Yongde Peng

Gut bacteria selectively promoted by dietary fibers alleviate type 2 diabetes

Microbial modulation of diabetes Short-chain fatty acids (SCFAs) are produced by various human gut microbes. SCFAs act as an energy source to the colonic epithelium and are also sensed by host signaling pathways that modulate appetite and inflammation. Deficiency of gut SCFAs is associated with type 2 diabetes. Zhao et al. found that adopting a high-fiber diet promoted the growth of SCFA-producing organisms in diabetic humans. The high-fiber diet induced changes in the entire gut microbe community and correlated with elevated levels of glucagon-like peptide-1, a decline in acetylated hemoglobin levels, and improved blood-glucose regulation. Science, this issue p. 1151 Increasing dietary fiber intake increases the abundance of short-chain fatty acid–producing gut microbes and relieves diabetes. The gut microbiota benefits humans via short-chain fatty acid (SCFA) production from carbohydrate fermentation, and deficiency in SCFA production is associated with type 2 diabetes mellitus (T2DM). We conducted a randomized clinical study of specifically designed isoenergetic diets, together with fecal shotgun metagenomics, to show that a select group of SCFA-producing strains was promoted by dietary fibers and that most other potential producers were either diminished or unchanged in patients with T2DM. When the fiber-promoted SCFA producers were present in greater diversity and abundance, participants had better improvement in hemoglobin A1c levels, partly via increased glucagon-like peptide-1 production. Promotion of these positive responders diminished producers of metabolically detrimental compounds such as indole and hydrogen sulfide. Targeted restoration of these SCFA producers may present a novel ecological approach for managing T2DM.

Toll‐like receptor 2/4 links to free fatty acid‐induced inflammation and β‐cell dysfunction

T2D is a metabolic and inflammatory disease characterized by deteriorating β‐cell function and increased levels of inflammatory cytokines. Low‐grade inflammation and innate immune system activation lead to β‐cell failure. Recently, SFAs have been proposed as triggers of metabolism‐associated inflammation through the TLR family of PRRs. In this review, recent progress in defining the molecular basis of FFA‐associated TLR2/4 activation and signaling in β‐cell dysfunction and apoptosis is summarized. Furthermore, we highlight links between TLRs and diabetic complications, insulin resistance, and autophagy. This knowledge may facilitate novel strategies to abrogate inflammation in T2D.

Rapamycin Improves Palmitate-Induced ER Stress/NF κ B Pathways Associated with Stimulating Autophagy in Adipocytes

Obesity-induced endoplasmic reticulum (ER) stress and inflammation lead to adipocytes dysfunction. Autophagy helps to adapt to cellular stress and involves in regulating innate inflammatory response. In present study, we examined the activity of rapamycin, a mTOR kinase inhibitor, against endoplasmic reticulum stress and inflammation in adipocytes. An in vitro model was used in which 3T3-L1 adipocytes were preloaded with palmitate (PA) to generate artificial hypertrophy mature adipocytes. Elevated autophagy flux and increased number of autophagosomes were observed in response to PA and rapamycin treatment. Rapamycin attenuated PA-induced PERK and IRE1-associated UPR pathways, evidenced by decreased protein levels of eIF2α phosphorylation, ATF4, CHOP, and JNK phosphorylation. Inhibiting autophagy with chloroquine (CQ) exacerbated these ER stress markers, indicating the role of autophagy in ameliorating ER stress. In addition, cotreatment of CQ abolished the anti-ER stress effects of rapamycin, which confirms the effect of rapamycin on ERs is autophagy-dependent. Furthermore, rapamycin decreased PA-induced nuclear translocation of NFκB P65 subunit, thereby NFκB-dependent inflammatory cytokines MCP-1 and IL-6 expression and secretion. In conclusion, rapamycin attenuated PA-induced ER stress/NFκB pathways to counterbalance adipocytes stress and inflammation. The beneficial of rapamycin in this context partly depends on autophagy. Stimulating autophagy may become a way to attenuate adipocytes dysfunction.

Follistatin-Like 1: A Potential Mediator of Inflammation in Obesity

Obesity is associated with a state of chronic low-grade inflammation, which contributes to insulin resistance and type 2 diabetes. However, the molecular mechanisms that link obesity to inflammation are not fully understood. Follistatin-like 1 (FSTL1) is a novel proinflammatory cytokine that is expressed in adipose tissue and secreted by preadipocytes/adipocytes. We aimed to test whether FSTL1 could have a role in obesity-induced inflammation and insulin resistance. It was found that FSTL1 expression was markedly decreased during differentiation of 3T3-L1 preadipocytes but reinduced by TNF-α. Furthermore, a significant increase in FSTL1 levels was observed in adipose tissue of obese ob/ob mice, as well as in serum of overweight/obese subjects. Mechanistic studies revealed that FSTL1 induced inflammatory responses in both 3T3-L1 adipocytes and RAW264.7 macrophages. The expression of proinflammatory mediators including IL-6, TNF-α, and MCP-1 was upregulated by recombinant FSTL1 in a dose-dependent manner, paralleled with activation of the IKKβ-NFκB and JNK signaling pathways in the two cell lines. Moreover, FSTL1 impaired insulin signaling in 3T3-L1 adipocytes, as revealed by attenuated phosphorylation of both Akt and IRS-1 in response to insulin stimulation. Together, our results suggest that FSTL1 is a potential mediator of inflammation and insulin resistance in obesity.

Spexin peptide is expressed in human endocrine and epithelial tissues and reduced after glucose load in type 2 diabetes.

Spexin mRNA and protein are widely expressed in rat tissues and associate with weight loss in rodents of diet-induced obesity. Its location in endocrine and epithelial cells has also been suggested. Spexin is a novel peptide that involves weight loss in rodents of diet-induced obesity. Therefore, we aimed to examine its expression in human tissues and test whether spexin could have a role in glucose and lipid metabolism in type 2 diabetes mellitus (T2DM). The expression of the spexin gene and immunoreactivity in the adrenal gland, skin, stomach, small intestine, liver, thyroid, pancreatic islets, visceral fat, lung, colon, and kidney was higher than that in the muscle and connective tissue. Immunoreactive serum spexin levels were reduced in T2DM patients and correlated with fasting blood glucose (FBG, r=-0.686, P<0.001), hemoglobin A1c (HbA1c, r=-0.632, P<0.001), triglyceride (TG, r=-0.236, P<0.001) and low density lipoprotein-cholesterol (LDL-C, r=-0.382, P<0.001). A negative correlation of blood glucose with spexin was observed during oral glucose tolerance test (OGTT). Spexin is intensely expressed in normal human endocrine and epithelial tissues, indicating that spexin may be involved in physiological functions of endocrine and in several other tissues. Circulating spexin levels are low in T2DM patients and negatively related to blood glucose and lipids suggesting that the peptide may play a role in glucose and lipid metabolism in T2DM.

Palmitate induces endoplasmic reticulum stress and autophagy in mature adipocytes: Implications for apoptosis and inflammation

Endoplasmic reticulum (ER) stress and inflammation induced by obesity lead to adipocyte dysfunction, with the impairment of the insulin pathway. Recent studies have indicated that understanding the physiological role of autophagy is of great significance. In the present study, an in vitro model was used in which 3T3-L1 adipocytes were pre-loaded with palmitate (PA) to generate artificially hypertrophied mature adipocytes. PA induced an autophagic flux, determined by an increased microtubule-associated protein 1 light chain 3 (LC3)-II formation, as shown by western blot analysis and fluorescence microscopy, and was confirmed using transmission electron microscopy (TEM). Using TEM and western blot analysis, we observed increased ER stress in response to PA, as indicated by the increased levels of the ER stress markers, BiP, activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP), and the phosphoralytion of eukaryotic translation initiation factor 2α and c-Jun N-terminal kinase (JNK). Of note, we observed that the PA-induced ER stress occurred prior to the activation of autophagy. We confirmed that autophagy was induced in response to JNK-dependent ER stress, as autophagy was suppressed by treatment with the ER stress inhibitor, 4-phenyl butyrate (4-PBA), and the JNK inhibitor, SP600125. Upon the inhibition of autophagy using chloroquine (CQ), we observed exacerbated ER stress and an increased level of cell death. Importantly, to determine whether autophagy is linked to inflammation, the autophagy inhibitor, 3-methyladenine (3-MA) was used. The inhibition of autophagy led to a further increase in the PA-induced expression of monocyte chemoattractant protein-1 (MCP-1) and interleukin-6 (IL-6). Consistently, such an increase was also observed following treatment with SP600125. In conclusion, our data indicate that PA elicits a ER stress-JNK-autophagy axis, and that this confers a pro-survival effect against PA-induced cell death and stress in hypertrophied adipocytes. The JNK-dependent activation of autophagy diminishes PA-induced inflammation. Therefore, the stimulation of autophagy may become a method with which to attenuate adipocyte dysfunction and inflammation.

Association of two glyoxalase I gene polymorphisms with nephropathy and retinopathy in Type 2 diabetes

Background: Glyoxalase I (GLO1), which is the major enzyme that catalyzes the metabolism of methylglyoxal (MG), may play an important role in the pathogenesis of diabetic microvascular complications. Aim: To investigate whether the C-7T and A419C polymorphisms of the GLO1 gene are associated with nephropathy and retinopathy in Chinese Type 2 diabetic patients. Subjects and methods: A total of 364 Type 2 diabetic patients and 301 healthy controls were enroled in the study. Diabetic microvascular complications were determined by urinary albumin excretion measurements and ophthalmological examinations. Genetic analyses were performed using either Taqman PCR or direct sequencing. The effect of C-7T polymorphism on promoter activity was measured by reporter gene assays. Results: The albumin/creatinine ratio (ACR) and prevalence of nephropathy and retinopathy were significantly higher in diabetic patients with GLO1 -7CC genotype than in patients with -7CT and -7TT genotypes (p=0.02, p=0.02, and p=0.04, respectively). The 7CC genotype is independently associated with ACR (β=0.13, p=0.01) and the risk for retinopathy [odds ratio (OR): 2.30, 95% confidence interval (CI): 1.25–4.24, p<0.01]. The luciferase activity of the -7T promoter was higher than that of the -7C promoter (13.2±0.2 vs 11.7±0.8, p=0.04). No differences were found between ACR and the prevalence of nephropathy and retinopathy for A419C polymorphism in Type 2 diabetic patients. Conclusions: GLO1 C-7T polymorphism alters promoter activity and confers susceptibility to nephropathy and retinopathy to Type 2 diabetic patients.

Impaired β Cell Function in Chinese Newly Diagnosed Type 2 Diabetes Mellitus with Hyperlipidemia

The objective is to explore the effects of hyperlipidemia on β cell function in newly diagnosed type 2 diabetes mellitus (T2DM). 208 patients were enrolled in the study and were divided into newly diagnosed T2DM with hyperlipidemia (132 patients) and without hyperlipidemia (76 patients). Demographic data, glucose levels, insulin levels, lipid profiles, homeostasis model assessment for β cell function index (HOMA-β), homeostasis model assessment for insulin resistance index (HOMA-IR), and quantitative insulin-sensitivity check index (QUICKI) were compared between the two groups. We found that comparing with those of normal lipid levels, the subjects of newly diagnosed T2DM with hyperlipidemia were younger, and had declined HOMA-β. However, the levels of HOMA-β were comparable regardless of different lipid profiles (combined hyperlipidemia, hypertriglyceridemia, and hypercholesterolemia). Multiple stepwise linear regression analysis showed that high fasting plasma glucose (FPG), decreased fasting insulin level (FINS), and high triglyceride (TG) were independent risk factors of β cell dysfunction in newly diagnosed T2DM. Therefore, the management of dyslipidemia, together with glucose control, may be beneficial for T2DM with hyperlipidemia.

Identification of a Novel Function of Adipocyte Plasma Membrane-Associated Protein (APMAP) in Gestational Diabetes Mellitus by Proteomic Analysis of Omental Adipose Tissue.

Gestational diabetes mellitus (GDM) is considered as an early stage of type 2 diabetes mellitus. In this study, we compared demographic and clinical data between six GDM subjects and six normal glucose tolerance (NGT; healthy controls) subjects and found that homeostasis model of assessment for insulin resistance index (HOMA-IR) increased in GDM. Many previous studies demonstrated that omental adipose tissue dysfunction could induce insulin resistance. Thus, to investigate the cause of insulin resistance in GDM, we used label-free proteomics to identify differentially expressed proteins in omental adipose tissues from GDM and NGT subjects (data are available via ProteomeXchange with identifier PXD003095). A total of 3528 proteins were identified, including 66 significantly changed proteins. Adipocyte plasma membrane-associated protein (APMAP, a.k.a. C20orf3), one of the differentially expressed proteins, was down-regulated in GDM omental adipose tissues. Furthermore, mature 3T3-L1 adipocytes were used to simulate omental adipocytes. The inhibition of APMAP expression by RNAi impaired insulin signaling and activated NFκB signaling in these adipocytes. Our study revealed that the down-regulation of APMAP in omental adipose tissue may play an important role in insulin resistance in the pathophysiology of GDM.

Glyoxalase I and Aldose Reductase Gene Polymorphisms and Susceptibility to Carotid Atherosclerosis in Type 2 Diabetes

AIMS To investigate the association of polymorphisms of glyoxalase I (GLO1) A419C, GLO1 C-7T, and aldose reductase C-106T with type 2 diabetes and diabetic carotid atherosclerosis in a Chinese Han population. METHODS The study population included 362 patients with type 2 diabetes and 301 nondiabetic control subjects. Genetic analyses were performed using either the Taqman polymerase chain reaction or direct sequencing. All patients with diabetes underwent carotid ultrasonography to assess the intima-media thickness and the presence of atherosclerotic plaques. RESULTS There were no differences between the genotype frequencies of GLO1 A419C, GLO1 C-7T, and aldose reductase C-106T polymorphisms, in the control and diabetic groups. The value of mean carotid intima-media thickness and the prevalence of carotid atherosclerotic plaques were significantly increased in patients with type 2 diabetes with the GLO1-7CC genotype compared with those with the -7CT and TT genotypes (permutation p=0.003 and 0.031, respectively). Multiple regression analysis showed that the GLO1-7CC genotype was an independent determinant of carotid intima-media thickness (β=0.12, p=0.014), but not an independent risk factor for carotid atherosclerotic plaques (odds ratio [OR]=1.74, 95% CI 0.89-3.42, p=0.10) in patients with type 2 diabetes. CONCLUSIONS The GLO1 C-7T polymorphism is associated with carotid atherosclerosis in Chinese patients with type 2 diabetes.