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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]

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.)

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.)

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.)

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.)