A comparison among three maximal mathematical models of the glucose-insulin system.

The most well-known and widely used mathematical representations of the physiology of a diabetic individual are the Sorensen and Hovorka models as well as the UVAPadova Simulator. While the Hovorka model and the UVAPadova Simulator only describe the glucose metabolism of a subject with type 1 diabetes, the Sorensen model was formulated to simulate the behaviour of both normal and diabetic individuals. The UVAPadova model is the most known model, accepted by the FDA, with a high level of complexity. The Hovorka model is the simplest of the three models, well documented and used primarily for the development of control algorithms. The Sorensen model is the most complete, even though some modifications were required both to the model equations (adding useful compartments for modelling subcutaneous insulin delivery) and to the parameter values. In the present work several simulated experiments, such as IVGTTs and OGTTs, were used as tools to compare the three formulations in order to establish to what extent increasing complexity translates into richer and more correct physiological behaviour. All the equations and parameters used for carrying out the simulations are provided.

Elevated glucose increases genomic instability by inhibiting nucleotide excision repair.

We investigated potential mechanisms by which elevated glucose may promote genomic instability. Gene expression studies, protein measurements, mass spectroscopic analyses, and functional assays revealed that elevated glucose inhibited the nucleotide excision repair (NER) pathway, promoted DNA strand breaks, and increased levels of the DNA glycation adduct N 2 -(1-carboxyethyl)-2'-deoxyguanosine (CEdG). Glycation stress in NER-competent cells yielded single-strand breaks accompanied by ATR activation, γH2AX induction, and enhanced non-homologous end-joining and homology-directed repair. In NER-deficient cells, glycation stress activated ATM/ATR/H2AX, consistent with double-strand break formation. Elevated glucose inhibited DNA repair by attenuating hypoxia-inducible factor-1α-mediated transcription of NER genes via enhanced 2-ketoglutarate-dependent prolyl hydroxylase (PHD) activity. PHD inhibition enhanced transcription of NER genes and facilitated CEdG repair. These results are consistent with a role for hyperglycemia in promoting genomic instability as a potential mechanism for increasing cancer risk in metabolic disease. Because of the pleiotropic functions of many NER genes beyond DNA repair, these results may have broader implications for cellular pathophysiology.

Extracellular levels of glucose in the hippocampus and striatum during maze training for food or water reward in male rats.

Glucose potently enhances cognitive functions whether given systemically or directly to the brain. The present experiments examined changes in brain extracellular glucose levels while rats were trained to solve hippocampus-sensitive place or striatum-sensitive response learning tasks for food or water reward. Because there were no task-related differences in glucose responses, the glucose results were pooled across tasks to form combined trained groups. During the first 1-3 min of training for food reward, glucose levels in extracellular fluid (ECF) declined significantly in the hippocampus and striatum; the declines were not seen in untrained, rewarded rats. When trained for water reward, similar decreases were observed in both brain areas, but these findings were less consistent than those seen with food rewards. After the initial declines in ECF glucose levels, glucose increased in most groups, approaching asymptotic levels ∼15-30 min into training. Compared to untrained food controls, training with food reward resulted in significant glucose increases in the hippocampus but not striatum; striatal glucose levels exhibited large increases to food intake in both trained and untrained groups. In rats trained to find water, glucose levels increased significantly above the values seen in untrained rats in both hippocampus and striatum. The decreases in glucose early in training might reflect an increase in brain glucose consumption, perhaps triggering increased brain uptake of glucose from blood, as evident in the increases in glucose later in training. The increased brain uptake of glucose may provide additional neuronal metabolic substrate for metabolism or provide astrocytic substrate for production of glycogen and lactate.

Uncarboxylated osteocalcin alleviates the inhibitory effect of high glucose on osteogenic differentiation of mouse bone marrow-derived mesenchymal stem cells by regulating TP63.

BACKGROUND: Progressive population aging has contributed to the increased global prevalence of diabetes and osteoporosis. Inhibition of osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) by hyperglycemia is a potential pathogenetic mechanism of osteoporosis in diabetic patients. Uncarboxylated osteocalcin (GluOC), a protein secreted by mature osteoblasts, regulates bone development as well as glucose and lipid metabolism. In our previous studies, GluOC was shown to promote osteoblastic differentiation of BMSCs; however, the underlying mechanisms are not well characterized. Tumor protein 63 (TP63), as a  transcription factor, is closely related to bone development and glucose metabolism. RESULTS: In this study, we verified that high glucose suppressed osteogenesis and upregulated adipogenesis in BMSCs, while GluOC alleviated this phenomenon. In addition, high glucose enhanced TP63 expression while GluOC diminished it. Knock-down of TP63 by siRNA transfection restored the inhibitory effect of high glucose on osteogenic differentiation. Furthermore, we detected the downstream signaling pathway PTEN/Akt/GSK3ß. We found that diminishing TP63 decreased PTEN expression and promoted the phosphorylation of Akt and GSK3ß. We then applied the activator and inhibitor of Akt, and concluded that PTEN/Akt/GSK3ß participated in regulating the differentiation of BMSCs. CONCLUSIONS: Our results indicate that GluOC reduces the inhibitory effect of high glucose on osteoblast differentiation by regulating the TP63/PTEN/Akt/GSK3ß pathway. TP63 is a potential novel target for the prevention and treatment of diabetic osteoporosis.

[Regulatory effect of microRNA-126 on macrophage proliferation caused by high glucose stimulation].

Objective: To explore the effects of microRNA-126 (miR-126) on the proliferation of human myeloid leukemia mononuclear cells (THP-1)-derived macrophages in high glucose environment and the regulatory role of miR-126 in periodontitis with diabetes. Methods: THP-1 cells were cultured in vitro and 5 µg/L phorbol-12-myristate-13-acetate was applied to induce THP-1 cells differentiating into macrophages for 48 h in low glucose culture medium (5.5 mmol/L). THP-1-derived macrophages were then cultured with low glucose, medium glucose (15 mmol/L) or high glucose (25 mmol/L) media respectively. The proliferation of THP-1-derived macrophages was detected by cell counting kit-8 (CCK-8) method and the expressions of miR-126 and proliferation-associated factors were detected by quantitative real time PCR (qRT-PCR). The miR-126 mimic or inhibitor was transfected into THP-1-derived macrophages for 72 h. The proliferation of cells was detected by CCK-8 method and the expressions of miR-126 or proliferation-associated factors were detected by qRT-PCR. Results: Increasing glucose concentration decreased the proliferation of THP-1-derived macrophages (day 7, A values in low, medium and high glucose groups were 0.369±0.014, 0.214±0.009 and 0.200±0.010, respectively, P<0.01) as well as the survival rate (P<0.05), promoted the expression of miR-126, B-cell lymphoma-2 (Bcl-2)-associated X protein (BAX) and caspase-3 (P<0.05), and suppressed Bcl-2, phosphoinositol-3 kinase regulatory subunit 2 (PIK3R2) expression (P<0.05). After the miR-126 mimic was transfected in cells in low glucose medium for 72 h, compared with negative control (1.005±0.118), the expression of miR-126 significantly increased (2 980.227±170.431, P<0.05), and the proliferation of THP-1 derived macrophages decreased (negative control: 1.816±0.013, mimic group: 1.310±0.048, P<0.01), the level of BAX and caspase-3 significantly increased (P<0.01, P<0.05), PIK3R2 and Bcl-2 significantly decreased (P<0.05, P<0.01). After the miR-126 inhibitor was transfected in cells cultured in high glucose medium for 72 h, compared with negative control (0.723±0.133), the proliferation of inhibitor group increased (0.984±0.049, P<0.05), the level of BAX and caspase-3 significantly decreased (P<0.01, P<0.05), PIK3R2 and Bcl-2 significantly increased (P<0.01, P<0.05). Conclusions: High glucose condition can inhibit the proliferation of THP-1-derived macrophages and increase the expression of miR-126. MiR-126 can inhibit the proliferation of THP-1-derived macrophages in high glucose environment through up-regulating the expression of BAX and caspase-3 and down-regulating the expression of PIK3R2 and Bcl-2.

Circumventing the Crabtree effect: forcing oxidative phosphorylation (OXPHOS) via galactose medium increases sensitivity of HepG2 cells to the purine derivative kinetin riboside.

Small-molecule compound-based therapies have provided new insights into cancer treatment against mitochondrial impairment. N6-furfuryladenosine (kinetin riboside, KR) is a purine derivative and an anticancer agent that selectively affects the molecular pathways crucial for cell growth and apoptosis by interfering with mitochondrial functions and thus might be a potential mitotoxicant. Metabolism of cancer cells is predominantly based on the Crabtree effect that relies on glucose-induced inhibition of cell respiration and thus on oxidative phosphorylation (OXPHOS), which supports the survival of cancer cells in metabolic stress conditions. The simplest way to circumvent this phenomenon is to replace glucose with galactose in the culture environment. Consequently, cells become more sensitive to mitochondrial perturbations caused by mitotoxicants. In the present study, we evaluated several cellular parameters and investigated the effect of KR on mitochondrial functions in HepG2 cells forced to rely mainly on OXPHOS. We showed that KR in the galactose environment is a more potent apoptosis-inducing agent. KR decreases the mitochondrial membrane potential, reduces glutathione level, depletes cellular ATP, and induces reactive oxygen species (ROS) production in the OXPHOS state, leading to the loss of cell viability. Taken together, these results demonstrate that KR directly acts on the mitochondria to limit their function and that the sensitivity of cells is dependent on their ability to cope with energetic stress.

The relationship between serum adipokines and glucose homeostasis in normal-weight and obese patients on hemodialysis: a preliminary study.

PURPOSE: Insulin resistance (IR) is a prevalent disorder in advanced renal failure irrespective of diabetes. Adipokines might play a role in IR, which has not been well-documented in uremic conditions. This study investigated the relationship of Zinc-α2-glycoprotein (ZAG), adipose triglyceride lipase (ATGL), and adipolin with glucose-insulin homeostasis in normal weight (NW) and obese (OB) patients with hemodialysis. METHODS: In this cross-sectional study, 59 patients (29 NW; 18.5 ≤ BMI < 25 kg/m2, and 30 OB; BMI ≥ 30 kg/m2) were studied. Anthropometries, circulating ZAG, adipolin, ATGL, free fatty acids (FFAs), fasting blood glucose (FBG), insulin, and homeostasis model assessment of IR (HOMA)-IR were assessed. RESULTS: There were no significant differences in age, gender, hemodialysis duration, dialysis adequacy and diabetes between the two groups. ZAG (100.9 ± 37.1 vs. 107.5 ± 30.5 ng/mL, P = 0.03) and adipolin (12.4 ± 1.6 vs. 13.2 ± 2.8 ng/mL, P = 0.002) concentrations were significantly lower, and FFAs (228.1 ± 112.6 vs. 185 ± 119 ng/mL, P = 0.014) were significantly higher in the OB than NW group. No significant differences were observed in ATGL, FBG, insulin and HOMA-IR between the two groups. Patients with lower IR had higher ZAG (112.9 ± 31.7 vs. 94.9 ± 34.5 ng/mL; P = 0.046), lower FFAs (167.8 ± 98.4 vs. 249.9 ± 120.8 ng/mL; P = 0.004), and marginally lower ATGL (9.1 ± 5.2 vs. 12.3 ± 9.6 mIU/mL; P = 0.079) concentrations than those with higher IR. ZAG was negatively (r = - 0.323, P = 0.018 and r = - 0.266, P = 0.054) and FFAs were positively (r = 0.321, P = 0.019 and r = 0.353, P = 0.009) correlated with insulin and HOMA-IR, respectively. ATGL was directly correlated with FFAs (r = 0.314, P = 0.018). CONCLUSIONS: Novel adipokines, ZAG and ATGL, might contribute to glucose-insulin homeostasis in hemodialysis. Understanding potential causative, diagnostic or therapeutic roles of adipokines in IR require further studies.

Glucose modulates proliferation in root apical meristems via TOR in maize during germination.

The Glucose-Target of Rapamycin (Glc-TOR) pathway has been studied in different biological systems, but scarcely during early seed germination. This work examines its importance for cell proliferation, expression of cell cycle key genes, their protein levels, besides morphology and cellularization of the root apical meristem of maize (Zea mays) embryo axes during germination under the influence of two simple sugars, glucose and sucrose, and a specific inhibitor of TOR activity, AZD 8055. The two sugars promote germination similarly and to an extent, independently of TOR activity. However, the Glc-TOR pathway increases the number of cells committed to proliferation, increasing the expression of a cell cycle gene, ZmCycD4;2, a putative G1/S regulator. Also, Glc-TOR may have influence on the protein stability of another G1/S cyclin, ZmCycD3, but had no influence on ZmCDKA;1 or ZmKRP3 or their proteins. Results suggest that the Glc-TOR pathway participates in the regulation of proliferation through different mechanisms that, in the end, modify the timing of seed germination.

Insulin Resistance Does Not Impair Mechanical Overload-Stimulated Glucose Uptake, but Does Alter the Metabolic Fate of Glucose in Mouse Muscle.

Skeletal muscle glucose uptake and glucose metabolism are impaired in insulin resistance. Mechanical overload stimulates glucose uptake into insulin-resistant muscle; yet the mechanisms underlying this beneficial effect remain poorly understood. This study examined whether a differential partitioning of glucose metabolism is part of the mechanosensitive mechanism underlying overload-stimulated glucose uptake in insulin-resistant muscle. Mice were fed a high-fat diet to induce insulin resistance. Plantaris muscle overload was induced by unilateral synergist ablation. After 5 days, muscles were excised for the following measurements: (1) [3H]-2-deoxyglucose uptake; (2) glycogen; 3) [5-3H]-glucose flux through glycolysis; (4) lactate secretion; (5) metabolites; and (6) immunoblots. Overload increased glucose uptake ~80% in both insulin-sensitive and insulin-resistant muscles. Overload increased glycogen content ~20% and this was enhanced to ~40% in the insulin-resistant muscle. Overload did not alter glycolytic flux, but did increase muscle lactate secretion 40-50%. In both insulin-sensitive and insulin-resistant muscles, overload increased 6-phosphogluconate levels ~150% and decreased NADP:NADPH ~60%, indicating pentose phosphate pathway activation. Overload increased protein O-GlcNAcylation ~45% and this was enhanced to ~55% in the insulin-resistant muscle, indicating hexosamine pathway activation. In conclusion, insulin resistance does not impair mechanical overload-stimulated glucose uptake but does alter the metabolic fate of glucose in muscle.

The sialidase inhibitor 2,3-dehydro-2-deoxy-N-acetylneuraminic acid is a glucose-dependent potentiator of insulin secretion.

Sialidase cleaves sialic acid residues from a sialoglycoconjugate: oligosaccharides, glycolipids and glycoproteins that contain sialic acid. Histochemical imaging of the mouse pancreas using a benzothiazolylphenol-based sialic acid derivative (BTP3-Neu5Ac), a highly sensitive histochemical imaging probe used to assess sialidase activity, showed that pancreatic islets have intense sialidase activity. The sialidase inhibitor 2,3-dehydro-2-deoxy-N-acetylneuraminic acid (DANA) remarkably enhances glutamate release from hippocampal neurons. Since there are many similar processes between synaptic vesicle exocytosis and secretory granule exocytosis, we investigated the effect of DANA on insulin release from ß-cells. Insulin release was induced in INS-1D cells by treatment with 8.3 mM glucose, and the release was enhanced by treatment with DANA. In a mouse intraperitoneal glucose tolerance test, the increase in serum insulin levels was enhanced by intravenous injection with DANA. However, under fasting conditions, insulin release was not enhanced by treatment with DANA. Calcium oscillations induced by 8.3 mM glucose treatment of INS-1D cells were not affected by DANA. Blood insulin levels in sialidase isozyme Neu3-deficient mice were significantly higher than those in WT mice under ad libitum feeding conditions, but the levels were not different under fasting conditions. These results indicate that DANA is a glucose-dependent potentiator of insulin secretion. The sialidase inhibitor may be useful for anti-diabetic treatment with a low risk of hypoglycemia.

Adaptive short-term associative conditioning in the pancreatic ß-cell.

This study associates cholinergic stimulation of the pancreatic ß-cell electrical activity with a short-term memory phenomenon. Glucose pulses applied to a basal glucose concentration induce depolarizing waves which are used to estimate the evolution of the ß-cell glucose sensitivity. Exposure to carbamoylcholine (carbachol) increases the size of the glucose-induced depolarizing waves. This change appears after carbachol withdrawal and implies a temporal potentiation of sensitivity (TPS) lasting up to one hour. TPS induction requires the simultaneous action of carbachol and glucose. The substitution of glucose with the secretagogues glyceraldehyde or 2-ketoisocaproate mimics glucose-induced TPS, while palmitate does not. TPS is not produced if the membrane is kept hyperpolarized by diazoxide. Glucose can be replaced by tolbutamide, suggesting a role of depolarization and a subsequent increase in intracellular calcium concentration. A role for kinases is suggested because staurosporine prevents TPS induction. Cycloheximide does not impair TPS induction, indicating that de novo protein synthesis is not required. The fact that the two inputs acting simultaneously produce an effect that lasts up to one hour without requiring de novo protein synthesis suggests that TPS constitutes a case of short-term associative conditioning in non-neural tissue. The convergence of basal glucose levels and muscarinic activation happens physiologically during the cephalic phase of digestion, in order to later absorb incoming fuels. Our data reveals that the role of the cephalic phase may be extended, increasing nutrient sensitivity during meals while remaining low between them.

High Glucose Content Abrogated the Normal Activity of Heat Shock Protein Signaling Pathway in Human Neuroblastoma Cells.

BACKGROUND: Detrimental effects of high glucose content (HGC) were proved in different tissues such as the central nervous system. It seems that diabetic conditions could also alter the functional behavior of stem cells residing in the context of the nervous system. METHODS: The possible effects of 40 and 70 mmol glucose were examined on HSP70 signaling pathways with a specific focus on protein translation, folding values of human neuroblastoma cell line SHSY-5Y after 72 h. Human neuroblastoma cells were exposed to 5, 40 and 70 mmol glucose doses. The transcription level of genes related to HSP70 signaling was also evaluated by PCR array. RESULTS: The data from PCR array showed high glucose especially 70 mmol could potentially modulate the normal function of protein folding, endoplasmic reticulum derived protein folding and synthesis in neuroblastoma cells (p <0.05). CONCLUSIONS: Data showed that high glucose condition makes neuroblastoma cells prone to biochemical insufficiency by affecting the function of HSP70 signaling pathway and protein synthesis.

Glutaminolysis and Glycolysis Are Essential for Optimal Replication of Marek's Disease Virus.

Viruses may hijack glycolysis, glutaminolysis, or fatty acid ß-oxidation of host cells to provide the energy and macromolecules required for efficient viral replication. Marek's disease virus (MDV) causes a deadly lymphoproliferative disease in chickens and modulates metabolism of host cells. Metabolic analysis of MDV-infected chicken embryonic fibroblasts (CEFs) identified elevated levels of metabolites involved in glutamine catabolism, such as glutamic acid, alanine, glycine, pyrimidine, and creatine. In addition, our results demonstrate that glutamine uptake is elevated by MDV-infected cells in vitro Although glutamine, but not glucose, deprivation significantly reduced cell viability in MDV-infected cells, both glutamine and glucose were required for virus replication and spread. In the presence of minimum glutamine requirements based on optimal cell viability, virus replication was partially rescued by the addition of the tricarboxylic acid (TCA) cycle intermediate, α-ketoglutarate, suggesting that exogenous glutamine is an essential carbon source for the TCA cycle to generate energy and macromolecules required for virus replication. Surprisingly, the inhibition of carnitine palmitoyltransferase 1a (CPT1a), which is elevated in MDV-infected cells, by chemical (etomoxir) or physiological (malonyl-CoA) inhibitors, did not reduce MDV replication, indicating that MDV replication does not require fatty acid ß-oxidation. Taken together, our results demonstrate that MDV infection activates anaplerotic substrate from glucose to glutamine to provide energy and macromolecules required for MDV replication, and optimal MDV replication occurs when the cells do not depend on mitochondrial ß-oxidation.IMPORTANCE Viruses can manipulate host cellular metabolism to provide energy and essential biosynthetic requirements for efficient replication. Marek's disease virus (MDV), an avian alphaherpesvirus, causes a deadly lymphoma in chickens and hijacks host cell metabolism. This study provides evidence for the importance of glycolysis and glutaminolysis, but not fatty acid ß-oxidation, as an essential energy source for the replication and spread of MDV. Moreover, it suggests that in MDV infection, as in many tumor cells, glutamine is used for generation of energetic and biosynthetic requirements of the MDV infection, while glucose is used biosynthetically.

Lateral hypothalamic orexin glucose-inhibited neurons may regulate reward-based feeding by modulating glutamate transmission in the ventral tegmental area.

Glucose inhibits ∼60% of lateral hypothalamic (LH) orexin neurons. Fasting increases the activation of LH orexin glucose-inhibited (GI) neurons in low glucose. Increases in spontaneous glutamate excitatory postsynaptic currents (sEPSCs) onto putative VTA DA neurons in low glucose are orexin dependent (Sheng et al., 2014). VTA DA neurons modulate reward-based feeding. We tested the hypothesis that increased activation of LH orexin-GI neurons in low glucose increases glutamate signaling onto VTA DA neurons and contributes to reward-based feeding in food restricted animals. N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) currents on putative VTA DA neurons were measured using whole cell voltage clamp recording in horizontal brain slices containing the LH and VTA. Decreased glucose increased the NMDA receptor current for at least one hour after returning glucose to basal levels (P < 0.05; N = 8). The increased current was blocked by an orexin 1 receptor antagonist (P < 0.05; N = 5). Low glucose caused a similar persistent enhancement of AMPA receptor currents (P < 0.05; N = 7). An overnight fast increased the AMPA/NMDA receptor current ratio, an in vivo index of glutamate plasticity, on putative VTA DA neurons. Conditioned place preference (CPP) for palatable food was measured during LH dialysis with glucose. CPP score was negatively correlated with increasing LH glucose (P < 0.05; N = 20). These data suggest that increased activation of LH orexin-GI neurons in low glucose after weight loss, leads to enhanced glutamate signaling on VTA DA neurons, increases the drive to eat rewarding food, and may contribute to weight regain.

Insulin signaling in the whole spectrum of GH deficiency

ABSTRACT GH is one of the insulin counterregulatory hormones which acts in the opposite way to insulin, increasing the glucose production by the liver and kidneys and decreasing glucose uptake from peripheral tissues, thus being a hyperglycemic hormone. When in excess, as in acromegaly, it induces glucose intolerance and diabetes. As expected, patients with GH deficiency (GHD) have hypoglycemia, especially in early childhood, but as GH is also a lipolytic hormone, these patients are becoming obese with higher percentages of body fat. Although obesity in general is directly related to insulin resistance, in patients with GH secretion disorders this relationship may be altered. In acromegaly there is a decrease in fat mass with worsening insulin sensitivity and mice with isolated GHD are characterized by greater insulin sensitivity despite excess fat mass. In humans with GHD, body composition shows increased body fat and decreased free fat mass, but the results regarding insulin sensitivity are still controversial in these patients. These discrepant results regarding insulin sensitivity in patients with GHD suggest the existence of other variables influencing these results. In the present review, we will try to follow the path of the different researches conducted on this subject, both in animal and human models, with the goal of understanding the current knowledge of insulin sensitivity across the spectrum of GHD. Arch Endocrinol Metab. 2019;63(6):582-91

Arabidopsis GSM1 is involved in ABI4-regulated ABA signaling under high-glucose condition in early seedling growth.

In plants, sugar acts as an essential signaling molecule that modulates various aspects of metabolism, growth and development, which are also controlled by phytohormones. However, the molecular mechanism of cross-talk between sugar and phytohormones still remains to be elucidated. We have identified gsm1 (glucose-hypersensitive mutant 1) as a mutant with impaired cotyledon development that shows sensitivity to exogenous abscisic acid (ABA). The addition of fluridone can reverse the glucose (Glc) inhibitory effect in gsm1, implying that endogenous ABA is involved in the Glc response of gsm1. In 4.5% Glc, the expression of Glc-induced ABA-responsive genes in gsm1-1 was nearly two times higher than that in the wild type. Compared to gsm1-1, the gsm1-1 abi4-1 double mutant exhibited reduced sensitivity to Glc and ABA, which was similar to the Glc and ABA insensitive phenotype of abi4-1, suggesting that ABI4 is epistatic to GSM1. In the treatment with 4.5% Glc, the GSM1 transcript level was greatly increased in abi4-1 by almost 4-fold of that in the wild type. These data suggest that GSM1 plays an important role in the ABI4-regulated Glc-ABA signaling cascade during Arabidopsis early seedling growth.

Hepatic deficiency of Poldip2 in type 2 diabetes dampens lipid and glucose homeostasis.

Moderate or low level hydrogen peroxides has been shown to play an important role in vascular smooth muscle cell (VSMC) function, in which the polymerase DNA-directed interacting protein 2 (Poldip2), functioned as a key regulator of NOX4 activity. In current study, we unexpectedly found that type 2 diabetes mellitus (T2DM) substantially suppresses the hepatic Poldip2 expression, and that the hepatic deficiency of Poldip2 may be correlated with dysregulation of hepatic cholesterol and plasma triglycerides. In cultured hepatocytes, we found that both insulin and leptin may inhibit hepatic expression of Poldip2 under high glucose concentration, but these suppressions were totally abolished under normoglycemic condition. POLDIP2 siRNA knockdown significantly impaired the H2O2 induction by insulin or leptin under normoglycemic condition, contributing the accumulation of cholesterol in cultured liver cells. The in vivo restoration of hepatic Poldip2 expression in T2DM mice remarkably rescued the moderate H2O2 generation in livers versus control mice, resulting in significant amelioration of hepatic cholesterol accumulation and plasma triglyceride levels. Importantly, the moderate induction of H2O2 in livers dramatically improved the hepatic PI3K-C1/AKT signaling or dampened PI3K-C2γ/AKT signaling through suppression of PTEN and PTP1B activities, thereby inhibiting the hepatic expression of HMGCR and SREBP2 for cholesterol synthesis. Moreover, the restitution of hepatic Poldip2 expression in diabetic mice significantly lowered the VLDL-cholesterol production rate, and substantially suppressed PEPCK and G6Pase expressions for gluconeogenesis, thus significantly improving the plasma insulin and glucose levels, and ITT and GTT outcomes in diabetic mice. Our findings suggest that hepatic dysregulation of Poldip2 may contribute to diabetic dyslipidemia and hyperglycemia.

Tripartite cell networks for glucose homeostasis.

Controlling the excess and shortage of energy is a fundamental task for living organisms. Diabetes is a representative metabolic disease caused by the malfunction of energy homeostasis. The islets of Langerhans in the pancreas release long-range messengers, hormones, into the blood to regulate the homeostasis of the primary energy fuel, glucose. The hormone and glucose levels in the blood show rhythmic oscillations with a characteristic period of 5-10 min, and the functional roles of the oscillations are not clear. Each islet has [Formula: see text] and [Formula: see text] cells that secrete glucagon and insulin, respectively. These two counter-regulatory hormones appear sufficient to increase and decrease glucose levels. However, pancreatic islets have a third cell type, [Formula: see text] cells, which secrete somatostatin. The three cell populations have a unique spatial organization in islets, and they interact to perturb their hormone secretions. The mini-organs of islets are scattered throughout the exocrine pancreas. Considering that the human pancreas contains approximately a million islets, the coordination of hormone secretion from the multiple sources of islets and cells within the islets should have a significant effect on human physiology. In this review, we introduce the hierarchical organization of tripartite cell networks, and recent biophysical modeling to systematically understand the oscillations and interactions of [Formula: see text], [Formula: see text], and [Formula: see text] cells. Furthermore, we discuss the functional roles and clinical implications of hormonal oscillations and their phase coordination for the diagnosis of type II diabetes.

Glucose Homeostasis following Diesel Exhaust Particulate Matter Exposure in a Lung Epithelial Cell-Specific IKK2-Deficient Mouse Model.

BACKGROUND: Pulmonary inflammation is believed to be central to the pathogenesis due to exposure to fine particulate matter with aerodynamic diameter [Formula: see text] ([Formula: see text]). This central role, however, has not yet been systemically examined. OBJECTIVE: In the present study, we exploited a lung epithelial cell-specific inhibitor [Formula: see text] kinase 2 (IKK2) knockout mouse model to determine the role of pulmonary inflammation in the pathophysiology due to exposure to diesel exhaust particulate matter (DEP). METHODS: [Formula: see text] (lung epithelial cell-specific IKK2 knockout, KO) and [Formula: see text] (wild-type, tgWT) mice were intratracheally instilled with either vehicle or DEP for 4 months, and their inflammatory response and glucose homeostasis were then assessed. RESULTS: In comparison with tgWT mice, lung epithelial cell-specific IKK2-deficient mice had fewer DEP exposure-induced bronchoalveolar lavage fluid immune cells and proinflammatory cytokines as well as fewer DEP exposure-induced circulating proinflammatory cytokines. Glucose and insulin tolerance tests revealed that lung epithelial cell-specific IKK2 deficiency resulted in markedly less DEP exposure-induced insulin resistance and greater glucose tolerance. Akt phosphorylation analyses of insulin-responsive tissues showed that DEP exposure primarily targeted hepatic insulin sensitivity. Lung epithelial cell-specific IKK2-deficient mice had significantly lower hepatic insulin resistance than tgWT mice had. Furthermore, this difference in insulin resistance was accompanied by consistent differences in hepatic insulin receptor substrate 1 serine phosphorylation and inflammatory marker expression. DISCUSSION: Our findings suggest that in a tissue-specific knockout mouse model, an IKK2-dependent pulmonary inflammatory response was essential for the development of abnormal glucose homeostasis due to exposure to DEP. https://doi.org/10.1289/EHP4591.

Integrated multiscale mathematical modeling of insulin secretion reveals the role of islet network integrity for proper oscillatory glucose-dose response.

The integrated multiscale mathematical model we present in this paper is built on two of our previous ones: a model of electrical oscillation in ß-cells connected to neighboring cells within a three-dimensional (3D) network, and a model of glucose-induced ß-cell intracellular insulin granule trafficking and insulin secretion. In order to couple these two models, we assume that the rate at which primed and release-ready insulin granules fuse at the cell membrane increases with the intracellular calcium concentration. Moreover, by assuming that the fraction of free KATP-channels decreases with increasing glucose concentration, we take into account the effect of glucose dose on membrane potential and, indirectly via the effect on the potential, on intracellular calcium. Numerical analysis of our new model shows that a single step increase in glucose concentration yields the experimentally observed characteristic biphasic insulin release. We find that the biphasic response is typically oscillatory in nature for low and moderate glucose concentrations. The plateau fraction (the time that the ß-cells spend in their active firing phase) increases with increasing glucose dose, as does the total insulin secretion. At high glucose concentrations, the oscillations tend to vanish due to a constantly elevated membrane potential of the ß-cells. Our results also demonstrate how insulin secretion characteristics in various glucose protocols depend on the degree of ß-cell loss, highlighting the potential impact from disease. In particular, both the secretory capacity (average insulin secretion rate per ß-cell) and the oscillatory response diminish as the islet cell network becomes compromised.