BackgroundThe German Diabetes Study (GDS) is a prospective longitudinal cohort study describing the impact of subphenotypes on the course of the disease. GDS aims at identifying prognostic factors and mechanisms underlying the development of related comorbidities.Study design and methodsThe study comprises intensive phenotyping within 12 months after clinical diagnosis, at 5-year intervals for 20 years and annual telephone interviews in between. Dynamic tests, including glucagon, mixed meal, intravenous glucose tolerance and hyperinsulinemic clamp tests, serve to assess beta-cell function and tissue-specific insulin sensitivity. Magnetic resonance imaging and multinuclei spectroscopy allow quantifying whole-body fat distribution, tissue-specific lipid deposition and energy metabolism. Comprehensive analyses of microvascular (nerve, eye, kidney) and macrovascular (endothelial, cardiorespiratory) morphology and function enable identification and monitoring of comorbidities. The GDS biobank stores specimens from blood, stool, skeletal muscle, subcutaneous adipose tissue and skin for future analyses including multiomics, expression profiles and histology. Repeated questionnaires on socioeconomic conditions, patient-reported outcomes as quality of life, health-related behavior as physical activity and nutritional habits are a specific asset of GDS. This study will recruit 3000 patients and a group of humans without familiy history of diabetes. 237 type 1 and 456 type 2 diabetes patients have been already included.Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-016-0374-9) contains supplementary material, which is available to authorized users.

OBJECTIVEIngestion 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 METHODSA prospective, double-blind, randomized trial was performed in 21 glucose-tolerant humans (11 lean: age 49 6 7 years, BMI 23.6 6 1.7 kg/m 2 ; 10 obese: age 51 6 7 years, BMI 35.5 6 4.9 kg/m 2 ). Participants ingested 10 10 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 euglycemichyperinsulinemic clamps with [6, H 2 ]glucose were used to measure peripheral insulin sensitivity and endogenous glucose production. Muscle and hepatic lipid contents were assessed by 1 H-magnetic resonance spectroscopy, and immune status, cytokines, and endotoxin were measured with specific assays. RESULTSIn 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. CONCLUSIONSEnrichment 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.Type 2 diabetes results from decreased insulin sensitivity and inadequate insulin secretion, which associate with diminished incretin response and subclinical chronic inflammation and subsequent impaired glucose tolerance (1-4). These pathogenic factors, frequently accompanied by hypercaloric high-fat low-fiber diets, may be associated with alterations in gut microbiota, which also occur in obesity (5) and type 2 diabetes (6).

H and ex vivo2 H magnetic resonance spectroscopy before and during hyperinsulinemiceuglycemic clamps with isotope dilution. Mice underwent identical clamp procedures and hepatic transcriptome analyses.RESULTS. PO administration decreased whole-body, hepatic, and adipose tissue insulin sensitivity by 25%, 15%, and 34%, respectively. Hepatic triglyceride and ATP content rose by 35% and 16%, respectively. Hepatic gluconeogenesis increased by 70%, and net glycogenolysis declined by 20%. Mouse transcriptomics revealed that PO differentially regulates predicted upstream regulators and pathways, including LPS, members of the TLR and PPAR families, NF-κB, and TNF-related weak inducer of apoptosis (TWEAK). CONCLUSION.Saturated fat ingestion rapidly increases hepatic lipid storage, energy metabolism, and insulin resistance. This is accompanied by regulation of hepatic gene expression and signaling that may contribute to development of NAFLD. PO results in increased circulating TG, glucagon, and incretins. After PO administration, TG in plasma rose by 59% (area under the time curve [AUC], P < 0.001) and by 156% in chylomicrons (AUC, P = 0.009) (Figure 2A). The AUC for plasma free fatty acids (FFA) ( Figure 2B) and insulin concentrations ( Figure 2C) was unchanged, while the AUC for plasma C-peptide was 28% higher after PO ingestion versus VCL (P < 0.005, Figure 2D). Of note, FFA were increased at 300, 420, and 480 minutes. Blood glucose levels were not different between PO-and VCL-treated groups ( Figure 2E). Plasma glucagon rose by 41% (AUC, P < 0.0001) only after PO ingestion ( Figure 2F). Also, glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP) levels were markedly increased and remained elevated after PO ingestion (both P < 0.005) (Supplemental Figure 2; supplemental material available online with this article; https://doi.org/10.1172/ JCI89444DS1). Circulating levels of TNF-α, IL-6, fetuin-A, chemerin, omentin, and cortisol were not different between PO and VCL groups (P > 0.5 for all) (Supplemental Table 1). REGISTRATION. The Journal of Clinical Investigation C L I N I C A L M E D I C I N EPO induces insulin resistance at whole-body, liver, and adipose tissue levels. Insulin sensitivity was measured using hyperinsulinemic-euglycemic clamp tests in healthy humans. Steady state was reached (Supplemental Figure 1), and pertinent parameters were analyzed during this time. PO ingestion reduced WBIS by 25% compared with VCL treatment (P = 0.0005, Figure 3A). Furthermore, after PO, volunteers also showed a decrease of 22% (P = 0.002) in the rate of glucose disappearance (Rd), mostly due to a 33% (P = 0.01) reduction in glucose oxidation (GOX), while the rate of nonoxidative glucose disposal remained unchanged

ContextHepatic steatosis, defined as increased hepatocellular lipid content (HCL), associates with visceral obesity and glucose intolerance. As exact HCL quantification by 1H-magnetic resonance spectroscopy (1H-MRS) is not generally available, various clinical indices are increasingly used to predict steatosis.ObjectiveThe purpose of this study was to test the accuracy of NAFLD liver fat score (NAFLD-LFS), hepatic steatosis index (HSI) and fatty liver index (FLI) against 1H-MRS and their relationships with insulin sensitivity and secretion.Design, Setting and ParticipantsNinety-two non-diabetic, predominantly non-obese humans underwent clinical examination, 1H-MRS and an oral glucose tolerance test (OGTT) to calculate insulin sensitivity and β-cell function. Accuracy of indices was assessed from the area under the receiver operating characteristic curve (AROC).ResultsMedian HCL was 2.49% (0.62;4.23) and correlated with parameters of glycemia across all subjects. NAFLD-LFS, FLI and HSI yielded AROCs of 0.70, 0.72, and 0.79, respectively, and related positively to HCL, insulin resistance, fasting and post-load β-cell function normalized for insulin resistance. Upon adjustment for age, sex and HCL, regression analysis revealed that NAFLD-LFS, FLI and HSI still independently associated with both insulin sensitivity and β-cell function.ConclusionThe tested indices offer modest efficacy to detect steatosis and cannot substitute for fat quantification by 1H-MRS. However, all indices might serve as surrogate parameters for liver fat content and also as rough clinical estimates of abnormal insulin sensitivity and secretion. Further validation in larger collectives such as epidemiological studies is needed.

Several mechanisms, such as innate immune responses via Toll-like receptor-4, accumulation of diacylglycerols (DAG)/ceramides, and activation of protein kinase C (PKC), are considered to underlie skeletal muscle insulin resistance. In this study, we examined initial events occurring during the onset of insulin resistance upon oral high-fat loading compared with lipid and low-dose endotoxin infusion. Sixteen lean insulin-sensitive volunteers received intravenous fat (iv fat), oral fat (po fat), intravenous endotoxin (lipopolysaccharide [LPS]), and intravenous glycerol as control. After 6 h, whole-body insulin sensitivity was reduced by iv fat, po fat, and LPS to 60, 67, and 48%, respectively (all P < 0.01), which was due to decreased nonoxidative glucose utilization, while hepatic insulin sensitivity was unaffected. Muscle PKCθ activation increased by 50% after iv and po fat, membrane Di-C18:2 DAG species doubled after iv fat and correlated with PKCθ activation after po fat, whereas ceramides were unchanged. Only after LPS, circulating inflammatory markers (tumor necrosis factor-α, interleukin-6, and interleukin-1 receptor antagonist), their mRNA expression in subcutaneous adipose tissue, and circulating cortisol were elevated. Po fat ingestion rapidly induces insulin resistance by reducing nonoxidative glucose disposal, which associates with PKCθ activation and a rise in distinct myocellular membrane DAG, while endotoxin-induced insulin resistance is exclusively associated with stimulation of inflammatory pathways.

Aims/hypothesis This study aimed to perform a comprehensive analysis of interlobular, intralobular and parenchymal pancreatic fat in order to assess their respective effects on beta cell function. Methods Fifty-six participants (normal glucose tolerance [NGT] (n=28), impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) (n=14) and patients with type 2 diabetes (n=14)) underwent a frequent-sampling OGTT and non-invasive magnetic resonance imaging (MRI; whole-body and pancreatic) and proton magnetic resonance spectroscopy ( 1 H-MRS; liver and pancreatic fat). Total pancreatic fat was assessed by a standard 2 cm H-MRS techniques revealed an inhomogeneous distribution of interlobular and intralobular adipose tissue, which increased with decreasing glucose tolerance. mDIXON-MRI measurements provided evidence against uniform steatosis, revealing regions of parenchymal tissue void of lipid accumulation in all participants. Total (r=0.385, p<0.01) and intralobular pancreas adipose tissue infiltration (r=0.310, p< 0.05) positively associated with age, but not with fasting or 2 h glucose levels, BMI or visceral fat content (all p>0.5). Furthermore, no associations were found between total and intralobular pancreatic adipose tissue infiltration and insulin secretion or beta cell function within NGT, IFG/IGT or patients with type 2 diabetes (all p>0.2). Conclusions/interpretation The pancreas does not appear to be another target organ for abnormal endocrine function because of ectopic parenchymal fat storage. No relationship was found between pancreatic adipose tissue infiltration and beta cell function, regardless of glucose tolerance status.

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Differential, metabolic, monitor-specific deviations are the primary determinants for lack of accuracy, comparability, and transferability of results. This problem can be overcome by the present postcalorimetric ICcE procedure.