Insulin Sensitivity Index Research Articles

Enterohepatic, Gluco-metabolic, and Gut Microbial Characterization of Individuals With Bile Acid Malabsorption.

Bile acid malabsorption (BAM) is a debilitating disease characterized by loose stools and high stool frequency. The pathophysiology of BAM is not well-understood. We investigated postprandial enterohepatic and gluco-metabolic physiology, as well as gut microbiome composition and fecal bile acid content in patients with BAM. Twelve participants with selenium-75 homocholic acid taurine test-verified BAM and 12 healthy controls, individually matched on sex, age, and body mass index, were included. Each participant underwent 2 mixed meal tests (with and without administration of the bile acid sequestrant colesevelam) with blood sampling and evaluation of gallbladder motility; bile acid content and microbiota composition were evaluated in fecal specimens. Patients with BAM were characterized by increased bile acid synthesis as assessed by circulating 7-alpha-hydroxy-4-cholesten-3-one, fecal bile acid content, and postprandial concentrations of glucose, insulin, C-peptide, and glucagon. The McAuley index of insulin sensitivity was lower in patients with BAM than that in healthy controls. In patients with BAM, colesevelam co-administered with the meal reduced postprandial concentrations of bile acids and fibroblast growth factor 19 and increased 7-alpha-hydroxy-4-cholesten-3-one concentrations but did not affect postprandial glucagon-like peptide 1 responses or other gluco-metabolic parameters. Patients with BAM were characterized by a gut microbiome with low relative abundance of bifidobacteria and high relative abundance of Blautia, Streptococcus, Ruminococcus gnavus, and Akkermansia muciniphila. Patients with BAM are characterized by an overproduction of bile acids, greater fecal bile acid content, and a gluco-metabolic profile indicative of a dysmetabolic prediabetic-like state, with changes in their gut microbiome composition potentially linking their enterohepatic pathophysiology and their dysmetabolic phenotype. ClinicalTrials.gov number NCT03009916.

Adiponectin resist in ratio beneficial index of insulin sensitivity in women with PCOS

Adiponectin resist in ratio beneficial index of insulin sensitivity in women with PCOS

Effects of oligosaccharides on the markers of glycemic control: a systematic review and meta-analysis of randomized controlled trials.

Objective: To investigate the effect of oligosaccharides on the markers of glycemic control, including fasting blood glucose (FBG), fasting blood insulin (FBI), glycated hemoglobin (HbA1c), homeostasis model assessment of insulin resistance (HOMA-IR), and quantitative insulin sensitivity index (QUICKI). Methods: PubMed, Embase, and the Cochrane Library databases were systematically searched to find randomized controlled trials (RCTs) on the effect of oligosaccharide intervention on FBG, FBI, HbA1c, HOMA-IR, and QUICKI up to 7 June 2021. Data were pooled using weighted mean difference (WMD) and 95% confidence intervals (95% CI), with a p-value ≤0.05 indicating statistical significance. Risk of bias was assessed with the Cochrane tool and the quality of the literature with the new Jadad scale. Results: A total of 46 randomized controlled trials were included. Oligosaccharides significantly reduced FBG (WMD: -0.295 mmol L-1; 95% CI: -0.396 to -0.193; p < 0.001; I2 = 90.9%; 46 trials; 2412 participants), FBI (WMD: -0.559 pmol L-1; 95% CI: -0.939 to -0.178; p < 0.01; I2 = 99.1%; 29 trials; 1462 participants), HbA1c (WMD: -0.365; 95% CI: -0.725 to -0.005; p < 0.05; I2 = 86.6%; 11 trials; 661 participants), and HOMA-IR (WMD: -0.793; 95% CI: -1.106 to -0.480; p < 0.001; I2 = 96.1%; 24 trials; 1382 participants). Oligosaccharides were more beneficial for the participants with obesity or diabetes than for healthy participants. Multiple interventions per day consolidated the effectiveness of oligosaccharides. Regardless of the processing manner (starch-modified or naturally extracted) of the oligosaccharides, their intervention was overall beneficial for the patients with diabetes. Conclusions: This study is by far the most extensive systematic review to evaluate the role of oligosaccharides on the markers of glycemic control. Oligosaccharide interventions can exert beneficial effects on FBG, FBI, HbA1c, and HOMA-IR.

Potential Therapeutic Activity of Mango (Mangifera indica L.) Leaves on Excess Consumption of Fructose in Rats

Background and Objective: High fructose consumption has increased worldwide. It causes various metabolic, genetic and histologic alterations. Alternative medicine, primarily herbal plants, has been proposed to alleviate the negative effects of high fructose consumption. The main objective of this study was to explore the efficacy of supplementation or treatment with mango leaves against high fructose induced alterations in male rats.&#x0D; Methodology: Mango leaves nutritional and active components were determined. A total of sixty male adult rats were used in this study. Fifteen rats were kept as healthy (negative control group; rats fed on balanced diet) while in others metabolic alterations were induced by consumption of high fructose diet ad libitum. Rats fed on high fructose diet were splited into 3 groups (15 rats in each), one group set as positive control group; rats fed on high fructose diet only and the other 2 groups; mango treated group; rats fed on high fructose diet until induction of hyperglycemia (one month and half) then fed on high fructose diet with replacement of fiber with 5% mango leaves and mango supplemented group; rats fed on high fructose diet with 5% mango leaves replacing fiber.&#x0D; Results: Mango leaves contain significant amounts of crude protein, crude fat, carbohydrates, crude fiber, ash, total flavonoids and polyphenols that controlled and corrected the following high fructose consumption results. Consumption of high fructose diet significantly (p≤0.05) increased final body weight (FBW), body weight gain (BWG), abdominal circumference (AC), Lee index and body mass index (BMI). High fructose also significantly (p≤0.05) increased levels of systolic blood pressure (SBP), serum triacylglycerol (TAG), total cholesterol (TC), fasting blood glucose, insulin, homeostasis model assessment-insulin resistance (HOMA-IR), serum tumor necrosis factor-α (TNF-α), leptin, malondialdehyde (MDA), advanced glycation end products (AGEs) and adipocyte size as well as blood histone deacetylase (HDAC) enzyme activity. High fructose consumption contrarily caused significant decrease (p≤0.05) in levels of quantitative insulin check index of insulin sensitivity (QUICKI), adiponectin, muscular insulin receptor substrate-1 (IRS-1) and glucose transporter-4 (GLUT-4) gene expression as well as blood reduced glutathione (GSH). Furthermore, microscopic examinations of the pancreatic and adipose tissues corroborated the biochemical findings.&#x0D; Conclusion: Mango leaves are a cheap source of macro and micronutrients as well as active constituents. By limiting metabolic and genetic abnormalities caused by high fructose consumption, either mango leaf supplementation or therapy improved and ameliorated all biochemical and microscopic data. The mango leaves supplemented group showed the most improvement.

Apolipoprotein D and transthyretin are reduced in female adolescent offspring of women with type 1 diabetes: The EPICOM study.

Adolescent offspring exposed to maternal diabetes during intrauterine life show a less favourable metabolic profile than the background population. Here, we hypothesize that offspring of women with type 1 diabetes (T1D), possess sex-specific alterations in the serum profile of proteins involved in lipid, metabolic and transport processes and that these alterations are associated with lipid profile and indices of insulin sensitivity and secretion. A prospective nationwide follow-up study (EPICOM) in a Danish population. Blood samples were assessed from offspring of women with T1D (index offspring, n=267, 13-20years), and matched control offspring (n=290). Serum proteins were analysed using a 25-plex cardio-metabolic targeted proteomics assay, which includes 12 apolipoproteins and 13 transport and inflammatory proteins. Apolipoprotein D (ApoD) and transthyretin (TTR) were reduced in index females as compared to female controls (-8.1%, p<0.001 and -6.1%, p=0.006 respectively), but not in index males (2.2%, p=0.476 and -2.4%, p=0.731 respectively). Sex-dependent inverse associations between exposure to maternal T1D in utero and ApoD and TTR were significant after adjusting for age, BMI-SDS and Tanner stage (OR=0.252 [95% CI 0.085, 0.745], p=0.013 and OR=0.149 [95% CI 0.040, 0.553], p=0.004). ApoD correlated to indices of insulin sensitivity and secretion in a similar sex-specific pattern in crude and adjusted analyses. Low ApoD may be regarded as an early risk marker of metabolic syndrome. A possible link between ApoD and cardiovascular disease needs further investigation.

Autonomic Nervous System Function in Newly Diagnosed Multiple Sclerosis: Association With Lipid Levels and Insulin Resistance.

Autonomic nervous system (ANS) disorders are common in multiple sclerosis (MS). Previous studies showed differences in insulin resistance (IR) and lipoprotein levels in MS subjects compared to controls. Lipolysis caused by increased sympathetic activity could be one of the possible linking mechanisms leading to dyslipidemia in MS. Our study aimed to evaluate ANS activity in the context of glucose and lipid metabolism in people with MS. We prospectively measured short-term heart rate variability (HRV), fasting lipoprotein concentrations, and calculated IR indices based on plasma glucose and insulin levels during oral glucose tolerance test (oGTT) in 32 patients with MS and 29 healthy controls matched for age, sex and body mass index in our study. There was no significant difference in HRV parameters and lipoprotein levels between MS and controls. A significant positive correlation was found between low/high-frequency power ratio (LF/HF) and triglycerides (r=0.413, p=0.021) in MS subjects but not in controls. A significantly lower whole-body insulin sensitivity index (ISIMat) was found in patients with MS compared to the control group (7.3±3.7 vs. 9.8±5.6, p=0.041). No significant correlations were found between LF/HF and IR parameters. In MS subjects, the positive correlation of LF/HF with triglycerides could reflect the effects of sympathetic activity on lipolysis. Positive correlations of sympathetic activity with increased lipoprotein levels could rather reflect processes associated with immune system activation/inflammation, than processes involved in glucose homeostasis maintenance.

Correlation between total testosterone levels and insulin resistance in patients with acanthosis nigricans and non-acanthosis nigrican

To investigate the correlation of the total testosterone (TT) level with insulin secretion and resistance in patients with acanthosis nigricans (AN) and non-acanthosis nigricans (NAN). This study was conducted in a total of 639 overweight patients (body mass index ≥24 kg/m2), including 137 female AN patients, 277 female NAN patients, 129 male AN patients, and 146 male NAN patients. Each group was further divided into 4 subgroups according to the quartile of TT level for comparison of insulin secretion and insulin resistance parameters. Both female and male patients with AN showed obvious hyperinsulinemia with increased area under the curve for insulin (AUC-INS) (P < 0.05), increased homeostatic model assessment of insulin resistance (HOMA-IR) index (P < 0.05) and decreased whole-body insulin sensitivity index (WBISI) (P < 0.01) as compared with those in NAN groups, but these parameters did not show significant variations with the change of TT levels. In female patients with NAN, insulin secretion level increased progressively as the TT level increased; the AUC-INS increased (P < 0.01) and WBISI decreased significantly (P < 0.05) when the TT levels increased to Q4. In male patients with NAN, insulin secretion level increased progressively as the TT levels decreased, and the AUC-INS increased (P < 0.05) and the WBISI decreased significantly (P < 0.05) when the TT levels decreased to Q1. The TT level has a significant effect on insulin resistance and insulin secretion, but its effect varies between genders and is more significant in NAN patients than in AN patients.

Obesity complicated with insulin resistance treated with the electroacupuncture at the combination of back-shu and front-mu points电针俞募配穴治疗胕胖合并胰岛素抵抗的临床观察

ObjectiveTo observe the influences of electroacupuncture at the combination of back-shu and front-mu points on insulin sensitivity indicators and somatological parameter indicators in the patients with obesity complicated with insulin resistance. MethodsA total of 60 patients with obesity and insulin resistance were randomized into a control group (30 cases, 4 cases of them dropped out) and a trial group (30 cases, 2 cases of them dropped out). In the control group, the intervention with diet and exercise were provided. In the trial group, on the base of the treatment as the control group, electroacupuncture was added at the combination of back-shu points and front-mu points, 3 times weekly. The duration of treatment was 12 weeks in two groups. The therapeutic effect and the somatological parameter indicators (body mass [BW], body mass index [BMI], waist circumference [WC], waist-to-hip ratio [WHR]) as well as the insulin sensitivity indicators (fasting plasma glucose [FPG], fasting insulin [FIN], insulin sensitivity index [ISI] and insulin resistance index [HOMA-IR]) before and after treatment were compared between two groups. Results① The effective rate was 92.86% in the trial group and was 57.69% in the control group. The effective rate of the trial group was higher than the control group, indicating the statistical difference (P < 0.01). ② BW, BMI, WC and WHR after treatment were all reduced obviously as compared with before treatment in two groups (all P < 0.01). After treatment, BMI, WC and WHR in the trial group were all lower than those in the control group (all P < 0.05) and the differences in BW, BMI, WC and WHR before and after treatment in the trial group were larger than those in the control group (all P < 0.01). ③ After treatment, FIN and HOMA-IR were all lower significantly than those before treatment in two group and ISI was increased significantly as compared with before treatment (all P < 0.01). After treatment, FPG was reduced significantly as compared with before treatment in the trial group (P < 0.01) and the difference in FPG was not significant statistically in the control group (P > 0.05). After treatment, FPG and HOMA-IR in the trial group were lower than the control group and ISI was higher than the control group (all P < 0.05). Besides, the differences in FPG, FIN, ISI and HOMA-IR before and after treatment in the trial group were larger significantly than those in the control group (P < 0.01, P < 0.05). ConclusionElectroacupuncture at the combination of back-shu and front-mu points in association with the intervention with diet and exercise is effective on obesity complicated with insulin resistance. The effects of this combined therapy are superior as compared with simple intervention with diet and exercise in body mass, body mass index, waist circumference and waist-to-lip ratio as well as fasting blood glucose, fasting insulin, insulin sensitivity index and insulin resistance index in patients.

Pancreatic and gut hormone responses to mixed meal test in post-chronic pancreatitis diabetes mellitus

ObjectiveMore than one-third of chronic pancreatitis patients will eventually develop diabetes, recently classified as post-chronic pancreatitis diabetes mellitus (PPDM-C). This study was aimed to investigate the pancreatic and gut hormone responses to a mixed meal test in PPDM-C patients, compared with non-diabetic chronic pancreatitis (CP), and type 2 diabetes patients or healthy controls. Design and methodsSixteen patients with PPDM-C, 12 with non-diabetic CP as well as 10 with type 2 diabetes and healthy controls were recruited. All participants underwent mixed meal tests, and blood samples were collected for measurements of blood glucose, C-peptide, insulin, glucagon, pancreatic polypeptide (PP), ghrelin, peptide YY, glucagon like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP). Indices of insulin sensitivity and secretion were calculated. Repeated measures analysis of variance was performed. ResultsParticipants with PPDM-C exhibited decreases in both fasting and postprandial responses of C-peptide (P < 0.001), insulin (P < 0.001), ghrelin (P < 0.001) and PYY (P = 0.006) compared to participants with type 2 diabetes and healthy controls. Patients with CP showed blunted glucagon, PP and incretin reactions, while the responses were increased in patients with PPDM-C compared to controls. The level of insulin sensitivity was higher for PPDM-C than type 2 diabetes (P < 0.01), however the indices for early/late-phase and overall insulin secretion (P < 0.01) were lower. ConclusionsPatients with PPDM-C are characterized by decreased C-peptide, insulin, ghrelin and PYY responses, and similar levels of glucagon, PP, GIP and GLP-1 compared to those with type 2 diabetes. The above findings, when confirmed in a larger population, may prove helpful to establish the diagnosis of PPDM-C, and should promote study on underlying pathophysiological mechanisms.

Effects of Weight Loss on Adipose and Muscular Neuropilin 1 mRNA Expression in Obesity: Potential Implication in SARS-CoV-2 Infections?

Introduction: Neuropilin 1 (NRP-1) is a novel co-receptor promoting SARS-CoV-2 infectivity. Animal data indicate a role in trans-endothelial lipid transport and storage. As human data are sparse, we aimed to assess the role of NRP-1 in 2 metabolic active tissues in human obesity and in the context of weight loss-induced short- and long-term metabolic changes. Methods: After a standardized 12-week weight reduction program, 143 subjects (age >18; body mass index ≥27 kg/m², 78% female) were randomized to a 12-month lifestyle intervention or a control group using a stratified randomization scheme. This was followed by 6-month follow-up without any intervention. Phenotyping was performed before and after weight loss, after 12-month intervention and after subsequent 6 months of follow-up. Tissue-specific insulin sensitivity was estimated by HOMA-IR (whole body and mostly driven by liver), insulin sensitivity index (ISI)_Clamp (predominantly skeletal muscle), and free fatty acid (FFA) suppression during hyperinsulinemic-euglycemic clamp (FFA_Supp) (predominantly adipose tissue). NRP-1 mRNA expression was measured in subcutaneous adipose tissue (NRP-1_AT) and skeletal muscle (NRP-1_SM) before and after weight loss. Results: NRP-1 was highly expressed in adipose tissue (7,893 [7,303–8,536] counts), but neither NRP-1_AT nor NRP-1_SM were related to estimates of obesity. Higher NRP-1_AT was associated with stronger FFA_Supp (r = −0.343, p = 0.003) and a tendency to higher ISI_Clamp (r = 0.202, p = 0.085). Weight loss induced a decline of NRP-1_AT but not NRP-1_SM. This was more pronounced in subjects with stronger reduction of adipose ACE-2 mRNA expression (r = 0.250; p = 0.032) but was not associated with short- and long-term improvement of FFA_Supp and ISI_Clamp. Conclusion: NRP-1_AT is related to adipose insulin sensitivity in obesity. Weight loss-induced decline of NRP-1_AT seems not to be involved in metabolic short- and long-term improvements after weight loss. However, weight loss-induced reduction of both NRP-1_AT and ACE-2_AT indicates a lower susceptibility of adipose tissue for SARS-CoV-2 after body weight reduction.

In vivo therapeutic exploring for Mori folium extract against type 2 diabetes mellitus in rats.

Background: The study was aimed to investigate the potential therapeutic effect of Mori folium aqueous extracts (MFAE) on type 2 diabetes mellitus (T2DM) in vivo.Methods and results: A rat model of T2DM was established with the combination of high sugar and high-fat diet (HSFD) and streptozotocin (STZ). The T2DM rats were administrated with low (2 g.kg−1) and high (5 g.kg−1) doses of MFAE for 60 consecutive days. The biochemical indices of glucose metabolism disorders, insulin resistance and oxidative stress were observed. The results indicated that MFAE significantly promoted the synthesis of hepatic glycogen, reduced the levels of fasting blood glucose and fasting blood insulin, and improved the insulin sensitivity index (ISI). MFAE administration also remarkably increased the levels of superoxide dismutase (SOD) and reduced the levels of malondialdehyde (MDA).Conclusion: MFAE showed a therapeutic effect on T2DM with the bioative effect of improve glucose metabolism disorders, decrease insulin resistance, and ameliorate the antioxidative ability.

Comparison of Carotid Intima-Media Thickness in Children and Adults With and Without Obesity: A Hysteresis Model

ObjectiveTo describe a third-degree polynomial function (hysteresis) of the effect size of age, obesity, and insulin sensitivity over the carotid intima-media thickness (c-IMT), in the pediatric and adult groups. MethodsA quasi-experimental study with fixed factor analysis of age (children aged 8-12 years, n = 73; adults aged 21-45 years, n = 82) and obesity (yes, n = 76; no, n = 79) was conducted to analyze the effect on the c-IMT and Matsuda insulin sensitivity index values. This quasi-experimental design was analyzed with robust regression modeling. ResultsThe additive effect of obesity, independent of age, was evident in the case of the c-IMT values. There was no interaction effect, but a significant difference between participants with normal weight and those with obesity was found (P < .0001). The difference between adults and children was also significant, but the effect size was smaller. A model was created based on age, Tanner stage, and obesity using the c-IMT and Matsuda insulin sensitivity index values. A linear function fit as R2, and the cubic function estimated parameters like a polynomial model. ConclusionThis practical study design showed that children with obesity displayed the same levels of carotid intima-media abnormalities as adults with obesity. The polynomial shape of the model suggests potentially poor outcomes that resemble the hysteresis process and may predict chronic cardiometabolic events during early adulthood.

The Beta-Cell Function and Glucose Profile of Newly Diagnosed Acromegalic Patients with Normal Glucose Tolerance.

Objectives Untreated acromegaly is a nature model for unveiling the diabetogenic effects of GH. CGMS can uncover more glucose profile of acromegaly. This study aimed to evaluate the insulin resistance (IR), β-cell function, and glycemic spectrum of patients with newly diagnosed acromegaly with normal glucose tolerance (NGT). Methods This study was conducted in Huashan Hospital from January 2015 to February 2019. Eight newly diagnosed acromegalic patients without history of diabetes and eight age- and gender-matched healthy subjects were enrolled. All participants underwent oral glucose tolerance test (OGTT) and 72 h continuous glucose monitoring (CGM). Parameters on β-cell function and IR were calculated. Mean blood glucose (MBG) in 24 hours was adopted for the evaluation of the glycemic level, and standard deviation of blood glucose (SDBG) and mean amplitude of glycemic excursion (MAGE) were used for glucose fluctuation. Results HbA1c in the acromegaly group was significantly higher than in the control. During OGTT, glucose peaked at 60 min in acromegaly and at 30 min in controls. After glucose load, the acromegaly group had significantly higher insulin levels than controls, especially in 120 min and 180 min. Both insulin sensitivity index and disposal index after glucose load of acromegaly were significantly lower than those of controls. Moreover, acromegalic subjects had significantly higher MBG than controls. Conclusions The newly diagnosed acromegalic patients with NGT were characterized by IR and impaired β-cell function after glucose load. CGM showed that MBG of NGT acromegaly patients was higher than that of normal people.

The Beneficial Effects of Astaxanthin on Glucose Metabolism and Modified Low-Density Lipoprotein in Healthy Volunteers and Subjects with Prediabetes.

Astaxanthin (ASTX) is an antioxidant agent. Recently, its use has been focused on the prevention of diabetes and atherosclerosis. We examined the effects of astaxanthin supplementation for 12 weeks on glucose metabolism, glycemic control, insulin sensitivity, lipid profiles and anthropometric indices in healthy volunteers including subjects with prediabetes with a randomized, placebo-controlled trial. Methods: We enrolled 53 subjects who met our inclusion criteria and administered them with 12 mg astaxanthin or a placebo once daily for 12 weeks. Subsequently, their HbA1c levels, lipid profiles and biochemical parameters were determined. The participants also underwent a 75 g oral glucose tolerance test (OGTT), vascular endothelial function test and measurement of the visceral fat area. Results: After astaxanthin supplementation for 12 weeks, glucose levels after 120 min in a 75 g OGTT significantly decreased compared to those before supplementation. Furthermore, the levels of HbA1c (5.64 ± 0.33 vs. 5.57 ± 0.39%, p < 0.05), apo E (4.43 ± 1.29 vs. 4.13 ± 1.24 mg/dL, p < 0.05) and malondialdehyde-modified low-density lipoprotein (87.3 ± 28.6 vs. 76.3 ± 24.6 U/L, p < 0.05) were also reduced, whereas total cholesterol (TC), triglyceride (TG) and high-density lipoprotein-C (HDL-C) levels were unaltered. The Matuda index, which is one of the parameters of insulin resistance, was improved in the ASTX group compared to that before supplementation. Conclusions: our results suggest that ASTX may have preventive effects against diabetes and atherosclerosis and may be a novel complementary treatment option for the prevention of diabetes in healthy volunteers, including subjects with prediabetes, without adverse effects.

The choice of the insulin basal rate regimen at initiation of insulin pump therapy in routine clinical practice

Background: Numbers of patients with diabetes mellitus using insulin pumps have been increasing every year. Successful achievement of glycemic targets with continuous subcutaneous insulin infusion (CSII) is based on an adequate basal rate of infusion, carbohydrate coefficient and insulin sensitivity index. There are two approaches to basal insulin infusion rate, namely the flat one and the circadian; however, at present there is no convincing data on which one should be chosen at the start of insulin pump therapy.Aim: To compare two regimens of basal insulin infusion rate at initiation of insulin pump therapy in routine clinical practice.Materials and methods: We analyzed data from 120 patients with Type 1 diabetes mellitus, who were switched on insulin pump therapy in the Department of Endocrinology from 2017 to 2018. At initiation of CSII, 60 patients used the flat basal rate profile and the other 60 patients used the circadian basal rate, calculated with the Renner's scale. Safety of the two basal rate regimens was assessed based on glucose variability measured with continuous glucose monitoring during the first two days after the start of insulin pump therapy.Results: Mean (± SD) coefficients of variation in the groups with circadian and flat basal rate at Day 1 were 31.06±12.13 and 32.74±10.7, respectively (p=0.423); at Day 2, 26.78±11.27 and 28.83±10.7 (p=0.309). Median [Q1; Q3] areas under glucose curve (AUC) values above the glucose targets in the groups with circadian and flat basal rate at Day 1 were 0.37 [0.03; 0.89] and 0.48 [0.08; 1.75], respectively, at Day 2 0.44 [0.03; 1.57] and 0.31 [0.1; 1.5], respectively (p&gt;0.05). Median glucose AUC values below the goal in groups with circadian basal rate and flat basal rate on the first day were 0.01 [0; 0.06] and 0.02 [0; 0.1], respectively (p=0.855), on the second day – 0.00 [0; 0.01] and 0.00 [0; 0.02], respectively (р=0.085). We also haven’t found any between-group differences in the prevalence of glucose deviations below and above the target, as well as in the time spent in normoglycaemia.Conclusion: The comparative analysis of two basal insulin rate regimens in Type 1 diabetic patients switched to insulin pump therapy has shown no significant differences between them. The use of Renner’s scale has no clinical advantages over the fixed basal insulin regimen at initiation of insulin pump therapy in adults.

Genomics and transcriptomics landscapes associated to changes in insulin sensitivity in response to endurance exercise training

Despite good adherence to supervised endurance exercise training (EET), some individuals experience no or little improvement in peripheral insulin sensitivity. The genetic and molecular mechanisms underlying this phenomenon are currently not understood. By investigating genome-wide variants associated with baseline and exercise-induced changes (∆) in insulin sensitivity index (Si) in healthy volunteers, we have identified novel candidate genes whose mouse knockouts phenotypes were consistent with a causative effect on Si. An integrative analysis of functional genomic and transcriptomic profiles suggests genetic variants have an aggregate effect on baseline Si and ∆Si, focused around cholinergic signalling, including downstream calcium and chemokine signalling. The identification of calcium regulated MEF2A transcription factor as the most statistically significant candidate driving the transcriptional signature associated to ∆Si further strengthens the relevance of calcium signalling in EET mediated Si response.

Selective targeting of angiopoietin-like 3 (ANGPTL3) with vupanorsen for the treatment of patients with familial partial lipodystrophy (FPLD): results of a proof-of-concept study

BackgroundFamilial partial lipodystrophy (FPLD) is a rare disease characterized by selective loss of peripheral subcutaneous fat, associated with dyslipidemia and diabetes mellitus. Reductions in circulating levels of ANGPTL3 are associated with lower triglyceride and other atherogenic lipids, making it an attractive target for treatment of FPLD patients. This proof-of-concept study was conducted to assess the efficacy and safety of targeting ANGPTL3 with vupanorsen in patients with FPLD.MethodsThis was an open-label study. Four patients with FPLD (two with pathogenic variants in LMNA gene, and two with no causative genetic variant), diabetes (HbA1c ≥ 7.0 % and ≤ 12 %), hypertriglyceridemia (≥ 500 mg/dL), and hepatic steatosis (hepatic fat fraction, HFF ≥ 6.4 %) were included. Patients received vupanorsen subcutaneously at a dose of 20 mg weekly for 26 weeks. The primary endpoint was the percent change from baseline in fasting triglycerides at Week 27. Other endpoints analyzed at the same time point included changes in ANGPTL3, fasting lipids and lipoproteins, insulin secretion/sensitivity, postprandial lipids, and glycemic changes in response to a mixed meal test, HFF measured by MRI, and body composition measured by dual-energy absorptiometry (DEXA).ResultsBaseline mean ± SD fasting triglyceride level was 9.24 ± 4.9 mmol/L (817.8 ± 431.9 mg/dL). Treatment resulted in reduction in fasting levels of triglycerides by 59.9 %, ANGPTL3 by 54.7 %, and in several other lipoproteins/lipids, including very low-density lipoprotein cholesterol by 53.5 %, non-high-density lipoprotein cholesterol by 20.9 %, and free fatty acids (FFA) by 41.7 %. The area under the curve for postprandial triglycerides, FFA, and glucose was reduced by 60 %, 32 %, and 14 %, respectively. Treatment with vupanorsen also resulted in 55 % reduction in adipose tissue insulin resistance index, while other insulin sensitivity indices and HbA1c levels were not changed. Additional investigations into HFF and DEXA parameters suggested dynamic changes in fat partitioning during treatment. Adverse events observed were related to common serious complications associated with diabetes and FPLD. Vupanorsen was well tolerated, and there was no effect on platelet count.ConclusionsAlthough limited, these results suggest that targeting ANGPTL3 with vupanorsen could address several metabolic abnormalities in patients with FPLD.

Pharmacodynamic effects of direct AMP kinase activation in humans with insulin resistance and non-alcoholic fatty liver disease: A phase 1b study

SummaryAMPK is an energy sensor modulating metabolism, inflammation, and a target for metabolic disorders. Metabolic dysfunction results in lower AMPK activity. PXL770 is a direct AMPK activator, inhibiting de novo lipogenesis (DNL) and producing efficacy in preclinical models. We aimed to assess pharmacokinetics, safety, and pharmacodynamics of PXL770 in humans with metabolic syndrome-associated fatty liver disease. In a randomized, double-blind four-week trial, 12 overweight/obese patients with non-alcoholic fatty liver disease (NAFLD) and insulin resistance received PXL770 500 mg QD; 4 subjects received matching placebo. Endpoints included pharmacokinetics, hepatic fractional DNL, oral glucose tolerance testing, additional pharmacodynamic parameters, and safety. PK parameters show adequate plasma exposure in NAFLD patients for daily oral dosing. PXL770 decreases DNL—both peak and AUC are reduced versus baseline—and improves glycemic parameters and indices of insulin sensitivity versus baseline. Assessment of specific lipids reveals decrease in diacyglycerols/triacylglycerols. Safety/tolerability are similar to placebo. These results unveil initial human translation of AMPK activation and support this therapeutic strategy for metabolic disorders.

Progranulin and chemerin plasma level in obese patients with type 2 diabetes treated with a long-acting insulin analogue and premixed insulin analogue.

Diabetes, referred to as the first non-infectious epidemic, covers a heterogenous group of metabolic diseases marked by hyperglycemia resulting from a defect of insulin secretion and/or insulin resistance. Highly endocrine active adipocytes, particularly those located in white adipose tissue, constitute a source of cytokines, growth factors and complement component as well as adipocytokines including chemerin and progranulin could be the key molecules in the pathomechanism of hypertension, dyslipidemia, metabolic disorders or diabetes type 2. In this study, it was decided to verify the existence of possible relationships between the plasma concentration of progranulin and chemerin and the values of intermediate indices of insulin sensitivity and insulin resistance in patients, both before and after the 6-month insulin therapy by long-acting insulin analogue and premixed insulin analogue. The level of laboratory parameters in blood plasma collected from the control group and from obese individuals with type 2 diabetes mellitus was estimated with the test kits using enzyme-linked immunosorbent assay (ELISA): the test of Mediagnost E103 GmbH GmbH, Reutlingen, Germany for progranulin; the test of BioVendor R&D, Brno, Czech Republic for chemerin. The aim of this study was to assess the progranulin and chemerin plasma level in obese individuals with type 2 diabetes, before and after 6 months of pharmacological treatment with a long-acting analogue human insulin or premixed insulin. In the blood plasma of untreated diabetics - in contrary to progranulin plasma concentration in diabetic patients after management implementation - progranulin was found to occur in a significantly higher concentration in relation to the level of this protein in the blood plasma of control group individuals. Despite the fact that 6-month therapy, both with the insulin mixture and with the long-acting analogue in people with diabetes, does not significantly affect the plasma chemerin concentration, the high, negative correlation between the progranulin and chemerin levels in the blood of individuals of the control group, and a positive one between the levels of progranulin and chemerin in people with diabetes before and after treatment was found. The conducted studies indicated the modified, in the course of diabetes type 2, mutual quantitative relations between progranulin and chemerin - the biological mediators of systemic metabolism, reflecting their active participation in the pathogenetic changes underlying type 2 diabetes. The obtained study results indicate a modification of mutual relationships of the adipocytokines assessed in the paper - progranulin and chemerin, associated with the development of the systemic inflammatory response occurring in the course of obesity which, by inducing insulin resistance, may consequently lead to type 2 diabetes. Taking into consideration the fact that the plasma progranulin and chemerin concentrations in obese patients with type 2 diabetes subjected to pharmacotherapy have not been assessed so far, it is possible that the obtained study results may cast light on the potential influence of the applied treatment on the systemic changes of the both adipocytokines involved in the pathomechanism of the mentioned disorder and thus create the possibility of implementing new therapeutic strategies in the management of patients with diabetes, which is an increasingly common, fast-spreading metabolic disease considered as a non-infectious epidemic of the 21st century.

Effects of Mixed of a Ketogenic Diet in Overweight and Obese Women with Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is a commonly occurring endocrine disorder characterized by hirsutism, anovulation, and polycystic ovaries. Often comorbid with insulin resistance, dyslipidemia, and obesity, it also carries significant risk for the development of cardiovascular and metabolic sequelae, including diabetes and metabolic syndrome. The relationship between central obesity and the development of insulin resistance is widely verified. Adipose tissue excess and the coexistent dysregulation of adipocyte functions directly contribute to the pathogenesis of the metabolic complications observed in women with PCOS. In the light of these evidence, the most therapeutic option prescribed to obese women with PCOS, regardless of the phenotype e from the severity of clinical expression, is lifestyle correction by diet and physical activity. The aim of this study is to evaluate the beneficial effects of ketogenic diet in 17 obese women with PCOS. Our results showed that the ketogenic diet inducing therapeutic ketosis, improves the anthropometric and many biochemical parameters such as LH, FSH, SHBG, insulin sensitivity and HOMA index. In addition, it induces a reduction in androgenic production, whereas the contextual reduction of fat mass reduced the acyclic production of estrogens deriving from the aromatization in the adipose tissue of the androgenic excess, with an improvement of the LH/FSH ratio. This is the first study on the effects of the ketogenic diet on PCOS, however, further studies are needed to elucidate the mechanism underlying ketogenic diet effects.