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Publications and source records attributed to C H Gravholt.
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Cortisol's effects on lipid metabolism are controversial and may involve stimulation of both lipolysis and lipogenesis. This study was undertaken to define the role of physiological hypercortisolemia on systemic and regional lipolysis in humans. We investigated seven healthy young male volunteers after an overnight fast on two occasions by means of microdialysis and palmitate turnover in a placebo-controlled manner with a pancreatic pituitary clamp involving inhibition with somatostatin and substitution of growth hormone, glucagon, and insulin at basal levels. Hydrocortisone infusion increased circulating concentrations of cortisol (888 +/- 12 vs. 245 +/- 7 nmol/l). Interstitial glycerol concentrations rose in parallel in abdominal (327 +/- 35 vs. 156 +/- 30 micromol/l; P = 0.05) and femoral (178 +/- 28 vs. 91 +/- 22 micromol/l; P = 0.02) adipose tissue. Systemic [(3)H]palmitate turnover increased (165 +/- 17 vs. 92 +/- 24 micromol/min; P = 0.01). Levels of insulin, glucagon, and growth hormone were comparable. In conclusion, the present study unmistakably shows that cortisol in physiological concentrations is a potent stimulus of lipolysis and that this effect prevails equally in both femoral and abdominal adipose tissue.
Clinical and epidemiological studies suggest that premature ageing and increased morbidity and mortality is present in Ullrich-Turner syndrome. We studied telomere restriction fragment length (TRFL) in 30 women with Ullrich-Turner syndrome and 30 age-matched control women. All Turner women had the 45,X karyotype verified by karyotyping. We found no difference in the mean TRFL in the young age group (TS: 7011+/-521 vs C: 7285+/-917 bp, P = 0.3), or in the older age group (TS: 7357+/-573 vs C: 7221+/-621 bp, P = 0.6). In conclusion, our data suggest that Ullrich-Turner syndrome is not associated with excessive telomere loss, at least when studied in peripheral blood leucocytes, and thus quite different from other premature ageing syndromes.
The bioactivity of the growth hormone-insulin-like growth factor (IGF) system is reduced in Turner syndrome and may explain the reduction seen in final height. We compared levels of free and total IGF-I, immunoreactive and Western ligand blot IGF-binding protein (IGFBP)-3, and IGFBP-3 proteolysis in women with Turner syndrome (n = 23) before (T(B)) and during 6 mo treatment with 17beta-estradiol and norethisterone. An age-matched group of controls (n = 24) was included. Total IGF-I and immunoreactive levels of IGFBP-3 were comparable in T(B) and controls, whereas free IGF-I (P = 0.02) in T(B) was less than in controls. Western ligand blotting (WLB)-IGFBP-3 was significantly lower in T(B) than in controls (P = 0.0005). Accordingly, IGFBP-3 proteolysis was greater in Turner syndrome (P = 0.001). Female sex steroid treatment increased WLB-IGFBP-3 (P = 0.0005), whereas immunoreactive IGFBP-3 and IGFBP-3 proteolysis were normalized (P = 0.004). Free IGF-I remained unchanged (P = 0.8), with a tendency toward a decrease in total IGF-I (P = 0.1). In conclusion, despite normal total IGF-I and immunoreactive IGFBP-3, free serum IGF-I is less and IGFBP-3 proteolysis is greater in Turner syndrome than in controls. During sex steroid treatment, IGFBP-3 proteolysis normalized, without any change in free IGF-I.
Several issues should be addressed when managing women with Turner's syndrome. Female sex hormone substitution should be offered to help prevent the increased morbidity seen in Turner's women, which consists of an increased risk of fractures and osteoporosis, and a clustering of diseases such as ischaemic heart disease, hypertension, stroke and type 2 diabetes, the latter entities being part of the insulin resistance syndrome. Furthermore, hypothyroidism is often seen, and the risk of type 1 diabetes may also be increased. Congenital malformations of the heart are frequently seen in Turner's syndrome, possibly increasing the risk of dissecting aorta aneurysm. Liver enzymes are often elevated and there may be an increased risk of liver cirrhosis. Mortality seems to be increased in Turner's syndrome, women with the "pure" 45,X karyotype being the most severely affected. In clinical practice, careful monitoring of glucose and bone metabolism, weight, thyroid function and blood pressure should be carried out. A cardiovascular risk profile should be determined and the patient informed of the risks and benefits of sex hormone replacement therapy. Sex hormone replacement therapy is highly recommended, although at present there are no longitudinal data documenting the long-term positive effect of sex steroid substitution. However, hypogonadism is expected to explain at least part of the decreased lifespan found in Turner's syndrome. Since general physicians only encounter these patients infrequently, it is recommended that the care and treatment of Turner's syndrome be centralized.
It remains uncertain whether close imitation of the physiological pulsatile GH pattern determines the effects of GH treatment in humans. However, human studies have reported comparable metabolic responses to short-term constant and intermittent GH exposure. The aim of the study was to compare the metabolic effects of GH after continuous and intermittent sc delivery. In a parallel design, 14 GH-treated GH-deficient patients (mean age, 37 yr; mean body mass index, 27.4 kg/m(2)) were studied during steady state at the start of the study and after 6 months. Seven patients received daily injections (inj) in the evening as usual, and 7 received a continuous infusion (inf) of GH by means of a portable pump. The GH dose was kept unchanged before and during the study. Serum levels of insulin-like growth factor I (IGF-I) tended to increase in the patients switched to constant infusion (from 175 +/- 36 to 209 +/- 50 microg/L), but the differences obtained during the two regimens [+34.3 (inf) vs. -11.9 (inj)] were not significant (P = 0.34). Serum levels of IGF-II (P = 0.71) and IGF-binding protein (IGFBP)-3 (P = 0.75) were identical during the two modes of treatment. Serum levels of IGFBP-1 (P = 0.72), IGFBP-2 (P = 0.34), and GH-binding protein (P = 0.75) were unaffected by treatment regimen. Serum levels of free fatty acids, reflecting lipolysis, decreased significantly (16%) in the group switched to GH infusion (difference, -99.8 vs. +5 micromol/L; P < 0.03). The GH pattern did not influence insulin sensitivity (P = 0.71) or glucose effectiveness (P = 0.15) derived from Bergman's minimal model. Similarly, the two treatment regimens had no differential impact on lipoprotein levels, bone metabolism, or body composition. In conclusion, continuous and intermittent administrations of GH for 6 months are comparable with respect to the IGF-IGFBP axis, whereas intermittent exposure may be of importance for the lipolytic effect of GH. The data on insulin sensitivity and lipoproteins suggest that constant GH exposure is as safe as intermittent GH administration.
To determine whether glucagon stimulates lipolysis in adipose tissue, seven healthy young male volunteers were studied, with indwelling microdialysis catheters placed sc in abdominal adipose tissue. Subjects were studied three times: 1) during euglucagonemia (EG; glucagon infusion rate, 0.5 ng/kg.min); 2) during hyperglucagonemia (HG; (glucagon infusion rate, 1.5 ng/kg.min); and 3) during EG and a concomitant glucose infusion mimicking the glucose profile from the day of HG (EG+G). Somatostatin (450 microg/h) was infused to suppress hormonal secretion, and replacement doses of insulin and GH were administered. Sampling was done every 30 min for 420 min. Baseline circulating values of insulin, C-peptide, glucagon, GH, glycerol, and free fatty acids were comparable in all three conditions. During EG and EG+G, plasma glucagon was maintained at fasting level (20-40 ng/L); whereas, during HG, it increased (110-130 ng/L). Interstitial concentrations of glycerol were similar in the three conditions [30,870 +/- 5,946 (EG) vs. 31,074 +/- 7,092 (HG) vs. 29,451 +/- 6,217 (EG+G) micromol/L.120 min, P = 0.98]. Plasma glycerol (ANOVA, P = 0.5) and free fatty acids (ANOVA, P = 0.3) were comparable during the different glucagon challenges. We conclude that HG per se does not increase interstitial glycerol (and thus lipolysis) in abdominal sc adipose tissue; nor does modest hyperglycemia, during basal insulinemia and glucagonemia, influence indices of abdominal sc lipolysis.
Comprehensive recommendations on the diagnosis of Turner syndrome (TS) and the care of affected individuals were published in 1994. In the light of recent advances in diagnosis and treatment of TS, an international multidisciplinary workshop was convened in March 2000, in Naples, Italy, in conjunction with the Fifth International Symposium on Turner Syndrome to update these recommendations. The present paper details the outcome from this workshop. The genetics and diagnosis of the syndrome are described, and practical treatment guidelines are presented.
Several issues have to be considered when taking care of girls and women with Turner syndrome. During childhood, short stature is the primary concern and treatment with growth hormone (GH) is now widely used, often in conjunction with the androgen, oxandrolone. Recent studies indicate that doses used previously in the treatment of short stature have been too small. Induction of puberty should be performed at an appropriate age with reference to the peers of the patient. In adulthood, female sex hormone substitution should be offered to possibly prevent the increased morbidity seen in Turner syndrome, which consists of increased risk of fractures and osteoporosis, a clustering of diseases like ischaemic heart disease, hypertension, stroke and Type 2 diabetes, the latter entities being involved in the insulin resistance syndrome. Furthermore, hypothyreosis are often seen and the risk of Type 1 diabetes may also be increased. Congenital malformations of the heart are frequently seen in Turner syndrome, possibly increasing the risk of dissecting aorta aneurism. Liver enzymes are often elevated in Turner syndrome and there may be an increased risk of cirrhosis of the liver. Mortality does seem to be increased in Turner syndrome and women with the 'pure' 45,X karyotype do seem to be most severely affected. In the clinical practice of Turner syndrome, a careful monitoring of glucose and bone metabolism, weight, thyroid function and blood pressure should be performed. A cardiovascular risk profile should be determined and the patient informed concerning risks and benefits from sex hormone replacement therapy. Based on the available literature, sex hormone replacement therapy is highly recommended, although at present there are no longitudinal data documenting the long-term positive effect of sex steroid substitution. However, hypogonadism is expected to explain at least part of the decreased lifespan found in Turner syndrome. Since general physicians encounter Turner patients infrequently, it is recommended that the care and treatment of Turner syndrome is centralised.
OBJECTIVE: To assess muscle fiber composition and capillary density in Turner syndrome, a condition linked with insulin resistance and increased frequency of type 2 diabetes, and link these findings with insulin sensitivity and physical fitness. RESEARCH DESIGN AND METHODS: A total of 10 patients with Turner syndrome who were off hormone replacement therapy (aged 32.7 +/- 8.9 years) and a control group of 14 normal women (aged 35.6 +/- 9.3 years) were studied. None of the participants had diabetes or any family history of type 2 diabetes. An oral glucose tolerance test was performed, and insulin sensitivity was assessed by homeostasis model assessment (HOMA) and a composite whole-body insulin sensitivity index (ISI(comp)). Physical fitness was assessed, and a muscle biopsy was obtained. RESULTS: Women with Turner syndrome were insulin resistant, as seen by a lower ISI(comp) (P = 0.003) and increased glucose (P < 0.0005) and insulin (P = 0.01) levels at 120 min. Impaired glucose tolerance was present in most Turner syndrome patients (6 of 10), but not in the control subjects. Women with Turner syndrome had an increased size of type IIa fibers (P = 0.01), whereas the size of their type I and IIa fibers were comparable with the control group. The groups did not differ in percentage of type I, Iia, or IIx fibers, and there was no difference in the capillary density. Significant correlations were found among ISI(comp), the HOMA index (R(HOMA)), and the mean area of type IIa fibers (ISI(comp): r = -0.632, P = 0.002; R(HOMA): r = 0.570, P = 0.006). Furthermore, capillaries/type IIa fibers correlated significantly with ISI(comp) (r = -0.618, P = 0.01). There were no significant correlations between VO(2max) and muscle fiber composition. CONCLUSIONS: Healthy women with Turner syndrome are characterized by impaired glucose tolerance, insulin resistance, low physical capacity, and enlarged type IIa muscle fibers, indicating diminished oxygen and substrate supply for metabolic processes. These findings could be indicative of a prediabetic state.
UNLABELLED: Timing of 17beta-estradiol (E2) administration in relation to that of GH could influence the "first pass effect" of E2 on hepatic IGF-I secretion. In order to test this hypothesis, a randomized double-blind placebo-controlled crossover study was conducted. Nine Turner girls (12.8-20.0y) were treated for 2 mo periods with GH 0.1 IU/kg/d sc at bedtime, and oral E2 6-11 microg/kg/d in the morning and placebo in the evening in one 2-mo period and vice versa in the other period. After each period, 24-h blood sampling was performed. IGF-I and mean 24-h integrated GH were comparable. However, the IGF-I/IGFBP-3 ratio was higher (p = 0.05) and insulin levels were lower after evening administration of E2 (24 h: p = 0.03). During an oral glucose tolerance test in the morning, glucagon and insulin were lower following evening E2 administration (ANOVA: glucagon, p = 0.03; insulin, p = 0.04), as well as insulin resistance tended to be lower (p = 0.09). CONCLUSION: The timing of oral E2 supplementation modulates the IGF-I/IGFBP-3 ratio, insulin and glucagon levels in Turner syndrome during GH treatment, Evening administration of oral estrogen together with evening injections of GH may be preferable.
Turner's syndrome is associated with a high incidence of cardiovascular disease and hypothyreosis; conditions which are associated with abnormal lipid metabolism. To test whether alterations of lipid metabolism is present in healthy Turner's women, we compared lipids in a group of adult women with Turner's syndrome with an age matched group of healthy women. In addition the impact of sex steroid replacement therapy was studied in the women with Turner's syndrome. Patients were studied before and during treatment with hormonal replacement therapy, consisting of either oral 17beta-estradiol or transdermal 17beta-estradiol, and oral norethisterone. Control subjects were studied once in the early follicular stage of the menstrual cycle. The study group consisted of 26 (33.2+/-7.9 years) patients with Turner's syndrome and an age matched control group of 24 (32.7+/-7.6 years) normal women. Body composition measures, apolipoprotein (apo) B and apo A-I, Lp(a), cholesterol, HDL, LDL, triglycerides, thyroxine (TT4), free thyroxine (FT4), triiodothyronine (TT3), free triiodothyronine (FT3), TSH, and leptin were determined. Apo A-I levels were higher in Turner's patients (P45 g/l) Lp(a), more women with Turner's syndrome had high levels of Lp(a) than controls (P=0.024), while all other measures of lipid metabolism were comparable to controls. The level of TSH, FT3, and FT4 were significantly higher in Turner's patients, while TT4, TT3 and adjusted 24h energy expenditure were comparable to controls. Lp(a) (P=0.005), HDL (P=0.045) and apo A-I (P=0.039) decreased significantly, while there was a tendency towards a decrease in apo B (P=0.063) during treatment with sex hormones. In conclusion more women with Turner's syndrome than controls have high levels of apolipoprotein A-I and Lp(a), but only after dichomitization, while other markers of lipid metabolism are normal. Replacement therapy with female sex hormones lowered Lp(a), HDL cholesterol and apolipoprotein A-I.
Insulin resistance is of pathogenetic importance for the development of non-insulin-dependent diabetes mellitus (NIDDM). However, not much is known about the variation in insulin sensitivity in the individual over longer periods. Consequently, we measured insulin sensitivity (Si) and glucose effectiveness (Sg) in healthy young men (N = 10) 5 times over a period of 15 months using a frequently sampled intravenous glucose tolerance test (FSIVGTT) with minimal-model analysis (study of seasonality). The maximal aerobic capacity (V(O2)max), fat-free mass, body mass index (BMI), and 24-hour ambulatory blood pressure (BP) were also assessed. Furthermore, we performed a study designed to evaluate the day-to-day variation in Si and Sg (study of day-to-day variation). Here, we studied Si and Sg in healthy young men (n = 8) within 2 weeks. In the study of seasonality, the coefficient of variation (CV) for Si was 24.0%, whereas the CV for Sg was 26.0%. Anticipating a seasonal variation in Si following a sine curve with a cycle length of 1 year and an unknown phase and amplitude, we tested this hypothesis with a multiple linear regression model that allows for different levels of Si between individuals, and failed to detect any impact due to this. Si (mean +/- SD, 1.17 +/- 0.28 x 10(-4) x min(-1) x pmol/L(-1), P = .38), Sg (0.023 +/- 0.006 min(-1), P= .71), fasting insulin (21.2 +/- 7.3 pmol/L, P= .98), V(O2)max (3.8 +/- 0.6 L/min, P= .13), and fat-free mass (64.9 +/- 2.5 kg, P = .92) were constant over time. In the study of day-to-day variation, we found a CV for Si of 17.3% and a CV for Sg of 23.3%. In conclusion, we found that the variations in Si and Sg were slightly higher than those found in studies performed to establish the day-to-day variation. However, no significant seasonal variation in Si and Sg was evident in this group of healthy young lean caucasian men. Consequently, indices of Si and Sg obtained at different times of the year appear comparable.
BACKGROUND: Vitamin D is essential for normal bone metabolism. Polymorphisms in exon 2, intron 8 and exon 9 of the vitamin D receptor (VDR) gene have previously been found to be associated with bone mass and bone turnover. MATERIALS AND METHODS: We examined the effect of these polymorphisms, separately and in combination, on bone mineral density (BMD), bone turnover, and the prevalence of osteoporotic fractures in 192 osteoporotic patients and 207 normal controls. The four polymorphisms were determined by RFLP using Fok I (T2-C), Bsm I (intron 8), Apa I (intron 8) and Taq I (T1055-C) after PCR. RESULTS: We did not find any association between the Fok I polymorphism and bone mass, bone turnover or prevalence of osteoporotic fractures. We found that BB + Bb-genotypes were more frequent in patients with osteoporotic fractures (chi2 = 3.50, P = 0. 06). Furthermore, BMD of the intertrochanteric region (P < 0.0001, ANOVA) as well as the total hip (P < 0.01, ANOVA) were higher in individuals with the bb-genotype. The Apa I and the Taq I polymorphisms were not distributed differently among osteoporotic patients and normal controls. Apa I was not associated with differences in BMD. BMD of the intertrochanteric region was higher in individuals with the TT-genotype compared with individuals with the Tt- or tt-genotypes (P < 0.01, ANOVA), while no differences could be demonstrated in BMD of the lumbar spine, femoral neck, trochanter or Wards triangle. Combining the genotypes generally reflected the differences caused by the Bsm I polymorphism. CONCLUSION: We have found that the B-allele of the Bsm I polymorphism in the 3' untranslated region of the VDR was associated with low BMD at the hip, and tended to be associated with osteoporotic fractures. The translation initiation polymorphism in the VDR does not affect BMD and is not associated with osteoporotic fractures in men or women.
To examine beta-cell function in glucose-tolerant offspring of type 2 diabetic families, 41 insulin-resistant (hyperinsulinemic-euglycemic clamp, P < .001) first-degree relatives and 32 controls underwent oral (OGTT) and intravenous (IVGTT) glucose tolerance tests and a constant intravenous glucose infusion (4.0 or 4.5 mg/kg/min) with blood sampling every minute for insulin determinations. Insulin concentration time-series were analyzed with complementary mathematical models (deconvolution and autocorrelation analysis, approximate entropy [ApEn], and coefficient of variation [CV] for a 6-point moving average, together with a combined index for regularity and stationarity [RaS] based on the last 2 measures). During the OGTT, the area under the curve (AUC) for plasma glucose was moderately (11%) but significantly (P < .01) elevated in the relatives despite a trend for increased serum insulin (AUC, P = .14). The acute-phase serum insulin response (IVGTT) did not differ between groups (2,055 +/- 330 v 1,766 +/- 229 pmol/L x 10 min, P = .84) but was inappropriately low (individually, P < .05 v control group) for the degree of insulin resistance in 16 relatives. Deconvolution analysis of the insulin time-series did not uncover differences in either the intersecretory pulse interval (5.8 +/- 0.2 v5.7 +/- 0.2 min/pulse) or the fractional secretory burst amplitude (133% +/- 10% v 116% +/- 7% over basal) between the 2 groups. Similarly, significant autocorrelation coefficients were observed in a comparable number of relatives and control subjects (P = .74). In contrast, the RaS index was significantly higher (ie, insulin time-series was more irregular and nonstationary) in the relatives (0.221 +/- 0.194) than in the controls (-0.318 +/- 0.176, P < .05), primarily attributed to the pattern of insulin secretion in relatives with a strong genetic burden. In conclusion, nonstationary and disorderly insulin secretion patterns during glucose stimulation and a low acute-phase serum insulin response associated with significant insulin resistance suggest early beta-cell regulatory dysfunction in individuals genetically predisposed to type 2 diabetes mellitus prior to any evident alterations in insulin secretory burst frequency or mass.
The presence of Y chromosome material in patients with Turner syndrome is a risk factor for the development of gonadoblastoma. However, no cases with gonadoblastoma or other ovarian malignancies have been found in epidemiological studies of cancer, morbidity, or mortality in Turner syndrome. We examined 114 females with Turner syndrome for the presence of Y chromosome material by PCR. Initially, five different primer sets were used. Y Chromosome-positive individuals were further examined with an additional four primer sets. We found 14 (12.2%; 95% confidence interval, 6.9-19.7%) patients who had Y chromosome material. The karyotype in 7 of these patients did not suggest the presence of Y chromosome material. Seven of the patients had been ovariectomized before entering the study due to verified Y chromosome material, whereas three patients were operated upon after the DNA analysis. The histopathological evaluations showed that 1 of the 10 ovariectomized patients actually had a gonadoblastoma. The rest of the patients did not have gonadoblastoma or carcinoma in situ on histopathological evaluation. Three patients (age, >50 yr) positive for Y chromosome material chose not to have ovariectomy performed, and detailed ultrasonographies did not suggest the presence of gonadoblastoma. The frequency of Y chromosome material is high in Turner syndrome (12.2%), but the occurrence of gonadoblastoma among Y-positive patients seems to be low (7-10%), and the risk may have been overestimated in previous studies, perhaps due to problems with selection bias. This study emphasizes the need for prospective unbiased studies.
AIMS/HYPOTHESIS: Insulin resistance is a common feature in relatives of patients with Type II (non-insulin-dependent) diabetes mellitus and abnormalities in beta-cell function can also exist. Insight into non-fasting carbohydrate metabolism in these potentially prediabetic subjects relies almost exclusively on studies in which glucose is infused or ingested or both. We aimed to characterize insulin secretion and aspects of hormonal and metabolic patterns in relatives using a physiological approach. METHODS: We examined profiles of insulin, C peptide, proinsulin, gut incretin hormones and fuel substrates in 26 glucose tolerant but insulin resistant (clamp) relatives and 17 control subjects during a 24-hour period including three meals. RESULTS: During the day plasma glucose was slightly raised in relatives (p < 0.05). Overall insulin secretion calculated on the basis of C peptide kinetics were increased in relatives (p < 0.0005) whereas incremental insulin secretion after all three meals were similar. Peak incremental insulin secretion tended, however, to be reduced in relatives (p < 0.10). Despite considerably increased insulin concentrations in relatives (70 %, p < 0.001), serum NEFA did not differ. Postprandial proinsulin concentrations (p < 0.05), but not proinsulin:insulin ratios, were increased in relatives. After meals concentrations of glucose-dependent-insulinotropic polypeptide (p < 0.05) were increased in relatives. Glucagon-like peptide-1 concentrations were similar. CONCLUSION/INTERPRETATION: Several hormonal and metabolic aberrations are present in healthy relatives of Type II diabetic patients during conditions that simulate daily living. Increased concentrations of glucose-dependent-insulinotropic polypeptide could indicate a beta-cell receptor defect for glucose-dependent-insulinotropic polypeptide in the prediabetic stage of Type II diabetes. Incremental insulin secretion after mixed meals appear normal in relatives, although a trend towards diminished peak values possibly signifies early beta-cell dysfunction. [Diabetologia (1999) 42: 1314-1323]
To explore further the effects of the human amylin analog pramlintide on overall glycemic control and postprandial responses of circulating glucose, glucagon, and metabolic intermediates in type 1 diabetes mellitus, 14 male type 1 diabetic patients were examined in a double-blind, placebo-controlled, crossover study. Pramlintide (30 microg four times daily) or placebo were administered for 4 weeks, after which a daytime blood profile (8:30 AM to 4:30 PM) was performed. Serum fructosamine was decreased after pramlintide (314+/-14 micromol/L) compared with placebo (350+/-14 micromol/L, P = .008). On the profile day, the mean plasma glucose (8.3+/-0.7 v 10.2+/-0.8 mmol/L, P = .04) and postprandial concentrations (incremental areas under the curve [AUCs] from 0 to 120 minutes) were significantly decreased during pramlintide administration (P < .01 for both) despite comparable circulating insulin levels (359+/-41 v 340+/-35 pmol/L). Mean blood glycerol values were reduced (0.029+/-0.004 v 0.040+/-0.004 mmol/L, P = .01) and blood alanine levels were elevated (0.274+/-0.012 v 0.246+/-0.008 mmol/L, P = .03) after pramlintide versus placebo. Blood lactate concentrations did not differ during the two regimens. During pramlintide administration, the AUC (0 to 120 minutes) for plasma glucagon after breakfast was diminished (P = .02), and a similar trend was observed following lunch. In addition, peak plasma glucagon concentrations 60 minutes after breakfast (45.8+/-7.3 v 72.4+/-8.0 ng/L, P = .005) and lunch (47.6+/-9.0 v 60.9+/-8.2 ng/L, P = .02) were both decreased following pramlintide. These data indicate that pramlintide (30 microg four times daily) is capable of improving metabolic control in type 1 diabetics. This may relate, in part, to suppression of glucagon concentrations. Longer-term studies are required to ascertain whether these findings are sustained over time.