Impaired first-phase insulin response predicts postprandial blood glucose increment in patients with recently diagnosed type 2 diabetes.

OBJECTIVE: The aim of the study was to evaluate the relationship between postprandial blood glucose and first-phase insulin response and, furthermore, to assess whether the intravenous glucagon stimulation test can be used as a predictor for increased postprandial glucose in patients with recently diagnosed type 2 diabetes. MATERIAL AND METHODS: Twenty patients with diet-treated type 2 diabetes, diagnosed within the past 5 years, were included. In random order, on three different days, the patients underwent: 1) a standardized meal tolerance test, 2) an intravenous glucose tolerance test, and 3) an intravenous glucagon stimulation test. The postprandial blood glucose response was defined as the incremental area under the blood glucose curve 0-240 min after the meal. RESULTS: The first-phase insulin response at an intravenous glucose stimulation test was significantly correlated to the postprandial blood glucose increment (R(2)=0.21, p<0.05) and the maximal increment in plasma glucose concentration (R(2)=0.40, p<0.01) during the meal tolerance test. However, the incremental C-peptide value at 6 min in response to intravenous glucagon stimulation did not correlate to the postprandial blood glucose increment (R(2)=0.09, p=0.14). CONCLUSION: Impaired first-phase insulin response is a significant predictor of the increase in postprandial blood glucose in patients with type 2 diabetes in near normal metabolic control, whereas beta-cell function, assessed by glucagon stimulation test, is not.

Hyperproinsulinaemia in normoglycaemic lipodystrophic HIV-infected patients.

BACKGROUND: We aimed to investigate whether the insulin precursors, intact (IP) and 32-33 split proinsulin (SP), which are elevated in states of insulin resistance and predict type 2 diabetes, would be elevated in human immunodeficiency virus (HIV)-infected patients with lipodystrophy (LIPO). MATERIALS AND METHODS: Forty-three normoglycaemic HIV-infected patients [18 LIPO and 18 without lipodystrophy (NONLIPO) receiving antiretroviral drugs, and seven patients naïve to antiretroviral drugs (NAIVE)] were examined. Insulin precursors were measured during fasting, during an intravenous glucose tolerance test and during a hyperinsulinaemic-euglycaemic clamp, respectively. Insulin secretion rates (ISR) were determined by deconvolution of C-peptide concentrations. Disposition index (DI) was calculated as insulin sensitivity (Si(RD)) multiplied by the first-phase insulin response to intravenous glucose. RESULTS: LIPO exhibited increased fasting IP and SP (P < 0.05), a higher proportion of elevated fasting IP (3.1 pmol L(-1), 66% vs. 33% and 28%, P < 0.05) and SP (7.2 pmol L(-1), 50%, 11% and 0%, P < 0.01), reduced Si(RD) (> 50%, P < 0.001) and increased ISR (P < 0.001) compared with NONLIPO and NAIVE. Fasting SP and IP correlated positively with ISR (P < 0.001) and inversely and hyperbolically with Si(RD) (P < 0.001). Fasting SP/insulin ratio correlated inversely with Si(RD) (P < 0.05). Incremental IP + SP/insulin ratio after an intravenous glucose bolus correlated inversely with DI (P < 0.01), but did not differ between study groups. CONCLUSIONS: Proinsulin appeared to be increased in HIV-lipodystrophy, but no more than caused by the increased ISR. Nevertheless, the inverse correlations between SP/insulin ratio versus Si(RD) and incremental total proinsulin/insulin ratio versus DI may argue for a subtle beta-cell dysfunction in those patients with insulin resistance and low DI.

A low-fat diet improves peripheral insulin sensitivity in patients with Type 1 diabetes.

AIMS: To compare the effects on insulin sensitivity, body composition and glycaemic control of the recommended standard weight-maintaining diabetes diet and an isocaloric low-fat diabetes diet during two, 3-month periods in patients with Type 1 diabetes. METHODS: Thirteen Type 1 patients were included, of whom 10 completed the cross-over study. Ten non-diabetic, matched control subjects were also examined. Body composition was estimated by dual-energy X-ray absorptiometry (DXA) whole-body scanning, diet intake was monitored by 7-day dietary record and insulin sensitivity was measured by the insulin clamp technique at baseline and after each of the diet intervention periods. RESULTS: On an isocaloric low-fat diet, Type 1 diabetic patients significantly reduced the proportion of fat in the total daily energy intake by 12.1% (or -3.6% of total energy) as compared with a conventional diabetes diet (P = 0.039). The daily protein and carbohydrate intake increased (+4.4% of total energy intake, P = 0.0049 and +2.5%, P = 0.34, respectively), while alcohol intake decreased (-3.2% of total energy intake, P = 0.02). There was a significant improvement in insulin sensitivity on the isocaloric, low-fat diet compared with the standard diabetes diet [7.06 +/- 2.16 mg/kg/min (mean +/- sd) vs. 5.52 +/- 2.35 mg/kg/min (P = 0.03)]. However, insulin sensitivity remained 33% lower than in the control subjects (P = 0.021). No significant changes occurred in body weight or body composition. Glycated haemoglobin rose during both diet intervention periods (P = 0.18), with no difference between the two diets. CONCLUSIONS: Change to an isocaloric, low-fat diet in Type 1 diabetic patients during a 3-month period resulted in significant improvement in insulin sensitivity without improvement in glycaemic control. However, insulin sensitivity remained 33% lower than in control subjects.

Body composition in adults with Type 1 diabetes at onset and during the first year of insulin therapy.

AIMS: To describe body composition in patients with Type 1 diabetes at diagnosis and during the first year after initiation of insulin therapy. RESEARCH DESIGN AND METHODS: In 10 (eight male and two female) newly onset Type 1 patients, age 31.5 +/- 3.2 years (27-37 years) (sd and range), body mass index (BMI) 20.8 +/- 1.6 (19.2-23.4) kg/m2, body composition was estimated by means of dual-energy X-ray absorptiometry (DXA) whole body scanning supplemented by estimation of total body water (TBW) (isotope dilution technique with 3H2O) at diagnosis and after 1, 3, 6 and 12 months of insulin therapy. RESULTS: During the first year after onset of diabetes body weight (BW) increased 4.3 +/- 2.9 (0.1-8.3) kg (P = 0.0012) distributed as a 13.3% (1.6 kg) increase in total fat mass (FM) and 4.9% (2.5 kg) increase in lean body soft tissue mass (LBM). The self-reported weight loss at onset was 6.3 +/- 2.5 kg (1.5-10.0 kg). Compared with two reference populations the Metropolitan Life Insurance Co. and a healthy age and sex-matched local DXA scanned group the initial body composition data demonstrated BW 6.2 kg below ideal weight and a significant reduction of the FM (25% or -0.87 sd), whereas LBM was within the expected range. CONCLUSIONS: During the first year after onset of Type 1 diabetes the mean increase in BW is 6.5% with a 13.3% increase in FM and a 4.9% increase in LBM. Self-reported data on premorbid BW suggest an approximately 10% reduction in BW at onset of Type 1 diabetes. Compared with a healthy reference population initial body composition data demonstrate a 25% reduction of the FM, whereas only a minor and non-significant reduction in the LBM is encountered. These data indicate that uncontrolled diabetes is rather a fat catabolic state than, as previously believed, a protein catabolic state.

Minor long-term changes in weight have beneficial effects on insulin sensitivity and beta-cell function in obese subjects.

AIM: To evaluate the long-term effect of changes in body composition induced by weight loss on insulin sensitivity (SI), non-insulin mediated glucose disposal, glucose effectiveness (SG)and beta-cell function. DESIGN: Glucose metabolism was evaluated before and after participation in a two-year weight loss trial of Orlistat vs. placebo, combined with an energy and fat restricted diet. SUBJECTS: Twelve obese patients (11 women, 1 man), age 45.8 +/- 10.5 years, body weight (BW) 99.7 +/- 13.3 kg, BMI 35.3 +/- 2.8 kg/m(2). MEASUREMENTS: At inclusion and 2 years later an oral glucose tolerance test (OGTT) and a frequently sampled intravenous glucose tolerance test (FSIGT) were performed. Body composition was estimated by a dual-energy X-ray absorptiometry (DXA) whole body scanning. RESULTS: The patients obtained varying changes in BW ranging from a weight loss of 17.8 kg to a weight gain of 6.0 kg. Corresponding changes in fat mass (FM) varied from a 40% reduction to a19% increase. A significant decrease in both fasting (p = 0.038) and 2 h (p = 0.047) blood glucose at OGTT was found. The improvement in insulin sensitivity (SI) estimated by means of Bergmans Minimal Model, was significantly and linearly correlated to change in total FM (r = - 0.83,p = 0.0026). A multiple regression analysis showed that changes in truncal FM was the strongest predictor of change in S(I) explaining 67% of the variation. First phase insulin response (AIRg)remained unchanged whereas insulin disposition index increased significantly (p = 0.044). At inclusion five patients had impaired glucose tolerance of which four, who lost weight, were normalized at the retest 2 years later. CONCLUSION: In obese subjects long-term minimal or moderate changes in weight were found to be linearly associated with changes in insulin sensitivity. In obese subjects with impaired glucose tolerance even a minor weight loss was able to normalize glucose tolerance.

GH strongly affects serum concentrations of mannan-binding lectin: evidence for a new IGF-I independent immunomodulatory effect of GH.

Studies in animals and humans indicate that GH and IGF-I modulate immune function. Recently, it was reported that GH therapy increased the mortality in critically ill patients. The excessive mortality was almost entirely attributable to septic shock or multiorgan failure, suggesting that a GH-induced modulation of immune function was involved. In the present study, we examined whether GH or IGF-I influences the serum concentrations of mannan-binding lectin (MBL). MBL is a plasma protein of the innate immune system that initiates the complement cascade and activates inflammation after binding to carbohydrate structures on microbial surfaces. We performed a cross-over study of 16 healthy men examined during a control period, and during treatment with either GH or IGF-I for 6 d. The levels of MBL were more than doubled during GH treatment, whereas no changes were observed in the IGF-I group or during the control period (P < 0.001). IGF-I levels were elevated similarly during treatment with GH and IGF-I. Subsequently, we studied 30 healthy persons and 25 GH-deficient (GHD) patients randomized to treatment with GH or placebo in a double-blinded manner, and further included samples from 23 patients with active acromegaly examined before and after treatment with octreotide or the GH-receptor antagonist pegvisomant for 3 months. Baseline concentrations of MBL were lower in GHD patients and higher in acromegalic patients than in healthy subjects (P < 0.02). Treatment with GH doubled the MBL concentrations in healthy subjects and almost quadrupled the concentrations in GHD patients; whereas in acromegalic patients, the levels of MBL were reduced to approximately two thirds of the initial values during treatment with octreotide or pegvisomant. Our results demonstrate that treatment with GH, but not IGF-I, significantly increases MBL concentrations. The clinical consequences of this new link between the endocrine and the immune system remain to be elucidated.

Obesity and sarcopenia after menopause are reversed by sex hormone replacement therapy.

OBJECTIVE: Menopause is linked to an increase in fat mass and a decrease in lean mass exceeding age-related changes, possibly related to reduced output of ovarian steroids. In this study we examined the effect of combined postmenopausal hormone replacement therapy (HRT) on the total and regional distribution of fat and lean body mass. RESEARCH METHODS AND PROCEDURES: Sixteen healthy postmenopausal women (age: 55 +/- 3 years) were studied in a placebo-controlled, crossover study and were randomized to 17beta estradiol plus cyclic norethisterone acetate (HRT) or placebo in two 12-week periods separated by a 3-month washout. Total and regional body composition was measured by DXA at baseline and in the 10th treatment week in both periods. Changes were compared by a paired Student's t test. RESULTS: The change in body weight during HRT was equal to the change during placebo (-24.6 g vs. -164 g, p = 0.42), but relative fat mass was significantly reduced (-0.5% vs. +1.24%, p < 0.01). During HRT, compared with during placebo, lean body mass increased (+347 g vs. -996 g, p < 0.01) and total fat mass decreased (-400 g vs. +836 g, p = 0.06). Total bone mineral content increased (+28.9 g vs. -4.4 g, p = 0.04) and abdominal fat decreased (-185 g vs. +253 g, p = 0.04) during HRT compared with placebo. DISCUSSION: HRT is linked to the reversal of both menopause-related obesity and loss of lean mass, without overall change in body weight. The increase in lean body mass during HRT is likely explained by muscle anabolism, which in turn, prevents disease in the elderly.

Gene expression of a truncated and the full-length growth hormone (GH) receptor in subcutaneous fat and skeletal muscle in GH-deficient adults: impact of GH treatment.

In humans at least two GH receptors are significantly expressed. One is the full-length receptor (GHR); the other is a truncated form (GHRtr), that lacks most of the intracellular domain. This receptor may inhibit the action of the full-length receptor. Circulating GH-binding protein (GHBP) is a proteolytically cleaved product from both of these receptors. The clinical relevance of the different receptor types is unknown. We examined the gene expression of GHR and GHRtr in human adipose tissue and skeletal muscle and the influence of GH treatment on this expression. Furthermore, we studied the relationship of circulating GHBP and body composition to GHR and GHRtr gene expression. Eleven adult GH-deficient patients were studied before and after 4 months of GH substitution therapy. Abdominal fat obtained by liposuction and femoral muscle biopsies were taken at baseline and after 4 months. Gene expression of GHR and GHRtr in adipose tissue and skeletal muscle was determined and expressed relative to the expression of beta-actin. Gene expression of GHR in abdominal sc adipose tissue was not altered, whereas the expression of GHRtr increased significantly. In skeletal muscle inverse changes were seen in the expression of messenger ribonucleic acid (mRNA) levels for the two GH receptor forms: expression of GHR increased significantly, whereas mRNA levels for GHRtr decreased. As expected, body composition changed with reduction of body fat mass after 4 months of GH treatment. Levels of circulating GHBP decreased significantly. We conclude that GH treatment in GH-deficient adults changes the expression of mRNA for GHR and GHRtr in adipose tissue and skeletal muscle. Whether these changes are responsible for the observed changes in body composition in response to GH treatment and the observed changes in levels of circulating GHBP, however, needs further elucidation.

The effect of 30 months of low-dose replacement therapy with recombinant human growth hormone (rhGH) on insulin and C-peptide kinetics, insulin secretion, insulin sensitivity, glucose effectiveness, and body composition in GH-deficient adults.

The aim of the present study was to evaluate the long-term (30 months) metabolic effects of recombinant human GH (rhGH) given in a mean dose of 6.7 microg/kg x day (= 1.6 IU/day), in 11 patients with adult GH deficiency. Glucose metabolism was evaluated by an oral glucose tolerance test and an iv (frequently sampled iv glucose tolerance test) glucose tolerance test, and body composition was estimated by dual-energy x-ray absorptiometry. Treatment with rhGH induced persistent favorable changes in body composition, with a 10% increase in lean body mass (P < 0.001) and a 12% reduction of fat mass (P < 0.002); however, the glucose tolerance deteriorated significantly, and three patients developed impaired glucose tolerance. Fasting insulin level (P < 0.003) and the homeostasis model assessment insulin resistance score increased significantly, indicating a deterioration in insulin sensitivity; whereas the insulin sensitivity index, calculated from the frequently sampled iv glucose tolerance test, only decreased slightly. The clearance of C-peptide and insulin increased 100% and 60%, respectively, and the prehepatic insulin secretion was tripled during rhGH treatment; but related to the impairment in glucose tolerance, beta-cell response was still inappropriate. Our conclusion is that long-term rhGH-replacement therapy in GH deficiency adults induced a significant deterioration in glucose tolerance, profound changes in kinetics of C-peptide, and insulin and prehepatic insulin secretion, despite an increase in lean body mass and a reduction of fat mass. Therefore, rhGH treatment may precipitate diabetes in some patients already susceptible to the disorder.

Circulating levels of incretin hormones and amylin in the fasting state and after oral glucose in GH-deficient patients before and after GH replacement: a placebo-controlled study.

OBJECTIVE: Hyperinsulinemia in association with GH excess is considered a compensatory response to insulin resistance, but the possibility of alternative insulinotropic mechanisms has not been investigated in vivo. It is also unknown how GH influences the secretion from pancreatic beta-cells of amylin, a peptide which regulates prandial glucose homeostasis and may be linked to development of beta-cell dysfunction. We therefore measured plasma concentrations of two gut insulinotropic hormones, glucagon-like peptide 1 (GLP-1) and glucose-dependent insulin-releasing peptide (GIP), and total as well as non-glycosylated amylin, in 24 GH-deficient adults before and after 4 months of GH replacement (daily evening injections of 2 IU GH/m). DESIGN: Double-blind, placebo-controlled, parallel study. METHODS: All participants underwent an oral glucose tolerance test (OGTT) at 0 and 4 months. RESULTS: A 33% suppression of fasting GLP-1 concentrations was measured in the GH group at 4 months (P=0.02), whereas a non-significant increase occurred in the placebo group (P=0.08). Fasting levels of GIP and amylin did not change significantly after 4 months in either group. The incremental response in GLP-1 during the OGTT was significantly lower after GH treatment as compared with both baseline (P=0.02) and the response in the placebo group (P=0. 03). The stimulation of GIP secretion following OGTT was similar on all occasions. The OGTT-induced incremental response in non-glycosylated amylin was moderately elevated after GH treatment as compared with placebo (P=0.05). Plasma concentrations of glucose and insulin, both in the fasting state and after the OGTT, were higher after GH treatment, but the ratio between amylin and insulin remained unchanged. CONCLUSIONS: GH-induced hyperinsulinemia is accompanied by proportionate elevations in amylin concentrations and a blunting of gut GLP-1 secretion. The mechanisms underlying the suppression of GLP-1 remain to be elucidated.

Improved postprandial glycaemic control with insulin Aspart in type 2 diabetic patients treated with insulin.

The effect on postprandial blood glucose control of an immediately pre-meal injection of the rapid acting insulin analogue Aspart (IAsp) was compared with that of human insulin Actrapid injected immediately or 30 minutes before a test meal in insulin-treated type 2 diabetic patients with residual beta-cell function. In a double-blind, double dummy crossover design, patients attended three study days where the following insulin injections in combination with placebo were given in a random order: IAsp (0.15 IU/kg body weight) immediately before the meal, or insulin Actrapid (0.15 IU/kg) immediately (Act0) or 30 minutes before (Act-30) a test meal. We studied 25 insulin-requiring type 2 diabetic patients, including 14 males and 11 females, with a mean age of 59.7 years (range, 43-71), body mass index 28.3 kg/m2 (range, 21.9-35.0), HbA1c 8.5% (range, 6.8-10.0), glucagon-stimulated C-peptide 1.0 nmol/l (range, 0.3-2.5) and diabetes duration 12.5 years (range, 3.0-26.0). Twenty-two patients completed the study. A significantly improved postprandial glucose control was demonstrated with IAsp as compared to Act0, based on a significantly smaller postprandial blood glucose excursion (IAsp, 899 +/- 609 (SD) mmol/l.min versus Act0, 1102 +/- 497 mmol/l min, p < 0.01) and supported by a significantly lower maximum serum glucose concentration (Cmax) up to 360 min after dosing (IAsp, 10.8 +/- 2.2 mmol/l vs. Act0, 12.0 +/- 2.4 mmol/l, p < 0.02). No difference was demonstrated in glucose endpoints between IAsp, administered with a meal and Actrapid injected 30 minutes before the meal (AUCglucose IAsp, 899 +/- 609 mmol/l min vs. Act-30, 868 +/- 374 mmol/l min; Cmax IAsp, 10.8 +/- 2.2 mmol/l vs. Act-30, 11.1 +/- 1.8 mmol/l). No concerns about the safety of IAsp were raised. Immediate pre-meal administration of the rapid-acting insulin analogue Aspart in patients with type 2 diabetes resulted in an improved postprandial glucose control compared to Actrapid injected immediately before the meal, but showed similar control compared to Actrapid injected 30 minutes before the meal. These results indicate that the improved glucose control previously demonstrated with insulin Aspart compared to human insulin in healthy subjects and type 1 diabetic patients also applies to insulin-treated type 2 diabetic patients.

Bone mineral metabolism, bone mineral density, and body composition in patients with chronic pancreatitis and pancreatic exocrine insufficiency.

BACKGROUND: Calcium and vitamin D homeostasis seem to be abnormal in patients with exocrine pancreatic dysfunction resulting from cystic fibrosis. Only a few studies have evaluated and described bone mineral metabolism in patients with chronic pancreatitis and pancreatic insufficiency. METHODS: Thirty-two patients with chronic pancreatitis and residual exocrine pancreatic function (group 1) and 26 patients with pancreatic exocrine insufficiency (i.e., meal-stimulated intraduodenal lipase <10% of lowest normal range and steatorrhea) (group 2) were studied. Serum levels of total calcium, phosphate, 25 (OH)D, 1.25(OH)2D, alkaline phosphatase, and parathyroid hormone were measured. Bone mineral density (BMD), bone mineral content (BMC), lean body mass (LBM), and fat mass (FM) were measured using a dual-energy X-ray absorptiometry (DXA) scanner. RESULTS: Alcohol was a causative factor in 79% of the patients. Fifty-six percent in group 1 and 69% in group 2 had Z-scores of the BMD < -1. The mean Z-score was -1.16 +/- 1.29 in group 1 and -1.32 +/- 0.90 in group 2. The mean Z-score of the BMC was -1.02 +/- 1.17 vs -1.39 +/- 0.987. In both groups mean 25 (OH)D and mean 1.25(OH)2D were below reference range. Plasma concentrations of albumin-corrected calcium, alkaline phosphatase, and parathyroid hormone were in the upper range of the reference range. Mean Z-scores of LBM were -0.69 +/- 1.34 in group 1 vs -1.01 +/- 1.12 in group 2 and Z-scores of FM were -0.27 +/- 1.70 in group 1 vs -0.95 +/- 1.01 in group 2 (p <0.05). CONCLUSION: Patients with chronic pancreatitis, in particular patients with advanced disease and steatorrhea, are at risk of developing significant bone loss. Despite normal body mass index the patients are characterized by loss of lean body mass and fat mass. The present study shows that these patients have decreased serum levels of vitamin D metabolites and low bone mass.

The effect of the deterioration of insulin sensitivity on beta-cell function in growth-hormone-deficient adults following 4-month growth hormone replacement therapy.

The purpose of the present study was to evaluate the combined effect of GH treatment on body composition and glucose metabolism, with special focus on beta-cell function in adult GHD patients. In a double-blind placebo-controlled design, 24 GHD adults (18M/6F), were randomized to 4 months treatment with biosynthetic GH 2 IU/m2s.c. daily (n =13) or placebo (n =11). At inclusion and 4 months later an oral glucose tolerance test (OGTT), a frequently sampled intravenous glucose tolerance test (FSIGT) and dual-energy X-ray absorptiometry (DXA) whole-body scanning were performed. During the study period, body weight decreased 1.6 kg from 94.0 +/- 18.7 to 92.4 +/- 19.4 kg (mean +/- SD) (P<0.05) in the GH-treated group, but remained unchanged in the placebo group. Fat mass decreased from 32.4 +/- 9.6 to 28.1 +/- 10.5 kg (P<0.001), whereas lean body mass increased from 58.3 +/- 11.5 to 61.0 +/- 11.7 kg (P<0.01) in the GH-treated group. Treatment with GH for 4 months resulted in a significant increase in fasting blood glucose (before GH 5.0 +/- 0.3 and after 5.4 +/- 0.6 mmol/l, P<0.05), fasting plasma insulin (before GH 38.4 +/- 30.2 and after 55.3 +/- 34.7 pmol/l, P<0.02) and fasting proinsulin (before 8. 1 +/- 6.7 and after 14.6 +/- 16.1 pmol/l, P<0.05). The insulin sensitivity index SI, estimated by Bergmans Minimal Model, decreased significantly [before GH 1.1 +/- 0.7 and after 0.4 +/- 0.2 10(-4)(min x pmol/l), P<0.003]. The non-insulin-dependent glucose uptake (glucose effectiveness SG did not change (before GH 0.017 +/- 0.005 and after 0.015 +/- 0.006 min-1, NS). Insulin secretion was enhanced during GH therapy, but insufficiently to match the changes in SI, resulting in a higher blood glucose level during an OGTT. Blood glucose at 120 min was 5.5 and 6.3 mmol/l before and after GH treatment, respectively (P = 0.07). One patient developed impaired glucose tolerance. Short-term GH replacement therapy in a dose of about 2 IU/m2 daily in GHD adults induces a reduction in insulin sensitivity, despite favourable changes in body composition, and an inadequate enhancement of insulin secretion.

Long-term effects of growth hormone (GH) on body fluid distribution in GH deficient adults: a four months double blind placebo controlled trial.

OBJECTIVE: Short-term growth hormone (GH) treatment normalises body fluid distribution in adult GH deficient patients, but the impact of long-term treatment on body fluid homeostasis has hitherto not been thoroughly examined in placebo controlled trials. To investigate if the water retaining effect of GH persists for a longer time we examined the impact of 4 months GH treatment on extracellular volume (ECV) and plasma volume (PV) in GH deficient adults. DESIGN: Twenty-four (18 male, 6 female) adult GH deficient patients aged 25-64 years were included and received either GH (n=11) or placebo (n=13) in a double blind parallel design. METHODS: Before and at the end of each 4 month period ECV and PV were assessed directly using 82Br- and 125I-albumin respectively, and blood samples were obtained. RESULTS: During GH treatment ECV increased significantly (before: 20.48+/-0.99 l, 4 months: 23.77+/-1.38 l (P<0.01)), but remained unchanged during placebo administration (before: 16.92+/-1.01 l, 4 months: 17.60+/-1.24 l (P=0.37)). The difference between the groups was significant (P<0.05). GH treatment also increased PV (before: 3.39+/-0.27 l. 4 months: 3.71+/-0.261 (P=0.01)), although an insignificant increase in the placebo treated patients (before: 2.81+/-0.18 l, 4 months: 2.89+/-0.20 l (P=0.37)) resulted in an insignificant treatment effect (P=0.07). Serum insulin-like growth factor-I increased significantly during GH treatment and was not affected by placebo treatment. Plasma renin (mIU/l) increased during GH administration (before: 14.73+/-2.16, 4 months: 26.00+/-6.22 (P=0.03)) and remained unchanged following placebo (before: 20.77+/-5.13, 4 months: 20.69+/-6.67 (P=0.99)) leaving no significant treatment effect (P=0.08). CONCLUSION: The long-term impact of GH treatment on body fluid distribution in adult GH deficient patients involves expansion of ECV and probably also PV. These data substantiate the role of GH as a regulator of fluid homeostasis in adult GH deficiency.

Serum leptin levels and leptin expression in growth hormone (GH)-deficient and healthy adults: influence of GH treatment, gender, and fasting.

Growth hormone (GH) treatment is associated with a reduction in fat mass in healthy and GH-deficient (GHD) subjects. This is mainly mediated via a direct GH action on adipose cells and stimulation of lipolysis. Leptin is secreted from adipose tissue and may be involved in signaling information about adipose tissue stores to the brain. Hormonal regulation of leptin is still not fully elucidated, and in the present study, we investigated both the long-term (4-month) and short-term (28-hour) GH effects on serum leptin and leptin gene expression in subcutaneous adipose tissue. In GHD adults (n = 24), leptin correlated with most estimates of adiposity (r = .62 to .86), as previously found in healthy subjects. However, no correlation was observed with intraabdominal fat determined by computed tomographic (CT) scan (INTRA-CT). GH treatment for 4 months had no independent effect on either serum leptin or leptin gene expression. In a short-term study, we found that fasting gradually reduced leptin levels in both healthy men and GHD adults, with a maximum reduction of 58% to 60% (P < .01) after 31 hours. No independent effect of GH suppression or GH substitution on serum leptin was found during fasting. Adipose tissue leptin mRNA correlated with serum leptin (r = .51, P < .01) and the body mass index ([BMI] r = .55, P < .05). Serum leptin levels and gene expression were significantly higher in women compared with men (26.6 +/- 5.8 v 10.0 +/- 1.30 ng/mL, P < .05). However, in regression analysis accounting for the gender differences in subcutaneous femoral adipose tissue (FEM-CT), the difference in serum leptin disappeared, indicating that subcutaneous femoral fat or factors closely related to femoral fat (eg, sex hormones) may be causal factors for the gender difference in leptin.

Body composition in normal subjects: relation to lipid and glucose variables.

OBJECTIVE: To describe sex- and age-dependent values of total and regional body composition as determined by dual-energy X-ray absorptiometry (DXA) in normal subjects, and furthermore to relate body composition measurements to blood lipids, glucose and insulin concentrations. DESIGN: A cross-sectional study. SUBJECTS: 173 (84 male and 89 female) healthy subjects, BMI < 30 kg/m2. MEASUREMENTS: Body composition parameters including data on total bone mineral content (TBMC), total bone mineral density (TBMD), lean body soft tissue mass (LTM), total and regional fat mass (FM) were estimated in all subjects. In 87 of the subjects fasting blood glucose, S-insulin and lipid profile were measured. RESULTS: The study population was for each sex divided into five decades for which results on body composition and blood lipids are presented. Body weight increased 2 kg per age decade, representing a significant increase in both total FM and relative FM (FM%BW) with age, and in males a central accumulation of FM. LTM decreased significantly in males but not in females, whereas TBMC and TBMD remained constant in males, but decreased in females. A significant correlation between relative FM and S-cholesterol, S-triglyceride, and in males S-insulin was found. CONCLUSION: The present study gives coherent data on bone mineral content, lean body soft tissue mass total and regional fat mass for 173 healthy subjects with a BMI below 30 kg/m2. Total body fat mass increases, and lean mass decreases with age. In males a simultaneous central accumulation of fat mass is observed. The well-known relationship between central obesity and lipids is confirmed even in non-obese subjects.

Validity of dual X-ray absorptiometry scanning for determination of body composition in IDDM patients.

Data on body composition in patients with insulin-dependent diabetes mellitus (IDDM) are scarce. Dual X-ray absorptiometry (DXA) scanning has proved useful for this purpose in other groups of patients. We tested the validity of the DXA scanner for the determination of fat-free mass (FFM) and fat mass in IDDM patients and control subjects, as compared to other reference methods, i.e. total body potassium by 40K whole body counting (TBK), total body water by tritiated water (TBW), bioelectrical impedance analysis (BIA) and 24-h urinary creatinine excretion (Ucrea). A total of 13 healthy controls, 5 males and 8 females, aged 34.2 years +/- SD 10.4, and 11 IDDM patients, 5 males, 6 females, aged 28.1 years +/- 7.3, diabetes duration 4.2 +/- 2.9 (1.0-9.9), were examined. The patients had no long-term diabetic complications and they had normal ophthalmoscopy and urine albumin excretion. The agreement between FFM estimated by DXA and the other methods, expressed as mean difference +/- 2 SD was; for DXA vs. TBK, 0.09 +/- 6.26 and 0.50 +/- 5.26 kg for controls and IDDM patients respectively; DXA vs. TBW, -2.07 +/- 2.56 and -1.07 +/- 4.58 kg; DXA vs. Ucrea, -2.62 +/- 8.02 and 2.00 +/- 10.0 kg; DXA vs. BIA, -7.90 +/- 8.92 and -7.85 +/- 2.32 kg. The results obtained with BIA were significantly different from the other methods for both control subjects and IDDM patients. In conclusion, DXA scanning is a precise and valid method for estimation of fat-free mass in IDDM patients.

Creatinine height index and lean body mass in adult patients with insulin-dependent diabetes mellitus followed for 7 years from onset.

The 24-hour urinary creatinine excretion value can be used as an index of protein nutrition; the creatinine height index and lean body mass can be estimated from this value. On the basis of longitudinally measured 24-hour urinary creatinine excretions during the initial 7 years of type 1 diabetes in an incidence cohort of 147 adult patients, we studied creatinine height index and lean body mass and possible relationships to sequential measurements of glycated hemoglobin (HbA1c). The patients were divided into four groups according to their glycemic control during these 7 years: I, HbA1c < 7.4% (n = 37); II, HbA1c 7.4% to 8.2% (n = 37); III, HbA1c 8.3% to 8.9% (n = 38); IV, HbA1c > 8.9% (n = 35). One year after the onset of diabetes, height indices were as follows (% of normal values, median and quartiles): I, 104% (90 to 116); II, 101% (78 to 105); III, 121% (92 to 128); IV, 87% (78 to 109) ([IV] < [I to III]; p < .05). During the following 6 years no significant differences in height index were observed among the four groups of patients at any point in time. Slightly higher calculated lean body mass values were found in the most well-controlled patients, but otherwise no differences were found in lean body mass. It is concluded that, apart from the first year, indices of protein nutrition remain normal during the initial 7 years of type 1 diabetes, even in patients with poor glycemic control.

Nocturnal versus diurnal hormonal counterregulation to hypoglycemia in type 1 (insulin-dependent) diabetic patients.

UNLABELLED: Asymptomatic hypoglycemia in IDDM patients seems to be more frequent during the night than during the day, with reported frequencies as high as 56%. Hormonal counterregulation to diurnal and nocturnal hypoglycemia was studied in 10 insulin-dependent diabetic patients without diabetic complications in order to test whether hormonal responses were lower at night than during daytime. A lower catecholamine response might imply less marked symptoms and therefore one reason why patients are not awakened by hypoglycemia. Blood glucose was stabilized to around 6 mmol/l by iv insulin infusion and hypoglycemia was induced by increasing the insulin infusion rate--in the night studies at 01.30, in the day studies at 08.00. Blood glucose nadirs were 1.5 +/- 0.4 (1.2-1.9) mmol/l at night and 1.9 +/- 0.3 (1.3-2.2) mmol/l during the day; in the three patients the nadirs were identical during both the night and day. One patient had no adrenaline response to daytime hypoglycemia. In general, nocturnal hypoglycemia elicited greater catecholamine responses correlated to the duration of hypoglycemia. Glucagon responses showed a great heterogeneity independently of diabetes duration and hypoglycemic level. Growth hormone secretion was reduced during the night study; however, no refractory periods were found after sleep-related growth hormone secretion. IN CONCLUSION: counter-regulatory hormonal responses tend to be greater at night than during the day and do not explain why patients are not awakened by nocturnal hypoglycemia.

The Diva System, a computerized diary, used in young type 1 diabetic patients.

UNLABELLED: The purpose of the present study was to evaluate the clinical efficiency of a computer bases registration- and analysis-system, Diva System, designed for the support of diabetes care. Fifty six boys aged 14-20 years with a diabetes duration of more than two years and HbA1c above 8% were allocated to one of three groups: 1) Diva group: Diva supported intensified outpatient regimen n = 9, 2) Control group A: Intensified outpatient control n = 7, and 3) Control group B: Conventional outpatient control n = 40. The patients were followed for a period of twelve months, in which the Diva group patients used the system during the first six months. In this period the HbA1c decreased significantly in the Diva group, 1.6% p < 0.001, compared to only a slight decrease in the two control groups, 0.3 and 0.4% respectively, ns. IN CONCLUSION: The Diva System seems to be a supportive tool, which might assist the patients to better self care and thereby to improved metabolic control. However, the use of the computer system is time consuming.