Repeated hypoglycemia remodels neural inputs and disrupts mitochondrial function to blunt glucose-inhibited GHRH neuron responsiveness.

Hypoglycemia is a frequent complication of diabetes, limiting therapy and increasing morbidity and mortality. With recurrent hypoglycemia, the counterregulatory response (CRR) to decreased blood glucose is blunted, resulting in hypoglycemia-associated autonomic failure (HAAF). The mechanisms leading to these blunted effects are only poorly understood. Here, we report, with ISH, IHC, and the tissue-clearing capability of iDISCO+, that growth hormone releasing hormone (GHRH) neurons represent a unique population of arcuate nucleus neurons activated by glucose deprivation in vivo. Repeated glucose deprivation reduces GHRH neuron activation and remodels excitatory and inhibitory inputs to GHRH neurons. We show that low glucose sensing is coupled to GHRH neuron depolarization, decreased ATP production, and mitochondrial fusion. Repeated hypoglycemia attenuates these responses during low glucose. By maintaining mitochondrial length with the small molecule mitochondrial division inhibitor-1, we preserved hypoglycemia sensitivity in vitro and in vivo. Our findings present possible mechanisms for the blunting of the CRR, significantly broaden our understanding of the structure of GHRH neurons, and reveal that mitochondrial dynamics play an important role in HAAF. We conclude that interventions targeting mitochondrial fission in GHRH neurons may offer a new pathway to prevent HAAF in patients with diabetes.

The effects of recurrent hypoglycaemia and opioid antagonists on the adrenal catecholamine synthetic capacity in a rat model of HAAF.

In this study, we investigated the effects of recurrent hypoglycaemia on the adrenal catecholamine synthetic enzymes in a rat model of hypoglycaemia-associated autonomic failure (HAAF). We found that plasma adrenaline was significantly reduced by about 50% in response to recurrent hypoglycaemia versus single hypoglycaemia. However, tyrosine hydroxylase (TH) protein and phosphorylation at Ser31 and Ser40 were increased in HAAF; similarly, aromatic aminoacid decarboxylase protein was also increased indicating a likely increase in catecholamine synthesis in the adrenal gland. Opioid antagonists, naloxone and methylnaltrexone did not restore plasma adrenaline in HAAF; however, naloxone increased TH phosphorylation at Ser31 and Ser40.

Hypoglycemia-associated autonomic failure in healthy humans: comparison of two vs three periods of hypoglycemia on hypoglycemia-induced counterregulatory and symptom response 5 days later.

CONTEXT: Hypoglycemia-associated autonomic failure (HAAF) limits the ability of patients with diabetes to achieve target glycemia. Animal models have provided insights into the pathogenesis of HAAF, but a robust human model of HAAF in which recurrent hypoglycemia impacts the counterregulatory responses to hypoglycemia days later is lacking. OBJECTIVE: The aim of this study was to determine the impact of two or three episodes of moderate hypoglycemia on counterregulatory responses to subsequent hypoglycemia induced 5 days later. DESIGN AND SUBJECTS: Six healthy subjects participated in each of the two study protocols. In both protocol 1 and 2, subjects underwent two 2-hour hypoglycemic clamp studies during the morning and afternoon of day 1. In protocol 2, subjects underwent an additional third hypoglycemic clamp during the morning of day 2. All subjects in both protocols underwent a final hypoglycemic clamp on the morning of day 5. RESULTS: In protocol 1, there were no significant differences in the hypoglycemia-induced hormone response or in symptoms scores between the mornings of days 1 and 5. In protocol 2, hypoglycemia-induced epinephrine (P = .02) and cortisol (P = .04) secretions were significantly lower on day 5 compared with day 1, whereas glucagon (P = .08) and norepinephrine (P = .59) were not different. Also in protocol 2, neurogenic (P = .02) and neuroglycopenic (P = .04) symptoms during hypoglycemia were decreased on day 5 compared with day 1. CONCLUSION: These results demonstrate that exposure of healthy humans to three 2-hour hypoglycemic episodes over 30 hours leads to significant blunting in counterregulatory and symptom response to subsequent hypoglycemia on day 5.

Neurogenic orthostatic hypotension as the initial feature of Parkinson disease.

Autonomic failure is a common finding in patients with Parkinson disease (PD). Here we describe a patient with PD in whom autonomic symptoms began 3 years before motor deficits.

Naloxone, but not valsartan, preserves responses to hypoglycemia after antecedent hypoglycemia: role of metabolic reprogramming in counterregulatory failure.

OBJECTIVE: Hypoglycemia-associated autonomic failure (HAAF) constitutes one of the main clinical obstacles to optimum treatment of type 1 diabetes. Neurons in the ventromedial hypothalamus are thought to mediate counterregulatory responses to hypoglycemia. We have previously hypothesized that hypoglycemia-induced hypothalamic angiotensin might contribute to HAAF, suggesting that the angiotensin blocker valsartan might prevent HAAF. On the other hand, clinical studies have demonstrated that the opioid receptor blocker naloxone ameliorates HAAF. The goal of this study was to generate novel hypothalamic markers of hypoglycemia and use them to assess mechanisms mediating HAAF and its reversal. RESEARCH DESIGN AND METHODS: Quantitative PCR was used to validate a novel panel of hypothalamic genes regulated by hypoglycemia. Mice were exposed to one or five episodes of insulin-induced hypoglycemia, with or without concurrent exposure to valsartan or naloxone. Corticosterone, glucagon, epinephrine, and hypothalamic gene expression were assessed after the final episode of hypoglycemia. RESULTS: A subset of hypothalamic genes regulated acutely by hypoglycemia failed to respond after repetitive hypoglycemia. Responsiveness of a subset of these genes was preserved by naloxone but not valsartan. Notably, hypothalamic expression of four genes, including pyruvate dehydrogenase kinase 4 and glycerol 3-phosphate dehydrogenase 1, was acutely induced by a single episode of hypoglycemia, but not after antecedent hypoglycemia; naloxone treatment prevented this failure. Similarly, carnitine palmitoyltransferase-1 was inhibited after repetitive hypoglycemia, and this inhibition was prevented by naloxone. Repetitive hypoglycemia also caused a loss of hypoglycemia-induced elevation of glucocorticoid secretion, a failure prevented by naloxone but not valsartan. CONCLUSIONS: Based on these observations we speculate that acute hypoglycemia induces reprogramming of hypothalamic metabolism away from glycolysis toward ß-oxidation, HAAF is associated with a reversal of this reprogramming, and naloxone preserves some responses to hypoglycemia by preventing this reversal.

Other autonomic neuropathies associated with ganglionic antibody.

The acetylcholine receptor ganglionic (G-AchR) antibody is a very specific serologic test for autoimmune autonomic ganglionopathy. The spectrum of autoimmune (or presumed to be autoimmune) autonomic disorders, however, is quite broad and positivity to this antibody has been reported in a variety of other conditions, albeit infrequent and with low titer. This review describes the autonomic neuropathies most frequently encountered in clinical practice in which an autoimmune etiology is suspected. They include a chronic form (pure autonomic failure) and limited autonomic neuropathies with predominant involvement of one neurotransmitter type (i.e., cholinergic vs. adrenergic) or one system (such as the gastrointestinal system) or a distal small fiber dysfunction. In each of these conditions, occasional positivity to the G-AchR antibody has been found, but the pathogenetic significance of such finding is still uncertain. Other antigens and antibodies yet to be identified are more likely to be responsible in these disorders.

Autonomic failure in primary amyloidosis.

Amyloidosis is an uncommon plasma cell dyscrasia affecting Multisystem, characterized by deposition of amyloid proteins in extracellular spaces and the tissues. Reported incidence of amyloidosis is 8 cases per million per year. Deposition of amyloid fibrils occurs in peripheral nerves in 20% of the cases in Primary Amyloidosis. Though. polyneuropathy is one of the presenting manifestations in cases of Primary Amyloidosis, pure autonomic failure without involving peripheral nerves is not a documented entity. Here, we present a case of Primary Amyloidosis presenting as Pure Autonomic Failure (Dysautonomia).