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Aims/hypothesis: The role of the intestine in the pathogenesis of metabolic diseases is gaining much attention. We therefore sought to validate, using an animal model, the use of positron emission tomography (PET) in the estimation of intestinal glucose uptake (GU), and thereafter to test whether intestinal insulin-stimulated GU is altered in morbidly obese compared with healthy human participants. Methods: In the validation study, pigs were imaged using [F]fluorodeoxyglucose ([F]FDG) and the image-derived data were compared with corresponding ex vivo measurements in tissue samples and with arterial-venous differences in glucose and [F]FDG levels. In the clinical study, GU was measured in different regions of the intestine in lean ( n = 8) and morbidly obese ( n = 8) humans at baseline and during euglycaemic hyperinsulinaemia. Results: PET- and ex vivo-derived intestinal values were strongly correlated and most of the fluorine-18-derived radioactivity was accumulated in the mucosal layer of the gut wall. In the gut wall of pigs, insulin promoted GU as determined by PET, the arterial-venous balance or autoradiography. In lean human participants, insulin increased GU from the circulation in the duodenum (from 1.3 ± 0.6 to 3.1 ± 1.1 μmol [100 g] min, p < 0.05) and in the jejunum (from 1.1 ± 0.7 to 3.0 ± 1.5 μmol [100 g] min, p < 0.05). Obese participants failed to show any increase in insulin-stimulated GU compared with fasting values (NS). Conclusions/interpretation: Intestinal GU can be quantified in vivo by [F]FDG PET. Intestinal insulin resistance occurs in obesity before the deterioration of systemic glucose tolerance. [ABSTRACT FROM AUTHOR]

Context: Proneurotensin (pNT) is associated with obesity and type 2 diabetes (T2D), but the effects of Roux-en-Y gastric bypass (RYGB) on postprandial pNT levels are not well studied., Objective: This work aimed to assess the effects of RYGB vs a very low-energy diet (VLED) on pNT levels in response to mixed-meal tests (MMTs), and long-term effects of RYGB on fasting pNT., Methods: Cohort 1: Nine normoglycemic (NG) and 10 T2D patients underwent MMT before and after VLED, immediately post RYGB and 6 weeks post RYGB. Cohort 2: Ten controls with normal weight and 10 patients with obesity and T2D, who underwent RYGB or vertical sleeve gastrectomy (VSG), underwent MMTs and glucose-dependent insulinotropic polypeptide (GIP) infusions pre surgery and 3 months post surgery. Glucagon-like peptide-1 (GLP-1) infusions were performed in normal-weight participants. Cohort 3: Fasting pNT was assessed pre RYGB (n = 161), 2 months post RYGB (n = 92), and 1year post RYGB (n = 118) in NG and T2D patients. pNT levels were measured using enzyme-linked immunosorbent assay., Results: Reduced fasting and postprandial pNT were evident after VLED and immediately following RYGB. Reintroduction of solid food post RYGB increased fasting and postprandial pNT. Prior to RYGB, all patients lacked a meal response in pNT, but this was evident post RYGB/VSG. GIP or GLP-1 infusion had no effect on pNT levels. Fasting pNTs were higher 1-year post RYGB regardless of glycemic status., Conclusion: RYGB causes a transient reduction in pNT as a consequence of caloric restriction. The RYGB/VSG-induced rise in postprandial pNT is independent of GIP and GLP-1, and higher fasting pNTs are maintained 1 year post surgically., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

We examined the effect of increased levels of plasma ketones on left ventricular (LV) function, myocardial glucose uptake (MGU), and myocardial blood flow (MBF) in patients with type 2 diabetes (T2DM) with heart failure. Three groups of patients with T2DM (n = 12 per group) with an LV ejection fraction (EF) ≤50% received incremental infusions of β-hydroxybutyrate (β-OH-B) for 3-6 h to increase the plasma β-OH-B concentration throughout the physiologic (groups I and II) and pharmacologic (group III) range. Cardiac MRI was performed at baseline and after each β-OH-B infusion to provide measures of cardiac function. On a separate day, group II also received a sodium bicarbonate (NaHCO3) infusion, thus serving as their own control for time, volume, and pH. Additionally, group II underwent positron emission tomography study with 18F-fluoro-2-deoxyglucose to examine effect of hyperketonemia on MGU. Groups I, II, and III achieved plasma β-OH-B levels (mean ± SEM) of 0.7 ± 0.3, 1.6 ± 0.2, 3.2 ± 0.2 mmol/L, respectively. Cardiac output (CO), LVEF, and stroke volume (SV) increased significantly during β-OH-B infusion in groups II (CO, from 4.54 to 5.30; EF, 39.9 to 43.8; SV, 70.3 to 80.0) and III (CO, from 5.93 to 7.16; EF, 41.1 to 47.5; SV, 89.0 to 108.4), and did not change with NaHCO3 infusion in group II. The increase in LVEF was greatest in group III (P < 0.001 vs. group II). MGU and MBF were not altered by β-OH-B. In patients with T2DM and LVEF ≤50%, increased plasma β-OH-B level significantly increased LV function dose dependently. Because MGU did not change, the myocardial benefit of β-OH-B resulted from providing an additional fuel for the heart without inhibiting MGU., (© 2024 by the American Diabetes Association.)

Objective: The glycemic-independent actions of glucagon-like peptide-1 (GLP-1) in the prandial state in humans are unknown. We examined the contribution of GLP-1 to β-cell secretory response (primary endpoint) and glucose metabolism during protein ingestion under basal glycemia, as well as whether these responses are affected by rerouted gut after gastric bypass (GB) or sleeve gastrectomy (SG)., Methods: Insulin secretion rate (ISR) and glucose fluxes during a 50-g oral protein load were compared among 10 nondiabetic individuals with GB, 9 with SG, and 7 non-operated controls (CN), with and without intravenous infusion of exendin(9-39) (Ex-9), a GLP-1 receptor (GLP-1R) antagonist., Results: Blocking GLP-1R increased glucose before and after protein ingestion and decreased β-cell sensitivity to glucose in the first 30 min of protein ingestion in all three groups (p < 0.05). Reduction in the premeal ISR by Ex-9 infusion was only observed in CN, whereas diminished prandial ISR 3h by GLP-1R blockade was only observed in GB and SG (p < 0.05 for interaction). GLP-1R blockade enhanced post-protein insulin action in GB and SG, but not in CN, and exaggerated endogenous glucose production only GB (p < 0.05 for interaction)., Conclusions: These findings are consistent with both pancreatic and extra-pancreatic roles for GLP-1 during protein ingestion in humans that are exaggerated by bariatric surgery., (© 2024 The Obesity Society.)

Aim: To determine the effect of endogenous glucagon-like peptide 1 (GLP-1) on prandial counterregulatory response to hypoglycaemia after gastric bypass (GB)., Materials and Methods: Glucose fluxes, and islet-cell and gut hormone responses before and after mixed-meal ingestion, were compared during a hyperinsulinaemic-hypoglycaemic (~3.2 mmol/L) clamp with and without a GLP-1 receptor (GLP-1R) antagonist exendin-(9-39) infusion in non-diabetic patients who had previously undergone GB compared to matched participants who had previously undergone sleeve gastrectomy (SG) and non-surgical controls., Results: Exendin-(9-39) infusion raised prandial endogenous glucose production (EGP) response to insulin-induced hypoglycaemia in the GB group but had no consistent effect on EGP response among the SG group or non-surgical controls (p < 0.05 for interaction). The rates of systemic appearance of ingested glucose or prandial glucose utilization did not differ among the three groups or between studies with and without exendin-(9-39) infusion. Blockade of GLP-1R had no effect on insulin secretion or insulin action but enhanced prandial glucagon in all three groups., Conclusions: These results indicate that impaired post-meal glucose counterregulatory response to hypoglycaemia after GB is partly mediated by endogenous GLP-1, highlighting a novel pathogenic mechanism of GLP-1 in developing hypoglycaemia in this population., (© 2024 John Wiley & Sons Ltd.)

Background: Altered prandial glycemic response after Roux-en-Y gastric bypass (RYGB) is exaggerated in patients with post-RYGB hypoglycemia. Increased contribution of glucagon-like peptide 1 (GLP-1) to prandial insulin secretion plays a key role in developing hypoglycemia after RYGB, but the role of nonhormonal gut factors remains unknown. Here, the effect of vagal activation on prandial bile acid (BA) composition in relation to glucose, insulin and gut hormone responses was examined in a small size group of nondiabetic subjects after RYGB with intact gallbladder compared to nonoperated controls., Methods: Concentrations of blood glucose, hormones, and BAs were measured in two RYGB subjects with documented hypoglycemia (HGB), three asymptomatic RYGB-treated subjects (AGB), and four nonoperated controls with intact gallbladders during a meal-tolerance test with (MTT-Sham) and without (MTT) preceding modified sham feeding (chew and spit)., Key Results: Meal ingestion raised serum total BAs in RYGB-treated subjects without any effect in nonoperated controls. Modified sham feeding similarly increased meal-induced responses of conjugated BAs (CBAs) in all subjects (p < 0.05 compared to MTT alone), whereas unconjugated BAs (UBAs), mainly deoxycholic and chenodeoxycholic acid, were raised only in the HGB group (p < 0.001 for interaction). Prandial UBAs had an inverse correlation with glucose nadir (r = -0.75, p < 0.05) and were directly associated with ISR and GLP-1 during MTT-Sham., Conclusions & Inferences: In this small cohort, vagal activation by modified sham feeding increases prandial CBAs in both operated and nonoperated subjects but enhances UBAs only in patients with documented post-RYGB hypoglycemia. Our findings highlight a potential role for nonhormonal gut factors, such as BA and gut microbiome, in glucose abnormalities after RYGB., (© 2024 John Wiley & Sons Ltd.)

We have previously shown that prandial endogenous glucose production (EGP) during insulin-induced hypoglycemia is smaller in non-diabetic subjects with gastric bypass (GB), where prandial glucagon-like peptide 1 (GLP-1) concentrations are 5-10 times higher than those in non-operated controls. Here, we sought to determine the effect of endogenous GLP-1 on prandial counterregulatory response to hypoglycemia after GB. Glucose fluxes, and islet-cell and gut hormone responses before and after mixed-meal ingestion were compared during a hyperinsulinemic hypoglycemic (~3.2 mmol/l) clamp with and without a GLP-1 receptor (GLP-1R) antagonist exendin-(9-39) (Ex-9) in non-diabetic subjects with prior GB compared to matched subjects with SG and non-surgical controls. In this setting, GLP-1R blockade had no effect on insulin secretion or insulin action, whereas prandial glucagon was enhanced in all 3 groups. Ex-9 infusion raised prandial EGP response to hypoglycemia in every GB subject but had no consistent effects on EGP among subjects with SG or non-operated controls (P < 0.05 for interaction). These results indicate that impaired post-meal glucose counterregulatory response to hypoglycemia after GB is partly mediated by endogenous GLP-1, highlighting a novel mechanism of action of GLP-1R antagonists for the treatment of prandial hypoglycemia in this population.

Roux-en-Y gastric bypass (GB) and sleeve gastrectomy (SG) surgeries increase prandial insulin and glucagon secretion but reduce the endogenous glucose production (EGP) response to hypoglycemia in comparison with control subjects who had not undergone gastric surgery (CN), suggesting that parasympathetic nervous system (PNS) plays a role. Here, we investigated the effect of acute PNS blockade on the post-meal counterregulatory response to insulin-induced hypoglycemia in GB and SG compared with CN. Glucose kinetics and islet cell secretion were measured in nine subjects without diabetes with GB and seven with SG and five CN during hyperinsulinemic-hypoglycemic clamp (∼3.2 mmol/L) combined with meal ingestion on two separate days with and without intravenous atropine infusion. Glucose and hormonal levels were similar at baseline and during steady-state hypoglycemia before meal ingestion in three groups and unaffected by atropine. Atropine infusion diminished prandial systemic appearance of ingested glucose (RaO) by 30%, EGP by 40%, and glucagon response to hypoglycemia by 90% in CN. In GB or SG, blocking PNS had no effect on the RaO or meal-induced hyperglucagonemia but increased EGP in SG without any effect in GB (P < 0.05 interaction). These findings indicate that cholinergic signal contributes to the recovery from hypoglycemia by meal consumption in humans. However, bariatric surgery dissipates PNS-mediated physiologic responses to hypoglycemia in the fed state., Article Highlights: Rerouted gut after Roux-en-Y gastric bypass (GB) and, to a lesser degree, after sleeve gastrectomy (SG) leads to larger glucose excursion and lower nadir glucose, predisposing individuals to hypoglycemia. Despite prandial hyperglucagonemia, endogenous glucose production response to hypoglycemia is reduced after GB or SG. Parasympathetic nervous system (PNS) activity plays a key role in regulation of glucose kinetics and islet cell function. We examined the effect of acute PNS blockade on counterregulatory glucose and islet cell response to meal ingestion during insulin-induced hypoglycemia among GB, SG, and control subjects who had not had gastric surgery. Our findings demonstrate that cholinergic signal is critical in the recovery from hypoglycemia by meal ingestion in humans who have not had gastric surgery, although prandial PNS-mediated physiologic responses to hypoglycemia are differentially changed by GB and SG., (© 2023 by the American Diabetes Association.)

Context: Glucose-dependent insulinotropic peptide (GIP) and meal ingestion increase subcutaneous adipose tissue (SAT) perfusion in healthy individuals. The effects of GIP and a meal on visceral adipose tissue (VAT) perfusion are unclear., Objective: Our aim was to investigate the effects of meal and GIP on VAT and SAT perfusion in obese individuals with type 2 diabetes mellitus (T2DM) before and after bariatric surgery., Methods: We recruited 10 obese individuals with T2DM scheduled for bariatric surgery and 10 control individuals. Participants were studied under 2 stimulations: meal ingestion and GIP infusion. SAT and VAT perfusion was measured using 15O-H2O positron emission tomography-magnetic resonance imaging at 3 time points: baseline, 20 minutes, and 50 minutes after the start of stimulation. Obese individuals were studied before and after bariatric surgery., Results: Before bariatric surgery the responses of SAT perfusion to meal (P = .04) and GIP-infusion (P = .002) were blunted in the obese participants compared to controls. VAT perfusion response did not differ between obese and control individuals after a meal or GIP infusion. After bariatric surgery SAT perfusion response to a meal was similar to that of controls. SAT perfusion response to GIP administration remained lower in the operated-on than control participants. There was no change in VAT perfusion response after bariatric surgery., Conclusion: The vasodilating effects of GIP and meal are blunted in SAT but not in VAT in obese individuals with T2DM. Bariatric surgery improves the effects of a meal on SAT perfusion, but not the effects of GIP. Postprandial increase in SAT perfusion after bariatric surgery seems to be regulated in a GIP-independent manner., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

Context: Gastric bypass (GB) increases postprandial glucose excursion, which in turn can predispose to the late complication of hypoglycemia. Diagnosis remains challenging and requires documentation of symptoms associated with low glucose and relief of symptom when glucose is normalized (Whipple triad)., Objective: To compare the yield of mixed meal test (MMT) and continuous glucose monitoring system (CGMS) in detecting hypoglycemia after GB., Setting: The study was conducted at General Clinical Research Unit, Cincinnati Children's Hospital (Cincinnati, OH, USA)., Methods: Glucose profiles were evaluated in 15 patients with documented recurrent clinical hypoglycemia after GB, 8 matched asymptomatic GB subjects, and 9 healthy weight-matched nonoperated controls using MMT in a control setting and CGMS under free-living conditions., Results: Patients with prior GB had larger glucose variability during both MMT and CGMS when compared with nonsurgical controls regardless of their hypoglycemic status. Sensitivity (71 vs 47%) and specificity (100 vs 88%) of MMT in detecting hypoglycemia was superior to CGMS., Conclusions: Our findings indicate that a fixed carbohydrate ingestion during MMT is a more reliable test to diagnose GB-related hypoglycemia compared with CGMS during free-living state., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The mechanisms responsible for the positive and unexpected cardiovascular effects of sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes remain to be defined. It is likely that some of the beneficial cardiac effects of these antidiabetic drugs are mediated, in part, by altered myocardial metabolism. Common cardiometabolic disorders, including the metabolic (insulin resistance) syndrome and type 2 diabetes, are associated with altered substrate utilization and energy transduction by the myocardium, predisposing to the development of heart disease. Thus, the failing heart is characterized by a substrate shift toward glycolysis and ketone oxidation in an attempt to meet the high energetic demand of the constantly contracting heart. This review examines the metabolic pathways and clinical implications of myocardial substrate utilization in the normal heart and in cardiometabolic disorders, and discusses mechanisms by which antidiabetic drugs and metabolic interventions improve cardiac function in the failing heart., Competing Interests: Funding Support and Author Disclosures Dr. Honka was supported by the grant form Finnish Cultural Foundation (no. 00180071). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021. Published by Elsevier Inc.)

Background and Aims: Computed tomography (CT)-derived adipose tissue radiodensity represents a potential noninvasive surrogate marker for lipid deposition and obesity-related metabolic disease risk. We studied the effects of bariatric surgery on CT-derived adipose radiodensities in abdominal and femoral areas and their relationships to circulating metabolites in morbidly obese patients., Methods and Results: We examined 23 morbidly obese women who underwent CT imaging before and 6 months after bariatric surgery. Fifteen healthy non-obese women served as controls. Radiodensities of the abdominal subcutaneous (SAT) and visceral adipose tissue (VAT), and the femoral SAT, adipose tissue masses were measured in all participants. Circulating metabolites were measured by NMR. At baseline, radiodensities of abdominal fat depots were lower in the obese patients as compared to the controls. Surprisingly, radiodensity of femoral SAT was higher in the obese as compared to the controls. In the abdominal SAT depot, radiodensity strongly correlated with SAT mass (r = -0.72, p < 0.001). After surgery, the radiodensities of abdominal fat increased significantly (both p < 0.01), while femoral SAT radiodensity remained unchanged. Circulating ApoB/ApoA-I, leucine, valine, and GlycA decreased, while glycine levels significantly increased as compared to pre-surgical values (all p < 0.05). The increase in abdominal fat radiodensity correlated negatively with the decreased levels of ApoB/ApoA-I ratio, leucine and GlycA (all p < 0.05). The increase in abdominal SAT density was significantly correlated with the decrease in the fat depot mass (r = -0.66, p = 0.002)., Conclusion: Higher lipid content in abdominal fat depots, and lower content in femoral subcutaneous fat, constitute prominent pathophysiological features in morbid obesity. Further studies are needed to clarify the role of non-abdominal subcutaneous fat in the pathogenesis of obesity., Clinical Trial Registration Number: NCT01373892., Competing Interests: Declaration of Competing Interest No potential conflicts of interest related to the article were reported., (Copyright © 2020 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Objective: Sodium-glucose cotransporter 2 (SGLT2) inhibition causes an increase in endogenous glucose production (EGP). However, the mechanisms are unclear. We studied the effect of SGLT2 inhibitors on EGP in subjects with type 2 diabetes (T2D) and without diabetes (non-DM) in kidney transplant recipients with renal denervation., Research Design and Methods: Fourteen subjects who received a renal transplant (six with T2D [A1C 7.2 ± 0.1%] and eight non-DM [A1C 5.6 ± 0.1%) underwent measurement of EGP with [3- 3 H]glucose infusion following dapagliflozin (DAPA) 10 mg or placebo. Plasma glucose, insulin, C-peptide, glucagon, and titrated glucose-specific activity were measured., Results: Following placebo in T2D, fasting plasma glucose (FPG) (143 ± 14 to 124 ± 10 mg/dL; P = 0.02) and fasting plasma insulin (12 ± 2 to 10 ± 1.1 μU/mL; P < 0.05) decreased; plasma glucagon was unchanged, and EGP declined. After DAPA in T2D, FPG (143 ± 15 to 112 ± 9 mg/dL; P = 0.01) and fasting plasma insulin (14 ± 3 to 11 ± 2 μU/mL; P = 0.02) decreased, and plasma glucagon increased (all P < 0.05 vs. placebo). EGP was unchanged from baseline (2.21 ± 0.19 vs. 1.96 ± 0.14 mg/kg/min) in T2D ( P < 0.001 vs. placebo). In non-DM following DAPA, FPG and fasting plasma insulin decreased, and plasma glucagon was unchanged. EGP was unchanged from baseline (1.85 ± 0.10 to 1.78 ± 0.10 mg/kg/min) after DAPA, whereas EGP declined significantly with placebo. When the increase in EGP production following DAPA versus placebo was plotted against the difference in urinary glucose excretion (UGE) for all patients, a strong correlation ( r = 0.824; P < 0.001) was observed., Conclusions: Renal denervation in patients who received a kidney transplant failed to block the DAPA-mediated stimulation of EGP in both individuals with T2D and non-DM subjects. The DAPA-stimulated rise in EGP is strongly related to the increase in UGE, blunting the decline in FPG., (© 2020 by the American Diabetes Association.)

Purpose of Review: The Roux-en-Y gastric bypass surgery (RYGB) improves glucose control in majority of patients with type 2 diabetes. However, a minority group of individuals develop a life-threatening complication of hyperinsulinemic hypoglycemia. The goal of this review is to identify underlying mechanisms by which RYGB cause hypoglycemia and describe pathogenesis-driven strategies to diagnose and treat this condition., Recent Findings: Gastric bypass leads to higher and earlier peak levels of glucose and lower nadir glucose after eating along with larger insulin and glucagon-like peptide 1 (GLP-1) secretion, resetting the balance between glucose appearance and clearance after this procedure. These weight-loss independent glycemic effects of RYGB have been attributed to changes in ingested glucose appearance as a result of rapid nutrient emptying from stomach pouch to the intestine and increased glucose clearance as a result of prandial hyperinsulinemia. The exaggerated effect of RYGB on postmeal glucose metabolism is a syndrome of postprandial hyperinsulinemic hypoglycemia manifesting in a group of individuals several years after this surgery. Affected patients have larger systemic appearance of ingested glucose and greater postmeal secretion of insulin and GLP-1 compared to those with history of RYGB without symptomatic hypoglycemia. Current evidence supporting a multifactorial model of glucose dysregulation among patients with hypoglycemia will be highlighted in this review., Summary: Hypoglycemia after RYGB is a life-threatening condition and likely represents the extreme glycemic phenotype of this procedure. Diagnosis is challenging and treatment options are limited.

Aims/hypothesis: The mechanisms for improved glycemic control after bariatric surgery in subjects with type 2 diabetes (T2D) are not fully known. We hypothesized that dynamic hepatic blood responses to a mixed-meal are changed after bariatric surgery in parallel with an improvement in glucose tolerance., Methods: A total of ten morbidly obese subjects with T2D were recruited to receive a mixed-meal and a glucose-dependent insulinotropic polypeptide (GIP) infusion before and early after (within a median of less than three months) bariatric surgery, and hepatic blood flow and volume (HBV) were measured repeatedly with combined positron emission tomography/MRI. Ten lean non-diabetic individuals served as controls., Results: Bariatric surgery leads to a significant decrease in weight, accompanied with an improved β-cell function and glucagon-like peptide 1 (GLP-1) secretion, and a reduction in liver volume. Blood flow in portal vein (PV) was increased by 1.65-fold ( P  = 0.026) in response to a mixed-meal in subjects after surgery, while HBV decreased in all groups ( P  < 0.001). When the effect of GIP infusion was tested separately, no change in hepatic arterial and PV flow was observed, but HBV decreased as seen during the mixed-meal test., Conclusions/interpretation: Early after bariatric surgery, PV flow response to a mixed-meal is augmented, improving digestion and nutrient absorption. GIP influences the post-prandial reduction in HBV thereby diverting blood to the extrahepatic sites., (© 2018 The authors.)

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/m 2 ) 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 18 F-FTHA) and blood flow (with H 2 15 O); 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., (Copyright © 2017 the American Physiological Society.)

Bariatric surgery results in notable weight loss and alleviates hyperglycemia in patients with type 2 diabetes (T2D). We aimed to characterize the vascular effects of a mixed meal and infusion of exogenous glucose-dependent insulinotropic polypeptide (GIP) in the splanchnic region in 10 obese patients with T2D before and after bariatric surgery and in 10 lean control subjects. The experiments were carried out on two separate days. Pancreatic and intestinal blood flow (BF) were measured at baseline, 20 min, and 50 min with 15 O-water by using positron emission tomography and MRI. Before surgery, pancreatic and intestinal BF responses to a mixed meal did not differ between obese and lean control subjects. Compared with presurgery, the mixed meal induced a greater increase in plasma glucose, insulin, and GIP concentrations after surgery, which was accompanied by a marked augmentation of pancreatic and intestinal BF responses. GIP infusion decreased pancreatic but increased small intestinal BF similarly in all groups both before and after surgery. Taken together, these results demonstrate that bariatric surgery leads to enhanced splanchnic vascular responses as a likely consequence of rapid glucose appearance and GIP hypersecretion., (© 2017 by the American Diabetes Association.)

Objective: Meal ingestion is followed by a redistribution of blood flow (BF) within the splanchnic region contributing to nutrient absorption, insulin secretion and glucose disposal, but factors regulating this phenomenon in humans are poorly known. The aim of the present study was to evaluate the organ-specific changes in BF during a mixed-meal and incretin infusions., Design: A non-randomized intervention study of 10 healthy adults to study splanchnic BF regulation was performed., Methods: Effects of glucose-dependent insulinotrophic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) infusions and mixed-meal were tested in 10 healthy, glucose tolerant subjects using PET-MRI multimodal imaging technology. Intestinal and pancreatic BF and blood volume (BV) were measured with 15 O-water and 15 O-carbon monoxide, respectively., Results: Ingestion of a mixed-meal led to an increase in pancreatic and jejunal BF, whereas duodenal BF was unchanged. Infusion of GIP and GLP-1 reduced BF in the pancreas. However, GIP infusion doubled blood flow in the jejunum with no effect of GLP-1., Conclusion: Together, our data suggest that meal ingestion leads to increases in pancreatic BF accompanied by a GIP-mediated increase in jejunal but not duodenal blood flow., (© 2017 The authors.)

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 β-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 β-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.

Context: Glucolipotoxicity is believed to induce pancreatic β-cell dysfunction in obesity. Previously, it has not been possible to study pancreatic metabolism and blood flow in humans., Objective: The objective of the study was to investigate whether pancreatic metabolism and blood flow are altered in obesity using positron emission tomography (PET). In the preclinical part, the method was validated in animals., Design: This was a cross-sectional study., Setting: The study was conducted in a clinical research center., Participants: Human studies consisted of 52 morbidly obese and 25 healthy age-matched control subjects. Validation experiments were done with rodents and pigs., Interventions: PET and magnetic resonance imaging studies using a glucose analog ([(18)F]fluoro-2-deoxy-d-glucose), a palmitate analog [14(R,S)-[(18)F]fluoro-6-thia-heptadecanoic acid], and radiowater ([(15)O]H2O) were performed. In animals, a comparison between ex vivo and in vivo data was performed., Main Outcome Measures: Pancreatic glucose/fatty acid (FA) uptake, fat accumulation, and blood flow parameters of β-cell function were measured., Results: PET proved to be a feasible method to measure pancreatic metabolism. Compared with healthy participants, obese participants had elevated pancreatic FA uptake (P < .0001), more fat accumulation (P = .0001), lowered glucose uptake both during fasting and euglycemic hyperinsulinemia, and blunted blood flow (P < .01) in the pancreas. Blood flow, FA uptake, and fat accumulation were negatively associated with multiple markers of β-cell function., Conclusions: Obesity leads to changes in pancreatic energy metabolism with a substrate shift from glucose to FAs. In morbidly obese humans, impaired pancreatic blood flow may contribute to β-cell dysfunction and in the pathogenesis of type 2 diabetes.

Objectives: Diabetes induces osteoporosis and during osteoporosis, vertebral bone marrow (VBM) adipose tissue amount increases. The association between this adiposity and bone marrow metabolism is unclear. Here, we compared VBM glucose metabolism and fat content in healthy and diabetic pigs, in vivo, using positron emission tomography (PET), in-phase and out-of-phase magnetic resonance imaging and magnetic resonance proton spectroscopy ((1)H MR spectroscopy)., Materials/methods: Eleven pigs (n=11) were used. The intervention group had five diabetic and the control group had six healthy pigs. To measure metabolism, PET-imaging with [(18)F]fluoro-deoxy-glucose ([(18)F]FDG) intravenous tracer was used. 1.5-T MRI with (1)H spectroscopy, in-phase and out-of-phase imaging and chemical TAG analysis of the VBM were performed., Results: We found a significant inverse correlation between VBM glucose uptake (GU) and VBM fat content (R=-0.800, p<0.01) and TAG concentration assay (R=-0.846, p<0.05). There was a trend, although non-significant, of a linear correlation between VBM (1)H MR spectroscopy and TAG concentration (R=0.661) and (1)H MR spectroscopy and in-phase and out-of-phase MR imaging (R=0.635)., Conclusions: VBM glucose metabolism coupled with VBM fat content may impact diabetic induced osteoporosis., (Copyright © 2013. Published by Elsevier Inc.)