Association of adipokines and estradiol with bone and carotid calcifications in postmenopausal women.

OBJECTIVES: Carotid artery calcifications (CAC) and high carotid artery intima-media thickness (cIMT) are associated with low bone mineral density (BMD) by unknown mechanisms in postmenopausal women. Leptin, adiponectin and estradiol may mediate these associations. Our aim was to study the relationships of the aforementioned factors to bone health (BMD) and carotid atherosclerosis (CAC and cIMT). METHOD: Participants (n = 290, mean age 73.6 years) for this cross-sectional OSTPRE-BBA study (Kuopio Osteoporosis Risk Factor and Prevention - Bone, Brain and Atherosclerosis) were randomly selected from the OSTPRE cohort in 2009. Femoral neck and total body BMDs, trunk and total body fat mass were measured with dual-energy X-ray absorptiometry, and cIMT (mm) and CAC (no/yes) were measured with B-type ultrasound. Free estradiol, adiponectin and leptin were measured from serum samples. RESULTS: Circulating estradiol levels were associated with leptin (ß = 0.131, p < 0.001), but not with adiponectin (p > 0.05), when adjusted for total body fat mass. There were no associations between estradiol tertiles and BMDs, or with cIMT or CAC. Adiponectin levels were inversely associated with femoral neck BMD (p = 0.019, ß = -0.138) and total body BMD (p = 0.009, ß = -0.142), adjusted for total body fat mass, age, current smoking and estradiol, but showed no relationship with CAC or cIMT. Leptin levels were not associated with BMDs or cIMT; but the odds ratio was 1.5 between the CAC and leptin quartiles (p = 0.014), adjusted for total body fat mass, age, statin use and calcium intake. CONCLUSION: The adipokines are associated with vascular calcification and low BMD. Moreover, estradiol was not independently associated with BMD or CAC.

Efficacy and tolerability of saxagliptin compared with glimepiride in elderly patients with type 2 diabetes: a randomized, controlled study (GENERATION).

AIMS: To assess the efficacy and safety of adjunctive saxagliptin vs glimepiride in elderly patients with type 2 diabetes (T2D) and inadequate glycaemic control. METHODS: In this multinational, randomized, double-blind, phase IIIb/IV study (GENERATION; NCT01006603), patients aged ≥65 years were randomized (1 : 1) to receive saxagliptin 5 mg/day or glimepiride ≤6 mg/day, added to metformin, during a 52-week treatment period. The primary endpoint was achievement of glycated haemoglobin (HbA1c) <7.0% at week 52 without confirmed/severe hypoglycaemia. The key secondary endpoint was incidence of confirmed/severe hypoglycaemia. Safety and tolerability were also assessed. RESULTS: Of 720 patients randomized (360 in each treatment group; mean age 72.6 years; mean T2D duration 7.6 years), 574 (79.8%) completed the study (saxagliptin 80.3%; glimepiride 79.2%). Similar proportions of patients achieved the primary endpoint with saxagliptin and glimepiride (37.9 vs 38.2%; odds ratio 0.99, 95% confidence interval 0.73, 1.34; p = 0.9415); however, a significant treatment-by-age interaction effect was detected (p = 0.0389): saxagliptin was numerically (but not significantly) superior to glimepiride for patients aged <75 years (39.2 vs 33.3%) and numerically inferior for patients aged ≥75 years (35.9 vs 45.5%). The incidence of confirmed/severe hypoglycaemia was lower with saxagliptin vs glimepiride (1.1 vs 15.3%; nominal p < 0.0001). Saxagliptin was generally well tolerated, with similar incidences of adverse events compared with glimepiride. CONCLUSION: As avoiding hypoglycaemia is a key clinical objective in elderly patients, saxagliptin is a suitable alternative to glimepiride in patients with T2D aged ≥65 years.

Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide.

OBJECTIVE: Having demonstrated short-term weight loss with liraglutide in this group of obese adults, we now evaluate safety/tolerability (primary outcome) and long-term efficacy for sustaining weight loss (secondary outcome) over 2 years. DESIGN: A randomized, double-blind, placebo-controlled 20-week study with 2-year extension (sponsor unblinded at 20 weeks, participants/investigators at 1 year) in 19 European clinical research centers. SUBJECTS: A total of 564 adults (n=90-98 per group; body mass index 30-40 kg m(-2)) enrolled, 398 entered the extension and 268 completed the 2-year trial. Participants received diet (500 kcal deficit per day) and exercise counseling during 2-week run-in, before being randomly assigned (with a telephone or web-based system) to once-daily subcutaneous liraglutide (1.2, 1.8, 2.4 or 3.0 mg, n=90-95), placebo (n=98) or open-label orlistat (120 mg × 3, n=95). After 1 year, liraglutide/placebo recipients switched to liraglutide 2.4 mg, then 3.0 mg (based on 20-week and 1-year results, respectively). The trial ran from January 2007-April 2009 and is registered with Clinicaltrials.gov, number NCT00480909. RESULTS: From randomization to year 1, liraglutide 3.0 mg recipients lost 5.8 kg (95% confidence interval 3.7-8.0) more weight than those on placebo and 3.8 kg (1.6-6.0) more than those on orlistat (P0.0001; intention-to-treat, last-observation-carried-forward). At year 2, participants on liraglutide 2.4/3.0 mg for the full 2 years (pooled group, n=184) lost 3.0 kg (1.3-4.7) more weight than those on orlistat (n=95; P<0.001). Completers on liraglutide 2.4/3.0 mg (n=92) maintained a 2-year weight loss of 7.8 kg from screening. With liraglutide 3.0 mg, 20-week body fat decreased by 15.4% and lean tissue by 2.0%. The most frequent drug-related side effects were mild to moderate, transient nausea and vomiting. With liraglutide 2.4/3.0 mg, the 2-year prevalence of prediabetes and metabolic syndrome decreased by 52 and 59%, with improvements in blood pressure and lipids. CONCLUSION: Liraglutide is well tolerated, sustains weight loss over 2 years and improves cardiovascular risk factors.

Association of a leucine(7)-to-proline(7) polymorphism in the signal peptide of neuropeptide Y with high serum cholesterol and LDL cholesterol levels.

High serum levels of total and LDL cholesterol are important risk factors in the development of atherosclerotic coronary artery disease. Cholesterol metabolism is affected by nutritional, environmental and genetic factors. Neuropeptide Y (NPY), which is widely expressed in both the central and peripheral nervous systems, has an important role in the hypothalamic regulation of energy balance by stimulating food intake and favoring energy storage through increased lipoprotein lipase activity in white adipose tissue. As a part of ongoing study of the genetic basis of obesity, we screened the NPY gene for sequence variants. We report here the identification of a common Leu(7)-to-Pro(7) polymorphism in the signal peptide of NPY. Presence of this Pro(7) in NPY was associated with higher serum levels of total and LDL cholesterol in obese subjects participating in two independent Finnish and Dutch studies. Furthermore, normal-weight Finns with Pro(7) also had higher serum levels of total and LDL cholesterol than did subjects with Leu(7)/Leu(7), as analyzed in three subsequent determinations at 5-year intervals during a 10-year follow-up period. The NPY polymorphism was not associated with higher cholesterol levels in normal-weight Dutch. Our study provides evidence that NPY is linked to cholesterol metabolism and that the polymorphism producing Pro(7) in NPY is one of the strongest genetic factors identified thus far affecting serum cholesterol, particularly in obese subjects.

Serum adiponectin and resistin levels in major depressive disorder.

OBJECTIVE: To examine the role of the adipose-tissue-derived low-grade inflammation markers adiponectin and resistin in major depressive disorder (MDD) in a population-based sample. METHOD: Serum levels of adiponectin and resistin were measured from 70 DSM-IV MDD subjects and 70 healthy controls. Depression severity was assessed with the 29-item Hamilton Depression Rating Scale. RESULTS: The MDD group had lowered serum adiponectin levels. Regression modelling with adjustments for age, gender, overweight, several socioeconomic and lifestyle factors, coronary heart disease and metabolic syndrome showed that each 5.0 microg/ml decrease in serum adiponectin increased the likelihood of MDD by approximately 20% (P = 0.01). The resistin levels correlated with atypical (P = 0.02), but not with typical depressive symptoms (P = 0.12). CONCLUSION: Our findings suggest that the lowered adiponectin levels in MDD are depression-specific and not explained by conventional low adiponectin-related factors such as such as coronary heart disease and metabolic disorders.

Association of depressive symptoms and metabolic syndrome in men.

OBJECTIVE: To explore the relationship between several indicators of depression and metabolic syndrome (MetS). METHOD: A population-based sample with high (HMS group) or low (LMS group) levels of mental symptoms, including those of depression, in three follow-ups participated in a clinical examination in 2005 (n = 223). MetS was determined according to the NCEP criteria. RESULTS: The prevalence of MetS was 49% in men and 21% in women. Men with MetS had higher rates of major depressive disorder than other men. They also displayed higher Hamilton Rating Scale for Depression (HDRS) scores and more often signs of suicidality. In logistic regression analyses, higher HDRS scores (OR 1.31, 95% CI 1.04-1.64) and belonging to the HMS group (OR 10.1, 95% CI 1.98-51.3) were independent associates for MetS but only in men. CONCLUSION: The results highlight that there is an association between long-term depressive symptoms and the emergence of MetS, especially in men.

Effect of diet-induced weight loss on plasma apelin and cytokine levels in individuals with the metabolic syndrome.

BACKGROUND AND AIMS: Adipose tissue is an active endocrine organ that secretes signaling molecules involved in the regulation of insulin sensitivity, food intake and inflammation. Apelin is a peptide secreted by adipose tissue that has been shown to modulate cardiovascular tone in animals. The aim of this study was to measure abdominal fat, blood pressure and circulating apelin, adiponectin, leptin, ghrelin, TNF-alpha and IL-6 levels in patients with the metabolic syndrome after a diet-induced weight loss. METHODS AND RESULTS: 35 obese individuals with the metabolic syndrome underwent an 8-week very-low-calorie diet (VLCD) and a 6-month weight maintenance period (WM) with 120mg orlistat or placebo administered 3 times daily. VLCD and WM (-15.1+/-1.0kg) decreased mean arterial pressure (MAP), insulin, leptin, triglycerides and visceral and subcutaneous adipose tissue. Moreover, adiponectin increased in response to the weight loss. However, the overall changes in plasma apelin, TNF-alpha and IL-6 were non-significant. A correlation between plasma apelin and TNF-alpha was observed at baseline (0.41, p<0.05), and the minor changes in plasma apelin levels were associated with changes in BMI during VLCD and MAP and TNF-alpha during VLCD and WM periods. CONCLUSION: Despite reductions in BMI, body adiposity, MAP and enhancement of glucose metabolism and adiponectin in response to weight loss, no significant changes in plasma apelin, TNF-alpha and IL-6 were observed. However, apelin significantly correlated with TNF-alpha and MAP. These results suggest that apelin may not be that strongly correlated with the fat mass as an adipokine like the more abundant adipokines adiponectin or leptin and it might be involved in the regulation of inflammation and cardiovascular tone.

The effect of glycaemic control on the quantitative characteristics of retinopathy lesions in patients with type 2 diabetes mellitus: 10-year follow-up study.

BACKGROUND: Diabetic retinopathy (DR) represents a common complication of type 2 diabetes mellitus. Appearance of DR lesions such as microaneurysms, haemorrhages, hard and soft exudates, IRMA and neovascularisation reflect the severity of DR. The aim of our study was to investigate the association of selected glycaemic parameters with particular DR abnormalities and their characteristics in patients with type 2 diabetes. METHODS: Eighty-three middle-aged patients with newly diagnosed type 2 diabetes mellitus participated in this 10-year prospective study. The glycaemic parameters such as glycated haemoglobin A1c (HbA1c), fasting blood/plasma glucose as well as 1- and 2-hour post-load glucose values were recorded at baseline, 5-year and 10-year follow-up. The fundus photographs were taken at baseline and then at 5-year and 10-year follow-ups and used for quantitative evaluation. RESULTS: Statistically significant positive correlations were found between all investigated 5-year glucose values and the extent of DR lesions at 10-year follow-up (p < 0.003). The 1- and 2-hour post-load glucose values correlated with the DR lesions with the highest significance (p

Weight reduction modulates expression of genes involved in extracellular matrix and cell death: the GENOBIN study.

OBJECTIVE: Lifestyle and genetic factors interact in the development of obesity and the metabolic syndrome. The molecular mechanisms underlying the beneficial dietary modifications are, however, unclear. We aimed to examine the effect of the long-term moderate weight reduction on gene expression in adipose tissue (AT) and to identify genes and gene clusters responsive to treatment and thereby likely contributing to the development of the metabolic syndrome. DESIGN: Randomized controlled and individualized weight reduction intervention. SUBJECTS: Forty-six subjects with impaired fasting glycemia or impaired glucose tolerance and features of metabolic syndrome, aged 60+/-7 years were randomized either to a weight reduction (WR) (n=28) or a control (n=18) group lasting for 33 weeks. MEASUREMENTS: Oral and intravenous glucose tolerance tests and subcutaneous AT biopsies were performed before and after the intervention. Gene expression of AT was studied using microarray technology in subgroups of WR (with weight reduction > or =5%, n=9) and control group (n=10). The results were confirmed using quantitative PCR. RESULTS: In the WR group, glucose metabolism improved. Moreover, an inverse correlation between the change in S (I) and the change in body weight was found (r=-0.44, P=0.026). Downregulation of gene expression (P<0.01) involving gene ontology groups of extracellular matrix and cell death was seen. Such changes did not occur in the control group. The tenomodulin-gene was one of the most downregulated genes (-39+/-16%, P<0.0001). Moreover, its expression correlated with insulin sensitivity (r=-0.34, P=0.005) before the intervention and with body adiposity both before (r=0.42, P=0.007) and after (r=0.30, P=0.056) the intervention. CONCLUSION: Genes regulating the extracellular matrix and cell death showed a strong downregulation after long-term weight reduction. This likely reflects a new stable state at the molecular level in AT. Further studies are warranted to elucidate the mechanisms of these genetic factors.

Glucose regulation and chronic pain at multiple sites.

OBJECTIVE: To analyse how glucose regulation status is associated with chronic regional pain and chronic widespread pain (CWP) in the adult population. METHODS: A structured interview and health examination study with 480 participants aged 30-65 yrs was carried out in Lapinlahti municipality in eastern Finland. The number of painful sites in the right or left upper and lower extremities, shoulders and hips, and in neck and back was summated. Those subjects with chronic pain in at least four sites were defined as having CWP. Diabetes and glucose tolerance status diagnosis were based on self-reported diagnoses, reimbursed medication and laboratory tests. Subjects with impaired fasting plasma glucose and/or elevated 2-h glucose level were combined into a group of impaired glucose regulation (IGR). RESULTS: Of the total sample, 55 subjects (11%) had diabetes. The prevalence of CWP was 13% (n = 62) in all subjects. The corresponding percentages for subjects with normal glucose regulation, IGR and diabetes were 9, 18 and 28%. In the multivariate analysis, diabetes was associated with CWP (odds ratio = 2.99; 95% CI 1.19, 7.53; P = 0.020). CONCLUSIONS: These results point to a significant association between diabetes and CWP in the adult population.

Defects in insulin secretion and insulin action in non-insulin-dependent diabetes mellitus are inherited. Metabolic studies on offspring of diabetic probands.

No studies are available that have compared early defects in glucose metabolism in the offspring of insulin-deficient and insulin-resistant probands with non-insulin-dependent diabetes mellitus (NIDDM). To investigate this issue, we evaluated insulin secretion capacity with oral and intravenous glucose tolerance tests and with the hyperglycemic clamp, and insulin action with the euglycemic insulin clamp in 20 offspring of NIDDM patients with low fasting C-peptide (+/-450 pmol/liter), reflecting deficient insulin secretion (IS-group), 18 offspring of NIDDM patients with high fasting C-peptide (>/= 880 pmol/liter), reflecting insulin resistance (IR-group), and 14 healthy control subjects without a family history of NIDDM. The frequency of impaired glucose tolerance was 45.0% in the IS-group and 50% in the IR-group. The IS-group had lower insulin-glucose response at 30 min in the oral glucose tolerance test (85.2+/-10.0 pmol insulin per mmol glucose) than the control group (136.4+/-23.1 pmol insulin per mmol glucose; P < 0.05) and the IR-group (115.6+/-11.8 pmol insulin per mmol glucose; P = 0.05). Furthermore, the acute insulin response during the first 10 min of an intravenous glucose tolerance test was lower in the IS-group than in the IR-group. Maximal insulin secretion capacity evaluated by C-peptide levels during the hyperglycemic clamp did not differ between the groups. The IR-group had lower rates of whole body glucose uptake (60.1+/-4.6 micromol per lean body mass per minute) than did the control group (84.2+/-5.0 micromol per lean body mass per minute; P < 0.001) or the IS-group (82.6+/-5.9 micromol per lean body mass per minute; P < 0.01) and this was due to reduced glucose nonoxidation. To conclude, both impaired insulin secretion and insulin action seem to be inherited and could represent the primary defects in glucose metabolism in the offspring of NIDDM probands.

Multiple endocrine neoplasia type 1 in Northern Finland; clinical features and genotype phenotype correlation.

OBJECTIVE: The existence of genotype-phenotype correlation in multiple endocrine neoplasia type 1 (MEN1) is controversial. Two founder mutations of the MEN1 gene in Northern Finland gave us an opportunity to compare clinical features among heterozygotes of different mutations. DESIGN AND METHODS: Study cohort included 82 MEN1 heterozygotes who were tested for MEN1 during the years 1982-2001. Medical records were reviewed for manifestations of MEN1, other tumours and cause of death by the end of August 2003. Logistic regression analysis was used in evaluating the impact of age, gender and mutational status of affected heterozygotes on the likelihood of developing manifestations of MEN1. RESULTS: Founder mutations 1466del12 and 1657insC were found in 39 and 29 individuals, and D418N, G156R and R527X mutations in 9, 3 and 2 individuals respectively. Except for pituitary adenoma and nonfunctional pancreatic tumour (NFPT), age was a risk factor for all the disease manifestations. For NFPT, frameshift/nonsense mutations (1657insC, R527X) gave an odds ratio (OR) of 3.26 (95% confidence intervals (CI), 1.27-8.33; P = 0.014) compared with in-frame/missense mutations (1466del12, D418N, G156R); including the founder mutation carriers (n = 68) only, the 1657insC mutation gave an OR of 3.56 (CI, 1.29-9.83; P = 0.015). For gastrinoma, in-frame/missense mutations predicted the risk with an OR of 6.77 (CI, 1.31-35.0; P = 0.022), and in the founder mutations group the 1466del12 mutation gave an OR of 15.09 (CI, 1.73-131.9, P = 0.014). CONCLUSIONS: In this study population, NFPT was more common in the frameshift/nonsense or 1657insC mutation carriers, whereas gastrinoma was more common in the in-frame/missense or 1466del12 mutation carriers.

Is discordance in bone measurements affected by body composition or anthropometry? A comparative study between peripheral and central devices.

Screening of osteoporosis using peripheral bone measurements has become more common, even though diagnostic discrepancies are known to exist between peripheral dual-energy X-ray (pDXA) or quantitative ultrasound (QUS) and central DXA measurements. Values of diagnostic parameters such as bone mineral density, speed of (ultra)sound, and broadband ultrasound attenuation are affected by bone size and soft tissue composition. However, their significance for the discordance between peripheral and central techniques is unclear. In this study, bone status and total body composition of 139 women (mean age 68.3 yr [1.7 SD], mean body mass index 26.5 kg/m2 [3.6 SD]) were assessed by 3 GE Lunar devices. Heel pDXA and heel QUS were conducted using peripheral instantaneous X-ray imaging (PIXI) and Achilles, respectively, and central DXA measurements were taken at the posterior-anterior lumbar spine (L2-L4) and at the left femoral neck using Prodigy. Positive significant associations were found between body height or fat (%) and most DXA or QUS parameters. The discordance between the site-dependent DXA or QUS T-score values typically increased (p<0.05) as a function of body weight or fat (%), but not with body height. On an average, body adiposity accounted for less than 11% of the differences between the techniques; however, increase of total body fat from 20% to 45% led to a discrepancy of one T-score between DXA(HEEL) and QUS(HEEL). To avoid diagnostic bias, comparative assessment of the devices using the same population is recommended.

Cardiac power during exercise and the risk of stroke in men.

BACKGROUND AND PURPOSE: Low maximal oxygen uptake (VO2max) has been shown to predict the risk of stroke. However, VO2max does not take into account the differences in cardiac afterload between subjects. The aim of this study was to examine the relationship of exercise cardiac power (ECP), defined as a ratio of VO2max with peak systolic blood pressure (SBP) during exercise, with the risk for stroke. METHODS: Population-based cohort study with an average follow-up of 12 years from eastern Finland. A total of 1761 men with no history of stroke or coronary heart disease at baseline participated. Among these men, 91 strokes occurred, of which 69 were attributable to ischemic causes. RESULTS: The relative risk of any stroke in men with low ECP (<10.3 mL/mm Hg) was 2.7 (95% CI, 1.2 to 6.0; P=0.01; P=0.02 for the trend across the quartiles), and the relative risk for ischemic stroke was 2.7 (95% CI, 1.1 to 7.0; P=0.03; P=0.04 for trend across the quartiles) compared with men having high ECP (>14.3 mL/mm Hg) during exercise after adjusting for age, examination year, cigarette smoking, alcohol consumption, body mass index, diabetes, serum total cholesterol level, energy expenditure of physical activity, exercise-induced myocardial ischemia, and the use of antihypertensive medication. After further adjustment for resting SBP, results were statistically nonsignificant. CONCLUSIONS: Low ECP provides noninvasive and easily available measure for stroke risk. One of the most potential explanations for the association between ECP and the increased risk of stroke is an elevated afterload and peripheral resistance indicated by elevated SBP.

Occurrence, predictors, and clinical significance of autonomic neuropathy in NIDDM. Ten-year follow-up from the diagnosis.

Little is known about the occurrence and predictive factors of autonomic neuropathy and its relationship to cardiovascular mortality in NIDDM patients, and no long-term follow-up studies including nondiabetic control subjects are available. A total of 133 patients with newly diagnosed NIDDM (70 men) and 144 control subjects (62 men) were examined at baseline and after 5 and 10 years of follow-up. Deep-breathing tests (baseline, 5-year, and 10-year) and active orthostatic tests (5- and 10-year) were performed. Criteria for autonomic neuropathy were parasympathetic (expiration-to-inspiration ratio /- 30 mmHg in the orthostatic test), and combined autonomic neuropathy (parasympathetic with sympathetic neuropathy). The frequency of parasympathetic neuropathy (NIDDM patients versus control subjects) was 4.9 vs. 2.2% (P = 0.224) at baseline, 19.6 vs. 8.5% (P = 0.017) at 5 years, and 65.0 vs. 28.0% (P < 0.001) at 10 years of follow-up. The frequency of sympathetic neuropathy was 6.8 vs. 5.6% (P = 0.709) at 5 years and 24.4 vs. 9.0% (P = 0.003) at 10 years of follow- up. These figures for combined autonomic neuropathy were 2.1 vs. 1.8% (P = 0.869) at 5 years and 15.2 vs. 4.2% (P = 0.007) at 10 years of follow-up. NIDDM patients with parasympathetic neuropathy at the 10-year examination showed worse glycemic control and higher insulin values than those without parasympathetic neuropathy. Furthermore, in our subjects, women were more prone to have parasympathetic neuropathy than men. Parasympathetic neuropathy at baseline was more frequent in those who died from a cardiovascular cause than those who did not (13 vs. 3%, P = 0.045). Similarly, sympathetic autonomic nervous dysfunction at the 5-year examination predicted the 10-year cardiovascular mortality. In conclusion, the frequency of autonomic neuropathy in NIDDM patients increases sharply with time. The development of autonomic neuropathy is connected with poor glycemic control. Interestingly, a high insulin level seems to have a predictive role in the development of parasympathetic autonomic neuropathy irrespective of obesity and glycemia.

Power spectral analysis of heart rate variability during hyperinsulinemia in nondiabetic offspring of type 2 diabetic patients: evidence for possible early autonomic dysfunction in insulin-resistant subjects.

Sympathetic activation has been considered as a link between insulin resistance, hyperinsulinemia, and hypertension. However, little is known about the association between insulin sensitivity and autonomic regulation or about the effect of acute hyperinsulinemia on cardiac sympathovagal balance. The aim of this study was to investigate heart rate variability (HRV) during the euglycemic-hyperinsulinemic clamp in nondiabetic offspring of patients with type 2 diabetes. We studied 35 nondiabetic offspring of patients with type 2 diabetes and 19 control subjects. Probands were chosen from a 10-year follow-up study of patients with well-characterized type 2 diabetes according to their fasting C-peptide level (selected from both ends of the distribution) and from control subjects to form three groups: 1) a group including subjects who were offspring of type 2 diabetic patients with low C-peptide levels (deficient insulin secretion group [IS group], n = 17), 2) a group including subjects who were offspring of type 2 diabetic patients with high C-peptide levels (insulin-resistant group [IR group], n = 18), and 3) a control group without a history of type 2 diabetes in first-degree relatives (n = 19). HRV was assessed at baseline and at the steady state during the euglycemic-hyperinsulinemic clamp. Rates of whole-body glucose uptake (M value) were lower in the IR group than in the IS group and the control group (41+/-3 vs. 54+/-2 vs. 60+/-4 micromol x kg(-1) x min(-1), P < 0.01 and P < 0.01, respectively). In all groups, heart rate increased significantly during hyperinsulinemia. In the IR group, insulin infusion increased total power of HRV [from 7.70+/-0.15 to 8.05+/-0.15 ln(ms2), P < 0.01] and the low frequency-to-high frequency ratio (from 0.62+/-0.14 to 1.14+/-0.18, P < 0.01) and decreased power of the high frequency spectral component (from 5.73+/-0.17 to 5.43+/-0.16 ln(ms2), P < 0.05), whereas in other groups, changes in HRV were not significant. We conclude that the HRV response to acute hyperinsulinemia in the offspring of type 2 diabetic probands was likely to be modulated by the type 2 diabetic phenotype of the parent. In insulin-resistant subjects, autonomic dysfunction may be an earlier defect than hitherto acknowledged.

Cross-calibration of Lunar DPX-IQ and DPX dual-energy x-ray densitometers for bone mineral measurements in women: effect of body anthropometry.

When dual-energy X-ray absorptiometry (DXA) instruments are replaced, it is essential to determine if systematic differences in measurements occur. As a part of the Kuopio Osteoporosis Risk Factor and Prevention study (N=14,220), a group of women, aged 36 to 69 yr underwent anteroposterior lumbar spine L2 to L4 (n=89) and proximal femur scans (n=88) by the Lunar DPX and DPX-IQ, respectively, during the same visit. A high linear association (r from 0.944 to 0.989, p<0.001) between the two scanners was established for lumbar spine and proximal femur bone mineral density (BMD). The average DPX values for BMD were 1.1% and 2.0% higher than those of DPX-IQ for the lumbar spine (p<0.001) and Ward's triangle (p=0.001), respectively. Femoral neck BMD values by the DPX were 1.4% lower (p<0.001) compared to DPX-IQ. The difference between trochanter BMD results (0.1%) was not significant (p=0.809). In the femoral neck and trochanter, but not in the lumbar spine or Ward's triangle, the differences in BMD values of the two machines were found to depend on body mass index. After linear formulas based on simple and multivariate linear regression analyses were calculated, the differences were negligible, enabling objective comparison of longitudinal measurements.

Short-term and long-term memory in elderly patients with NIDDM.

OBJECTIVE: To determine cognitive and memory dysfunction associated with non-insulin-dependent diabetes mellitus (NIDDM) and its relationship with depression, metabolic control, and serum lipids. RESEARCH DESIGN AND METHODS: We studied a well-characterized group of 20 elderly patients with NIDDM and 22 control subjects with normal glucose tolerance recruited from a larger population-based sample. In addition to clinical and laboratory examinations, self-rating questionnaires that assess minor psychiatric disorder (General Health Questionnaire) and depression (Zung scale) were completed by patients and control subjects. Memory was examined with digit and block-span tests, word-list learning, Heaton Visual Memory Test, and Moss Visual Span Test. Executive functions were examined by Trail-Making A and B test and by Verbal and Category Fluency Tests. Visuoconstructive reasoning was examined with the block design subtest of the Wechsler Adult Intelligence Scale. RESULTS: The NIDDM patients showed preserved memory span, but poor performance in learning tasks compared with control subjects. The patients recalled no fewer words than the control subjects, but the process of of learning seemed to be different in the two groups. The recognition of the learned words was not impaired. Elevated serum total and very-low-density lipoprotein triglyceride levels, measured either before examinations or 5 or 10 years earlier, were associated with effects on retrieval from semantic memory in NIDDM patients. CONCLUSIONS: The NIDDM patients had impaired control of their learning processes. Elevated serum triglyceride levels may be related to control of mental processing in diabetic patients.

Medial artery calcification predicts cardiovascular mortality in patients with NIDDM.

OBJECTIVE: To study the predictive value of medial artery calcification (Mönckeberg's sclerosis) in relation to 10-year cardiovascular mortality in patients with non-insulin-dependent diabetes mellitus (NIDDM). RESEARCH DESIGN AND METHODS: We studied the predictive value of thigh medial and intimal artery calcifications to 10-year cardiovascular mortality in a well-characterized group of 133 middle-aged, newly diagnosed patients with NIDDM (70 men and 63 women). RESULTS: At baseline, medial artery calcifications were found in 17% of the patients and intimal-type calcifications were found in 23%. During the follow-up, 21% of the diabetic patients died from cardiovascular causes. The age-adjusted odds ratio for cardiovascular mortality was 4.2 (95% confidence intervals: 1.5-11.3) for medial-type and 1.6 (0.6-4.3) for intimal-type calcifications. In multiple logistic regression analysis, including age, sex, systolic blood pressure, low-density- and high-density-lipoprotein cholesterol, very-low-density lipoprotein triglycerides, smoking, body mass index, fasting serum insulin, blood glucose, urinary albumin, and ischemic ECG changes, as well as the intimal artery calcification, the medial artery calcification was the dominant factor predicting cardiovascular mortality. CONCLUSIONS: In this study medial artery calcification was a strong independent predictor of cardiovascular mortality in patients with newly diagnosed NIDDM. Whether these subjects had a longer duration of hyperglycemia before the diagnosis than those without medial artery calcifications remains unknown.