Long-term intensive therapy of IDDM patients with clinically overt autonomic neuropathy: effects on hypoglycemia awareness and counterregulation

Fanelli, Carmine G.; Pampanelli, S.; Lalli, C.; Sindaco, P. Del; Ciofetta, M.; Lepore, M.; Porcellati, Francesca; Bottini, P.; Vincenzo, A. Di; Brunetti, P.; Bolli, Geremia B.

doi:10.2337/diabetes.46.7.1172

Cited by 27 publications

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“…Reasonable agreement has been shown between this definition and self-reported state of awareness (35). These studies did not demonstrate an association between autonomic neuropathy and an altered glycemic threshold for generation of autonomic symptoms (14,16,17), which mainly concurs with the conclusions of the current study. Although the magnitude of symptomatic responses may be lower in people with autonomic neuropathy (14)(15)(16), it is the initial symptoms that are important for hypoglycemia awareness (10), and we have demonstrated previously that impaired awareness is not associated with reduced intensity of autonomic symptoms (9).…”

Section: Discussionsupporting

confidence: 81%

“…A few studies have investigated the association between hypoglycemia awareness and autonomic neuropathy using experimentally induced hypoglycemia and have defined impaired awareness based on higher glycemic thresholds, defined as blood glucose at a lower level, before autonomic symptoms appear (14,16,17). Reasonable agreement has been shown between this definition and self-reported state of awareness (35).…”

Section: Discussionmentioning

confidence: 99%

“…Deficient autonomic responses were also observed to be associated with an increased risk of severe hypoglycemia in a large European study (11). Although most people with type 1 diabetes and autonomic neuropathy experience autonomic symptoms during hypoglycemia (12,13), some studies have suggested that autonomic neuropathy may be associated with attenuated autonomic symptomatic responses (14)(15)(16) and accompanied by delayed or diminished catecholamine secretion to hypoglycemia (14,17). However, catecholamine secretion is not essential for symptom generation (18), and hypoglycemia awareness depends primarily on the generation of symptoms and their interpretation rather than symptom intensity (10,19).…”

mentioning

confidence: 99%

“…However, catecholamine secretion is not essential for symptom generation (18), and hypoglycemia awareness depends primarily on the generation of symptoms and their interpretation rather than symptom intensity (10,19). Studies of people with type 1 diabetes that have examined the glycemic thresholds for symptom generation in those with and without autonomic neuropathy (13,14,16) have found no differences, and autonomic symptom generation was not delayed.…”

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confidence: 99%

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Impaired Awareness of Hypoglycemia in Adults With Type 1 Diabetes Is Not Associated With Autonomic Dysfunction or Peripheral Neuropathy

et al. 2015

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OBJECTIVEImpaired awareness of hypoglycemia (IAH) is a risk factor for severe hypoglycemia in people with insulin-treated diabetes; autonomic neuropathy has been suggested to underlie its development. The aim was to evaluate a putative association between IAH and autonomic dysfunction using novel and sensitive measures of autonomic neural function. RESEARCH DESIGN AND METHODSSixty-six adults with type 1 diabetes were studied, 33 with IAH and 33 with normal awareness of hypoglycemia (NAH), confirmed by formal testing. Participants were matched for age, sex, and diabetes duration. Clinical and laboratory evaluations included extensive autonomic function testing, peripheral nerve conduction studies, and quantitative sensory testing. Composite abnormality Z scores were used for group comparisons. RESULTSThe IAH and NAH group had similar median (interquartile range) age of 48 (14.5) vs. 47 (14.5) years, diabetes duration of 30 (13.5) vs. 31 (13.5) years, and mean 6 SD HbA 1c 7.8 6 2.2% vs. 8.1 6 1.9%, respectively. The autonomic composite Z score did not differ between the two groups (mean difference 20.15, 95% CI 20.46, 0.16; P = 0.33), nor did the thermal detection (mean difference 0.15, 95% CI 20.31, 0.61; P = 0.51) or nerve conduction scores (mean difference 0.03, 95% CI 20.43, 0.49; P = 0.89). CONCLUSIONSIn adults with type 1 diabetes, IAH was not associated with autonomic dysfunction or peripheral neuropathy.Impaired awareness of hypoglycemia (IAH), defined as a diminished ability to perceive the onset of hypoglycemia, is associated with an increased risk of severe hypoglycemia in people with insulin-treated diabetes (1-3). Elucidation of the pathogenesis of IAH may help to minimize the risk of severe hypoglycemia.The glycemic thresholds for counterregulatory responses, generation of symptoms, and cognitive impairment are reset at lower levels of blood glucose in people who have developed IAH (4). This cerebral adaptation appears to be induced by

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Impaired Awareness of Hypoglycemia in Adults With Type 1 Diabetes Is Not Associated With Autonomic Dysfunction or Peripheral Neuropathy

et al. 2015

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“…It should be noted that diabetic autonomic neuropathy probably does not impair glucose counterregulation and hypoglycaemia awareness as expected. Although the neuronal and hormonal activation might be less, there could be increased sensitivity to the activation that does occur, presumably conferring some degree of protection [24,60,76,77,78,79].…”

Section: Glucose Sensing In Hypoglycaemiamentioning

confidence: 99%

Hypoglycaemia unawareness and the brain

Smith

Amiel

2002

Diabetologia

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The intention of this paper is to critically review the current state of knowledge of the role of the brain in the syndrome of hypoglycaemia unawareness.Both the role of the brain in the detection of hypoglycaemia and initiation of the counterregulatory responses and the function of the cerebral cortex during acute hypoglycaemia are considered. The evidence for and against the brain as the primary site of mammalian hypoglycaemia sensing and the mechanisms whereby such sensing may occur and change in hypoglycaemia unawareness are discussed.Current evidence supports a major role for the central nervous system in hypoglycaemia sensing and there is increasing understanding of the mechanisms of counterregulatory failure and cognitive dysfunction in hypoglycaemia unawareness. More needs to be done to expand this understanding and translate it into therapeutic strategies to defend against severe hypoglycaemia in diabetes therapy. [Diabetologia (2002) -002-0877-7 Hypoglycaemia unawareness and the brainDiabetologia (2002) 45:949-958 DOI 10.1007/s00125 D. Smith, S. A. AmielGuy's, King's and St Thomas' School of Medicine, London, UK subjects. As blood glucose decreases, pancreatic insulin secretion decreases and glucagon secretion increases, stimulating endogenous glucose production and slowing the blood glucose fall. Later, sympathetic activation and catecholamine secretion, with release of growth hormone and adrenocorticotrophin, driving release of adrenal cortical steroids, contribute by supporting endogenous glucose production and reducing consumption of glucose by peripheral tissues. An associated complex of symptoms, including hunger, encourages an eating response. The functional anatomy of these responses indicate a central coordinating structure involving the regions around the hypothalamus, hippocampus and caudate nuclei. Failure of some or all of these counterregulatory mechanisms allows a more severe decrease in plasma glucose concentrations, resulting in cortical dysfunction. Thus counterregulatory failure is associated with impaired awareness of hypoglycaemia and an increased risk of severe hypoglycaemia, in which cognitive function is so disturbed that the patient can become drowsy, unco-ordinated, confused or even comatose. This is a Iatrogenic hypoglycaemia was described in the very first days of insulin therapy and hypoglycaemia without subjective awareness was described shortly thereafter. The British pioneer of diabetes therapy, R.D. Lawrence, himself diabetic, gave a clear account of neuroglycopenic hypoglycaemia with reduced subjective awareness more than 60 years ago [1]. Over 20 years ago the site of coordination of glucoregulatory responses was located in the hypothalamus [2].Hypoglycaemia sufficient to cause clinically significant cortical dysfunction does not occur in healthy

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The relationship between glycaemic variability and cardiovascular autonomic dysfunction in patients with type 1 diabetes: A systematic review

Helleputte

Backer

Lapauw

et al. 2020

Diabetes Metabolism Res

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Rigorous glycaemic control -reflected by low HbA1c goals -is of utmost importance in the prevention and management of complications in patients with type 1 diabetes mellitus (T1DM). However, previous studies suggested that short-term glycaemic variability (GV) is important to consider as well, as excessive glucose fluctuations may have an additional impact on the development of diabetic complications. The potential relationship between GV and the risk for cardiovascular autonomic neuropathy (CAN), a clinical expression of cardiovascular autonomic dysfunction, is of increasing interest. This systematic review aimed to summarize existing evidence concerning the relationship between GV and cardiovascular autonomic dysfunction in T1DM.Electronic database search of Medline (Pubmed), Web of Science and Embase was performed, up to October 2019. There were no limits concerning year of publication. Methodological quality was evaluated with the Newcastle Ottawa Scale for observational studies. Six studies (four cross-sectional and two prospective cohorts) were included. Methodological quality of the studies varied from level C to A2. Two studies examined the association between GV and heart rate variability (HRV) and both found significant negative correlations.Regarding cardiovascular autonomic reflex tests (CARTs), two studies did not while two other studies did find significant associations between GV parameters and CART-scores. However, associations were attenuated after adjusting for covariates such as HbA1c, age and disease duration. In conclusion, this systematic review found some preliminary evidence supporting an association between GV and cardiovascular autonomic dysfunction in T1DM. Hence, uncertainty remains whether high GV can independently contribute to the onset or progression of CAN. The heterogeneity in methodological approach made it difficult to compare different studies. Future studies should therefore use uniformly evaluated CGM-derived parameters of GV, while standardised assessment of HRV, CARTs and other potential cardiac autonomic function parameters is needed for an unambiguous definition of CAN. KEYWORDSType 1 diabetes • Complications • Glycaemic variability • Cardiovascular autonomic dysfunction • Cardiovascular autonomic neuropathy • Cardiovascular reflex tests • Heart rate variability ABBREVIATIONS This article is protected by copyright. All rights reserved. BRS Baroreflex sensitivity CAN Cardiovascular autonomic neuropathy CART Cardiovascular autonomic reflex test CGM Continuous glucose monitoring CONGA Continuous overlap net glycaemic action COV Coefficient of variation DAN Diabetic autonomic neuropathy DCCT Diabetes Control and Complications Trial GV Glycaemic variability HBGI High blood glucose index HRV Heart rate variability LBGI Low blood glucose index MBG Mean blood glucose MAG Mean absolute glucose difference MAGE Mean amplitude of glycaemic excursions MODD Mean of daily differences SDT Total standard deviation of glucose values T1DM Type 1 diabetes mellitus RESEARCH IN CONTEXT BOXWha...

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Long-term intensive therapy of IDDM patients with clinically overt autonomic neuropathy: effects on hypoglycemia awareness and counterregulation

Cited by 27 publications

References 0 publications

Impaired Awareness of Hypoglycemia in Adults With Type 1 Diabetes Is Not Associated With Autonomic Dysfunction or Peripheral Neuropathy

Impaired Awareness of Hypoglycemia in Adults With Type 1 Diabetes Is Not Associated With Autonomic Dysfunction or Peripheral Neuropathy

Hypoglycaemia unawareness and the brain

The relationship between glycaemic variability and cardiovascular autonomic dysfunction in patients with type 1 diabetes: A systematic review

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