Clinical significance of CYP11B2 immunostaining in unilateral primary aldosteronism.

Objective: The associations between adrenal histopathology, lateralization studies, and surgical outcomes in primary aldosteronism remain poorly characterized. We examined the value of immunohistochemical analysis of CYP11B2 for evaluation of adrenalectomy outcomes after anatomical versus functional subtyping. Design: A retrospective multicenter study of 277 patients operated for primary aldosteronism who had an adrenalectomy sample available in the Finnish biobanks from 1 January 2000 to 31 December 2019. Adrenal slides from biobanks were analyzed centrally after CYP11B2 and CYP11B1 staining. Clinical data were obtained from patient registries. Histopathological diagnosis and cure after surgery were assessed as outcome measures. Results: Re-evaluation with CYP11B2 staining changed the histopathological diagnosis in 91 patients (33%). The presence of a CYP11B2-positive adenoma and the use of functional subtyping independently predicted clinical cure of primary aldosteronism. CYP11B2-positive <7 mm nodules were more frequent in patients without clinical cure, whereas CYP11B2-positive micronodules were common in all patients and had no impact on adrenalectomy outcomes. Small CYP11B2-positive nodules and micronodules were equally prevalent regardless of the subtyping method applied. Clinical cure rates were lower and CYP11B2-negative adenomas more common after adrenalectomy based on anatomical imaging than functional studies. Conclusions: Incorporating CYP11B2 staining in histopathological diagnosis enhances the prediction of surgical outcomes in primary aldosteronism. A finding of CYP11B2-positive adenoma is indicative of cure of primary aldosteronism, whereas smaller CYP11B2-positive nodules associate with poorer results at postoperative evaluation. Functional subtyping methods decrease the operations of CYP11B2-negative adenomas and are superior to anatomical imaging in identifying unilateral primary aldosteronism.

Adrenal androgens versus cortisol for primary aldosteronism subtype determination in adrenal venous sampling.

OBJECTIVE: We examined if measurement of adrenal androgens adds to subtype diagnostics of primary aldosteronism (PA) under cosyntropin-stimulated adrenal venous sampling (AVS). DESIGN: A prospective pre-specified secondary endpoint analysis of 49 patients with confirmed PA, of whom 29 underwent unilateral adrenalectomy with long-term follow-up. METHODS: Concentrations of androstenedione, dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulphate (DHEAS) were measured during AVS in addition to aldosterone and cortisol. Subjects with lateralisation index (LI) of ≥4 were treated with unilateral adrenalectomy, and the immunohistochemical subtype was determined with CYP11B2 and CYP11B1 stains. The performance of adrenal androgens was evaluated by receiver operating characteristics (ROC) curve analyses in adrenalectomy and medical therapy groups. RESULTS: During AVS, the correlations between cortisol and androstenedione, DHEA and DHEAS for LI and selectivity index (SI) were highly significant. The right and left side SIs for androstenedione and DHEA were higher (p < .001) than for cortisol. In ROC analysis, the optimal LI cut-off values for androstenedione, DHEA and DHEAS were 4.2, 4.5 and 4.6, respectively. The performance of these LIs for adrenal androgens did not differ from that of cortisol. CONCLUSIONS: Under cosyntropin-stimulated AVS, the measurement of androstenedione and DHEA did not improve the cannulation selectivity. The performance of cortisol and adrenal androgens are confirmatory but not superior to cortisol-based results in lateralisation diagnostics of PA.

Long-term morbidity and mortality in patients diagnosed with an insulinoma.

OBJECTIVE: Insulinomas are rare functional pancreatic neuroendocrine tumours. As previous data on the long-term prognosis of insulinoma patients are scarce, we studied the morbidity and mortality in the Finnish insulinoma cohort. DESIGN: Retrospective cohort study. METHODS: Incidence of endocrine, cardiovascular, gastrointestinal and psychiatric disorders, and cancers was compared in all the patients diagnosed with an insulinoma in Finland during 1980-2010 (n = 79, including two patients with multiple endocrine neoplasia type 1 syndrome), vs 316 matched controls, using the Mantel-Haenszel method. Overall survival was analysed with Kaplan-Meier and Cox regression analyses. RESULTS: The median length of follow-up was 10.7 years for the patients and 12.2 years for the controls. The long-term incidence of atrial fibrillation (rate ratio (RR): 2.07 (95% CI: 1.02-4.22)), intestinal obstruction (18.65 (2.09-166.86)), and possibly breast (4.46 (1.29-15.39) and kidney cancers (RR not applicable) was increased among insulinoma patients vs controls, P < 0.05 for all comparisons. Endocrine disorders and pancreatic diseases were more frequent in the patients during the first year after insulinoma diagnosis, but not later on. The survival of patients with a non-metastatic insulinoma (n = 70) was similar to that of controls, but for patients with distant metastases (n = 9), the survival was significantly impaired (median 3.4 years). CONCLUSIONS: The long-term prognosis of patients with a non-metastatic insulinoma is similar to the general population, except for an increased incidence of atrial fibrillation, intestinal obstruction, and possibly breast and kidney cancers. These results need to be confirmed in future studies. Metastatic insulinomas entail a markedly decreased survival.

Characteristics and outcomes of the Finnish ectopic ACTH syndrome cohort.

PURPOSE: Ectopic ACTH syndrome (EAS) is rare. We established a national cohort to increase awareness and address unmet needs. METHODS: The Finnish national EAS cohort includes 60 patients diagnosed in 1997-2016. We assessed clinical features, diagnostic work-ups, treatments, incidence, and outcomes of subgroups occult tumor (OT), well-differentiated neuroendocrine tumor G1/G2 (NETG1/G2) and NET G3/neuroendocrine carcinoma (NETG3/NEC). RESULTS: The distribution of OT, NETG1/G2, and NETG3/NEC was 10 (17%), 20 (33%), and 30 (50%), respectively; and median follow-up 22 months (0-249). Annual incidence (0.20-0.93 per million inhabitants) and tumor subgroups (OT vs. NEC) varied across the country. The longest diagnostic delay from EAS onset to radiological tumor identification was 48 months. In NET/NEC, 6/50 (12%) were diagnosed 1-24 years before EAS onset. Osteoporotic fractures (32%) and severe infections (55%) were common. The CRH stimulation test accurately diagnosed EAS in 25/31 (81%). Metyrapone (≤6 g daily, prescribed in 88%) was well tolerated. In NETG1/G2, 13/20 (65%) underwent curative resection of the primary tumor; four experienced recurrence within 2-12 years. In OT, 70% underwent bilateral adrenalectomy. Five-year overall survival in OT, NETG1/G2, and NETG3/NEC was 90%, 55%, and 0%, respectively (P < 0.001). Morning cortisol, hypokalemia, infections, metastatic disease, and acute onset were negative, whereas resection of the primary tumor and bilateral adrenalectomy were positive predictors of survival. CONCLUSIONS: NET/NEC may precede EAS onset by several years. In NETG1/G2, recurrences may occur > 10 years after successful primary surgery. Tumor subgroup (OT, NETG1/G2, NEC) was an independent predictor of survival.

Long-term health-related quality of life in persons diagnosed with an insulinoma in Finland 1980-2010.

OBJECTIVE: Insulinomas are rare pancreatic neoplasms, which can usually be cured by surgery. As the diagnostic delay is often long and the prolonged hyperinsulinemia may have long-term effects on health and the quality of life, we studied the long-term health-related quality of life (HRQoL) in insulinoma patients. DESIGN, PATIENTS AND MEASUREMENTS: The HRQoL of adults diagnosed with an insulinoma in Finland in 1980-2010 was studied with the 15D instrument, and the results were compared to those of an age- and gender-matched sample of the general population. The minimum clinically important difference in the total 15D score has been defined as ±0.015. The clinical characteristics, details of insulinoma diagnosis and treatment, and the current health status of the subjects were examined to specify the possible determinants of long-term HRQoL. RESULTS: Thirty-eight insulinoma patients participated in the HRQoL survey (response rate 75%). All had undergone surgery with a curative aim, a median of 13 (min 7, max 34) years before the survey. The insulinoma patients had a clinically importantly and statistically significantly better mean 15D score compared with the controls (0.930 ± 0.072 vs 0.903 ± 0.039, P = .046) and were significantly better off regarding mobility, usual activities and eating. Among the insulinoma patients, younger age at the time of survey, higher level of education and smaller number of chronic diseases were associated with better overall HRQoL. CONCLUSIONS: In the long term, the overall HRQoL of insulinoma patients is slightly better than that of the general population.

Functional imaging with 11C-metomidate PET for subtype diagnosis in primary aldosteronism.

OBJECTIVE: Endocrine Society guidelines recommend adrenal venous sampling (AVS) in primary aldosteronism (PA) if adrenalectomy is considered. We tested whether functional imaging of adrenal cortex with 11C-metomidate (11C-MTO) could offer a noninvasive alternative to AVS in the subtype classification of PA. DESIGN: We prospectively recruited 58 patients with confirmed PA who were eligible for adrenal surgery. METHODS: Subjects underwent AVS and 11C-MTO-PET without dexamethasone pretreatment in random order. The lateralization of 11C-MTO-PET and adrenal CT were compared with AVS in all subjects and in a prespecified adrenalectomy subgroup in which the diagnosis was confirmed with immunohistochemical staining for CYP11B2. RESULTS: In the whole study population, the concordance of AVS and 11C-MTO-PET was 51% and did not differ from that of AVS and adrenal CT (53%). The concordance of AVS and 11C-MTO-PET was 55% in unilateral and 44% in bilateral PA. In receiver operating characteristics analysis, the maximum standardized uptake value ratio of 1.16 in 11C-MTO-PET had an AUC of 0.507 (P = n.s.) to predict allocation to adrenalectomy or medical therapy with sensitivity of 55% and specificity of 44%. In the prespecified adrenalectomy subgroup, AVS and 11C-MTO-PET were concordant in 10 of 19 subjects with CYP11B2-positive adenoma and in 6 of 10 with CYP11B2-positivity without an adenoma. CONCLUSIONS: The concordance of 11C-MTO-PET with AVS was clinically suboptimal, and did not outperform adrenal CT. In a subgroup with CYP11B2-positive adenoma, 11C-MTO-PET identified 53% of cases. 11C-MTO-PET appeared to be inferior to AVS for subtype classification of PA.

Brain glucose uptake is associated with endogenous glucose production in obese patients before and after bariatric surgery and predicts metabolic outcome at follow-up.

AIMS: To investigate further the finding that insulin enhances brain glucose uptake (BGU) in obese but not in lean people by combining BGU with measures of endogenous glucose production (EGP), and to explore the associations between insulin-stimulated BGU and peripheral markers, such as metabolites and inflammatory markers. MATERIALS AND METHODS: A total of 20 morbidly obese individuals and 12 lean controls were recruited from the larger randomized controlled SLEEVEPASS study. All participants were studied under fasting and euglycaemic hyperinsulinaemic conditions using fluorodeoxyglucose-positron emission tomography. Obese participants were re-evaluated 6 months after bariatric surgery and were followed-up for ~3 years. RESULTS: In obese participants, we found a positive association between BGU and EGP during insulin stimulation. Across all participants, insulin-stimulated BGU was associated positively with systemic inflammatory markers and plasma levels of leucine and phenylalanine. Six months after bariatric surgery, the obese participants had achieved significant weight loss. Although insulin-stimulated BGU was decreased postoperatively, the association between BGU and EGP during insulin stimulation persisted. Moreover, high insulin-stimulated BGU at baseline predicted smaller improvement in fasting plasma glucose at 2 and 3 years of follow-up. CONCLUSIONS: Our findings suggest the presence of a brain-liver axis in morbidly obese individuals, which persists postoperatively. This axis might contribute to further deterioration of glucose homeostasis.

Physical Activity Associates with Muscle Insulin Sensitivity Postbariatric Surgery.

PURPOSE: Bariatric surgery is considered as an effective therapeutic strategy for weight loss in severe obesity. Remission of type 2 diabetes is often achieved after the surgery. We investigated whether increase in self-reported habitual physical activity associates with improved skeletal muscle insulin sensitivity and reduction of fat depots after bariatric surgery. METHODS: We assessed self-reported habitual physical activity using Baecke questionnaire in 18 diabetic and 28 nondiabetic patients with morbid obesity (median age, 46 yr; body mass index, 42.0 kg·m) before and 6 months after bariatric surgery operation. Insulin-stimulated femoral muscle glucose uptake was measured using fluorodeoxyglucose positron emission tomography method during hyperinsulinemia. In addition, abdominal subcutaneous and visceral fat masses were quantified using magnetic resonance imaging and liver fat content using magnetic resonance spectroscopy. Also, serum proinflammatory cytokines were measured. RESULTS: Patients lost on average 22.9% of weight during the follow-up period of 6 months (P < 0.001). Self-reported habitual physical activity level increased (P = 0.017). Improvement in skeletal muscle insulin sensitivity was observed only in those patients who reported increase in their physical activity postoperatively (P = 0.018). The increase in self-reported physical activity associated with the loss of visceral fat mass (P = 0.029). Postoperative self-reported physical activity correlated also positively with postoperative hepatic insulin clearance (P = 0.02) and tended to correlate negatively with liver fat content (P = 0.076). Postoperative self-reported physical activity also correlated negatively with serum TNFα, methyl-accepting chemotaxis protein and interleukin 6 levels. CONCLUSIONS: Self-reported physical activity is associated with reversal of skeletal muscle insulin resistance after bariatric surgery as well as with the loss of visceral fat content and improved postoperative metabolism in bariatric surgery patients. TRIAL REGISTRATION: Clinicaltrials.gov, NCT00793143 (SLEEVEPASS), NCT01373892 (SLEEVEPET2).

Effects of bariatric surgery on retinal microvascular architecture in obese patients.

STUDY AIM: Retinal microvasculature changes reflect systemic small vessel damage from obesity. The impact of bariatric surgery induced weight loss on the microvasculature is relatively unknown. We hypothesized that weight loss following bariatric surgery would be associated with improved structural changes in the retinal microvasculature, reflecting an overall improvement in microvascular health. METHODS: The study included 22 obese subjects scheduled for bariatric surgery (laparoscopic Roux-en-Y gastric bypass or a sleeve gastrectomy) and 15 lean, age-matched controls. Ophthalmic examination, including fundus photography, was performed at baseline and 6-months. Retinal microvasculature caliber was analysed quantitatively using a semi-automated computer program and summarized as central retinal artery equivalent (CRAE) and venular equivalent (CRVE). RESULTS: Mean weight loss at 6 months was 26.1 kg ± 8 kg in the bariatric surgery group. Retinal artery caliber increased (136.0 ± 1.4 to 141.4 ± 1.4 µm, p = 0.013) and venular caliber decreased (202.9 ± 1.9 to 197.3 ± 1.9 µm, p = 0.046) in the bariatric surgery group by 6 months, with no change in arteriolar (136.6 ± 1.1 to 134.5 ± 1.2, p = 0.222) or venular (195.1 ± 2.1 to 193.3 ± 2.2, p = 0.550) caliber in the control group. The arteriolar to venular ratio increased in the bariatric surgery group, with no change in the control group at 6 months. CONCLUSIONS: The findings suggest obesity-related microvascular changes are reversible after bariatric surgery-induced weight loss. The capacity for the retinal microvasculature to improve following bariatric surgery suggests plasticity of the human microvasculature early in the disease course.

Characteristics and Outcomes of 79 Patients with an Insulinoma: A Nationwide Retrospective Study in Finland.

OBJECTIVE: Insulinomas are rare pancreatic tumours. Population-based data on their incidence, clinical picture, diagnosis, and treatment are almost nonexistent. The aim of this study was to clarify these aspects in a nationwide cohort of insulinoma patients diagnosed during three decades. DESIGN AND METHODS: Retrospective analysis on all adult patients diagnosed with insulinoma in Finland during 1980-2010. RESULTS: Seventy-nine patients were diagnosed with insulinoma over the research period. The median follow-up from diagnosis to last control visit was one (min 0, max 31) year. The incidence increased from 0.5/million/year in the 1980s to 0.9/million/year in the 2000s (p = 0.002). The median diagnostic delay was 13 months and did not change over the study period. The mean age at diagnosis was 52 (SD 16) years. The overall imaging sensitivity improved from 39% in the 1980s to 98% in the 2000s (p < 0.001). Seventy-one (90%) of the patients underwent surgery with a curative aim, two (3%) had palliative surgery, and 6 (8%) were inoperable. There were no significant differences in the types of surgical procedures between the 1980s, 1990s, and 2000s; tumour enucleations comprised 43% of the operations, distal pancreatic resections 45%, and pancreaticoduodenectomies 12%, over the whole study period. Of the patients who underwent surgery with a curative aim, 89% had a full recovery. Postoperative complications occurred in half of the patients, but postoperative mortality was rare. CONCLUSIONS: The incidence of insulinomas has increased during the past three decades. Despite the improved diagnostic options, diagnostic delay has remained unchanged. To shorten the delay, clinicians should be informed and alert to consider the possibility of hypoglycemia and insulinoma, when symptomatic attacks are investigated in different sectors of the healthcare system. Developing the surgical treatment is another major target, in order to lower the overall complication rate, without compromising the high cure rate of insulinomas.

The effect of bariatric surgery on intraocular pressure.

PURPOSE: Study purpose was to investigate the effects of bariatric surgery on intraocular pressure (IOP) and other ophthalmic parameters in a prospective observational follow-up study. METHODS: Ophthalmic examination was performed on 22 obese women before and 6 months after bariatric surgery. A control group of 15 non-obese age-matched women were studied twice 6 months apart. IOP was measured with the Goldmann applanation tonometer (GAT) and the Pascal dynamic contour tonometer (PDCT). None of the subjects had glaucoma. RESULTS: Average weight loss 6 months after bariatric surgery was 25 ±8 kg, (p < 0.05). Visual acuity (VA), pachymetry and systolic as well as diastolic blood pressures did not differ between the obese and control groups and no change between the visits was detected. At baseline, IOP was significantly higher in the obese group than in the controls (16.6 ± 3.0 mmHg GAT and 18.1 ± 2.2 mmHg PDCT compared with 14.3 ± 1.5 mmHg GAT and 16.5 ± 1.9 mmHg PDCT respectively). After bariatric surgery, IOP was significantly lower (15.2 ± 2.7 mmHg GAT and 16.5 ± 2.0 mmHg PDCT, p < 0.05) and no significant difference was detected between the operated and control groups. In the whole data at baseline, IOP correlated with weight, body mass index, waist circumference, body fat per cent and systolic blood pressure values. CONCLUSION: Intraocular pressure (IOP) is significantly higher in obese women than in non-obese age-matched controls. Obese subjects had a decrease in IOP after bariatric surgery with no change in IOP in the control group. This change in obese group may be related to weight loss. Different measures of obesity correlated with IOP at baseline.

Effect of Laparoscopic Sleeve Gastrectomy vs Laparoscopic Roux-en-Y Gastric Bypass on Weight Loss at 5 Years Among Patients With Morbid Obesity: The SLEEVEPASS Randomized Clinical Trial.

Importance: Laparoscopic sleeve gastrectomy for treatment of morbid obesity has increased substantially despite the lack of long-term results compared with laparoscopic Roux-en-Y gastric bypass. Objective: To determine whether laparoscopic sleeve gastrectomy and laparoscopic Roux-en-Y gastric bypass are equivalent for weight loss at 5 years in patients with morbid obesity. Design, Setting, and Participants: The Sleeve vs Bypass (SLEEVEPASS) multicenter, multisurgeon, open-label, randomized clinical equivalence trial was conducted from March 2008 until June 2010 in Finland. The trial enrolled 240 morbidly obese patients aged 18 to 60 years, who were randomly assigned to sleeve gastrectomy or gastric bypass with a 5-year follow-up period (last follow-up, October 14, 2015). Interventions: Laparoscopic sleeve gastrectomy (n = 121) or laparoscopic Roux-en-Y gastric bypass (n = 119). Main Outcomes and Measures: The primary end point was weight loss evaluated by percentage excess weight loss. Prespecified equivalence margins for the clinical significance of weight loss differences between gastric bypass and sleeve gastrectomy were -9% to +9% excess weight loss. Secondary end points included resolution of comorbidities, improvement of quality of life (QOL), all adverse events (overall morbidity), and mortality. Results: Among 240 patients randomized (mean age, 48 [SD, 9] years; mean baseline body mass index, 45.9, [SD, 6.0]; 69.6% women), 80.4% completed the 5-year follow-up. At baseline, 42.1% had type 2 diabetes, 34.6% dyslipidemia, and 70.8% hypertension. The estimated mean percentage excess weight loss at 5 years was 49% (95% CI, 45%-52%) after sleeve gastrectomy and 57% (95% CI, 53%-61%) after gastric bypass (difference, 8.2 percentage units [95% CI, 3.2%-13.2%], higher in the gastric bypass group) and did not meet criteria for equivalence. Complete or partial remission of type 2 diabetes was seen in 37% (n = 15/41) after sleeve gastrectomy and in 45% (n = 18/40) after gastric bypass (P > .99). Medication for dyslipidemia was discontinued in 47% (n = 14/30) after sleeve gastrectomy and 60% (n = 24/40) after gastric bypass (P = .15) and for hypertension in 29% (n = 20/68) and 51% (n = 37/73) (P = .02), respectively. There was no statistically significant difference in QOL between groups (P = .85) and no treatment-related mortality. At 5 years the overall morbidity rate was 19% (n = 23) for sleeve gastrectomy and 26% (n = 31) for gastric bypass (P = .19). Conclusions and Relevance: Among patients with morbid obesity, use of laparoscopic sleeve gastrectomy compared with use of laparoscopic Roux-en-Y gastric bypass did not meet criteria for equivalence in terms of percentage excess weight loss at 5 years. Although gastric bypass compared with sleeve gastrectomy was associated with greater percentage excess weight loss at 5 years, the difference was not statistically significant, based on the prespecified equivalence margins. Trial Registration: clinicaltrials.gov Identifier: NCT00793143.

Reversibility of myocardial metabolism and remodelling in morbidly obese patients 6 months after bariatric surgery.

AIMS: To study myocardial substrate uptake, structure and function, before and after bariatric surgery, to clarify the interaction between myocardial metabolism and cardiac remodelling in morbid obesity. METHODS: We studied 46 obese patients (age 44 ± 10 years, body mass index [BMI] 42 ± 4 kg/m2 ), including 18 with type 2 diabetes (T2D) before and 6 months after bariatric surgery and 25 healthy age-matched control group subjects. Myocardial fasting free fatty acid uptake (MFAU) and insulin-stimulated myocardial glucose uptake (MGU) were measured using positron-emission tomography. Myocardial structure and function, and myocardial triglyceride content (MTGC) and intrathoracic fat were measured using magnetic resonance imaging and magnetic resonance spectroscopy. RESULTS: The morbidly obese study participants, with or without T2D, had cardiac hypertrophy, impaired myocardial function and substrate metabolism compared with the control group. Surgery led to marked weight reduction and remission of T2D in most of the participants. Postoperatively, myocardial function and structure improved and myocardial substrate metabolism normalized. Intrathoracic fat, but not MTGC, was reduced. Before surgery, BMI and MFAU correlated with left ventricular hypertrophy, and BMI, age and intrathoracic fat mass were the main variables associated with cardiac function. The improvement in whole-body insulin sensitivity correlated positively with the increase in MGU and the decrease in MFAU. CONCLUSIONS: In the present study, obesity and age, rather than myocardial substrate uptake, were the causes of cardiac remodelling in morbidly obese patients with or without T2D. Cardiac remodelling and impaired myocardial substrate metabolism are reversible after surgically induced weight loss and amelioration of T2D.

Fatty acid uptake and blood flow in adipose tissue compartments of morbidly obese subjects with or without type 2 diabetes: effects of bariatric surgery.

Body fat accumulation, distribution, and metabolic activity are factors in the pathophysiology of obesity and type 2 diabetes (T2D). We investigated adipose blood flow, fatty acid uptake (FAU), and subcutaneous and visceral fat cellularity in obese patients with or without T2D. A total of 23 morbidly obese (mean body mass index = 42 kg/m2) patients were studied before and 6 mo after bariatric surgery; 15 nonobese subjects served as controls. Positron emission tomography was used to measure tissue FAU (with 18F-FTHA) and blood flow (with H215O); MRI was used for fat distribution and fat biopsy for adipocyte size. Obese subjects had subcutaneous hyperplasia and hypertrophy and lower blood flow; when expressed per cell, flow was similar to controls. FAU into subcutaneous and visceral depots was increased in the obese; per unit tissue mass, however, FAU was similar to controls but reduced in skeletal muscle. Fatty acid fractional extraction in subcutaneous fat and muscle was only increased in obese patients with T2D. We conclude that surgery reduces subcutaneous fat hyperplasia and hypertrophy; subcutaneous blood flow and FAU decrease in absolute terms and per cell while fractional FAU remains unchanged in T2D. In the obese, subcutaneous blood flow is a determinant of FAU and is coupled with cellularity; efficiency of FAU is enhanced in subcutaneous fat and muscle in T2D.

Changes in bone metabolism after bariatric surgery by gastric bypass or sleeve gastrectomy.

Bariatric surgery results in rapid weight loss and beneficial metabolic effects, but may have negative effects on the skeleton. The objective of this prospective study was to evaluate changes in bone metabolism in response to bariatric surgery with two surgical techniques. 46 morbidly obese subjects (mean 44.9years, BMI 42.1) with (n=19) or without (n=27) type 2 diabetes (T2DM) at baseline underwent either Roux-en-Y gastric bypass (RYGB, n=21) or sleeve gastrectomy (SG, n=25). Bone turnover markers (CTX, PINP, TRAcP5b, TotalOC and ucOC) were measured before and six months after surgery. Volumetric bone mineral density (vBMD) at lumbar spine and vertebral bone marrow (VBM) fat were measured in 21 subjects (7 RYGB and 14 SG) with three-dimensional quantitative computer tomography and 1H MR spectroscopy, respectively. 25 non-obese subjects were recruited as controls (mean 45.8years, BMI 23.0) and assessed at a single cross-sectional visit. Obese subjects had significantly lower bone turnover at baseline when compared to non-obese controls. Bone metabolic markers markedly increased post-operatively (p<0.0001 for all). The activation of bone remodeling was significantly higher after RYGB than after SG and was particularly observed in patients, whose type 2 diabetes was in remission after weight loss. There was no change in volumetric BMD or marrow fat at lumbar spine six months after surgery in our sample. In conclusion, severe obesity decreases bone remodeling, which is activated after bariatric surgery. The increase in bone turnover after surgery is affected by the choice of surgical technique and by the post-surgery remission of T2DM.

Effect of Bariatric Surgery on Adipose Tissue Glucose Metabolism in Different Depots in Patients With or Without Type 2 Diabetes.

OBJECTIVE: We investigated fat distribution and tissue-specific insulin-stimulated glucose uptake (GU) in seven fat compartments (visceral and subcutaneous) and skeletal muscle in morbidly obese patients with (T2D) and without (ND) type 2 diabetes before and 6 months after bariatric surgery. RESEARCH DESIGN AND METHODS: A total of 23 obese patients (BMI 43.0 ± 3.6 kg/m(2); 9 T2D and 14 ND) were recruited from a larger, randomized multicenter SLEEVEPASS study. MRI (for fat distribution) and [(18)F]-fluorodeoxyglucose PET (for GU) studies were performed for the obese patients before and 6 months postsurgery; 10 lean subjects served as control subjects and were studied once. RESULTS: At baseline, visceral fat GU was 30 ± 7% of muscle GU in control subjects and 57 ± 5% in obese patients. Visceral and deep subcutaneous fat were more abundant (despite same total fat mass) and less insulin sensitive in T2D than ND; in both, GU was impaired compared with control subjects. Postsurgery, visceral fat mass decreased (∼40%) more than subcutaneous fat (7%). Tissue-specific GU was improved, but not normalized, at all sites in T2D and ND alike. The contribution of visceral fat to whole-body GU was greater in T2D than ND but decreased similarly with surgery. Subcutaneous fat made a fourfold greater contribution to whole-body GU in obese versus lean subjects (15% vs. 4%) both before and after surgery. CONCLUSIONS: Bariatric surgery leads to sustained weight loss and improves tissue-specific glucose metabolism in morbidly obese patients. We conclude that 1) enhanced visceral fat accumulation is a feature of T2D, 2) severe obesity compromises muscle insulin sensitivity more than fat insulin sensitivity, and 3) fat mass expansion is a sink for plasma glucose.

The effects of bariatric surgery on pancreatic lipid metabolism and blood flow.

CONTEXT: Bariatric surgery leads to a rapid and sustained weight loss often accompanied with improvement in glucose homeostasis. OBJECTIVE: The objective of this study was to investigate the effects of bariatric surgery on pancreatic lipid metabolism, blood flow, and glycemic control. DESIGN: This was a longitudinal study. SETTING: The study was conducted in a clinical research center. PARTICIPANTS: This study included 27 morbidly obese and 15 healthy control subjects. INTERVENTIONS: Measurements were performed using positron emission tomography with the palmitate analog 14(R,S)-[(18)F]fluoro-6-thia-heptadecanoic acid and radiowater ([(15)O]H2O) and computed tomography. In morbidly obese subjects, positron emission tomography/computed tomography imaging studies were performed before and 6 months after bariatric surgery (either Roux-en-Y gastric bypass or sleeve gastrectomy). MAIN OUTCOME MEASURES: Pancreatic fat and fat-free volume, fatty acid uptake and blood flow were measured as well as parameters of ß-cell function, glucose tolerance, and insulin sensitivity. RESULTS: Six months after bariatric surgery, 23% excess weight loss was observed (P < .0001), and diabetes remission was seen in 7 of 10 patients. When compared with preoperative values, after surgery, notable decreases in pancreatic fat volume (P < .01), fatty acid uptake, and blood flow (both P < .05) were seen, whereas no change was seen in pancreatic fat-free volume. The decrease in pancreatic fat volume and the preservation of blood flow were associated with favorable glucose homeostasis and ß-cell function. CONCLUSIONS: Bariatric surgery elicits marked alterations in pancreatic lipid metabolism and blood flow, which may contribute to the observed improvement in glucose homeostasis and remission of type 2 diabetes.

Obesity-associated intestinal insulin resistance is ameliorated after bariatric surgery.

AIMS/HYPOTHESIS: The intestine is the main site for glucose absorption and it has been suggested that it exhibits insulin resistance. Bariatric surgery has been shown to reverse insulin resistance and type 2 diabetes, but its effects on human intestinal metabolism are unknown. Our aim was to evaluate the effects of insulin on intestinal glucose metabolism before and after bariatric surgery. METHODS: Twenty-one morbidly obese individuals undergoing bariatric surgery and ten age-matched healthy individuals were recruited and intestinal and skeletal muscle glucose uptake (GU) was measured using [(18)F]fluoro-2-deoxyglucose and positron emission tomography at fast and during hyperinsulinaemia. MRI was used as anatomical reference. Obese participants were studied again 6 months postoperatively. RESULTS: In contrast to healthy individuals, insulin had no effect on intestinal GU in obese participants with or without diabetes, suggesting that intestinal insulin resistance is present early in morbid obesity. Postoperatively, jejunal GU increased in line with whole-body and muscle GU. Postoperative GU values in the intestine correlated with whole-body insulin sensitivity, indicating that the intestinal mucosa may reflect the overall glycaemic state and potentially mediate obesity-associated insulin resistance. CONCLUSIONS/INTERPRETATION: This study shows that insulin is a potent stimulator of GU in the healthy intestine and that intestinal insulin resistance is ameliorated after bariatric surgery. In our study, obese individuals had intestinal insulin resistance regardless of their glycaemic status. Persistent changes in intestinal glucose metabolism are likely to influence both local processes in the gut and systemic glucose homeostasis.