Peripheral Tissue Insulin Research Articles

Potential Association of The Pathogenic Kruppel-like Factor 14 (KLF14) and Adiponectin (ADIPOQ) SNVs with Susceptibility to T2DM.

To evaluate the associations of the pathogenic variants in Kruppel-like Factor 14 (KLF 14) and Adiponectin (ADIPOQ) with susceptibility to type 2 diabetes mellitus (T2DM). Type 2 diabetes mellitus (T2DM) is a pandemic metabolic disease characterized by increased blood sugar and caused by resistance to insulin in peripheral tissues and damage to pancreatic beta cells. Kruppel-like Factor 14 (KLF-14) is proposed to be a regulator of metabolic diseases, such as diabetes mellitus (DM) and obesity. Adiponectin (ADIPOQ) is an adipocytokine produced by the adipocytes and other tissues and was reported to be involved in T2DM. To study the possible association of the KLF-14 rs972283 and ADIPOQ-rs266729 with the risk of T2DM in the Saudi population. We have evaluated the association of KLF-14 rs972283 C>T and ADIPOQ-rs266729 C>G SNV with the risk to T2D in the Saudi population using the Amplification Refractory Mutation System PCR (ARMS-PCR), and blood biochemistry analysis. For the KLF-14 rs972283 C>T SNV we included 115 cases and 116 healthy controls, and ADIPOQ-rs266729 C>G SNV, 103 cases and 104 healthy controls were included. Results indicated that the KLF-14 rs972283 GA genotype and A allele were associated with T2D risk with OR=2.14, p-value= 0.014 and OR=1.99, p-value=0.0003, respectively. Results also ADIPOQ-rs266729 CG genotype and C allele were associated with an elevated T2D risk with an OR=2.53, p=0.003 and OR=1.66, p-value =0.012, respectively. We conclude that SNVs in KLF-14 and ADIPOQ are potential loci for T2D risk. Future large-scale studies to verify these findings are recommended. These results need further verifications in protein functional and large-scale case control studies before being introduced for genetic testing.

THU251 Diagnostic Performance For Predicting Hepatic And Peripheral Tissue Insulin Resistance In Young Adult Men Using 1Hour Post Load Serum Glucose And Insulin Levels A Pilot Study

Abstract Disclosure: A.J. Ledezma: None. C.F. Espinel Pachón: None. S.S. Perea: None. J.E. Caminos: None. Insulin resistance (RI) is a risk factor for prediabetes and DM2, and other non communicable diseases. Different studies have demonstrated that 1h post load serum glucose levels during an oral glucose test tolerance OGTT seem to be a better predictor of peripheral RI than 2h post load serum glucose among individuals without DM2. On the other hand, HOMA IR reflects primarily hepatic sensitivity/resistance, meanwhile, Matsuda index, may reflect both hepatic and peripheral tissue insulin sensitivity/resistance. Thus, this study aimed to evaluate the diagnostic performance, to identify hepatic and peripheral RI, of 1h post load serum glucose and insulin levels during an OGTT in young adult men, using ROC AUC analysis. This cross-sectional study was conducted on a total of 91 young adult men (18-31-year-olds), 47 healthy lean (BMI <25 kg/m2), and 44 obese nondiabetic subjects (BMI ≥30 kg/m2). Subjects underwent a standard 75g OGTT and blood samples were drawn at 0, 30, 60, and 120 min to obtain serum glucose and insulin levels. Clinical and anthropometric and biochemical variables were determined. Participants were classified as RI based on a predefined Matsuda index cutoff 4.3 value. Cut-offs, sensitivity, and specificity for glucose, insulin, and anthropometrics parameters were determined by AUC ROC analysis for predicting RI diagnosis, and Spearman´s correlation was established between biochemical variables and waist/height ratio and Delong test analysis. Our results showed that 1h post load glucose levels had higher sensitivity 84.1% vs 47.7% and AUC 83.9% [CI 95% 75.6; 92.1%] vs 72.4% [CI 95% 61.8%; 83.0%] than 2h post load during OGTT, however lower specificity was found 70.2% vs 89.4%. Additionally, 1h post load insulin levels had higher sensitivity 90.9% vs 77% and AUC 97.1% [CI 95% 94; 100%] vs 91.9% [CI 95% 86.3; 97.5%] than 2h post load during OGTT, without changes in specificity 97.9% vs 97.8%. It is important to highlight that waist/height ratio reached a 100% AUC 95% CI diagnostic performance for RI in our sample. Additionally, HOMA IR index 99.8% [CI 95% 99.1; 100%], 1/fasting insulin 100% [CI 95% 0.99; 100%], and fasting glucose/insulin ratio 99.7% [CI 95% 99.2; 100%], showed a high diagnostic performance for RI. In the Spearman correlation, Waist/height ratio presented a high correlation with respect to Matsuda -0.8672; p<0.01 G/I1H -0.7454; p<0.01, 1/I1H -0.7783; p< 0.01; Delong test, the best performance comparing 1H vs 2H, G1H/G2H with Z value 2.0668 and P 0.03 In conclusion, 1h post load glucose and insulin levels and the waist/height ratio show greater diagnostic performance than 2h post load for detecting peripheral tissue and hepatic RI in young men. Therefore, Cut-offs values of glucose and insulin levels 1h post load provide simple but useful test for early detection of different prevalent diseases related to RI. Presentation: Thursday, June 15, 2023

Insulin and Its Key Role for Mitochondrial Function/Dysfunction and Quality Control: A Shared Link between Dysmetabolism and Neurodegeneration.

Insulin was discovered and isolated from the beta cells of pancreatic islets of dogs and is associated with the regulation of peripheral glucose homeostasis. Insulin produced in the brain is related to synaptic plasticity and memory. Defective insulin signaling plays a role in brain dysfunction, such as neurodegenerative disease. Growing evidence suggests a link between metabolic disorders, such as diabetes and obesity, and neurodegenerative diseases, especially Alzheimer's disease (AD). This association is due to a common state of insulin resistance (IR) and mitochondrial dysfunction. This review takes a journey into the past to summarize what was known about the physiological and pathological role of insulin in peripheral tissues and the brain. Then, it will land in the present to analyze the insulin role on mitochondrial health and the effects on insulin resistance and neurodegenerative diseases that are IR-dependent. Specifically, we will focus our attention on the quality control of mitochondria (MQC), such as mitochondrial dynamics, mitochondrial biogenesis, and selective autophagy (mitophagy), in healthy and altered cases. Finally, this review will be projected toward the future by examining the most promising treatments that target the mitochondria to cure neurodegenerative diseases associated with metabolic disorders.

The relationship between thyroid hormone levels, insulin resistance and body mass index, in patients with subclinical hypothyroidism andeuthyroid patients

Background. Hypothyroidism is a common thyroid disorder with female predominance. In general population its prevalance is 2–5% while 10 times higher in female than in men. Insulin resistance, one of the most discussed issues recently, is an inadequate response to insulin in peripheral tissues despite the normal secretory function of pancreatic islet cells. In this study, we analyzed relationship between thyroid hormone levels, body mass index and insulin resistance calculated with Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), Quantitative Insulin Sensitivity Check Index (QUICKI) and Atherogenic Index of Plasma (AIP) in SCH and euthyroid patients under levothyroxine treatment. Materials and methods. The clinical and laboratory data of approximately 14000 patients between the ages of 18–60 were retrospectively evaluated. After these exclusion criteria were applied, 371 eligible individuals were included in the study. All 371 individuals divided into three groups according to TSH levels. Group 1 is eutyhroid patients under levothyroxine treatment with TSH levels between 0.27–4.2μIU/mL. Group 2 is subclinical hypothyroid patients with TSH levels between 4.2–10 μIU/mL. Group 3 is healthy control group with TSH levels between 0.27–4.2 μIU/mL. Results. The euthyroid patient group has the highest (25.66±3.36 kg/m2) mean BMI. On the other hand the mean BMI was higher in SCH (24.0400±3.8436kg/m2) group than in control group (22.48±2.74 kg/m2) (p<0.05). Fasting plasma glucose (FPG), serum triglyserid, low density lipoprotein (LDL), anti-thyroid peroxidase (TPO) and insulin levels were significantly higher in euthyroid patient and SCH groups (p<0.05). Notably, total cholesterol, LDL and TPO levels were higher in euthyroid patient group (p<0.05). On the other hand, there were no difference between euthyroid patients and SCH group. Conclusions. This study found significantly elevated insulin resistance and cholesterol levels in SCH patients, so we hypothesized that SCH is also a risk factor for insulin resistance disorders such as cardiovascular diseases and metabolic syndrome. As a consequence, lipid metabolism defects and insulin resistance should be screened and treated in SCH patients. Thanks to the strong and significant correlation between HOMA and QUICKI in our study, we suggest the combined use of HOMA and QUICKI in these patients. Further and large-scale studies are needed to evaluate the relationship of HOMA, QUICKI, AIP, and BMI in detecting insulin resistance in SCH patients.

ФУНКЦИОНАЛЬНАЯ МОРФОЛОГИЯ ЖИРОВОЙ ТКАНИ И ЕЁ РОЛЬ В ФОРМИРОВАНИИ МЕТАБОЛИЧЕСКОГО СИНДРОМА

The article provides an overview of modern literature on the morphological and functional features of adipose tis- sue, as an organ that performs endocrine and immune function. Obesity plays a leading role in the formation of insulin resistance and metabolic syndrome. An increase in the mass of visceral adipose tissue leads to the dysregulation of the secretion of adipocytokines, which have a direct or indirect effect on the implementation of the effects of insulin in peripheral tissues and glucose metabolism, systemic inflammation, endothelial dysfunction, atherogenic status, accel- erating the development and progression of cardiovascular diseases, type 2 diabetes mellitus and other pathological conditions preceding their occurrence.

Berberine in the Treatment of Diabetes Mellitus: A Review.

Berberine is an alkaloid found in plants. It has neuroprotective, anti-inflammatory and hypolipidemic activities. The research proves that it also strongly impacts carbohydrate metabolism. The compound also protects pancreatic β-cells and increases sensitivity to insulin in peripheral tissues via the induction of GLUT-1, GLUT-4 and insulin type 1 (Ins-1) receptors activity. It also stimulates glycolysis and leads to a decrease in insulin resistance by macrophages polarization, lipolytic processes induction and energy expenditure enhancement (by reducing body mass and limiting insulin resistance caused by obesity). In liver berberine inhibits FOX01, SREBP1 and ChREBP pathways, and HNF-4α (hepatocyte nuclear factor 4 alpha) mRNA that hinder gluconeogenesis processes. In the intestines it blocks α-glucosidase contributing to glucose absorption decrease. Its interference in intestinal flora reduces levels of monosaccharides and suppresses diabetes mellitus complications development.

Comparative anti‐inflammatory effects of insulin and dexamethasone on cardiovascular biomarkers and antioxidants in miniature donkeys subjected to induced carbohydrate overload

SummaryBackgroundInflammatory responses as a result of carbohydrate (CHO) engorgement have been associated with peripheral tissue insulin resistance.ObjectivesThe aim of this study was to comparatively evaluate the anti‐inflammatory effects of intravenous (i.v.) administration of insulin and dexamethasone on clinical parameters, antioxidants and cardiovascular biomarkers in miniature donkeys subjected to induced CHO overload.Study designProspective, experimental study.MethodsEighteen clinically healthy male miniature donkeys with the age of 5 ± 1 years, weight of 105 ± 6 kg, body condition score of 5 (moderate) and height at the withers of 0.9 ± 0.06 m were used for this study. The animals were randomly assigned into three experimental groups (2 treatments and 1 negative control). Oligofructose (OF) at 10 g/kg of bodyweight was administered via nasogastric tube to induce CHO overload. Six hours later, animals in the treatment groups received IV 3 IU/kg bwt of insulin and 2 mg/kg bwt dexamethasone, respectively.ResultsThe results of this study revealed that heart rate (HR), respiratory rate (RR) and rectal temperature (RT), packed cell volume (PCV), white blood cell (WBC), glucose, homocysteine (Hcy) and cardiac troponin I (cTnI) increased, while the values of superoxide dismutase (SOD) and glutathione peroxidase (GPX) decreased in miniature donkeys subjected to CHO engorgement. All variables (except PCV) returned to normal values within 24 h in treatment groups. In treatment groups, HR and RR were significantly lower than the control group after 12 h. There were no significant differences between insulin and dexamethasone in levels of cTnI, Hcy, SOD, GPX, glucose, PCV and WBC after 24 h.Main limitationsRecording of only antioxidants and cardiovascular biomarkers is insufficient to well define the anti‐inflammatory effects of insulin.ConclusionsIt could be suggested that insulin (3 IU/kg bwt) and dexamethasone (2 mg/kg bwt) may be useful during CHO overload in miniature donkeys.

Sampling insulin in different tissue compartments using microdialysis: methodological aspects

Sampling the concentration of insulin in human skin using microdialysis is challenging because of low intracutaneous concentrations and low recovery, presumably due to adsorption of insulin to the microdialysis system. In this study, we aimed to (1) measure how the concentration of insulin varies in three different tissue compartments (intracutaneous, subcutaneous and intravenous) and (2) to study how much insulin is adsorbed to the microdialysis catheter membranes and tubing during a typical microdialysis experiment, both in vivo and in vitro. We hypothesized that (1) the concentration of insulin decreases from the intravenous compartment to the intracutaneous and subcutaneous tissue, and that (2) adsorption of insulin to the microdialysis membrane and tubing impairs the recovery of insulin from the tissue. In this experimental study, microdialysis catheters were inserted intracutaneously, subcutaneously and intravenously in 11 healthy subjects. Systemic endogenous hyperinsulinemia was induced by intake of an oral glucose load. Insulin concentration was measured in the dialysate and in the extracted samples from the catheter membrane and tubings. In vitro microdialysis was performed to investigate the temporal resolution of the adsorption. After an oral glucose load insulin concentration increased intravenously, but not in the intracutaneous or subcutaneous compartments, while glucose, lactate and pyruvate concentrations increased in all compartments. The adsorption of insulin to the microdialysis membrane in vivo was highest in the intravenous compartment (p = 0.01), compared to the intracutaneous and subcutaneous compartments. In vitro, the adsorption to the microdialysis membrane was highest one hour after sampling, then the concentration gradually decreased after three and five hours of sampling. The concentration of insulin in peripheral tissues is low, probably due to decreasing tissue vascularity. Adsorption of insulin to the microdialysis membrane is modest but time-dependent. This finding highlights the importance of a stabilization time for the microdialysis system before sampling tissue analytes.

Role of Phosphodiesterase in the Biology and Pathology of Diabetes.

Glucose metabolism is the initiator of a large number of molecular secretory processes in β cells. Cyclic nucleotides as a second messenger are the main physiological regulators of these processes and are functionally divided into compartments in pancreatic cells. Their intracellular concentration is limited by hydrolysis led by one or more phosphodiesterase (PDE) isoenzymes. Literature data confirmed multiple expressions of PDEs subtypes, but the specific roles of each in pancreatic β-cell function, particularly in humans, are still unclear. Isoforms present in the pancreas are also found in various tissues of the body. Normoglycemia and its strict control are supported by the appropriate release of insulin from the pancreas and the action of insulin in peripheral tissues, including processes related to homeostasis, the regulation of which is based on the PDE- cyclic AMP (cAMP) signaling pathway. The challenge in developing a therapeutic solution based on GSIS (glucose-stimulated insulin secretion) enhancers targeted at PDEs is the selective inhibition of their activity only within β cells. Undeniably, PDEs inhibitors have therapeutic potential, but some of them are burdened with certain adverse effects. Therefore, the chance to use knowledge in this field for diabetes treatment has been postulated for a long time.

Prospects of intranasal insulin for correction of cognitive impairments, in particular those associated with diabetes mellitus.

Despite the well-studied effect of insulin in peripheral tissues, its role in functioning of the central nervous system is much less understood. The effects of insulin in the brain are extremely diverse: insulin plays an important role in neuron growth and differentiation, affects higher cognitive functions (in particular, the formation of long-term memory), and also has a neuroprotective effect. Both peripheral and central insulin resistance as well as absolute insulin deficiency impairs the functional activity of neurons and neurogenesis. Several studies have investigated intranasal administration of insulin as a potential way for correction of these disorders. The review presents data on abnormalities of the insulin signaling system in the brain in diabetes mellitus, which is accompanied by cognitive dysfunction of varying severity and is associated with the development of neurodegenerative disorders, including Alzheimer's disease. We analyzed the results of studies on the use of intranasal insulin in animal models with diabetes mellitus, healthy volunteers, and patients with cognitive impairments.

THE EFFECT OF STEW BEANS TO BLOOD SUGAR LEVEL IN DIABETES MELLITUS PATIENTS

AbstractDiabetes Mellitus is a group of metabolic diseases with characteristic hyperglycemia that accurs due to abnormalities in insulin secretion, insulin action or both disorders. Management of Diabetes Mellitus one of which is the bean stew. Bean stew contain substances stigmasterol and sitisterol that can stimulate the pancreatic β- cells to secrete insulin in peripheral tissues. The purpose of this study was to determine the influence of bean stew on blood sugar levels in people with DM .The research method used experimental research design that is one group pre test-post test design, which reveal a causal relationship by engaging a group of subjects were observed prior to treatment. Samples taken by 32 respondents. The resulting data were analyzed using the Wilcoxon test with 0,05 significance level.The results showed that there was a bean stew effect on blood sugar levels. In the experimental group before the treated bean stew almost 100% had hyperglycemia number of 32 respondents. Then after being given treatment hampit 100% decrease, slthough not within normal limits number of 32 respondents. After calculation by Wilcoxon test was obtained count value (4,89) table (1,96), then the alternative hypothesis is accepted and the null hypothesis is rejected, it means there chickpea stew influence on blood sugar levels in people with DM.Bean stew can lower blood sugar levels in DM patients. Expected DM patients experiencing hyperglycemia can use in addition to pharmacological therapies that bean stew in addressing the problem of blood sugar levels.

Abstract 4380: Role of FAM3B/PANDER in inhibition of cell death and tumor growth in breast and prostate cancer

Abstract FAM3B/PANDER is a novel cytokine-like protein that induces apoptosis in beta-cells and regulates the effects of insulin in peripheral tissues. Since previous data revealed that FAM3B can be expressed by prostate and breast tumors, we evaluated the role of this cytokine in prostate and breast tumor progression. FAM3B expression was compared by quantitative PCR in LnCAP, PC-3 and DU145 prostate tumor cell lines and MCF-7 and MDA-MB- 231 breast tumor cell lines. After treatment with either recombinant FAM3B protein or secreted FAM3B obtained from conditioned media (CM) derived from FAM3B-overexpressing 293T cells, the cell death and viability of DU145 and MDA-MB- 231 cell lines were evaluated. DU145 and MDA-MB- 231 cells overexpressing FAM3B protein were produced by lentiviral-mediated transduction of full-length FAM3B cDNA. Cell viability and apoptosis were analyzed in DU145-FAM3B and MDA-231-FAM3B cells after treatment with cell death inducers. Anchorage-independent growth and scratch wound assays were used to evaluate in vitro tumorigenicity and cell migration, respectively. In vivo tumorigenicity and invasiveness were evaluated by tumor xenograft growth in nude mice. We observed that FAM3B was highly expressed by hormone responsive cells (LnCAP and MCF-7) and low expressed in unresponsive hormone cells (PC-3, DU145 and MDA-MB- 231). Cell viability and survival of DU145 and MDA-MB- 231 cells increased after exogenous treatment with recombinant FAM3B protein or CM containing FAM3B-secreted protein. Overexpression of FAM3B in DU145 and MDA-MB- 231 cells promoted an inhibition of apoptosis triggered by TNF-alpha and staurosporine. Cell death inhibition was accompanied by increased gene expression of the anti-apoptotic Bcl-2 and Bcl-xL genes, and by slight decrease in expression of pro-apoptotic gene Bax and with a decrease of caspases proteolytic activities. When compared to control, cells overexpressing FAM3B displayed a decreased anchorage independent growth and increased motility in vitro, as well as an increased tumor growth in xenografted nude mice. In agreement Immunohistochemistry analysis from tumor xenografts revealed similar anti-apoptotic phenotype in FAM3B overexpression, with an increase of Bcl-2. The results showed that FAM3B was capable to activates pro-survival mechanisms with an increasing of tumor growth by, activation of Bcl-2 and Bcl-xl pathways, suggesting the role of this cytokine in breast and in prostate tumors progression. Citation Format: Izabela D. Caldeira. Role of FAM3B/PANDER in inhibition of cell death and tumor growth in breast and prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4380.

A heterogeneous response of liver and skeletal muscle fat to the combination of a Paleolithic diet and exercise in obese individuals with type 2 diabetes: a randomised controlled trial

Aims/hypothesisThe aim of the study was to investigate ectopic fat deposition and insulin sensitivity, in a parallel single-blinded randomised controlled trial, comparing Paleolithic diet alone with the combination of Paleolithic diet and exercise in individuals with type 2 diabetes.MethodsThirty-two individuals with type 2 diabetes with BMI 25–40 kg/m2 and 30–70 years of age followed a Paleolithic diet ad libitum for 12 weeks. In addition, study participants were randomised by computer program to either supervised combined exercise training (PD-EX group) or standard care exercise recommendations (PD group). Staff performing examinations and assessing outcomes were blinded to group assignment. Thirteen participants were analysed in each group: hepatic and peripheral insulin sensitivity were measured using the hyperinsulinaemic–euglycaemic clamp technique combined with [6,6-2H2]glucose infusion, and liver fat was assessed by proton magnetic resonance spectroscopy; both analyses were secondary endpoints. Intramyocellular lipid (IMCL) content was measured by magnetic resonance spectroscopy as a secondary analysis. All examinations were performed at Umeå University Hospital, Umeå, Sweden.ResultsBoth study groups showed a median body weight loss of 7 kg. Fat mass decreased by 5.7 kg in the PD group and by 6.5 kg in the PD-EX group. Maximum oxygen uptake increased in the PD-EX group only. Liver fat showed a consistent reduction (74% decrease) in the PD group, while the response in the PD-EX group was heterogeneous (p < 0.05 for the difference between groups). IMCL content of the soleus muscle decreased by 40% in the PD group and by 22% in the PD-EX group (p < 0.05 for the difference between groups). Both groups improved their peripheral and adipose tissue insulin sensitivity, but not their hepatic insulin sensitivity. Plasma fetuin-A decreased by 11% in the PD group (p < 0.05) and remained unchanged in the PD-EX group. Liver fat changes during the intervention were correlated with changes in fetuin-A (rS = 0.63, p < 0.01). Participants did not report any important adverse events caused by the intervention.Conclusions/interpretationA Paleolithic diet reduced liver fat and IMCL content, while there was a tissue-specific heterogeneous response to added exercise training.Trial registrationClinicalTrials.gov NCT01513798FundingSwedish Diabetes Research Foundation, County Council of Västerbotten, Swedish Heart and Lung Foundation, King Gustav V and Queen Victoria’s Foundation

Unraveling the Paradox of Selective Insulin Resistance in the Liver: the Brain-Liver Connection.

The insulin receptor (IR) is expressed widely throughout the brain (1); however, unlike insulin in peripheral tissues whose major function is regulation of glucose metabolism, the actions of insulin in the brain are less glucocentric. Glucose enters neurons and glia of the brain primarily through the facilitative glucose transporters GLUT1 and GLUT3 (2), which are not insulin dependent. Despite being dispensable for glucose entry into the brain, early work by Woods et al. (3) and others (reviewed in ref. 1) demonstrated that intracerebroventricular (ICV) delivery of insulin into the brain could produce a multitude of effects, including suppression of feeding behavior and hepatic glucose production, activation of thermogenesis in brown adipose tissue, and stimulation of lipogenesis in white adipose tissue, all without significantly altering systemic insulin levels. Using a conditional knockout of the IR in the brain, Bruning and colleagues (4,5) demonstrated that the actions of insulin in the brain require IRs and can produce a range of phenotypes including mild obesity, decreased counterregulatory responsiveness to hypoglycemia, and hypothalamic hypogonadism. This has been confirmed and refined by region-specific IR knockouts and knockdowns of the IR using antisense technology (6,7). Studies using animal models and in vitro systems have uncovered many other …

Insulin Resistance and Obesity Affect Lipid Profile in the Salivary Glands.

In today's world wrong nutritional habits together with a low level of physical activity have given rise to the development of obesity and its comorbidity, insulin resistance. More specifically, many researches indicate that lipids are vitally involved in the onset of a peripheral tissue (e.g., skeletal muscle, heart, and liver) insulin resistance. Moreover, it seems that diabetes can also induce changes in respect of lipid composition of both the salivary glands and saliva. However, judging by the number of research articles, the salivary glands lipid profile still has not been sufficiently explored. In the current study we aim to assess the changes in the main lipid fractions, namely, triacylglycerols, phospholipids, free fatty acids, and diacylglycerols, in the parotid and the submandibular salivary glands of rats exposed to a 5-week high fat diet regimen. We observed that the high caloric fat diet caused a significant change in the salivary glands lipid composition, especially with respect to PH and TG, but not DAG or FFAs, classes. The observed reduction in PH concentration is an interesting phenomenon frequently signifying the atrophy and malfunctions in the saliva secreting organs. On the other hand, the increased accumulation of TG in the glands may be an important clinical manifestation of metabolic syndrome and type 2 diabetes mellitus.

SH2‐Containing Inositol 5′‐Phosphatase 2 Selectively Impairs Hypothalamic Insulin Signalling and Regulation of Food Intake in Mice

SH2-containing inositol 5'-phosphatase 2 (SHIP2) is a lipid phosphatase that negatively regulates the metabolic signalling of insulin in peripheral tissues; however, the expression of SHIP2 in the hypothalamus and its functional roles are largely unknown. In the present study, immunohistochemical analysis demonstrated that SHIP2 protein exists in neuronal cells expressing neuropeptide Y and pro-opiomelanocortin in the arcuate nucleus of the hypothalamus in C57BL/6J mice. Interestingly, the expression levels of SHIP2 in the hypothalamus were elevated in aged C57BL/6J mice and diabetic db/db mice. To clarify the significance of the increased expression of SHIP2 in the hypothalamus, we examined the central effects of insulin and leptin in transgenic mice overexpressing SHIP2 (SHIP2-Tg). Accumulation of phosphatidylinositol (3,4,5)-trisphosphate and phosphorylation of Akt in the hypothalamus, induced by i.c.v. injection of insulin, were attenuated in SHIP2-Tg compared to wild-type mice, whereas leptin-induced phosphorylation of signal transducer and activator of transcription 3 in the hypothalamus was comparable between them. The suppression of food intake after i.c.v. administration of insulin (but not leptin) was attenuated consistently in SHIP2-Tg. In addition, SHIP2-Tg showed increased food consumption after starvation and become heavier with visceral fat accumulation than wild-type mice, despite normal levels of oxygen consumption and spontaneous movement. These results suggest that SHIP2 contributes to the regulation of food intake mainly via the attenuation of insulin signalling in the hypothalamus of mice.

Insulin receptor activation through its accumulation in lipid rafts by mild electrical stress

Insulin resistance is due to the reduced cellular response to insulin in peripheral tissues. The interaction of insulin with its receptor is the first step in insulin action and thus the identified target of insulin resistance. It has been well established that defects or mutations in the insulin receptor (IR) cause insulin resistance. Therefore, an IR activator might be a novel therapeutic approach for insulin resistance. Our previous report showed that mild electrical stress (MES) enhanced the insulin-induced signaling pathway. However, the molecular mechanism of the effect of MES remains unclear. We assessed the effect of MES, which is characterized by low-intensity direct current, on insulin signaling in vitro and in vivo. Here, we showed that MES activated the insulin signaling in an insulin-independent manner and improved insulin resistance in peripheral tissues of high fat-fed mice. Moreover, we found that MES increased the localization of IR in lipid rafts and enhanced the level of phosphorylated Akt in insulin-resistant hepatic cells. Ablation of lipid rafts disrupted the effect of MES on Akt activation. Our findings indicate that MES has potential as an activator of IR in an insulin-independent manner, and might be beneficial for insulin resistance in type 2 diabetes.

Glitazones Exert Multiple Effects onβ-Cell Stimulus-Secretion Coupling

Earlier studies suggest that glitazones exert beneficial effects in patients with type 2 diabetes by directly affecting insulin secretion of β-cells, besides improving the effectiveness of insulin in peripheral tissues. The effects of glitazones on stimulus-secretion coupling (SSC) are poorly understood. We tested the influence of troglitazone and pioglitazone on different parameters of SSC, including insulin secretion (radioimmunoassay), cell membrane potential, various ion currents (patch-clamp), mitochondrial membrane potential (ΔΨ), and cytosolic Ca(2+) concentration (fluorescence). Troglitazone exerted stimulatory, inhibitory, or no effects on insulin secretion depending on the drug and glucose concentration. It depolarized the ΔΨ, thus lowering ATP production, which resulted in opening of ATP-dependent K(+) channels (K(ATP) channels) and reduced insulin secretion. However, it also exerted direct inhibitory effects on K(ATP) channels that can explain enhanced insulin secretion. Troglitazone also inhibited the currents through voltage-dependent Ca(2+) and K(+) channels. Pioglitazone was less effective than troglitazone on all parameters tested. The effects of both glitazones were markedly reduced in the presence of bovine serum albumin. Glitazones exert multiple actions on β-cell SSC that have to be considered as undesired side effects because the influence of these compounds on β-cells is not controllable. The final effect on insulin secretion depends on many parameters, including the actual glucose and drug concentration, protein binding of the drug, and the drug by itself. Troglitazone and pioglitazone differ in their influence on SSC. It can be assumed that the effects of pioglitazone on β-cells are negligible under in vivo conditions.

Glucose metabolism after normalization of markers of iron overload by venesection in subjects with hereditary hemochromatosis

Hereditary hemochromatosis (HH) is associated with abnormal glucose metabolism (AGM). We investigated the effect on glucose metabolism of normalization of the markers of iron overload by phlebotomy in subjects with HH. We prospectively studied 11 newly diagnosed subjects with HH and AGM using a standard 75-g oral glucose tolerance test. Basal quantitative insulin sensitivity check index (QUICKI) and stimulated oral glucose insulin sensitivity index (OGIS) insulin sensitivity was calculated from glucose and insulin data, whereas β-cell function was assessed using C-peptide concentration after adjusting for ambient insulin sensitivity. After normalization of ferritin and transferrin saturations by venesection for 12 (range, 8-16) months, subjects were studied again using the same methods. From 11 subjects with AGM at the time that HH was diagnosed, 7 had impaired glucose tolerance (IGT) and 4 had type 2 diabetes mellitus (T2DM). Normalization of the iron stores (ferritin and transferrin) improved the glucose tolerance status of 4 patients with IGT (to normal glucose tolerance), whereas 2 of those with IGT progressed to T2DM. In 5 patients, glucose tolerance status did not change (4 T2DM and 1 IGT). The area under the insulin and the C-peptide curve during the oral glucose tolerance test and the hepatic insulin extraction increased ( P = .05), whereas no statistically significant changes occurred in insulin sensitivity. However, the disposition index, a measure of the ability of insulin release to compensate for insulin resistance, improved significantly ( P = .02). Normalization of ferritin and transferrin saturation by venesection in subjects with HH and AGM led to improvements in some, but not all, measures of insulin secretion and action. Most patients with AGM had an improvement in glucose tolerance status, probably due to the augmented action of insulin in peripheral tissues.

Prepartum 2,4-Thiazolidinedione Alters Metabolic Dynamics and Dry Matter Intake of Dairy Cows

Thiazolidinediones (TZD) are potent, synthetic ligands for peroxisome proliferator activated receptor-gamma (PPAR-γ) that reduce plasma nonesterified fatty acids (NEFA) and potentiate the action of insulin in peripheral tissues of several species. Holstein cows (n=9) entering their second or greater lactation were used to determine whether late prepartum administration of TZD would affect periparturient metabolism and milk production. Cows were limit-fed a total mixed ration (TMR) during the prepartum period to provide no more than 130% of predicted energy requirements. During the postpartum period cows were fed a common TMR for ad libitum intake. Cows were administered either 2,4-TZD (4.0 mg/kg of body weight) or saline (control) by intrajugular infusion once daily from 25 d before expected parturition until parturition. Plasma samples were collected daily from 26 d before expected parturition through 7 d postpartum. Plasma NEFA concentrations decreased during the prepartum period (d −21 to −1; 70 vs. 83±4μEq/L) and tended to be decreased during the peripartum period (d −7 to d +7; 113 vs. 205±32μEq/L) due to prepartum TZD administration. Plasma concentrations of glucose were not affected by treatment; however, plasma β-hydroxybutyrate concentrations decreased in TZD-treated cows (8.6 vs. 10.7±1.7 mg/dL) as parturition approached, and plasma insulin concentrations increased during the peripartum period (0.65 vs. 0.38±0.07 ng/mL). Postpartum liver triglyceride and glycogen content was not affected by treatment. Prepartum TZD administration tended to increase dry matter intake during the peripartum and postpartum periods (16.6 vs. 14.6±0.8 kg/d and 20.0 vs. 17.2±1.2 kg/d, respectively). Milk yield for the first 30 d postpartum and milk composition measured on d 8 postpartum were not affected by treatment. There was no effect of prepartum TZD administration on insulin-dependent glucose utilization assessed using insulin challenge during either the prepartum or postpartum periods. These results suggest that administration of TZD during the late prepartum period has the potential to improve metabolic health and DMI of periparturient dairy cows and warrants further investigation.