An early, reversible cholesterolgenic etiology of diet-induced insulin resistance.

Objective: A buildup of skeletal muscle plasma membrane (PM) cholesterol content in mice occurs within 1 week of a Western-style high-fat diet and causes insulin resistance. The mechanism driving this cholesterol accumulation and insulin resistance is not known. Promising cell data implicate that the hexosamine biosynthesis pathway (HBP) triggers a cholesterolgenic response via increasing the transcriptional activity of Sp1.

Changes in Skeletal Muscle PAK1 Levels Regulate Tissue Crosstalk to Impact Whole Body Glucose Homeostasis.

Skeletal muscle accounts for ~80% of insulin-stimulated glucose uptake. The Group I p21-activated kinase 1 (PAK1) is required for the non-canonical insulin-stimulated GLUT4 vesicle translocation in skeletal muscle cells. We found that the abundances of PAK1 protein and its downstream effector in muscle, ARPC1B, are significantly reduced in the skeletal muscle of humans with type 2 diabetes, compared to the non-diabetic controls, making skeletal muscle PAK1 a candidate regulator of glucose homeostasis.

Excess membrane cholesterol is an early contributing reversible aspect of skeletal muscle insulin resistance in C57BL/6NJ mice fed a Western-style high-fat diet.

Skeletal muscle insulin resistance manifests shortly after high-fat feeding, yet mechanisms are not known. Here we set out to determine whether excess skeletal muscle membrane cholesterol and cytoskeletal derangement known to compromise glucose transporter (GLUT)4 regulation occurs early after high-fat feeding. We fed 6-wk-old male C57BL/6NJ mice either a low-fat (LF, 10% kcal) or a high-fat (HF, 45% kcal) diet for 1 wk.

Type 2 diabetes mellitus and cerebrospinal fluid Alzheimer's disease biomarker amyloid β1-42 in Alzheimer's Disease Neuroimaging Initiative participants.

Introduction: Type 2 diabetes mellitus (T2DM) is a risk factor for Alzheimer's disease. Cerebrospinal fluid (CSF) amyloid β (Aβ) 1-42 is an important Alzheimer's disease biomarker. However, it is inconclusive on how T2DM is related to CSF Aβ1-42.

The actin-related p41ARC subunit contributes to p21-activated kinase-1 (PAK1)-mediated glucose uptake into skeletal muscle cells.

Defects in translocation of the glucose transporter GLUT4 are associated with peripheral insulin resistance, preclinical diabetes, and progression to type 2 diabetes. GLUT4 recruitment to the plasma membrane of skeletal muscle cells requires F-actin remodeling. Insulin signaling in muscle requires p21-activated kinase-1 (PAK1), whose downstream signaling triggers actin remodeling, which promotes GLUT4 vesicle translocation and glucose uptake into skeletal muscle cells.

Exercise training prevents skeletal muscle plasma membrane cholesterol accumulation, cortical actin filament loss, and insulin resistance in C57BL/6J mice fed a western-style high-fat diet.

Insulin action and glucose disposal are enhanced by exercise, yet the mechanisms involved remain imperfectly understood. While the causes of skeletal muscle insulin resistance also remain poorly understood, new evidence suggest excess plasma membrane (PM) cholesterol may contribute by damaging the cortical filamentous actin (F-actin) structure essential for GLUT4 glucose transporter redistribution to the PM upon insulin stimulation. Here, we investigated whether PM cholesterol toxicity was mitigated by exercise.

Effect of Corncob bedding on feed conversion efficiency in a high-fat diet-induced prediabetic model in C57Bl/6J mice.

Laboratory facilities use many varieties of contact bedding, including wood chips, paper products, and corncob, each with its own advantages and disadvantages. Corncob bedding, for example, is often used because of its high absorbency, ability to minimize detectable ammonia, and low cost. However, observations that mice eat the corncob lead to concerns that its use can interfere with dietary studies.

Signaling of the p21-activated kinase (PAK1) coordinates insulin-stimulated actin remodeling and glucose uptake in skeletal muscle cells.

Skeletal muscle accounts for ∼ 80% of postprandial glucose clearance, and skeletal muscle glucose clearance is crucial for maintaining insulin sensitivity and euglycemia. Insulin-stimulated glucose clearance/uptake entails recruitment of glucose transporter 4 (GLUT4) to the plasma membrane (PM) in a process that requires cortical F-actin remodeling; this process is dysregulated in Type 2 Diabetes. Recent studies have implicated PAK1 as a required element in GLUT4 recruitment in mouse skeletal muscle in vivo, although its underlying mechanism of action and requirement in glucose uptake remains undetermined.

Chromium enhances insulin responsiveness via AMPK.

Trivalent chromium (Cr(3+)) is known to improve glucose homeostasis. Cr(3+) has been shown to improve plasma membrane-based aspects of glucose transporter GLUT4 regulation and increase activity of the cellular energy sensor 5' AMP-activated protein kinase (AMPK). However, the mechanism(s) by which Cr(3+) improves insulin responsiveness and whether AMPK mediates this action is not known.

Hexosamine biosynthesis impairs insulin action via a cholesterolgenic response.

Plasma membrane cholesterol accumulation has been implicated in cellular insulin resistance. Given the role of the hexosamine biosynthesis pathway (HBP) as a sensor of nutrient excess, coupled to its involvement in the development of insulin resistance, we delineated whether excess glucose flux through this pathway provokes a cholesterolgenic response induced by hyperinsulinemia. Exposing 3T3-L1 adipocytes to physiologically relevant doses of hyperinsulinemia (250pM-5000pM) induced a dose-dependent gain in the mRNA/protein levels of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGR).

AMPK enhances insulin-stimulated GLUT4 regulation via lowering membrane cholesterol.

AMP-activated protein kinase (AMPK) enhances glucose transporter GLUT4 regulation. AMPK also suppresses energy-consuming pathways such as cholesterol synthesis. Interestingly, recent in vitro and in vivo data suggest that excess membrane cholesterol impairs GLUT4 regulation.

Evidence coupling increased hexosamine biosynthesis pathway activity to membrane cholesterol toxicity and cortical filamentous actin derangement contributing to cellular insulin resistance.

Hyperinsulinemia is known to promote the progression/worsening of insulin resistance. Evidence reveals a hidden cost of hyperinsulinemia on plasma membrane (PM) phosphatidylinositol 4,5-bisphosphate (PIP(2))-regulated filamentous actin (F-actin) structure, components critical to the normal operation of the insulin-regulated glucose transport system. Here we delineated whether increased glucose flux through the hexosamine biosynthesis pathway (HBP) causes PIP(2)/F-actin dysregulation and subsequent insulin resistance.

Munc18c phosphorylation by the insulin receptor links cell signaling directly to SNARE exocytosis.

How the Sec1/Munc18-syntaxin complex might transition to form the SNARE core complex remains unclear. Toward this, Munc18c tyrosine phosphorylation has been correlated with its dissociation from syntaxin 4. Using 3T3-L1 adipocytes subjected to small interfering ribonucleic acid reduction of Munc18c as a model of impaired insulin-stimulated GLUT4 vesicle exocytosis, we found that coordinate expression of Munc18c-wild type or select phosphomimetic Munc18c mutants, but not phosphodefective mutants, restored GLUT4 vesicle exocytosis, suggesting a requirement for Munc18c tyrosine phosphorylation at Tyr219 and Tyr521.

Evidence that chromium modulates cellular cholesterol homeostasis and ABCA1 functionality impaired by hyperinsulinemia--brief report.

Objective: Trivalent chromium (Cr3+) is an essential micronutrient. Findings since the 1950s suggest that Cr3+ might benefit cholesterol homeostasis. Here we present mechanistic evidence in support of this role of Cr3+.

Signaling, cytoskeletal and membrane mechanisms regulating GLUT4 exocytosis.

Solving how insulin regulates glucose transport into skeletal muscle and adipose tissue remains a fundamental challenge in biology and a significant issue in medicine. A central feature of this process is the coordinated accumulation of the glucose transporter GLUT4 into the plasma membrane. New signaling and cytoskeletal mechanisms of insulin-stimulated GLUT4 exocytosis are of emerging interest, particularly those at or just beneath the plasma membrane.

Hexosamine biosynthesis pathway flux contributes to insulin resistance via altering membrane phosphatidylinositol 4,5-bisphosphate and cortical filamentous actin.

We recently found that plasma membrane phosphatidylinositol 4,5-bisphosphate (PIP(2))-regulated filamentous actin (F-actin) polymerization was diminished in hyperinsulinemic cell culture models of insulin resistance. Here we delineated whether increased glucose flux through the hexosamine biosynthesis pathway (HBP) causes the PIP(2)/F-actin dysregulation and insulin resistance induced by hyperinsulinemia. Increased HBP activity was detected in 3T3-L1 adipocytes cultured under conditions closely resembling physiological hyperinsulinemia (5 nm insulin for 12 h) and in cells where HBP activity was amplified by 2 mm glucosamine (GlcN).

A novel membrane-based anti-diabetic action of atorvastatin.

We recently found that chromium picolinate (CrPic), a nutritional supplement thought to improve insulin sensitivity in individuals with impaired glucose tolerance, enhances insulin action by lowering plasma membrane (PM) cholesterol. Recent in vivo studies suggest that cholesterol-lowering statin drugs benefit insulin sensitivity in insulin-resistant patients, yet a mechanism is unknown. We report here that atorvastatin (ATV) diminished PM cholesterol by 22% (P<0.

"Actin"g on GLUT4: membrane & cytoskeletal components of insulin action.

The dissection of mechanisms that regulate glucose transport by insulin has revealed an intricate network of signaling molecules scattered from the insulin receptor to the intracellular glucose transporter GLUT4. It is also appreciated that some insulin receptor signals jaunt in different directions to regulate events essential for the efficient redistribution of GLUT4 to the plasma membrane. Moreover key assists in the process appear to be arranged by membrane lipids and cytoskeletal proteins.

Interactions of endothelin and insulin: expanding parameters of insulin resistance.

Since the discovery of endothelin peptides in the mid-1980s by Yanigasawa and colleagues, accumulating evidence demonstrates that these peptides may function beyond vasoconstriction. Strong epidemiologic associations between insulin resistance and increased endothelin levels or activity have been found, and these associations have prompted studies investigating the interactions of endothelin with insulin. In this review we explore the evidence for such interactions at multiple levels of physiology, ranging from effects on tissue perfusion through modulation of vascular tone to subcellular interactions of endothelin signaling with insulin signaling.

Antidiabetogenic effects of chromium mitigate hyperinsulinemia-induced cellular insulin resistance via correction of plasma membrane cholesterol imbalance.

Previously, we found that a loss of plasma membrane (PM) phosphatidylinositol 4,5-bisphosphate (PIP2)-regulated filamentous actin (F-actin) structure contributes to insulin-induced insulin resistance. Interestingly, we also demonstrated that chromium picolinate (CrPic), a dietary supplement thought to improve glycemic status in insulin-resistant individuals, augments insulin-regulated glucose transport in insulin-sensitive 3T3-L1 adipocytes by lowering PM cholesterol. Here, to gain mechanistic understanding of these separate observations, we tested the prediction that CrPic would protect against insulin-induced insulin resistance by improving PM features important in cytoskeletal structure and insulin sensitivity.

GLUT4's itinerary in health & disease.

Following the discovery of insulin 85 yr ago and the realization thereafter that in some individuals, tissues lose their responsiveness to this hormone, an enormous world-wide effort began to dissect the cellular mechanisms of insulin action and define abnormalities in the insulin-resistant state. A clear goal through the years has been to unravel the insulin signal transduction network regulating glucose transport. This line of investigation has provided tremendous insight into the physiology and pathophysiology surrounding the cellular processes controlled by insulin.

Chromium picolinate positively influences the glucose transporter system via affecting cholesterol homeostasis in adipocytes cultured under hyperglycemic diabetic conditions.

Since trivalent chromium (Cr(3+)) enhances glucose metabolism, interest in the use of Cr(3+)as a therapy for type 2 diabetes has grown in the mainstream medical community. Moreover, accumulating evidence suggests that Cr(3+) may also benefit cardiovascular disease (CVD) and atypical depression. We have found that cholesterol, a lipid implicated in both CVD and neurodegenerative disorders, also influences cellular glucose uptake.

Loss of cortical actin filaments in insulin-resistant skeletal muscle cells impairs GLUT4 vesicle trafficking and glucose transport.

Study has demonstrated an essential role of cortical filamentous actin (F-actin) in insulin-regulated glucose uptake by skeletal muscle. Here, we tested whether perturbations in F-actin contributed to impaired insulin responsiveness provoked by hyperinsulinemia. In L6 myotubes stably expressing GLUT4 that carries an exofacial myc-epitope tag, acute insulin stimulation (20 min, 100 nM) increased GLUT4myc translocation and glucose uptake by approximately 2-fold.

Chromium activates glucose transporter 4 trafficking and enhances insulin-stimulated glucose transport in 3T3-L1 adipocytes via a cholesterol-dependent mechanism.

Evidence suggests that chromium supplementation may alleviate symptoms associated with diabetes, such as high blood glucose and lipid abnormalities, yet a molecular mechanism remains unclear. Here, we report that trivalent chromium in the chloride (CrCl3) or picolinate (CrPic) salt forms mobilize the glucose transporter, GLUT4, to the plasma membrane in 3T3-L1 adipocytes. Concomitant with an increase in GLUT4 at the plasma membrane, insulin-stimulated glucose transport was enhanced by chromium treatment.