Epidemiological studies have shown that increased circulating branched-chain amino acids (BCAAs) are associated with insulin resistance and type 2 diabetes (T2D). This may result from altered energy ...metabolism or dietary habits.
We hypothesized that a lower intake of BCAAs improves tissue-specific insulin sensitivity.
This randomized, placebo-controlled, double-blinded, crossover trial examined well-controlled T2D patients receiving isocaloric diets (protein: 1 g/kg body weight) for 4 wk. Protein requirements were covered by commercially available food supplemented ≤60% by an AA mixture either containing all AAs or lacking BCAAs. The dietary intervention ensured sufficient BCAA supply above the recommended minimum daily intake. The patients underwent the mixed meal tolerance test (MMT), hyperinsulinemic-euglycemic clamps (HECs), and skeletal muscle and white adipose tissue biopsies to assess insulin signaling.
After the BCAA− diet, BCAAs were reduced by 17% during fasting (P < 0.001), by 13% during HEC (P < 0.01), and by 62% during the MMT (P < 0.001). Under clamp conditions, whole-body and hepatic insulin sensitivity did not differ between diets. After the BCAA− diet, however, the oral glucose sensitivity index was 24% (P < 0.01) and circulating fibroblast-growth factor 21 was 21% higher (P < 0.05), whereas meal-derived insulin secretion was 28% lower (P < 0.05). Adipose tissue expression of the mechanistic target of rapamycin was 13% lower, whereas the mitochondrial respiratory control ratio was 1.7-fold higher (both P < 0.05). The fecal microbiome was enriched in Bacteroidetes but depleted of Firmicutes.
Short-term dietary reduction of BCAAs decreases postprandial insulin secretion and improves white adipose tissue metabolism and gut microbiome composition. Longer-term studies will be needed to evaluate the safety and metabolic efficacy in diabetes patients.
This trial was registered at clinicaltrials.gov as NCT03261362.
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.
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/m(2); 10 obese: age 51 ± 7 years, BMI 35.5 ± 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 euglycemic-hyperinsulinemic clamps with 6,6-(2)H2glucose 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.
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.
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.
The rs738409(G) single nucleotide polymorphism (SNP) in the patatin-like phospholipase domain-containing 3 (
) gene associates with increased risk and progression of nonalcoholic fatty liver disease ...(NAFLD). As the recently described severe insulin-resistant diabetes (SIRD) cluster specifically relates to NAFLD, this study examined whether this SNP differently associates with hepatic lipid content (hepatocellular lipids HCL) and insulin sensitivity in recent-onset diabetes.
A total of 917 participants in the German Diabetes Study (GDS) underwent genotyping, hyperinsulinemic-euglycemic clamps with stable isotopic tracer dilution, and MRS.
The G allele associated positively with HCL (β = 0.36,
< 0.01), independent of age, sex, and BMI across the whole cohort, but not in the individual clusters. Those with SIRD exhibited lowest whole-body insulin sensitivity compared with those with severe insulin-deficient (SIDD), moderate obesity-related (MOD), moderate age-related (MARD), and severe autoimmune diabetes (SAID) clusters (all
< 0.001). Interestingly, the SIRD group presented with higher prevalence of the rs738409(G) SNP compared with other clusters and the glucose-tolerant control group (
< 0.05). HCL was higher in the SIRD group (median 13.6% 1st quartile 5.8; 3rd quartile 19.1 compared with the MOD (6.4 % 2.1; 12.4,
< 0.05), MARD (3.0% 1.0; 7.9,
< 0.001), SAID (0.4% 0.0; 1.5,
< 0.001), and glucose-tolerant (0.9% 0.4; 4.9),
< 0.001) group. Although the
polymorphism did not directly associate with whole-body insulin sensitivity in SIRD, the G-allele carriers had higher circulating free fatty acid concentrations and greater adipose tissue insulin resistance compared with noncarriers (both
< 0.001).
Members of the SIRD cluster are more frequently carriers of the rs738409(G) variant. The SNP-associated adipose tissue insulin resistance and excessive lipolysis may contribute to their NAFLD.
Aims/hypothesis
In men with diabetes, the prevalence of erectile dysfunction increases with advanced age and longer diabetes duration and is substantially higher in men with type 2 diabetes than ...those with type 1 diabetes. This study aimed to evaluate the prevalence of erectile dysfunction among the five novel subgroups of recent-onset diabetes and determine the strength of associations between diabetes subgroups and erectile dysfunction.
Methods
A total of 351 men with recent-onset diabetes (<1 year) from the German Diabetes Study baseline cohort and 124 men without diabetes were included in this cross-sectional study. Erectile dysfunction was assessed with the International Index of Erectile Function (IIEF) questionnaire. Poisson regression models were used to estimate associations between diabetes subgroups (each subgroup tested against the four other subgroups as reference) and erectile dysfunction (dependent binary variable), adjusting for variables used to define diabetes subgroups, high-sensitivity C-reactive protein and depression.
Results
The prevalence of erectile dysfunction was markedly higher in men with diabetes than in men without diabetes (23% vs 11%,
p
= 0.004). Among men with diabetes, the prevalence of erectile dysfunction was highest in men with severe insulin-resistant diabetes (SIRD) (52%), lowest in men with severe autoimmune diabetes (SAID) (7%), and intermediate in men with severe insulin-deficient diabetes (SIDD), mild obesity-related diabetes (MOD) and mild age-related diabetes (MARD) (31%, 18% and 29%, respectively). Men with SIRD had an adjusted RR of 1.93 (95% CI 1.04, 3.58) for prevalent erectile dysfunction (
p
= 0.038). Similarly, men with SIDD had an adjusted RR of 3.27 (95% CI 1.18, 9.10) (
p
= 0.023). In contrast, men with SAID and those with MARD had unadjusted RRs of 0.26 (95% CI 0.11, 0.58) (
p
= 0.001) and 1.52 (95% CI 1.04, 2.22) (
p
= 0.027), respectively. However, these associations did not remain statistically significant after adjustment.
Conclusions/interpretation
The high RRs for erectile dysfunction in men with recent-onset SIRD and SIDD point to both insulin resistance and insulin deficiency as major contributing factors to this complication, suggesting different mechanisms underlying erectile dysfunction in these subgroups.
Graphical abstract
Aims/hypothesis
The aim of this study was to investigate the modifying effect of the glucose transporter (GLUT2) gene
SLC2A2
(rs8192675) variant on the glycaemic response to metformin in individuals ...recently diagnosed with type 2 diabetes.
Methods
Individuals with type 2 diabetes (
n
= 508) from the prospective German Diabetes Study (age mean ± SD 53 ± 10 years; 65% male; BMI 32 ± 6 kg/m
2
, metformin use 57%) underwent detailed metabolic characterisation (hyperinsulinaemic–euglycaemic clamp, IVGTT) during the first year after diagnosis. Participants provided self-reported data from the time of diagnosis. The change in fasting glucose was assessed in relation to
SLC2A2
genotype and glucose-lowering treatment using two-way ANCOVA with gene×treatment interactions adjusted for age, sex, BMI and diabetes duration.
Results
The C variant allele of rs8192675 was associated with a higher prevalence of diabetes symptoms at diabetes diagnosis. In the metformin monotherapy group only, patients with a C allele showed a larger adjusted blood glucose reduction during the first year after diabetes diagnosis than patients with the TT genotype (6.3 mmol/l vs 3.9 mmol/l; genotype difference 2.4 mmol/l,
p
= 0.02;
p
value for genotype interaction metformin monotherapy vs non-pharmacological therapy <0.01). The greater decline in fasting glucose (CC/CT vs TT) in metformin monotherapy persisted after further adjusting for glucose values at diagnosis (genotype difference 1.0 mmol/l,
p
= 0.01; genotype×treatment interaction
p
= 0.06).
Conclusions/interpretation
The variant rs8192675 in the
SLC2A2
gene (C allele) is associated with an improved glucose response to metformin monotherapy during the first year after diagnosis in type 2 diabetes.
Trial registration
ClinicalTrials.gov
NCT01055093
Human heat shock protein 60 (hsp60) elicits a potent proinflammatory response in cells of the innate immune system and therefore has been proposed as a danger signal of stressed or damaged cells. We ...report here that macrophages of C3H/HeJ mice, carrying a mutant Toll-like-receptor (Tlr) 4 are nonresponsive to hsp60. Both the induction of TNF-alpha and NO formation were found dependent on a functional Tlr4 whereas stimulation of macrophages by CpG DNA was Tlr4 independent. We conclude that Tlr4 mediates hsp60 signaling. This is the first report of a putative endogenous ligand of the Tlr4 complex.
Obesity is frequently associated with excessive accumulation of lipids in ectopic tissue and presents a major risk factor for type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD). ...Diacylglycerols (DAGs) and ceramides (CERs) were identified as key players in lipid-induced insulin resistance, typical for such diseases. Recent results suggest that the subcellular distribution of these lipids affects their lipotoxic properties. However, the subcellular dynamics of these lipids and the role of lipid droplets (LDs) as a potential storage site is not understood. Here, we developed a liquid chromatography triple quadrupole mass spectrometry (LC-MS/MS)-method for the rapid and simultaneous quantification of DAG and CER species in tissue sample fractions. The assay is characterized by excellent recovery of analytes, limit of quantification, accuracy and precision. We established a fractionation protocol that allows the separation of subcellular tissue fractions. This method was subsequently tested to measure the concentration of DAGs and CERs in subcellular fractions of human muscle and several mouse tissues. In a mouse model of NAFLD, application of this method revealed a prominent role for LDs as repository for lipotoxic DAG and CER species. In conclusion, the new method proved as a valuable tool to analyse the subcellular dynamics of lipotoxins, related to the pathogenesis of insulin resistance, T2D and NAFLD.
Toll-like receptors (TLR) mediate the recognition of microbial constituents and stress-induced endogenous ligands by the immune system. They may also be involved in the maintenance or break down of ...tolerance against autologous antigens. The aim of our investigation was to study the consequence of TLR4 deficiency on the development of insulin-deficient diabetes in the NOD mouse.
The TLR4 defect of the C57BL/10ScN mouse was backcrossed onto the NOD background and the effect of TLR4 deficiency on diabetes development was analysed by in vivo and in vitro studies.
Compared to animals with wildtype TLR4 expression (TLR4(+/+)), female NOD mice carrying a homozygous TLR4 defect (TLR4(-/-)), showed significant acceleration of diabetes development, with a younger age at diabetes onset (TLR4 (+/+) 177±22 d, TLR(-/-): 118±21 d; p<0.01). Pancreata of 120 d old TLR4(-/-) NOD mice revealed increased proportions of islets with advanced stages of immune cell infiltration compared to TLR4(+/+) mice (p<0.05). TLR4 deficiency did not affect the susceptibility of islet cells to the beta cell damaging mediators nitric oxide or the inflammatory cytokines tumor necrosis factor alpha, interleukin-1 beta and interferon gamma. The lack of TLR4 further had no effect on the frequency of regulatory T-cells but reduced their capacity to inhibit T-cell proliferation.
Our findings demonstrate that TLR4 deficiency results in an acceleration of diabetes development and immune cell infiltration of islets in NOD mice. We conclude that TLR4 is involved in the progression of the insulitis process thereby controlling the development of insulin-deficient diabetes in NOD mice.
Abstract
Context
Vitamin B12 and folate deficiency are not only linked to hematological, neurological, and cardiovascular diseases, but are also associated with insulin resistance. Metformin can ...decrease vitamin B12 and folate concentrations.
Objective
To examine (1) effects of short-term metformin treatment on serum holotranscobalamin (holoTC) and folate and (2) their association with insulin sensitivity in recent-onset type 2 diabetes.
Design
This cross-sectional analysis comprised patients (known disease duration <12 months) on metformin monotherapy (MET, n = 123, 81 males, 53 ± 12 years) or nonpharmacological treatment (NPT, n = 126, 77 males, 54 ± 11 years) of the German Diabetes Study.
Main Outcome Measures
HoloTC (enzyme-linked immunosorbent assay), cobalamin, and folate (electrochemiluminescence); beta-cell function and whole-body insulin sensitivity, measured during fasting (HOMA-B, HOMA-IR) and intravenous glucose tolerance tests combined with hyperinsulinemic–euglycemic clamp tests.
Results
HoloTC (105.4 82.4, 128.3 vs 97 79.7, 121.9 pmol/L) and folate concentrations (13.4 9.3, 19.3 vs 12.7 9.3, 22.0 nmol/L) were similar in both groups. Overall, holoTC was not associated with fasting or glucose-stimulated beta-cell function and insulin-stimulated glucose disposal. Cobalamin measurements yielded similar results in representative subgroups. In NPT but not MET, folate levels were inversely correlated with HOMA-IR (r = –0.239, P = .007). Folate levels did not relate to insulin sensitivity or insulin secretion in the whole cohort and in each group separately after adjustment for age, body mass index, and sex.
Conclusions
Metformin does not affect circulating holoTC and folate concentrations in recent-onset type 2 diabetes, rendering monitoring of vitamin B12 and folate dispensable, at least during the first 6 months after diagnosis or initiation of metformin.
Purpose
Recent trials demonstrated remission of type 2 diabetes and non-alcoholic fatty liver disease (NAFLD) following formula diet-induced weight loss. To improve the outreach for populations in ...need, many mobile health apps targeting weight loss have been developed with limited scientific evaluation of these apps. The present feasibility study investigated the effects of a novel approach incorporating a regular ‘whole food-based’ low-calorie diet combined with app-based digital education and behavioral change program on glucose metabolism and disease management.
Methods
Twenty-four individuals with type 2 diabetes followed this approach supported by weekly coaching calls for 12 weeks. Phenotyping included bioimpedance analysis, mixed-meal tolerance test, magnetic resonance spectroscopy and transient elastography for assessing liver fat content and liver stiffness.
Results
Over 12 weeks, participants reduced their body weight by 9% (97 ± 13 to 88 ± 12 kg), body mass index (BMI; 33 ± 5 to 29 ± 4 kg/m
2
), total fat mass (31 ± 10 to 27 ± 10%) (all
p
< 0.01) and liver fat by 50% alongside with decreased liver stiffness. Target HbA1c (< 6.5%) was achieved by 38% and resolution of NAFLD (liver fat content < 5.6%) was observed in 30% of the participants.
Conclusion
This novel approach combining digital education with a low-calorie diet results in effective improvements of body weight, glycemic control and NAFLD and could complement existing care for patients with type 2 diabetes.
Trial registration
NCT04509245
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