Marie-Christine Simon

Intake of Lactobacillus reuteri Improves Incretin and Insulin Secretion in Glucose Tolerant Humans: A Proof of Concept

OBJECTIVE Ingestion of probiotics can modify gut microbiota and alter insulin resistance and diabetes development in rodents. We hypothesized that daily intake of Lactobacillus reuteri increases insulin sensitivity by changing cytokine release and insulin secretion via modulation of the release of glucagon-like peptides (GLP)-1 and -2. RESEARCH DESIGN AND METHODS A prospective, double-blind, randomized trial was performed in 21 glucose-tolerant humans (11 lean: age 49 ± 7 years, BMI 23.6 ± 1.7 kg/m2; 10 obese: age 51 ± 7 years, BMI 35.5 ± 4.9 kg/m2). Participants ingested 1010 b.i.d. L. reuteri SD5865 or placebo over 4 weeks. Oral glucose tolerance and isoglycemic glucose infusion tests were used to assess incretin effect and GLP-1 and GLP-2 secretion, and euglycemic-hyperinsulinemic clamps with [6,6-2H2]glucose were used to measure peripheral insulin sensitivity and endogenous glucose production. Muscle and hepatic lipid contents were assessed by 1H-magnetic resonance spectroscopy, and immune status, cytokines, and endotoxin were measured with specific assays. RESULTS In glucose-tolerant volunteers, daily administration of L. reuteri SD5865 increased glucose-stimulated GLP-1 and GLP-2 release by 76% (P < 0.01) and 43% (P < 0.01), respectively, compared with placebo, along with 49% higher insulin (P < 0.05) and 55% higher C-peptide secretion (P < 0.05). However, the intervention did not alter peripheral and hepatic insulin sensitivity, body mass, ectopic fat content, or circulating cytokines. CONCLUSIONS Enrichment of gut microbiota with L. reuteri increases insulin secretion, possibly due to augmented incretin release, but does not directly affect insulin sensitivity or body fat distribution. This suggests that oral ingestion of one specific strain may serve as a novel therapeutic approach to improve glucose-dependent insulin release.

Improved Preservation of Residual Beta Cell Function by Atorvastatin in Patients with Recent Onset Type 1 Diabetes and High CRP Levels (DIATOR Trial)

Background A recent randomized placebo-controlled trial of the effect of atorvastatin treatment on the progression of newly diagnosed type 1 diabetes suggested a slower decline of residual beta cell function with statin treatment. Aim of this secondary analysis was to identify patient subgroups which differ in the decline of beta cell function during treatment with atorvastatin. Methodology/Principal Findings The randomized placebo-controlled Diabetes and Atorvastatin (DIATOR) Trial included 89 patients with newly diagnosed type 1 diabetes and detectable islet autoantibodies (mean age 30 years, 40% females), in 12 centers in Germany. Patients received placebo or 80 mg/d atorvastatin for 18 months. As primary outcome stimulated serum C-peptide levels were determined 90 min after a standardized liquid mixed meal. For this secondary analysis patients were stratified by single baseline characteristics which were considered to possibly be modified by atorvastatin treatment. Subgroups defined by age, sex or by baseline metabolic parameters like body mass index (BMI), total serum cholesterol or fasting C-peptide did not differ in C-peptide outcome after atorvastatin treatment. However, the subgroup defined by high (above median) baseline C-reactive protein (CRP) concentrations exhibited higher stimulated C-peptide secretion after statin treatment (pu200a=u200a0.044). Individual baseline CRP levels correlated with C-peptide outcome in the statin group (r2u200a=u200a0.3079, p<0.004). The subgroup with baseline CRP concentrations above median differed from the corresponding subgroup with lower CRP levels by higher median values of BMI, IL-6, IL-1RA, sICAM-1 and E-selectin. Conclusions/Significance Atorvastatin treatment may be effective in slowing the decline of beta cell function in a patient subgroup defined by above median levels of CRP and other inflammation associated immune mediators. Trial Registration ClinicalTrials.gov NCT00974740

Leukocyte Profiles Differ Between Type 1 and Type 2 Diabetes and Are Associated With Metabolic Phenotypes: Results From the German Diabetes Study (GDS)

OBJECTIVE Altered immune reactivity precedes and accompanies type 1 and type 2 diabetes. We hypothesized that the metabolic phenotype relates to the systemic cellular immune status. RESEARCH DESIGN AND METHODS A total of 194 metabolically well-controlled patients with type 1 diabetes (n = 62, mean diabetes duration 1.29 years) or type 2 diabetes (n = 132, 1.98 years) and 60 normoglycemic persons underwent blood sampling for automated white blood cell counting (WBC) and flow cytometry. Whole-body insulin sensitivity was measured with hyperinsulinemic-euglycemic clamp tests. RESULTS Patients with type 2 diabetes had higher WBC counts than control subjects along with a higher percentage of T cells and activated T helper (Th) and cytotoxic T (Tc) cells but lower proportions of natural killer (NK) cells. In type 1 diabetes, the percentage of activated Th and Tc cells was also higher compared with control subjects, whereas the ratio of regulatory T (Treg) cells to activated Th cells was lower, suggesting diminished regulatory capacity. Parameters of glycemic control related positively to Treg cells only in type 2 diabetes. Upon age, sex, and body mass adjustments, insulin sensitivity correlated positively with monocytes, while circulating lipids correlated positively with T cell subsets in type 1 diabetes. CONCLUSIONS Immune cell phenotypes showed distinct frequencies of occurrence in both diabetes types and associate with insulin sensitivity, glycemia, and lipidemia.

Cellular interferon-γ and interleukin-13 immune reactivity in type 1, type 2 and latent autoimmune diabetes: Action LADA 6

OBJECTIVEnType 1 diabetes and latent autoimmune diabetes in adults (LADA) are thought to result from immune-mediated β-cell destruction. It remains unclear why LADA is clinically less severe compared to type 1 diabetes. This study aimed to compare the pro-inflammatory (interferon-γ, IFN-γ) and anti-inflammatory (interleukin-13, IL-13) T-cell responses in humans with LADA and type 1 diabetes.nnnRESEARCH DESIGN AND METHODSnIFN-γ and IL-13 T-cell responses to a panel of 16 (auto)-antigens were tested using an enzyme linked immune-spot technique and peripheral T-cells from 35 patients with type 1 diabetes, 59 patients with type 2 diabetes, 23 LADA patients, and 42 control subjects.nnnRESULTSnLADA and type 1 diabetes patients did not display any statistically significant differences in the frequency of IFN-γ or IL-13 responses to auto-antigenic stimuli, positive control or mitogen. Overall very low T cell reactivity to autoantigens was detected in all groups. IL-13 responses but not IFN-γ responses to recall antigen tetanus toxoid were higher in healthy control subjects compared to patients with type 1 or type 2 diabetes or LADA (P<0.05). Diabetes, independent of type, was associated with weaker response to recall antigen tetanus toxoid.nnnCONCLUSIONSnLADA patients are indistinguishable from type 1 diabetes patients for cellular IFN-γ and IL-13 responses upon mitogen and recall antigen stimulation. These results extend previous findings showing that systemic cytokine/chemokine and humoral responses in type 1 diabetes and LADA are similar.

Fatty acids modulate cytokine and chemokine secretion of stimulated human whole blood cultures in diabetes.

Fatty acids, uric acid and glucose are thought to contribute to subclinical inflammation associated with diabetes mellitus. We tested whether co‐incubation of free fatty acids and uric acid or glucose influences the secretion of immune mediators from stimulated human whole blood in vitro. Fresh whole blood samples from 20 healthy subjects, 20 patients with type 1 diabetes and 23 patients with type 2 diabetes were incubated for 24u2009h with palmitic acid (PAL), linolenic acid (LIN) or eicosapentaenoic acid (EPA) alone or together with elevated concentrations of uric acid or glucose. Concentrations of proinflammatory cytokines interleukin (IL)‐1β, IL‐2, IL‐12(p70), IL‐18, IFN‐γ, of regulatory cytokines IL‐4, IL‐10, IL‐17 and chemokine CCL2 (MCP‐1) were measured by multiplex‐bead technology from supernatants. Co‐incubation of fatty acids with uric acid resulted in a significant reduction of IL‐10, IL‐12(p70), IFN‐γ and CCL2 (MCP‐1) concentrations in supernatants compared to incubation with uric acid alone (Pu2009<u20090·0001). In contrast, IL‐18 was up‐regulated upon co‐stimulation with fatty acids and uric acid. Similarly, co‐incubation of fatty acids with glucose diminished secretion of IL‐10, IFN‐γ and CCL2 (monocyte chemotactic protein‐1), while IL‐8 was up‐regulated (Pu2009<u20090·001). Samples from healthy and diabetic subjects did not differ after adjustment for age, sex, body mass index and diabetes type. All three fatty acids similarly influenced whole blood cytokine release in vitro and modulated uric acid or glucose‐stimulated cytokine secretion. Although the ω‐3‐fatty acid EPA showed slightly stronger effects, further studies are required to elaborate the differential effects of PAL, LIN and EPA on disease risk observed previously in epidemiological studies.

Biomarker und Typ-1-Diabetes

ZusammenfassungDie Prävalenz des immun-mediierten Diabetes mellitus Typxa01 liegt bei etwa 10% aller Diabetesfälle. Die Erkrankung resultiert aus der selektiven β-Zell-Zerstörung und dem daraus resultierenden Insulinmangel. Die Diagnose des Typ-1-Diabetes basiert auf der Erfassung der klinischen Symptome, der metabolischen und immunologischen Biomarker wie Blutglukose, HbA1c und Inselautoantikörpern. Eine erhöhte Anzahl an Inselautoantikörpern [Antikörper gegen Glutamatdecarboxylase (GADA), Inselzellantikörper (ICA), Insulinautoantikörper (IAA), Antikörper Insel-assoziiertes Antigen (IA-2A) und Antikörper gegen Zinktransporter 8 (ZnT8A)] ist positiv assoziiert mit dem Risiko, an Typ-1-Diabetes zu erkranken, so dass die Bestimmung der Autoantikörper für die Risikoprädiktion genutzt wird. Der Immunstatus von Patienten mit Typ-1-Diabetes kann mithilfe von zellulären, immunologischen, antigenspezifischen T-Zell-Assays und systemischen, löslichen Immunmediatoren wie Zytokinen, Chemokinen und Adhäsionsmolekülen charakterisiert werden. Die β-Zell-Funktion wird mittels C-Peptid-Konzentration gemessen. In diesem Artikel wird ein Überblick der Biomarker des Typ-1-Diabetes sowie deren Einsatzmöglichkeiten in der Prädiktion, Diagnose, klinischen Klassifikation und Überwachung des Krankheitsverlaufes gegeben.AbstractThe prevalence of immune-mediated type 1 diabetes is approximately 10% of all cases of diabetes. The disease is the consequence of selective β-cell destruction and subsequent insulin deficiency. Diagnosis of type 1 diabetes is based on clinical symptoms and evaluation of metabolic and immunologic biomarkers including blood glucose, HbA1c and autoantibodies. An increased risk for developing type 1 diabetes is positively associated with increased numbers of islet autoantibodies (GADA, ICA, IAA, IA-2A and ZnT8A), therefore, evaluation of islet autoantibodies is also used for risk prediction. Currently, the immune status of patients with type 1 diabetes can be determined using cellular immunoassays for antigen-specific T cells and soluble immune mediators including cytokines, chemokines and adhesion molecules. Endogenous ß-cell capacity is measured by the C-peptide concentration. In the present review a general overview of current biomarkers and their potential applications for prediction, diagnosis, clinical classification and monitoring of the disease progression of type 1 diabetes is given.

The Impact of Dietary Factors on Glycemic Control, Insulin Sensitivity and Secretion in the First Years after Diagnosis of Diabetes

BACKGROUNDnDietary factors play an important role in the prevention of diabetes mellitus. We tested the hypothesis that dietary factors related to diabetes onset also associate with its progression, i.u2009e., early time courses of insulin sensitivity and secretion in both type 1 and type 2 diabetes.nnnMETHODSnIn a prospective observational study, well-controlled recent-onset diabetes patients (n=127) underwent detailed metabolic characterization within the first year after diagnosis. A follow-up was conducted 2 years after the first examination. Insulin secretion and sensitivity were assessed by intravenous glucose tolerance testing. Baseline food consumption was analyzed by a food propensity questionnaire. Multivariate linear regression analysis was used to assess associations between consumption frequencies at baseline with metabolic changes during the first 2 years.nnnRESULTSnWithin the first 2 years, metabolic control did not change in patients with type 1 and type 2 diabetes on average. In type 1 diabetes, an increased consumption frequency of refined grains by one time/day at baseline associated with higher HbA1c by 0.60% (95% CI: 0.04; 1.16), P=0.04 after 2 years compared to baseline. In type 2 diabetes, an increased consumption frequency of meat/meat products by one time/day at baseline associated with lower beta-cell adaptation index (-7.25% (95% CI: -13.16; -0.93), P=0.03) after adjustment for age, sex, BMI, and changes of BMI and glucose-lowering medication.nnnCONCLUSIONnDietary factors associate with the initial course of diabetes. Reduced consumption of refined grains in type 1 diabetes and of meat products in type 2 diabetes may contribute to preservation of insulin secretion and sensitivity.

Habitual Fructose Intake Relates to Insulin Sensitivity and Fatty Liver Index in Recent-Onset Type 2 Diabetes Patients and Individuals without Diabetes

The association between the amount and sources of fructose intake with insulin sensitivity and liver fat needs further elucidation. This study aimed at examining whether habitual intake of sucrose plus non-sucrose bound as well as of non-sucrose bound fructose (total fructose, fruit-derived, juice-derived, sugar sweetened beverages (SSB)-derived fructose) is cross-sectionally associated with insulin sensitivity and fatty liver index (FLI). Fructose intake was estimated using the EPIC food frequency questionnaire from 161 participants with type 2 diabetes (T2D) in the ongoing German Diabetes Study (GDS) (age 53 ± 9 years; HbA1c 6.4 ± 0.9%) and 62 individuals without diabetes (CON) (47 ± 14 years; 5.3 ± 0.3%). Peripheral (M-value) and hepatic insulin resistance were assessed by hyperinsulinemic-euglycemic clamps with stable isotope dilution. FLI was calculated based on body mass index, waist circumference, triglyceride and gamma glutamyl transferase concentrations. Multivariable linear regression analyses were performed. A doubling of SSB-derived sucrose plus non-sucrose bound as well as of non-sucrose bound fructose intake was independently associated with a reduction of the M-value by −2.6% (−4.9; −0.2) and −2.7% (−5.2; −0.1) among T2D, respectively, with an increase in the odds of fatty liver by 16% and 17%, respectively among T2D (all p < 0.05). Doubling fruit-derived sucrose plus non-sucrose bound fructose intake independently related to a reduction in the odds of fatty liver by 13% (p = 0.033) among T2D. Moderate SSB-derived fructose intake may detrimentally affect peripheral insulin sensitivity, whereas fruit-derived fructose intake appeared beneficial for liver fat content.

Reduced expression of stearoyl-CoA desaturase-1, but not free fatty acid receptor 2 or 4 in subcutaneous adipose tissue of patients with newly diagnosed type 2 diabetes mellitus

BackgroundIn subcutaneous adipose tissue (SAT), higher stearoyl-CoA desaturase-1 (SCD1) expression has been related to improved insulin sensitivity in thiazolidinedione-treated type 2 diabetes mellitus patients. In animal models, deficiency of the free fatty acid receptor (FFAR) 2 associated with higher and FFAR4-deficiency with lower insulin sensitivity. We hypothesized that increased FFAR2 expression and reductions in FFAR4 and SCD1 expression in SAT of type 2 diabetes mellitus patients associate positively with insulin resistance and impaired beta cell function.MethodsTwenty-five type 2 diabetes mellitus patients and 25 glucose-tolerant humans (CON) matched for sex, age, and BMI underwent mixed-meal tests to assess insulin sensitivity (OGIS) and beta cell function (ΔAUC(C-peptide)0–180u2009min/ΔAUC(glucose)0–180u2009min) in a cross-sectional study. Gene and protein expression of SCD1 and FFAR2/4 were quantified in SAT biopsies.ResultsInsulin sensitivity was 14% and beta cell function 71% (both pu2009<u20090.001) lower in type 2 diabetes mellitus patients. In type 2 diabetes mellitus, SCD1 mRNA was fivefold (pu2009<u20090.001) and protein expression twofold (pu2009<u20090.01) lower. While FFAR2/4 mRNA and protein expression did not differ between groups, FFAR2 protein levels correlated negatively with beta cell function only in CON (ru2009=u2009−0.74, pu2009<u20090.01). However, neither SCD1 nor FFAR2/4 protein expression correlated with insulin sensitivity in both groups.ConclusionsType 2 diabetes patients have lower SCD1, which does not associate with insulin resistance. Only in non-diabetic humans, FFAR2 associated with impaired beta cell function.

Ein komplexes Zusammenspiel mit Zukunftspotenzial

Weltweit steigt die Diabetesinzidenz. Die Pathogenese von Typ-1- wie Typ-2-Diabetes ist noch nicht eindeutig geklärt und sehr unterschiedlich. Neuere Erkenntnisse legen nahe, dass die Mikrobiota im Darm einen Einfluss darauf hat. Dies könnte die Tür aufstoßen zu neuen, personalisierten Therapiemöglichkeiten gegen Adipositas und Diabetes.