Acromegaly management in the Nordic countries: A Delphi consensus survey.

OBJECTIVE: Acromegaly is associated with increased morbidity and mortality if left untreated. The therapeutic options include surgery, medical treatment, and radiotherapy. Several guidelines and recommendations on treatment algorithms and follow-up exist. However, not all recommendations are strictly evidence-based. To evaluate consensus on the treatment and follow-up of patients with acromegaly in the Nordic countries. METHODS: A Delphi process was used to map the landscape of acromegaly management in Denmark, Sweden, Norway, Finland, and Iceland. An expert panel developed 37 statements on the treatment and follow-up of patients with acromegaly. Dedicated endocrinologists (n = 47) from the Nordic countries were invited to rate their extent of agreement with the statements, using a Likert-type scale (1-7). Consensus was defined as ≥80% of panelists rating their agreement as ≥5 or ≤3 on the Likert-type scale. RESULTS: Consensus was reached in 41% (15/37) of the statements. Panelists agreed that pituitary surgery remains first line treatment. There was general agreement to recommend first-generation somatostatin analog (SSA) treatment after failed surgery and to consider repeat surgery. In addition, there was agreement to recommend combination therapy with first-generation SSA and pegvisomant as second- or third-line treatment. In more than 50% of the statements, consensus was not achieved. Considerable disagreement existed regarding pegvisomant monotherapy, and treatment with pasireotide and dopamine agonists. CONCLUSION: This consensus exploration study on the management of patients with acromegaly in the Nordic countries revealed a relatively large degree of disagreement among experts, which mirrors the complexity of the disease and the shortage of evidence-based data.

Glucose management team significantly improves glycaemic care and commitment to in-hospital guidelines within arthroplastic patients.

BACKGROUND: Perioperative dysglycaemias are a risk for harm but guidelines to improve glucose management are poorly adhered to. AIM: To determine whether a specialized team and diabetes education improves the implementation of guidelines and glucose values. METHODS: We conducted a prospective study of 611 nonselected, consecutive patients attending for elective hip or knee arthroplasty. The first 209 patients received conventional care and the following 402 patients received intervention (Acute Glucose Service, AGS) in two chronological groups; either perioperatively (AGS1) or also preoperatively (AGS2). The AGS-team provided diabetes education, identified the patients with diabetes risk and adjusted the medication when needed. Capillary plasma glucose (CPG) was repeatedly measured and glycated haemoglobin (HbA1c) obtained before and after the surgery. The study objectives were to evaluate the staff actions when hyperglycaemia was severe (CPG >10 mmol/L), and to assess improvement of the glycaemic values and the complication rate within 3 months. RESULTS: None of the severely hyperglycaemic events in the reference group were treated according to guidelines. In the AGS 1 group, 50% and in the AGS2 group, 53% were appropriately managed (p < .001). The events of hyperglycaemia (CPG >7.8 mmol/L at least twice) and of severe hyperglycaemia (CPG >10 mmol/L) decreased in all patient groups. The medians of the highest, mean and variability of CPG values improved. The mean HbA1c improved significantly within AGS 2. There was no association between improved glycaemic care and early complications. CONCLUSIONS: AGS intervention significantly improves adherence to guidelines and glucose values.

Perioperative hyperglycaemia in elective arthroplasties. Should we do better?

BACKGROUND: Perioperative dysglycaemia is associated with deleterious outcomes but guidelines to improve glucose management are poorly or inconsistently adhered to. We evaluated glucose management among diabetic and non-diabetic patients undergoing elective hip or knee arthroplasty. METHODS: Capillary plasma glucose (CPG) was measured prospectively four times daily of 209 patients undergoing elective hip or knee surgery. Actions of the attending teams to CPG values and detection of patients at risk were analysed. RESULTS: A total of 209 patients were enrolled. All diabetic patients on insulin (6/6) had hyperglycaemia (≥7.8 mmol/l) more than twice and severe hyperglycaemia (>10 mmol/l) at least once. Of the 27 diabetic patients not on insulin 26 (96.3%) had CPG ≥ 7.8 mmol/l ≥ 2 times and 17 (63%) >10 mmol/l. The corresponding figures of the 176 non-diabetic patients were 137 (77.8%) and 61 (34.7%). Severe hyperglycaemia occurred in 54/176 (30.1%) of the non-diabetic patients with pre-operative HbA1c < 42 mmol/mol and random plasma glucose < 7.8 mmol/l. Of the 84 hyperglycaemic episodes > 10 mmol/l, none was treated. Patients with a FINDRISC score ≥ 12 (corresponding to moderate to high risk of diabetes) and hyperglycaemia went unnoticed. CONCLUSIONS: Hyperglycaemia is common among elective orthopaedic surgery patients with or without diabetes. More than 80% of the 209 patients had hyperglycaemia and 40% had severe hyperglycaemia. None of the patients was treated according to guidelines and none of the patients at risk of hyperglycaemia or diabetes was noticed. There is an obvious need for further education and support by diabetes specialists. CLINICAL TRIAL REGISTRATION: Clinical trials, gov. NCT03306810.

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.

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.

Effect of bariatric surgery on liver glucose metabolism in morbidly obese diabetic and non-diabetic patients.

BACKGROUND & AIMS: Bariatric surgery reduces weight and improves glucose metabolism in obese patients. We investigated the effects of bariatric surgery on hepatic insulin sensitivity. METHODS: Twenty-three morbidly obese (nine diabetic and fourteen non-diabetic) patients and ten healthy, lean control subjects were studied using positron emission tomography to assess hepatic glucose uptake in the fasting state and during euglycemic hyperinsulinemia. Magnetic resonance spectroscopy was performed to measure liver fat content and magnetic resonance imaging to obtain liver volume. Obese patients were studied before bariatric surgery (either sleeve gastrectomy or Roux-en-Y gastric bypass) and six months after surgery. RESULTS: Insulin-induced hepatic glucose uptake was increased by 33% in non-diabetic and by 36% in diabetic patients at follow-up compared with baseline, but not totally normalized. The liver fat content was reduced by 76%, liver volume by 26% and endogenous glucose production by 19% in non-diabetic patients. The respective changes in diabetic patients were 73%, 24%, and 25%. Postoperatively, liver fat content and endogenous glucose production were almost normalized to lean controls, but liver volume remained greater than in control subjects. CONCLUSIONS: This study shows that bariatric surgery leads to a significant improvement in hepatic insulin sensitivity: insulin-stimulated hepatic glucose uptake was improved and endogenous glucose production reduced when measured, six-months, after surgery. These metabolic effects were accompanied by a marked reduction in hepatic volume and fat content. Overall, the gain in hepatic insulin sensitivity in diabetic patients was quite similar to non-diabetic patients for the same weight reduction.

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).

Increased Liver Fatty Acid Uptake Is Partly Reversed and Liver Fat Content Normalized After Bariatric Surgery.

OBJECTIVE: Changes in liver fatty acid metabolism are important in understanding the mechanisms of diabetes remission and metabolic changes after bariatric surgery. RESEARCH DESIGN AND METHODS: Liver fatty acid uptake (LFU), blood flow, and fat content (LFC) were measured in 25 obese subjects before bariatric surgery and 6 months after using positron emission tomography/computed tomography and MRS; 14 lean individuals served as the control subjects. RESULTS: The increased LFU in obese subjects was associated with body adiposity. LFU was reduced postoperatively but was still high compared with the control subjects. LFC was normalized. Liver blood flow (per unit volume) was higher in obese subjects than in the control subjects at baseline and was further increased postoperatively; however, the total organ blood flow was unchanged as the liver volume decreased. CONCLUSIONS: The findings suggest that in a postoperative state, intrahepatic fatty acids are not stored in the liver but are used for oxidation to provide energy. Changes in perfusion may contribute to improved liver metabolism postoperatively.

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.

Dorsal striatum and its limbic connectivity mediate abnormal anticipatory reward processing in obesity.

Obesity is characterized by an imbalance in the brain circuits promoting reward seeking and those governing cognitive control. Here we show that the dorsal caudate nucleus and its connections with amygdala, insula and prefrontal cortex contribute to abnormal reward processing in obesity. We measured regional brain glucose uptake in morbidly obese (n = 19) and normal weighted (n = 16) subjects with 2-[¹8F]fluoro-2-deoxyglucose ([¹8F]FDG) positron emission tomography (PET) during euglycemic hyperinsulinemia and with functional magnetic resonance imaging (fMRI) while anticipatory food reward was induced by repeated presentations of appetizing and bland food pictures. First, we found that glucose uptake rate in the dorsal caudate nucleus was higher in obese than in normal-weight subjects. Second, obese subjects showed increased hemodynamic responses in the caudate nucleus while viewing appetizing versus bland foods in fMRI. The caudate also showed elevated task-related functional connectivity with amygdala and insula in the obese versus normal-weight subjects. Finally, obese subjects had smaller responses to appetizing versus bland foods in the dorsolateral and orbitofrontal cortices than did normal-weight subjects, and failure to activate the dorsolateral prefrontal cortex was correlated with high glucose metabolism in the dorsal caudate nucleus. These findings suggest that enhanced sensitivity to external food cues in obesity may involve abnormal stimulus-response learning and incentive motivation subserved by the dorsal caudate nucleus, which in turn may be due to abnormally high input from the amygdala and insula and dysfunctional inhibitory control by the frontal cortical regions. These functional changes in the responsiveness and interconnectivity of the reward circuit could be a critical mechanism to explain overeating in obesity.