Retinol-binding protein 4 and insulin resistance in lean, obese, and diabetic subjects.

BACKGROUND Insulin resistance has a causal role in type 2 diabetes. Serum levels of retinol-binding protein 4 (RBP4), a protein secreted by adipocytes, are increased in insulin-resistant states. Experiments in mice suggest that elevated RBP4 levels cause insulin resistance. We sought to determine whether serum RBP4 levels correlate with insulin resistance and change after an intervention that improves insulin sensitivity. We also determined whether elevated serum RBP4 levels are associated with reduced expression of glucose transporter 4 (GLUT4) in adipocytes, an early pathological feature of insulin resistance. METHODS We measured serum RBP4, insulin resistance, and components of the metabolic syndrome in three groups of subjects. Measurements were repeated after exercise training in one group. GLUT4 protein was measured in isolated adipocytes. RESULTS Serum RBP4 levels correlated with the magnitude of insulin resistance in subjects with obesity, impaired glucose tolerance, or type 2 diabetes and in nonobese, nondiabetic subjects with a strong family history of type 2 diabetes. Elevated serum RBP4 was associated with components of the metabolic syndrome, including increased body-mass index, waist-to-hip ratio, serum triglyceride levels, and systolic blood pressure and decreased high-density lipoprotein cholesterol levels. Exercise training was associated with a reduction in serum RBP4 levels only in subjects in whom insulin resistance improved. Adipocyte GLUT4 protein and serum RBP4 levels were inversely correlated. CONCLUSIONS RBP4 is an adipocyte-secreted molecule that is elevated in the serum before the development of frank diabetes and appears to identify insulin resistance and associated cardiovascular risk factors in subjects with varied clinical presentations. These findings provide a rationale for antidiabetic therapies aimed at lowering serum RBP4 levels.

[1]  M. Kasuga,et al.  RBP4, an unexpected adipokine , 2006, Nature Medicine.

[2]  R. Paschke,et al.  Association of interleukin-6, C-reactive protein, interleukin-10 and adiponectin plasma concentrations with measures of obesity, insulin sensitivity and glucose metabolism. , 2005, Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association.

[3]  Nimesh Mody,et al.  Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes , 2005, Nature.

[4]  G. Reaven.  The insulin resistance syndrome: definition and dietary approaches to treatment. , 2005, Annual review of nutrition.

[5]  J. Flier,et al.  Adipose Tissue as an Endocrine Organ , 2014 .

[6]  T. Funahashi,et al.  Fat distribution, lipid accumulation in the liver, and exercise capacity do not explain the insulin resistance in healthy males with a family history for type 2 diabetes. , 2003, The Journal of clinical endocrinology and metabolism.

[7]  T. Funahashi,et al.  A novel cellular marker of insulin resistance and early atherosclerosis in humans is related to impaired fat cell differentiation and low adiponectin , 2003, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[8]  Y. Miyazaki,et al.  Abdominal fat distribution and peripheral and hepatic insulin resistance in type 2 diabetes mellitus. , 2002, American journal of physiology. Endocrinology and metabolism.

[9]  U. Smith.  Impaired (‘diabetic’) insulin signaling and action occur in fat cells long before glucose intolerance—is insulin resistance initiated in the adipose tissue? , 2002, International Journal of Obesity.

[10]  P. Wilson,et al.  A Genome-Wide Scan for Loci Linked to Plasma Levels of Glucose and HbA1c in a Community-Based Sample of Caucasian Pedigrees: The Framingham Offspring Study , 2002 .

[11]  R. Paschke,et al.  Relation between glycaemic control, hyperinsulinaemia and plasma concentrations of soluble adhesion molecules in patients with impaired glucose tolerance or Type II diabetes , 2002, Diabetologia.

[12]  J. Buring,et al.  Abdominal and total adiposity and risk of coronary heart disease in men , 2001, International Journal of Obesity.

[13]  P. Jansson,et al.  insulin resistance with low cellular IRS‐1 expression is also associated with low GLUT4 expression and impaired insulin‐stimulated glucose transport 1 , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[14]  G. Shulman,et al.  Adipose-selective targeting of the GLUT4 gene impairs insulin action in muscle and liver , 2001, Nature.

[15]  M. Newcomer,et al.  Plasma retinol binding protein: structure and function of the prototypic lipocalin. , 2000, Biochimica et biophysica acta.

[16]  J. Flier,et al.  Obesity and insulin resistance. , 2000, The Journal of clinical investigation.

[17]  J. Dickerson,et al.  Retinol, α-tocopherol and carotenoids in diabetes , 1999, European Journal of Clinical Nutrition.

[18]  B. Kahn,et al.  Glucose transporters and insulin action--implications for insulin resistance and diabetes mellitus. , 1999, The New England journal of medicine.

[19]  P. O'Connell,et al.  Linkage of type 2 diabetes mellitus and of age at onset to a genetic location on chromosome 10q in Mexican Americans. , 1999, American journal of human genetics.

[20]  G A Colditz,et al.  Abdominal adiposity and coronary heart disease in women. , 1998, JAMA.

[21]  B. Kahn.  Type 2 Diabetes: When Insulin Secretion Fails to Compensate for Insulin Resistance , 1998, Cell.

[22]  T. Basu,et al.  Vitamin A homeostasis and diabetes mellitus. , 1997, Nutrition.

[23]  G. Shulman,et al.  Metabolic Defects in Lean Nondiabetic Offspring of NIDDM Parents: A Cross-Sectional Study , 1997, Diabetes.

[24]  E. E. Wein,et al.  Vitamin A (retinol) status of first nation adults with non-insulin-dependent diabetes mellitus. , 1997, Journal of the American College of Nutrition.

[25]  C. R. Kahn,et al.  Genetics of non-insulin-dependent (type-II) diabetes mellitus. , 1996, Annual review of medicine.

[26]  G. Reaven.  Resistance to insulin-stimulated glucose uptake and hyperinsulinemia: role in non-insulin-dependent diabetes, high blood pressure, dyslipidemia and coronary heart disease. , 1991, Diabete & metabolisme.

[27]  R. DeFronzo,et al.  Insulin Resistance: A Multifaceted Syndrome Responsible for NIDDM, Obesity, Hypertension, Dyslipidemia, and Atherosclerotic Cardiovascular Disease , 1991, Diabetes Care.

[28]  N. Dimitrov,et al.  Alteration of retinol-binding-protein concentrations by the synthetic retinoid fenretinide in healthy human subjects. , 1990, The American journal of clinical nutrition.

[29]  R. Henry,et al.  Intracellular glucose oxidation and glycogen synthase activity are reduced in non-insulin-dependent (type II) diabetes independent of impaired glucose uptake. , 1990, The Journal of clinical investigation.

[30]  L. Groop,et al.  Early metabolic defects in persons at increased risk for non-insulin-dependent diabetes mellitus. , 1989, The New England journal of medicine.

[31]  W. Blaner.  Retinol-binding protein: the serum transport protein for vitamin A. , 1989, Endocrine reviews.

[32]  R. DeFronzo,et al.  Glucose clamp technique: a method for quantifying insulin secretion and resistance. , 1979, The American journal of physiology.