Insulin Sensitivity In Diabetes Research Articles

The VENERE Study: EffectiVenEss of a Rehabilitation Treatment With Nordic Walking in ObEse or OveRweight Diabetic PatiEnts With Cardiovascular Disease

BackgroundNordic walking (NW) has several potential benefits for individuals with cardiovascular (CV) disease, type 2 diabetes, and obesity and/or overweight. NW improves cardiovascular health, including exercise capacity and blood pressure control. NW enhances glycemic control and insulin sensitivity in diabetes, and aids in weight management and body composition improvement. NW offers additional advantages, such as improvement in muscular strength, joint mobility, physical activity levels, and psychological well-being. MethodsThis open-label study with 3 arms will aim to evaluate the efficacy, safety, and adherence to exercise prescription in obese and/or overweight diabetic patients with CV complications. The primary objective will be to assess the CV performance of participants after a 6-month and a 12-month follow-up period, following a 3-month NW intervention, compared with standard rehabilitation, and with cardiological counseling (control group) training lasting 3 months. ResultsThe results of the study will provide valuable insights into the comparative effectiveness of a NW intervention vs standard rehabilitation and control group training in improving CV performance in obese and/or overweight diabetic patients with CV complications. Additionally, safety and adherence data will help inform the feasibility and sustainability of the exercise prescription over an extended period. ConclusionsThese findings may have implications for the development of tailored exercise programs for this specific patient population, with the aim of optimizing CV health outcomes. Clinical Trials RegistrationNCT05987410

Combination Therapy with GABA and MgSO4 Improves Insulin Sensitivity in Type 2 Diabetic Rat.

Background Gamma-aminobutyric acid (GABA) and magnesium sulfate (MgSO4) play a crucial role in glycemic control. Therefore, we studied the effect of combination therapy with GABA and MgSO4 to improve insulin sensitivity in diabetes induced by streptozotocin as well as high-fat diet in a diabetic rat model. Design and Methods. Forty randomly selected rats were assigned to four groups: nondiabetic control group was fed the normal diet, insulin-resistant diabetic rat model was induced by streptozotocin and high-fat diet, GABA + MgSO4 group received GABA and MgSO4, and insulin group was treated with insulin. Body weight, abdominal fat, blood glucose, serum insulin, and glucagon concentration were measured. The glucose clamp technique, glucose tolerance test, and insulin tolerance test were performed to study insulin sensitivity. Also, the expressions of glucose 6 phosphatase, glucagon receptor, and phosphoenolpyruvate carboxykinase genes in liver were assessed for the gluconeogenesis pathway. Protein translocation and glucose transporter 4 (Glut4) genes expression in muscle were also assessed. Results Combination of GABA + MgSO4 or insulin therapy enhanced insulin level, glycemic control, glucose and insulin tolerance test, some enzymes expression in the gluconeogenesis pathway, body fat, body weight, and glucagon receptor in diabetic rats. Moreover, an increase was observed in protein and gene expression of Glut4. Insulin sensitivity in combination therapy was more than the insulin group. Conclusions GABA and MgSO4 enhanced insulin sensitivity via increasing Glut4 and reducing the gluconeogenesis enzyme and glucagon receptor gene expressions.

227-LB: GLP-1 Activation of HCN Channels Increases Glucose-Stimulated β- and δ- Cell Ca2+ Oscillation Frequency

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels control human β-cell insulin secretion. Here, we examined if HCN channels impact glucagon-like-peptide 1 (GLP-1) receptor modulation of islet Ca2+ handling. We found that Liraglutide (100nM LIRA), a GLP-1 analog, increased mouse β-cell Ca2+ oscillation frequency and cAMP levels in high (11 mM) but not low glucose. Similarly, a subset of human β-cells (65%) show LIRA-induced elevations in Ca2+ oscillation frequency (by 70%, P<0.001) under stimulatory glucose (7 mM) conditions. While mouse islet HCN inhibition (20 μM ivabradine) did not alter glucose-stimulated (9 mM) Ca2+ oscillation frequency, it prevented LIRA-induced changes of islet Ca2+ fluctuations. As LIRA is used to treat type-2-diabetes, we examined and demonstrated that islets from high fat diet-fed, glucose intolerant mice also responded to LIRA with increased Ca2+ oscillation frequency (by 93%, P<0.01). These changes in β-cell Ca2+ handling may contribute to LIRA-mediated increased insulin secretion, which could also play a role in LIRA inhibition of glucagon secretion. However, as somatostatin also inhibits glucagon secretion, we next investigated the influence of LIRA on 𝛿;-cells. Interestingly, LIRA increased Ca2+ oscillation frequency equivalently in β- and 𝛿;-cells (by 85%, P<0.0001), which showed synchronized Ca2+ fluctuations. To establish the origin of synchronization cues, we ablated either β- or δ-cells and determined the LIRA-mediated effect on Ca2+ handling in remaining δ- or β-cells, respectively. Although δ-cell ablation did not affect the LIRA-mediated elevations in β-cell Ca2+ oscillation frequency, β-cell ablation interfered with glucose- and LIRA-mediated δ-cell Ca2+ fluctuations. As the kinetics of pulsatile insulin secretion dictate insulin sensitivity, the data presented here suggests that GLP-1 stimulation of islet HCN channels may improve peripheral insulin sensitivity in diabetics treated with LIRA. Disclosure K. E. Zaborska: None. K. L. Jordan: None. P. Dadi: None. M. Dickerson: None. S. M. Graff: None. D. Jacobson: None.

Quality characteristics and hypoglycaemic effects of rice bread containing Helianthus tuberosus powder

This study aimed to investigate the quality characteristics of rice bread containing Helianthus tuberosus powder that shows excellent physiological functions, and the effect of its intake on blood glucose. Five samples were tested, H. tuberosus powder 5% (HRB1), 10% (HRB2), 15% (HRB3), 20% (HRB4) and control. HRB2 had the highest specific volume. The moisture content of rice bread tended to increase as the concentration of H. tuberosus powder increased. The L value and crumb colour value tended to decrease significantly with an increasing amount of H. tuberosus powder, whereas the b value was increased significantly. Hardness was the lowest in HRB2 and HRB3. In sensory evaluation, there was no significant difference in the appearance among the four groups. HRB1 had the highest values for flavour, texture, and overall evaluation. Taste showed no significant difference until HRB1. Rice bread samples with 15% HRB were selected to measure the hypoglycaemic effect of H. tuberosus compared to that of control rice bread (RB) and wheat bread (WB). The results showed significantly different blood glucose levels (p < 0.05) among treatments. Calculation of the glycaemic index (GI) showed HRB to have the lowest GI. As a result, rice bread containing H. tuberosus powder is expected to increase insulin sensitivity in diabetes.

Hepatic tristetraprolin promotes insulin resistance through RNA destabilization of FGF21.

The role of posttranscriptional metabolic gene regulatory programs in diabetes is not well understood. Here, we show that the RNA-binding protein tristetraprolin (TTP) is reduced in the livers of diabetic mice and humans and is transcriptionally induced in response to insulin treatment in murine livers in vitro and in vivo. Liver-specific Ttp-KO (lsTtp-KO) mice challenged with high-fat diet (HFD) have improved glucose tolerance and peripheral insulin sensitivity compared with littermate controls. Analysis of secreted hepatic factors demonstrated that fibroblast growth factor 21 (FGF21) is posttranscriptionally repressed by TTP. Consistent with increased FGF21, lsTtp-KO mice fed HFD have increased brown fat activation, peripheral tissue glucose uptake, and adiponectin production compared with littermate controls. Downregulation of hepatic Fgf21 via an adeno-associated virus-driven shRNA in mice fed HFD reverses the insulin-sensitizing effects of hepatic Ttp deletion. Thus, hepatic TTP posttranscriptionally regulates systemic insulin sensitivity in diabetes through liver-derived FGF21.

Comparative pharmacokinetics and safety assessment of transdermal berberine and dihydroberberine.

The natural alkaloid berberine has been ascribed numerous health benefits including lipid and cholesterol reduction and improved insulin sensitivity in diabetics. However, oral (PO) administration of berberine is hindered by poor bioavailability and increasing dose often elicits gastro-intestinal side effects. To overcome the caveats associated with oral berberine, we developed transdermal (TD) formulations of berberine (BBR) and the berberine precursor dihydroberberine (DHB). These formulations were compared to oral BBR using pharmacokinetics, metabolism, and general safety studies in vivo. To complete this work, a sensitive quantitative LC-MS/MS method was developed and validated according the FDA guidelines for bioanalytical methods to simultaneously measure berberine, simvastatin, and simvastatin hydroxy acid with relative quantification used for the berberine metabolite demethylene berberine glucuronide (DBG). Acute pharmacokinetics in Sprague-Dawley rats demonstrated a statistically relevant ranking for berberine bioavailability based upon AUC0-8 as DHB TD > BBR TD >> BBR PO with similar ranking for the metabolite DBG, indicating that transdermal administration achieves BBR levels well above oral administration. Similarly, chronic administration (14 days) resulted in significantly higher levels of circulating BBR and DBG in DHB TD treated animals. Chronically treated rats were given a single dose of simvastatin with no observed change in the drugs bioavailability compared with control, suggesting the increased presence of BBR had no effect on simvastatin metabolism. This observation was further supported by consistent CYP3A4 expression across all treatment groups. Moreover, no changes in kidney and liver biomarkers, including alanine aminotransferase and alkaline phosphatase, were observed between treatment formats, and confirming previous reports that BBR has no effect on HMG-CoA expression. This study supports the safe use of transdermal compositions that improve on the poor bioavailability of oral berberine and have the potential to be more efficacious in the treatment of dyslipidemia or hypercholesterolemia.

ELDERLY MEN AND HEALTH SERVICE PROVISION FOR TYPE 2 DIABETES MANAGEMENT: SYNTHESIS OF KNOWLEDGE GAPS AND IDENTIFICATION OF RESEARCH NEEDS

Chronic long-standing type 2 diabetes and subsequent complications (comorbidities) represent a major clinical and public health challenge for elderly men from a prevention and management viewpoint. In the developed western countries, evidence suggests that 80% of premature deaths and disability due to diabetes and heart disease can be prevented. Diabetes care in the elderly include further challenges in management of comorbidities such as hypertension, the metabolic syndrome (MetS), kidney problems including nephropathy and chronic renal failure, vision abnormalities such as cataract and retinopathy. The comorbidities are subsequent to complex mechanistic processes incurred by the hyperglycemia and reduced insulin sensitivity in diabetes. Management of diabetic elderly patients with type 2 diabetes is further challenged by lack of specific clinical guidelines tailored to this population. Existing clinical guidelines are based on evidence from clinical trials conducted in younger (&lt; 65 years of age) patients. There is a need for designing improved models of health care delivery, assessment of comorbidities and polypharmacy in elderly men, including mental health issues such as depression and dementia that may persist with diabetes. An integrated, comprehensive, and patient-oriented management care plan seems the best practice clinical approach to ensure that the risk of hypoglycemia does not increase while treating elderly diabetic men with existent multimorbidity.

Potential Role of Curcumin Against Biofilm-Producing Organisms on the Skin: A Review.

Turmeric root (Curcuma longa) is predominantly used as a spice, but has also long been known to possess antimicrobial, analgesic, antiinflammatory, and anticancer properties. One predominant group of active compounds in turmeric are curcuminoids, namely bright yellow-pigmented curcumin. While modern science has yet to fully investigate the therapeutic claims of turmeric and its derivatives, results have proven promising in decreasing pain and inflammation in arthritis, improving insulin sensitivity in diabetes, and even curing a variety of infections. The purpose of this review is to discuss the potential for curcumin as an agent against microbial infections, with a special focus on the skin and in the development of bacterial biofilms. Curcumin has demonstrated bactericidal efficacy against a variety of infections when administered with antibiotics in several clinical studies, with consistent antimicrobial activity demonstrated in vitro, as well as in urinary tract infections, gingival infections, and chronic wound infections. Hypothesized mechanisms of action include curcumin's ability to perturb bacterial membranes, disturb protofillament assembly, and even impair bacterial virulence factors. Further investigation is needed to fully understand which organisms are most susceptible to the effects of curcumin and how curcumin can be implemented in dermatology to treat skin conditions such as chronic wounds and acne vulgaris. Copyright © 2017 John Wiley & Sons, Ltd.

Relationship between HHV8 infection markers and insulin sensitivity in ketosis-prone diabetes

Background and objectivesPeripheral tissue resistance to insulin action is a characteristic of type 2 diabetes mellitus (T2DM). It has also been reported that some chronic viral infections can contribute to insulin resistance. Human herpesvirus (HHV)-8 infection has been detected in T2DM patients in previous studies. Our study investigated whether the presence of the virus is associated with insulin resistance in patients with ketosis-prone type 2 diabetes (KPD), as reported with other viruses. Research design and methodsA total of 11 insulin-free KPD patients positive (+) and seven patients who were negative (−) for HHV-8 infection were recruited; the latter had KPD that was well controlled (HbA1c=6.2±0.7%). A two-step euglycaemic–hyperinsulinaemic clamp test coupled with deuterated [6,6-2H2]glucose was used to assess insulin sensitivity, non-esterified fatty acid (NEFA) suppression and endogenous glucose production. ResultsIn KPD patients, whether HHV-8+ or HHV-8−, there were no differences in NEFA release, endogenous glucose production or insulin sensitivity (M value). ConclusionAsymptomatic HHV-8 infection does not appear to be associated with decreased insulin sensitivity in diabetic patients. These results should now be confirmed in a larger sample population.

L-Cysteine supplementation increases adiponectin synthesis and secretion, and GLUT4 and glucose utilization by upregulating disulfide bond A-like protein expression mediated by MCP-1 inhibition in 3T3-L1 adipocytes exposed to high glucose.

Adiponectin is an anti-diabetic and anti-atherogenic adipokine; its plasma levels are decreased in obesity, insulin resistance, and type 2 diabetes. An adiponectin-interacting protein named disulfide bond A-like protein (DsbA-L) plays an important role in the assembly of adiponectin. This study examined the hypothesis that L-cysteine (LC) regulates glucose homeostasis through the DsbA-L upregulation and synthesis and secretion of adiponectin in diabetes. 3T3L1 adipocytes were treated with LC (250 and 500 µM, 2 h) and high glucose (HG, 25 mM, 20 h). Results showed that LC supplementation significantly (p < 0.05) upregulated the DsbA-L, adiponectin, and GLUT-4 protein expression and glucose utilization in HG-treated adipocytes. LC supplementation significantly (p < 0.05) promoted the secretion of total and HMW adiponectin secretion in HG-treated adipocytes. In addition, LC significantly (p < 0.05) decreased ROS production and MCP-1 secretion in HG-treated cells. We further investigated whether MCP-1 has any role of LC on DsbA-L expression and adiponectin levels in 3T3-L1 cells. Treatment with LC prevented the decrease in DsbA-L, adiponectin, and GLUT-4 expression in 3T3L1 adipocyte cells exposed to MCP-1. Thus, this study demonstrates that DsbA-L and adiponectin upregulation mediates the beneficial effects of LC on glucose utilization by inhibiting MCP-1 secretion in adipocytes and provides a novel mechanism by which LC supplementation can improve insulin sensitivity in diabetes.

PIP3 but not PIP2 increases GLUT4 surface expression and glucose metabolism mediated by AKT/PKCζ/λ phosphorylation in 3T3L1 adipocytes

Phosphatidylinositol-3,4,5-triphosphate (PIP3) and phosphatidylinositol-4,5-biphosphate (PIP2) are two well-known membrane bound polyphosphoinositides. Diabetes is associated with impaired glucose metabolism. Using a 3T3L1 adipocyte cell model, this study investigated the role of PIP3 and PIP2 on insulin stimulated glucose metabolism in high glucose (HG) treated cells. Exogenous PIP3 supplementation (1, 5, or 10 nM) increased the phosphorylation of AKT and PKCζ/λ, which in turn upregulated GLUT4 total protein expression as well as its surface expression, glucose uptake, and glucose utilization in cells exposed to HG (25 mM); however, PIP2 had no effect. Comparative signal silencing studies with antisense AKT2 and antisense PKCζ revealed that phosphorylation of PKCζ/λ is more effective in PIP3 mediated GLUT4 activation and glucose utilization than in AKT phosphorylation. Supplementation with PIP3 in combination with insulin enhanced glucose uptake and glucose utilization compared to PIP2 with insulin, or insulin alone, in HG-treated adipocytes. This suggests that a decrease in cellular PIP3 levels may cause impaired insulin sensitivity in diabetes. PIP3 supplementation also prevented HG-induced MCP-1 and resistin secretion and lowered adiponectin levels. This study for the first time demonstrates that PIP3 but not PIP2 plays an important role in GLUT4 upregulation and glucose metabolism mediated by AKT/PKCζ/λ phosphorylation. Whether PIP3 levels in blood can be used as a biomarker of insulin resistance in diabetes needs further investigation.

PPARδ Activation Protects Endothelial Function in Diabetic Mice

Recent evidence highlights the therapeutic potential of peroxisome proliferator–activated receptor-δ (PPARδ) agonists to increase insulin sensitivity in diabetes. However, the role of PPARδ in regulating vascular function is incompletely characterized. We investigate whether PPARδ activation improves endothelial function in diabetic and obese mice. PPARδ knockout (KO) and wild-type (WT) mice fed with high-fat diet and db/db mice were used as diabetic mouse models, compared with PPARδ KO and WT mice on normal diet and db/m+ mice. Endothelium-dependent relaxation (EDR) was measured by wire myograph. Flow-mediated vasodilatation (FMD) was measured by pressure myograph. Nitric oxide (NO) production was examined in primary endothelial cells from mouse aortae. PPARδ agonist GW1516 restored EDRs in mouse aortae under high-glucose conditions or in db/db mouse aortae ex vivo. After oral treatment with GW1516, EDRs in aortae and FMDs in mesenteric resistance arteries were improved in obese mice in a PPARδ-specific manner. The effects of GW1516 on endothelial function were mediated through phosphatidylinositol 3-kinase (PI3K) and Akt with a subsequent increase of endothelial nitric oxide synthase (eNOS) activity and NO production. The current study demonstrates an endothelial-protective effect of PPARδ agonists in diabetic mice through PI3K/Akt/eNOS signaling, suggesting the therapeutic potential of PPARδ agonists for diabetic vasculopathy.

L-Arginine enhances glucose and lipid metabolism in rat L6 myotubes via the NO/ c-GMP pathway

ObjectiveThe amino acid Arginine (Arg) is the main biological precursor of nitric oxide (NO) and has been described to improve insulin sensitivity in diabetes and obesity. We investigated the molecular mechanisms involved in the long-term effects of Arg on glucose and lipid metabolism. Materials and MethodsL6 myotubes were treated with Arg (7mmol/L) for 6days. D-Mannitol (7mmol/L) was used as control; spermine NONOate (10μmol/L) and L-NAME (100μmol/L) were used to evaluate the NO/c-GMP pathway role. Basal and insulin-induced (120 nmol/L) glycogen synthesis, glucose uptake and lipid oxidation, c-GMP and nitrite levels, and the intracellular signaling pathways were evaluated. ResultsArg-treatment increased: 1) basal and insulin-stimulated glycogen synthesis; 2) glucose uptake; 3) palmitate oxidation; 4) p-Akt (Ser473), total and plasma membrane GLUT4 content, total and p-AMPK-α and p-ACC (Ser79), p-GSK-3α/β (Ser21/9) and 5) nitrite and c-GMP levels. L-NAME treatment suppressed Arg effects on: 1) nitrite and c-GMP content; 2) glycogen synthesis and glucose uptake; 3) basal and insulin-stimulated p-Akt (Ser473), total and p-AMPK-α and ACC, and nNOS expression. ConclusionWe provide evidence that Arg improves glucose and lipid metabolism in skeletal muscle, in parallel with increased phosphorylation of Akt and AMPK-α. These effects were mediated by the NO/c-GMP pathway. Thus, arginine treatment enhances signal transduction and has a beneficial effect of metabolism in skeletal muscle through direct activation of Akt and AMPK pathways.

Abstract 17733: PPARdelta Activation Protects Endothelial Function In Diabetic Mice via PI3K/Akt/eNOS Signaling Pathway

Introduction: Recent evidence highlights therapeutic potentials of peroxisome proliferator-activated receptor-delta (PPARdelta) agonists to increase insulin sensitivity in diabetes. The significance of PPARdelta in the regulation of vascular function remains unclear. Hypothesis: The present study investigates whether PPARdelta activation improves endothelial function in type 2 diabetes. Methods: Vascular reactivity of mouse aortae was studied in myograph. Protein expression was detected by Western blotting. Nitric oxide (NO) production was measured by DAF-FM fluorescence using confocal microscopy. Results: PPARdelta agonists GW0742 and GW1516 improved endothelium-dependent relaxations in diabetic mouse aortae. PPARdelta agonists prevented high glucose-induced impairment of endothelium-dependent relaxations in aortae of wild type mice, but not in PPARdelta knockout mice. PPARdelta antagonist, PI3K inhibitors, or Akt inhibitor reversed the effect of PPARdelta activation on endothelial function. Western blotting showed an increased phosphorylation of eNOS and Akt upon PPARdelta activation under hyperglycaemia in primary endothelial cells (ECs) from mouse aortae. PPARdelta activation enhanced the NO production in ECs under hyperglycemia. Transient transfection with dominant-negative Akt inhibited the effect of GW1516 in ECs on NO production and eNOS and Akt phosphorylation. Chronic treatment with GW1516 (5 mg/kg/day for one week) improved endothelium-dependent relaxation in db/db mice, and diet-induced obese PPARdelta wild type mice, but not in PPARdelta knockout mice. Conclusions: The present study demonstrates an endothelial protective effect of PPARdelta activation in diabetes through PI3K/Akt signaling which increases eNOS activity, suggesting the potential of PPARdelta agonists in the treatment of diabetic vasculopathy.

Cytotoxic effect of different statins and thiazolidinediones on malignant glioma cells

Glioblastoma multiforme is still a tumor with very poor prognosis. Statins are actually used for the treatment of dyslipidemias and thiazolidinediones for improving insulin sensitivity in diabetes. Statins are inhibitors of the cholesterol pathway, while thiazolidinediones are peroxisomal proliferator activator receptor γ (PPAR) agonists. For both, a potent pro-apoptotic activity has been suggested. We compared the antiglioma effect of simvastatin, atorvastatin, lovastatin, pravastatin, rosuvastatin, rosiglitazone, pioglitazone and their combinations at several concentrations on human glioblastoma cell lines U87, U 138, LN 405 and rat RG II. The cytotoxic effect was assessed using a cell proliferation assay after 48 and 144 h. Caspase 3 activity and the addition of isoprenoids and PPAR-y inhibitor GW9662 were assessed. Experiments were as well conducted under hypoxia for 24 h. We demonstrated a significant cytotoxic effect with a combination of statins plus pioglitazone. The effect was observed after 48 h and dramatically increased after 144 h. The combination of 2 types of statins (synthetic and natural) allowed a fivefold dose reduction. Statin effect was reversed with isoprenoids and partially with PPAR-γ antagonists, while thiazolidinediones effect was slightly affected by PPAR-γ antagonists. A marked increase in caspase 3 activity was achieved by combining atorvastatin with lovastatin. Cytotoxicity of the combination of statins and thiazolidinediones did not decrease under hypoxia. The assessed combination of statins with thiazolidinediones shows a synergistic cytotoxic effect against glioblastoma cells in vitro, which could represent a feasible therapeutic schema.

Resistance Exercise Did Not Alter Intramuscular Adipose Tissue but Reduced Retinol-binding Protein-4 Concentration in Individuals with Type 2 Diabetes Mellitus

Lipid accumulation in muscle is associated with diminished insulin sensitivity. It was hypothesized that resistance exercise decreases muscular adipose tissue and reduces the level of retinol-binding protein-4 (RBP4), which is linked to adipose tissue and insulin sensitivity in diabetics. Forty-four women with type 2 diabetes were randomly assigned to three groups for a period of 12 weeks: control (asked to maintain a sedentary lifestyle); resistance exercise (elastic band exercise at moderate intensity five times per week); and aerobic exercise (walking for 60 min at moderate intensity five times per week). Subcutaneous (SCAT), subfascial (SFAT) and intramuscular (IMAT) adipose tissues at mid-thigh level were assessed using computed tomography, and RBP4 level and insulin sensitivity (fractional disappearance rate of insulin, k(ITT)) were assessed before and after intervention. Changes in SCAT, SFAT, IMAT, RBP4 and k(ITT) were similar among the three groups. Within-group analysis revealed that body mass index and waist circumference decreased significantly in both exercise groups, but RBP4 decreased significantly only with resistance exercise. Resistance exercise did not alter muscular adipose tissue or improve insulin sensitivity.

The effect of exercise, training, and inactivity on insulin sensitivity in diabetics and their relatives: what is new?

Insulin resistance is a hallmark characteristic of type 2 diabetes. However, in healthy first-degree relatives of type 2 diabetics, insulin resistance is often present years before glucose intolerance or diabetes becomes clinically manifest. The mechanisms of insulin resistance involve conditions leading to an increased supply of fatty acids (e.g., high energy intake, obesity) and conditions in which the degradation/oxidation of muscular fatty acids is impaired. Several large-scale studies have documented the fact that increased physical activity can reduce or at least postpone the development of type 2 diabetes, and low physical fitness is a clear independent risk factor for the development of type 2 diabetes. The mechanisms responsible for the improvement in insulin sensitivity after exercise training have been studied extensively, but are not fully understood. This review focuses on insulin resistance in skeletal muscle and, in particular, its relation to changes in aerobic fitness in type 2 diabetics and their first-degree relatives.

Therapeutic potential of curcumin in non-alcoholic steatohepatitis

Non-alcoholic steatohepatitis (NASH) may be associated with a number of clinical conditions, but it occurs most commonly in patients with insulin resistance. There is as yet no established disease-modifying treatment, and a safe and broadly available agent that targets hepatic steatosis, insulin resistance, inflammation and fibrosis is necessary. The polyphenolic compound curcumin exhibits antioxidant and anti-inflammatory properties, inhibits NF-kappaB and activates PPAR-gamma. In rodents, curcumin prevents dietary-induced hepatic steatosis, hepatic stellate cell activation and production of fibrotic proteins, and ameliorates steatohepatitis induced by the intake of alcohol or a methionine-choline-deficient diet. Indirect evidence suggests that curcumin may improve insulin sensitivity in diabetes and inflammatory states. The present paper reviews the numerous cellular and animal studies indicating that curcumin attenuates many of the pathophysiological processes involved in the development and progression of NASH. It is suggested that basic and clinical studies on curcumin in the development and progression of NASH are indicated.

Divergent effects of rosiglitazone on protein-mediated fatty acid uptake in adipose and in muscle tissues of Zucker rats

Thiazolidinediones (TZDs) increase tissue insulin sensitivity in diabetes. Here, we hypothesize that, in adipose tissue, skeletal muscle, and heart, alterations in protein-mediated FA uptake are involved in the effect of TZDs. As a model, we used obese Zucker rats, orally treated for 16 days with 5 mg rosiglitazone (Rgz)/kg body mass/day. In adipose tissue from Rgz-treated rats, FA uptake capacity increased by 2.0-fold, coinciding with increased total contents of fatty acid translocase (FAT/CD36; 2.3-fold) and fatty acid transport protein 1 (1.7-fold) but not of plasmalemmal fatty acid binding protein, whereas only the plasmalemmal content of FAT/CD36 was changed (increase of 1.7-fold). The increase in FA uptake capacity of adipose tissue was associated with a decline in plasma FA and triacylglycerols (TAGs), suggesting that Rgz treatment enhanced plasma FA extraction by adipocytes. In obese hearts, Rgz treatment had no effect on the FA transport system, yet the total TAG content decreased, suggesting enhanced insulin sensitivity. Also, in skeletal muscle, the FA transport system was not changed. However, the TAG content remained unaltered in skeletal muscle, which coincided with increased cytoplasmic adipose-type FABP content, suggesting that increased extramyocellular TAGs mask the decline of intracellular TAG in muscle. In conclusion, our study implicates FAT/CD36 in the mechanism by which Rgz increases tissue insulin sensitivity.

Glucose, insulin, and somatostatin infusion for the determination of insulin sensitivity in vivo

Shen et al. 1 and Reaven et al. 2 have recently reported increased insulin resistance in adult-onset type diabetes based on the steady state plasma glucose (SSPG) method. In this method, epinephrine and propranolol were used to suppress endogenous insulin secretion. Epinephrine and propranolol themselves elevate SSPG levels. 3 Also, plasma levels of growth hormone (HGH) and glucagon may not be suppressed under these conditions, since paradoxical rises or less suppressibility of HGH 4 and glucagon 5 following glucose loads have been reported in diabetic subjects. We have therefore used somatostatin, which has been shown to have no direct effect on glucose and lipid metabolism, 6 to suppress endogenous secretion of insulin, glucagon, and HGH. Using the newly revised method, we have assessed insulin sensitivity in diabetics treated with diet alone, sulfonylureas, or insulin, and in obese nondiabetic subjects with hyperinsulinism.