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1.  Pathophysiology of Non Alcoholic Fatty Liver Disease 
The physiopathology of fatty liver and metabolic syndrome are influenced by diet, life style and inflammation, which have a major impact on the severity of the clinicopathologic outcome of non-alcoholic fatty liver disease. A short comprehensive review is provided on current knowledge of the pathophysiological interplay among major circulating effectors/mediators of fatty liver, such as circulating lipids, mediators released by adipose, muscle and liver tissues and pancreatic and gut hormones in relation to diet, exercise and inflammation.
doi:10.3390/ijms17122082
PMCID: PMC5187882  PMID: 27973438
fatty liver; insulin resistance; free fatty acids; cholesterol; adiponectin; leptin; insulin; glucagon; glucagon-like peptide 1; ghrelin; irisin; selenoprotein P
2.  Genome-scale study reveals reduced metabolic adaptability in patients with non-alcoholic fatty liver disease 
Nature Communications  2016;7:8994.
Non-alcoholic fatty liver disease (NAFLD) is a major risk factor leading to chronic liver disease and type 2 diabetes. Here we chart liver metabolic activity and functionality in NAFLD by integrating global transcriptomic data, from human liver biopsies, and metabolic flux data, measured across the human splanchnic vascular bed, within a genome-scale model of human metabolism. We show that an increased amount of liver fat induces mitochondrial metabolism, lipolysis, glyceroneogenesis and a switch from lactate to glycerol as substrate for gluconeogenesis, indicating an intricate balance of exacerbated opposite metabolic processes in glycemic regulation. These changes were associated with reduced metabolic adaptability on a network level in the sense that liver fat accumulation puts increasing demands on the liver to adaptively regulate metabolic responses to maintain basic liver functions. We propose that failure to meet excessive metabolic challenges coupled with reduced metabolic adaptability may lead to a vicious pathogenic cycle leading to the co-morbidities of NAFLD.
Non-alcoholic fatty liver disease (NAFLD) is a risk factor for other types of liver diseases. Here, the authors integrate transcriptomic and metabolomic data from patients with NAFLD with a genome-scale metabolic model to paint a comprehensive picture of liver function in NAFLD.
doi:10.1038/ncomms9994
PMCID: PMC4742839  PMID: 26839171
3.  The Subtle Balance between Lipolysis and Lipogenesis: A Critical Point in Metabolic Homeostasis 
Nutrients  2015;7(11):9453-9474.
Excessive accumulation of lipids can lead to lipotoxicity, cell dysfunction and alteration in metabolic pathways, both in adipose tissue and peripheral organs, like liver, heart, pancreas and muscle. This is now a recognized risk factor for the development of metabolic disorders, such as obesity, diabetes, fatty liver disease (NAFLD), cardiovascular diseases (CVD) and hepatocellular carcinoma (HCC). The causes for lipotoxicity are not only a high fat diet but also excessive lipolysis, adipogenesis and adipose tissue insulin resistance. The aims of this review are to investigate the subtle balances that underlie lipolytic, lipogenic and oxidative pathways, to evaluate critical points and the complexities of these processes and to better understand which are the metabolic derangements resulting from their imbalance, such as type 2 diabetes and non alcoholic fatty liver disease.
doi:10.3390/nu7115475
PMCID: PMC4663603  PMID: 26580649
lipotoxicity; lipolysis; de novo lipogenesis; glyceroneogenesis; fatty liver; NAFLD; ectopic fat; HCC; SCD-1; saturated fat
4.  Evidence from a single individual that increased plasma GLP-1 and GLP-1-stimulated insulin secretion after gastric bypass are independent of foregut exclusion 
Diabetologia  2014;57(7):1495-1499.
doi:10.1007/s00125-014-3258-0
PMCID: PMC4077274  PMID: 24797288
Blockade of GLP-1r; Bypassing the foregut; Gastric bypass surgery; GLP-1; Glucagon; Glucose excursion; Insulin secretion; Meal tolerance test; Pancreatic polypeptide
5.  Baseline Adiponectin Levels Do Not Influence the Response to Pioglitazone in ACT NOW 
Diabetes Care  2014;37(6):1706-1711.
OBJECTIVE
Plasma adiponectin levels are reduced in type 2 diabetes mellitus (T2DM) and other insulin-resistant states. We examined whether plasma adiponectin levels at baseline and after pioglitazone treatment in impaired glucose tolerance (IGT) subjects were associated with improved insulin sensitivity (SI) and glucose tolerance status.
RESEARCH DESIGN AND METHODS
A total of 602 high-risk IGT subjects in ACT NOW were randomized to receive pioglitazone or placebo with a median follow-up of 2.4 years.
RESULTS
Pioglitazone reduced IGT conversion to diabetes by 72% in association with improved β-cell function by 64% (insulin secretion/insulin resistance index) and increased tissue sensitivity by 88% (Matsuda index). In pioglitazone-treated subjects, plasma adiponectin concentration increased threefold from 13 ± 0.5 to 38 ± 2.5 μg/mL (P < 0.001) and was strongly correlated with the improvement in SI (r = 0.436, P < 0.001) and modestly correlated with glucose area under the curve during oral glucose tolerance test (r = 0.238, P < 0.005) and insulin secretion/insulin resistance index (r = 0.306, P < 0.005). The increase in adiponectin was a strong predictor of reversion to normal glucose tolerance and prevention of T2DM. In the placebo group, plasma adiponectin did not change and was not correlated with changes in glucose levels. There was an inverse association between baseline plasma adiponectin concentration and progression to diabetes in the placebo group but not in the pioglitazone group.
CONCLUSIONS
Baseline adiponectin does not predict the response to pioglitazone. The increase in plasma adiponectin concentration after pioglitazone therapy in IGT subjects is strongly related to improved glucose tolerance status and enhanced tissue sensitivity to insulin.
doi:10.2337/dc13-1745
PMCID: PMC4179517  PMID: 24705615
6.  Blockade of Glucagon-like Peptide 1 Receptor Corrects Post-prandial Hypoglycemia After Gastric Bypass 
Gastroenterology  2013;146(3):669-680.e2.
Background & Aims
Post-prandial glycemia excursions increase after gastric bypass surgery; this effect is even greater among individuals with recurrent hypoglycemia (blood glucose levels <50 mg/dL). These patients also have increased post-prandial levels of insulin and glucagon-like peptide 1 (GLP1). We performed a clinical trial to determine the role of GLP1 in post-prandial glycemia in patients with hyperinsulinemic hypoglycemia syndrome after gastric bypass.
Methods
Nine patients with recurrent hypoglycemia after gastric bypass (H-GB), 7 asymptomatic individuals with previous gastric bypass (A-GB), and 8 non-diabetic subjects who did not receive surgery (controls) were studied with a mixed-meal tolerance test (350 kcal) using a dual glucose tracer method on 2 days. On 1 day they received continuous infusion of GLP-1 receptor (GLP1R) antagonist, exendin-(9–39) (Ex-9), and on the other day, a saline control. Glucose kinetics and islet and gut hormone responses were measured before and after the meal.
Results
Infusion of Ex9 corrected hypoglycemia in all H-GB individuals. The reduction of post-prandial insulin secretion by Ex9 was greater in the H-GB group than other groups (H-GB, 50%±8%; A-GB, 13%±10%; and controls, 14%±10%) (P<.05). Meal-derived glucose (RaOral) was significantly greater among subjects who had undergone gastric bypass than controls, and in H-GB patients compared with A-GB subjects. Ex9 shortened the time to peak RaOral in all groups without any significant effect on the overall glucose flux. Post-prandial glucagon levels were higher among patients who had undergone gastric bypass than controls, and increased with Ex9 administration.
Conclusions
Hypoglycemia following gastric bypass can be corrected by administration of a GLP1R antagonist, which might be used to treat this disorder. These findings are consistent with reports that increased GLP1 activity contributes to hypoglycemia following gastric bypass. ClinicalTrials.gov number, NCT01803451
doi:10.1053/j.gastro.2013.11.044
PMCID: PMC3943944  PMID: 24315990
Roux-en-Y gastric bypass surgery; hyperinsulinemic hypoglycemia syndrome; Glucagon-like peptide 1; islet function
7.  Matched weight loss induced by sleeve gastrectomy or gastric bypass similarly improves metabolic function in obese subjects 
Obesity (Silver Spring, Md.)  2014;22(9):2026-2031.
Objective
We evaluated the effects of marked weight loss, induced by Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) surgeries, on insulin sensitivity, β-cell function and the metabolic response to a mixed meal.
Design and Methods
Fourteen non-diabetic insulin-resistant patients who were scheduled to undergo SG (n=7) or RYGB (n=7) procedures completed a hyperinsulinemic-euglycemic clamp procedure and a mixed-meal tolerance test before surgery and after losing ∼20% of their initial body weight.
Results
Insulin sensitivity (insulin-stimulated glucose disposal during a clamp procedure), oral glucose tolerance (postprandial plasma glucose area under the curve), and β-cell function (insulin secretion in relationship to insulin sensitivity) improved after weight loss, and were not different between surgical groups. The metabolic response to meal ingestion was similar after RYGB or SG, manifested by rapid delivery of ingested glucose into the systemic circulation and a large early postprandial increase in plasma glucose, insulin and C-peptide concentrations in both groups.
Conclusions
We conclude that, when matched on weight loss, RYGB and SG surgeries result in similar improvements in the two major factors involved in regulating plasma glucose homeostasis, insulin sensitivity and β-cell function in obese people without diabetes.
doi:10.1002/oby.20803
PMCID: PMC4149594  PMID: 24891156
Bariatric surgery; sleeve gastrectomy; insulin resistance; gastric bypass
8.  Effects of sitagliptin on ectopic fat contents and glucose metabolism in type 2 diabetic patients with fatty liver: A pilot study 
Aims/Introduction
Recent data have shown that ectopic fat accumulation in the liver worsens hepatic glucose metabolism, suggesting that fatty liver in patients with type 2 diabetes is a therapeutic target. Glucagon-like peptide (GLP)-1 improves fatty liver, but the effect of dipeptidyl peptidase-4 inhibitor on fatty liver is still unclear. The present pilot study determined the effects of 12-week treatment with sitagliptin, a dipeptidyl peptidase-4 inhibitor, on liver fat content in type 2 diabetes with fatty liver. We also evaluated intramyocellular lipid (IMCL) and glucose kinetics during oral glucose tolerance test (OGTT) before and after the treatment.
Materials and Methods
The study participants were seven type 2 diabetes patients with fatty liver who were studied at baseline and 12 weeks after sitagliptin treatment. Intrahepatic lipid (IHL) and IMCL were assessed by 1H magnetic resonance spectroscopy. Glucose kinetics was assessed during double-tracer OGTT (U-[13C]-glucose orally and 6,6-[2H2]-glucose intravenously).
Results
Sitagliptin significantly reduced glycated hemoglobin (from 7.1 ± 0.2 to 6.5 ± 0.3%, P < 0.005), but had no effects on IHL and IMCL. The glucose level diminished, whereas GLP-1 concentration increased during OGTT at the end of treatment. These changes were not accompanied by significant changes in insulin or glucagon levels. However, long-term sitagliptin treatment partially decreased the rate of appearance of oral glucose during OGTT, but did not affect endogenous glucose production or the rate of disappearance.
Conclusions
It was found that 12-week sitagliptin treatment improved glycated hemoglobin and glucose excursion during OGTT in type 2 diabetes with fatty liver, independent of changes in lipid accumulation in the liver. This trial was registered with the Japan Clinical Trials Registry (UMIN-CTR000005666).
doi:10.1111/jdi.12262
PMCID: PMC4364851  PMID: 25802724
Dipeptidyl peptidase-4 inhibitor; Double tracer; Fatty liver
9.  Motor Activity in Aging: An Integrated Approach for Better Quality of Life 
Old age is normally associated with stereotypical structural and physiological changes in the brain that are caused by deterioration in elementary cognitive, sensory, and sensorimotor functions as well as increased susceptibility to stress. These changes are connected with gait impairment and falls, especially among patients with common neurological diseases. Even in the absence of history of falling or when there is no physical injury after a fall, many older people develop a fear of falling that leads to restricted mobility, reduced activity, depression, social isolation, worsened metabolic disease, and increasing risk of cardiovascular morbidity and mortality. Although links between cognitive decline and age-associated brain changes have been clarified, relationships between gait disorders and psychophysiological alterations in aging are less well understood. This review focuses on two crucial elements of aged individuals with gait disorders: characteristic comorbidities in the elderly and the psychophysiological effects of physical exercise in the elderly with gait disorder. We propose an integrated approach to studying elderly subjects with gait disorder before starting a program of motor rehabilitation with wearable robotic devices, in order to investigate the effectiveness and safety of the ambulatory training.
doi:10.1155/2014/257248
PMCID: PMC4897547  PMID: 27351018
10.  Long-Term Effects of Bariatric Surgery on Meal Disposal and β-Cell Function in Diabetic and Nondiabetic Patients 
Diabetes  2013;62(11):3709-3717.
Gastric bypass surgery leads to marked improvements in glucose tolerance and insulin sensitivity in obese type 2 diabetes (T2D); the impact on glucose fluxes in response to a physiological stimulus, such as a mixed meal test (MTT), has not been determined. We administered an MTT to 12 obese T2D patients and 15 obese nondiabetic (ND) subjects before and 1 year after surgery (10 T2D and 11 ND) using the double-tracer technique and modeling of β-cell function. In both groups postsurgery, tracer-derived appearance of oral glucose was biphasic, a rapid increase followed by a sharp drop, a pattern that was mirrored by postprandial glucose levels and insulin secretion. In diabetic patients, surgery lowered fasting and postprandial glucose levels, peripheral insulin sensitivity increased in proportion to weight loss (∼30%), and β-cell glucose sensitivity doubled but did not normalize (compared with 21 nonsurgical obese and lean controls). Endogenous glucose production, however, was less suppressed during the MMT as the combined result of a relative hyperglucagonemia and the rapid fall in plasma glucose and insulin levels. We conclude that in T2D, bypass surgery changes the postprandial response to a dumping-like pattern and improves glucose tolerance, β-cell function, and peripheral insulin sensitivity but worsens endogenous glucose output in response to a physiological stimulus.
doi:10.2337/db13-0321
PMCID: PMC3806605  PMID: 23835342
11.  Prediction of Diabetes Based on Baseline Metabolic Characteristics in Individuals at High Risk 
Diabetes Care  2013;36(11):3607-3612.
OBJECTIVE
Individuals with impaired glucose tolerance (IGT) are at high risk for developing type 2 diabetes mellitus (T2DM). We examined which characteristics at baseline predicted the development of T2DM versus maintenance of IGT or conversion to normal glucose tolerance.
RESEARCH DESIGN AND METHODS
We studied 228 subjects at high risk with IGT who received treatment with placebo in ACT NOW and who underwent baseline anthropometric measures and oral glucose tolerance test (OGTT) at baseline and after a mean follow-up of 2.4 years.
RESULTS
In a univariate analysis, 45 of 228 (19.7%) IGT individuals developed diabetes. After adjusting for age, sex, and center, increased fasting plasma glucose, 2-h plasma glucose, ∆G0–120 during OGTT, HbA1c, adipocyte insulin resistance index, ln fasting plasma insulin, and ln ∆I0–120, as well as family history of diabetes and presence of metabolic syndrome, were associated with increased risk of diabetes. At baseline, higher insulin secretion (ln [∆I0–120/∆G0–120]) during the OGTT was associated with decreased risk of diabetes. Higher β-cell function (insulin secretion/insulin resistance or disposition index; ln [∆I0–120/∆G0–120 × Matsuda index of insulin sensitivity]; odds ratio 0.11; P < 0.0001) was the variable most closely associated with reduced risk of diabetes.
CONCLUSIONS
In a stepwise multiple-variable analysis, only HbA1c and β-cell function (ln insulin secretion/insulin resistance index) predicted the development of diabetes (r = 0.49; P < 0.0001).
doi:10.2337/dc13-0520
PMCID: PMC3816921  PMID: 24062330
12.  Prevention of Diabetes With Pioglitazone in ACT NOW 
Diabetes  2013;62(11):3920-3926.
We examined the metabolic characteristics that attend the development of type 2 diabetes (T2DM) in 441 impaired glucose tolerance (IGT) subjects who participated in the ACT NOW Study and had complete end-of-study metabolic measurements. Subjects were randomized to receive pioglitazone (PGZ; 45 mg/day) or placebo and were observed for a median of 2.4 years. Indices of insulin sensitivity (Matsuda index [MI]), insulin secretion (IS)/insulin resistance (IR; ΔI0–120/ΔG0–120, ΔIS rate [ISR]0–120/ΔG0–120), and β-cell function (ΔI/ΔG × MI and ΔISR/ΔG × MI) were calculated from plasma glucose, insulin, and C-peptide concentrations during oral glucose tolerance tests at baseline and study end. Diabetes developed in 45 placebo-treated vs. 15 PGZ-treated subjects (odds ratio [OR] 0.28 [95% CI 0.15–0.49]; P < 0.0001); 48% of PGZ-treated subjects reverted to normal glucose tolerance (NGT) versus 28% of placebo-treated subjects (P < 0.005). Higher final glucose tolerance status (NGT > IGT > T2DM) was associated with improvements in insulin sensitivity (OR 0.61 [95% CI 0.54–0.80]), IS (OR 0.61 [95% CI 0.50–0.75]), and β-cell function (ln IS/IR index and ln ISR/IR index) (OR 0.26 [95% CI 0.19–0.37]; all P < 0.0001). Of the factors measured, improved β-cell function was most closely associated with final glucose tolerance status.
doi:10.2337/db13-0265
PMCID: PMC3806596  PMID: 23863810
13.  Circulating Lysophosphatidylcholines Are Markers of a Metabolically Benign Nonalcoholic Fatty Liver 
Diabetes Care  2013;36(8):2331-2338.
OBJECTIVE
Nonalcoholic fatty liver (NAFL) is thought to contribute to insulin resistance and its metabolic complications. However, some individuals with NAFL remain insulin sensitive. Mechanisms involved in the susceptibility to develop insulin resistance in humans with NAFL are largely unknown. We investigated circulating markers and mechanisms of a metabolically benign and malignant NAFL by applying a metabolomic approach.
RESEARCH DESIGN AND METHODS
A total of 265 metabolites were analyzed before and after a 9-month lifestyle intervention in plasma from 20 insulin-sensitive and 20 insulin-resistant subjects with NAFL. The relevant plasma metabolites were then tested for relationships with insulin sensitivity in 17 subjects without NAFL and in plasma from 29 subjects with liver tissue samples.
RESULTS
The best separation of the insulin-sensitive from the insulin-resistant NAFL group was achieved by a metabolite pattern including the branched-chain amino acids leucine and isoleucine, ornithine, the acylcarnitines C3:0-, C16:0-, and C18:0-carnitine, and lysophosphatidylcholine (lyso-PC) C16:0 (area under the ROC curve, 0.77 [P = 0.00023] at baseline and 0.80 [P = 0.000019] at follow-up). Among the individual metabolites, predominantly higher levels of lyso-PC C16:0, both at baseline (P = 0.0039) and at follow-up (P = 0.001), were found in the insulin-sensitive compared with the insulin-resistant subjects. In the non-NAFL groups, no differences in lyso-PC C16:0 levels were found between the insulin-sensitive and insulin-resistant subjects, and these relationships were replicated in plasma from subjects with liver tissue samples.
CONCLUSIONS
From a plasma metabolomic pattern, particularly lyso-PCs are able to separate metabolically benign from malignant NAFL in humans and may highlight important pathways in the pathogenesis of fatty liver–induced insulin resistance.
doi:10.2337/dc12-1760
PMCID: PMC3714475  PMID: 23514731
14.  HCC Development Is Associated to Peripheral Insulin Resistance in a Mouse Model of NASH 
PLoS ONE  2014;9(5):e97136.
NAFLD is the most common liver disease worldwide but it is the potential evolution to NASH and eventually to hepatocellular carcinoma (HCC), even in the absence of cirrhosis, that makes NAFLD of such clinical importance. Aim: we aimed to create a mouse model reproducing the pathological spectrum of NAFLD and to investigate the role of possible co-factors in promoting HCC. Methods: mice were treated with a choline-deficient L-amino-acid-defined-diet (CDAA) or its control (CSAA diet) and subjected to a low-dose i.p. injection of CCl4 or vehicle. Insulin resistance was measured by the euglycemic-hyperinsulinemic clamp method. Steatosis, fibrosis and HCC were evaluated by histological and molecular analysis. Results: CDAA-treated mice showed peripheral insulin resistance at 1 month. At 1–3 months, extensive steatosis and fibrosis were observed in CDAA and CDAA+CCl4 groups. At 6 months, equal increase in steatosis and fibrosis was observed between the two groups, together with the appearance of tumor. At 9 months of treatment, the 100% of CDAA+CCl4 treated mice revealed tumor versus 40% of CDAA mice. Insulin-like Growth Factor-2 (IGF-2) and Osteopontin (SPP-1) were increased in CDAA mice versus CSAA. Furthermore, Immunostaining for p-AKT, p-c-Myc and Glypican-3 revealed increased positivity in the tumors. Conclusions: the CDAA model promotes the development of HCC from NAFLD-NASH in the presence of insulin resistance but in the absence of cirrhosis. Since this condition is increasingly recognized in humans, our study provides a model that may help understanding mechanisms of carcinogenesis in NAFLD.
doi:10.1371/journal.pone.0097136
PMCID: PMC4031080  PMID: 24853141
15.  Comparison of Liver Fat Indices for the Diagnosis of Hepatic Steatosis and Insulin Resistance 
PLoS ONE  2014;9(4):e94059.
Context
Hepatic steatosis, defined as increased hepatocellular lipid content (HCL), associates with visceral obesity and glucose intolerance. As exact HCL quantification by 1H-magnetic resonance spectroscopy (1H-MRS) is not generally available, various clinical indices are increasingly used to predict steatosis.
Objective
The purpose of this study was to test the accuracy of NAFLD liver fat score (NAFLD-LFS), hepatic steatosis index (HSI) and fatty liver index (FLI) against 1H-MRS and their relationships with insulin sensitivity and secretion.
Design, Setting and Participants
Ninety-two non-diabetic, predominantly non-obese humans underwent clinical examination, 1H-MRS and an oral glucose tolerance test (OGTT) to calculate insulin sensitivity and β-cell function. Accuracy of indices was assessed from the area under the receiver operating characteristic curve (AROC).
Results
Median HCL was 2.49% (0.62;4.23) and correlated with parameters of glycemia across all subjects. NAFLD-LFS, FLI and HSI yielded AROCs of 0.70, 0.72, and 0.79, respectively, and related positively to HCL, insulin resistance, fasting and post-load β-cell function normalized for insulin resistance. Upon adjustment for age, sex and HCL, regression analysis revealed that NAFLD-LFS, FLI and HSI still independently associated with both insulin sensitivity and β-cell function.
Conclusion
The tested indices offer modest efficacy to detect steatosis and cannot substitute for fat quantification by 1H-MRS. However, all indices might serve as surrogate parameters for liver fat content and also as rough clinical estimates of abnormal insulin sensitivity and secretion. Further validation in larger collectives such as epidemiological studies is needed.
doi:10.1371/journal.pone.0094059
PMCID: PMC3986069  PMID: 24732091
16.  The Ontogeny of the Endocrine Pancreas in the Fetal/Newborn Baboon 
The Journal of endocrinology  2012;214(3):289-299.
Background
Erratic regulation of glucose metabolism including hyperglycemia is a common condition of premature infants and is associated with increased morbidity and mortality.
Objective
To examine histological and ultra-structural differences in the endocrine pancreas in fetal (throughout gestation) and neonatal baboons.
Methods
Twelve fetal baboons were delivered at 125 days (d) gestational age (GA), 140dGA, or 175dGA. Eight animals were delivered at term (185dGA); half were fed for 5d. Seventy-three non-diabetic adult baboons were used for comparison. Pancreatic tissue was studied utilizing light microscopy, confocal imaging and electron microscopy.
Results
The fetal and neonatal endocrine pancreas islet architecture became more organized as GA advanced. The percent areas of α-β-δ-cell type were similar within each fetal and newborn GA (NS), but were higher than the adults (P<0.05) regardless of GA. The ratio of β-cells within the islet (whole and core) increased with gestation (P<0.01). Neonatal baboons who survived for 5 days (feeding), had a 2.5-fold increase in pancreas weight compared to their counterparts euthanized at birth (P=0.01). Endocrine cells were found amongst exocrine ductal and acinar cells in 125,140 and 175dGA fetuses. Subpopulation of cells that co-expressed trypsin and glucagon/insulin show the presence of cells with mixed endo-exocrine lineage in fetuses.
Conclusions
The fetal endocrine pancreas has no prevalence of a of α-β-δ-cell type with larger endocrine cell percent areas than adults. Cells with mixed endocrine/exocrine phenotype occur during fetal development. Developmental differences may play a role in glucose homeostasis during the neonatal period and may have long term implications.
doi:10.1530/JOE-12-0070
PMCID: PMC3686495  PMID: 22723715
Insulin; glucagon; fetus; islet cells; primates
17.  Non-Alcoholic Fatty Liver Disease (NAFLD) and Its Connection with Insulin Resistance, Dyslipidemia, Atherosclerosis and Coronary Heart Disease 
Nutrients  2013;5(5):1544-1560.
Non-alcoholic fatty liver disease is marked by hepatic fat accumulation not due to alcohol abuse. Several studies have demonstrated that NAFLD is associated with insulin resistance leading to a resistance in the antilipolytic effect of insulin in the adipose tissue with an increase of free fatty acids (FFAs). The increase of FFAs induces mitochondrial dysfunction and development of lipotoxicity. Moreover, in subjects with NAFLD, ectopic fat also accumulates as cardiac and pancreatic fat. In this review we analyzed the mechanisms that relate NAFLD with metabolic syndrome and dyslipidemia and its association with the development and progression of cardiovascular disease.
doi:10.3390/nu5051544
PMCID: PMC3708335  PMID: 23666091
non-alcoholic fatty liver(NAFLD); steatosis; visceral fat; lipotoxicity; insulin resistance; free fatty acids; dyslipidemia; cardiometabolic risk
18.  Glucokinase links Krüppel-like factor 6 to the regulation of hepatic insulin sensitivity in non-alcoholic fatty liver disease 
Hepatology (Baltimore, Md.)  2012;55(4):1083-1093.
The polymorphism, KLF6-IVS1-27A, in the Krüppel-like factor 6 (KLF6) transcription factor gene enhances its splicing into antagonistic isoforms and is associated with delayed histological progression of non-alcoholic fatty liver disease (NAFLD). To explore a potential role for KLF6 in the development of insulin resistance, central to NAFLD pathogenesis, we genotyped KLF6-IVS1-27 in healthy subjects and assayed fasting plasma glucose (FPG) and insulin sensitivities. Furthermore, we quantified mRNA expression of KLF6 and glucokinase (GCK), as an important mediator of insulin sensitivity, in human livers and in liver tissues derived from a murine Klf6 knockdown model (DeltaKlf6). Klf6 overexpression studies in a mouse hepatocyte line were utilized to mechanistically link KLF6 with Gck promoter activity.
Results
KLF6-IVS1-27Gwt (ie., less KLF6 splicing) was associated with stepwise increases in FPG and insulin and reduced hepatic insulin sensitivity. KLF6 binds to the liver-specific Gck promoter and activates a GCK promoter-reporter, identifying GCK as a KLF6 direct transcriptional target. Accordingly, in DeltaKlf6 hepatocytes, Gck expression was reduced and stable transfection of Klf6 led to upregulation of Gck. GCK and KLF6 mRNAs correlate directly in human NAFLD tissues and immunohistochemistry studies confirm falling levels of both KLF6 and GCK in fat laden hepatocytes. In contrast to full length KLF6, splice variant KLF6-SV1 increases in NAFLD hepatocytes and inversely correlates with glucokinase regulatory protein, which negatively regulates GCK activity.
Conclusion
KLF6 regulation of GCK contributes to the development of hepatic insulin resistance. The KLF6-IVS1-27A polymorphism, which generates more KLF6-SV1, combats this, lowering hepatic insulin resistance and blood glucose.
doi:10.1002/hep.24793
PMCID: PMC3295906  PMID: 22095588
Krüppel-like Factor 6; non-alcoholic fatty liver disease; hepatic insulin sensitivity; insulin resistance; glucokinase
19.  Gastric bypass and banding equally improve insulin sensitivity and β cell function 
The Journal of Clinical Investigation  2012;122(12):4667-4674.
Bariatric surgery in obese patients is a highly effective method of preventing or resolving type 2 diabetes mellitus (T2DM); however, the remission rate is not the same among different surgical procedures. We compared the effects of 20% weight loss induced by laparoscopic adjustable gastric banding (LAGB) or Roux-en-Y gastric bypass (RYGB) surgery on the metabolic response to a mixed meal, insulin sensitivity, and β cell function in nondiabetic obese adults. The metabolic response to meal ingestion was markedly different after RYGB than after LAGB surgery, manifested by rapid delivery of ingested glucose into the systemic circulation, by an increase in the dynamic insulin secretion rate, and by large, early postprandial increases in plasma glucose, insulin, and glucagon-like peptide–1 concentrations in the RYGB group. However, the improvement in oral glucose tolerance, insulin sensitivity, and overall β cell function after weight loss were not different between surgical groups. Additionally, both surgical procedures resulted in a similar decrease in adipose tissue markers of inflammation. We conclude that marked weight loss itself is primarily responsible for the therapeutic effects of RYGB and LAGB on insulin sensitivity, β cell function, and oral glucose tolerance in nondiabetic obese adults.
doi:10.1172/JCI64895
PMCID: PMC3512168  PMID: 23187122
20.  Liver Enzymes Are Associated With Hepatic Insulin Resistance, Insulin Secretion, and Glucagon Concentration in Healthy Men and Women 
Diabetes  2011;60(6):1660-1667.
OBJECTIVE
The pathophysiological mechanisms to explain the association between risk of type 2 diabetes and elevated concentrations of γ-glutamyltransferase (GGT) and alanineaminotransferase (ALT) remain poorly characterized. We explored the association of liver enzymes with peripheral and hepatic insulin resistance, insulin secretion, insulin clearance, and glucagon concentration.
RESEARCH DESIGN AND METHODS
We studied 1,309 nondiabetic individuals from the Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) study; all had a euglycemic-hyperinsulinemic clamp and an oral glucose tolerance test (OGTT) with assessment of insulin secretion and hepatic insulin extraction. The hepatic insulin resistance index was calculated in 393 individuals.
RESULTS
In both men and women, plasma concentrations of GGT and ALT were inversely related with insulin sensitivity (M/I) (all P < 0.01). Likewise, the hepatic insulin resistance index was positively correlated with both GGT (r = 0.37, P < 0.0001, men; r = 0.36, P < 0.0001, women) and ALT (r = 0.25, P = 0.0005, men; r = 0.18, P = 0.01, women). These associations persisted in multivariable models. Increased GGT and ALT were significantly associated with higher insulin secretion rates and with both reduced endogenous clearance of insulin and hepatic insulin extraction during the OGTT (P = 0.0005 in men; P = 0.003 in women). Plasma fasting glucagon levels increased over ALT quartiles (men, quartile 4 vs. quartile 1 11.2 ± 5.1 vs. 9.3 ± 3.8 pmol/L, respectively, P = 0.0002; women, 9.0 ± 4.3 vs. 7.6 ± 3.1, P = 0.001).
CONCLUSIONS
In healthy individuals, increased GGT and ALT were biomarkers of both systemic and hepatic insulin resistance with concomitant increased insulin secretion and decreased hepatic insulin clearance. The novel finding of a positive correlation between ALT and fasting glucagon level concentrations warrants confirmation in type 2 diabetes.
doi:10.2337/db10-1806
PMCID: PMC3114399  PMID: 21521874
21.  Fatty Liver Index Predicts Further Metabolic Deteriorations in Women with Previous Gestational Diabetes 
PLoS ONE  2012;7(2):e32710.
Background and Aims
Determinants of fatty liver (FL) might be predictive for further deterioration in insulin resistance (IR) in women with previous gestational diabetes (pGDM). The aim was to evaluate the association between pGDM, FL and future manifestation of type 2 diabetes (T2DM) by a detailed pathophysiological characterization early after pregnancy.
Methods
68 pGDM and 29 healthy controls were included 3–6 months after delivery and underwent specific metabolic assessments: status of IR was determined via oral- and intravenous-glucose-tolerance-tests with analysis of proinflammatory factors and kinetics of free-fatty-acids (FFA). According to the fatty-liver-index (FLI), pGDMs were categorized into three groups with low (FLI≤20), intermediate (20
Results
FL was strongly associated with IR in pGDM. pGDM with FLI≥60 showed significantly increased interleukin-6, plasminogen-activator-inhibitor-1, tissue-plasminogen-activator, fibrinogen and increased ultrasensitive-C-reactive-protein compared to the low risk group (FLI≤20). Analysis of FFA indicated a less pronounced decrease of plasma FFA levels during the oral-glucose-tolerance-test in subjects with FLI≥60. History of GDM plus FLI≥60 conferred a high risk for the manifestation of diabetes over 10 years of observation as compared to pGDMs with FLI≤20 (HR:7.85, Cl:2.02–30.5, p = 0.003).
Conclusion
FL is closely linked to GDM, especially to IR and inflammation. Most interestingly, subjects with the highest FLI values showed significant alterations in FFA kinetics and a higher risk to develop T2DM in future.
doi:10.1371/journal.pone.0032710
PMCID: PMC3290578  PMID: 22393439
Clinical Endocrinology  2010;73(3):339-345.
Summary
Objectives
By using tracer techniques, we explored the metabolic mechanisms by which pioglitazone treatment for 16 weeks improves oral glucose tolerance in patients with type 2 diabetes when compared to subjects without diabetes.
Methods
In all subjects, before and after treatment, we measured rates of tissue glucose clearance (MCR), oral glucose appearance (RaO) and endogenous glucose production (EGP) during a (4-h) double tracer oral glucose tolerance test (OGTT) (1-14C-glucose orally and 3-3H-glucose intravenously). Basal hepatic insulin resistance index (HepIR) was calculated as EGPxFPI. β-cell function was assessed as the incremental ratio of insulin to glucose (ΔI/ΔG) during the OGTT.
Results
Pioglitazone decreased fasting plasma glucose concentration (10·5 ± 0·7 to 7·8 ± 0·6 mM, P < 0·0003) and HbA1c (9·7 ± 0·7 to 7·5 ± 0·5%, P < 0·003) despite increased body weight and no change in plasma insulin concentrations. This was determined by a decrease both in fasting EGP (20·0 ± 1·1 to 17·3 ± 0·8 μmol/kgffm min, P < 0·005) and HepIR (from 8194 declined by 49% to 3989, P < 0·002). During the OGTT, total glucose Ra during the 0- to 120-min time period following glucose ingestion decreased significantly because of a reduction in EGP. During the 0- to 240-min time period, pioglitazone caused only a modest increase in MCR (P < 0·07) but markedly increased ΔI/ΔG (P = 0·003). The decrease in 2h-postprandial hyperglycaemia correlated closely with the increase in ΔI/ΔG (r = −0·76, P = 0·004) and tissue clearance (r = −0·74, P = 0·006) and with the decrease in HepIR (r = 0·62, P = 0·006).
Conclusions
In diabetic subjects with poor glycaemic control, pioglitazone improves oral glucose tolerance mainly by enhancing the suppression of EGP and improving β-cell function.
doi:10.1111/j.1365-2265.2010.03811.x
PMCID: PMC3265037  PMID: 20455891
PLoS ONE  2011;6(11):e27617.
Non-Alcoholic fatty liver disease (NAFLD) is characterized by accumulation of triglycerides (TG) in hepatocytes, which may also trigger cirrhosis. The mechanisms of NAFLD are not fully understood, but insulin resistance has been proposed as a key determinant.
Aims
To determine the TG content and long chain fatty acyl CoA composition profile in liver from obese non-diabetic insulin resistant (IR) and lean insulin sensitive (IS) baboons in relation with hepatic and peripheral insulin sensitivity.
Methods
Twenty baboons with varying grades of adiposity were studied. Hepatic (liver) and peripheral (mainly muscle) insulin sensitivity was measured with a euglycemic clamp and QUICKI. Liver biopsies were performed at baseline for TG content and LCFA profile by mass spectrometry, and histological analysis. Findings were correlated with clinical and biochemical markers of adiposity and insulin resistance.
Results
Obese IR baboons had elevated liver TG content compared to IS. Furthermore, the concentration of unsaturated (LC-UFA) was greater than saturated (LC-SFA) fatty acyl CoA in the liver. Interestingly, LC-FA UFA and SFA correlated with waist, BMI, insulin, NEFA, TG, QUICKI, but not M/I. Histological findings of NAFLD ranging from focal to diffuse hepatic steatosis were found in obese IR baboons.
Conclusion
Liver TG content is closely related with both hepatic and peripheral IR, whereas liver LC-UFA and LC-SFA are closely related only with hepatic IR in non-human primates. Mechanisms leading to the accumulation of TG, LC-UFA and an altered UFA: LC-SFA ratio may play an important role in the pathophysiology of fatty liver disease in humans.
doi:10.1371/journal.pone.0027617
PMCID: PMC3220682  PMID: 22125617
Objective
We sought to determine the effect of daily soy supplementation on abdominal fat, glucose metabolism, and circulating inflammatory markers and adipokines in obese, postmenopausal Caucasian and African American women.
Study Design
In a double-blinded controlled trial, 39 postmenopausal women were randomized to soy supplementation or to a casein placebo without isoflavones. Thirty-three completed the study and were analyzed. At baseline and at 3 months, glucose disposal and insulin secretion were measured using hyperglycemic clamps, body composition and body fat distribution were measured by CT scan and DXA, and serum levels of CRP, IL-6, TNF-α, leptin, and adiponectin were measured by immunoassay.
Results
Soy supplementation reduced total and subcutaneous abdominal fat, and IL-6. No difference between groups was noted for glucose metabolism, CRP, TNF-α, leptin, or adiponectin.
Conclusion(s)
Soy supplementation reduced abdominal fat in obese postmenopausal women. Caucasians primarily lost subcutaneous and total abdominal fat, and African Americans primarily lost total body fat.
doi:10.1016/j.ajog.2010.02.058
PMCID: PMC3206645  PMID: 20435291
Menopause; obesity; soy; isoflavones; body composition; body fat distribution; race; insulin secretion; glucose metabolism

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