Worsen Glucose Metabolism Research Articles

Longitudinal study on hippocampal subfields and glucose metabolism in early psychosis

Altered hippocampal morphology and metabolic pathology, but also hippocampal circuit dysfunction, are established phenomena seen in psychotic disorders. Thus, we tested whether hippocampal subfield volume deficits link with deviations in glucose metabolism commonly seen in early psychosis, and whether the glucose parameters or subfield volumes change during follow-up period using one-year longitudinal study design of 78 first-episode psychosis patients (FEP), 48 clinical high-risk patients (CHR) and 83 controls (CTR). We also tested whether hippocampal morphology and glucose metabolism relate to clinical outcome. Hippocampus subfields were segmented with Freesurfer from 3T MRI images and parameters of glucose metabolism were determined in fasting plasma samples. Hippocampal subfield volumes were consistently lower in FEPs, and findings were more robust in non-affective psychoses, with strongest decreases in CA1, molecular layer and hippocampal tail, and in hippocampal tail of CHRs, compared to CTRs. These morphometric differences remained stable at one-year follow-up. Both non-diabetic CHRs and FEPs had worse glucose parameters compared to CTRs at baseline. We found that, insulin levels and insulin resistance increased during the follow-up period only in CHR, effect being largest in the CHRs converting to psychosis, independent of exposure to antipsychotics. The worsening of insulin resistance was associated with deterioration of function and symptoms in CHR. The smaller volume of hippocampal tail was associated with higher plasma insulin and insulin resistance in FEPs, at the one-year follow-up. Our longitudinal study supports the view that temporospatial hippocampal subfield volume deficits are stable near the onset of first psychosis, being more robust in non-affective psychoses, but less prominent in the CHR group. Specific subfield defects were related to worsening glucose metabolism during the progression of psychosis, suggesting that hippocampus is part of the circuits regulating aberrant glucose metabolism in early psychosis. Worsening of glucose metabolism in CHR group was associated with worse clinical outcome measures indicating a need for heightened clinical attention to metabolic problems already in CHR.

Growth hormone therapy in Turner Syndrome (TS): A focused review on glucose metabolism outcomes

Introduction: Turner Syndrome (TS) patients inherently possess a higher risk of developing glycemic abnormalities due to their unique genetic makeup, and the administration of growth hormone (GH) therapy, while beneficial for growth, might exacerbate this tendency towards disturbed glucose metabolism. Objective of the Review: To evaluate the existing literature on the effects of GH therapy on glucose metabolism in TS patients, highlighting the balance between therapeutic benefits and potential metabolic risks. Methods: This review scrutinizes studies published from 2000 to 2024, focusing on the outcomes related to glucose metabolism in TS individuals undergoing GH therapy, encompassing aspects like insulin sensitivity, glucose tolerance, and metabolic health. Results: Insulin Sensitivity and Resistance: Initial findings suggest that GH therapy may exacerbate insulin resistance and elevate insulin levels, although these effects appear transient and potentially reversible after the cessation of therapy. Long-term Metabolic Outcomes: Later studies indicate that long-term GH therapy may lead to an improvement in insulin sensitivity and a normalization of carbohydrate metabolism, particularly after the therapy is discontinued. Variable Impacts on Glucose Tolerance: The reviewed literature shows mixed effects on glucose tolerance, with some studies reporting no significant changes, while others highlight a potential risk for worsening glucose metabolism. Body Composition and Metabolic Profile: Positive changes in body composition and lipid profiles were noted, which could confer metabolic benefits, yet the therapy's role in increasing insulin levels warrants careful consideration. Individual Variability and Monitoring Needs: The diverse responses to GH therapy underscore the necessity for individualized treatment plans and diligent metabolic monitoring to mitigate potential risks and optimize therapeutic outcomes. Conclusion: The administration of GH therapy in TS requires a delicate balance, considering its potential to both benefit and pose risks to glucose metabolism. Tailored monitoring and a comprehensive understanding of the individual patient’s metabolic response are essential for maximizing the therapy's efficacy while minimizing associated metabolic complications.

SAH is a major metabolic sensor mediating worsening metabolic crosstalk in metabolic syndrome

In this study, we observed worsening metabolic crosstalk in mouse models with concomitant metabolic disorders such as hyperhomocysteinemia (HHcy), hyperlipidemia, and hyperglycemia and in human coronary artery disease by analyzing metabolic profiles. We found that HHcy worsening is most sensitive to other metabolic disorders. To identify metabolic genes and metabolites responsible for the worsening metabolic crosstalk, we examined mRNA levels of 324 metabolic genes in Hcy, glucose-related and lipid metabolic systems. We examined Hcy-metabolites (Hcy, SAH and SAM) by LS-ESI-MS/MS in 6 organs (heart, liver, brain, lung, spleen, and kidney) from C57BL/6J mice. Through linear regression analysis of Hcy-metabolites and metabolic gene mRNA levels, we discovered that SAH-responsive genes were responsible for most metabolic changes and all metabolic crosstalk mediated by Serine, Taurine, and G3P. SAH-responsive genes worsen glucose metabolism and cause upper glycolysis activation and lower glycolysis suppression, indicative of the accumulation of glucose/glycogen and G3P, Serine synthesis inhibition, and ATP depletion. Insufficient Serine due to negative correlation of PHGDH with SAH concentration may inhibit the folate cycle and transsulfurarion pathway and consequential reduced antioxidant power, including glutathione, taurine, NADPH, and NAD+. Additionally, we identified SAH-activated pathological TG loop as the consequence of increased fatty acid (FA) uptake, FA β-oxidation and Ac-CoA production along with lysosomal damage. We concluded that HHcy is most responsive to other metabolic changes in concomitant metabolic disorders and mediates worsening metabolic crosstalk mainly via SAH-responsive genes, that organ-specific Hcy metabolism determines organ-specific worsening metabolic reprogramming, and that SAH, acetyl-CoA, Serine and Taurine are critical metabolites mediating worsening metabolic crosstalk, redox disturbance, hypomethylation and hyperacetylation linking worsening metabolic reprogramming in metabolic syndrome.

WITHDRAWN: SAH is a major metabolic sensor mediating worsening metabolic crosstalk in metabolic syndrome

In this study, we observed worsening metabolic crosstalk in mouse models with concomitant metabolic disorders such as hyperhomocysteinemia (HHcy), hyperlipidemia, and hyperglycemia and in human coronary artery disease by analyzing metabolic profiles. We found that HHcy worsening is most sensitive to other metabolic disorders. To identify metabolic genes and metabolites responsible for the worsening metabolic crosstalk, we examined mRNA levels of 324 metabolic genes in Hcy, glucose-related and lipid metabolic systems. We examined Hcy-metabolites (Hcy, SAH and SAM) by LS-ESI-MS/MS in 6 organs (heart, liver, brain, lung, spleen, and kidney) from C57BL/6J mice. We discovered that SAH-responsive genes account for most metabolic changes and all metabolic crosstalk through Serine, Taurine and G3P by linear regression analyses between Hcy-metabolites and mRNA levels of metabolic genes. SAH-responsive genes worsen glucose metabolism and cause upper glycolysis activation and lower glycolysis suppression, indicative of the accumulation of glucose/glycogen and G3P, Serine synthesis inhibition, and ATP depletion. Insufficient Serine due to negative correlation of PHGDH with SAH concentration may inhibit the folate cycle and transsulfurarion pathway and consequential reduced antioxidant power, including glutathione, taurine, NADPH, and NAD+. Additionally, we identified SAH-activated pathological TG loop as the consequence of increased fatty acid (FA) uptake, FA β-oxidation and Ac-CoA production along with lysosomal damage. We concluded that HHcy is most responsive to other metabolic changes in concomitant metabolic disorders and mediates worsening metabolic crosstalk mainly via SAH-responsive genes, that organ-specific Hcy metabolism determines organ-specific worsening metabolic reprogramming, and that SAH, acetyl-CoA, Serine and Taurine are critical metabolites mediating worsening metabolic crosstalk, redox disturbance, hypomethylation and hyperacetylation linking worsening metabolic reprogramming in metabolic syndrome.

Pathological roles of bone marrow adipocyte-derived monocyte chemotactic protein-1 in type 2 diabetic mice.

Type 2 diabetes mellitus (T2DM) has become a prevalent public health concern, with beta-cell dysfunction involved in its pathogenesis. Bone marrow adipose tissue (BMAT) increases in both the quantity and area in individuals with T2DM along with heightened monocyte chemotactic protein-1 (MCP-1) secretion. This study aims to investigate the influence and underlying mechanisms of MCP-1 originating from bone marrow adipocytes (BMAs) on systemic glucose homeostasis in T2DM. Initially, a substantial decrease in the proliferation and glucose-stimulated insulin secretion (GSIS) of islet cells was observed. Moreover, a comparative analysis between the control (Ctrl) group and db/db mice revealed significant alterations in the gene expression profiles of whole bone marrow cells, with a noteworthy upregulation of Mcp-1. And the primary enriched pathways included chemokine signaling pathway and AGE-RAGE signaling pathway in diabetic complications. In addition, the level of MCP-1 was distinctly elevated in BMA-derived conditional media (CM), leading to a substantial inhibition of proliferation, GSIS and the protein level of phosphorylated Akt (p-Akt) in Min6 cells. After blocking MCP-1 pathway, we observed a restoration of p-Akt and the proliferation of islet cells, resulting in a marked improvement in disordered glucose homeostasis. In summary, there is an accumulation of BMAs in T2DM, which secrete excessive MCP-1, exacerbating the abnormal accumulation of BMAs in the bone marrow cavity through paracrine signaling. The upregulated MCP-1, in turn, worsens glucose metabolism disorder by inhibiting the proliferation and insulin secretion of islet cells through an endocrine pathway. Inhibiting MCP-1 signaling can partially restore the proliferation and insulin secretion of islet cells, ultimately ameliorating glucose metabolism disorder. It's worth noting that to delve deeper into the impact of MCP-1 derived from BMAs on islet cells and its potential mechanisms, it is imperative to develop genetically engineered mice with conditional Mcp-1 knockout from BMAs.

BRSK2 in pancreatic β cells promotes hyperinsulinemia-coupled insulin resistance and its genetic variants are associated with human type 2 diabetes.

Brain-specific serine/threonine-protein kinase 2 (BRSK2) plays critical roles in insulin secretion and β-cell biology. However, whether BRSK2 is associated with human type 2 diabetes mellitus (T2DM) has not been determined. Here, we report that BRSK2 genetic variants are closely related to worsening glucose metabolism due to hyperinsulinemia and insulin resistance in the Chinese population. BRSK2 protein levels are significantly elevated in β cells from T2DM patients and high-fat diet (HFD)-fed mice due to enhanced protein stability. Mice with inducible β-cell-specific Brsk2 knockout (βKO) exhibit normal metabolism with a high potential for insulin secretion under chow-diet conditions. Moreover, βKO mice are protected from HFD-induced hyperinsulinemia, obesity, insulin resistance, and glucose intolerance. Conversely, gain-of-function BRSK2 in mature β cells reversibly triggers hyperglycemia due to β-cell hypersecretion-coupled insulin resistance. Mechanistically, BRSK2 senses lipid signals and induces basal insulin secretion in a kinase-dependent manner. The enhanced basal insulin secretion drives insulin resistance and β-cell exhaustion and thus the onset of T2DM in mice fed an HFD or with gain-of-function BRSK2 in β cells. These findings reveal that BRSK2 links hyperinsulinemia to systematic insulin resistance via interplay between β cells and insulin-sensitive tissues in the populations carrying human genetic variants or under nutrient-overload conditions.

One Year of Recombinant Human Growth Hormone Treatment in Adults with Prader-Willi Syndrome Improves Body Composition, Motor Skills and Brain Functional Activity in the Cerebellum.

We compared body composition, biochemical parameters, motor function, and brain neural activation in 27 adults with Prader–Willi syndrome and growth-hormone deficiency versus age-and sex-matched controls and baseline versus posttreatment values of these parameters after one year of recombinant human growth hormone (rhGH) treatment. To study body composition, we analyzed percentage of fat mass, percentage of lean mass, and muscle-mass surrogate variables from dual X-ray absorptiometry. Biochemical parameters analyzed included IGF-I, glucose metabolism, and myokines (myostatin, irisin, and IL6). To explore muscle function, we used dynamometer-measured handgrip strength, the Timed Up and Go (TUG) test, and the Berg Balance Scale (BBS). To study brain activation, we acquired functional magnetic resonance images during three motor tasks of varying complexity. After one year of treatment, we observed an increase in lean mass and its surrogates, a decrease in fat mass, improvements in TUG test and BBS scores, and increased neural activation in certain cerebellar areas. The treatment did not significantly worsen glucose metabolism, and no side-effects were reported. Our findings support the benefits of rhGH treatment in adults with Prader–Willi syndrome and growth-hormone deficiency on body composition and suggest that it may also improve balance and brain neural activation.

Increased alpha cell to beta cell ratio in patients with pancreatic cancer.

The development of pancreatic cancer (PC) is associated with worsening of glucose tolerance. However, there is limited information about the effects of PC on islet morphology. The aim of this study was to elucidate changes in alpha and beta cell mass in patients with PC. We enrolled 30 autopsy cases with death due to PC (9 with diabetes; DM) and 31 age- and BMI-matched autopsy cases without PC (controls, 12 with DM). Tumor-free pancreatic sections were stained for insulin and glucagon, and fractional beta cell (BCA) and alpha cell area (ACA) were quantified. In addition, expression of de-differentiation markers, i.e., ALDH1A3 and UCN3, was qualitatively evaluated. The pancreas of subjects with PC showed atrophic and fibrotic changes. There was no significant difference in BCA in subjects with PC compared to controls (1.53 ± 1.26% vs. 0.95 ± 0.42%, p = 0.07). However, ACA and ACA to BCA ratio were significantly higher in subjects with PC compared to controls (2.48 ± 2.39% vs. 0.53 ± 0.26% and 1.94 ± 1.93 vs. 0.59 ± 0.26, respectively, both p < 0.001). Increased ACA to BCA ratio was observed in subjects with PC irrespective of the presence of DM. Qualitative evaluation of ALDH1A3 and UCN3 expression showed no significant difference between the groups. In conclusion, in subjects with PC, alpha to beta cell mass ratio is increased, which may contribute to the increased risk of worsening glucose metabolism. Further studies are warranted to elucidate the mechanisms of increased alpha to beta cell mass in patients with PC.

Association of obesity with serum free fatty acid levels in individuals at different stages of prediabetes

We investigated the associations of prediabetes categories and obesity with serum free fatty acid (FFA) levels and adipose tissue insulin resistance. This study included 5006 male participants (1779, 1025, 629, 874, and 699 with normal fasting glucose/normal glucose tolerance, isolated impaired fasting glucose [IFG], isolated impaired glucose tolerance [IGT], IFG plus IGT, and diabetes, respectively). Serum FFA levels were assessed before and 30, 60, and 120 min after glucose ingestion, and the total area under the FFA curve (AUCFFA ) was calculated. Adipose insulin resistance index (adipo-IR) was assessed based on fasting FFA and insulin concentrations. Isolated IFG was associated with high fasting FFA levels (OR, 1.35; p < 0.001) and high adipo-IR (OR, 1.82; p < 0.001) only in the nonobesity group. Isolated IGT, IFG plus IGT, and diabetes were associated with high fasting FFA levels, regardless of obesity. Obesity was significantly associated with AUCFFA , and the duration of obesity-related impairment in lipolysis inhibition after glucose ingestion was prolonged in IFG plus IGT and diabetes. These results suggest that IFG and obesity may overlap in their effects on FFA metabolism whereas IGT has significant effects on FFA independent of obesity. Obesity impact on lipolysis may be involved in worsening glucose metabolism.

Effect of Fermented Rice Drink “Amazake” on Patients with Nonalcoholic Fatty Liver Disease and Periodontal Disease: A Pilot Study

The worldwide increase in nonalcoholic fatty liver disease (NAFLD) is a major public health problem. Obesity and diabetes are risk factors for NAFLD and the development of liver fibrosis is a risk factor for liver cancer. Periodontal disease bacteria can also exacerbate NAFLD. We previously reported that amazake, a traditional Japanese fermented food, improves the quality of life (QOL) of patients with liver cirrhosis. In this study, we investigated the effect of amazake intake on NAFLD patients with periodontal disease. Ten patients (mean age: 57.1 ± 19.2 years) consumed 100 g of amazake daily for 60 days. On days 0 and 60, their body mass index (BMI), body fat percentage, serum biochemical parameters, periodontal disease bacteria in saliva, and ten visual analog scales (VASs), namely, sense of abdomen distension, edema, fatigue, muscle cramps, loss of appetite, taste disorder, constipation, diarrhea, depression, and sleep disorder, were measured. For periodontal bacteria, the numbers of six types of bacteria in saliva (Porphyromonas gingivalis, Tannerella forsythia, Treponema denticola, Aggregatibacter actinomycetemcomitans, Prevotella intermedia, and Fusobacterium necleatum) and P. gingivalis-specific fimA genotype were determined. After 60 days of amazake consumption, eosinophils (p &lt; 0.05), immune reactive insulin (IRI) (p &lt; 0.01), and HOMA-IR (p &lt; 0.05) had significantly increased and tumor necrosis factor α (TNFα) (p &lt; 0.01), muscle cramps (p &lt; 0.05), and depression (p &lt; 0.05) had significantly decreased. All subjective symptoms improved after amazake intake. No change was observed in the periodontal bacteria. In conclusion, amazake significantly decreased TNFα and improved the QOL of the patients with NAFLD and periodontitis. However, caution should be exercised because amazake, which is manufactured using techniques that lead to concentrations of glucose from the saccharification of rice starch, may worsen glucose metabolism in NAFLD patients. Amazake may be an effective food for improving the symptoms of a fatty liver if energy intake is regulated.

Prediabetes influences the structure of the macula: thinning of the macula in the Northern Finland Birth Cohort

Background/AimThe aim of this study was to evaluate the effect of prediabetes and diabetes on macular thickness and retinal vascular calibres in our population-based cohort (Northern Finland Birth Cohort).MethodsThe population...

Contrasting impact of rural, versus urban, living on glucose metabolism and blood pressure in Uganda

Background:The burden of cardiometabolic diseases, including cardiovascular diseases and diabetes, is increasing in sub-Saharan Africa and this has been linked to urbanisation. Helminths, through their immunomodulatory properties, may protect against these disorders. We hypothesised that the rural environment protects against cardiometabolic diseases and that helminths may influence rural-urban disparity of cardiometabolic disease risk. Methods:We compared metabolic parameters of individuals aged ≥10 years living in rural, high-helminth-transmission and urban, lower-helminth-transmission settings in Uganda. Cross-sectional surveys were conducted in rural Lake Victoria island fishing communities and in urban sub-wards in Entebbe municipality. Helminth infection and outcomes, including insulin resistance (computed using the homeostatic model assessment of insulin resistance [HOMA-IR]), fasting blood glucose, fasting blood lipids, blood pressure, body mass index (BMI), waist and hip circumference, were assessed. Results:We analysed 1,898 rural and 930 urban participants. Adjusting for BMI, exercise, smoking, alcohol intake, age and sex, urban residents had lower mean fasting glucose (adjusted mean difference [95%CI] 0.18 [-0.32, -0.05] p=0.01) and HOMA-IR (-0.26 [-0.40, -0.11] p=0.001) but higher blood pressure (systolic, 5.45 [3.75, 7.15] p<0.001; diastolic, 1.93 [0.57, 3.29] p=0.006). Current helminth infection did not explain the observed differences. Conclusions:In the Ugandan context, living in rural fishing communities may protect against hypertension but worsen glucose metabolism.

Contrasting impact of rural, versus urban, living on glucose metabolism and blood pressure in Uganda

Background: The burden of cardiometabolic diseases, including cardiovascular diseases and diabetes, is increasing in sub-Saharan Africa and this has been linked to urbanisation. Helminths, through their immunomodulatory properties, may protect against these disorders. We hypothesised that the rural environment protects against cardiometabolic diseases and that helminths may influence rural-urban disparity of cardiometabolic disease risk. Methods: We compared metabolic parameters of individuals aged ≥10 years living in rural, high-helminth-transmission and urban, lower-helminth-transmission settings in Uganda. Cross-sectional surveys were conducted in rural Lake Victoria island fishing communities and in urban sub-wards in Entebbe municipality. Helminth infection and outcomes, including insulin resistance (computed using the homeostatic model assessment of insulin resistance [HOMA-IR]), fasting blood glucose, fasting blood lipids, blood pressure, body mass index (BMI), waist and hip circumference, were assessed. Results: We analysed 1,898 rural and 930 urban participants. Adjusting for BMI, exercise, smoking, alcohol intake, age and sex, urban residents had lower mean fasting glucose (adjusted mean difference [95%CI] 0.18 [-0.32, -0.05] p=0.01) and HOMA-IR (-0.26 [-0.40, -0.11] p=0.001) but higher blood pressure (systolic, 5.45 [3.75, 7.15] p<0.001; diastolic, 1.93 [0.57, 3.29] p=0.006). Current helminth infection did not explain the observed differences. Conclusions: In the Ugandan context, living in rural fishing communities may protect against hypertension but worsen glucose metabolism.

HDL Triglycerides: A New Marker of Metabolic and Cardiovascular Risk.

While cholesterol content in high-density lipoproteins (HDLs) is a well-established inverse marker of cardiovascular risk, the importance of HDL–triglyceride (HDL-TG) concentration is not well known. We aim to examine plasma HDL-TG concentrations, assessed by 1H-NMR, in patients with metabolic diseases and their association with classical biomarkers. In this cross-sectional study, we included 502 patients with type 2 diabetes or metabolic syndrome attending the lipid unit of our University Hospital. The presence of arteriosclerotic plaques was assessed by ultrasonography. A complete lipoprotein profile was performed by 1H-NMR (Liposcale test). HDL-TG was strongly positively correlated with total triglycerides, glycerol, and fatty liver index, while a strong negative correlation was observed with HDL-cholesterol (HDL-C) and HDL-particle number (HDL-P). HDL-TG was associated with all triglyceride-rich lipoprotein parameters and had an opposite association with HDL-C and HDL-P. It was also significantly correlated with circulating cholesterol ester transfer protein (CETP). HDL-TG concentrations were higher as metabolic syndrome components increased. HDL-TG was also higher with worsening glucose metabolism. Patients with carotid plaques also showed higher HDL-TG. In contrast to HDL-C, HDL-TG is directly associated with metabolism and arteriosclerotic vascular alterations. HDL-TG should be considered a biomarker of metabolic and cardiovascular risk and could be a marker of HDL dysfunction.

Water intake keeps type 2 diabetes away? Focus on copeptin.

In both diabetic subjects and animal models high levels of vasopressin (AVP) have beendetected. The relationship between AVP and glucose metabolism is mediated through several direct andindirect effects and most of them are still unknown. We have reviewed 100 manuscripts retrieved from Cochrane Library, Embase and Pubmeddatabases in order to highlight a possible relationship between copeptin and type 2 diabetes and to provideinsights on the molecular mechanism that could explain this association. AVP potentiates CRH action at pituitary level resulting in an increased ACTH secretion and in turn in an increased cortisol secretion that escapes the negative feedback loop. Further, AVP regulates insulin and glucagon secretion through V1b receptor and promotes hepatic glycogenolysis and gluconeogenesis through V1a receptor. In addition to worsen glucose metabolism, AVP has been reported to have a role in the pathogenesis of diabetic complications such as cardiovascular diseases, kidney and ocular complications. Due to the very low concentration of AVP in the blood, the small size and poor stability, the assay of AVP is very difficult to perform. Thus, copeptin, the stable C-terminal portion of the prepro-vasopressin peptide has been identified as an easier assay to be measured and that mirrors AVP activity. Although there are promising evidence that copeptin could be involved in the pathogenesis of type 2 diabetes, further studies need to demonstrate the importance of copeptin as clinical marker to predict glucose metabolism derangements.

Consensus on the Statin of Choice in Patients with Impaired Glucose Metabolism: Results of the DIANA Study.

Introduction and ObjectivesDespite the recognized clinical benefit of statins on cardiovascular prevention, providing correct management of hypercholesterolaemia, possible adverse effects of their use cannot be disregarded. Previously published data shows that there is a risk of developing diabetes mellitus or experiencing changes in glucose metabolism in statin-treated patients. The possible determining factors are the drug characteristics (potency, dose), patient characteristics (kidney function, age, cardiovascular risk and polypharmacy because of multiple disorders) and the pre-diabetic state.MethodsIn order to ascertain the opinion of the experts (primary care physicians and other specialists with experience in the management of this type of patient) we conducted a Delphi study to evaluate the consensus rate on diverse aspects related to the diabetogenicity of different statins, and the factors that influence their choice.ResultsConsensus was highly significant concerning aspects such as the varying diabetogenicity profiles of different statins, as some of them do not significantly worsen glucose metabolism. There was an almost unanimous consensus that pitavastatin is the safest statin in this regard.ConclusionsFactors to consider in the choice of a statin regarding its diabetogenicity are the dose and patient-related factors: age, cardiovascular risk, diabetes risk and baseline metabolic parameters (which must be monitored during the treatment), as well as kidney function.

Jejunal administration of glucose enhances acyl ghrelin suppression in obese humans.

Ghrelin is a gastric hormone that stimulates hunger and worsens glucose metabolism. Circulating ghrelin is decreased after Roux-en-Y gastric bypass (RYGB) surgery; however, the mechanism(s) underlying this change is unknown. We tested the hypothesis that jejunal nutrient exposure plays a significant role in ghrelin suppression after RYGB. Feeding tubes were placed in the stomach or jejunum in 13 obese subjects to simulate pre-RYGB or post-RYGB glucose exposure to the gastrointestinal (GI) tract, respectively, without the confounding effects of caloric restriction, weight loss, and surgical stress. On separate study days, the plasma glucose curves obtained with either gastric or jejunal administration of glucose were replicated with intravenous (iv) infusions of glucose. These "isoglycemic clamps" enabled us to determine the contribution of the GI tract and postabsorptive plasma glucose to acyl ghrelin suppression. Plasma acyl ghrelin levels were suppressed to a greater degree with jejunal glucose administration compared with gastric glucose administration (P < 0.05). Jejunal administration of glucose also resulted in a greater suppression of acyl ghrelin than the corresponding isoglycemic glucose infusion (P ≤ 0.01). However, gastric and isoglycemic iv glucose infusions resulted in similar degrees of acyl ghrelin suppression (P > 0.05). Direct exposure of the proximal jejunum to glucose increases acyl ghrelin suppression independent of circulating glucose levels. The enhanced suppression of acyl ghrelin after RYGB may be due to a nutrient-initiated signal in the jejunum that regulates ghrelin secretion.

Factors influencing glucose metabolism in young obese subjects with obstructive sleep apnea hypopnea syndrome

To explore the factors influencing glucose metabolism in young obese subjects with obstructive sleep apnea hypopnea syndrome (OSAHS). A total of 106 young obese subjects[18-44 years old, body mass index (BMI) ≥30 kg/m(2)]were enrolled and divided into two groups based on full-night polysomnography (PSG), OSAHS group[apnea hypopnea index (AHI) ≥5 events/h]and non-OSAHS group (AHI<5 events/h). Oral glucose tolerance-insulin releasing test (OGTT-IRT) was performed and serum glycosylated hemoglobin A1 (HbA1c) levels were measured after an overnight fast. Homeostasis model assessment-IR (HOMA-IR), Matsuda insulin sensitivity index (MI), homeostasis model assessment-β (HOMA-β), the early phase insulinogenic index (ΔI(30)/ΔG(30)), total area under the curve of insulin in 180 minutes (AUC-I180) and oral disposition index (DIo) were calculated to evaluate insulin resistance and pancreatic β cell function. Stepwise multiple linear regressions were conducted to determine the independent linear correlation of glucose measurements with PSG parameters. Prevalence of diabetes was higher in OSAHS than in non-OSAHS group (22.0% vs 4.3%, P=0.009). OGTT 0, 30, 60 min glucose and HbA1c levels were higher in OSAHS group than those in non-OASHS group (all P<0.05). DIo were lower in OSAHS group than those in non-OASHS group (P=0.024), HOMA-IR, MI, HOMA-β, ΔI(30)/ΔG(30), and AUC-I(180) were similar between two groups (all P>0.05). In stepwise multiple linear regressions, OGTT 0, 30 and 60 min glucose were positively correlated with oxygen desaturation index (ODI) (β=0.243, 0.273 and 0.371 respectively, all P<0.05). HOMA-β was negatively correlated with AHI (β=-0.243, P=0.011). DIo was negatively correlated with ODI (β=-0.234, P=0.031). OSAHS worsens glucose metabolism and compensatory pancreatic β-cell function in young obese subjects, which could probably be attributed to sleep apnea related oxygen desaturation during sleep.

Alcohol modulates autophagy and apoptosis in pig liver tissue

BackgroundAutophagy serves as a cellular protective mechanism against alcohol-induced tissue injury but excessive autophagy can also be detrimental leading to apoptosis. Our laboratory has previously shown that moderate alcohol consumption alters expression of proteins in the insulin signaling pathway and worsens glucose metabolism in the liver in a swine model of metabolic syndrome. We examined the effect of alcohol consumption on apoptosis and autophagy signaling in the liver in our clinically relevant animal model of chronic hypercholesterolemia. Material and methodsTwenty-six Yorkshire swine were fed a high-fat diet for 4 wks and were then split into three groups: hypercholesterolemic diet alone (HCC, n = 9), hypercholesterolemic diet with vodka (hypercholesterolemic vodka [HCV], n = 9), and hypercholesterolemic diet with wine (hypercholesterolemic wine [HCW], n = 8) for 7 wks. Animals underwent euthanasia, and liver tissue samples were harvested for analysis. Liver tissue was analyzed via Western blot analysis. Protein density data were normalized to GAPDH and is reported as fold-change values ± standard error of the mean compared to the high-cholesterol diet control group. A Kruskal–Wallis test with a Dunn's multiple comparison test was used to compare the means among groups. ResultsThe HCV group showed significant increases in several proapoptotic proteins (including caspase 3, caspase 8, caspase 9, and cleaved caspase 9) compared with the HCC group. There was a decrease in the proapoptotic protein (BAD) and an increase in anti-apoptotic signal (B-cell lymphoma-2) in the HCW group compared with HCC control. There were increases in pro-survival proteins (AKT, p-AKT, mTOR, p-mTOR) in the HCW and the HCV group compared with control (HCC). There were decreases in autophagy protein LCB-3 in the HCW and HCV compared with the control. ConclusionsWe found that moderate alcohol consumption altered protein expression related to apoptosis and autophagy signaling in pig liver in the setting of hypercholesterolemia. Interestingly, vodka may induce proapoptotic pathways in liver tissue, whereas wine may induce anti-apoptotic signaling. These results provide a mechanism by which vodka may contribute to alcoholic liver disease and supports the notion that wine, containing resveratrol, may prevent cellular apoptosis in liver tissue in the setting of hypercholesterolemia.

15. Acyl Ghrelin Is a “Negative Incretin Hormone” Responsible for Improved Acute Glucose Responses following Roux-en-Y Gastric Bypass (RYGB) (161-OR)

Ghrelin stimulates appetite, promotes adiposity, and worsens glucose metabolism. Ghrelin levels vary according to both chronic and acute nutritional status, but the regulation of ghrelin secretion is not well understood. The primary site of production of ghrelin is the stomach; however, evidence suggests that there is post-gastric regulation of ghrelin secretion. A reduction in fasting and postprandial ghrelin levels is implicated in the efficacy of RYGB to produce metabolic improvements in the immediate postoperative period. In this study, we determined if the enhanced postprandial ghrelin suppression observed after RYGB could be attributed to more rapid intestinal nutrient stimulation. We studied 9, Class III obese, non-diabetic but insulin resistant subjects on two occasions, where we simulated pre- and post-RYGB nutrient delivery by administering a 50 g glucose load either to the stomach or to proximal jejunum, in random order. The next day, plasma glucose excursions for each was replicated with an isoglycemic IV glucose clamp. Gastric administration of glucose produced a ~35% suppression of ghrelin, which was equally matched by the isoglycemic clamp. Jejunal administration of glucose caused a ~65% suppression of plasma ghrelin, while in the concurrent isoglycemic clamp ghrelin was only suppressed ~35%, matching the suppression observed with gastric glucose. These data demonstrate that acyl ghrelin suppression with gastric glucose delivery is primarily due to the elevated post-absorptive glucose levels. However, the suppression seen with administration of a glucose load directly to the proximal jejunum is due to additional suppression of acyl ghrelin that is independent of circulating glucose levels. In conclusion, it appears that the postprandial ghrelin suppression observed after RYGB could be attributed to a ‘negative incretin response’ resulting from rapid intestinal nutrient stimulation.