Hepatic insulin resistance both in prediabetic and diabetic patients determines postprandial lipoprotein metabolism: from the CORDIOPREV study

Abstract Background Dipeptidyl peptidase 4 (DPP4) is a serine exopeptidase able to inactivate various oligopeptides, and also a hepatokine. Hepatocyte-specific overexpression of DPP4 is associated with hepatic insulin resistance and liver steatosis. Method We examined whether weekly DPP4 inhibitor omarigliptin (OMG) can improve liver function as well as levels of inflammation and insulin resistance in type 2 diabetic patients with non-alcoholic fatty liver disease (NAFLD). Further, we investigated the effects of OMG in a diabetic patient with biopsy-confirmed nonalcoholic steatohepatitis (NASH). Results In NAFLD patients, OMG significantly decreased levels of aminotransferase, aspartate aminotransferase, gamma-glutamyl transpeptidase, homeostatic model assessment of insulin resistance (HOMA-IR), and high-sensitivity C-reactive protein (hsCRP), while no significant change was seen in hemoglobin A1c or body mass index. In the NASH patient, liver function improved markedly, and levels of the hepatic fibrosis marker FIB-4 decreased in parallel with HOMA-IR and hsCRP. Slight but clear improvements in intrahepatic fat deposition and fibrosis appeared to be seen on diagnostic ultrasonography. Conclusion Weekly administration of the DPP4 inhibitor OMG in ameliorating hepatic insulin resistance may cause beneficial effects in liver with NAFLD/NASH.

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Visceral fat dominant distribution in male type 2 diabetic patients is closely related to hepatic insulin resistance, irrespective of body type

Cardiovascular Diabetology ◽

10.1186/1475-2840-8-44 ◽

2009 ◽

Vol 8 (1) ◽

pp. 44 ◽

Cited By ~ 47

Author(s):

Yoshinori Miyazaki ◽

Ralph A DeFronzo

Keyword(s):

Insulin Resistance ◽

Visceral Fat ◽

Hepatic Insulin Resistance ◽

Diabetic Patients ◽

Body Type ◽

Type 2 Diabetic Patients ◽

Male Type ◽

Type 2 Diabetic

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Ceramide Content in Liver Increases Along with Insulin Resistance in Obese Patients

Journal of Clinical Medicine ◽

10.3390/jcm8122197 ◽

2019 ◽

Vol 8 (12) ◽

pp. 2197 ◽

Cited By ~ 1

Author(s):

Hady Razak Hady ◽

Agnieszka U. Błachnio-Zabielska ◽

Łukasz Szczerbiński ◽

Piotr Zabielski ◽

Monika Imierska ◽

...

Keyword(s):

Insulin Resistance ◽

Glucose Tolerance ◽

Glycosylated Hemoglobin ◽

Hepatic Insulin Resistance ◽

Oral Glucose ◽

Diabetic Patients ◽

Obese Patients ◽

Men And Women ◽

Percentage Body Fat ◽

Ceramide Content

The liver plays a central role in the glucose and lipid metabolism. Studies performed on animal models have shown an important role of lipid accumulation in the induction of insulin resistance. We sought to explain whether in obese humans, the insulin resistance is associated with hepatic ceramide accumulation. The experiments were conducted on obese men and women. Each gender was divided into three groups: Normal glucose tolerance group (NGT), Impaired glucose tolerance group (IGT), and Type 2 diabetic subjects (T2D). Ceramide (Cer) content was analyzed with the use of LC/MS/MS. An oral glucose tolerance test (OGTT), glycosylated hemoglobin (HbA1c), percentage body fat (FAT%), and body mass index (BMI) was also measured. Total hepatic ceramide was significantly higher in T2D females as compared to NGT females (p < 0.05), whereas in males, total ceramide was significantly higher in IGT and T2D as compared to NGT (p < 0.05). In both, men and women, the highest increase in T2D subjects, was observed in C16:0-Cer, C18:0:-Cer, C22:0-Cer, and C24:0-Cer (p < 0.05) as compared to NGT group. Interestingly, glucose (at 0′ and at 120′ in OGTT) and HbA1c positively correlated with the ceramide species that most increased in T2D patients (C16:0-Cer, C18:0-Cer, C22:0-Cer, and C24:0-Cer). In men glucose and HbA1c significantly correlated with only C22:0-Cer. This is one of the few studies comparing hepatic ceramide content in severely obese patients. We found that, ceramide content increased in diabetic patients, both in men and women, and the content of ceramide correlated with glycemic parameters. These data indicate ceramide contribution to the induction of hepatic insulin resistance.

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MECHANISMS IN ENDOCRINOLOGY: Biological role, clinical significance, and therapeutic possibilities of the recently discovered metabolic hormone fibroblastic growth factor 21

Acta Endocrinologica ◽

10.1530/eje-12-0357 ◽

2012 ◽

Vol 167 (3) ◽

pp. 301-309 ◽

Cited By ~ 65

Author(s):

Pedro Iglesias ◽

Rafael Selgas ◽

Sara Romero ◽

Juan J Díez

Keyword(s):

Insulin Resistance ◽

Blood Glucose ◽

Growth Factor ◽

Glucose Tolerance ◽

Hepatic Insulin Resistance ◽

Fibroblast Growth Factor 21 ◽

Diabetic Patients ◽

Glucose Transporter 1 ◽

Insulin Resistant ◽

The Metabolic Syndrome

Fibroblast growth factor 21 (FGF21), a 181 amino acid circulating protein, is a member of the FGF superfamily, with relevant metabolic actions. It acts through the interaction with specific FGF receptors and a cofactor called β-Klotho, whose expression is predominantly detected in metabolically active organs. FGF21 stimulates glucose uptake in adipocytes via the induction of glucose transporter-1. This action is additive and independent of insulin. β-Cell function and survival are preserved, and glucagon secretion is reduced by this protein, thus decreasing hepatic glucose production and improving insulin sensitivity. Lipid profile has been shown to be improved by FGF21 in several animal models. FGF21 increases energy expenditure in rodents and induces weight loss in diabetic nonhuman primates. It also exerts favorable effects on hepatic steatosis and reduces tissue lipid content in rodents. Adaptive metabolic responses to fasting, including stimulation of ketogenesis and fatty acid oxidation, seem to be partially mediated by FGF21. In humans, serum FGF21 concentrations have been found elevated in insulin-resistant states, such as impaired glucose tolerance and type 2 diabetes. FGF21 levels are correlated with hepatic insulin resistance index, fasting blood glucose, HbA1c, and blood glucose after an oral glucose tolerance test. A relationship between FGF21 levels and long-term diabetic complications, such as nephropathy and carotid atheromatosis, has been reported. FGF21 levels decreased in diabetic patients after starting therapy with insulin or oral agents. Increased FGF21 serum levels have also been found to be associated with obesity. In children, it is correlated with BMI and leptin levels, whereas in adults, FGF21 levels are mainly related to several components of the metabolic syndrome. Serum FGF21 levels have been found to be elevated in patients with ischemic heart disease. In patients with renal disease, FGF21 levels exhibited a progressive increase as renal function deteriorates. Circulating FGF21 levels seem to be related to insulin resistance and inflammation in dialysis patients. In summary, FGF21 is a recently identified hormone with antihyperglycemic, antihyperlipidemic, and thermogenic properties. Direct or indirect potentiation of its effects might be a potential therapeutic target in insulin-resistant states.

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Peripheral insulin resistance is associated with copeptin in patients with chronic kidney disease

Kidney360 ◽

10.34067/kid.0002622021 ◽

2021 ◽

pp. 10.34067/KID.0002622021

Author(s):

Juan Pablo Arroyo ◽

Elvis A. Akwo ◽

Andrew S. Terker ◽

Aseel Alsouqi ◽

Gautam Bhave ◽

...

Keyword(s):

Insulin Resistance ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Disease Risk ◽

Cardiovascular Disease Risk ◽

Hepatic Insulin Resistance ◽

Diabetic Patients ◽

Cross Sectional ◽

Peripheral Insulin Resistance ◽

The Relationship

Background - Insulin resistance is associated to cardiovascular disease risk and worsened kidney function. Patients with CKD have higher levels of insulin resistance. Elevated levels of copeptin (a surrogate for vasopressin levels), has been associated to increased incidence and progression of CKD as well as incident diabetes mellitus. The purpose of our study was to study the relationship between insulin resistance, copeptin, and CKD. Methods - We performed a cross-sectional study to investigate if insulin resistance was associated with higher copeptin levels in non-diabetic patients with stage 3-4 CKD vs controls. We measured plasma copeptin levels and utilized data from 52 patients with stage 3-4 CKD and 85 controls (eGFR ≥ 60mL/min/1.73m2) enrolled in The Insulin Resistance in Chronic Kidney Disease (IRCKD) study. We then used a multivariable linear regression model to assess the independent relationship between peripheral or hepatic insulin resistance and copeptin across levels of eGFR. Results - We found that in patients with CKD (eGFR 30-60 mL/min/1.73m2), but not in controls, peripheral insulin resistance was significantly correlated with higher levels of log copeptin (r = -0.21, p = 0.04). In patients with CKD when adjusted for age, sex, BMI, serum osmolality, log IL6, and log leptin-adiponectin ratio, each 1 SD decrease in insulin sensitivity was associated to a 38.9% increase in serum copeptin levels. The relationship between hepatic insulin resistance, copeptin, and eGFR is similar between controls and patients with reduced eGFR. Conclusion -Peripheral insulin resistance is associated with elevated copeptin levels in non-diabetic patients with stage 3-4 CKD. Further research into how the interaction between peripheral insulin resistance and elevated vasopressin impacts CKD progression could be of interest.

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Effect of Pioglitazone on Abdominal Fat Distribution and Insulin Sensitivity in Type 2 Diabetic Patients

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.87.6.8567 ◽

2002 ◽

Vol 87 (6) ◽

pp. 2784-2791 ◽

Cited By ~ 322

Author(s):

Yoshinori Miyazaki ◽

Archana Mahankali ◽

Masafumi Matsuda ◽

Srikanth Mahankali ◽

Jean Hardies ◽

...

Keyword(s):

Insulin Resistance ◽

Visceral Fat ◽

Fat Distribution ◽

Abdominal Fat ◽

Hepatic Insulin Resistance ◽

Diabetic Patients ◽

Visceral Fat Area ◽

Insulin Clamp ◽

Pioglitazone Treatment

We examined the effect of pioglitazone on abdominal fat distribution to elucidate the mechanisms via which pioglitazone improves insulin resistance in patients with type 2 diabetes mellitus. Thirteen type 2 diabetic patients (nine men and four women; age, 52 ± 3 yr; body mass index, 29.0 ± 1.1 kg/m2), who were being treated with a stable dose of sulfonylurea (n = 7) or with diet alone (n = 6), received pioglitazone (45 mg/d) for 16 wk. Before and after pioglitazone treatment, subjects underwent a 75-g oral glucose tolerance test (OGTT) and two-step euglycemic insulin clamp (insulin infusion rates, 40 and 160 mU/m2·min) with [3H]glucose. Abdominal fat distribution was evaluated using magnetic resonance imaging at L4–5. After 16 wk of pioglitazone treatment, fasting plasma glucose (179 ± 10 to 140 ± 10 mg/dl; P < 0.01), mean plasma glucose during OGTT (295 ± 13 to 233 ± 14 mg/dl; P < 0.01), and hemoglobin A1c (8.6 ± 0.4% to 7.2 ± 0.5%; P < 0.01) decreased without a change in fasting or post-OGTT insulin levels. Fasting plasma FFA (674 ± 38 to 569 ± 31 μEq/liter; P < 0.05) and mean plasma FFA (539 ± 20 to 396 ± 29 μEq/liter; P < 0.01) during OGTT decreased after pioglitazone. In the postabsorptive state, hepatic insulin resistance [basal endogenous glucose production (EGP) × basal plasma insulin concentration] decreased from 41 ± 7 to 25 ± 3 mg/kg fat-free mass (FFM)·min × μU/ml; P < 0.05) and suppression of EGP during the first insulin clamp step (1.1 ± 0.1 to 0.6 ± 0.2 mg/kg FFM·min; P < 0.05) improved after pioglitazone treatment. The total body glucose MCR during the first and second insulin clamp steps increased after pioglitazone treatment [first MCR, 3.5 ± 0.5 to 4.4 ± 0.4 ml/kg FFM·min (P < 0.05); second MCR, 8.7 ± 1.0 to 11.3 ± 1.1 ml/kg FFM·min (P < 0.01)]. The improvement in hepatic and peripheral tissue insulin sensitivity occurred despite increases in body weight (82 ± 4 to 85 ± 4 kg; P < 0.05) and fat mass (27 ± 2 to 30 ± 3 kg; P < 0.05). After pioglitazone treatment, sc fat area at L4–5 (301 ± 44 to 342 ± 44 cm2; P < 0.01) increased, whereas visceral fat area at L4–5 (144 ± 13 to 131 ± 16 cm2; P < 0.05) and the ratio of visceral to sc fat (0.59 ± 0.08 to 0.44 ± 0.06; P < 0.01) decreased. In the postabsorptive state hepatic insulin resistance (basal EGP × basal immunoreactive insulin) correlated positively with visceral fat area (r = 0.55; P < 0.01). The glucose MCRs during the first (r = −0.45; P < 0.05) and second (r = −0.44; P < 0.05) insulin clamp steps were negatively correlated with the visceral fat area. These results demonstrate that a shift of fat distribution from visceral to sc adipose depots after pioglitazone treatment is associated with improvements in hepatic and peripheral tissue sensitivity to insulin.

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Beneficial effect of omarigliptin on diabetic patients with non-alcoholic fatty liver disease/non-alcoholic steatohepatitis

10.21203/rs.3.rs-128674/v1 ◽

2020 ◽

Author(s):

Sachiko Hattori ◽

Kazuhiro Nomoto ◽

Tomohiko Suzuki ◽

Seishu Hayashi

Keyword(s):

Insulin Resistance ◽

Liver Disease ◽

Liver Function ◽

Fatty Liver ◽

Fatty Liver Disease ◽

Hepatic Insulin Resistance ◽

Diabetic Patients ◽

Model Assessment ◽

Alcoholic Fatty Liver ◽

Alcoholic Fatty Liver Disease

Abstract Background: Dipeptidyl peptidase 4 (DPP4) is a serine exopeptidase able to inactivate various oligopeptides and also a hepatokine. Hepatocyte-specific overexpression of DPP4 is associated with hepatic insulin resistance and liver steatosis. Method: We examined whether weekly DPP4 inhibitor omarigliptin (OMG) improves liver function as well as levels of inflammation and insulin resistance in type 2 diabetic patients with non-alcoholic fatty liver disease (NAFLD). Furthermore, we tried OMG in a diabetic patient with biopsy-confirmed nonalcoholic steatohepatitis (NASH). Results: In NAFLD patients, OMG significantly decreased levels of aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (gGTP), homeostatic model assessment of insulin resistance (HOMA-IR), and high-sensitivity C-reactive protein (hsCRP), while no significant change was seen in hemoglobin A1c (HbA1c) or body mass index (BMI). In a NASH patient, liver function had improved markedly, and the hepatic fibrosis marker FIB-4 decreased in parallel with HOMA-IR and hsCRP. Improvements in intrahepatic fat deposition and fibrosis appeared to be seen on ultrasonography.Conclusion: The effects of OMG in ameliorating hepatic insulin resistance may lead to decreasing intrahepatic fat accumulation and improving intrahepatic adipose inflammation in NAFLD/NASH.Trial registration: UMIN Clinical Registry (UMIN000029288). Registered 22 September, 2017, https://upload.umin.ac.jp/UMIN000029288

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