Peripheral Insulin Action Research Articles

Brain insulin responsiveness is linked to age and peripheral insulin sensitivity.

Insulin action in the brain influences cognitive processes, peripheral metabolism and eating behaviour. However, the influence of age and peripheral insulin sensitivity on brain insulin action remains unclear. We used intranasal administration of insulin and functional magnetic resonance imaging in a randomized, placebo-controlled within-subject design in 110 participants (54 women, body mass index 18-49 kg/m2 , age 21-74 years). Cerebral blood flow was measured before and after nasal spray application to assess brain insulin action. Peripheral insulin sensitivity was assessed by a five-point oral glucose tolerance test. Linear regressions were used to investigate associations between age and peripheral insulin sensitivity with brain insulin action in predefined region of interests (i.e. insulin-sensitive brain regions). We found significant negative associations between age and insulin action in the hippocampus (β = -0.215; p = .017) and caudate nucleus (β = -0.184; p = .047); and between peripheral insulin sensitivity and insulin action in the amygdala (β = -0.190, p = .023). Insulin action in the insular cortex showed an interaction effect between age and peripheral insulin sensitivity (β = -0.219 p = .005). Furthermore, women showed the strongest negative association between age and hippocampal insulin action, while men showed the strongest associations with peripheral insulin sensitivity and age in reward-related brain regions. We could show a region-specific relationship between brain insulin responsiveness, age and peripheral insulin sensitivity. Our findings underline the need to study brain insulin action in both men and women and further substantiate that brain insulin sensitivity is a possible link between systemic metabolism and neurocognitive functions.

Diazoxide improves muscle function in association with improved dyslipidemia and decreased muscle oxidative stress in streptozotocin-induced diabetic rats.

Diabetes Mellitus is a chronic degenerative disease, and its main biochemical characteristic is hyperglycemia due to impaired insulin secretion, resistance to peripheral actions of insulin, or both. Hyperglycemia causes dyslipidemia and stimulates oxidative damage, leading to the main symptoms, such as fatigue and culminates in diabetic complications. Previous studies have shown that ATP-sensitive potassium channels counteract muscle fatigue and metabolic stress in healthy mouse models. To determine the effect of diazoxide on muscle strength development during diabetes, we tested the effect of diazoxide in streptozotocin-diabetic rats in muscle function, lipid profile and oxidative stress biomarkers. Wistar rats were divided into 4 groups of six animals each: (1) Control group, (2) diabetes group, (3) Control group + diazoxide, and (4) Diabetic + diazoxide (DB + DZX). 4 weeks after rats were sacrificed, soleus and extensor digitorum longus muscles (EDL) were extracted to prepare homogenates and serum was obtained for biochemical measurements. Oxidative damage was evaluated by the thiobarbituric acid method and the fluorescent for reactive oxygen species (ROS) probe 2,4-H2DCFDA, respectively. Diabetic rats with diazoxide administration showed an increase in the development of muscle strength in both muscles; in turn, the onset of fatigue was longer compared to the group of diabetic rats without treatment. Regarding the lipid profile, diazoxide decreased total cholesterol levels in the group of diabetic rats treated with diazoxide (x̅46.2mg/dL) compared to the untreated diabetic group (x̅=104.4mg/dL); secondly, diazoxide decreased triglyceride concentrations (x̅=105.3mg/dL) compared to the untreated diabetic rats (x̅=412.2mg/dL) as well as the levels of very low-density lipoproteins (x̅=20.4mg/dL vs. x̅=82.44mg/dL). Regarding the various markers of oxidative stress, the diabetic group treated with diazoxide was able to reduce the concentrations of TBARS and total reactive oxygen species as well as preserve the concentrations of reduced glutathione. Diazoxide administration in diabetic rats increases muscle strength development in EDL and soleus muscle, decreases fatigue, reduces cholesterol and triglyceride concentrations and improves oxidative stress parameters such as TBARS, ROS, and glutathione status.

Effects of the central melanocortin system on feed intake, metabolic hormones and insulin action in the sheep.

Voluntary feed intake is insufficient to meet the nutrient demands associated with late pregnancy in prolific ewes and early lactation in high-yielding dairy cows. Under these conditions, peripheral signals such as growth hormone and ceramides trigger adaptations aimed at preserving metabolic well-being. Recent work in rodents has shown that the central nervous system-melanocortin (CNS-MC) system, consisting of alpha-melanocyte-stimulating hormone (α-MSH) and agouti-related peptide (AGRP) acting respectively as agonist and antagonist on central MC receptors, contributes to the regulation of some of the same adaptations. To assess the effects of the CNC-MC on peripheral adaptations in ruminants, ewes were implanted with an intracerebroventricular cannula in the third ventricle and infused over days with artificial cerebrospinal fluid (aCSF), the α-MSH analog melanotan-I (MTI), or AGRP. Infusion of MTI at 0.03 nmol/h reduced intake, expressed as a fold of maintenance energy requirement (M), from 1.8 to 1.1 M (P < 0.0001), whereas AGRP at 0.3 nmol/h increased intake from 1.8 to 2.0 M (P < 0.01); these doses were used in all subsequent experiments. To assess the effect of MTI on plasma variables, sheep were fed ad libitum and infused with aCSF or MTI or pair-fed to MTI-treated sheep and infused with aCSF (aCSFPF). Feed intake of the MTI and aCSFPF groups was 40% lower than the aCSF group (P < 0.0001). MTI increased plasma triiodothyronine and thyroxine in an intake-independent manner (P < 0.05 or less) but was devoid of effects on plasma glucose, insulin, and cortisol. None of these variables were altered by AGRP infusion in sheep fed at a fixed intake of 1.6 M. To assess the effect of CNS-MC activation on insulin action, ewes were infused with aCSF or MTI over the last 3 d of a 14-d period when energy intake was limited to 0.3 M and studied under basal conditions and during hyperinsulinemic-euglycemic clamps. MTI had no effect on plasma glucose, plasma insulin, or glucose entry rate under basal conditions but blunted the ability of insulin to inhibit endogenous glucose production during hyperinsulinemic-euglycemic clamps (P < 0.0001). Finally, MTI tended to reduce plasma leptin in sheep fed at 0.3 M (P < 0.08), and this effect became significant at 0.6 M (P < 0.05); MTI had no effect on plasma adiponectin irrespective of feeding level. These data suggest a role for the CNC-MC in regulating metabolic efficiency and peripheral insulin action.

Protocatechuic Acid Ameliorates High Fat Diet-Induced Obesity and Insulin Resistance in Mice.

Insulin resistance is a common feature of obesity and type 2 diabetes and partly results from an imbalance between food intake and energy expenditure. Therefore, efficient and safe insulin resistance treatment therapies are warranted. This work is aim to access the impact of protocatechuic acid (PCA), a catechol-type O-diphenol phenolic acid, in high fat diet (HFD)-induced glucose, and lipid dysregulation. Five-week-old male C57BL/6 mice are fed with HFD for 4 weeks and then are randomly divided into two cohorts: one cohort feed with HFD is free access to sterile water for 4 weeks, another cohort is free access to PCA-containing water (2.7mM) for 4 weeks with HFD. In this study, using a hyperinsulinemic-euglycemic mouse clamp, it is showed that PCA-treated mice display improved systemic insulin resistance via enhanced fatty acid mobilization and utilization, thereby reducing ectopic lipid accumulation and promoting hepatic and peripheral insulin action. This study provides insights on the potent pharmacological effects of PCA from food sources on improving high fat diet (HFD)-induced whole-body insulin resistance and type 2 diabetes.

A study of Hepcidin levels and other Biochemical parameters in woman with Osteoporosis with Type 2 Diabetes Mellitus

Background: Diabetes mellitus (DM) could be regarded as a set of chronic metabolic disorders which have a common aspect of hyperglycemia. The resistance in the peripheral actions of insulin or impaired insulin secretion could be the reason hepcidin which is a peptide hormone derived from liver, in systemic iron homeostasis is an essential regulator, and its lopsided production participates in the pathogenesis of iron disorders in spectrum. Osteoporosis often accompanies many diseases like ß-thalassemia, hemochromatosis, sickle liver diseases, cell disease and hemosiderosis featured by iron overload, evidences suggest that Iron overload and iron deficiency are suggested by evidences that they affect bone in a negative way, acting straightway on the cells of the bone. Aim: The current study aims to find the direct relationship between the levels of Hepcidin, DHVD3 and other parameters in Osteoporosis with type 2 DM, in a female patient Methods: This study involved 60 subjects divided to two groups 30 female Osteoporosis with type 2 DM patients and 30 healthy controls . Over the period from November 2021 until the end of June 2021, this study was conducted. The ranges of age were (40-55) years. All diabetic patients examined by an endocrinologist in the Al-Yarmouk Teaching Hospital and Al- Mahmudiya Hospital . They were treated with oral anti-diabetic agents, mainly Metformin and Glibenclamide. The control subjects were referred to Laboratories Yarmouk Teaching Hospital, where all measurements were made. Control subjects were collected with glycemic control inclusion criteria when fasting serum glucose (FSG) &lt; 100 mg/dL and HbA1c &lt; 5.7%. BMI, Hb, hepcidin, Ferritin, Iron, DHVD3, Ca, PO4 were determined. Results: results was showed significant increase compared with control group in glycemic profile and lipid profile ,also, results showed a significant decrease compared with control group in Hb, Ferritin ,Iron , Vit D ,Ca , PO4 ,also the results showed a significant increase in hepcidin. Conclusion; By linking Ferritin, Iron vitamin D3 , Ca , PO4 deficiency and Hepcidin overload to women was diagnosed Osteoporosis with T2DM which indicated vit D3 deficiency related with hepcidin dysfunction. as an influencing factor on osteoarthritis women

Is type 2 diabetes mellitus another intercellular junction-related disorder?

Type 2 diabetes mellitus (T2D) is nowadays a worldwide epidemic and has become a major challenge for health systems around the world. It is a multifactorial disorder, characterized by a chronic state of hyperglycemia caused by defects in the production as well as in the peripheral action of insulin. This minireview highlights the experimental and clinical evidence that supports the novel idea that intercellular junctions (IJs)-mediated cell-cell contacts play a role in the pathogenesis of T2D. It focuses on IJs repercussion for endocrine pancreas, intestinal barrier, and kidney dysfunctions that contribute to the onset and evolution of this metabolic disorder.

Extreme Variations in Muscle Fiber Composition Enable Detection of Insulin Resistance and Excessive Insulin Secretion.

Muscle fiber composition is associated with peripheral insulin action. We investigated whether extreme differences in muscle fiber composition are associated with alterations in peripheral insulin action and secretion in young, healthy subjects who exhibit normal fasting glycemia and insulinemia. Relaxation time following a tetanic contraction was used to identify subjects with a high or low expression of type I muscle fibers: group 1 (n = 11), area occupied by type I muscle fibers = 61.0 ± 11.8%, and group 2 (n = 8), type I area = 36.0 ± 4.9% (P < 0.001). Biopsies were obtained from the vastus lateralis muscle and analyzed for mitochondrial respiration on permeabilized fibers, muscle fiber composition, and capillary density. An intravenous glucose tolerance test was performed and indices of glucose tolerance, insulin sensitivity, and secretion were determined. Glucose tolerance was similar between groups, whereas whole-body insulin sensitivity was decreased by ~50% in group 2 vs group 1 (P = 0.019). First-phase insulin release (area under the insulin curve during 10 minutes after glucose infusion) was increased by almost 4-fold in group 2 vs group 1 (P = 0.01). Whole-body insulin sensitivity was correlated with percentage area occupied by type I fibers (r = 0.54; P = 0.018) and capillary density in muscle (r = 0.61; P = 0.005) but not with mitochondrial respiration. Insulin release was strongly related to percentage area occupied by type II fibers (r = 0.93; P < 0.001). Assessment of muscle contractile function in young healthy subjects may prove useful in identifying individuals with insulin resistance and enhanced glucose-stimulated insulin secretion prior to onset of clinical manifestations.

The Potential Therapeutic Effect of Orexin-Treated versus Orexin-Untreated Adipose Tissue-Derived Mesenchymal Stem Cell Therapy on Insulin Resistance in Type 2 Diabetic Rats.

Type 2 diabetes mellitus is a chronic metabolic disease characterized by resistance to peripheral insulin actions. Mesenchymal stem cells have been studied for years in T2DM therapy, including adipose tissue-derived mesenchymal stem cells (AD-MSCs). Orexin neuropeptides (A and B) are well-known regulators of appetite and physical activity. The aim of this work was to elucidate the possible therapeutic effect of AD-MSC preconditioning with orexin A (OXA) on insulin resistance in rats. Twenty-eight adult male albino rats were divided into 4 equal groups: a normal control group and 3 diabetic groups (a control T2DM group, diabetic rats treated by an AD-MSCs group, and diabetic rats treated by AD-MSCs preconditioned with OXA). We noticed that the treated groups showed a significant alleviation of insulin resistance parameters as shown in lowering the serum levels of glucose, insulin, total cholesterol, inflammatory markers, and HOMA-IR as compared to the control diabetic group with more significant reduction observed in the OXA-pretreated AD-MSCs-administrated group. More improvement was also noted in the glucose uptake and GLUT-4 gene expression in the skeletal muscle and adipose tissue in the OXA-pretreated AD-MSCs-administrated group compared to the untreated diabetic group. Conclusion. Preconditioning of AD-MSCs with OXA can significantly increase their potential to reduce the insulin resistance in the rat model of T2DM.

Implicações da Farmacoterapia anti-hiperglicémica na Avaliação da Aptidão em Trabalhadores com Diabetes Mellitus

Introduction/Framework Diabetes mellitus is a chronic disease resulting from deficient secretion and/or peripheral insulin action, causing hyperglycemia, with multiple organ damage. The worldwide Diabetes mellitus incidence has increased in recent decades, with an estimated worldwide prevalence close to 415 million adults. In this context, a lot of workers with this disease will be accessed through medical examination to evaluate fitness for work, so it is essential that the Occupational Physician remains updated about the clinic and the available pharmacological options to deliberate on aptitude, restrictions and recommendations for a specific job/task. Methodology It’s a narrative review of the available evidence from the PubMed database, complemented by the national and international guidelines and the Portuguese law. Contents/Discussion DM complications can affect the ability to work and should motivate periodic evaluation by the Occupational Physician. Some chronic complications are evident in their likelihood of disability, such as retinopathy or neuro-ischemic disease, which often motivate work restrictions. On the other hand, acute complications, although often mild and self-limited, can put the worker at serious risk of an occupational accident. Severe hypoglycemia, with neuroglycopenic symptoms, is the most obvious example. The pharmacotherapy itself can cause hypoglycemic episodes or other symptoms that put the safety of the worker and even others at risk. Workers with DM who work at heights, who handle dangerous equipment or who drive professionally, must be carefully evaluated by the Occupational Physician. Although most will not have work restrictions, it may be necessary to adapt the workplace or limit certain tasks to achieve adequate glycemic control, a determining factor for preventing complications. Recommendations for workers with diabetes include breaks for glycaemic control, food ingestion and/or therapeutic administration, appropriate choice of protective equipment and, eventually, restriction of night shifts or some tasks with high metabolic expenditure. Those recommendations depend on the awareness of hypoglycaemea, the pharmacotherapy used to control diabetes and the complications of the disease. Conclusion Occupational Physician needs to be updated about Diabetes Mellitus management tools, pharmacotherapy, with particular attention to eventual side effects, to control and prevent professional risks arising from poor control. Keywords: Diabetes mellitus; Antihyperglycemic Pharmacotherapy; Fitness for Work Assessment; Occupational Health.

The Role of HbA1c as a Positive Perioperative Predictor of Surgical Site and Other Postoperative Infections: An Explorative Analysis in Patients Undergoing Minor to Major Surgery

BackgroundPatients with diabetes mellitus type 2 (DM2) inhere impaired peripheral insulin action leading to higher perioperative morbidity and mortality rates, with hospital-acquired infections being one important complication. This post hoc, observational study aimed to analyze the impact of surgical and metabolic stress as defined by the surrogate marker hemoglobin A1c (HbA1c), in relation to self-reported DM2, on perioperative infection rates in a subcohort of the Surgical Site Infection (SSI) Trial population.MethodsAll patients of the SSI study were screened for HbA1c levels measured perioperatively for elective or emergency surgery and classified according to the American Diabetes Association HbA1c cutoff values. SSI and nosocomial infections, self-reported state of DM2 and type of surgery (minor, major) were assessed.ResultsHbA1c levels were measured in 139 of 5175 patients (2.7%) of the complete SSI study group. Seventy patients (50.4%) self-reported DM2, while 69 (49.6%) self-reported to be non-diabetic. HbA1c levels indicating pre-diabetes were found in 48 patients (34.5%) and diabetic state in 64 patients (46%). Forty-five patients of the group self-reporting no diabetes (65.2%) were previously unaware of their metabolic derangement (35 pre-diabetic and 10 diabetic). Eighteen infections were detected. Most infections (17 of 18 events) were found in patients with HbA1c levels indicating pre-/diabetic state. The odds for an infection was 3.9-fold (95% CI 1.4 to 11.3) higher for patients undergoing major compared to minor interventions. The highest percentage of infections (38.5%) was found in the group of patients with an undiagnosed pre-/diabetic state undergoing major surgery.ConclusionsThese results encourage investment in further studies evaluating a more generous and specific use of HbA1c screening in patients without self-reported diabetes undergoing major surgery.Trial registration Clinicaltrials.gov identifier: NCT 01790529

Insulin secretion and action and the response of endogenous glucose production to a lack of glucagon suppression in nondiabetic subjects.

Type 2 diabetes is a disease characterized by impaired insulin secretion and defective glucagon suppression in the postprandial period. We examined the effect of impaired glucagon suppression on glucose concentrations and endogenous glucose production (EGP) at different degrees of insulin secretory impairment. The contribution of anthropometric characteristics, peripheral, and hepatic insulin action to this variability was also examined. To do so, we studied 54 nondiabetic subjects on two occasions in which endogenous hormone secretion was inhibited by somatostatin, with glucagon infused at a rate of 0.65 ng/kg/min, at 0 min to prevent a fall in glucagon (nonsuppressed day) or at 120 min to create a transient fall in glucagon (suppressed day). Subjects received glucose (labeled with [3-3H]-glucose) infused to mimic the systemic appearance of 50-g oral glucose. Insulin was infused to mimic a prandial insulin response in 18 subjects, another 18 received 80% of the dose, and the remaining 18 received 60%. EGP was measured using the tracer-dilution technique. Decreased prandial insulin resulted in greater % increase in peak glucose but not in integrated glucose concentrations attributable to nonsuppressed glucagon. The % change in integrated EGP was unaffected by insulin dose. Multivariate regression analysis, adjusted for age, sex, weight, and insulin dose, did not show a relationship between the EGP response to impaired suppression of glucagon and insulin action as measured at the time of screening by oral glucose tolerance. A similar analysis for hepatic insulin action also did not show a relationship with the EGP response. These data indicate that the effect of impaired glucagon suppression on EGP is independent of anthropometric characteristics and insulin action.NEW & NOTEWORTHY In prediabetes, anthropometric characteristics as well as insulin action do not alter the hepatic response to glucagon. The postprandial suppression or lack of suppression of glucagon secretion is an important factor governing postprandial glucose tolerance independent of insulin secretion.

Insulin Pulse Characteristics and Insulin Action in Non-diabetic Humans.

Pulsatile insulin secretion is impaired in diseases such as type 2 diabetes that are characterized by insulin resistance. This has led to the suggestion that changes in insulin pulsatility directly impair insulin signaling. We sought to examine the effects of pulse characteristics on insulin action in humans, hypothesizing that a decrease in pulse amplitude or frequency is associated with impaired hepatic insulin action. We studied 29 nondiabetic subjects on two occasions. On 1 occasion, hepatic and peripheral insulin action was measured using a euglycemic clamp. The deuterated water method was used to estimate the contribution of gluconeogenesis to endogenous glucose production. On a separate study day, we utilized nonparametric stochastic deconvolution of frequently sampled peripheral C-peptide concentrations during fasting to reconstruct portal insulin secretion. In addition to measuring basal and pulsatile insulin secretion, we used approximate entropy to measure orderliness and Fourier transform to measure the average, and the dispersion of, insulin pulse frequencies. In univariate analysis, basal insulin secretion (R2 = 0.16) and insulin pulse amplitude (R2 = 0.09) correlated weakly with insulin-induced suppression of gluconeogenesis. However, after adjustment for age, sex, and weight, these associations were no longer significant. The other pulse characteristics also did not correlate with the ability of insulin to suppress endogenous glucose production (and gluconeogenesis) or to stimulate glucose disappearance. Overall, our data demonstrate that insulin pulse characteristics, considered independently of other factors, do not correlate with measures of hepatic and peripheral insulin sensitivity in nondiabetic humans.

Peripheral and central regulation of insulin by the intestine and microbiome.

Blood glucose and insulin homeostasis is disrupted during the progression of type 2 diabetes. Insulin levels and action are regulated by both peripheral and central responses that involve the intestine and microbiome. The intestine and its microbiota process nutrients and generate molecules that influence blood glucose and insulin. Peripheral insulin regulation is regulated by gut-segment-dependent nutrient sensing and microbial factors such as short-chain fatty acids and bile acids that engage G-protein-coupled receptors. Innate immune sensing of gut-derived bacterial cell wall components and lipopolysaccharides also alter insulin homeostasis. These bacterial metabolites and postbiotics influence insulin secretion and insulin clearance in part by altering endocrine responses such as glucagon-like peptide-1. Gut-derived bacterial factors can promote inflammation and insulin resistance, but other postbiotics can be insulin sensitizers. In parallel, activation of small intestinal sirtuin 1 increases insulin sensitivity by reversing high fat-induced hypothalamic insulin resistance through a gut-brain neuronal axis, whereas high fat-feeding alters small intestinal microbiome and increases taurochenodeoxycholic acid in the plasma and the dorsal vagal complex to induce insulin resistance. In summary, emerging evidence indicates that intestinal molecular signaling involving nutrient sensing and the host-microbe symbiosis alters insulin homeostasis and action. Gut-derived host endocrine and paracrine factors as well as microbial metabolites act on the liver, pancreas, and the brain, and in parallel on the gut-brain neuronal axis. Understanding common nodes of peripheral and central insulin homeostasis and action may reveal new ways to target the intestinal host-microbe relationship in obesity, metabolic disease, and type 2 diabetes.

Clinical efficacy of unani formulation in type ii diabetes-A randomized, single blind standard control clinical study

Background and objectives: Diabetes mellitus is a chronic metabolic disorder characterized by persistent hyperglycaemia. It may be due to impaired insulin secretion, resistance to peripheral actions of insulin, or both. Unani system claimed for the efficacy of many anti-hyperglycaemic drugs, and all such drugs required validated on scientifically. Hence a clinical study was intended to evaluate the clinical efficacy of the Unani formulation in the management of diabetes. Methods: This trial was conducted as single blind randomized standard control, on 60 patients of type 2 diabetes with the test (n =30) and control (n=30) groups for 45 days. Test group received Unani Formulation twice daily at a dosage of 5 g powder, and control group received 500 mg tablet metformin twice a day before meal. The subjective (at 0, 15th, 30th, 45th), and objective parameters were evaluated respectively as pre-post care. Results: After treatment with Unani Formulation significant reduction was observed in subjective parameters (viz. polyuria, polydipsia, polyphagia and tiredness) in connotation of control group. In both groups the objective parameters FBS, PPBS, and HbA1c were found to be significantly reduced. The findings were statistically analysed using paired and non-paired tests. Conclusion: Based on the above observation, it is concluded that there is substantial anti-diabetic effect of the Unani Formulation without any adverse drug reaction.

1749-P: The TNFa Inhibitor Infliximab Decreases Inflammation in High-Fat Fed Mice but Does Not Alleviate Insulin Resistance

The insulin resistance of diet-induced obesity (DIO) is accompanied by inflammation. Previous studies suggest that the anti-inflammatory effects of infliximab, an anti-TNFα chimeric monoclonal antibody, decreases DIO-associated inflammation in mice fed a 60% fat diet. The effectiveness of infliximab at 10 mg/kg Infliximab (IF10) and 100 mg/kg infliximab (IF100) in C57Bl/6J DIO mice was studied in comparison to C57Bl/6J DIO mice administered chimeric IgG (IgG; 10 mg/kg). Treatment consisted of IP injections of infliximab or IgG once per week for 4 weeks. Body weight and fasting arterial glucose was not different in IF10, IF100, and IgG. IF10 and IF100 mice had a decreased presence of crown-like structures in white adipose tissue compared to IgG treated mice. Infliximab resulted in a dose-dependent reduction in macrophage F4/80 staining in white adipose tissue (4.3±0.7% and 1.8±0.2% in IF10 and IF100, respectively) compared to 8.1±1.6% in IgG, validating the anti-inflammatory effect. Insulin action was measured in mice with arterial and venous catheters using the hyperinsulinemic, euglycemic clamp method (insulin dose of 4 mU/kg/min) combined with [3-3H]glucose in conscious, unstressed mice. Glucose infusion rates (GIR) in IgG mice were higher (25±3 mg/kg/min) as compared to IF10 (17±2 mg/kg/min) and IF100 (19±2 mg/kg/min). The greater GIR in IgG as compared to IF10 was due to changes in hepatic endogenous glucose production (suppression of 12±3 mg/kg/min and 5±1 mg/kg/min, respectively) without a difference in glucose utilization. IF100 exhibited small reductions in both hepatic and peripheral insulin action, neither of which reached significance. Mice treated with saline alone were used as an additional control, but neither IF10 nor IF100 had significant effects on insulin action compared to saline controls. In summary, despite profound anti-inflammatory effects of the anti-TNFα drug, Infliximab causes a paradoxically greater hepatic insulin resistance. Disclosure D.A. Roby: None. C. Guan: None. F. James: None. D. Bracy: None. L. Lantier: None. D. Wasserman: None.

Intermittent Fasting as Part of the Management for T2DM: from Animal Models to Human Clinical Studies.

Diet is a pillar of type 2 diabetes mellitus (T2DM) management. Intermittent fasting (IF) is postulated as a novel approach, able to improve glucose control and potentially capable of reversing some of the pathophysiological alterations of this condition. In this review, the molecular and clinical evidence of diets based on intermittent energy restriction (IER) in laboratory animal models and subjects with type 2 diabetes is discussed. The mechanisms through which IF are thought to improve glucose homeostasis and reverse β cell failure are also reviewed. Studies derived from murine models suggest that IER is associated with improvements in β cell function and insulin resistance. Two main mechanisms have been demonstrated, one derived from the autophagy-lysosome pathway and, the other from an increase in neurogenin3 (Ngn3) levels (a marker for endocrine progenitor cells like β cells during development). Notably, IER also promotes reconstruction of gut microbiota. In mice, all effects were independent of weight loss. By contrast, in human studies, outcomes are widely attributable to weight loss. The more consistent results are reductions in body weight, visceral fat, and glucose and insulin levels. Increases in HDL cholesterol levels are also frequently reported. The decrease in insulin levels observed in humans is in opposition with the increase reported in mice, suggesting that the main mechanism in humans is an improvement in peripheral insulin action. Recommending diets based on intermittent fasting in humans is based on the promising results found in animal models where an improvement in β cell function has been recorded. β cell function after IF has not been assessed in human subjects with T2DM. This review provides information regarding different protocols for the implementation of IF in diabetic persons and also provides important safety advice in order to avoid adverse effects. Clinical studies do not show an increased risk of hypoglycemia, and a recent case series reported reversal of T2DM.

A novel fast-slow model of diabetes progression: Insights into mechanisms of response to the interventions in the Diabetes Prevention Program.

Several models for the long-term development of T2DM already exist, focusing on the dynamics of the interaction between glycemia, insulinemia and β-cell mass. Current models consider representative (fasting or daily average) glycemia and insulinemia as characterizing the compensation state of the subject at some instant in slow time. This implies that only these representative levels can be followed through time and that the role of fast glycemic oscillations is neglected. An improved model (DPM15) for the long-term progression of T2DM is proposed, introducing separate peripheral and hepatic (liver and kidney) insulin actions. The DPM15 model no longer uses near-equilibrium approximation to separate fast and slow time scales, but rather describes, at each step in slow time, a complete day in the life of the virtual subject in fast time. The model can thus represent both fasting and postprandial glycemic levels and describe the effect of interventions acting on insulin-enhanced tissue glucose disposal or on insulin-inhibited hepatic glucose output, as well as on insulin secretion and β-cell replicating ability. The model can simulate long-term variations of commonly used clinical indices (HOMA-B, HOMA-IR, insulinogenic index) as well as of Oral Glucose Tolerance or Euglycemic Hyperinsulinemic Clamp test results. The model has been calibrated against observational data from the Diabetes Prevention Program study: it shows good adaptation to observations as a function of very plausible values of the parameters describing the effect of such interventions as Placebo, Intensive LifeStyle and Metformin administration.

Carcinoembryonic Cell Adhesion-Related Molecule 2 Regulates Insulin Secretion and Energy Balance.

The Carcinoembryonic Antigen-Related Cell Adhesion Molecule (CEACAM) family of proteins plays a significant role in regulating peripheral insulin action by participating in the regulation of insulin metabolism and energy balance. In light of their differential expression, CEACAM1 regulates chiefly insulin extraction, whereas CEACAM2 appears to play a more important role in regulating insulin secretion and overall energy balance, including food intake, energy expenditure and spontaneous physical activity. We will focus this review on the role of CEACAM2 in regulating insulin metabolism and energy balance with an overarching goal to emphasize the importance of the coordinated regulatory effect of these related plasma membrane glycoproteins on insulin metabolism and action.

Mechanisms of diabetes and dementia

Mechanisms of diabetes and dementia

Trigonella Foenum Graecum Extract Benefits on Hematological, Biochemical and Male Reproductive System of as a Complementary Therapy with Glimepiride in Treating Streptozotocin Induced Diabetic Rats

Diabetes mellitus (DM) is a chronic metabolic disorder. Streptozotocin is a naturally occurring cytotoxic chemical, particularly toxic to the pancreas and insulin producing beta cells in mammals and induces diabetes. Glimepiride is a second generation sulfonylurea, used as second-line or add-on treatment options for type 2 diabetes. Fenugreek (Trigonellafoenum graecum) seeds have been documented as a traditional plant treatment for diabetes. Soluble dietary fiber of Fenugreek significantly improved oral glucose tolerance in diabetic rats. It also exerts anti-diabetic effects mediated through the inhibition of carbohydrate digestion and absorption and the enhancement of peripheral insulin action. Most herbal remedies can interact with allopathic drugs resulting in altered activity and toxicity. At the same time, herbal remedies might produce the same kind of effects as the drug produce. Current published research information on herb-drug interactions is scanty. So, the aim of this study was to investigate the possible interaction between conventional drug used for the management of diabetes; (Glimepiride) and a traditional herbal remedy; Fenugreek aqueous extract in Streptozotocin induced diabetic male albino rats. In conclusion, combination therapy induces better hematological, biochemical effects and improves the oxidative stress biomarkers and antioxidant enzymes. Histological studies showed better results on some organ functions. The results emphasize the benefit of using the combination of Fenugreek seeds aqueous extracts as supportive complementary anti-diabetic therapy.