leptin and Diabetic-Neuropathies

There has been an advance in our understanding of the mechanisms of diabetic nephropathy over the past few years and much of that has occurred because of studies in animal models of diabetic nephropathy.. Studies in animal models of diabetic nephropathy, especially in mice, have underlined the multifactorial nature of the pathogenesis of the disease process and the recognition that these models only partly replicate the changes found in human disease. Despite these limitations, recent animal model studies have identified a number of new, specific molecular abnormalities that point to pathways and specific molecules as potential targets for preventive or therapeutic intervention. These specific targets include the diabetic nephropathy related decreases in endothelial nitric oxide synthase activity and renal dopamine production and the increases in Nrf-2, JAK/STAT, and mammalian target of rapamycin complex 1 signaling. These and other altered signaling pathways are described in this review. We emphasize the use of a unique investigative resource, Nephromine, to utilize a library of mRNA expression data obtained from the kidney biopsies of humans with diabetic nephropathy, to compare and validate findings in mouse models with human disease.. Several new pathways have been implicated in the progression of diabetic nephropathy through studies of animal models. Some of these appear to be altered in human diabetic nephropathy and may be targets for therapy.

Topics: Animals; Bone Morphogenetic Proteins; Diabetic Neuropathies; Dopamine; Humans; Janus Kinases; Leptin; Mechanistic Target of Rapamycin Complex 1; Multiprotein Complexes; NADPH Oxidases; NF-E2-Related Factor 2; Nitric Oxide Synthase Type III; Proteins; Receptors, Leptin; Signal Transduction; STAT Transcription Factors; TOR Serine-Threonine Kinases

Topics: Autonomic Nervous System Diseases; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Female; Humans; Insulin Resistance; Leptin; Male; Middle Aged; Syndrome

Here, we investigated inflammatory signs of peripheral nerves in leptin-deficient obese ob/ob mice and the modulating effects of the exogenous iron load.. Ob/ob and ob/+ control mice were fed with high, standard, or low iron diet for four months.. We found intraepidermal nerve fiber degeneration in foot skin and low-grade neuropathic abnormalities including mildly slowed motor and compound sensory nerve conduction velocities and low-grade macrophage and T-cell infiltration without overt neuropathology in sciatic nerves of all ob/ob mice. Low dietary iron load caused more pronounced abnormalities than high iron load in ob/ob mice.. Our data suggest that dietary non-heme iron deficiency may be a modulating factor in the pathogenesis of peripheral neuropathy in obese ob/ob mice with metabolic syndrome. Once the mechanisms can be further elucidated, how low dietary iron augments peripheral nerve degeneration and dysfunction via pro-inflammatory pathways and new therapeutic strategies could be developed.. CMAP: compound muscle action potential; cSNCV: compound sensory nerve conduction velocity; IENFD: intraepidermal nerve fiber density; LDL: low-density lipoprotein; MetS: metabolic syndrome; MNCV: motor conduction velocity; NCV: nerve conduction velocity; PN: peripheral neuropathy; PNS: peripheral nervous system; STZ: streptozotocin; T2D: type 2 diabetes mellitus; TNF alpha: tumor necrosis factor alpha; WHO: World Health Organization.

Topics: Animals; Calcium-Binding Proteins; Cytokines; Diabetic Neuropathies; Disease Models, Animal; Iron, Dietary; Leptin; Male; Mice; Mice, Mutant Strains; Microfilament Proteins; Microscopy, Electron, Transmission; Nerve Fibers; Nerve Tissue Proteins; Neural Conduction; Neurogenic Inflammation; Sciatic Nerve; Skin

The morphology of sciatic nerves from leptin-deficient ob/ob mice and leptin receptor-deficient db/db mice, both models for obesity, peripheral diabetic neuropathy, and the metabolic syndrome, has yet to be examined for changes in nerve fibers and in endoneural microvessels. Sciatic nerves from three groups of 4-month-old mice (WT C57BL6, ob/ob, and db/db) were investigated. In ultrathin sections, the thickness of myelin sheaths was significantly reduced in small, medium-sized, and large axons of db/db mice compared with WT mice. In ob/ob mice, only large fibers showed a decrease in myelin sheath thickness. The number of nonmyelinated nerve fibers was lower in ob/ob mice than in the db/db group. A thickened basal lamina of Schwann cells occurred in the ob/ob group only. In contrast, the basement membrane of endoneural microvessels was thickened in both obese groups. For this reason, laminin expression in Western blot analysis was lower in the db/db group than in the ob/ob one. Endoneural microvessels, which had been injected with fluorescein isothiocyanate, depicted signs of vasodilatation in the ob/ob and vasoconstriction in db/db mice. Endoneural vessels displayed two receptors of oxLDL. LOX-1 was strongly expressed in db/db mice, whereas TLR4 was at its maximum in the ob/ob group. We conclude that changes in nerve fibers and in endoneural microvessels are present in sciatic nerve of both mouse models of type 2 diabetes. Upregulation of oxLDL-dependent receptors in endoneural microvessels might be connected to different degrees of oxidative stress in severe diabetic db/db mice and in the mild diabetic ob/ob group.

Topics: Analysis of Variance; Animals; Basement Membrane; Body Weight; CD36 Antigens; Diabetic Neuropathies; Disease Models, Animal; Laminin; Leptin; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mice, Obese; Microscopy, Electron, Transmission; Microvessels; Myelin Sheath; Obesity; Oxidative Stress; Receptors, Leptin; Scavenger Receptors, Class E; Schwann Cells; Sciatic Nerve; Thiobarbituric Acid Reactive Substances; Toll-Like Receptor 4; von Willebrand Factor

Cardiac autonomic neuropathy (CAN) is a common complication of diabetes associated with poor prognosis. In addition, the autonomic imbalance is associated with cardiovascular disease (CVD) in diabetes. It is thought that adipocytokines contribute to the increased risk of vascular complications in patients with type 2 diabetes mellitus (T2DM). However, literature data on the association between CAN with adipocytokines such as leptin, tumor necrosis factor-alpha (TNF-alpha), adiponectin in subjects with T2DM is limited.Therefore, in the present study, we examined the relationship between fasting serum leptin, TNF- alpha and adiponectin and CAN in Korean T2DM patients.. A total of 142 T2DM patients (94 males, 48 females) were recruited. CAN was assessed by the five tests according to the Ewing's protocol and the time and frequency domain of the heart rate variability (HRV) was evaluated. Serum TNF-alpha and adiponectin levels were measured using enzyme-linked immunosorbent assay and serum leptin levels were measured using radioimmunoassay.. Although, the mean levels of leptin, TNF-alpha and adiponectin were not significantly different between the groups with and without CAN, the levels of leptin and adiponectin had a tendency to increase as the score of CAN increased (p = 0.05, p = 0.036). Serum leptin levels demonstrated a negative correlation with low frequency (LF) in the upright position (p = 0.037). Regarding TNF-alpha, a significant negative correlation was observed with SDNN and RMSSD in the upright position (p = 0.023, p = 0.019). Adiponectin levels were not related to any HRV parameters. Multivariate logistic regression analysis demonstrated that the odds of CAN increased with a longer duration of diabetes (1.25, [1.07-1.47]) and higher homeostatic model of assessment-insulin resistance (HOMA-IR) (5.47, [1.8-16.5]). The relative risks for the presence of CAN were 14.1 and 51.6 for the adiponectin 2nd, 3rd tertiles when compared with first tertile (p-value for trend = 0.022).. In the present study, the higher serum adiponectin levels and HOMA-IR were associated with an increased risk for the presence of CAN. Also, the CAN score correlated with the serum adiponectin. Serum adipocytokines such as leptin and TNF-alpha were significantly correlated with parameters of HRV, representative markers of CAN. Future prospective studies with larger number of patients are required to establish a direct relationship between plasma adipocytokine concentrations and the development or severity of CAN.

Topics: Adipokines; Adiponectin; Adult; Aged; Biomarkers; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Female; Heart Diseases; Heart Rate; Humans; Korea; Leptin; Logistic Models; Male; Middle Aged; Severity of Illness Index; Tumor Necrosis Factor-alpha

Insulin signaling depends on tyrosine phosphorylation of insulin receptor substrates (IRSs) to mediate downstream effects; however, elevated serine phosphorylation of IRS impairs insulin signaling. Here, we investigated IRS protein expression patterns in dorsal root ganglia (DRG) of mice and whether their signaling was affected by diabetes. Both IRS1 and IRS2 are expressed in DRG; however, IRS2 appears to be the prevalent isoform and is expressed by many DRG neuronal subtypes. Phosphorylation of Ser(731)IRS2 was significantly elevated in DRG neurons from type 1 and type 2 diabetic mice. Additionally, Akt activation and neurite outgrowth in response to insulin were significantly decreased in DRG cultures from diabetic ob/ob mice. These results suggest that DRG neurons express IRS proteins that are altered by diabetes similar to other peripheral tissues, and insulin signaling downstream of the insulin receptor may be impaired in sensory neurons and contribute to the pathogenesis of diabetic neuropathy.

Topics: Animals; Cells, Cultured; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Disease Models, Animal; Ganglia, Spinal; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurites; Neurons; Obesity; Phosphorylation; Proto-Oncogene Proteins c-akt; Signal Transduction; Streptozocin

The objective of this study is to explore whether diabetes play roles on histopathological change of Achilles tendon in leptin-deficient mice. Ob mice (specific-pathogen free SPF) were identified at 10 days after birth and killed via dislocation of cervical spine at 12 weeks. Achilles tendon was isolated as quickly as possible and histopathological changes were investigated. Degeneration of tendinocytes, vascular proliferation, chondrocyte-like tendon cell and ruptures at insertion areas were observed. We conclude that diabetes is associated with histopathologic change in Achilles tendon of ob mice.

Topics: Achilles Tendon; Animals; Diabetic Neuropathies; Disease Models, Animal; Gene Silencing; Genotype; Leptin; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Specific Pathogen-Free Organisms; Tendinopathy

Topics: Adiponectin; Adult; Biomarkers; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Diet, Diabetic; Female; Humans; Insulin; Leptin; Lipodystrophy, Congenital Generalized

Whereas functional, metabolic, neurotrophic, and morphological abnormalities of peripheral diabetic neuropathy (PDN) have been extensively explored in streptozotocin-induced diabetic rats and mice (models of type 1 diabetes), insufficient information is available on manifestations and pathogenetic mechanisms of PDN in type 2 diabetic models. The latter could constitute a problem for clinical trial design because the vast majority of subjects with diabetes have type 2 (non-insulin dependent) diabetes. This study was aimed at characterization of PDN in leptin-deficient (ob/ob) mice, a model of type 2 diabetes with relatively mild hyperglycemia and obesity. ob/ob mice ( approximately 11 weeks old) clearly developed manifest sciatic motor nerve conduction velocity (MNCV) and hind-limb digital sensory nerve conduction velocity (SNCV) deficits, thermal hypoalgesia, tactile allodynia, and a remarkable ( approximately 78%) loss of intraepidermal nerve fibers. They also had increased sorbitol pathway activity in the sciatic nerve and increased nitrotyrosine and poly(ADP-ribose) immunofluorescence in the sciatic nerve, spinal cord, and dorsal root ganglion (DRG). Aldose reductase inhibition with fidarestat (16 mg . kg(-1) . d(-1)), administered to ob/ob mice for 6 weeks starting from 5 weeks of age, was associated with preservation of normal MNCV and SNCV and alleviation of thermal hypoalgesia and intraepidermal nerve fiber loss but not tactile allodynia. Sciatic nerve nitrotyrosine immunofluorescence and the number of poly(ADP-ribose)-positive nuclei in sciatic nerve, spinal cord, and DRGs of fidarestat-treated ob/ob mice did not differ from those in nondiabetic controls. In conclusion, the leptin-deficient ob/ob mouse is a new animal model that develops both large motor and sensory fiber and small sensory fiber PDN and responds to pathogenetic treatment. The results support the role for increased aldose reductase activity in functional and structural changes of PDN in type 2 diabetes.

Topics: Animals; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Disease Models, Animal; Leptin; Mice; Mice, Knockout; Mice, Obese; Nerve Fibers; Neural Conduction; Obesity; Sciatic Nerve

Leptin levels are elevated in end-stage renal disease, suggesting an impairment of renal leptin degradation. The present study aimed to determine whether leptin levels are also elevated in patients with earlier stages of renal disease, ie, microalbuminuric and macroalbuminuric nephropathy. A total of 60 subjects were assigned to two study groups. Group A contained 10 type 2 diabetics with macroalbuminuria, 10 type 2 diabetics with normoalbuminuria, and 10 healthy control subjects. Group B contained 10 type 2 diabetics with microalbuminuria, 10 type 2 diabetics with normoalbuminuria, and 10 healthy controls. The subgroups of both study groups were matched for sex and body fatness. In group A, macroalbuminuric diabetic patients had higher serum leptin levels than the normoalbuminuric diabetics (11.90 +/- 2.98 v 4.13 +/- 0.92 ng/mL, P < .002) and control subjects (4.78 +/- 1.37 ng/mL, P < .006). In group B, microalbuminuric diabetics had higher serum leptin levels than the normoalbuminuric diabetics (21.16 +/- 5.80 v8.74 +/- 1.89 ng/mL, P < .04) and control subjects (10.06 + 3.00 ng/mL, P < .06). In both groups A and B, creatinine clearance was inversely correlated with the serum leptin level after adjusting for body fat. In conclusion, serum leptin levels are elevated in type 2 diabetic patients with microalbuminuria and macroalbuminuria, suggesting that renal leptin degradation is already impaired in the early stages of renal disease.

Topics: Adipose Tissue; Aged; Albuminuria; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Female; Humans; Hypertension; Leptin; Male; Middle Aged; Reference Values; Triglycerides