glycogen and Diabetic-Neuropathies

Proinsulin C-peptide, released in equimolar amounts with insulin by pancreatic β cells, since its discovery in 1967 has been thought to be devoid of biological functions apart from correct insulin processing and formation of disulfide bonds between A and B chains. However, in the last two decades research has brought a substantial amount of data indicating a crucial role of C-peptide in regulating various processes in different types of cells and organs. C-peptide acts presumably via either G-protein-coupled receptor or directly inside the cell, after being internalized. However, a receptor binding this peptide has not been identified yet. This peptide ameliorates pathological changes induced by type 1 diabetes mellitus, including glomerular hyperfiltration, vessel endothelium inflammation and neuron demyelinization. In diabetic patients and diabetic animal models, C-peptide substitution in physiological doses improves the functional and structural properties of peripheral neurons and protects against hyperglycemia-induced apoptosis, promoting neuronal development, regeneration and cell survival. Moreover, it affects glycogen synthesis in skeletal muscles. In vitro C-peptide promotes disaggregation of insulin oligomers, thus enhancing its bioavailability and effects on metabolism. There are controversies concerning the biological action of C-peptide, particularly with respect to its effect on Na⁺/K⁺-ATPase activity. Surprisingly, the excess of circulating peptide associated with diabetes type 2 contributes to atherosclerosis development. In view of these observations, long-term, large-scale clinical investigations using C-peptide physiological doses need to be conducted in order to determine safety and health outcomes of long-term administration of C-peptide to diabetic patients.

Topics: Animals; Apoptosis; Atherosclerosis; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diabetic Neuropathies; Disease Models, Animal; Glycogen; Humans; Hyperglycemia; Muscle, Skeletal; Peripheral Nervous System

Topics: Autonomic Nervous System Diseases; Blood Glucose; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Energy Intake; Energy Metabolism; Glucose; Glycogen; Humans; Hypoglycemia; Hypotension, Orthostatic; Insulin; Liver; Muscles; Oxygen Consumption; Physical Exertion

Explore whether Glycogen synthesis kinase-3β (GSK3β) involved in the analgesic effect of liraglutide on diabetic neuropathic pain (DNP).. DNP was induced by streptozocin (STZ) in WT and GSK3β(S9A) mice, which carried a constitutively active form of GSK3β. DNP mice were intracerebroventricularly injected with liraglutide 5 weeks after STZ injection. The behavior of neuropathic pain was evaluated 2 h after drugs administration. The microglial activation and the expression of NOD-like receptor protein 3 (NLRP3) in microglia in cortex were evaluated. The role of GSK3β in the inhibitory effect of liraglutide on the NLRP3 inflammasome was explored in BV2 microglia.. Intracerebroventricular administration of liraglutide significantly relieved neuropathic pain and inhibited the activation of cortical microglia in WT mice with DNP. But the effect of liraglutide disappeared in GSK3β(S9A) mice. In BV2 microglia, GSK3β inhibitor significantly suppressed NLRP3 inflammasome activation. And activating GSK3β through GSK3β(S9A) lentivirus significantly blocked the inhibitory effect of liraglutide on NLRP3 inflammasome in BV2 microglia. Intracerebroventricular administration of liraglutide significantly inhibited the expression of NLRP3 in cortex microglia of DNP group in WT mice but failed in GSK3β(S9A) mice.. GSK3β involves in the analgesic effect of liraglutide on DNP through NLRP3 inflammasome in microglia.

Topics: Analgesics; Animals; Diabetes Mellitus; Diabetic Neuropathies; Glycogen; Glycogen Synthase Kinase 3 beta; Inflammasomes; Liraglutide; Mice; Neuralgia; NLR Family, Pyrin Domain-Containing 3 Protein

This study aims to establish the corneal nerve fiber (CNF) morphological alterations in a large cohort of type 2 diabetic patients and to investigate the association between the bead size, a novel parameter representing composite of accumulated mitochondria, glycogen particles, and vesicles in CNF, and the neurophysiological dysfunctions of the peripheral nerves. 162 type 2 diabetic patients and 45 healthy control subjects were studied in detail with a battery of clinical and neurological examinations and corneal confocal microscopy. Compared with controls, patients had abnormal CNF parameters. In particular the patients had reduced density and length of CNF and beading frequency and increased bead size. Alterations in CNF parameters were significant even in patients without neuropathy. The HbA1c levels were tightly associated with the bead size, which was inversely related to the motor and sensory nerve conduction velocity (NCV) and to the distal latency period of the median nerve positively. The CNF density and length positively correlated with the NCV and amplitude. The hyperglycemia-induced expansion of beads in CNF might be a predictor of slow NCV in peripheral nerves in type 2 diabetic patients.

Topics: Case-Control Studies; Cornea; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Female; Glycated Hemoglobin; Glycogen; Humans; Intravital Microscopy; Male; Median Nerve; Microscopy, Confocal; Middle Aged; Mitochondria; Nerve Fibers, Unmyelinated; Neural Conduction; Peripheral Nerves; Sensory Thresholds; Synaptic Vesicles

Even though many aspects of glycogen nephrosis in diabetes have already been studied, adhesion interactions between the glycogen-accumulating clear cells and the tubular basement membranes have not been addressed. As integrins play key roles in cell-to-matrix interactions, we investigated the expression and distribution of alpha3-, alphaV-, beta1- and beta3-integrin subunits in renal tissues from streptozotocin-induced hyperglycemic rats (3 months old) and their age-matched controls as well as from streptozotocin-injected normoglycemic animals.. The levels and distribution of integrins were studied by immunocytochemistry and Western blot analysis.. Immunoblotting analysis of fractions enriched in glycogen-accumulating clear cells demonstrated enhanced expression of alpha3, alphaV and beta1 subunits while expression of beta3 did not differ from controls. The most striking cytochemical result was the redistribution of the alpha3-, alphaV-, and the beta1-integrin subunits to the apical plasma membrane of these cells. This was found by light and electron microscopy.. Our results suggest that the altered expression and distribution of integrins in clear cells of diabetic animals must have defined roles in the development of the renal tubulopathy.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Epithelial Cells; Glycogen; Integrins; Kidney; Kidney Tubular Necrosis, Acute; Male; Rats; Rats, Sprague-Dawley; Streptozocin

Topics: Animals; Axons; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Glycogen; Islets of Langerhans Transplantation; Male; Postoperative Complications; Rats; Rats, Inbred Lew; Sciatic Nerve; Transplantation, Isogeneic

We report here findings in a 51-year-old Japanese man with non-insulin-dependent diabetes mellitus who complained of exercise-induced cramps. Muscle biopsy showed scattered regenerating fibers, small angular fibers and increased PAS positive particles. Electron microscopic examination revealed an abnormal accumulation of glycogen particles in subsarcolenmmal areas and between myofibrils while chemical studies showed an increased glycogen concentration and decreased phosphoglycerate mutase (PGAM), 46.9% of the normal mean value. Thus, partial PGAM deficiency, insulin resistance and mild diabetic sensory-motor polyneuropathy can induce severe cramps.

Topics: Biopsy; Chromosomes, Human, Pair 7; Diabetic Neuropathies; Exercise Test; Glycogen; Humans; Japan; Male; Middle Aged; Muscle Cramp; Muscle, Skeletal; Myofibrils; Phosphoglycerate Mutase; Point Mutation; Tomography, X-Ray Computed

To answer the crucial question regarding reversibility of diabetic somatic neuropathy by whole-pancreas transplantation, metabolic studies and electron microscopic morphometry of the sciatic and testicular nerves were performed monthly for 2 years in three groups of highly inbred rats: (1) NC, 47 nondiabetic controls; (2) DC, 90 untreated alloxan-induced diabetic controls; and (3) DT, 230 diabetic rats given syngeneic pancreaticoduodenal transplants 6, 9, 12, 15, 18, and 21 months after induction of diabetes mellitus (DM). Six diabetic nerve lesions were quantitated by a "blind" protocol: (1) loss of myelinated axons, (2) intraaxonal glycogen deposits, (3) axons with glycogen deposits, (4) demyelinated axons, (5) degenerating axons, and (6) loss of intact axoglial junctions in paranodal terminal myelin loops. In the DT group, testicular nerve specimens were obtained just before transplantation and at death so that each animal served as its own control. As we have observed previously in untreated diabetic controls, all six nerve lesions progressed relentlessly for 2 years, in contrast to nondiabetic controls (p less than 0.01). Whole-pancreas transplants produced complete metabolic control of DM for life and reversed all six lesions in both sciatic and testicular nerves, even when done late in the course of DM. There was complete reversal of the nerve lesions when pancreatic transplantation was done within 15 months of the onset of DM. These results provide the first demonstration of reversal of diabetic somatic neuropathy by any form of DM therapy and extend our previous work in which whole-pancreas transplants were found to prevent both diabetic neuropathy and nephropathy and reverse mesangial enlargement in the kidney.

Topics: Animals; Axons; Blood Glucose; Diabetic Neuropathies; Glycogen; Insulin; Male; Microscopy, Electron; Nerve Degeneration; Nervous System; Osmolar Concentration; Pancreas Transplantation; Rats; Rats, Inbred Lew; Sciatic Nerve; Testis

Disorders of the autonomic nervous system are a frequent late complication of human diabetes. They have been extensively studied clinically, yet their pathologic aspects are still poorly understood. Also, reports on the autonomic nervous system in animal models for diabetes are scanty. Therefore we have investigated sympathetic preganglionic and postganglionic nerve fibers, vagal fibers, as well as sympathetic and enteric neurons of male Wistar rats 1 year after streptozotocin or vehicle injection. By light and electron microscopic morphology we observed: various degenerative changes in sympathetic neurons and in Schwann cells of the sympathetic fibers; intraaxonal glycogen deposits in all fiber types; and a large amount of lipoid material in intraganglionic and endoneural mesenchymal cells. By morphometry, the cytoplasmic area and perimeter as well as the cytoplasmic to nuclear ratio were significantly reduced in the sympathetic neurons of diabetic rats. Further we found axonal dwindling, enlarged myelin-axons space and an increased number of Schwann cell pi-granules in the sympathetic preganglionic fibers of diabetic animals. Axonal glycogenosomes were absent in the vagus of control and were present in that of diabetic rats. By stereology, the mitochondria and smooth endoplasmic reticulum were reduced in the sympathetic neurons of diabetic rats, whereas in the same animals the volume density of the Golgi complex was increased in the sympathetic neurons and decreased in the enteric neurons. In conclusion, relevant changes occur in the sympathetic preganglionic nerve fibers which suggest a causal relationship between fiber and neuronal lesions. Further, the stereologic findings imply decreased cellular activity and imbalance between cellular synthesis and secretion in the sympathetic neurons.

Topics: Animals; Autonomic Nervous System Diseases; Axons; Cytoplasm; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Endoplasmic Reticulum; Glycogen; Golgi Apparatus; Male; Microscopy, Electron; Mitochondria; Nerve Fibers; Neurons; Rats; Rats, Inbred Strains; Schwann Cells; Sympathetic Nervous System

The ultrastructure of the iris muscles and innervating nerves in patients with diabetes mellitus and approximately age-matched controls was examined by electron-microscopy. The specimens were obtained during cataract surgery. There were definite histopathological alterations at the nerve terminal innervating the dilator muscle, e.g. the presence of mitochondrial abnormalities, dense bodies and lamellar structures. No change was noted at the nerve terminal to the sphincter muscle. Moderate involvement of the muscle, especially at the sphincter, was observed in the specimens of diabetics. The control specimens had no change at the nerve terminals, while moderate change was observed at the sphincter muscle. Therefore, the change in the sphincter seen in the specimens of diabetics seemed to be mainly the result of the aging process, though the existence of early sympathetic neuropathy was confirmed.

Topics: Aged; Axons; Cataract Extraction; Cytoplasmic Granules; Diabetic Neuropathies; Glycogen; Humans; Iris; Microscopy, Electron; Middle Aged; Mitochondria, Muscle; Muscle, Smooth; Nerve Degeneration; Reflex, Pupillary

Peripheral nerves of the diabetic insulin-dependent BB-Wistar-rat were studied ultrastructurally. Conspicuous early changes consisted of mitochondrial accumulation of glycogen in the axons and the development of honey-combed Schwann cell-axon networks. The later stages of the diabetic syndrome showed axonal dwindling and disintegration in both myelinated and unmyelinated fibers. The present findings are compared with those of other experimental diabetic models.

Topics: Animals; Axons; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Glycogen; Microscopy, Electron; Mitochondria; Peripheral Nerves; Rats; Rats, Inbred Strains; Schwann Cells; Time Factors

Topics: Adult; Aged; Carbohydrate Metabolism; Diabetes Complications; Diabetic Neuropathies; Electromyography; Female; Glycogen; Humans; Male; Microscopy, Electron; Middle Aged; Mitochondria, Muscle; Muscular Diseases; Vision Disorders

Topics: Adipose Tissue; Animals; Carbohydrate Metabolism; Carbon Dioxide; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Glucose; Glycogen; Humans; Insulin; Lactates; Muscles; Nervous System; Pentoses; Peripheral Nervous System Diseases; Permeability; Rabbits; Research; Sciatic Nerve