Showing papers on "Insulin published in 2011"

Interventions for latent autoimmune diabetes (LADA) in adults.

Abstract: Background Latent autoimmune diabetes in adults (LADA) is a slowly developing type 1 diabetes. Objectives To compare interventions used for LADA. Search methods Studies were obtained from searches of electronic databases, supplemented by handsearches, conference proceedings and consultation with experts. Date of last search was December 2010. Selection criteria Randomised controlled trials (RCT) and controlled clinical trials (CCT) evaluating interventions for LADA or type 2 diabetes with antibodies were included. Data collection and analysis Two authors independently extracted data and assessed risk of bias. Studies were summarised using meta-analysis or descriptive methods. Main results Searches identified 13,306 citations. Fifteen publications (ten studies) were included, involving 1019 participants who were followed between three months to 10 years (1060 randomised). All studies had a high risk of bias. Sulphonylurea (SU) with insulin did not improve metabolic control significantly more than insulin alone at three months (one study, n = 15) and at 12 months (one study, n = 14) of treatment and follow-up. SU (with or without metformin) gave poorer metabolic control compared to insulin alone (mean difference in glycosylated haemoglobin A1c (HbA1c) from baseline to end of study, for insulin compared to oral therapy: -1.3% (95% confidence interval (CI) -2.4 to -0.1; P = 0.03, 160 participants, four studies, follow-up/duration of therapy: 12, 30, 36 and 60 months; however, heterogeneity was considerable). In addition, there was evidence that SU caused earlier insulin dependence (proportion requiring insulin at two years was 30% in the SU group compared to 5% in conventional care group (P < 0.001); patients classified as insulin dependent was 64% (SU group) and 12.5% (insulin group, P = 0.007). No intervention influenced fasting C-peptide, but insulin maintained stimulated C-peptide better than SU (one study, mean difference 7.7 ng/ml (95% CI 2.9 to 12.5)). In a five year follow-up of GAD65 (glutamic acid decarboxylase formulated with aluminium hydroxide), improvements in fasting and stimulated C-peptide levels (20 μg group) were maintained after five years. Short term (three months) follow-up in one study (n = 74) using Chinese remedies did not demonstrate a significant difference in improving fasting C-peptide levels compared to insulin alone (0.07 µg/L (95% CI -0.05 to 0.19). One study using vitamin D with insulin showed steady fasting C-peptide levels in the vitamin D group but declining fasting C-peptide levels (368 to 179 pmol/L, P = 0.006) in the insulin alone group at 12 months follow-up. Comparing studies was difficult as there was a great deal of heterogeneity in the studies and in their selection criteria. There was no information regarding health-related quality of life, complications of diabetes, cost or health service utilisation, mortality and limited evidence on adverse events (studies on oral agents or insulin reported no adverse events in terms of severe hypoglycaemic episodes). Authors' conclusions Two studies show SU leading to earlier insulin dependence and a meta-analysis of four studies with considerable heterogeneity showed poorer metabolic control if SU is prescribed for patients with LADA compared to insulin. One study showed that vitamin D with insulin may protect pancreatic beta cells in LADA. Novel treatments such as GAD65 in certain doses (20 μg) have been suggested to maintain fasting and stimulated C-peptide levels. However, there is no significant evidence for or against other lines of treatment of LADA.

The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance

Abstract: Obesity is generally considered an inflammatory state. Vishwa Dixit and his colleagues have now shown that excess dietary lipids leads to the activation of the Nlrp3 inflammasome, a sensor of the innate immune system, and that its genetic deficiency results in decreased inflammation and improved insulin sensitivity. These results suggest a possible new therapeutic avenue to treat the effects of obesity.

Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol

Abstract: Aims/hypothesis Type 2 diabetes is regarded as inevitably progressive, with irreversible beta cell failure. The hypothesis was tested that both beta cell failure and insulin resistance can be reversed by dietary restriction of energy intake. Methods Eleven people with type 2 diabetes (49.5± 2.5 years, BMI 33.6±1.2 kg/m 2 , nine male and two female) were studied before and after 1, 4 and 8 weeks of a 2.5 MJ (600 kcal)/day diet. Basal hepatic glucose output, hepatic and peripheral insulin sensitivity and beta cell function were measured. Pancreas and liver triacylglycerol content was measured using three-point Dixon magnetic resonance imaging. An age-, sex- and weight-matched group of eight non-diabetic participants was studied. Results After 1 week of restricted energy intake, fasting plasma glucose normalised in the diabetic group (from 9.2± 0.4 to 5.9±0.4 mmol/l; p=0.003). Insulin suppression of hepatic glucose output improved from 43±4% to 74±5% (p= 0.003 vs baseline; controls 68±5%). Hepatic triacylglycerol content fell from 12.8±2.4% in the diabetic group to 2.9± 0.2% by week 8 (p=0.003). The first-phase insulin response increased during the study period (0.19±0.02 to 0.46± 0.07 nmol min �1 m �2 ; p<0.001) and approached control

MicroRNAs 103 and 107 regulate insulin sensitivity

Abstract: Defects in insulin signalling are among the most common and earliest defects that predispose an individual to the development of type 2 diabetes. MicroRNAs have been identified as a new class of regulatory molecules that influence many biological functions, including metabolism. However, the direct regulation of insulin sensitivity by microRNAs in vivo has not been demonstrated. Here we show that the expression of microRNAs 103 and 107 (miR-103/107) is upregulated in obese mice. Silencing of miR-103/107 leads to improved glucose homeostasis and insulin sensitivity. In contrast, gain of miR-103/107 function in either liver or fat is sufficient to induce impaired glucose homeostasis. We identify caveolin-1, a critical regulator of the insulin receptor, as a direct target gene of miR-103/107. We demonstrate that caveolin-1 is upregulated upon miR-103/107 inactivation in adipocytes and that this is concomitant with stabilization of the insulin receptor, enhanced insulin signalling, decreased adipocyte size and enhanced insulin-stimulated glucose uptake. These findings demonstrate the central importance of miR-103/107 to insulin sensitivity and identify a new target for the treatment of type 2 diabetes and obesity.

Fatty Acids, Obesity, and Insulin Resistance: Time for a Reevaluation

Abstract: There is a widespread acceptance in the literature that plasma nonesterified fatty acids (NEFA), also called free fatty acids (FFA), can mediate many adverse metabolic effects, most notably insulin resistance. Elevated NEFA concentrations in obesity are thought to arise from an increased adipose tissue mass. It is also argued that the process of fatty acid mobilization from adipose tissue, normally suppressed by insulin, itself becomes insulin resistant—thus, lipolysis is further increased, potentially leading to a vicious cycle. Although we have also accepted this model for many years (1,2), recently there has been a steady accumulation of data, both in the literature and from our own research, that has forced us to realize that this simple story is not always true. Here we review the background to the idea of “fatty acids as metabolic villains,” together with data from the literature and from our own studies, which tend to show another side to the fatty acids/insulin resistance story. We will first examine the relationship between systemic concentrations of NEFA and obesity/insulin resistance and then study adipose tissue in the obese state with regard to its adaptation for NEFA release. NEFA circulate in the plasma bound to plasma albumin. Their function was largely elucidated in the 1950s through the work of Vincent Dole (3) at the Rockefeller Institute in New York and Robert Gordon (4,5) at the National Institutes of Health. Gordon demonstrated the origin of plasma NEFA from adipose tissue and their use by tissues such as the liver and myocardium, but not the brain. We now recognize that NEFA are the vehicle by which triacylglycerol (TG) stored in adipose tissue is transported to its sites of utilization. NEFA turnover is rapid, with a plasma half-life around 2–4 min (6). The only significant site of NEFA liberation …

Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and alpha cells

Abstract: Exercise, obesity and type 2 diabetes are associated with elevated plasma concentrations of interleukin-6 (IL-6). Glucagon-like peptide-1 (GLP-1) is a hormone that induces insulin secretion. Here we show that administration of IL-6 or elevated IL-6 concentrations in response to exercise stimulate GLP-1 secretion from intestinal L cells and pancreatic alpha cells, improving insulin secretion and glycemia. IL-6 increased GLP-1 production from alpha cells through increased proglucagon (which is encoded by GCG) and prohormone convertase 1/3 expression. In models of type 2 diabetes, the beneficial effects of IL-6 were maintained, and IL-6 neutralization resulted in further elevation of glycemia and reduced pancreatic GLP-1. Hence, IL-6 mediates crosstalk between insulin-sensitive tissues, intestinal L cells and pancreatic islets to adapt to changes in insulin demand. This previously unidentified endocrine loop implicates IL-6 in the regulation of insulin secretion and suggests that drugs modulating this loop may be useful in type 2 diabetes.

Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans.

Abstract: Mutations in growth signaling pathways extend life span, as well as protect against age-dependent DNA damage in yeast and decrease insulin resistance and cancer in mice. To test their effect in humans, we monitored for 22 years Ecuadorian individuals who carry mutations in the growth hormone receptor (GHR) gene that lead to severe GHR and IGF-1 (insulin-like growth factor-1) deficiencies. We combined this information with surveys to identify the cause and age of death for individuals in this community who died before this period. The individuals with GHR deficiency exhibited only one nonlethal malignancy and no cases of diabetes, in contrast to a prevalence of 17% for cancer and 5% for diabetes in control subjects. A possible explanation for the very low incidence of cancer was suggested by in vitro studies: Serum from subjects with GHR deficiency reduced DNA breaks but increased apoptosis in human mammary epithelial cells treated with hydrogen peroxide. Serum from GHR-deficient subjects also caused reduced expression of RAS, PKA (protein kinase A), and TOR (target of rapamycin) and up-regulation of SOD2 (superoxide dismutase 2) in treated cells, changes that promote cellular protection and life-span extension in model organisms. We also observed reduced insulin concentrations (1.4 μU/ml versus 4.4 μU/ml in unaffected relatives) and a very low HOMA-IR (homeostatic model assessment-insulin resistance) index (0.34 versus 0.96 in unaffected relatives) in individuals with GHR deficiency, indicating higher insulin sensitivity, which could explain the absence of diabetes in these subjects. These results provide evidence for a role of evolutionarily conserved pathways in the control of aging and disease burden in humans.

miR-33a/b contribute to the regulation of fatty acid metabolism and insulin signaling.

Abstract: Cellular imbalances of cholesterol and fatty acid metabolism result in pathological processes, including atherosclerosis and metabolic syndrome. Recent work from our group and others has shown that the intronic microRNAs hsa-miR-33a and hsa-miR-33b are located within the sterol regulatory element-binding protein-2 and -1 genes, respectively, and regulate cholesterol homeostasis in concert with their host genes. Here, we show that miR-33a and -b also regulate genes involved in fatty acid metabolism and insulin signaling. miR-33a and -b target key enzymes involved in the regulation of fatty acid oxidation, including carnitine O-octaniltransferase, carnitine palmitoyltransferase 1A, hydroxyacyl-CoA-dehydrogenase, Sirtuin 6 (SIRT6), and AMP kinase subunit-α. Moreover, miR-33a and -b also target the insulin receptor substrate 2, an essential component of the insulin-signaling pathway in the liver. Overexpression of miR-33a and -b reduces both fatty acid oxidation and insulin signaling in hepatic cell lines, whereas inhibition of endogenous miR-33a and -b increases these two metabolic pathways. Together, these data establish that miR-33a and -b regulate pathways controlling three of the risk factors of metabolic syndrome, namely levels of HDL, triglycerides, and insulin signaling, and suggest that inhibitors of miR-33a and -b may be useful in the treatment of this growing health concern.

Effect of Renal Sympathetic Denervation on Glucose Metabolism in Patients With Resistant Hypertension A Pilot Study

Abstract: Background—Hypertension is associated with impaired glucose metabolism and insulin resistance. Chronic activation of the sympathetic nervous system may contribute to either condition. We investigated the effect of catheter-based renal sympathetic denervation on glucose metabolism and blood pressure control in patients with resistant hypertension. Methods and Results—We enrolled 50 patients with therapy-resistant hypertension. Thirty-seven patients underwent bilateral catheter-based renal denervation, and 13 patients were assigned to a control group. Systolic and diastolic blood pressures, fasting glucose, insulin, C peptide, hemoglobin A1c, calculated insulin sensitivity (homeostasis model assessment–insulin resistance), and glucose levels during oral glucose tolerance test were measured before and 1 and 3 months after treatment. Mean office blood pressure at baseline was 178/963/2 mm Hg. At 1 and 3 months, office blood pressure was reduced by 28/10 mm Hg (P0.001) and 32/12 mm Hg (P0.001), respectively, in the treatment group, without changes in concurrent antihypertensive treatment. Three months after renal denervation, fasting glucose was reduced from 1183.4 to 1083.8 mg/dL (P0.039). Insulin levels were decreased from 20.83.0 to 9.32.5 IU/mL (P0.006) and C-peptide levels from 5.30.6 to 3.00.9 ng/mL (P0.002). After 3 months, homeostasis model assessment–insulin resistance decreased from 6.00.9 to 2.40.8 (P0.001). Additionally, mean 2-hour glucose levels during oral glucose tolerance test were reduced significantly by 27 mg/dL (P0.012). There were no significant changes in blood pressure or metabolic markers in the control group. Conclusions—Renal denervation improves glucose metabolism and insulin sensitivity in addition to a significantly reducing blood pressure. However, this improvement appeared to be unrelated to changes in drug treatment. This novel procedure may therefore provide protection in patients with resistant hypertension and metabolic disorders at high cardiovascular risk. Clinical Trial Registration—URL: http://www.ClinicalTrials.gov. Unique identifiers: NCT00664638 and NCT00888433. (Circulation. 2011;123:1940-1946.)

Lipid-induced insulin resistance mediated by the proinflammatory receptor TLR4 requires saturated fatty acid-induced ceramide biosynthesis in mice.

Abstract: Obesity is associated with an enhanced inflammatory response that exacerbates insulin resistance and contributes to diabetes, atherosclerosis, and cardiovascular disease. One mechanism accounting for the increased inflammation associated with obesity is activation of the innate immune signaling pathway triggered by TLR4 recognition of saturated fatty acids, an event that is essential for lipid-induced insulin resistance. Using in vitro and in vivo systems to model lipid induction of TLR4-dependent inflammatory events in rodents, we show here that TLR4 is an upstream signaling component required for saturated fatty acid–induced ceramide biosynthesis. This increase in ceramide production was associated with the upregulation of genes driving ceramide biosynthesis, an event dependent of the activity of the proinflammatory kinase IKKβ. Importantly, increased ceramide production was not required for TLR4-dependent induction of inflammatory cytokines, but it was essential for TLR4-dependent insulin resistance. These findings suggest that sphingolipids such as ceramide might be key components of the signaling networks that link lipid-induced inflammatory pathways to the antagonism of insulin action that contributes to diabetes.

Randomized Study of Basal Bolus Insulin Therapy in the Inpatient Management of Patients With Type 2 Diabetes Undergoing General Surgery (RABBIT 2 Surgery)

Abstract: OBJECTIVE The optimal treatment of hyperglycemia in general surgical patients with type 2 diabetes mellitus is not known. RESEARCH DESIGN AND METHODS This randomized multicenter trial compared the safety and efficacy of a basal-bolus insulin regimen with glargine once daily and glulisine before meals ( n = 104) to sliding scale regular insulin (SSI) four times daily ( n = 107) in patients with type 2 diabetes mellitus undergoing general surgery. Outcomes included differences in daily blood glucose (BG) and a composite of postoperative complications including wound infection, pneumonia, bacteremia, and respiratory and acute renal failure. RESULTS The mean daily glucose concentration after the 1st day of basal-bolus insulin and SSI was 145 ± 32 mg/dL and 172 ± 47 mg/dL, respectively ( P P P = 0.003]. Glucose P P = 0.057). CONCLUSIONS Basal-bolus treatment with glargine once daily plus glulisine before meals improved glycemic control and reduced hospital complications compared with SSI in general surgery patients. Our study indicates that a basal-bolus insulin regimen is preferred over SSI in the hospital management of general surgery patients with type 2 diabetes.

Insulin resistance and Alzheimer-like reductions in regional cerebral glucose metabolism for cognitively normal adults with prediabetes or early type 2 diabetes.

Abstract: Background—Insulin resistance is a causal factor in pre-diabetes and type 2 diabetes (T2D), and also increases the risk of developing Alzheimer’s disease (AD). Reductions in cerebral glucose metabolic rate (CMRglu) as measured by fluorodeoxyglucose positron emission tomography (FDG PET) in parietotemporal, frontal, and cingulate cortex are also associated with increased AD risk, and can be observed years before dementia onset. Objectives—We examined whether greater insulin resistance as indexed by the homeostasis model assessment (HOMA-IR) would be associated with reduced resting CMRglu in areas known to be vulnerable in AD in a sample of cognitively normal adults with newly diagnosed prediabetes or T2D (P-D/T2D). We also determined whether P-D/T2D adults have abnormal patterns of CMRglu during a memory encoding task. Design—Randomized crossover design of resting and activation [F-18] FDG-PET. Setting—University Imaging Center and VA Clinical Research Unit. Participants—Participants included 23 older adults (mean age±SEM=74.4±1.4) with no prior diagnosis of or treatment for diabetes, but who met American Diabetes Association glycemic criteria for pre-diabetes (n=11) or diabetes (n=12) based on fasting or 2-h oral glucose tolerance test (OGTT) glucose values, and 6 adults (mean age±SEM=74.3±2.8) with normal fasting glucose and glucose tolerance. No participant met Petersen criteria for mild cognitive impairment (MCI). Intervention—Fasting participants rested with eyes open in a dimly lit room and underwent resting and cognitive activation [F-18]FDG PET imaging on separate days, in randomized order, at 9 am. Following a 30-min transmission scan, subjects received an intravenous injection of 5 mCi [F-18]FDG, and the emission scan commenced 40 min post-injection. In the activation condition, a 35-min memory encoding task was initiated at the time of tracer injection. Subjects

Artificial Pancreas: Past, Present, Future

Abstract: The artificial pancreas (AP), known as closed-loop control of blood glucose in diabetes, is a system combining a glucose sensor, a control algorithm, and an insulin infusion device. AP developments can be traced back 50 years to when the possibility for external blood glucose regulation was established by studies in individuals with type 1 diabetes using intravenous glucose measurement and infusion of insulin and glucose. After the pioneering work by Kadish (1) in 1964, expectations for effectively closing the loop were inspired by the nearly simultaneous work of five teams reporting closed-loop control results between 1974 and 1978: Albisser et al. (2), Pfeiffer et al. (3), Mirouze et al. (4), Kraegen et al. (5), and Shichiri et al. (6). In 1977, one of these realizations (3) resulted in the first commercial device—the Biostator (7; Fig. 1), followed by another inpatient system, the Nikkiso STG-22 Blood Glucose Controller, now in use in Japan (8). FIG. 1. The Biostator (courtesy of William Clarke, University of Virginia). Although the intravenous route of glucose sensing and insulin infusion is unsuitable for outpatient use, these devices proved the feasibility of external glucose control and stimulated further technology development. Figure 2 presents key milestones in the timeline of AP progress. FIG. 2. Key milestones in the timeline of AP progress. EU, Europe; IP, intraperitoneal; NIH, National Institutes of Health; SC, subcutaneous. In 1979, landmark studies by Pickup et al. (9) and Tamborlane et al. (10) showed that the subcutaneous route was feasible for continuous insulin delivery. Three years later, Shichiri et al. (11) tested a prototype of a wearable AP, which was further developed in subsequent studies (12,13). In the late 1980s, an implantable system was introduced using intravenous glucose sensing and intraperitoneal insulin infusion (14). This technology was further developed, leading to clinical trials and …

Dipeptidyl Peptidase 4 Is a Novel Adipokine Potentially Linking Obesity to the Metabolic Syndrome

Abstract: OBJECTIVE—Comprehensive proteomic profiling of the human adipocyte secretome identified dipeptidyl peptidase 4 (DPP4) as a novel adipokine. This study assessed the functional implications of the adipokine DPP4 and its association to the metabolic syndrome. RESEARCH DESIGN AND METHODS—Human adipocytes and skeletal and smooth muscle cells were used to monitor DPP4 release and assess the effects of soluble DPP4 on insulin signaling. In lean and obese subjects, depot-specific expression of DPP4 and its release from adipose tissue explants were determined and correlated to parameters of the metabolic syndrome. RESULTS—Fully differentiated adipocytes exhibit a substantially higher release of DPP4 compared with preadipocytes or macrophages. Direct addition of DPP4 to fat and skeletal and smooth muscle cells impairs insulin signaling. A fivefold higher level of DPP4 protein expression was seen in visceral compared with subcutaneous fat of obese patients, with no regional difference in lean subjects. DPP4 serum concentrations significantly correlated with adipocyte size. By using adipose tissue explants from lean and obese subjects, we observed a twofold increase in DPP4 release that strongly correlated with adipocyte volume and parameters of the metabolic syndrome and was decreased to the lean level after weight reduction. DPP4 released from adipose tissue correlated positively with an increasing risk score for the metabolic syndrome. CONCLUSIONS—DPP4 is a novel adipokine that may impair insulin sensitivity in an autocrine and paracrine fashion. Furthermore, DPP4 release strongly correlates with adipocyte size, potentially representing an important source of DPP4 in obesity. Therefore, we suggest that DPP4 may be involved in linking adipose tissue and the metabolic syndrome.

Use of twice-daily exenatide in Basal insulin-treated patients with type 2 diabetes: a randomized, controlled trial.

Abstract: This randomized trial tested whether twice-daily exenatide reduces hemoglobin A1c levels more than placebo in people with type 2 diabetes who are receiving insulin glargine. After 30 weeks, exenati...

A genetically engineered human pancreatic β cell line exhibiting glucose-inducible insulin secretion

Abstract: Despite intense efforts over the past 30 years, human pancreatic β cell lines have not been available. Here, we describe a robust technology for producing a functional human β cell line using targeted oncogenesis in human fetal tissue. Human fetal pancreatic buds were transduced with a lentiviral vector that expressed SV40LT under the control of the insulin promoter. The transduced buds were then grafted into SCID mice so that they could develop into mature pancreatic tissue. Upon differentiation, the newly formed SV40LT-expressing β cells proliferated and formed insulinomas. The resulting β cells were then transduced with human telomerase reverse transcriptase (hTERT), grafted into other SCID mice, and finally expanded in vitro to generate cell lines. One of these cell lines, EndoC-βH1, expressed many β cell-specific markers without any substantial expression of markers of other pancreatic cell types. The cells secreted insulin when stimulated by glucose or other insulin secretagogues, and cell transplantation reversed chemically induced diabetes in mice. These cells represent a unique tool for large-scale drug discovery and provide a preclinical model for cell replacement therapy in diabetes. This technology could be generalized to generate other human cell lines when the cell type-specific promoter is available.

Lipid profiling identifies a triacylglycerol signature of insulin resistance and improves diabetes prediction in humans

Abstract: Dyslipidemia is an independent risk factor for type 2 diabetes, although exactly which of the many plasma lipids contribute to this remains unclear. We therefore investigated whether lipid profiling can inform diabetes prediction by performing liquid chromatography/mass spectrometry-based lipid profiling in 189 individuals who developed type 2 diabetes and 189 matched disease-free individuals, with over 12 years of follow up in the Framingham Heart Study. We found that lipids of lower carbon number and double bond content were associated with an increased risk of diabetes, whereas lipids of higher carbon number and double bond content were associated with decreased risk. This pattern was strongest for triacylglycerols (TAGs) and persisted after multivariable adjustment for age, sex, BMI, fasting glucose, fasting insulin, total triglycerides, and HDL cholesterol. A combination of 2 TAGs further improved diabetes prediction. To explore potential mechanisms that modulate the distribution of plasma lipids, we performed lipid profiling during oral glucose tolerance testing, pharmacologic interventions, and acute exercise testing. Levels of TAGs associated with increased risk for diabetes decreased in response to insulin action and were elevated in the setting of insulin resistance. Conversely, levels of TAGs associated with decreased diabetes risk rose in response to insulin and were poorly correlated with insulin resistance. These studies identify a relationship between lipid acyl chain content and diabetes risk and demonstrate how lipid profiling could aid in clinical risk assessment.

Obesity-induced overexpression of miRNA-143 inhibits insulin-stimulated AKT activation and impairs glucose metabolism

Abstract: The contribution of altered post-transcriptional gene silencing to the development of insulin resistance and type 2 diabetes mellitus so far remains elusive. Here, we demonstrate that expression of microRNA (miR)-143 and 145 is upregulated in the liver of genetic and dietary mouse models of obesity. Induced transgenic overexpression of miR-143, but not miR-145, impairs insulin-stimulated AKT activation and glucose homeostasis. Conversely, mice deficient for the miR-143-145 cluster are protected from the development of obesity-associated insulin resistance. Quantitative-mass-spectrometry-based analysis of hepatic protein expression in miR-143-overexpressing mice revealed miR-143-dependent downregulation of oxysterol-binding-protein-related protein (ORP) 8. Reduced ORP8 expression in cultured liver cells impairs the ability of insulin to induce AKT activation, revealing an ORP8-dependent mechanism of AKT regulation. Our experiments provide direct evidence that dysregulated post-transcriptional gene silencing contributes to the development of obesity-induced insulin resistance, and characterize the miR-143-ORP8 pathway as a potential target for the treatment of obesity-associated diabetes.

Aging as an Event of Proteostasis Collapse

Abstract: Aging cells accumulate damaged and misfolded proteins through a functional decline in their protein homeostasis (proteostasis) machinery, leading to reduced cellular viability and the development of protein misfolding diseases such as Alzheimer’s and Huntington’s. Metabolic signaling pathways that regulate the aging process, mediated by insulin/IGF-1 signaling, dietary restriction, and reduced mitochondrial function, can modulate the proteostasis machinery in many ways to maintain a youthful proteome for longer and prevent the onset of age-associated diseases. These mechanisms therefore represent potential therapeutic targets in the prevention and treatment of such pathologies.

Therapeutic Potential of Nrf2 Activators in Streptozotocin-Induced Diabetic Nephropathy

Abstract: OBJECTIVE To determine whether dietary compounds targeting NFE2-related factor 2 (Nrf2) activation can be used to attenuate renal damage and preserve renal function during the course of streptozotocin (STZ)-induced diabetic nephropathy. RESEARCH DESIGN AND METHODS Diabetes was induced in Nrf2 +/+ and Nrf2 −/− mice by STZ injection. Sulforaphane (SF) or cinnamic aldehyde (CA) was administered 2 weeks after STZ injection and metabolic indices and renal structure and function were assessed (18 weeks). Markers of diabetes including blood glucose, insulin, polydipsia, polyuria, and weight loss were measured. Pathological alterations and oxidative damage in glomeruli were also determined. Changes in protein expression of the Nrf2 pathway, as well as transforming growth factor-β1 (TGF-β1), fibronectin (FN), collagen IV, and p21/WAF1Cip1 (p21) were analyzed. The molecular mechanisms of Nrf2-mediated protection were investigated in an in vitro model using human renal mesangial cells (HRMCs). RESULTS SF or CA significantly attenuated common metabolic disorder symptoms associated with diabetes in Nrf2 +/+ but not in Nrf2 −/− mice, indicating SF and CA function through specific activation of the Nrf2 pathway. Furthermore, SF or CA improved renal performance and minimized pathological alterations in the glomerulus of STZ-Nrf2 +/+ mice. Nrf2 activation reduced oxidative damage and suppressed the expression of TGF-β1, extracellular matrix proteins and p21 both in vivo and in HRMCs. In addition, Nrf2 activation reverted p21-mediated growth inhibition and hypertrophy of HRMCs under hyperglycemic conditions. CONCLUSIONS We provide experimental evidence indicating that dietary compounds targeting Nrf2 activation can be used therapeutically to improve metabolic disorder and relieve renal damage induced by diabetes.

MicroRNA 144 Impairs Insulin Signaling by Inhibiting the Expression of Insulin Receptor Substrate 1 in Type 2 Diabetes Mellitus

Abstract: Background Dysregulation of microRNA (miRNA) expression in various tissues and body fluids has been demonstrated to be associated with several diseases, including Type 2 Diabetes mellitus (T2D). Here, we compare miRNA expression profiles in different tissues (pancreas, liver, adipose and skeletal muscle) as well as in blood samples from T2D rat model and highlight the potential of circulating miRNAs as biomarkers of T2D. In parallel, we have examined the expression profiles of miRNAs in blood samples from Impaired Fasting Glucose (IFG) and T2D male patients.

Mortality and cardiovascular risk associated with different insulin secretagogues compared with metformin in type 2 diabetes, with or without a previous myocardial infarction: a nationwide study.

Abstract: [Eur Heart J 2011;32:1900–1908, doi: 10.1093/eurheartj/ehr077]. Regrettably, on p. 1907, line …