Bone Mineral Density in Sixty Adult Patients with Marfan Syndrome

Sixty adult patients (40 women, 20 men) with Marfan syndrome (MFS) according to the Berlin criteria had a full clinical examination and bone mineral density (BMD) measurement by dual-energy X-ray absorptiometry of the hip and nondominant forearm. BMD was expressed as a Z-score and compared with the reference population of the Hologic database. In MFS men, BMD (g/cm²) was compared with the BMD of 45 normal tall Caucasian adults. Osteocalcin was measured by radioimmunoassay. In patients with MFS, BMD was compared between patients with and without previous fractures and according to the phenotypic severity of MFS. The mean age of the patients was 32.9 ± 9.3 years (women 32.5 ± 9.7, men 33.4 ± 8.6), mean height was 180.3 ± 10.3 cm (women 176.3 ± 9.2, men 188.1 ± 7.5) and mean body mass index 20.9 ± 3.6 kg/m² (women 20.8 ± 3.4, men 20.95 ± 3.97). Hyperlaxity score (Beighton criteria) was 6.9 ± 1.1. Six patients (10%) had a previous fracture. Thirty per cent of patients had had at least one previous operation for scoliosis, aortic dilatation or eye problems. BMD values in the 60 patients were as follows: Z-score of the hip, −1.26 ± 0.93, p<10⁻⁹ (neck, −0.93 ± 1.09, p<10⁻⁹; trochanter, −1.31 ± 0.85, p<10⁻⁹; intertrochanter, −1.39 ± 0.99, p<10⁻⁹; Ward’s triangle, −0.93 ± 1.88, p<10⁻⁹); Z-score of the radius: −1.6 ± 1.06, p<10⁻⁹ (1/3 proximal, −1.29 ± 1.03; mid-radius, −1.94 ± 1.04; ultradistal, −0.68 ± 1.1, p<10⁻⁹). The decrease in BMD was similar in men and women at both the hip and the radius. BMD in MFS patients was significantly decreased at cortical compared with trabecular sites (radius 1/3 proximal vs ultradistal, p<0.0001; total femur vs Ward’s triangle, p<0.0005). No difference in BMD was found between MFS patients with or without previous fractures and those with severe or less severe phenotypic expression of MFS. An influence of height and weight in MFS on BMD is suspected. Osteocalcin was not increased in our group of MFS patients. Thus both men and women with MFS have a significant deficit of BMD at the hip and radius. The decrease in BMD is present equally in both sexes and is more pronounced at predominantly cortical sites. In our group of patients we found no increase in fractures and no relation between decreased BMD and phenotypic expression of the syndrome. Received: 30 October 1998 / Accepted: 26 May 1999     

Abnormal cell calcium concentrations in cultured bone cells obtained from femurs of obese and noninsulin-dependent diabetic rats

Summary Cytoplasmic free calcium concentration [Ca²⁺]i was quantified in cultured bone cells with osteoblastic characteristics. The cells were obtained from femurs of obese (fa/fa) Wistar-Kyoto rats, from nonobese, noninsulin-dependent diabetic (NIDD) Sprague Dawley rats, and from their appropriate controls. [Ca²⁺]i was also determined in bone cells obtained fromin vivo insulin-treated NIDD rats. Obese (Wistar Kyoto) rats had increased body weight (313±13 vs. 249±4 g;P<0.01), decreased femur weights (0.68±0.05 vs. 0.89±0.05 g;P<0.05), similar glucose levels (148±5 vs. 139±3 mg/dl), and higher plasma insulin levels (6.0±0.5 vs. 0.7±0.1 ng/ml;P<0.01) when compared with their nonobese [(fa/+); (+/+)] littermates. Nonobese, NIDD rats, compared with their appropriate controls (nondiabetic Sprague Dawley rats) had higher plasma glucose levels (235±32 vs. 145±3 mg/dl;P<0.01) but their plasma insulins, body weights, and femur weights were similar to controls (0.7±0.1 vs 0.6±0.1 ng/ml; 302±4 vs. 318±14 g; 0.97±0.4 vs. 0.98±0.04 g, respectively). Long-term (4 weeks) daily insulin treatment (2 u/100 g) of the NIDD rats increased their plasma insulin (1.9 ng/ml;P<0.05) and body weight (369±13 g;P<0.05) but did not change their plasma glucose levels (225±5 mg/dl), or femur weights (0.98±0.4 g). [Ca²⁺]i in bone cells derived from the femurs of obese animals was higher than in cells derived from their nonobese littermates (156±22 vs. 71±13 nM;P<0.01). In bone cells from NIDD rats, [Ca²⁺]i was lower compared with controls (146±22 vs. 229±19 nM;P<0.001). Insulin treatment of the diabetic animals augmented the decrease in [Ca²⁺]i in their bone cells (68±11 nM;P<0.005 compared with nontreated rats). These data reveal that [Ca²⁺]i in cultured bone cells from obese nondiabetic and nonobese NIDD rats differs from that of their controls. Compared with their controls, the changes in [Ca²⁺]i in bone cells from the NIDD and obese animals were in opposite directions. Whether the underlying mechanisms for the changes in cell [Ca²⁺]i in nondiabetic obese and nonobese NIDD animals differ, and whether the changes in [Ca²⁺]i observed in the cultured cells reflect thein vivo condition in bone cells of these animals are questions that await further investigations.     

The Effects of Liposuction Removal of Subcutaneous Abdominal Fat on Lipid Metabolism are Independent of Insulin Sensitivity in Normal-Overweight Individuals

Background Abdominal fat (both visceral and subcutaneous) accumulation is associated with an increased risk of developing insulin resistance. The latter stands as the basis upon which diabetes, hypertension, and atherogenic dyslipidemia tend to build up. Hence, abdominal liposuction (AL) could theoretically hold metabolic benefits. We undertook the present study to assess the effects of AL on carbohydrate and lipid metabolism. Methods This is a prospective study including 20 healthy volunteers (M2/F18) aged 39.6 ± 7.7 years old (24–52), body mass index (BMI) = 25.3 ± 4.7 kg/m² (19.8–36) who underwent AL. Before and 4 months after AL, we measured glucose and insulin concentrations, HOMA index [glucose (mM) × IRI (μUI/l)/22.5], free fatty acids (FFA), glycerol, total cholesterol and triglycerides, high-density lipoprotein (HDL)-cholesterol (HDL-c), low-density lipoprotein (LDL)-cholesterol (LDL-c), very low-density lipoprotein (VLDL)-cholesterol (VLDL-c) and apolipoproteins (apo) B, AI and AII, adiponectin (Adp), and ultra-sensitive C-reactive protein (CRP). Results Lipo-aspirate averaged 5.494 ± 5.297 cc (600–19.000). Weight, BMI, and waist circumference decreased significantly 4 months after surgery by 4.6, 4.6 and 5.9%, respectively. There were significant decrements in FFA (−35%, p < 0.0001), glycerol (−63%, p < 0.0005), VLDL-c (−15.2%; p < 0.001), and triglycerides (−21.3%, p < 0.002), an increase in HDL-c (+10%, p < 0.03), Apo AI (+10.1%, p < 0.02), and Apo AII (+11.8%, p < 0.001). Total cholesterol, LDL-c, ApoB, and the LDL-c/ApoB ratio raised by +15% (p < 0.0005), +27.3% (p < 0.000), +15.1% (p < 0.008) and +2.76% (p < 0.008), respectively. Glucose, insulin, the HOMA index, Adp, and CRP were not significantly altered after AL. Conclusion AL in healthy normal weight or slightly overweight subjects improves the major lipoprotein components of obesity-associated dyslipidemia. This improvement occurs independent of insulin sensitivity.     

Bariatric Surgery Cannot Prevent Tryptophan Depletion Due to Chronic Immune Activation in Morbidly Obese Patients

Background: Increased activity of the immuno-modulatory enzyme indoleamine-2,3-dioxygenase (IDO) during immune activation, results in tryptophan depletion. Tryptophan metabolic changes reduce serotonin production and cause mood disturbances, depression, and impaired satiety, ultimately leading to increased food intake and obesity. Bariatric surgery significantly diminishes immune mediators by substantial weight reduction. We examined IDO-mediated tryptophan-catabolism in morbidly obese patients compared to lean individuals. Methods: Serum concentrations of kynurenine and tryptophan, calculated kynurenine to tryptophan ratios (kyn trp-1) as an indirect estimate of IDO activity, and neopterin levels reflecting IFN-γ mediated immune activation, were assessed before and after bariatric surgery. The study population included 22 morbidly obese individuals and 20 normal-weight volunteers. Results: Median weight loss after 24.4±5.1 months was 40.6 kg resulting in a reduction of BMI from 44.1 kg/m² to 29.9 kg/m² (P<0.001). Preoperative kyn trp-1 in morbidly obese patients was significantly increased compared to the control group (41.6±20.1 mmol/mol vs 26.5±5.1 mmol/mol; P<0.001). Postoperative weight reduction did not lead to normalization of kyn trp-1 (37.9±14.0 mmol/mol). As a consequence, tryptophan levels were significantly lower in morbidly obese patients (pre-: 51.5±9.2 μmol L⁻¹ and postoperatively: 46.9±7.6 μmol L⁻¹) when compared with those of normal-weight controls (64.8±9.5 μmol L⁻¹; P<0.001). In addition, neopterin levels were elevated in the study population pre- and postoperatively compared to normal-weight volunteers (both P<0.001). Conclusions: Tryptophan depletion in morbidly obese patients is due to chronic immune activation and persists in spite of significant weight reduction following bariatric surgery. This might thereby be responsible for diminished serotonin functions, leading to unchanged satiety dysregulation and a reward-deficiency-syndrome.     

Optimal dose and duration of glucose administration during fasting period preceding surgery in rabbits

Purpose. We examined preoperative glucose administration to establish what dose and cutoff point were optimal for suppression of lipolysis and prevention of hypo- or hyperglycemia. Methods. Rabbits were preoperatively fasted and simultaneously received glucose at a constant rate of 0, 0.1, 0.2, 0.3, or 0.4 g·kg⁻¹·h⁻¹ in fluid infusion for 3 h. Plasma glucose, immunoreactive insulin activity, nonesterified fatty acids, and ketone bodies were measured 0, 1.5, 3 and 4 h after the start of infusion, and hepatic glycogen content was assessed 1 h after cessation of infusion. Results. Fluid infusion without glucose decreased plasma glucose. Glucose administration at more than 0.2 g·kg⁻¹·h⁻¹ caused hyperglycemia (>200 mg·dl⁻¹) in the infusion period; the differences were significant compared with the value at zero time or in the 0 g·kg⁻¹·h⁻¹ group (P < 0.01). The highest dose also raised plasma immunoreactive insulin activity, which was significantly higher than in the 0 g·kg⁻¹·h⁻¹ group (P < 0.01) at the midpoint of the infusion period. Plasma nonesterified fatty acids increased in all groups. The changes were, however, significantly reduced in both the 0.3 and 0.4 g·kg⁻¹·h⁻¹ groups (P < 0.05 and P < 0.01, respectively) by the end of infusion. All these effects of glucose supply, including suppression of lipolysis, disappeared regardless of dose within 1 h after the cessation of infusion. Conclusion. These results suggest that the optimal dose for preoperative glucose infusion, in order to preserve carbohydrate or fat metabolism, is 0.1–0.2 or 0.3 g·kg⁻¹·h⁻¹, respectively, and indicate that administration should not be discontinued until the start of surgery. Received for publication on July 16, 1998; accepted on August 23, 1999     

Increase of Osteopontin Plasma Concentrations After Bariatric Surgery Independent from Inflammation and Insulin Resistance

Background  Osteopontin (OPN) is a multifunctional matrix glycoprotein associated with bone metabolism and has been linked to chronic inflammation, insulin resistance, and atherosclerosis. Diet-induced weight loss decreases elevated OPN concentrations in obese patients. The aim of the current study was to investigate the role of OPN after bariatric surgery, where not only improvements of chronic inflammation, insulin resistance and comorbidities, but also malabsorption and altered bone metabolism have been reported. Methods  OPN plasma concentrations were determined in 31 morbidly obese patients (5 men, 26 women, BMI 46.2 ± 7.1 kg/m², age 41 ± 11 years; mean ± SD) before and 18 months after bariatric surgery, together with parameters of bone metabolism and inflammation. Results  OPN concentrations increased by +20.3 ± 26.6 ng/ml (mean ± SD, p < 0.01), concomitant to a weight loss of −38 ± 22 kg, and a decrease in BMI by −13.1 ± 7.7 kg/m² (both p < 0.01). HOMA-index improved from 5.2 ± 3.4 to 1.5 ± 1.0 (p < 0.01). Calcium concentrations slightly decreased, and phosphate increased (−0.06 ± 0.13 mmol/l and +0.08 ± 0.16 mmol/l, respectively; both p < 0.05), while 25-OH-VitaminD₃ remained unchanged and PTH tended to increase (+5.1 ± 14.0 pg/ml, p = 0.054). Monocyte chemoattractant protein 1 and interleukin 18 were significantly decreased and associated with HOMA both before and after bariatric surgery. ΔOPN was correlated with ΔPTH, but not with other parameters. Conclusions  OPN plasma concentrations increased concomitant to weight loss after bariatric surgery, which was independent from an improvement of insulin sensitivity and a decrease of inflammatory markers. Further studies are needed to differentiate whether these changes in bone metabolism after bariatric surgery are secondary to calcium deficiency or an adaptation to weight loss. This work has been submitted in abstract form and will be in part presented at the American Diabetes Association 68th Scientific Sessions 2008, June 6th–10th, San Francisco, CA, USA.     

Difference in estimated GFR with two different formulas in elderly individuals

The aim of this study was to characterize the differences between the prediction of GFR with Cockcroft-Gault formula (CG=(140–age)/(72×PCr (mg/ml), for females multiplied by 0.85) and the new formula based on the multicenter trial of the Modification of Diet in Renal Diseases (MDRD=186 × P _Cr ^−1.154 × age^−0.203; 0.742 if patient is female) in elderly subjects. The study involved 100 individuals aged 65–111 years (mean age 88.3±14.7; 79 females and 21 males). In all subjects GFR was estimated according to both formulas mentioned above and expressed in ml/min/1.73 m². Thereafter we calculated the difference between MDRD and CG (MDRD-CG) and analyzed its determinants in every subject. Mean GFR, obtained with MDRD was 76.0±24.0, whereas according to CG 67.9±18.6 (p < 0.0001). However, the mean MDRD-CG was up to 30.0±26.6 which means that MDRD results were much higher in comparison with CG. Using the multiple linear regression analysis we showed that MDRD-CG strongly depend on age (p < 0.0001), BMI (p < 0.0001) and serum creatinine concentration (p<0.0001). However, the gender has not effect on MDRD-CG value. The values of MDRD-CG strongly and positively correlated with age (r=0.7027, p < 0.0001) and negatively both with body mass index (r=−0.7171, p < 0.0001) and serum creatinine (r=−0.5590, p < 0.0001). In summary, our results show that the difference between MDRD and CG strongly depends on age, BMI and Scr. Investigators should be aware of these differences and take it into account in elderly.     

Decreased gallbladder response in leptin-deficient obese mice

Obesity is a major risk factor for gallstone formation, but the pathogenesis of this phenomenon remains unclear. Human data on gallbladder emptying are conflicting, and no animal data exist on the effect of obesity on gallbladder motility. Leptin, a hormone produced by adipocytes, is known to have central effects on neuropeptide Y and cholecystokinin, but the influence of leptin on the biliary effects of these hormones is unknown. Therefore we tested the hypothesis that leptin-deficient C57BL/6J-lep^ob obese mice would have decreased gallbladder responses to excitatory stimuli. Twelve-week-old lean control (C57BL/6J) (n = 22) and C57BL/6J-lep^ob obese (n = 20) female mice were fed a nonlithogenic diet. The mice were fasted overnight and underwent cholecystectomy. Whole gallbladders were placed in 3 ml muscle baths. After optimal length was determined with acetylcholine (10^-5 mol/L, responses to increasing doses of neuropeptide Y (10^-8 to 10^-6 mol/L) and cholecystokinin-8 (10^-10 to 10^-7 mol/L) were measured. Student’s t test and two-way analysis of variance were used where appropriate. Results were expressed as Newtons per cross-sectional area. The lean control mice had significantly greater excitatory responses to acetylcholine than the obese mice (0.37 ± 0.05 vs. 0.16 ± 0.02, P < 0.01). The gallbladder responses were also greater when mice were treated with neuropeptide Y (10^-8 mol/L: 0.00 ± 0.00 vs. 0.00 ± 0.00, NS; 10^-7 mol/L: 0.12 ± 0.02 vs. 0.05 ± 0.01, P < 0.01; 10^-6 mol/L: 0.26 ± 0.08 vs. 0.06 ± 0.01, P < 0.01) and cholecystokinin (10^-10 mol/L: 0.27 ± 0.04 vs. 0.13 ± 0.02, P < 0.01; 10^-9 mol/L: 0.59 ± 0.08 vs. 0.27 ± 0.04, P < 0.01; 10^-8 mol/L: 0.80 ± 0.11 vs. 0.37 ± 0.05, P < 0.01; 10^-7 mol/L: 0.86 ± 0.11 vs. 0.44 ± 0.06, P < 0.01). These data suggest that genetically obese, leptin-deficient mice have decreased responses to acetylcholine, neuropeptide Y, and cholecystokinin. We conclude that decreased gallbladder motility contributes to the increased incidence of gallstones associated with obesity. Presented at the Forty-Second Annual Meeting of The Society for Surgery of the Alimentary Tract, Atlanta, Georgia, May 20–23, 2001 (oral presentation). Supported by grant RO1-DK442 79–07 from the National Institutes of Health.     

Gene Expression of Leptin, Resistin, and Adiponectin in the White Adipose Tissue of Obese Patients with Non-Alcoholic Fatty Liver Disease and Insulin Resistance

Background: Adipose tissue is an active endocrine organ that secretes a variety of metabolically important substances including adipokines. These factors affect insulin sensitivity and may represent a link between obesity, insulin resistance, type 2 diabetes (DM), and nonalcoholic fatty liver disease (NAFLD). This study uses real-time polymerase chain reaction (PCR) quantification of mRNAs encoding adiponectin, leptin, and resistin on snap-frozen samples of intra-abdominal adipose tissue of morbidly obese patients undergoing bariatric surgery. Methods: Morbidly obese patients undergoing bariatric surgery were studied. Patients were classified into two groups: Group A (with insulin resistance) (N=11; glucose 149.84 ± 40.56 mg/dL; serum insulin 8.28 ± 3.52 μU/mL), and Group B (without insulin resistance) (N=10; glucose 102.2 ± 8.43 mg/dL; serum insulin 3.431 ± 1.162 μU/mL). Results: Adiponectin mRNA in intra-abdominal adipose tissue and serum adiponectin levels were significantly lower in Group A compared to Group B patients (P<0.016 and P<0.03, respectively). Although serum resistin was higher in Group A than in Group B patients (P<0.005), resistin gene expression was not different between the two groups. Finally, for leptin, neither serum level nor gene expression was different between the two groups. Serum adiponectin level was the only predictor of nonalcoholic steatohepatitis (NASH) in this study (P=0.024). Conclusions: Obese patients with insulin resistance have decreased serum adiponectin and increased serum resistin. Additionally, adiponectin gene expression is also decreased in the adipose tissue of these patients. This low level of adiponectin expression may predispose patients to the progressive form of NAFLD or NASH.     

Advanced Glycation End Products in Hemodialyzed Patients with Diabetes Mellitus Correlate with Leptin and Leptin/Body Fat Ratio

Advanced glycation end products (AGEs) and other carbonyl and oxidative stress compounds are supposed to play a critical role in the pathogenesis of several diseases and their complications, i.e., diabetes mellitus, diabetic retinopathy, atherosclerosis, and chronic renal failure. In the present investigation, we were interested in the relationship of AGEs in plasma to other prominent factors in the patients on chronic hemodialysis treatment—27 patients with diabetes mellitus, 35 patients without diabetes mellitus. AGE-group reactivity was estimated using a spectrofluorometric method (excitation 350 nm, emission 430 nm) and is expressed in arbitrary units (AU). We found significantly higher AGEs levels in diabetics than in non-diabetics on regular hemodialysis treatment both before (2.7 ± 0.7 × 10⁴ AU vs. 2.2 ± 0.6 × 10⁴ AU, p<0.001) and after the dialysis session (2.3 ± 0.5 × 10⁴ AU vs. 1.8 ± 0.7 × 10⁴ AU, p<0.005). AGEs were significantly reduced during hemodialysis in both groups of patients—by 15.4 % in the diabetic go (p<0.001) and by 17.3% in non-diabetics (p<0.005). In the patients with diabetes mellitus, AGEs did not correlate with parameters of the glucose metabolism correction (blood glucose, HbA1c). We observed a significant correlation between AGEs and leptin (r = 0.48, p < 0.05) as well as the leptin/body fat ratio (r = 0.56, p < 0.05) only in hemodialyzed patients with diabetes mellitus. These findings suggest more detailed studies to identify the molecular links between carbonyl stress, i.e., advanced glycation end products, and leptin metabolism, sign of microinflammation and hypertension.     

Is Lean Body Mass Decreased after Obesity Treatment by Adjustable Gastric Banding?

Background There is concern that surgically-induced weight loss in obese subjects is associated with a disproportionate decrease in lean body mass (LBM) and in skeletal muscle mass (SMM), a major constituent of LBM. To address this issue, 1) we measured total and regional body composition following gastric banding in a group of obese subjects, and 2) we compared these data to those of a non-surgical control group of similar age and body size. Methods Body composition was assessed by dualenergy X-ray absorptiometry (DEXA) before and after laparoscopic adjustable silicone gastric banding (LAGB) in 32 women (after 1 year: age 43.7 ± 8.4 years, BMI 36.4 ± 5.9 kg/m², mean ± SD), and in 117 control women (age 44.5 ± 7.5 years; BMI 36.7 ± 5.5 kg/m²) referred for non-surgical weight management, prior to weight loss. SMM was estimated using a published equation based on LBM of the extremities (appendicular LBM). Results 1 year after LAGB, body weight loss (−23.7 ± 11.6 kg, P < 10⁻⁶) was mainly due to decreased fat mass (−21.2 ± 11.2 kg, P < 10⁻⁶), and total LBM was modestly, although significantly, decreased (−2.1 ± 4.2 kg, P = 0.01). Appendicular LBM (−0.7 ± 2.7 kg) and total SMM (−0.9 ± 3.0 kg) were not significantly modified. None of the body composition variables was significantly decreased in weight-reduced subjects compared to the control group, especially appendicular LBM and total SMM. Conclusions Results provide no evidence for a decrease in appendicular LBM and total SMM with weight loss following LAGB. Follow-up of these obese patients revealed a very favorable pattern of change in total and regional body composition, with preservation of muscle mass.     

Improvement in Glycemic Control in Morbidly Obese Type 2 Diabetic Subjects by Gastric Stimulation

Background  Gastric electrical stimulation synchronized to the refractory period of gastric electrical activity and applied during meals was evaluated for safety and for improvement of body weight and glycemic control in obese type 2 diabetes. Methods  The study involved obese diabetic type 2 (ODM) patients in a multicenter open-label European feasibility trial. A total of 24 ODM (nine males, 15 females) treated with insulin and/or oral hyperglycemic agents and body mass index between 33.3 to 49.7 kg/m² were implanted laparoscopically with a TANTALUS system. Results  There were 18 adverse events related to the implant procedure or the device reported in 12 subjects. All were short lived and resolved with no sequelae. In the 21 subjects that reached the 1-year visit weight was reduced by 4.5 ± 2.7 kg (p < 0.05) and HbA1c by 0.5 ± 0.3% (p < 0.05). In a subgroup (n = 11) on stable or reduced oral medication, weight was reduced by 6.3 ± 3.4 kg (p < 0.05) and HbA1c by 0.9 ± 0.4% (p < 0.05). The group on insulin (n = 6) had no significant changes in weight and HbA1c. Conclusions  The TANTALUS system is well tolerated in obese type 2 diabetic subjects. Gastric electrical stimulation can potentially improve glucose metabolism and induce weight loss in obese diabetic patients, who are not well controlled on oral antidiabetic therapy. Further evaluation is required to determine whether this effect is due to induced weight loss and/or to direct signal dependent mechanisms.     

Temporal changes in glucose and insulin homeostasis after biliopancreatic diversion and laparoscopic adjustable gastric banding

BackgroundObesity surgery is associated with improvement in type 2 diabetes mellitus. Our aim was to examine the effects of biliopancreatic diversion (BPD) and laparoscopic adjustable gastric banding (LAGB) on the body mass index, fasting insulin level, glucose level, and insulin resistance in morbidly obese subjects with type 2 diabetes mellitus. The setting was the Department of Surgery, Morriston Hospital (Swansea, Wales, United Kingdom).MethodsA total of 13 morbidly obese patients (7 BPD, 6 LAGB) underwent serial measurements of fasting glucose and insulin at baseline, immediately after surgery (days 1–7), and 1, 6, and 12 months postoperatively. The homeostasis model of assessment–insulin resistance was calculated.ResultsIn the BPD group, the glucose levels had normalized by day 3 (5.6 ± 1 mmol/L) and the difference was statistically significant at 6 and 12 months postoperatively (5 ± .7 and 4.4 ± .5 mmol/L, respectively). The insulin levels had improved from day 1, and the difference was statistically significant at days 2, 5, 6, and 7 (19 ± 9, 14.2 ± 7, 15.2 ± 8, and 17.4 ± 8 mU/L, respectively). All diabetes medications were stopped on the fourth postoperative day. In the LAGB group, no statistically significant changes were seen in the glucose levels. Statistically significant changes in insulin were seen on days 1 and 2 (19 ± 13 and 13 ± 6.5 mU/L, respectively). The homeostatic model of assessment–insulin resistance had improved in both groups (BPD, 1.6 ± 1.2, P < .01; and LAGB, 4.3 ± 1.4, P < .05).ConclusionBPD causes immediate remission of type 2 diabetes mellitus. Leptin might play an important role in the early improvement of insulin resistance in fasting states after BPD. In the LAGB group, glucose homeostasis improved, but the patients still required diabetes medications, although the dosages were reduced.     

Evaluation of glucose tolerance,insulin secretion,and insulin action in patients with primary hyperparathyroidism before and after surgery

Summary Glucose tolerance, insulin secretion, and insulin sensitivity were evaluated in 8 asymptomatic patients with primary hyperparathyroidism (PHPT) before and at least 8 weeks after surgical correction of PHPT by means of the hyperglycemic clamp technique. In addition, 15 sex- and agematched control subjects were investigated for comparative reasons by the same technique. Glucose metabolized (M) during the hyperglycemic clamp was not significantly (NS) different between patients with PHPT and controls (7.9±2.3 vs. 6.3±1.9 mg/kg/min). However, insulin secretion (I) was significantly elevated in patients with PHPT compared to controls (87±17 vs. 45±12 μU/ml,P<0.05). The calculated insulin sensitivity index, (M/I) was significantly reduced in PHPT compared to controls (11.0±2.1 vs. 15.2±1.4 mg/kg/min per μU/ml×100,P<0.05). Comparing patients with PHPT before and after surgery, the M value, which is a measure of glucose tolerance, was not significantly different (7.9±2.3 vs. 7.8±1.5 mg/kg/min). However, insulin secretion was significantly lower after surgical correction of PHPT compared to the preoperative situation (48±9 μU/ml vs. 87±17 μU/7 ml,P<0.01). The calculated M/I rose significantly after surgery compared to the preoperative value (11±2.1 vs. 17.6±2.7 mg/kg/min per μU/ml ×100,P<0.001). We conclude that disturbed carbohydrate metabolism such as insulin hypersecretion and insulin resistance, in patients with PHPT is an early finding in this disease and that these early disturbances in glucose metabolism are, however, fully reversible. Correction of disturbed carbohydrate metabolism in PHPT might be a distinct argument for early surgical intervention in this disease.     

Experimental study of efficacy and optimal dose of intraoperative glucose in rabbits under general anesthesia

This experimental study was designed to investigate the efficacy of glucose loading during surgery. Rabbits, fasted overnight, received 20 ml·kg⁻¹·h⁻¹ fluid infusion containing glucose at various concentration (0,0.5, 1.0, 1.5, 2.0% w/v) for 3 h intraoperatively. Plasma glucose level increased after the beginning of operation, but the increase was slight in groups given 0.2 g·kg⁻¹·h⁻¹ or lower doses of glucose. Glucose at higher doses caused marked hyperglycemia. These higher doses also promoted urinary glucose excretion, and in the group given the maximum glucose dose (0.4 g·kg⁻¹·h⁻¹), this parameter was significantly elevated compared with findings in the 0.2 g·kg⁻¹·h⁻¹ group (P<0.05), whereas it showed no significant difference among groups given 0–0.2g·kg⁻¹·h⁻¹. The liver glycogen content in animals that received no glucose was significantly lower than that of the 0.2 g·kg⁻¹·h⁻¹ group (P <0.01). However, there was no correlation between glycogen level and glucose dose among groups receiving glucose. These results suggest that intraoperative glucose supplementation is effective in preventing glycogen depletion, and indicate that, to avoid glucose overloading, the optimal dose is 0.1–0.2 g·kg⁻¹·h⁻¹.     

Relationship of Androgens to Insulin Resistance and Chronic Inflammation in Morbidly Obese Premenopausal Women: Studies before and after Vertical Banded Gastroplasty

Background: Morbid obesity is associated with insulin resistance (IR), type 2 diabetes, lipid abnormalities, and hypertension. The association of obesity with increased androgen production and low concentrations of sex hormone-binding globulin (SHBG) in women has been demonstrated as well as a strong association of androgens with markers of inflammation such as high-sensitive C-reactive protein (hsCRP). Because weight loss results in a significant decrease in cardiovascular risk factors, IR and inflammation, we questioned a possible interrelationship between androgens, IR and inflammation in a prospective study with 43 morbidly obese female patients undergoing bariatric surgery. Methods: SHBG, dehydroepiandrosterone-sulfate (DHEA-S), and insulin were measured by ELISA, cortisol by fluorescence polarization immunoassay, androstendione by RIA, and testosterone by electrochemiluminescence immunoassay. The free androgen index (FAI) was calculated as the total testosterone/SHBG ratio. High sensitivity assays were used to obtain concentrations of fasting hsCRP, Interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Results: Weight loss resulted in a significant increase in SHBG (17±12 vs 70±30 nmol/l, P<0.0001). Serum concentrations of androstendione, total testosterone, DHEA-S and the FAI decreased significantly (2.05±0.78 vs 1.40±0.54 ng/ml, P<0.0001; 1.88±0.84 vs 1.16±0.57 nmol/L, P<0.0001; 1.72±0.86 vs 1.49±0.78 μg/ml, P<0.01; 0.15±0.10 vs 0.02±0.01, P<0.0001; respectively). Preoperatively and postoperatively, no association between androgens and IR, chronic subclinical inflammation and lipid parameters could be observed. Conclusion: Massive weight loss induced by bariatric surgery is associated with a significant reduction of androgen concentrations but not related to the concomitant decline of chronic inflammation, IR, glucose and lipid abnormalities in premenopausal morbidly obese women.     

The Effect of Acute Exercise on Undercarboxylated Osteocalcin and Insulin Sensitivity in Obese Men

Acute exercise improves insulin sensitivity for hours after the exercise is ceased. The skeleton contributes to glucose metabolism and insulin sensitivity via osteocalcin (OC) in its undercarboxylated (ucOC) form in mice. We tested the hypothesis that insulin sensitivity over the hours after exercise is associated with circulating levels of ucOC. Eleven middle‐aged (58.1 ± 2.2 years mean ± SEM), obese (body mass index [BMI] = 33.1 ± 1.4 kg/m²) nondiabetic men completed a euglycemic‐hyperinsulinemic clamp at rest (rest‐control) and at 60 minutes after exercise (4 × 4 minutes of cycling at 95% of HR_peak). Insulin sensitivity was determined by glucose infusion rate relative to body mass (GIR, mL/kg/min) as well as GIR per unit of insulin (M‐value). Blood samples and five muscle biopsies were obtained; two at the resting‐control session, one before and one after clamping, and three in the exercise session, at rest, 60 minutes after exercise, and after the clamp. Exercise increased serum ucOC (6.4 ± 2.1%, p = 0.013) but not total OC (p > 0.05). Blood glucose was ～6% lower and insulin sensitivity was ～35% higher after exercise compared with control (both p < 0.05). Phosphorylated (P)‐AKT (Ak thymoma) was higher after exercise and insulin compared with exercise alone (no insulin) and insulin alone (no exercise, all p < 0.05). In a multiple‐linear regression including BMI, age, and aerobic fitness, ucOC was associated with whole‐body insulin sensitivity at rest (β = 0.59, p = 0.023) and after exercise (β = 0.66, p = 0.005). Insulin sensitivity, after acute exercise, is associated with circulating levels of ucOC in obese men. Whether ucOC has a direct effect on skeletal muscle insulin sensitivity after exercise is yet to be determined. © 2014 American Society for Bone and Mineral Research.     

Hypovitaminosis D Myopathy Without Biochemical Signs of Osteomalacic Bone Involvement

The aims of this study were to investigate myopathy in relation to vitamin D status, and to study the muscular effects of vitamin D treatment on vitamin D-deficient individuals. Further, hypovitaminosis D myopathy was investigated in relation to alkaline phosphatase (ALP), the most commonly used marker for hypovitaminosis D osteopathy. Eight patients with osteomalacia had an isokinetic dynamometer test of all major muscle groups before and after 3 months of vitamin D treatment. The most pronounced improvements in muscle power were seen in the weight-bearing antigravity muscles of the lower limbs. A cross-sectional study was performed among 55 vitamin D-deficient veiled Arab women living in Denmark and 22 Danish controls. An isometric dynamometer model was used for determination of quadriceps muscle power. Both maximal voluntary contraction (MVC) and electrically stimulated values (single twitch, maximal production rate (MPR), and maximal relaxation rate (MRR)) were determined. The women underwent high-dose vitamin D treatment and were retested after 3 and 6 months. Prior to vitamin D treatment all parameters of muscle function in the group of vitamin D-deficient Arab women were significantly reduced compared with Danish controls. MVC: 259.4 ± 11.0 N (Newton) versus 392.6 ± 11.4 N (P < 10⁻⁶), single twitch: 47.0 ± 1.8 N versus 74.6 ± 2.2 N (P < 10⁻⁵), MPR 8.9 ± 0.3 N/10 ms versus 14.3 ± 0.4 N/10 ms (P < 10⁻⁶), MRR 4.5 ± 0.2 N/10 ms versus 6.2 ± 0.2 N/10 ms (P < 10⁻⁶). Muscle function was affected to a similar degree in women with and without bone involvement (as indicated by elevated ALP). After 3 months of vitamin D treatment all muscle-related parameters improved significantly. After 6 months only MVC was reduced compared with Danish controls (320.7 ± 14.3 N (P < 0.02)), whereas all other measurements were normalized. Hypovitaminosis D myopathy is a prominent symptom of vitamin D deficiency, and severely impaired muscle function may be present even before biochemical signs of bone disease develop. Full normalization of hypovitaminosis D myopathy demands high-dose vitamin D treatment for 6 months or more. Our findings indicate that serum levels of ALP cannot be used in the screening for hypovitaminosis D myopathy. Assessment of s-25OHD is the only reliable test. Received: 10 September 1999 / Accepted: 11 January 2000     

Effect of peak inspiratory flow on gas exchange, pulmonary mechanics, and lung histology in rabbits with injured lungs

Purpose The aim of this study was to evaluate, using a rabbit model, the little-known effect of different levels of peak inspiratory flow on acutely injured lungs. Methods Fourteen male rabbits (body weight, 2711 ± 146 g) were anesthetized and their lungs were injured by alveolar overstretch with mechanical ventilation until Pa_O2 was reduced below 300 mmHg. Injured animals were randomly assigned to: the P group—to receive pressure-regulated volume-control ventilation (PRVCV; n = 7); and the V group—to receive volume-control ventilation (VCV; n = 7). Other ventilator settings were: fraction of inspired oxygen (FI_O2), 1.0; tidal volume, 20 ml·kg⁻¹; positive end-expiratory pressure (PEEP) 5 cmH₂O; and respiratory rate, 20 min⁻¹. The animals were thus ventilated for 4 h. Throughout the protocol, ventilatory parameters and blood gas were measured every 30 min. After the protocol, the lung wet-to-dry ratio and histological lung injury score were evaluated in the excised lungs. Results Throughout the protocol, peak inspiratory flow and mean inspiratory flow values in the P group were significantly higher than those in the V group (26.7 ± 5.0 l·min⁻¹ vs 1.2 ± 0.2 l·min⁻¹, and 4.3 ± 0.3 l·min⁻¹ vs 1.1 ± 0.1 l·min⁻¹; P < 0.05). The wet-to-dry ratio in the P group was also significantly higher than that in the V group (7.7 ± 0.9 vs 6.3 ± 0.5; P < 0.05). More animals in the P group than in the V group had end-of-protocol Pa_O2/FI_O2 ratios below 200 mmHg (43% vs 0%; P = 0.06). Conclusion In rabbits with injured lungs, high peak inspiratory flow with high tidal volume (V_T) reduces the Pa_O2/FI_O2 ratio and increases the lung wet-to-dry ratio.     

Bone-Resorbing Cytokines from Peripheral Blood Mononuclear Cells after Hormone Replacement Therapy: A Longitudinal Study

Conflicting results have been reported in several cross-sectional studies measuring cytokine production from adherent monocytes in pre- and postmenopausal women. Furthermore, the target cells for the action of estrogen are still debated. We therefore assessed in a longitudinal manner the cytokine production from different fractions of peripheral blood mononuclear cells (PBMC) cultured for 48 h. PBMC were obtained from 30 postmenopausal women before and after 6 months of hormone replacement therapy (HRT). Women were randomly allocated to two groups: an adherent PBMC group (n= 20) and a total PBMC group (n= 9). After 6 months of treatment, urinary pyridinoline levels were markedly decreased in both groups (353 ± 24 vs 114 ± 13 μg/mmol creatinine and 325 ± 35 vs 164 ± 31 μg/mmol creatinine respectively, p<0.01). Culture supernatants were assayed for interleukin 1β (IL-1β), interleukin 6 (IL-6), soluble IL-6 receptor (IL-6rs) and tumor necrosis factor alpha (TNF-α). In the adherent PBMC group, HRT induced a nonsignificant trend toward decreased levels of IL-1β (35 ± 10 vs 13 ± 5 pg/ml), TNF-α (333 ± 58 vs 222 ± 30 pg/ml) and IL-6 (115 ± 70 vs 17 ± 10 pg/ml). In contrast, in the total PBMC group, HRT induced a consistent and dramatic decrease in levels of IL-1β (104 ± 22 vs 25 ± 8 pg/ml), IL-6 (5950 ± 1041 vs 1011 ± 361 pg/ml), IL-6rs (148 ± 33 vs 35 ± 12 pg/ml) (p<0.01) and TNF-α (1468 ± 315 vs 585 ± 207 pg/ml, p= 0.05). We then evaluated whether HRT had the same effect in vitro. Adherent or total PBMC of 8 postmenopausal women were cultured with or without 10⁻⁸M 17β-estradiol or tibolone for 48 h. Production of IL-1β, TNF-α, IL-6 and IL-6rs was not affected by the presence of 17β-estradiol or tibolone in cultures of these cell fractions. In conclusion, our data indicate that non-adherent PBMC could mediate the response to HRT. HRT may exert its action indirectly via noncirculating cells, as suggested by the absence of an in vitro effect. Received: 11 July 2000 / Accepted: 15 January 2001