Hypoglycemic Neuropathy Research Articles

Clinical and Experimental Evidence of Hypoglycemic Neuropathy

Clinical and Experimental Evidence of Hypoglycemic Neuropathy

Chapter 33 - Neurologic damage in hypoglycemia

Hypoglycemia occurs in diabetic patients as a consequence of treatment with hypoglycemic agents, in insulinoma patients as a result of excessive insulin production, and in infants as a result of abnormal regulation of metabolism. Profound hypoglycemia can cause structural and functional disturbances in both the central (CNS) and the peripheral nervous system (PNS). The brain is damaged by a short and severe episode of hypoglycemia, whereas PNS pathology appears after a mild and prolonged episode. In the CNS, damaged mitochondria, elevated intracellular Ca2(+) level, released cytochrome c to the cytosol, extensive production of superoxide, increased caspase-3 activity, release of aspartate and glutamate from presynaptic terminals, and altered biosynthetic machinery can lead to neuronal cell death in the brain. Considering the PNS, chronic hypoglycemia is associated with delayed motor and sensory conduction velocities in peripheral nerves. With respect to pathology, hypoglycemic neuropathy in the PNS is characterized by Wallerian-like axonal degeneration that starts at the nerve terminal and progresses to a more proximal part of the axon, and motor axons to the muscles may be more severely damaged than sensory axons. Since excitatory neurotransmitters primarily involve the neuron in the CNS, this "dying back" pattern of axonal damage in the PNS may involve mechanisms other than excitotoxicity.

Multiple endocrine neoplasia type 1 presenting as refractory epilepsy and polyneuropathy — A case report

Hypoglycemia is a well recognized cause of acute symptomatic seizures. The fact that hypoglycemia can cause peripheral neuropathy is less appreciated. We describe a case of insulinoma associated peripheral neuropathy. A 17 year-old previously healthy man was referred for investigation of refractory epilepsy. A history of recurrent seizures, slowly progressive weakness of his feet and hands, and weight gain was obtained. Physical examination showed signs of a chronic sensory–motor polyneuropathy. He was diagnosed with insulinoma and primary hyperparathyroidism, characterizing multiple endocrine neoplasia, type 1 syndrome. Cases of insulinoma associated peripheral neuropathy are very rare. The more characteristic clinical picture appears to be distal weakness, worse in the intrinsic hand and feet muscles, and no or mild sensory signs. Peripheral nervous system symptoms may not completely resolve, despite removal of the cause of hyperinsulinism/hypoglycemia and full reversion of central nervous system symptoms. Mechanisms underlying hypoglycemic neuropathy are still poorly understood.

Autophagy in insulin-induced hypoglycaemic neuropathy

Autophagy in neurons has been linked to a growing number of pathological conditions in the CNS, but the role of this process in peripheral neuropathy has received little attention. This study aimed to determine whether autophagy is involved in development of peripheral neuropathy in hypoglycaemic diabetic rats. The lateral plantar nerves, ventral roots, and dorsal roots of insulin-treated diabetic hypoglycaemic rats were examined for structural signs of autophagy by electron microscopy. Autophagy-associated vacuoles were found in myelinated axons exhibiting early pathological changes but not in the associated Schwann cells. When the damaged axons degenerated, their associated Schwann cells gradually died and were cleared from the endoneurium by macrophages. During axonal regeneration, extensive signs of autophagy-related structures such as autophagophores appeared in regenerating axons and in the cytoplasm of the associated Schwann cells in the Band of Büngner. Autophagy occurs in hypoglycaemic peripheral nerves in association with axonal de- and regeneration. The extensive signs of autophagy in regenerated axons suggest that autophagy may play a role in survival of the new axons.

Distal hypoglycemic neuropathy. An insulinoma-associated case, misdiagnosed as temporal lobe epilepsy

Peripheral distal neuropathy associated with hypoglycemia secondary to insulinoma is quite rare. So far, less than 40 cases have been reported in literature. In this report, we describe a 50-year-old patient with insulinoma-polineuropathy and neuropsychiatric symptoms, interpreted as temporal lobe epilepsy, over the preceding 7 years. Due to the variability of the clinical presentation, diagnostic mistakes are frequent, and diagnosis of insulinoma is often delayed. Thus, the hypoglycemic nature of neuropathy can be lately recognized.

Hypoglycaemic neuropathy: microvascular changes due to recurrent hypoglycaemic episodes in rat sciatic nerve

Intensive diabetes treatment causes a considerable increase in the number of severe hypoglycaemic episodes which could aggravate the progression of diabetic neuropathy. However, the effect of repeated hypoglycaemic episodes on nerve morphology has never been previously investigated. The aims of the present study were: (i) to establish a rat model of recurrent episodes of severe hypoglycaemia, and (ii) to assess morphological changes after repeated hypoglycaemic episodes in rat sciatic nerves. We induced hypoglycaemic episodes, blood glucose level <3.0 mmol/l for 3 h, by injecting regular insulin intravenously on 4 consecutive days. We found endothelial swelling of endoneurial microvessels at the thigh level of sciatic and tibial nerves 24 h after four daily episodes of hypoglycaemia. Endothelial swelling was confirmed by vascular morphometry which showed significantly increased endothelial and pericyte areas. No obvious abnormalities were seen on nerve fibres. In conclusion, recurrent hypoglycaemic episodes cause early vascular anomalies in endoneurial microvessels in rat sciatic nerves without any observable changes in nerve fibres.

Hypoglycemic neuropathy.

Hypoglycemia is a relatively common condition primarily affecting diabetic patients treated with insulin or other hypoglycemic drugs and insulinoma patients. Clinical experience and experimental studies show that hypoglycemia may cause alterations both in the central (CNS) and the peripheral (PNS) nervous system. Hypoglycemic effects on the CNS include various symptoms such as irritability and lack of concentration, disruption of cognitive functions, convulsions and unconsciousness. As for pathology, a loss of neurons has been noted, being more obvious in the cerebral cortex and the hippocampus than in the brain stem, cerebellum and spinal cord. Myelin damage and glial changes have also been observed in the CNS. The development of pathological changes in the brain has mainly been studied on autopsy material from patients who died in insulin coma and in animals exposed to a severe hypoglycemia and showing an isoelectric electroencephalogram. It has been suggested that hypoglycemic loss of neurons in the brain is related to excititoxic actions of aspartate on N-methyl-D-aspartate receptors. With respect to the PNS, scattered clinical observations in humans and experimental studies in animals show that hypoglycemia causes a distal axonopathy including both degenerative and regenerative events. In this respect, motor axons seem to be more vulnerable than sensory axons. Animal experiments show that a peripheral neuropathy may develop even in cases with a mild hypoglycemia compatible with a generally normal behavior. The cellular mechanisms behind the development of hypoglycemic PNS alterations are unknown. To elucidate the pathophysiology of hypoglycemic neuropathy more basic research is needed.

HYPOGLYCAEMIC NEUROPATHY: OCCURRENCE OF AXON TERMINALS IN PLANTAR SKIN AND PLANTAR MUSCLE OF DIABETIC BB/WOR RATS TREATED WITH INSULIN IMPLANTS

It is generally believed that diabetic neuropathy is due to chronic hyperglycaemia. However, experience from insulinoma patients and experimental studies show that hypoglycaemia may also cause neuropathy. Accordingly, the plantar nerves of diabetic eu‐/hypoglycaemic BB/Wor rats treated with insulin implants exhibit a distinct neuropathy. To what extent hypoglycaemic neuropathy affects axon terminals in skin and muscle is unknown. In the present study we examine the occurrence of epidermal axon profiles and the neuropeptide calcitonin gene‐related peptide (CGRP) in plantar skin, and of end plate axon terminals in a plantar muscle of diabetic BB/Wor rats subjected to long periods of hypoglycaemia. The number of protein gene product‐immunoreactive axon profiles was found to be normal in heel skin biopsy specimens from eu‐/hypoglycaemic rats, but many profiles were short and thin. The content of CGRP in the skin biopsy samples was significantly below normal. After staining with antibodies against the vesicular acetyl choline transporter protein, the occurrence of end plate axon terminals was significantly reduced in sections from the flexor hallucis brevis muscle of eu‐/hypoglycaemic rats. Moreover, the end plate axon terminals tended to be abnormally small in these rats. We conclude that the hypoglycaemic neuropathy seen in plantar nerve trunks of diabetic BB/Wor rats treated with insulin implants is accompanied by mild alterations in the epidermal innervation of plantar skin and a more obviously abnormal nerve terminal pattern in plantar muscle.

Hypoglycaemic neuropathy in diabetic BB/Wor rats treated with insulin implants affects ventral root axons but not dorsal root axons.

It is believed that hyperglycaemia underlies diabetic neuropathy. However, low blood glucose values may also cause pathological changes in peripheral nerves and in neuronal perikarya. This study examined spinal roots, dorsal root ganglia and the ventral horn at the segmental level L5 in long-term insulin-treated eu-/hypoglycaemic diabetic rats with an obvious plantar nerve pathology. The purpose was to determine whether hypoglycaemic neuropathy affects sensory and/or motor neurons at root and/or perikaryal levels. Electron microscopic examination of dorsal roots from eu-/hypoglycaemic rats showed a normal qualitative morphology and normal numbers of unmyelinated and myelinated axons. In ventral roots the picture varied. Whereas two rats exhibited an essentially normal morphology, three rats presented moderate or marked signs of pathology such as clusters of small and medium-sized myelinated axons, medium-sized myelinated axons with abnormally thin sheaths, large unmyelinated axons and signs of past or ongoing axonal degeneration. Light microscopic examination of the L5 dorsal root ganglion and ventral horn showed a qualitatively normal picture in eu-/hypoglycaemic rats and the mean number of large ventral horn neurons per section was normal. These results suggest that the type of eu-/hypoglycaemia examined here affects ventral root axons but not dorsal root axons, that the degree of ventral root pathology is variable and that sensory and motor neuron perikarya do not appear to be affected.

Hypoglycaemic neuropathy: occurrence of axon terminals in plantar skin and plantar muscle of diabetic BB/Wor rats treated with insulin implants.

It is generally believed that diabetic neuropathy is due to chronic hyperglycaemia. However, experience from insulinoma patients and experimental studies show that hypoglycaemia may also cause neuropathy. Accordingly, the plantar nerves of diabetic eu-/hypoglycaemic BB/Wor rats treated with insulin implants exhibit a distinct neuropathy. To what extent hypoglycaemic neuropathy affects axon terminals in skin and muscle is unknown. In the present study we examine the occurrence of epidermal axon profiles and the neuropeptide calcitonin gene-related peptide (CGRP) in plantar skin, and of end plate axon terminals in a plantar muscle of diabetic BB/Wor rats subjected to long periods of hypoglycaemia. The number of protein gene product-immunoreactive axon profiles was found to be normal in heel skin biopsy specimens from eu-/hypoglycaemic rats, but many profiles were short and thin. The content of CGRP in the skin biopsy samples was significantly below normal. After staining with antibodies against the vesicular acetylcholine transporter protein, the occurrence of end plate axon terminals was significantly reduced in sections from the flexor hallucis brevis muscle of eu-/hypoglycaemic rats. Moreover, the end plate axon terminals tended to be abnormally small in these rats. We conclude that the hypoglycaemic neuropathy seen in plantar nerve trunks of diabetic BB/Wor rats treated with insulin implants is accompanied by mild alterations in the epidermal innervation of plantar skin and a more obviously abnormal nerve terminal pattern in plantar muscle.

Hypoglycaemic neuropathy in BB/Wor rats treated with insulin implants: electron microscopic observations.

Insulin-dependent diabetes mellitus is a chronic metabolic disease that causes long-term secondary complications such as neuropathy. The occurrence of diabetic neuropathy has generally been thought of as being associated with hyperglycaemia. However, in a previous light microscopic examination of plantar nerves in diabetic BB/Wor rats treated with insulin implants we found that eu-/hyperglycaemic rats present a normal picture, whereas eu-/hypoglycaemic rats show severe changes. The aim of the present work is to supplement our previous light microscopic report with electron microsocpic data from the lateral plantar nerve of normal, eu-/hyperglycaemic and eu-/hypoglycaemic BB/Wor rats. Under the electron microscope lateral plantar nerves collected from eu-/hyperglycaemic rats presented a qualitatively normal picture. In addition, the fibre numbers and the size distribution of the myelinated fibres were normal. In contrast, specimens from eu-/hypoglycaemic BB/Wor rats showed severe qualitative changes, interpreted as signs of axonal de- and regeneration. The total number of axons was somewhat subnormal and the sizes of the myelinated fibres were strongly shifted towards smaller diameters. These data confirm our previous light microscopic observations. We conclude that eu-/hypoglycaemic BB/Wor rats treated with insulin implants, but not similarly treated eu-/hyperglycaemic animals, develop a neuropathy in their plantar nerves.

Spatial distribution of fiber degeneration in acute hypoglycemic neuropathy in rat.

Hypoglycemia may cause axonal nerve fiber degeneration, but to do so it must be severe (less than 1.5 mmol/L) and of long duration (greater than or equal to 12 hours). Since in our previous study, systemic PO2, PCO2, pH, blood pressure, temperature, and hematocrit were maintained within physiologic limits, fiber degeneration cannot be attributed to systemic hypoxia. In this study the spatial distribution of axonal degeneration was assessed in transverse epoxy sections and teased fibers from different proximal-to-distal levels of nerves of the lower limb of the rats. Reactions in lumbar spinal motor neurons, spinal ganglia, and fasciculus gracilis were also studied. Axonal degeneration was the characteristic fiber alteration and it predominated in central fascicular distributions of distal sciatic, proximal tibial, and proximal peroneal nerves. This proximal-to-distal and central fascicular spatial distribution is not typical of distal polyneuropathy or of neuronal degeneration, but it is characteristic of a focal or multifocal nerve trunk neuropathy. Although local hypoxic-ischemic injury, possibly mediated by enhanced sympathetic tone, has not been excluded, we postulate a generalized deficiency of energy substrate manifesting itself by fiber degeneration at watershed zones of poorest perfusion.

Diabetic and hypoglycemic neuropathy — a comparison in the BB rat

Functional and structural neuropathy was examined in hyperglycemic (diabetic) BB rats maintained on small maintenance doses of insulin, hyperglycemic BB rats receiving no insulin, and BB rats in whom hypoglycemia was induced by the administration of excessive insulin doses. The data were compared with those of non-diabetic age- and sex-matched BB rats. Functional deficits and structural abnormalities were comparable in diabetic rats with and without insulin supplementation, suggesting that the generally necessary insulin dosing in this model does not per se account for the neuropathy. Hypoglycemic neuropathy was characterized by slowing of nerve conduction velocity, marked loss of anterior horn motoneurons and Wallerian degeneration, as well as loss of large myelinated fibers, suggesting a neuropathy involving predominantly motoneurons. Diabetic neuropathy was not associated with nerve cell loss but showed marked axonal atrophy involving predominantly sensory fibers. Thus, diabetic and hypoglycemic neuropathies are two distinguishable entities under strict experimental conditions, but may overlap in human diabetic subjects in whom tight insulin control is desirable.

Hypoglycemic neuropathy in experimental diabetes

Morphological and electrophysiological observations were made over 4 weeks on 5 groups of 8-week-old male Sprague-Dawley rats. These were comprised of controls, untreated diabetics, and diabetic animals in which sustained hypoglycemia, moderate hypoglycemia, or normoglycemia was induced by continuous subcutaneous insulin infusion (CSII) therapy. Teased fiber studies showed a marked increase in the number of myelinated fibers undergoing axonal degeneration and regeneration in the tibial nerve of severe hypoglycemic and also in moderate hypoglycemic animals but not in controls, untreated diabetic and normoglycemic groups. There was also a significant correlation between episodes of hypoglycemia (≤2.0 mmol/l) and the prevalence of axonal degeneration and regeneration in CSII-treated diabetics. Motor nerve conduction velocity was significantly reduced in the moderate and severe hypoglycemic groups and also in untreated diabetic animals when compared with controls. However, it was significantly improved in the normoglycemic group over the untreated diabetic and severe hypoglycemic groups. In conclusion, this study has demonstrated that severe or even mild hypoglycemia produced a detrimental effect on peripheral nerve structure and function in experimental diabetes. Therefore, it may be desirable to avoid even asymptomatic hypoglycemia in the management of diabetes.