The Effects of Long-Term High Fat and/or High Sugar Feeding on Sources of Postprandial Hepatic Glycogen and Triglyceride Synthesis in Mice.

BACKGROUND: In MASLD (formerly called NAFLD) mouse models, oversupply of dietary fat and sugar is more lipogenic than either nutrient alone. Fatty acids suppress de novo lipogenesis (DNL) from sugars, while DNL inhibits fatty acid oxidation. How such factors interact to impact hepatic triglyceride levels are incompletely understood. METHODS: Using deuterated water, we measured DNL in mice fed 18-weeks with standard chow (SC), SC supplemented with 55/45-fructose/glucose in the drinking water at 30% (w/v) (HS), high-fat chow (HF), and HF with HS supplementation (HFHS). Liver glycogen levels and its sources were also measured. For HS and HFHS mice, pentose phosphate (PP) fluxes and fructose contributions to DNL and glycogen were measured using [U-13C]fructose. RESULTS: The lipogenic diets caused significantly higher liver triglyceride levels compared to SC. DNL rates were suppressed in HF compared to SC and were partially restored in HFHS but supplied a minority of the additional triglyceride in HFHS compared to HF. Fructose contributed a significantly greater fraction of newly synthesized saturated fatty acids compared to oleic acid in both HS and HFHS. Glycogen levels were not different between diets, but significant differences in Direct and Indirect pathway contributions to glycogen synthesis were found. PP fluxes were similar in HS and HFHS mice and were insufficient to account for DNL reducing equivalents. CONCLUSIONS: Despite amplifying the lipogenic effects of fat, the fact that sugar-activated DNL per se barely contributes suggests that its role is likely more relevant in the inhibition of fatty acid oxidation. Fructose promotes lipogenesis of saturated over unsaturated fatty acids and contributes to maintenance of glycogen levels. PP fluxes associated with sugar conversion to fat account for a minor fraction of DNL reducing equivalents.

GLP-1 receptor agonist treatment improved fasting and postprandial lipidomic profile independently of diabetes and weight loss.

Treatment with glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduces liver steatosis and cardiometabolic risk (CMR). Only few data are available on lipid metabolism and no information on the postprandial lipidomic profile. Thus, we investigated how exenatide treatment changes lipid metabolism and composition during fasting and after a meal tolerance test (MTT) in adults with severe obesity without diabetes. Thirty individuals (26F/4M, 30-60 years old, BMI>40 kg/m2, HbA1c=5.76%) were assigned (1:1) to diet with exenatide treatment (EXE, n=15, 10 µg twice-daily) or without treatment as control (CT, n=15) for 3 months. Fasting and postprandial lipidomic profile (by LC/MS-QTOF) and fatty acid metabolism (following a 6-hour MTT/tracer study) and composition (by GC/MS) were evaluated before and after treatment. Both groups had slight weight loss (EXE: -5.5% vs CT: -1.9%, p=0.052). During fasting, exenatide, compared to CT, reduced some ceramides (CER) and lysophosphocholines (LPC) previously associated with CMR, while relatively increasing unsaturated phospholipid species (PC, LPC) with protective effects on CMR, although concentrations of total lipid species were unchanged. During MTT, both groups suppressed lipolysis equally to baseline, but EXE exenatide significantly lowered free fatty acid clearance and postprandial triacyclglycerols (TAG) concentrations, particularly saturated TAGs with 44-54 carbons. Exenatide also reduced some postprandial CERs, PCs, LPCs previously linked to cardiometabolic risk. These changes in lipidomic profile remained statistically significant after adjusting for weight loss. Exenatide improved fasting and postprandial lipidomic profile associated with CMR mainly by reducing saturated postprandial TAGs and CERs, independently of weight loss and diabetes.

EASL-EASD-EASO Clinical Practice Guidelines on the Management of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD).

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously termed non-alcoholic fatty liver disease (NAFLD), is defined as steatotic liver disease (SLD) in the presence of one or more cardiometabolic risk factor(s) and the absence of harmful alcohol intake. The spectrum of MASLD includes steatosis, metabolic dysfunction-associated steatohepatitis (MASH, previously NASH), fibrosis, cirrhosis and MASH-related hepatocellular carcinoma (HCC). This joint EASL-EASD-EASO guideline provides an update on definitions, prevention, screening, diagnosis and treatment for MASLD. Case-finding strategies for MASLD with liver fibrosis, using non-invasive tests, should be applied in individuals with cardiometabolic risk factors, abnormal liver enzymes, and/or radiological signs of hepatic steatosis, particularly in the presence of type 2 diabetes (T2D) or obesity with additional metabolic risk factor(s). A stepwise approach using blood-based scores (such as FIB-4) and, sequentially, imaging techniques (such as transient elastography) is suitable to rule-out/in advanced fibrosis, which is predictive of liver-related outcomes. In adults with MASLD, lifestyle modification - including weight loss, dietary changes, physical exercise and discouraging alcohol consumption - as well as optimal management of comorbidities - including use of incretin-based therapies (e.g. semaglutide, tirzepatide) for T2D or obesity, if indicated - is advised. Bariatric surgery is also an option in individuals with MASLD and obesity. If locally approved and dependent on the label, adults with non-cirrhotic MASH and significant liver fibrosis (stage ≥2) should be considered for a MASH-targeted treatment with resmetirom, which demonstrated histological effectiveness on steatohepatitis and fibrosis with an acceptable safety and tolerability profile. No MASH-targeted pharmacotherapy can currently be recommended for the cirrhotic stage. Management of MASH-related cirrhosis includes adaptations of metabolic drugs, nutritional counselling, surveillance for portal hypertension and HCC, as well as liver transplantation in decompensated cirrhosis.

Baseline phenotypes with preserved ß-cell function and high insulin concentrations have the best improvements in glucose tolerance after weight loss: results from the prospective DEXLIFE and EGIR-RISC studies.

BACKGROUND: Weight loss and lifestyle intervention improve glucose tolerance delaying the onset of type 2 diabetes (T2D), but individual responses are highly variable. Determining the predictive factors linked to the beneficial effects of weight loss on glucose tolerance could provide tools for individualized prevention plans. Thus, the aim was to investigate the relationship between pre-intervention values of insulin sensitivity and secretion and the improvement in glucose metabolism after weight loss. METHODS: In the DEXLIFE cohort (373 individuals at high risk of T2D, assigned 3:1 to a 12-week lifestyle intervention or a control arm, Trial Registration: ISRCTN66987085), K-means clustering and logistic regression analysis were performed based on pre-intervention indices of insulin sensitivity, insulin secretion (AUC-I), and glucose-stimulated insulin response (ratio of incremental areas of insulin and glucose, iAUC I/G). The response to the intervention was evaluated in terms of reduction of OGTT-glucose concentration. Clusters' validation was done in the prospective EGIR-RISC cohort (n = 1538). RESULTS: Four replicable clusters with different glycemic and metabolomic profiles were identified. Individuals had similar weight loss, but improvement in glycemic profile and ß-cell function was different among clusters, highly depending on pre-intervention insulin response to OGTT. Pre-intervention high insulin response was associated with the best improvement in AUC-G, while clusters with low AUC-I and iAUC I/G showed no beneficial effect of weight loss on glucose control, as also confirmed by the logistic regression model. CONCLUSIONS: Individuals with preserved ß-cell function and high insulin concentrations at baseline have the best improvement in glucose tolerance after weight loss.

Differential effect of endogenous glucagon-like peptide-1 on prandial glucose counterregulatory response to hypoglycaemia in humans with and without bariatric surgery.

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.

Clusters of adipose tissue dysfunction in adults with type 2 diabetes identify those with worse lipidomic profile despite similar glycaemic control.

AIMS: To investigate clusters of adipose tissue dysfunction, that is, with adipose tissue insulin resistance (ADIPO-IR) and large waist circumference (WC), identify a worse lipidomic profile characterised by a high proportion of lipids rich in saturated fatty acids (SFA). MATERIALS AND METHODS: Hierarchical clustering based on WC and ADIPO-IR (calculated as fasting plasma non-esterified fatty acids times fasting plasma insulin, FFA×INS), was performed in 192 adults with overweight/obesity and type 2 diabetes (T2D) treated with metformin (HbA1c = 7.8%). Free fatty acid composition and lipidomic profile were measured by mass spectrometry (GC-MS and LC-MSQTOF). Indexes of fatty acid desaturation (stearoyl-coA desaturase-1 activity, SCD116 = palmitoleic acid/palmitic acid and SCD118 = oleic acid/stearic acid) and of insulin resistance (HOMA-IR) were also calculated. RESULTS: Three clusters were identified: CL1 (ADIPO-IR = 4.9 ± 2.4 and WC = 96±7 cm, mean ± SD), CL2 (ADIPO-IR = 6.5 ± 2.5 and WC = 114 ± 7 cm), and CL3 (ADIPO-IR = 15.0 ± 4.7 and WC = 107 ± 8 cm). Insulin concentrations, ADIPO-IR, and HOMA-IR significantly increased from CL1 to CL3 (all p < 0.001), while fasting glucose concentrations, HbA1c, dietary lipids and caloric intake were similar. Moreover, CL3 showed significantly higher concentrations of monounsaturated free fatty acids, oleic and palmitoleic acids, triglycerides (TAG) rich in saturated FA and associated with de novo lipogenesis (i.e., TAG 46-50), higher SCD116, SCD118, ceramide (d18:0/18:0), and phosphatidylcholine aa(36:5) compared with CL1/CL2 (all p < 0.005). CONCLUSIONS: High ADIPO-IR and large WC identify a worse lipid profile in T2D characterised by complex lipids rich in SFA, likely due to de novo synthesis given higher plasma monounsaturated FFA and increased desaturase activity indexes. REGISTRATION NUMBER TRIAL: ID NCT00700856 https://clinicaltrials.gov.

Vagal activation alters prandial bile acid composition and glycemia in patients with hypoglycemia after Roux-en-Y gastric bypass surgery.

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.

Hepatic glucose metabolism in the steatotic liver.

The liver is central in regulating glucose homeostasis, being the major contributor to endogenous glucose production and the greatest reserve of glucose as glycogen. It is both a target and regulator of the action of glucoregulatory hormones. Hepatic metabolic functions are altered in and contribute to the highly prevalent steatotic liver disease (SLD), including metabolic dysfunction-associated SLD (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). In this Review, we describe the dysregulation of hepatic glucose metabolism in MASLD and MASH and associated metabolic comorbidities, and how advances in techniques and models for the assessment of hepatic glucose fluxes in vivo have led to the identification of the mechanisms related to the alterations in glucose metabolism in MASLD and comorbidities. These fluxes can ultimately increase hepatic glucose production concomitantly with fat accumulation and alterations in the secretion and action of glucoregulatory hormones. No pharmacological treatment has yet been approved for MASLD or MASH, but some antihyperglycaemic drugs approved for treating type 2 diabetes have shown positive effects on hepatic glucose metabolism and hepatosteatosis. A deep understanding of how MASLD affects glucose metabolic fluxes and glucoregulatory hormones might assist in the early identification of at-risk individuals and the use or development of targeted therapies.

Insulin sensitivity and beta cell function after duodenal mucosal resurfacing: an open-label, mechanistic, pilot study.

BACKGROUND AND AIMS: The duodenum has been shown to play a key role in glucose homeostasis. Duodenal mucosal resurfacing (DMR) is an endoscopic procedure for patients with type 2 diabetes (T2D) in which the duodenal mucosa is hydrothermally ablated. DMR improves glycemic control, but the underlying mechanisms remain unclear. Here, we report changes in glucoregulatory hormones and indices of insulin sensitivity and beta cell function after DMR. METHODS: We included 28 patients on noninsulin glucose-lowering medications who underwent open-label DMR and a mixed meal test (MMT) in Revita-1 or Revita-2 studies. Inclusion criteria were a hemoglobin A1c from 7.6% to 10.4% and a body mass index of 24 to 40 kg/m2. Baseline and 3-month MMT data included plasma glucose, insulin, C-peptide, glucagon-like peptide-1 (GLP-1), and gastric inhibitory polypeptide (GIP) concentrations. Glucoregulatory hormones, insulin sensitivity indices (Homeostatic Model Assessment for Insulin Resistance [HOMA-IR], Matsuda index [MI], and hepatic insulin resistance) and beta cell function (insulinogenic index, disposition index [DI], and insulin secretion rate [ISR]) were assessed. RESULTS: Fasting insulin, glucagon, and C-peptide decreased significantly. Insulin sensitivity (HOMA-IR, MI, and hepatic insulin resistance) and beta cell function (DI and ISR) all improved significantly. Declines in postprandial glucose, mainly driven by a decrease in fasting levels, and in postprandial glucagon were observed, whereas GLP-1 and GIP did not change. CONCLUSIONS: Insulin sensitivity and insulin secretion improved 3 months after DMR. It is unlikely that incretin changes are responsible for improved glucose control after DMR. These data add to the growing evidence validating the duodenum as a therapeutic target for patients with T2D. (Clinical trial registration numbers: NCT02413567 and NCT03653091.).

GLP-1 enhances beta-cell response to protein ingestion and bariatric surgery amplifies it.

OBJECTIVE: Protein ingestion stimulates ß-cell secretion and alters glucose flux. Enhanced action of glucagon-like peptide 1 (GLP-1) and increased plasma glucose excursion contribute to prandial hyperinsulinemia after gastric bypass surgery (GB) and sleeve gastrectomy (SG). We examined the contribution of endogenous GLP-1 to glucose kinetics and ß-cell response to protein ingestion under basal glucose concentrations in humans, and whether these responses are affected by rerouted gut after GB or SG. DESIGN: Glucose fluxes, insulin secretion rate (ISR), and incretin responses to a 50-gram oral protein load were compared between 10 non-diabetic individuals with GB, 9 matched subjects with SG and 7 non-operated controls (CN) with and without intravenous infusion of exendin-(9- 39) [Ex-9), a specific GLP-1 receptor (GLP-1R) antagonist. RESULTS: Blocking GLP-1R increased the plasma glucose concentration before and after protein ingestion in all 3 groups (p<0.05) and decreased ß-cell sensitivity to glucose in the first 30 minutes of protein ingestion (p<0.05). Reduction in the prandial ISR3h by Ex-9 infusion, however, only was observed in GB and SG (p<0.05 for interaction) and not in controls. Also, GLP-1R blockade increased post-protein insulin action in GB and SG, but not CN (p=0.09 for interaction). Endogenous glucose production (EGP) during the first 60 minutes after protein ingestion was increased in all 3 groups but EGP3h only was accentuated in GB by Ex-9 infusion (p<0.05 for interaction). CONCLUSION: These findings are consistent with both a pancreatic and extrapancreatic role for GLP-1 during protein ingestion in humans, and GLP-1 actions are exaggerated by bariatric surgery.

A global action agenda for turning the tide on fatty liver disease.

BACKGROUND AND AIMS: Fatty liver disease is a major public health threat due to its very high prevalence and related morbidity and mortality. Focused and dedicated interventions are urgently needed to target disease prevention, treatment, and care. APPROACH AND RESULTS: We developed an aligned, prioritized action agenda for the global fatty liver disease community of practice. Following a Delphi methodology over 2 rounds, a large panel (R1 n = 344, R2 n = 288) reviewed the action priorities using Qualtrics XM, indicating agreement using a 4-point Likert-scale and providing written feedback. Priorities were revised between rounds, and in R2, panelists also ranked the priorities within 6 domains: epidemiology, treatment and care, models of care, education and awareness, patient and community perspectives, and leadership and public health policy. The consensus fatty liver disease action agenda encompasses 29 priorities. In R2, the mean percentage of "agree" responses was 82.4%, with all individual priorities having at least a super-majority of agreement (> 66.7% "agree"). The highest-ranked action priorities included collaboration between liver specialists and primary care doctors on early diagnosis, action to address the needs of people living with multiple morbidities, and the incorporation of fatty liver disease into relevant non-communicable disease strategies and guidance. CONCLUSIONS: This consensus-driven multidisciplinary fatty liver disease action agenda developed by care providers, clinical researchers, and public health and policy experts provides a path to reduce the prevalence of fatty liver disease and improve health outcomes. To implement this agenda, concerted efforts will be needed at the global, regional, and national levels.

Urinary Bisphenol-A (BPA) and Bis(2-ethylhexyl)phthalate (DEHP) metabolite concentrations in children with obesity: A case-control study.

Introduction Obesity is a worldwide public health problem. Experimental animal and in vitro studies suggest that the exposure to BPA and phthalates are associated to a higher risk of obesity. Objective To determine urinary excretion of bisphenol A and phthalates in obese and normal weight children. Methods A case-control study was conducted in 122 children. Sixty-six obese children 36 girls (mean age 8.41±1.27 years) and 30 boys (mean age 8.51 ± 1.33 years), and 56 normal weight children, 27 girls (mean age 7.64 ± 1.49 years) and 29 boys (mean age 7.77 ± 1.56 years) were studied. Urinary BPA and Bis(2-ethylhexyl) phthalate (DEHP) metabolites (MEHP, MEHHP and MEOHP) were measured respectively by gas chromatography and high-performance liquid chromatography. Individual determinants of exposure were evaluated through "ad hoc" questionnaires. Results BPA and DEHP metabolites were detectable in obese and normal weight children. Obese girls showed significantly higher BPA concentrations in comparison with normal weight girls (means 10.77, 95% CI 7.02-16.53 vs 5.50, 95% CI 3.93-7.71 µg/g creatinine, respectively, p< 0.02). The first step of DEHP metabolic rate was significantly higher in obese girls compared with controls (p<0.05). DEHP metabolites correlated significantly with leptin concentrations in obese girls (p< 0.03). A higher risk of obesity was found in children with BPA levels above the median values with the habit to eat food packaged (OR=11.09, 95% CI=1.28-95.78). Conclusions These findings show that a higher exposure to BPA is associated with the risk of obesity in girls. Further studies are needed to unveil the cause-effect relationship.

Endogenous glucagon-like peptide 1 diminishes prandial glucose counterregulatory response to hypoglycemia after gastric bypass surgery.

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.

Metabolic Dysfunction-Associated Steatotic Liver Disease and Metabolic Dysfunction-Associated Steatohepatitis: The Patient and Physician Perspective.

Diagnosing and managing metabolic dysfunction-associated steatotic liver disease (MASLD) remains a major challenge in primary care due to lack of agreement on diagnostic tools, difficulty in identifying symptoms and determining their cause, absence of approved pharmacological treatments, and limited awareness of the disease. However, prompt diagnosis and management are critical to preventing MASLD from progressing to more severe forms of liver disease. This highlights the need to raise awareness and improve understanding of MASLD among both patients and physicians. The patient perspective is invaluable to advancing our knowledge of this disease and how to manage it, as their perspectives have led to the growing recognition that patients experience subtle symptoms and that patient-reported outcomes should be incorporated into drug development. This review and expert opinion examine MASLD and metabolic dysfunction-associated steatohepatitis from the patient and physician perspective from pre-diagnosis to diagnosis and early care, through to progression to advanced liver damage. Specifically, the paper dives into the issues patients and physicians experience, and, in turn, what is required to improve diagnosis and management, including tips and tools to empower patients and physicians dealing with MASLD.

Reduced Insulin Clearance Differently Relates to Increased Liver Lipid Content and Worse Glycemic Control in Recent-Onset Type 2 and Type 1 Diabetes.

OBJECTIVE: Diabetes may feature impaired insulin kinetics, which could be aggravated by altered hepatic metabolism and glycemic control. Thus, we examined insulin clearance and its possible determinants in individuals with recent-onset diabetes. RESEARCH DESIGN AND METHODS: Participants of the German Diabetes Study (GDS) with type 1 diabetes (T1D) (n = 306), type 2 diabetes (T2D) (n = 489), or normal glucose tolerance (control [CON]) (n = 167) underwent hyperinsulinemic-euglycemic clamps for assessment of whole-body insulin sensitivity (M value) and insulin clearance (ICCLAMP). Insulin clearance rates were further calculated during intravenous glucose tolerance tests (ICIVGTT) and mixed-meal tests (ICMMT). Hepatocellular lipid content (HCL) was quantified with 1H-MRS. RESULTS: Both T1D and T2D groups had lower ICCLAMP (0.12 ± 0.07 and 0.21 ± 0.06 vs. 0.28 ± 0.14 arbitrary units [a.u.], respectively, all P < 0.05) and ICMMT (0.71 ± 0.35 and 0.99 ± 0.33 vs. 1.20 ± 0.36 a.u., all P < 0.05) than CON. In T1D, ICCLAMP, ICIVGTT, and ICMMT correlated negatively with HbA1c (all P < 0.05). M value correlated positively with ICIVGTT in CON and T2D (r = 0.199 and r = 0.178, P < 0.05) and with ICMMT in CON (r = 0.176, P < 0.05). HCL negatively associated with ICIVGTT and ICMMT in T2D (r = -0.005 and r = -0.037) and CON (r = -0.127 and r = -0.058, all P < 0.05). In line, T2D or CON subjects with steatosis featured lower ICMMT than those without steatosis (both P < 0.05). CONCLUSIONS: Insulin clearance is reduced in both T1D and T2D within the first year after diagnosis but correlates negatively with liver lipid content rather in T2D. Moreover, insulin clearance differently associates with glycemic control and insulin sensitivity in each diabetes type, which may suggest specific mechanisms affecting insulin kinetics.

Fatty Liver Index (FLI) Identifies Not Only Individuals with Liver Steatosis but Also at High Cardiometabolic Risk.

A fatty liver index (FLI) greater than sixty (FLI ≥ 60) is an established score for metabolic dysfunction-associated steatotic liver disease (MASLD), which carries a high risk for diabetes and cardiovascular disease, while a FLI ≤ 20 rules out the presence of steatosis. Thus, we investigated whether FLI was associated with cardiometabolic risk factors, i.e., visceral (VAT), subcutaneous (SC), epicardial (EPI), extrapericardial (PERI), and total cardiac (CARD-AT) adipose tissue, hepatic fat ((by magnetic resonance imaging, MRI, and spectroscopy, MRS), and insulin resistance (IR, HOMA-IR and OGIS-index), and components of metabolic syndrome. All individuals with FLI ≥ 60 had MASLD, while none with FLI ≤ 20 had steatosis (by MRS). Subjects with FLI ≥ 60 had a higher BMI and visceral and cardiac fat (VAT > 1.7 kg, CARD-AT > 0.2 kg). FLI was positively associated with increased cardiac and visceral fat and components of metabolic syndrome. FLI, VAT, and CARD-AT were all associated with IR, increased blood pressure, cholesterol, and reduced HDL. For FLI ≥ 60, the cut-off values for fat depots and laboratory measures were estimated. In conclusion, FLI ≥ 60 identified not only subjects with steatosis but also those with IR, abdominal and cardiac fat accumulation, increased blood pressure, and hyperlipidemia, i.e., those at higher risk of cardiometabolic diseases. Targeted reduction of FLI components would help reduce cardiometabolic risk.

Differential effect of gastric bypass versus sleeve gastrectomy on insulinotropic action of endogenous incretins.

OBJECTIVE: Prandial hyperinsulinemia after Roux-en-Y gastric bypass surgery (GB), and to lesser degree after sleeve gastrectomy (SG), has been attributed to rapid glucose flux from the gut and increased insulinotropic gut hormones. However, ß-cell sensitivity to exogenous incretin is reduced after GB. This study examines the effect of GB versus SG on prandial glycemia and ß-cell response to increasing concentrations of endogenous incretins. METHODS: Glucose kinetics, insulin secretion rate (ISR), and incretin responses to 50-g oral glucose ingestion were compared between ten nondiabetic participants with GB versus nine matched individuals with SG and seven nonoperated normal glucose tolerant control individuals (CN) with and without administration of 200 mg of sitagliptin. RESULTS: Fasting glucose and hormonal levels were similar among three groups. Increasing plasma concentrations of endogenous incretins by two- to three-fold diminished prandial glycemia and increased ß-cell secretion in all three groups (p < 0.05), but insulin secretion per insulin sensitivity (i.e., disposition index) was increased only in GB (p < 0.05 for interaction). However, plot of the slope of ISR (from premeal to peak values) versus plasma glucagon-like peptide-1 concentration was smaller after GB compared with SG and CN. CONCLUSIONS: After GB, increasing incretin activity augments prandial ß-cell response whereas the ß-cell sensitivity to increasing plasma concentrations of endogenous incretin is diminished.

Exposure profiles in pregnant women from a birth cohort in a highly contaminated area of southern Italy.

Protecting the health of pregnant women from environmental stressors is crucial for reducing the burden of non-communicable diseases. In industrially contaminated sites, this action is particularly challenging due to the heterogeneous pollutant mixtures in environmental matrices. The aim of this study was to evaluate distribution patterns of mercury, hexachlorobenzene and polychlorobiphenyls in the serum of 161 pregnant women recruited in the framework of the Neonatal Environment and Health Outcomes (NEHO) cohort and living both inside and outside the National Priority Contaminated Site (NPCS) of Priolo. Food macro-categories were determined, and serum levels of contaminants were used to perform k-means cluster analysis and identify the role of food in pollutant transfer from the environment. Two groups of mothers with high and low measured pollutant levels were distinguished. Concentrations in mothers in the high-exposure cluster were at least twofold for all the evaluated pollutants (p < 0.0001) and included mothers living inside and outside NPCS, with a predominance of individuals from the NPCS (p = 0.045). Fish consumption was higher in the high-exposure cluster (p = 0.019). These findings suggest a link between contamination of environmental matrices such as sediment with maternal exposure, through the intake of local food. Such consideration appears poorly investigated in the context of contaminated sites.