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Biomedical subjects

R S Sherwin

Publications and source records attributed to R S Sherwin.

At least 73 records · Page 4Linked to original sources
PubMed1995

Local ventromedial hypothalamus glucopenia triggers counterregulatory hormone release.

To test the hypothesis that nuclei of the ventromedial hypothalamus (VMH) play a key role in the detection of counterregulatory responses to hypoglycemia, we delivered the glucopenic agent 2-deoxyglucose via bilaterally placed microdialysis probes into the VMH of conscious, chronically catheterized rats. The goal was to produce cellular glucopenia localized to the VMH. The volume of brain tissue exposed to 2-deoxyglucose was determined by adding [3H]2-deoxyglucose to the dialysate; its distribution in cerebral tissue was almost exclusively limited to the VMH. Rats with microdialysis probes placed into the frontal lobes served as a control group. Local perfusion of 2-deoxyglucose (but not glucose) into the VMH caused a prompt twofold increase in plasma glucose in association with a striking elevation of plasma glucagon (3.5-fold), epinephrine (30-fold), and norepinephrine (3.5-fold). No effect was seen when 2-deoxyglucose was delivered into the frontal lobes. We conclude that glucopenia localized to the VMH triggers the release of counterregulatory hormones that defend against hypoglycemia. Thus, the neurons that sense glucopenia may be situated in the VMH.

Animals↗
PubMed1995

Brainstem dysfunction is provoked by a less pronounced hypoglycemic stimulus in diabetic BB rats.

Recent studies suggest that moderate hypoglycemia impairs brainstem function in normal humans and rats. To examine whether diabetes alters this response, simultaneous auditory-evoked potentials were recorded directly from the inferior colliculus (IC) and from the brainstem before and after controlled hypoglycemia (clamp) in awake insulin-dependent diabetic BB/Wor rats. Hyperglycemic diabetic animals were studied either during hyperinsulinemic euglycemia (5.6 mmol/l, n = 4) or mild hypoglycemia (3.5 mmol/l, n = 9). Nondiabetic controls were also studied at 3.5 mmol/l (n = 7) and at 2.8 mmol/l (n = 6). Brainstem function was not affected during euglycemia in diabetic rats. However, when plasma glucose was lowered to 3.5 mmol/l, the diabetic rats showed a 10% delay in IC evoked potential (ICEP) latency, whereas nondiabetic animals did not. This occurred despite similar counterregulatory hormones in both groups. The brainstem auditory-evoked potential (BAEP) localized the defect in the diabetic group to an area in or near the IC. When glucose levels were lowered to 2.8 mmol/l, however, brain function was impaired in nondiabetic rats as well. Again the defect was restricted to an area in or near the IC. We conclude that mild hypoglycemia causes a functional impairment in the IC region of the brainstem in both nondiabetic and diabetic rats. However, in the diabetic rats, this alteration occurs after a less pronounced hypoglycemic stimulus. Our findings suggest that chronic hyperglycemia leads to metabolic adaptions that render the diabetic brain more susceptible to mild hypoglycemia.

Animals↗
PubMed1994

Moderate hypoglycemia impairs the function of the inferior colliculus in the awake rat.

To assess the effect of acute hypoglycemia on the brain stem auditory pathway, we implanted electrodes into the inferior colliculus (IC) and subsequently recorded auditory-evoked potentials from the IC (ICEP) and brain stem (BAEP) in normal awake rats during euglycemic and hypoglycemic hyperinsulinemia (2 hours). Latencies of the ICEP and peak V of the BAEP were significantly prolonged by hypoglycemia (approximately 2.7 mmol/L). The change in the BAEP was principally between peak III and peak V. suggesting an effect in or near the IC. ICEP and BAEP latencies did not change during euglycemic hyperinsulinemia. We conclude that the function of the IC is very sensitive to episodes of moderate hypoglycemia. These data provide direct evidence that the scope of adverse central nervous system effects resulting from hypoglycemia extends beyond cognitive centers to include the brain stem.

Acute Disease↗
PubMed1994

Effects of puberty and diabetes on metabolism of insulin-sensitive fuels.

Insulin's ability to stimulate glucose metabolism is reduced during normal puberty; these changes are exaggerated in adolescents with insulin-dependent diabetes mellitus (IDDM). Because the effects of puberty and IDDM on the other actions of insulin have not been established, we studied leucine kinetics (using [1-13C]leucine) and fat metabolism during euglycemic hyperinsulinemia (20 mU.m2.min-1) for 3 h in eight healthy and nine IDDM (HbA1 14 +/- 2%) adolescents and six healthy young adult controls. IDDM subjects received overnight low-dose insulin infusion to normalize fasting glucose. Basal and steady-state insulin values (approximately 240 pM) during the study were similar in all three groups. Insulin-stimulated glucose metabolism was reduced by 40% in healthy adolescents vs. adults (P < 0.05) and by an additional 40% in poorly controlled IDDM (P < 0.05 vs, normal adolescents). Although basal glucose and lipid oxidation rates (measured by indirect calorimetry) were similar in all three groups, when insulin was infused, glucose oxidation increased and lipid oxidation decreased only in the two nondiabetic groups. Similarly, insulin significantly reduced plasma free fatty acid levels only in the nondiabetics. Basal leucine flux (an index of protein degradation) was similar in healthy controls but was markedly increased in IDDM adolescents. Despite similar increments in plasma insulin during the clamp, leucine flux remained higher in IDDM adolescents than in healthy controls. Basal leucine oxidation rates were also increased in IDDM subjects compared with nondiabetic groups and declined to a lesser extent during insulin infusion. We conclude that insulin resistance of puberty is selective for glucose metabolism, sparing amino acid/protein metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1994

Metabolic effects of insulin-like growth factor I in normal humans.

Since the development of recombinant DNA technology, there has been a rapid expansion of interest in the use of human insulin-like growth factor I (IGF-I) synthesized by recombinant DNA technology for the treatment of clinical disorders. This article reviews recent studies of the metabolic effects of recombinant human IGF-I in normal humans. These studies demonstrated that under euglycemic conditions, IGF-I had potent effects on glucose (hepatic and peripheral), lipid and amino acid metabolism that closely resemble those of insulin, despite a concomitant inhibitory effect on insulin secretion. Hypoglycemia produced by IGF-I infusions (free-fall study and glucose clamps) had a different effect on counterregulatory responses compared with insulin. The glucagon response was absent, growth hormone (GH) release was attenuated, while norepinephrine levels were increased. Suppression of glucagon release during hypoglycemia impaired glucose recovery. Paradoxically, awareness of hypoglycemia was enhanced with IGF-I, partly due to stimulation of sympathetic activity. Studies performed under hyperglycemic conditions showed that IGF-I inhibited glucose-stimulated insulin secretion, but that this inhibitory effect was partially overcome by increasing the hyperglycemic stimulus. Moreover, despite the decrease in insulin secretion, glucose disposal was accelerated by IGF-I. These observations imply that IGF-I might be effective in human diabetes. In particular, normalization of the decreased basal IGF-I levels, which are characteristic of poorly controlled patients with insulin-dependent diabetes mellitus (IDDM), in pubertal patients might lower glucagon and GH levels and improve cellular metabolism in muscle.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Comparison of the metabolic effects of recombinant human insulin-like growth factor-I and insulin. Dose-response relationships in healthy young and middle-aged adults.

The actions of recombinant human insulin-like growth factor-I (rhIGF-I) and insulin were compared in 21 healthy young (24 +/- 1 yr) and 14 healthy middle-aged (48 +/- 2 yr) subjects during 3-h paired euglycemic clamp studies using one of three doses (rhIGF-I 0.2, 0.4, and 0.8 micrograms/kg.min and insulin 0.2, 0.4, and 0.8 mU/kg.min, doses chosen to produce equivalent increases in glucose uptake). In younger subjects, rhIGF-I infusions suppressed insulin by 19-33%, C-peptide by 47-59% and glucagon by 33-47% (all, P < 0.02). The suppression of C-peptide was less pronounced with insulin than with rhIGF-I (P < 0.007). The metabolic responses to rhIGF-I and insulin were remarkably similar: not only did both hormones increase glucose uptake and oxidation in a nearly identical fashion, but they also produced similar suppression of glucose production, free fatty acid levels, and fat oxidation rates. In contrast, rhIGF-I had a more pronounced amino acid-lowering effect than did insulin (P < 0.004). In middle-aged subjects, basal IGF-I levels were 44% lower (P < 0.0001) whereas basal insulin and C-peptide were 20-25% higher than in younger subjects. Age did not alter the response to rhIGF-I. However, insulin-induced stimulation of glucose uptake was blunted in older subjects (P = 0.05). Our data suggest that absolute IGF-I and relative insulin deficiency contribute to adverse metabolic changes seen in middle age.

Adult↗
PubMed1994

Ventromedial hypothalamic lesions in rats suppress counterregulatory responses to hypoglycemia.

The central nervous system has been implicated in the activation of counterregulatory hormone release during hypoglycemia. However, the precise loci involved are not established. To determine the role of the ventromedial hypoglycemia, we performed hypoglycemic clamp studies in conscious Sprague-Dawley rats with bilateral VMH lesions produced by local ibotenic acid injection 2 wk earlier. Rats with lesions in the lateral hypothalamic area, frontal lobe, sham operated (stereotaxic needle placement into hypothalamus without injection), and naive animals served as control groups. The clamp study had two phases. For the first hour plasma glucose was fixed by a variable glucose infusion at euglycemia (approximately 5.9 mM). Thereafter, for an additional 90 min, glucose was either allowed to fall to (a) mild hypoglycemia (approximately 3.0 mM) or (b) more severe hypoglycemia (approximately 2.5 mM). Glucagon and catecholamine responses of lateral hypothalamic area-, frontal lobe-lesioned, sham operated, and naive animals were virtually identical at each hypoglycemic plateau. In contrast, glucagon, epinephrine, and norepinephrine responses in the VMH-lesioned rats were markedly inhibited; hormones were diminished by 50-60% during mild and by 75-80% during severe hypoglycemia as compared with the other groups. We conclude that the VMH plays a crucial role in triggering the release of glucagon and catecholamines during hypoglycemia.

Animals↗
PubMed1994

Glucocorticoids antagonize insulin's antiproteolytic action on skeletal muscle in humans.

Although chronic glucocorticoid elevations cause net skeletal muscle protein loss in man, the kinetic mechanisms responsible for this catabolic effect and the capacity of insulin to overcome it remain unclear. To examine this issue, we measured basal and insulin-stimulated rates of protein synthesis and breakdown in muscle using the phenylalanine forearm kinetic method in eight normal volunteers studied postabsorptively and after 4 days of dexamethasone treatment (8 mg/day). To avoid the confounding effects of systemic insulinization, local forearm insulin levels were raised by approximately 430 pmol/L using a 150-min brachial arterial infusion of insulin (0.251 pmol/kg.min). Postabsorptively, dexamethasone produced mild hyperglycemia (P < 0.003) and a 3-fold rise in plasma insulin (P < 0.001), but no change in forearm phenylalanine balance or kinetics. Before dexamethasone treatment, local hyperinsulinemia increased forearm glucose uptake 2.5-fold and caused a positive net balance of phenylalanine due to a marked 40% inhibition of proteolysis. After dexamethasone treatment, forearm glucose uptake was modestly reduced. However, forearm net phenylalanine balance remained negative due to a striking reduction in insulin's inhibitory effect on proteolysis. We conclude that 1) the effects of glucocorticoid on basal muscle protein turnover are minimized by compensatory hyperinsulinemia, and 2) glucocorticoids cause muscle resistance to insulin's antiproteolytic action.

Adolescent↗
PubMed1993

Effect of caffeine on the recognition of and responses to hypoglycemia in humans.

OBJECTIVE: To determine whether two effects of acute caffeine ingestion--decrease in cerebral blood flow and increase in brain glucose use--alter the recognition of and physiologic responses to hypoglycemia. DESIGN: On two occasions, a hyperinsulinemic glucose clamp technique (2 mU/kg body weight per minute) was used to maintain plasma glucose at 5 mmol/L for 90 minutes, followed by 60 minutes at 3.8 mmol/L, and then 2.8 mmol/L. After 30 minutes at 5 mmol/L, participants consumed, using a randomized, double-blind design, caffeine-free cola with or without caffeine (400 mg) added. SETTING: Yale Clinical Research Center. PARTICIPANTS: Eight healthy, nonobese volunteers (5 men; age range, 20 to 33 years). MEASUREMENTS: Middle cerebral artery velocity (V MCA), counter-regulatory hormone levels, hypoglycemic symptoms, and cognitive function (P300 evoked potentials). RESULTS: Caffeine caused an immediate and sustained 23% decrease in VMCA from 64 to 49 cm/s (point estimate of difference, +15 cm/s [95% CI, 10 to 21 cm/s], P < 0.001). At a glucose level of 3.8 mmol/L, only the participants given caffeine had warning symptoms and "felt hypoglycemic." Moreover, the level of epinephrine was 118% ([CI of point difference, 76% to 158%] [CI, P < 0.001]) higher after caffeine consumption compared with placebo. Similarly, levels of norepinephrine (41% [CI, 26% to 60%], P < 0.002), cortisol (65% [CI, 26% to 78%], P < 0.008), and growth hormone (60% [CI, 16% to 143%], P < 0.05) were higher after caffeine consumption compared with placebo. At 2.8 mmol/L, epinephrine (40% [point estimate of the percentage difference], P < 0.05), norepinephrine (27%, P < 0.05), and cortisol (24%, P < 0.05) levels were higher, participants were more aware (P < 0.02) of hypoglycemia, and P300 latency was prolonged in the group that consumed caffeine (7.2%, P < 0.05). CONCLUSIONS: Acute ingestion of caffeine is associated with sympathoadrenal activation and awareness of hypoglycemia at a glucose level not usually considered hypoglycemic. Our data suggest that individuals who ingest moderate amounts of caffeine may develop hypoglycemic symptoms if plasma glucose levels fall into the "low-normal" range, as might occur in the late postprandial period after ingestion of a large carbohydrate load.

Adult↗
PubMed1993

Type 1 diabetes mellitus: an imbalance between effector and regulatory T cells?

Abundant evidence now exists that autoimmunity plays a critical role in the pathogenesis of type 1 (insulin-dependent) diabetes mellitus. The non-obese diabetic (NOD) mouse is an extensively studied animal model of this T-cell-mediated autoimmune disease. Our laboratory has focused on isolating diabetogenic T cell clones from NOD mice as a means of elucidating the pathogenesis of type 1 diabetes. This experimental approach presupposes that type 1 diabetes in NOD mice results from the action of islet-reactive T cells that are not present in other mouse strains; the diabetogenic T cells would therefore represent "forbidden clones" which exist in NOD mice as a result of a failure of clonal deletion. While the inappropriate presence of diabetogenic T cells probably plays a central role in murine diabetes, it cannot explain all aspects of the disease. Type 1 diabetes is a chronic disorder with a lengthy preclinical stage; if the diabetogenic T cells acted in an unopposed fashion, one might expect to see a much more fulminant clinical course. This observation suggests that regulatory influences are likely to exist in this disease--a possibility supported by recent experimental data. If these regulatory influences could be identified and enhanced, specific immunotherapy for type 1 diabetes could be achieved.

Animals↗
PubMed1993

Gender influences counterregulatory hormone responses to hypoglycemia.

It has been generally assumed that counterregulatory hormone responses to hypoglycemia are not influenced by gender. To test this assumption, we analyzed three separate hypoglycemic insulin clamp studies in age-matched, healthy, non-obese females (n = 33) and males (n = 37). In one study (12 females, 17 males), plasma glucose level was rapidly decreased to about 57 mg/dL for 100 minutes with a 0.65-mU/kg/min insulin infusion. Despite an identical decrease in glucose level, the increase in epinephrine (361 +/- 64 v 188 +/- 38 pg/mL, P < .05), norepinephrine (132 +/- 28 v 47 +/- 19 pg/mL, P < .01), and growth hormone ([GH] 16.0 +/- 3.8 v 4.9 +/- 1.9 ng/mL, P < .05) levels, but not glucagon or cortisol levels, were significantly greater in males than in females, respectively. In the second study (10 females, eight males), a 5.0-mU/kg/min insulin infusion was used to decrease glucose levels to 55 mg/dL for 180 minutes. Epinephrine (P < .05) and GH (P < .01) responses were greater in males than in females. In a third study (11 females, 12 males), plasma glucose level was gradually decreased to about 50 mg/dL over 240 minutes. Again epinephrine (P < .01), norepinephrine (P < .01), GH (P < .05), and cortisol (P < .01) responses were nearly twofold greater in males (P < .01). Multivariate analysis of all 70 subjects identified gender as the most significant factor contributing to the epinephrine (P < .001) and norepinephrine (P < .005) responses, and also as a significant contributor to the GH response (P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Influence of counterregulatory hormones, independently of hypoglycaemia, on cognitive function, warning symptoms and glucose kinetics.

1. To assess the influence of counterregulatory hormones, independently of neuroglycopaenia, on higher cerebral (cognitive) function, 'hypoglycaemic' warning symptoms and glucose kinetics, 10 healthy subjects participated in two hyperinsulinaemic (2 m-units min-1 kg-1) glucose clamp studies. After 100 min of euglycaemia (plasma glucose level 5 mmol/l), the plasma glucose level was either (a) maintained at 5 mmol/l for 120 min by glucose infusion with concomitant replacement of counterregulatory hormones (continuous infusions of glucagon, adrenaline, noradrenaline, cortisol and growth hormone) to mimic the hormonal milieu normally associated with hypoglycaemia (hormone infusion study) or (b) lowered to 2.8 mmol/l for 120 min (hypoglycaemia study). Assessments were made of cognitive function (P300 auditory evoked responses), symptoms (visual analogue scales) and glucose kinetics (3-[3H]glucose). 2. Hypoglycaemia was associated with an increase in all symptoms (facial flushing, palpitations, tingling, trembling, sweating, hunger, light-headedness and sleepiness, P < 0.01) and all subjects were aware that blood glucose levels had fallen. P300 evoked potential latency increased from 280 +/- 6 to 312 +/- 5 ms (mean +/- SEM, P < 0.01). In contrast, P300 latency and several individual symptoms (hunger, facial flushing, sweating and light-headedness) did not change from baseline during the hormone infusion study (P < 0.05 versus hypoglycaemia). Hepatic glucose production was lower (1.5 +/- 0.4 versus 2.3 +/- 0.3 mg min-1 kg-1, P < 0.05) and peripheral glucose uptake was higher (7.4 +/- 1.0 versus 5.6 +/- 0.6 mg min-1 kg-1, P < 0.01) during infusion of the hormones compared with during hypoglycaemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Temporal changes in insulin resistance and secretion in 24-h-fasted conscious pregnant rats.

To determine the temporal sequence of pregnancy-induced changes in insulin action and secretion, awake midpregnant (11-12 days) and late pregnant (19-20 days) rats underwent a two-step euglycemic hyperinsulinemic or a hyperglycemic clamp study after a 24-h fast. During euglycemia, insulin-stimulated increments in glucose uptake and clearance in midpregnant rats were reduced by 60-70% at the lower dose (insulin approximately 360 pM) and by 20-30% at the higher dose (insulin approximately 1,750 pM; P < 0.01 vs. virgin controls). Insulin action was also diminished in late pregnant rats. However, the magnitude of resistance did not increase. Insulin-mediated suppression of glucose production was only minimally impaired in midpregnancy. In contrast, glucose production was virtually unchanged in late pregnancy, even at the highest insulin dose. During hyperglycemia, insulin responses in late pregnancy were markedly increased 5-fold above controls and 2.5-fold above midpregnant rats (P < 0.05). We conclude that rat pregnancy is characterized by the early appearance of peripheral insulin resistance. As pregnancy progresses toward term, marked hepatic insulin resistance and insulin hypersecretion develop, whereas peripheral insulin resistance demonstrates negligible changes. These data imply that insulin hypersecretion during late pregnancy is most closely linked to hepatic insulin resistance, at least in 24-h-fasted animals.

Animals↗
PubMed1993

Effect of insulin-like growth factor-1 on the responses to and recognition of hypoglycemia in humans. A comparison with insulin.

Recombinant human insulin-like growth factor-1 (rhIGF-1) lowers blood glucose in humans but its effect on counterregulatory responses has not been established. We therefore compared infusions of rhIGF-1 (0.7 micrograms/kg per min) and insulin (0.8 mU/kg.min) for 120 min in 10 healthy volunteers (glucose allowed to fall freely). With both, glucose fell rapidly because of stimulation of glucose uptake and suppression of hepatic glucose production. Despite similar plasma glucose nadirs (2.6 +/- 0.1 vs. 2.7 +/- 0.1 mM), the glucagon response was absent (P < 0.005), growth hormone release was attenuated (P < 0.03), and norepinephrine levels were increased (P < 0.05) by rhIGF-1 compared with insulin. Absent glucagon responses were associated with a blunting of the rebound increase in glucose production (P < 0.05 vs. insulin). After stopping the infusions, glucose recovery was delayed with rhIGF-1 (P < 0.001 vs. insulin). To further evaluate the effects of rhIGF-1 during a standard hypoglycemic stimulus, eight additional healthy subjects received rhIGF-1 or insulin while glucose was clamped at 2.8 mM. Again the rise in glucagon during insulin-induced hypoglycemia was totally abolished by rhIGF-1. Growth hormone responses were delayed, whereas increases in norepinephrine, heart rate, and symptomatic awareness of hypoglycemia were greater with rhIGF-1 compared with insulin (P < 0.05). It was concluded that rhIGF-1 suppression of glucagon release during hypoglycemia impairs glucose recovery. Paradoxically, awareness of hypoglycemia is enhanced with rhIGF-1 in part due to stimulation of the sympathetic activity.

Adult↗
PubMed1993

Impaired hormonal responses to hypoglycemia in spontaneously diabetic and recurrently hypoglycemic rats. Reversibility and stimulus specificity of the deficits.

To evaluate the roles of iatrogenic hypoglycemia and diabetes per se in the pathogenesis of defective hormonal counterregulation against hypoglycemia in insulin-dependent diabetes mellitus (IDDM), nondiabetic, and spontaneously diabetic BB/Wor rats were studied using a euglycemic/hypoglycemic clamp. In nondiabetic rats, recurrent (4 wk) insulin-induced hypoglycemia (mean daily glucose, MDG, 59 mg/dl) dramatically reduced glucagon and epinephrine responses by 84 and 94%, respectively, to a standardized glucose fall from 110 to 50 mg/dl. These deficits persisted for > 4 d after restoring normoglycemia, and were specific for hypoglycemia, with normal glucagon and epinephrine responses to arginine and hypovolemia, respectively. After 4 wk of normoglycemia, hormonal counterregulation increased, with the epinephrine, but not the glucagon response reaching control values. In diabetic BB rats (MDG 245 mg/dl with intermittent hypoglycemia), glucagon and epinephrine counterregulation were reduced by 86 and 90%, respectively. Chronic iatrogenic hypoglycemia (MDG 52 mg/dl) further suppressed counterregulation. Prospective elimination of hypoglycemia (MDG 432 mg/dl) improved, but did not normalize hormonal counterregulation. In diabetic rats, the glucagon defect appeared to be specific for hypoglycemia, whereas deficient epinephrine secretion also occurred during hypovolemia. We concluded that both recurrent hypoglycemia and the diabetic state independently lead to defective hormonal counterregulation. These data suggest that in IDDM iatrogenic hypoglycemia magnifies preexisting counterregulatory defects, thereby increasing the risk of severe hypoglycemia.

Animals↗
PubMed1993

Correction of hyperinsulinemia by glyburide treatment in nondiabetic patients with thalassemia major.

Hyperinsulinemia and insulin resistance precede the development of diabetes in patients with thalassemia major on hypertransfusion/desferoxamine therapy. To examine whether these early metabolic defects could be reversed, seven nondiabetic patients with thalassemia (17 +/- 4 y) were studied for 12 mo before and during 12 mo of low-dose treatment with glyburide (1.25 to 3.75 mg/d), a second-generation oral hypoglycemic agent. Plasma glucose responses to oral glucose (1.75 g/kg body weight) were normal before and after glyburide. Plasma insulin responses were markedly increased before glyburide therapy (area under insulin response curve 86 +/- 15 and 96 +/- 15 versus 40 +/- 5 nmol/min/L in normal controls, p < 0.001). However, insulin responses to glucose fell significantly after 3 mo of glyburide (to 52 +/- 7 nmol/min/L, p < 0.05 versus pretreatment) and were normalized after 12 mo (42 +/- 7 nmol/min/L, p = NS versus controls). The rate of insulin-stimulated glucose metabolism during euglycemic insulin clamps (40 mU/m2/min) was low in the patients before treatment (163 +/- 10 versus 215 +/- 17 mg/m2/min in controls, p < 0.05) and increased to 205 +/- 30 mg/m2/min after 3 mo of glyburide. The treatment was well tolerated. In conclusion, in nondiabetic, hyperinsulinemic, thalassemic patients, chronic glyburide therapy normalizes insulin responses to oral glucose. To the extent that insulin hypersecretion contributes to the development of diabetes in thalassemia, glyburide therapy may provide a means of postponing this complication of the disease.

Adolescent↗
PubMed1993

Insulin-like growth factor I inhibits glucose-stimulated insulin secretion but does not impair glucose metabolism in normal humans.

The effect of human recombinant insulin-like growth factor I (rhIGF-1) on glucose stimulated insulin secretion was studied in 14 healthy human volunteers. Each subject received a primed-continuous infusion of rhIGF-1 (20 micrograms kg prime, 0.4 micrograms kg-1 min-1) or saline while plasma glucose was raised +2.8 mmol/l (+50 mg/dl) (n = 6) or +7.0 mmol/l (+125 mg/dl) (n = 8) above baseline for 2 h using the hyperglycemic clamp technique. Total IGF-1 levels during the IGF-1 studies increased from 196 +/- 37 to 449 +/- 71 ng/ml. At the +2.8 mmol/l (+50 mg/dl) stimulus, first and second phase C-peptide levels were suppressed during IGF-1 infusion vs control (885 +/- 157 vs 544 +/- 99 pmol/l, p < 0.05 and 1379 +/- 246 vs 832 +/- 130 pmol/l, p < 0.05, respectively), whereas insulin levels were suppressed during the second phase only (215 +/- 43 vs 151 +/- 28 pmol/l, p < 0.05). Despite this, the rate of glucose metabolism was two-fold higher in the IGF-1 infused group (8.0 +/- 0.5 vs 3.5 +/- 0.1 mg kg-1 min-1, p < 0.01). At the higher glucose stimulus +7.0 mmol/l (+125 mg/dl) only second phase C-peptide levels were significantly reduced (1922 +/- 251 vs 1466 +/- 74 pmol/l, p < 0.05). Again, rates of glucose metabolism were higher during IGF-1 infusion (11.8 +/- 1.2 vs 8.9 +/- 0.8 mg kg-1 min-1, p < 0.01). These data suggest that rhIGF-1 inhibits glucose-stimulated insulin secretion in humans, but that this inhibitory effect is partially overcome by increasing the hyperglycemic stimulus. Moreover, despite the decrease in insulin secretion, glucose disposal is accelerated by rhIGF-1.

Adolescent↗