Glycaemic variability and hypoglycaemia are associated with C-peptide levels in insulin-treated type 2 diabetes.

AIM: The aim of the study was to evaluate the association between C-peptide levels, glycaemic variability and hypoglycaemia in patients with insulin-treated type 2 diabetes (T2D). METHODS: A total of 98 patients with T2D treated with basal-bolus insulin were enrolled in a cross-sectional study. Glycaemic variability and hypoglycaemia were assessed from continuous glucose monitoring (CGM) data recorded over 6 days: Glycemic variability was assessed by calculating the mean coefficient of variation (CV), while hypoglycemia was defined as sensor glucose levels ≤ 3.9 mmol/L or < 3.0 mmol/L. Fasting C-peptide and fasting glucose were measured on day 1. RESULTS: Low levels of fasting C-peptide correlated with higher CV (r = -0.53, P < 0.0001). In a multivariate regression model with HbA1c, body mass index, diabetes duration and total daily insulin dose, only C-peptide was significantly associated with CV. Patients with ≥ 1 episode of hypoglycaemia had significantly lower median C-peptide levels than patients without hypoglycaemia (274 (136-620) pmol/L vs. 675 (445-1013) pmol/L, respectively; P = 0.0004). Also, 17 patients clinically diagnosed with T2D had detectable glutamic acid decarboxylase (GAD) antibodies (≥ 5 U/mL). These GAD-positive patients had significantly lower fasting C-peptide, higher CV and greater frequency of hypoglycaemia than GAD-negative patients. CONCLUSION: In patients with insulin-treated T2D, low levels of C-peptide are associated with greater glycaemic variability and higher risk of hypoglycaemia, suggesting that C-peptide levels should be taken into consideration when optimizing insulin treatment and assessing hypoglycaemia risk.

Massive weight loss restores 24-hour growth hormone release profiles and serum insulin-like growth factor-I levels in obese subjects.

In the present study, we 1) determined whether the impaired spontaneous 24-h GH secretion as well as the blunted GH response to provocative testing in obese subjects are persistent disorders or transient defects reversed with weight loss and 2) investigated 24-h urinary GH excretion and basal levels of insulin-like growth factor-I (IGF-I), IGF-binding protein-3 (IGFBP-3), as well as insulin in obese subjects before and after a massive weight loss. We studied 18 obese subjects (age, 26 +/- 1 yr; body mass index, 40.9 +/- 1.1 kg/m2); 18 normal age-, and sex-matched control subjects; and 9 reduced weight obese subjects after a diet-induced average weight loss of 30.3 +/- 4.6 kg. Twenty-four-hour spontaneous GH secretion was estimated by obtaining 3240 integrated 20-min blood samples using a constant blood withdrawal technique and computerized algorithms. Body composition was determined using anthropometric measurements and dual energy x-ray absorptiometry scanning (DXA). In the obese subjects, 24-h spontaneous GH release profiles and the GH responses to insulin-induced hypoglycemia and L-arginine as well as basal IGF-I levels and the IGF-I/IGFBP-3 molar ratio were decreased, whereas insulin levels were elevated compared to those in normal subjects. In obese subjects, 24-h spontaneous GH secretion and serum IGF-I levels were inversely related to abdominal fat (r = -0.67; P < 0.01) and percent body fat (r = -0.69; P < 0.01), respectively. The decreased 24-h spontaneous GH release profiles, the decreased GH responses to insulin-induced hypoglycemia and L-arginine, the decreased basal IGF-I levels and IGF-I/IGFBP-3 molar ratio, as well as the elevated insulin levels were returned to normal after a massive weight loss in the obese subjects. In conclusion, the present study has shown reversible defects in 24-h spontaneous GH release profiles, basal IGF-I levels, and the IGF-I/IGFBP-3 molar ratio in obese subjects. The recovery of the 24-h GH release points to an acquired transient defect rather than a persistent preexisting disorder.

Measurement of body fat in elderly subjects by dual-energy x-ray absorptiometry, bioelectrical impedance, and anthropometry.

Body fat was measured in 46 elderly subjects by dual-energy x-ray absorptiometry [BF(DEXA)], bioelectrical impedance analysis (BIA), and anthropometry. Equations for prediction of the body fat (by DEXA) of elderly people by BIA and/or anthropometry were developed. The prediction of body fat (by DEXA) by anthropometric variables alone gave an r2 of 0.94 and the corresponding SEEs were 1.61 kg for men and 2.43 kg for women. When BIA variables were added as predictors, r2 increased by 2-5% (P less than 0.05) and the corresponding SEE decreased by 25% (P less than 0.05). The prediction of body fat (by DEXA) in elderly subjects and by BIA or anthropometry with equations developed in populations of young healthy adults (adapted from the literature) was generally not good although the correlation coefficients were high (r greater than 0.9, P less than 0.001), which suggests that our equations may improve prediction of body fat in elderly subjects.

Iliac crest biopsy: representativity for the amount of mineralized bone.

The aim of the study was to evaluate the representativity of iliac crest biopsy for the amount of mineralized trabecular and cortical bone in the skeleton. The following data were obtained on bone from 14 necropsies: right sided iliac crest biopsy, lumbar spine biopsy, dry fat free weight of lumbar spine, bone mineral density (BMD) in the lumbar spine and dry fat free weight of cortical and trabecular bone from the left distal forearm. The amount of mineralized cortical and trabecular bone from various sites was compared by linear regression analysis. The results confirm iliac crest biopsy as a good predictor of the amount of trabecular bone, but not of cortical bone. Furthermore, iliac crest biopsy is a better estimate of the amount of trabecular bone in the lumbar spine than spinal BMD.

Bone mass, bone structure and vertebral fractures in osteoporotic patients.

The clinical severity of bone disease was studied in 44 post-menopausal osteoporotic women. Spinal x-rays were assessed and compared to objective measurements of bone mass and bone structure; forearm bone mineral content (BMCarm) by single photon absorptiometry, total body bone mineral content (TBBM), and spinal bone mineral content (BMCspine) by dual photon absorptiometry, and corrected cortical width (C Cor W), trabecular bone volume (TBV), and indices of trabecular microstructure by iliac crest biopsy. For comparison data of BMCarm, TBBM and BMCspine in 25 post-menopausal normals are shown. The results showed a reduction in amount of both cortical and trabecular bone in the fracture patients compared to normals. A subdivision of the fracture patients into two groups constituting 26 patients with wedge fractures alone and 18 patients with compression (+wedge) fractures showed that the latter group had a further predominantly trabecular bone loss and a further deteriorated trabecular microstructure. On an individual basis no agreement between clinical severity of bone disease and amount and structure of bone could be demonstrated.

Comparison of single- and dual-photon absorptiometry in postmenopausal bone mineral loss.

We describe a single photon absorptiometric (SPA) technique, which enables differential estimation of the rates of loss from trabecular and cortical bone. Ten scans are obtained in the forearm: six in an area with about 7% trabecular bone and four scans in the adjacent distal area with a trabecular bone content of 25%. By comparing bone masses of these two sites in 19 postmenopausal and 53 premenopausal women, the postmenopausal trabecular bone loss was estimated to be approximately seven times greater than cortical loss within the first years of cessation of regular vaginal bleeding. On a group basis the bone loss at the distal forearm scan site (by SPA) corresponded closely to the spinal bone loss (by dual-photon absorptiometry). The reproducibility of the two scan sites in the forearm was 1-1.5% (CV%), which makes the method suitable for longitudinal studies. Corrections for variations in fatty tissue covering can be made without deterioration of the reproducibility. The high precision can only be achieved with a good calibration procedure; if calibration is not done the reproducibility error increases two- or threefold.

Usefulness of regional bone measurements in patients with osteoporotic fractures of the spine and distal forearm.

Bone mineral mass was measured in normal subjects and osteoporotic patients at two forearm sites (proximal and distal of the 8 mm site between the two forearm bones) by single photon absorptiometry and in the spine and whole body by dual photon absorptiometry. There were no signs of preferential low spinal bone mass in 28 patients with vertebral fractures. Their bone mass was at all sites 26% to 37% lower than the premenopausal mean value and 7% to 13% lower than in age-matched normal women. In 45 patients with forearm fractures bone reduction was also universal but only 3% to 6% lower than in healthy women of comparable age. The spinal bone mass in all the patients was significantly related to both forearm measurements with coefficients of correlation of 0.58-0.61 and s.e.e. of 18%. Compared to the premenopausal normal range the distal forearm site had a greater sensitivity in identifying patients with vertebral fractures than had the spinal measurement (chi-square test, p less than 0.01). We thus conclude that patients with vertebral fractures have universal osteoporosis and that measurement of spinal BMC had no predictive advantages over that of the forearm bone mass for population studies.

Accuracy of lumbar spine bone mineral content by dual photon absorptiometry.

The accuracy of measurement of the bone mineral content (BMC, g) and bone mineral density (BMD, g/cm2) of the lumbar spine by dual photon absorptiometry (DPA) was estimated by means of two different spine scanners (a Nuclear Data 2100 and a Lunar Radiation DP3). The lumbar spines of 13 cadavers were used. BMC and BMD were measured in situ and on the excised vertebrae in a solution of water/ethanol; and covered with ox muscle/porcine muscle/lard. The actual mineral weight and areal density were determined after chemical maceration, fat extraction, drying to a constant weight, ashing for 24 hr at 600 degrees C, and correction for the transverse processes. The true are was measured by parallax free X rays and planimetry. All measurements of BMC or BMD were highly interrelated (r = 0.94-0.99). The standard error of estimate (s.e.e.) of BMC in situ versus BMC in water/ethanol was 5.2%. The agreement between the BMD values of the two scanners was very good (s.e.e. = 2.9%). BMC in situ predicted the actual vertebral mineral mass with an s.e.e. of 8.1%. BMD in situ and BMD in water/ethanol predicted the actual area density with s.e.e.s of 10.3% and 5.0%, respectively. This study discloses the correlation and accuracy error of spinal DPA measurements in situ in whole cadavers versus the actual BMC and BMD. The error, which is underestimated in in vitro studies, amounts to 10%.

Prediction of body composition by age, height, weight, and skinfold thickness in normal adults.

In order to establish an easy and reliable method for estimating body composition, the lean body mass (LBM) and the fat mass (FM) were measured in vivo in 228 normal adults (130 women and 98 men) using dual photon (153Gd) absorptiometry. In addition, skinfold thickness was measured at two sites in each subject. Multiple regression equations of LBM and FM based on age, height, and weight were computed (r = .86 to .95, SEE = 2.1 to 2.9 kg). These correlations were only slightly improved in men, but not in women, when the results of the skinfold measurements were included in the calculations. We conclude that LBM and FM can be estimated in normal adults from age, height, and weight with a predictive error below 3 kg.

Measurement of lean body mass and total body fat using dual photon absorptiometry.

We describe a method for measuring the lean body mass (LBM) and total body fat (FAT) by dual photon absorptiometry (DPA). A total body rectilinear scan was employed with a radiation source of 1 Ci 153Gd. The reliability of estimating the lean percent was assessed in vitro using limb phantoms consisting of ox muscle, lard, and human bone. The precision and accuracy in vitro of the lean percent determination were 1.5% and 1.9%, respectively. The accuracy error in vivo of measuring the total mass of soft tissues (TMST) was approximately 1.4%, thus yielding an overall accuracy error of the LBM of about 2.5%. The precision in vivo of the lean percent and the LBM in kg of duplicate measurements on five healthy subjects was 2.5% and 2.2%, respectively. Other estimates of the LBM and FAT, ie, the calculation according to Boddy et al6 and the skinfold thickness measurement (triceps and subscapular), were compared to the DPA measurement in 100 healthy subjects. High correlations were found between the FAT or FAT% by DPA versus (1) the FAT or FAT% calculated according to the formulae of Boddy et al, and (2) the skinfold thickness. The correlations between the FAT and FAT% by Boddy et al and the skinfold thickness were, however, moderate. The correlation between LBM by DPA and LBM by Boddy et al was highly significant (r = 0.96, SEE = 4.4%). We conclude that LBM and FAT measurements using DPA have precision and accuracy errors that are commensurate with a reliable estimation of the gross body composition.(ABSTRACT TRUNCATED AT 250 WORDS)

Postmenopausal hormone replacement therapy prevents central distribution of body fat after menopause.

The reduction in cardiovascular risk induced by hormone replacement therapy is only partly explained by changes in serum lipids and lipoproteins. As body composition and body fat distribution in particular are independent predictors of cardiovascular disease, we investigated the effect of postmenopausal hormone therapy on body composition parameters directly measured. Sixty-two early postmenopausal women were followed up for 2 years in a prospective, randomized, placebo-controlled study. We found that combined estrogen-progestogen therapy prevented the increase in abdominal fat after menopause (P less than .05), and that this effect was independent of the effect on serum lipids and lipoproteins. The therapy reduced postmenopausal bone loss significantly (P less than .001), whereas it did not have a statistically significant influence on total body fat mass or total lean body mass. The findings of the present study suggest that some of the protective impact of postmenopausal hormone therapy on cardiovascular disease may be explained by the effect on body composition, in particular abdominal fat.

Body composition analysis by DEXA by using dynamically changing samarium filtration.

Dual-energy X-ray absorptiometry (DEXA) has a high accuracy for body composition analysis but is influenced by beam hardening and other error sources in the extremes of measurement. To compensate for beam hardening, the Norland XR-36 introduces a dynamically changing samarium filtration system, which depends on the current-absorber thickness. With this system we found a good agreement (r = 0.99) between reference and measured amounts of tissue or fat percentages in a plastic phantom and in smaller (approximately 0.5-4 kg) and larger (approximately 5-20 kg) piles of tissue (ox muscle and lard). Scans of six healthy volunteers covered with combinations of beef and lard (approximately 5-15 kg) showed a good agreement (r = 0.99) between reference and DEXA values of added soft tissue mass and fat percentage. We conclude that the DEXA method (and, in particular, the Norland XR-36 using dynamic filtration) has a high accuracy for body composition analysis. It has a potential for gaining status as a reference method in the future and may presently be used as a supplement to the traditional methods for body composition analysis.

Renal hypouricaemia in insulin treated diabetes mellitus.

Uric acid metabolism was investigated in 69 insulin-treated male diabetic outpatients and in 23 healthy male subjects, because of a reported coincidence between diabetes and gout. All subjects had normal serum creatinine concentrations and none received diuretic treatments. Compared with normal, the diabetics had significantly lower mean serum uric acid concentrations (0.34 +/- 0.08 (SD) mmol/l versus 0.23 +/- 0.06 mmol/l, p less than 0.001). 17% of the diabetic patients had serum concentrations below the normal mean--2 SD. In contrast, the diabetic patients had a 42% increase in renal uric acid excretion rate (p less than 0.01), and an 83% increase in the ratio of uric acid clearance/creatinine clearance (p less than 0.001). These indices of renal uric acid excretion were both positively correlated to fasting blood glucose levels (r=0.57, p less than 0.001, and r=0.50, p less than 0.001, respectively), to the degree of glycosuria (r=0.73, p less than 0.001, and r=0.63, p less than 0.001, respectively), and to the magnitude of water diuresis (r=0.60, p less than 0.001, and r=0.39, p less than 0.01, respectively). The hypouricaemia observed in these insulin-dependent diabetic male subjects may probably be caused by the increased renal excretion of uric acid in the presence of hyperglycaemia. The study gave no evidence of increased serum uric acid concentrations in insulin-dependent diabetics. It is therefore likely that any coincidence between gout and diabetes derives from other coexisting serum uric acid raising factors.

Effect of natural oestrogen/gestagen therapy on uric acid metabolism in post-menopausal women.

Uric acid metabolism was studied in groups of early post-menopausal women before and during long-term administration of natural oestrogen/gestagen (n = 21), bendroflumethiazide (n = 19) or placebo (n = 34). Serum uric acid rose definitely, by 13.0% during thiazide, and decreased slightly, by 4.9%, during hormone treatment. The latter deviation did not differ significantly from that of -2.9% seen in the placebo group. The urinary excretion rates of uric acid observed during thiazide and hormone treatment did not differ significantly from that of the placebo group. It is concluded, that within the present design of study, which readily permits detection of the well-known hyperuricaemic action of thiazide, oestrogen/gestagen hardly affects uric acid metabolism.

Precision in assessment of osteoporosis from spine radiographs.

Inter- and intra-observer variation in spine radiographs of 100 osteoporotic women and longitudinal change in roentgenologic status after 1 year of antiosteoporotic treatment were assessed. The method applied was naked eye inspection, and a score system estimating severity of fractures - vertebral deformation score (VDS). Agreement was assessed by the Kappa coefficient corrected for agreement by change. The results showed a satisfactory inter- and intraobserver agreement for wedge (Kappa = 0.72 and 0.90) and compression fractures (Kappa = 0.60 and 0.92). The method proved less reliable for endplate fractures (Kappa = 0.39 and 0.73). We think that the method of investigation is well suited for monitoring treatment effects in longitudinal studies.

Relationship between local and total bone mineral in patients with rheumatoid arthritis and normal subjects.

Total body bone mineral (TBBM) measured by dual photon absorptiometry and local bone mineral (BMC) measured by single photon absorptiometry were determined in 55 patients with definite or classical rheumatoid arthritis. All of them had been on a steady dose of anti-inflammatory drugs for at least 12 months, and furthermore, 13 patients were on glucocorticoids. The results were compared with 49 normal persons matched for sex, age and menopausal state. A highly significant correlation was found between BMC and TBBM in the patients (r = 0.84, SEE = 13.0%) as well as in the controls (r = 0.77, SEE 10.5%). Moreover, the intercepts and the slopes were virtually of the same order. Subdividing the patients according to glucocorticoid treatment the same high correlations were shown in the two subgroups. As a group the patients on glucocorticoids had a highly significant generalized osteopenia (a reduction of TBBM of 26% compared to normals). The patients on other anti-inflammatory drugs had a significant, but less pronounced generalized osteopenia (a reduction of TBBM by 11% compared to normals). It is concluded, that BMC of the forearm can be used as a valid estimate of total body calcium in groups of patients with rheumatoid arthritis and in normal subjects.

Does a single local absorptiometric bone measurement indicate the overall skeletal status? Implications for osteoporosis and osteoarthritis of the hip.

Regional bone mineral content (BMC) and density (BMD) (head, arms, chest, spine, pelvis, legs) of a total body dual photon 153Gd absorptiometry (DPA) scan were measured in 20 healthy postmenopausal women, 27 postmenopausal women with hip fracture, and 17 postmenopausal women with osteoarthritis of the hip. In addition, local BMC and BMD were measured in the proximal and distal regions of the distal forearm (BMCprox, BMDprox, BMCdist, BMDdist) by single photon absorptiometry (SPA); and in the lumbar spine (BMCL2-L4 and BMDL2-L4) by 153Gd DPA. The overall impression was a reduction of bone mass in hip fracture patients compared with healthy controls and an increase in the bone mass of osteoarthritic patients. These results were valid using both regional values of the total body scan, and local forearm and lumbar spine measurements, and statistically significant using one-way analysis of variance. There were, however, also significant within-group between-region differences (one-way analysis of variance), showing that the bone mass of the pelvis and legs in hip fracture patients was more reduced than in the remaining skeleton; in osteoarthritic patients it was not increased but rather unchanged or slightly reduced. The differences between the level of the three local measurements (BMDprox BMDdist BMDL2-L4), on the one hand, and the level of the six regional BMD values, on the other hand, were investigated by the two-way analysis of variance: local measurements = rows; regional values = columns. This analysis showed that none of the three local measurements was statistically better than the other two in predicting the overall level of skeletal bone mass as judged by the six regional values. We conclude that serious osteoporotic bone loss has a generalized nature, however, with a tendency towards lower values in the regions affected by fracture (viz: low bone mass in the legs of femoral neck fracture patients). Osteoarthritis may be associated with a high bone mass in most areas, but low values in the affected regions. Local lumbar spine measurement of bone mass by DPA is not superior to local forearm measurement of bone mass by SPA in predicting the nature of overall osteoporotic or osteoarthritic bone change.

[Non-invasive measurement of body composition]. / Ikkeinvasiv måling af kropssammensaetning.

The concept of body composition covers the division of the body into a number of compartments. The most important are the fat mass (FM), the fat-free mass (FFM), the total body protein and the total body bone mineral content. Numerous methods for the measurement of body composition are available. The three classical methods for the measurement of FM and FFM, namely underwater weighing, measurement of total body potassium and measurement of total body water by isotope dilution, are often regarded as reference methods. However, newer methods such as computed tomography, neutron activation analysis and dual energy X-ray absorptiometry are increasingly used because of their reliability and ability for independent measurement of two or more components. Bioelectrical impedance analysis has become popular because of its clinical applicability. Three- or four-compartment models involving combination of two, three or more separate methods are more accurate than single methods, but are usually confined to research purposes because of the laborious measurement procedures. Computed tomography and dual energy X-ray absorptiometry have the unique possibility of regional measurements of body composition. Fat distribution and relative overweight may be estimated by simple anthropometric measures such as skinfold thicknesses. There are many applications for body composition measurements in research and clinical practice. These include treatment of obesity, growth hormone deficiency, diabetes mellitus and climacteric changes, as well as clinical nutrition and estimation of the hydration of dialysis patients and of critically ill intensive or surgical patients.

[No increase in the prevalence of vertebral fractures among postmenopausal women over a 10-year period]. / Ingen stigning over ti år i praevalensen af columnafraktur blandt postmenopausale kvinder.

We examined whether the prevalence of vertebral fracture in otherwise healthy, 70-year-old Danish women had increased over a period of ten years. The population-based, epidemiological study included two age-matched, representative samples of postmenopausal women. Group 1 (1979) consisted of 173 healthy women without secondary causes of osteoporosis, Group 2 (1989) of 387 women. X-rays of the thoraco-lumbar spine were assessed for vertebral fracture by five radiological methods. There was no significant difference between the two groups in the prevalence of vertebral fracture and the 95% confidence intervals overlapped completely in all methods. The prevalence rates varied by method from 35% to 80% but the distribution of fracture types was similar in the two groups. We conclude that the prevalence of vertebral fractures due to postmenopausal osteoporosis has not increased since 1979 in suburban Copenhagen, and that comparison of prevalences requires the same method of radiological assessment.