Inflammation In Type 2 Diabetes Research Articles

Fatty acid overload to compromised oxidative phosphorylation activates inflammation in type2 diabetes: Hidden beasts and how to find them.

Fatty acid overload to compromised oxidative phosphorylation activates inflammation in type2 diabetes: Hidden beasts and how to find them.

The inflammatory effect of epigenetic factors and modifications in type 2 diabetes.

Inflammation has a central role in the etiology of type 2 diabetes (T2D) and its complications. Both genetic and epigenetic factors have been implicated in the development of T2D-associated inflammation. Epigenetic mechanisms regulate the function of several components of the immune system. Diabetic conditions trigger aberrant epigenetic alterations that contribute to the progression of insulin resistance and β-cell dysfunction by induction of inflammatory responses. Thus, targeting epigenetic factors and modifications, as one of the underlying causes of inflammation, could lead to the development of novel immune-based strategies for the treatment of T2D. The aim of this review is to provide an overview of the epigenetic mechanisms involved in the propagation and perpetuation of chronic inflammation in T2D. We also discuss the possible anti-inflammatory approaches that target epigenetic factors for the treatment of T2D.

Abdominal Fat Is Directly Associated With Inflammation In Persons With Type-2 Diabetes Regardless Of Glycemic Control -A Jordanian Study.

Background and aimSystemic inflammation is related to the progression of complications associated with diabetes. This study aimed to investigate the association between general and abdominal obesity and inflammation in patients with type-2 diabetes with or without glycemic control.MethodsA total of 198 men (n=73) and women (n=125) diagnosed with type 2 diabetes participated in this study. General obesity markers, body mass index (BMI), and abdominal fat were assessed. Circulating concentrations of glycated hemoglobin (HbA1C), C-reactive protein (CRP), and serum interleukin-6 (IL-6) were determined. Poor glycemic control and good glycemic control were defined as having fasting HbA1C concentrations ≥7% and <7%, respectively. Multivariate adjusted analysis of covariance was used to determine the relation between BMI and abdominal fat and markers of inflammation in patients with good and poor glycemic control.ResultsPatients in <7% HbA1C category, those with high abdominal fat had ≈262% higher CRP and ≈30.6% higher IL-6 compared to those with low abdominal fat (p˂0.05). Patients in ≥7% HbA1C category, those with high abdominal fat had ≈41.4% higher CRP and ≈33.9% higher IL-6 compared to those with low abdominal fat (p˂0.05). Abdominal fat was directly related to CRP (p˂0.023) and IL-6 (p˂0.002) concentrations in both groups of type-2 diabetic patients with <7% and ≥7% HbA1C. In patients with ≥7% HbA1C, BMI was directly related to CRP (p˂0.02) and IL-6 (p˂0.047). Whereas in patients with <7% HbA1C, BMI was not associated with CRP or IL-6 concentrations.ConclusionHigh level of abdominal fat is associated with systemic inflammation in type-2 diabetes regardless of glycemic control. Abdominal fat is a better predictor (determinant) of inflammation than BMI in patients with type-2 diabetes with or without glycemic control.

Role of autophagy in LPS‑induced inflammation in INS‑1 cells.

Inflammation has been implicated in the pathogenesis of type 2 diabetes (T2D), which is a progressive disease characterized by pancreatic β‑cell dysfunction and apoptosis with consequential insufficient insulin secretion. Autophagy is necessary to maintain the structure, mass and function of pancreatic β‑cells. The present study investigated the crosstalk between autophagy and inflammasome activation in T2D. INS‑1 cells were stimulated with lipopolysaccharide. Apoptosis and reactive oxygen species (ROS) formation were measured using flow cytometry, and cell proliferation was measured using Cell Counting Kit‑8 solution. Autophagy was assayed using western blotting and transmission electron microscopy. The expression levels of interleukin‑1β (IL‑1β) and caspase‑1 were detected by western blotting. The results demonstrated that inhibiting autophagy using 3‑methyladenine (3‑MA) promoted INS‑1 cell apoptosis. This response was correlated with an increase in ROS production and the inflammatory response, including IL‑1β maturation and caspase‑1 activation. Furthermore, when ROS were inhibited using N‑acetyl‑L‑cysteine, inflammation was decreased. These results demonstrated that inhibition of autophagy enhanced inflammatory injury via the ROS‑mediated activation of the Nod‑like receptor pyrin domain‑containing protein 3 inflammasome. Autophagy may have a protective effect by mitigating inflammation in T2D, which may provide a novel approach for T2D treatment.

Hyaluronan levels are increased systemically in human type 2 but not type 1 diabetes independently of glycemic control

Hyaluronan (HA), an extracellular matrix glycosaminoglycan, is implicated in the pathogenesis of both type 1 diabetes (T1D) as well as type 2 diabetes (T2D) and has been postulated to be increased in these diseases due to hyperglycemia. We have examined the serum and tissue distribution of HA in human subjects with T1D and T2D and in mouse models of these diseases and evaluated the relationship between HA levels and glycemic control. We found that serum HA levels are increased in T2D but not T1D independently of hemoglobin-A1c, C-peptide, body mass index, or time since diabetes diagnosis. HA is likewise increased in skeletal muscle in T2D subjects relative to non-diabetic controls. Analogous increases in serum and muscle HA are seen in diabetic db/db mice (T2D), but not in diabetic DORmO mice (T1D). Diabetes induced by the β-cell toxin streptozotozin (STZ) lead to an increase in blood glucose but not to an increase in serum HA. These data indicate that HA levels are increased in multiple tissue compartments in T2D but not T1D independently of glycemic control. Given that T2D but not T1D is associated with systemic inflammation, these patterns are consistent with inflammatory factors and not hyperglycemia driving increased HA. Serum HA may have value as a biomarker of systemic inflammation in T2D.

Hypoxia potentiates LPS-induced inflammatory response and increases cell death by promoting NLRP3 inflammasome activation in pancreatic β cells

Hypoxia and islet inflammation are involved in β-cell failure in type 2 diabetes (T2D). Elevated plasma LPS levels have been verified in patients with T2D, and hypoxia occurs in islets of diabetic mice. Activation of inflammasomes in ischemic or hypoxic conditions was identified in various tissues. Here, we investigated whether hypoxia activates the inflammasome in β cells and the possible mechanisms involved. In mouse insulinoma cell line 6 (MIN6), hypoxia (1% O2) primes the NLRP3 inflammasome along with NF-κB signaling activation. Our results demonstrate that hypoxia can activate the NLRP3 inflammasome in LPS-primed MIN6 to result in initiating the β cell inflammatory response and cell death in vitro. Reactive oxygen species (ROS) and the thioredoxin-interacting protein (TXNIP) are up-regulated in response to hypoxia. Finally, the role of the ROS-TXNIP axis in mediating the activation of the NLRP3 inflammasome and cell death was characterized by pretreating with the ROS scavenger N-acetylcysteine (NAC) and performing TXNIP knockdown experiments in MIN6. Our data indicate for the first time that the inflammasome is involved in the inflammatory response and cell death in hypoxia-induced β cells through the ROS-TXNIP-NLRP3 axis in vitro. This provides new insight into the relationship between hypoxia and inflammation in T2D.

TLR-induced secretion of novel cytokine IL-27 is defective in newly diagnosed type-2 diabetic subjects

Toll-like receptors (TLRs), the innate immune receptors, act as sentinels bridging both innate and adaptive arms of immunity. In the present study, we estimated TLR-induced secretion of IL-27, IL-12, IL-23, IL-8, IP-10, IL-17, IL-6 and TNF-α (by ELISA) and expression of Human Leukocyte Antigen- (Human Leukocyte Antigen - antigen D Related (HLA-DR), CD69, CD80 (also known asB7-1) (by flowcytometry) and Activating Transcription Factor 3(ATF3) (by qRT-PCR) in whole blood cultures of control and type-2 diabetic (both newly diagnosed/NDD and known/KDM) subjects. TLR-induced secretion of IL-27 was significantly reduced in the NDD group compared to the control (Normal Glucose Tolerance (NGT)) and KDM groups. On the other hand, the expression of CD80 was significantly upregulated in both the monocytes and B cells in KDM group. This was associated with increased T cell activation (CD3+CD69+HLA-DR+) with increased IL-17 and reduced TNF-α secretion in this group. Impaired TLR-induced IL-27 secretion and augmented expression of antigen presentation molecules result in chronic T cell activation which may fuel T cell-mediated inflammation in type-2 diabetes.

Abstract 235: Interaction Between a Macrophage Chemokine Receptor, CCR2, and Its Ligand Plays a Crucial Role in Macrophage Recruitment Aand Regulated Inflammation in Normal Wound Healing

Background: Wound healing in chronic diseases, such as type 2 diabetes (T2D), is impaired due to dysregulated inflammation. Innate immune cells, particularly macrophages, play a significant role in regulated inflammation following tissue injury. After injury, CCR2+ monocytes are recruited to the peripheral wound. This recruitment is mediated in part by the CCR2 ligand, CCL2. Thus, we hypothesized that the CCL2/CCR2 interaction is vital for normal wound healing and appropriate inflammation, and that this signaling cascade is impaired in T2D. Methods: CCR2 -/- mice and littermate controls underwent 4mm hindlimb wounds, and wound closure was compared daily. Wound macrophages (CD3-CD19-NK1.1-CD11b+ cells) were analyzed on day 3 by flow cytometry for intracellular cytokine production. Adoptive transfer was performed using blood CD11b+ cells from WT C57BL/6 or CCR2 -/- mice isolated by magnetic sorting and transferred into CCR2 -/- mice via tail vein injection. Mice were then wounded and wound closure was compared between the two groups. C57BL/6 mice were maintained on normal or high fat diet for 12-14 weeks, wounds were created, and CD11b+ cells were isolated from wounds on day 2. ELISA for CCL2 was performed. Results: CCR2 -/- mice showed significantly impaired wound healing on days 2-7 compared with littermate controls. Macrophages isolated on day 3 from wounds of CCR2 -/- mice expressed significantly less inflammatory cytokines (IL-1β, TNF-α) by qPCR. Flow cytometry analysis revealed less Ly6C hi macrophages in the wounds, as well as macrophages that made significantly less IL-1β, NOS2, and TNF-α. When adoptive transfer was performed, wound healing was restored to normal in the mice that received WT compared to those that received CCR2 -/- CD11b+ cells (P&lt; 0.01). Since CCR2 is important for normal wound inflammation, and we have previously shown that inflammation is impaired in the diet-induced obese (DIO) mice, we examined CCL2 in DIO wounds. CCL2 was significantly decreased in DIO wound macrophages on day 2. Conclusion: Appropriate CCR2/CCL2 interaction plays a crucial role in macrophage recruitment and regulated inflammation in normal wound healing. Impairment in CCR2/CCL2 signaling may be responsible, in part, for delayed early inflammation in T2D.

Fatty Acid Uptake Unexpectedly Supports a Th17 cytokine signature in Type 2 Diabetes (T2D) Inflammation

Abstract Metabolism controls T cell function, but the role of cellular metabolism in regulating our published T2D-associated Th17 cytokine signature is untested. Published work showed Th17 function requires fatty acid (FA) uptake, and suggested Th17s burn fat to support inflammation. We thus hypothesized that chronic exposure of immune cells to FAs, which occurs in T2D patients, drives Th17 inflammation. We used extracellular flux (XF) and cytokine analyses to show that CD3/CD28-stimulated PBMCs from BMI-matched T2D vs. non-T2D subjects were more glycolytic despite overall equal mitochondrial respiration. Consistent with this difference, T cell stimulation in glucose-free media followed by partial least squares analysis of cytokines showed glucose impacted cytokine profiles from T2D and non-T2D cells differently. To challenge the resulting prediction that PBMCs (predominantly T cells) from the two groups used different mechanisms to fuel cytokine responses, we performed XF analysis in the presence of FA +/− glucose. Non-T2D cells utilized FA as a fuel source, but T2D cells were dependent on glucose, despite data showing diabetic vs. non-T2D PBMCs store more lipid in response to elevated exogenous FA. Etomoxir, an inhibitor of FA transport into the mitochondria, caused non-T2D cells to increase glycolysis, but had no effect on T2D cells. These data confirmed that T2D cells exclusively burn glucose, not FA, to generate energy, and that T2D cells cannot be forced to use FA as a fuel. Finally, blockade of FA transport into the mitochondria revealed that FAs were associated with Th17 cytokine production. Together, our results support the unexpected conclusion that FA uptake is uncoupled from FA oxidation to drive the Th17 inflammation in T2D.

The Imbalance of B-Lymphocyte Subsets in Subjects with Different Glucose Tolerance: Relationship with Metabolic Parameter and Disease Status.

B lymphocytes are involved in inflammation and are related to insulin resistance in obesity and type 2 diabetes (T2D). This study investigated the phenotype and frequency of B-lymphocyte subsets in subjects recently diagnosed with T2D (n = 60), impaired glucose regulation (IGR, n = 73), and normal glucose tolerance (NGT, n = 169) by flow cytometry. T2D subjects had an increased percentage of CD19+CD23+ (B-2) cells and a decreased percentage of CD19+CD23− (B-1) cells attributing to CD19+CD23−CD5− (B-1b) cells, but not CD19+CD23−CD5+ (B-1a) cells, compared to NGT and IGR subjects. The proportion of CD19+CD5+CD1dhi (B10) cells did not differ between the IGR or T2D group and NGT controls. Of note, HbA1c and triglyceride showed a positive correlation with B-2 cells but an inverse correlation with B-1 and B-1b cells, which were independently associated with the presence of T2D by logistic regression models. In summary, this study shows an unbalanced proinflammatory phenotype of B-cell subsets correlated with glycemia and lipidemia in patients with T2D. Our data provide new insight into chronic activation of the immune system and subclinical inflammation in T2D. Further prospective studies are warranted to confirm our observations.

Hyporesponsiveness to the anti-inflammatory action of interleukin-10 in type 2 diabetes.

Chronic low-grade inflammation contributes to the pathology and complications of type 2 diabetes (T2D). Interleukin-10 (IL10), an anti-inflammatory cytokine, is suggested to play a protective role in T2D. However, the impact of T2D on IL10 function has not been previously assessed. We examined the ability of IL10 to inhibit inflammation in human T2D immune cells and explored underlying mechanisms using macrophage models. IL10 was less effective at inhibiting tumour necrosis factor (TNF)-α secretion in T2D whole blood cultures, which was not explained by altered IL10 receptor surface expression. These findings were observed in macrophages exposed to high glucose, which demonstrated similar IL10 resistance or hyporesponsiveness. These findings were also not explained by changes in IL10 receptor protein or other downstream signaling proteins. High glucose was also shown to impair the ability of IL10 to activate STAT3, a downstream signaling protein of IL10. Treatment with the SHIP1 agonist, AQX-MN100, reversed IL10 hyporesponsiveness in macrophages cultured in high glucose and showed equal effectiveness at different glucose conditions. This data supports the idea that IL10 hyporesponsiveness may contribute to chronic inflammation in T2D. These novel findings suggest that strategies aimed to overcome IL10 hyporesponsiveness may hold therapeutic potential for reducing inflammation in T2D.

Plasma Zonulin and its Association with Kidney Function, Severity of Heart Failure, and Metabolic Inflammation.

The tight junction regulator zonulin has attracted clinical attention as a biomarker of increased gastrointestinal permeability. Recent work also suggests zonulin to represent a general regulator of tissue barriers and a player in metabolic inflammation. Here, we investigated the associations of zonulin with chronic heart failure (CHF), kidney function, and metabolic inflammation. Using multiple linear regression (Generalized Linear Model), this study determined the association of plasma zonulin with different laboratory and clinical parameters in 225 patients carrying automatic implantable cardioverters/defibrillators (AICD) for primary or secondary prevention. In another 115 patients with diastolic or systolic CHF, we investigated a possible relationship between zonulin and CHF severity. In the AICD cohort, zonulin associated inversely with serum creatinine (p = 0.013), carboxymethyl-lysine calprotectin (p < 0.001), and kynurenine (p = 0.009) and positively with homoarginine (p < 0.001). In the subgroup with type-2 diabetes (T2D) (n = 51), zonulin increased significantly with high-sensitivity CRP (p = 0.014). In the CHF cohort, we found a highly significant rise of NT-proBNP, but not of zonulin with NYHA functional classes I-IV or other parameters of CHF severity. The inverse associations of zonulin with creatinine and markers of cardio-vascular risk (high CMLcalprotectin and kynurenine, low homoarginine) are novel findings that need further experimental and clinical clarification. Our study indicates zonulin involvement in metabolic inflammation in T2D, but no association with disease status in CHF.

An Islet-Targeted Genome-Wide Association Scan Identifies Novel Genes Implicated in Cytokine-Mediated Islet Stress in Type 2 Diabetes.

Genome-wide association studies in human type 2 diabetes (T2D) have renewed interest in the pancreatic islet as a contributor to T2D risk. Chronic low-grade inflammation resulting from obesity is a risk factor for T2D and a possible trigger of β-cell failure. In this study, microarray data were collected from mouse islets after overnight treatment with cytokines at concentrations consistent with the chronic low-grade inflammation in T2D. Genes with a cytokine-induced change of >2-fold were then examined for associations between single nucleotide polymorphisms and the acute insulin response to glucose (AIRg) using data from the Genetics Underlying Diabetes in Hispanics (GUARDIAN) Consortium. Significant evidence of association was found between AIRg and single nucleotide polymorphisms in Arap3 (5q31.3), F13a1 (6p25.3), Klhl6 (3q27.1), Nid1 (1q42.3), Pamr1 (11p13), Ripk2 (8q21.3), and Steap4 (7q21.12). To assess the potential relevance to islet function, mouse islets were exposed to conditions modeling low-grade inflammation, mitochondrial stress, endoplasmic reticulum (ER) stress, glucotoxicity, and lipotoxicity. RT-PCR revealed that one or more forms of stress significantly altered expression levels of all genes except Arap3. Thapsigargin-induced ER stress up-regulated both Pamr1 and Klhl6. Three genes confirmed microarray predictions of significant cytokine sensitivity: F13a1 was down-regulated 3.3-fold by cytokines, Ripk2 was up-regulated 1.5- to 3-fold by all stressors, and Steap4 was profoundly cytokine sensitive (167-fold up-regulation). Three genes were thus closely associated with low-grade inflammation in murine islets and also with a marker for islet function (AIRg) in a diabetes-prone human population. This islet-targeted genome-wide association scan identified several previously unrecognized candidate genes related to islet dysfunction during the development of T2D.

Type 2 diabetes mellitus: From a metabolic disorder to an inflammatory condition.

Diabetes mellitus is increasing at an alarming rate and has become a global challenge. Insulin resistance in target tissues and a relative deficiency of insulin secretion from pancreatic β-cells are the major features of type 2 diabetes (T2D). Chronic low-grade inflammation in T2D has given an impetus to the field of immuno-metabolism linking inflammation to insulin resistance and β-cell dysfunction. Many factors advocate a causal link between metabolic stress and inflammation. Numerous cellular factors trigger inflammatory signalling cascades, and as a result T2D is at the moment considered an inflammatory disorder triggered by disordered metabolism. Cellular mechanisms like activation of Toll-like receptors, Endoplasmic Reticulum stress, and inflammasome activation are related to the nutrient excess linking pathogenesis and progression of T2D with inflammation. This paper aims to systematically review the metabolic profile and role of various inflammatory pathways in T2D by capturing relevant evidence from various sources. The perspectives include suggestions for the development of therapies involving the shift from metabolic stress to homeostasis that would favour insulin sensitivity and survival of pancreatic β-cells in T2D.

Impact of resolvin E1 on murine neutrophil phagocytosis in type 2 diabetes.

Diabetic complications involve inflammation-mediated microvascular and macrovascular damage, disruption of lipid metabolism, glycosylation of proteins, and abnormalities of neutrophil-mediated events. Resolution of inflamed tissues to health and homeostasis is an active process mediated by endogenous lipid agonists, including lipoxins and resolvins. This proresolution system appears to be compromised in type 2 diabetes (T2D). The goal of this study was to investigate unresolved inflammation in T2D. Wild-type (WT) and genetically engineered mice, including T2D mice (db/db), transgenic mice overexpressing the human resolvin E1 (RvE1) receptor (ERV1), and a newly bred strain of db/ERV1 mice, were used to determine the impact of RvE1 on the phagocytosis of Porphyromonas gingivalis in T2D. Neutrophils were isolated and incubated with fluorescein isothiocyanate-labeled P. gingivalis, and phagocytosis was measured in a fluorochrome-based assay by flow cytometry. Mitogen-activated protein kinase (MAPK) (p42 and p44) and Akt (Thr308 and Ser473) phosphorylation was analyzed by Western blotting. The mouse dorsal air pouch model was used to evaluate the in vivo impact of RvE1. Results revealed that RvE1 increased the neutrophil phagocytosis of P. gingivalis in WT animals but had no impact in db/db animals. In ERV1-transgenic and ERV1-transgenic diabetic mice, phagocytosis was significantly increased. RvE1 decreased Akt and MAPK phosphorylation in the transgenic animals. In vivo dorsal air pouch studies revealed that RvE1 decreases neutrophil influx into the pouch and increases neutrophil phagocytosis of P. gingivalis in the transgenic animals; cutaneous fat deposition was reduced, as was macrophage infiltration. The results suggest that RvE1 rescues impaired neutrophil phagocytosis in obese T2D mice overexpressing ERV1.

B cells support a dominant Th17 cytokine signature in type 2 diabetes (HEM4P.255)

Abstract T cell inflammation plays critical roles in the development of obesity-associated type 2 diabetes (T2D). B cells support T cell-mediated inflammation in T2D, but the mechanisms underlying lymphocyte cross-talk and the relative importance of T cell inflammation in human T2D remain untested. Using peripheral blood mononuclear cells (PBMC) and/or purified cells from T2D and non-diabetic (ND) subjects, we show that B cell contact upregulates a pro-inflammatory CD4+ Th17 T cell program in T2D. Neutralization of either B cell CD80/86 or the downstream production of T cell IL-17A/F significantly decreased production of classical diabetogenic cytokines (TNFα, IL-6) in samples from T2D subjects. Although monocytes, B cells and T cells produced TNFα in response to treatment of PBMCs with αCD3/CD28, monocyte TNFα production was independent of IL-17A/F, while IL-17F was critical for maximal TNFα production by both T and B cells. IL-17A/F neutralization also reduced IL-17A and IL-17F production by CD4+ T cells, indicating Th17 function is auto-regulated. We conclude that human B cell co-stimulation broadly supports Th17 cells, which in turn stimulate lymphocytes (but not monocytes) to produce the classical diabetogenic cytokine TNFα.

Toll‐like receptors and NLRP3 as central regulators of pancreatic islet inflammation in type 2 diabetes

The global health and economic burden of type 2 diabetes (T2D) has reached staggering proportions. Current projections estimate that 592 million people will have diabetes by 2035. T2D-which comprises 90% of cases-is a complex disease, in most cases resulting from a combination of predisposing genes and an unhealthy environment. Clinical onset of the disease occurs when pancreatic β cells fail in the face of insulin resistance. It has long been appreciated that chronic activation of the innate immune system is associated with T2D, and many organs critical to the regulation of glucose homeostasis show signs of a chronic inflammatory process, including the pancreatic islets of Langerhans. Recent clinical trials using IL-1-targeting agents have confirmed that inflammation contributes to β-cell failure in humans with T2D. However, little is known about the nature of the pro-inflammatory response within the islet, and there is considerable debate about the triggers for islet inflammation, which may be systemically derived and/or tissue-specific. In this review, we present evidence that Toll-like receptors 2 and 4 and the NLRP3 (Nucleotide-binding oligomerization domain, Leucine-rich Repeat and Pyrin domain containing 3) inflammasome are triggers for islet inflammation in T2D and propose that the activation of macrophages by these triggers mediates islet endocrine cell dysfunction. Therapeutically targeting these receptors may improve hyperglycemia and protect the β cell in T2D.

B cells promote inflammation in obesity and type 2 diabetes through regulation of T-cell function and an inflammatory cytokine profile

Patients with type 2 diabetes (T2D) have disease-associated changes in B-cell function, but the role these changes play in disease pathogenesis is not well established. Data herein show B cells from obese mice produce a proinflammatory cytokine profile compared with B cells from lean mice. Complementary in vivo studies show that obese B cell-null mice have decreased systemic inflammation, inflammatory B- and T-cell cytokines, adipose tissue inflammation, and insulin resistance (IR) compared with obese WT mice. Reduced inflammation in obese/insulin resistant B cell-null mice associates with an increased percentage of anti-inflammatory regulatory T cells (Tregs). This increase contrasts with the sharply decreased percentage of Tregs in obese compared with lean WT mice and suggests that B cells may be critical regulators of T-cell functions previously shown to play important roles in IR. We demonstrate that B cells from T2D (but not non-T2D) subjects support proinflammatory T-cell function in obesity/T2D through contact-dependent mechanisms. In contrast, human monocytes increase proinflammatory T-cell cytokines in both T2D and non-T2D analyses. These data support the conclusion that B cells are critical regulators of inflammation in T2D due to their direct ability to promote proinflammatory T-cell function and secrete a proinflammatory cytokine profile. Thus, B cells are potential therapeutic targets for T2D.

Effect of high-dose zinc supplementation with oral hypoglycemic agents on glycemic control and inflammation in type-2 diabetic nephropathy patients

Objective:The study aims to evaluate the effect of zinc sulfate on markers of glycemic control, lipid profile and inflammation in type-2 diabetes with microalbuminuria patients.Materials and Methods:Type-2 diabetes with microalbuminuria patients on oral hypoglycemic agents (OHA) and angiotensin converting enzyme (ACE) inhibitors were selected and divided into 2 groups: One group (n = 27) continued with OHA alone, second group (n = 27) was on OHA and in addition 50 mg elemental zinc as zinc sulphate supplementation for 12 weeks. Fasting, post-prandial blood glucose, glycosylated hemoglobin, lipid profiles, inflammatory marker hs-CRP and urine microalbumin were measured.Results:There were no significant differences in biochemical status among groups at baseline. After receiving zinc, the mean fasting blood glucose (FBS), post-prandial blood glucose (PPBS) and glycosylated hemoglobin (HbA1c) were decreased significantly (P = 0.0001). Significant decrease was observed in TG (P = 0.002) and VLDL-cholesterol (P = 0.002), whereas there was no significant decrease in TC and LDL-cholesterol. The high-density lipoprotein (HDL) cholesterol was significantly (P = 0.0001) increased from baseline. Zinc supplementation had significant effects in decreasing serum hs-CRP from 10.51 ± 1.68 mg/L to 7.75 ± 1.56 mg/L (P = 0.0001) and microalbumin level from 146.87 ± 30.83 mg/day to 80.70 ± 33.99 mg/day (P = 0.0001). There were no significant changes in the levels of all these parameters in OHA group.Conclusion:Our results conclude that supplementation of zinc improved the effectiveness of OHA and may be beneficial in decreasing blood glucose, TG, urinary albumin excretion and inflammation in diabetic nephropathy patients and thus reducing the risk of complications.

State of the union between metabolism and the immune system in type 2 diabetes

Lymphocytes and myeloid cells (monocyte/macrophages) have important roles in multiple types of diseases characterized by unresolved inflammation. The relatively recent appreciation of obesity, insulin resistance and type 2 diabetes (T2D) as chronic inflammatory diseases has stimulated interest in understanding the role of immune cells in metabolic imbalance. Myeloid cells regulate inflammation through cytokine production and the adipose tissue remodeling that accompanies hyper-nutrition, thus are critical players in metabolic homeostasis. More recently, multiple studies have indicated a role for T cells in obesity-associated inflammation and insulin resistance in model organisms, with parallel work indicating that pro-inflammatory changes in T cells also associate with human T2D. Furthermore, the expansion of T cells with similar antigen-binding sites in obesity and T2D indicates these diseases share characteristics previously attributed to inflammatory autoimmune disorders. Parallel pro-inflammatory changes in the B-cell compartment of T2D patients have also been identified. Taken together, these studies indicate that in addition to accepted pro-inflammatory roles of myeloid cells in T2D, pro-inflammatory skewing of both major lymphocyte subsets has an important role in T2D disease pathogenesis. Basic immunological principles suggest that alterations in lymphocyte function in obesity and T2D patients are an integral part of a feed-forward pro-inflammatory loop involving additional cell types. Importantly, the pro-inflammatory loop almost inevitably includes adipocytes, known to respond to pro-inflammatory, pro-diabetogenic cytokines originating from the myeloid and lymphoid compartments. We propose a model for inflammation in T2D that functionally links lymphocyte, myeloid and adipocyte contributions, and importantly proposes that tools for B-cell ablation or regulation of T-cell subset balance may have a place in the endocrinologist's limited arsenal.