin per day, corresponding to 0.47 +/- 0.06 U/kg/24 h. Endogenous insulin production was markedly suppressed, since urinary C-peptide was reduced from 56 +/- 0.35 to 24 +/- 0.76 micrograms/24 h. Thus, physiological insulin replacement induced normoglycemia in NIDDM, indicating that insulin resistance is not clinically important. Gliclazide was given to group A following CSII and to 5 obese NIDDM patients (group B) in their habitual hyperglycemic state. Gliclazide maintained in group A and induced in group B excellent metabolic control. This was accompanied by the appearance of a small first-phase insulin response to iv glucose and by significant increases in the mean daily insulin to mean daily blood glucose ratio and in the 24-h urinary C-peptide to glucose ratio. The gliclazide effects tended to be more pronounced in group A. No significant effect was seen on sensitivity to endogenous insulin (slope of disappearance of blood glucose as function of insulin response to glucose infusion). During the 6 months of gliclazide treatment, excellent glycemic control was obtained in all patients. This was paralleled by unchanged stimulation by gliclazide of first-phase insulin response to glucose as well as mean by 48-h insulin to glucose and urinary C-peptide to glucose ratios. Again, sensitivity to endogenous insulin was not augmented. We conclude that gliclazide has a beta-cell-stimulating action which is maintained quantitatively unchanged for at least 6 months. The therapeutic effect of gliclazide in NIDDM seems to be mainly, if not exclusively, the result of its beta-cytotrophic action. Initial normoglycemia, induced here by CSII, may have a lasting enhancing effect on gliclazide action.

Blood Glucose↗
PubMed1991

Monolayer culture of adult rat pancreatic islets on extracellular matrix: modulation of B-cell function by chronic exposure to high glucose.

Studies in vivo indicate that chronic hyperglycemia is deleterious for insulin secretion. We have used an improved islet monolayer culture system to study chronic modulations of B-cell function. Adult rat islets maintained over several weeks on extracellular matrix in the presence of 11.1 mM glucose responded to an acute stimulation with 16.7 mM glucose by a 5- to 8-fold increase in insulin secretion. When cultured in the presence of higher glucose concentrations, the response to an acute glucose stimulus diminished time and dose dependently. In islets desensitized by exposure to 33.3 mM glucose for 1 week, reduction of the glucose level to 11.1 mM reversed the desensitization within 2 weeks. This desensitization was not limited to the glucose stimulus; responses to other nutrient secretagogues, such as glyceraldehyde and alpha-ketoisocaproic acid, were also reduced. In contrast, responses of insulin secretion to nonnutrient stimulators (tolbutamide and quinine) and amplifiers (isobutylmethylxanthine and carbachol) showed no desensitization in islets exposed to 33.3 mM glucose. Desensitization similar to that caused by 33.3 mM glucose could be induced by 11.1 mM glucose together with 0.1 mM isobutylmethylxanthine. High glucose also caused a time-dependent loss in compact monolayer organization with disruption of cell contacts. Our studies suggest that 1) generation of the reduced insulin response may be related to the prolonged high insulin secretion rate; 2) expression of the functional change is specific to the nutrient stimulus-secretion coupling; and 3) modifications in intercellular contacts may be involved in B-cell desensitization.

1-Methyl-3-isobutylxanthine↗
PubMed1990

Regulation of hexose transport in L8 myocytes by glucose: possible sites of interaction.

Previous work demonstrated that glucose controls its own transport rate in rat skeletal muscle: exposure to high glucose levels down-regulates muscle hexose transport, while glucose withdrawal results in elevated transport rates (J. Biol. Chem. 261:16827-16833, 1986). The present study investigates the mechanism of this autoregulatory system. Preincubation of L8 myocytes at 16 mM glucose reduced subsequent 2-deoxy-D-glucose (dGlc) uptake by 40% within 3 h. Cycloheximide (1 microM) mimicked the action of glucose; the effects of glucose and cycloheximide were not additive. At 50 microM, cycloheximide prevented the modulations of glucose transport induced by exposure of muscle cells to high or low glucose concentrations. Inhibition of glycosylation with tunicamycin A1 reduced the basal dGlc uptake, but did not prevent its up-regulation following glucose withdrawal. Inhibition of RNA synthesis by actinomycin D prevented the down-regulatory effect of glucose. These results indicate that continuous protein synthesis and protein glycosylation are required for the maintenance of the steady-state dGlc uptake. We suggest that glucose exerts its autoregulatory effect on hexose transport by modifying the incorporation of active glucose transporters into the plasma membrane rather than changing their rate of degradation. It is hypothesized that this effect is mediated by a non-glycosylated protein involved in the translocation or activation of glucose transporters.

Animals↗
PubMed1990

Regulation of insulin release in persistent hyperinsulinaemic hypoglycaemia of infancy studied in long-term culture of pancreatic tissue.

Pancreatic tissue was obtained during therapeutic subtotal pancreatectomy from five infants with persistent hyperinsulinaemic hypoglycaemia of infancy (so-called nesidioblastosis). Collagenase digests of the specimens were cultured in RPMI 1640 medium on extracellular matrix-coated plates. Acute insulin secretion showed minimal sensitivity to changes in glucose concentration. Sensitivity to other nutrient secretagogues such as glyceraldehyde, leucine, alpha-ketoisocaproic acid and arginine was variable, showing either diminished or absent response. On the other hand, stimulators of Beta cell cAMP and modulators of the phosphoinositide-protein kinase C pathway were effective inducers of insulin release. The response to cAMP stimulators was independent of the glucose concentration. Although insulin output was high in the absence of glucose, this was not due to passive leak of hormone, since both removal of calcium and addition of somatostatin and epinephrine inhibited the secretion. Beta cells were more sensitive to somatostatin than epinephrine; however, both agents failed to completely suppress the release even at suprapharmacological concentrations. Although it cannot be excluded that the culture conditions affected Beta cell function, the present findings may suggest that cultured Beta cells in persistent hyperinsulinaemic hypoglycaemia of infancy behave like fetal Beta cells at early developmental stages.

Cells, Cultured↗
PubMed1990

A glucose reduction challenge in the differential diagnosis of fasting hypoglycemia: a two-center study.

Investigation of patients with suspected or proven hypoglycemia is often a time-consuming and expensive process. We describe a glucose reduction challenge test which may be useful as an out-patient screening procedure. Insulin is infused for 3 h at 40 mU/kg.h. Plasma glucose was monitored at the bedside during the test, and blood samples were collected for measurement of C-peptide. Responses were examined in 17 normal controls, and 6 patients with insulinomas. In normal subjects, mean plasma glucose fell to a plateau value of 3.2 +/- 0.2 mmol/L (57 +/- 2.6 mg/dL) and remained at that level with few symptoms. In contrast, five of six patients with insulinomas developed severe hypoglycemia, with plasma glucose levels between 1.9 (34 mg/dL) and 2.2 mmol/L (39 mg/dL). Plasma C-peptide concentrations were suppressed to 0.08 pmol/mL or less in normal subjects, but in insulinoma patients remained at 0.32-1.6 pmol/mL i.e. outside the normal range, and diagnostic of nonsuppressible insulin secretion. These data demonstrate that moderate reduction of serum glucose maintained for a prolonged period results in marked suppression of plasma C-peptide, permitting improved discrimination between normal subjects and patients with insulinomas. This glucose reduction challenge can, therefore, be used as a test of glucose-regulating ability, where failure (hypoglycemia) per se represents a measurable abnormality. C-Peptide measurements will determine whether the cause of hypoglycemia is due to hyperinsulinemia.

Adult↗
PubMed1989

Failure of fenfluramine to affect basal and insulin-stimulated hexose transport in rat skeletal muscle.

Fenfluramine is an effective appetite suppressant that mediates its action via serotoninergic neurons. We studied the effect of pure d- and l-fenfluramine on in vitro hexose transport in isolated rat soleus muscles and skeletal muscle cells in culture. We found no evidence to suggest that the fenfluramine enantiomers affect the basal transport activity. Furthermore, the drugs did not interfere with the ability of glucose to regulate its own transport. Muscle responsiveness to insulin was not altered by the enantiomers, nor did insulin unmask any effect of fenfluramine on muscle hexose transport. These conclusions are based on experiments performed with a wide concentration range of drug and insulin, from the therapeutic to suprapharmacological levels. We discuss our results in view of published data on the effects of fenfluramine on peripheral glucose metabolism.

Animals↗
PubMed1989

Reduced early and late phase insulin response to glucose in isolated spiny mouse (Acomys cahirinus) islets: a defective link between glycolysis and adenylate cyclase.

The spiny mouse (Acomys cahirinus) exhibits low insulin responsiveness to glucose with a nearly absent early phase release. The alternative fuel-secretagogue glyceraldehyde (10 mmol/l) produced a maximal early insulin response in rat islets but failed to affect early response in Acomys; however, it potentiated the late insulin response in both species alike. Glucagon (1.5 mumol/l) potentiated the early insulin response to intermediate (8.3 mmol/l) glucose in rat and Acomys islets by two- and four-fold, respectively. Glucose doubled cyclic AMP levels in rat islets but no significant response was noted in Acomys islets. Isobutylmethylxanthine (0.1 mmol/l) and forskolin (25 mumol/l) caused a significant rise in islet cyclic AMP levels in both types of islets; however, neither agent restored the glucose stimulation of cyclic AMP in spiny mouse islets. Forskolin and isobutylmethylxanthine potentiated early and late phase insulin release in both species; however, neither augmented the early response in the Acomys to the degree observed in rat islets. Thus: (1) A deficient link exists in Acomys between glycolysis and subsequent signals. (2) These islets contain a glucose-insensitive adenylate cyclase. (3) The early insulin response may be potentiated by direct activation of adenylate cyclase. (4) The glucose effects on early and late phase insulin release are probably mediated by distinct pathways. (5) In the spiny mouse the signals mediating the early response are deranged to a greater extent than those activating the late phase insulin release.

1-Methyl-3-isobutylxanthine↗
PubMed1989

Beta-cell memory to insulin secretagogues: characterization of the time-dependent inhibitory control system in the isolated rat pancreas.

Most secretagogues, in addition to their acute stimulatory effect on insulin release, modify the responsiveness of the islet to subsequent stimulations. According to the nature and duration of the stimulus, the generated islet memory may either amplify [time-dependent potentiation, (TDP)] or diminish [time-dependent inhibition (TDI)] the responsiveness of the beta-cell. This work characterizes the kinetic parameters of TDI in the isolated rat pancreas. When subjected to a low dose (8.3 mmol/liter) glucose stimulus, maximal TDI was observed after 5 min of priming, while at a higher dose (16.7 mmol/liter) shorter exposures were sufficient. Longer periods of stimulation (10-40 min) resulted in the predominance of TDP, thus amplifying the release rate. TDI was not affected by previous generation of TDP; 40-min priming with 16.7 mmol/liter glucose markedly augmented the subsequent insulin responses to a pair of 6.9 mmol/liter stimuli, but the response to the second stimulus was inhibited, as in unprimed pancreas. Stimulation with arginine (5.0 mmol/liter) in the presence of basal (3.3 mmol/liter) glucose activated TDI only, and hence revealed monophasic insulin release. Tolbutamide (100 micrograms/ml), glucagon (5 micrograms/ml), and isobutylmethylxanthine (0.1 mmol/liter) also demonstrated TDI when given as a pair of 10-min stimuli; they all elicited monophasic insulin responses during prolonged stimulation. Arginine was chosen for detailed characterization of TDI because of its potency. Using identical concentrations of arginine for the generation and expression of TDI, a similar degree of inhibition (60-80%) was observed at all doses tested (0.5-5.0 mmol/liter). However, there existed competition between TDI and the acute secretory signal. Thus, TDI generated by 1.0 mmol/liter arginine had a minimal effect on insulin release induced by 2.0-5.0 mmol/liter amino acid, while it was fully inhibitory of the response to 1.0 mmol/liter arginine. Similarly, inhibition of the insulin response to 5.0 mmol/liter arginine was dependent on the dose (0.5-5.0 mmol/liter) of the priming pulse of arginine. The generation of TDI was unaffected by the insulin release rate during priming, since synergistic augmentation (combined arginine-glucose or arginine-isobutylmethylxanthine stimulation) or partial inhibition (arginine plus epinephrine) of the response had no effect on the subsequent expression of TDI. It is concluded that TDI and TDP are two distinct regulatory systems that independently control the rate of insulin release, most probably operating through different mechanisms.(ABSTRACT TRUNCATED AT 400 WORDS)

1-Methyl-3-isobutylxanthine↗
PubMed1988

Monolayer culture of adult rat pancreatic islets on extracellular matrix: long term maintenance of differentiated B-cell function.

Fragmented islets, obtained by mild overdigestion of the adult rat pancreas with collagenase, readily formed monolayer cultures on dishes coated with extracellular matrix derived from bovine corneal endothelial cells. Contaminating fibroblasts were removed by treatment with sodium ethylmercurithiosalicylate. The cultured islets remained functional for over 6 weeks in primary culture and up to 9 weeks in secondary culture, as indicated by their substantial insulin response to an acute glucose stimulus. Insulin secretion from islet monolayers showed biphasic kinetics. The functional competence of the monolayers was further evaluated by studying glucose-stimulated insulin release in the presence of various modulators of B-cell function. The response to physiological agents such as somatostatin, epinephrine, glucagon, and arginine was retained for at least 4 weeks in culture. The sensitivity to inhibition by somatostatin and epinephrine (ID50 = 10 ng/ml) and that to stimulation by glucagon (ED50 = 3 ng/ml) were similar to or better than those for freshly isolated islets. We have thus obtained a fibroblast-free monolayer culture of pancreatic islets from adult rats containing B-cells that retain normal function for long periods. This experimental system appears ideally suited for studying chronic modulations of islet cell function under controlled in vitro conditions, which can allow the stimulation of normal and diabetic environments.

1-Methyl-3-isobutylxanthine↗
PubMed1988

Immediate and time-dependent effects of glucose on insulin release: differential calcium requirements.

Glucose regulates insulin release in a complex manner; apart from its acute secretory action it induces time-dependent effects which modulate subsequent islet responses. The Ca2+ sensitivities of the diverse secretory events generated by glucose were investigated in the perfused rat pancreas. First- and second-phase insulin responses to 16.7 mmol/l glucose were obliterated in the presence of 5 mmol/l EgTA; threshold Ca2+ concentrations for significant responses were 0.25 mmol/l for second-phase, and 'O' (no Ca2+ added, approx 20 mumol/l) for first-phase release (both around 10% of control). The apparent Km of the Ca2+ dependencies were 0.6 mmol/l for first-phase, and 1.25 mmol/l for second-phase release. Time-dependent potentiation was demonstrated by subjecting the pancreas to two 40-min 16.7 mmol/l glucose stimuli separated by a 30-min rest period; this amplified the first-phase response to the second stimulus 2.5 +/- 0.9-fold. Also the generation of potentiation was Ca2+ dependent, with characteristics similar to those of the acute second-phase insulin response (apparent Km approximately 1.0 mmol/l Ca2+). In contrast, the amplified first-phase response to the second glucose pulse retained its high sensitivity to Ca2+, thus resembling the unprimed first-phase. The inhibitory message of glucose was demonstrated by applying two sequential 5-min pulses of 8.3 mmol/l glucose: the insulin response to the second stimulus was reduced by 43 +/- 9%. Addition of EgTA to the first glucose pulse had no effect on the inhibition of the second insulin response. Thus: 1. Despite its high sensitivity to Ca2+, also first-phase release is fully dependent on extracellular Ca2+.2.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Improved beta-cell function after intensive insulin treatment in severe non-insulin-dependent diabetes.

In Type II, non-insulin-dependent diabetes, insulin secretion is often reduced to the point where oral hypoglycaemic agents fail to control the plasma glucose level. We studied 12 patients (age 41-66 years; 4 lean, 8 obese) with Type II diabetes mellitus for 1-25 years who were uncontrolled despite maximal dose glibenclamide and metformin. After withdrawal of medication, blood glucose control was determined by measuring glucose before and 2 h after each meal for 48 h, and beta-cell function by insulin or C-peptide response to glucagon and to iv glucose. Following these tests, intensive insulin treatment (CSII) was initiated, and near-euglycaemia (mean of 7 daily glucose determinations less than 7.7 mmol/l) was maintained for 16.6 +/- 1.5 days, at which time the tests were repeated. Mean daily insulin requirement was 61 +/- 9 IU (0.81 +/- 0.09 IU/kg). Glucose control was improved after cessation of CSII (mean glucose 12.7 +/- 0.6 mmol/l after vs 20 +/- 1.5 mmol/l before, P less than 0.005). Maximum incremental C-peptide response improved both to glucagon (214 +/- 32 after vs 134 +/- 48 pmol/l before, P = 0.05) and to glucose iv bolus injection (284 +/- 53 vs 113 +/- 32 pmol/l, P less than 0.05). Peak insulin response, measured after iv glucose infusion, also tended to be higher in the post-CSII test (42 +/- 18 vs 22 +/- 5.6 mU/l). Basal and stimulated proinsulin concentrations were high relative to C-peptide levels during the pre-treatment period, but returned to normal after CSII.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Insulin deficiency and insulin resistance in type 2 (non-insulin-dependent) diabetes: quantitative contributions of pancreatic and peripheral responses to glucose homeostasis.

A non-steady state dose-response study was designed to quantitate peripheral sensitivity to insulin and pancreatic responsiveness to glucose, and to assess their relative contribution to glucose intolerance in Type 2 diabetes (Type 2 DM, non-insulin-dependent). Eleven lean and eleven obese patients with mild diabetes (fasting plasma glucose, FPG, 10.3 +/- 1.0 and 9.4 +/- 0.6 mmol l-1, respectively) were examined; twenty-six lean and twelve weight-matched obese subjects served as controls. Pancreatic response was measured by sequential injection of 0.1, 0.3 and 0.9 g kg-1 glucose; peripheral sensitivity to insulin was determined from the rate of clearance (Kgluc) of 0.3 g glucose injected sequentially together with 25, 50 and 100 mU insulin kg-1 or with 0, 12.5 and 50 mU kg-1, under somatostatin infusion. The mean dose-response curve describing glucose-induced insulin release showed increased maximal capacity to secrete insulin in obese controls, while the responses of lean as well as obese Type 2 DM were reduced by more than 80%. The mean dose-response curves relating plasma exogenous insulin levels to Kgluc were similar in lean diabetics and lean controls. The curves of both obese controls and obese diabetics were shifted to the right, demonstrating similar insulin resistance. In four lean controls, sensitivity to insulin was tested also during a hyperglycemic clamp set at 10.3 +/- 0.6 mmol l-1. Hyperglycemia reduced the Kgluc at all insulin levels. Individual dose-response curves were transformed to single weighted numerical pancreatic responsiveness scores [PRS], and peripheral sensitivity scores [PSS].(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Biphasic insulin release as the expression of combined inhibitory and potentiating effects of glucose.

The dynamics of insulin release were investigated in vitro in order to determine the regulatory processes governing its biphasic shape. When subjected to a square wave glucose stimulation, the isolated perfused rat pancreas responded with typical biphasic insulin release. Both the duration of the nadir between the two phases and the slope of recovery of insulin release during second-phase secretion exhibited glucose dose dependency. Successive 40-min stimuli with glucose (8.3 and 16.7 mM), separated by a 20-min rest period, resulted in 2.6- 3.3-fold potentiation of the early phase insulin release rate, previously described as glucose-primed time-dependent potentiation (TDP) of insulin secretion. A linear relationship (r = 0.89, P less than 0.001) was observed between the degree of TDP and the slope of second-phase insulin release. Successive short stimuli with glucose (5-10 min long, 5-10 min apart; 6.9, 8.3, and 16.7 mM) resulted in the inhibition of the response to the second stimulus; this effect was termed time-dependent inhibition (TDI) of insulin release. Arginine also induced TDI; this was completely overcome by synergistic interaction with glucose (8.3 mM). The glucose-arginine interaction was utilized to demonstrate that the interphasic nadir of insulin release was the expression of TDI. Thus, introduction of an arginine stimulus during the nadir in glucose-induced insulin release abolished the silent phase, the secretion rate reaching the level expected for the combined glucose-arginine stimulus. However, the continued presence of TDI could be demonstrated by removal of the arginine stimulus, at which time, despite ongoing glucose stimulation, insulin secretion was markedly inhibited. These observations support the concept that the biphasic dynamics of insulin release is the net expression of three regulatory processes: 1) the acute stimulus-secretion coupling system, best observed as the immediate, first-phase response to a stimulus; 2) TDI of insulin release, a relatively rapid signal responsible for the silent period; and 3) TDP of insulin release, a slow rising signal responsible for recovery from the silent phase, building up the second-phase of secretion.

Animals↗
PubMed1987

Somatostatin impairs clearance of exogenous insulin in humans.

Somatostatin has been widely used to suppress endogenous pancreatic hormone secretion in research studies. Many of these studies required the simultaneous infusion of a hormone together with somatostatin. A critical assumption for its use in metabolic investigation is that somatostatin has no effect on the action or clearance of a concomitantly infused hormone. To test whether clearance of an exogenously infused hormone is affected, we infused insulin with or without somatostatin in two sets of studies. Insulin (40 mU X kg-1 X h-1) was infused for 100 min (n = 6). Plasma glucose levels fell to 55 +/- 4.1 mg/dl with insulin alone and significantly lower, to 44 +/- 1.9 mg/dl, when somatostatin (250 micrograms/h) was also infused (P less than .01). Plasma immunoreactive insulin (IRI) rose to 57 +/- 12.5 microU/ml with insulin alone, which was significantly different from 88 +/- 15 microU/ml when insulin was infused together with somatostatin (P less than .01). When a smaller dose of insulin (30 mU X kg-1 X h-1) was infused for 100 min (n = 4), similar results were observed. When somatostatin was infused together with insulin, plasma glucose fell to lower levels (41 +/- 4.2 vs. 62 +/- 9.5 mg/dl; P less than .01) and plasma IRI rose higher (39 +/- 8.5 vs. 27 +/- 5.9 microU/ml; P less than .01) than when insulin was infused alone. C-peptide was equally suppressed by hypoglycemia regardless of whether somatostatin was administered, indicating suppression of endogenous insulin during these studies. We conclude that somatostatin infusion impairs the clearance of exogenous insulin.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Glucose↗
PubMed1987

In vitro autoregulation of glucose utilization in rat soleus muscle.

The possibility that glucose may directly regulate its rate of utilization in skeletal muscle was investigated in vitro with the rat soleus muscle. Preincubation of the muscles with varying glucose concentrations modulated the rate of glucose utilization through the glycolytic pathway during a subsequent incubation. At glucose concentrations below approximately 3.0 mM, utilization was maximal (26.8 +/- 2.4 and 87.5 +/- 4.8 nmol X g-1 X min-1 when assayed in the presence of 0.5 and 5.0 mM glucose, respectively). Preincubation with higher glucose concentrations (up to 20 mM) reduced the utilization by 40-60% in a biphasic manner: a rapid fall between 1 and 4 mM, followed by a gradual approximately 2% decrease per each millimolar increase of glucose. The effect of preexposure to glucose was not due to substrate dilution by the remaining glucose in the extracellular or intracellular space of the muscle. The uptake of the nonmetabolizable glucose analogues 3-O-methylglucose and 2-deoxyglucose was also modulated by extracellular glucose in a similar manner. Thus, the regulatory site seems to reside in the transport function of the hexose. The ATP content was very similar in muscles preexposed to 1.0 and 15.0 mM glucose for 3 h and therefore does not seem to be the mediator of the glucose effect. This substrate regulation of the rate of glucose transport and of the glycolytic flux may be operative in the in vivo glucose homeostatic system and may contribute to the reduced peripheral glucose utilization observed in diabetes.

3-O-Methylglucose↗