Hierarchy of glycemic thresholds for counterregulatory hormone secretion, symptoms, and cerebral dysfunction

Mitrakou, Asimina; Ryan, Christopher M.; Veneman, Thiemo F.; Mokáň, Marián; Jenssen, Trond; Kiss, Iván; Durrant, John D.; Cryer, Philip E.; Gerich, John E.

doi:10.1152/ajpendo.1991.260.1.e67

Cited by 368 publications

(411 citation statements)

References 25 publications

Supporting

Mentioning

368

Contrasting

Unclassified

Order By: Relevance

“…In the perfused rat pancreas, threshold, half-maximal and maximal alpha cell responses to glucose occur at approximately 2.5, 5.0 and 10.0 mmol/l glucose [2]. Following an overnight fast, plasma glucagon rises in humans if glucose falls below a threshold of approximately 3.8 mmol/l [3] and decreases progressively as plasma glucose rises above the normal range [4].…”

Section: Normal Alpha Cell Functionmentioning

confidence: 99%

“…Although other non-glucose secretagogues, such as isoproterenol, are also used in provocative tests of beta cell function [26], bolus administration of isoproterenol is less effective than arginine in stimulation of acute glucagon release in humans [27]. Acute insulin-induced hypoglycaemia has also been used to assess alpha cell [9] NEFA [8] Parasympathetic nerves [10] Ketones [7] Adrenaline (epinephrine) [112] Insulin [113] Oxytocin [114] Somatostatin [115] Vasopressin [116] Secretin [117] GIP [118] GLP-1 [54] PACAP [119] Carbohydrate meal [18] GRP [120] CCK [121] VIP [122] Protein meal [18] Stress [20] Hypoglycaemia [3] GRP gastrin-releasing peptide; PACAP pituitary adenylate cyclaseactivating polypeptide; VIP vasoactive intestinal polypeptide function in humans [28], although arginine stimulation tests clearly pose less risk and are more routinely employed.…”

Section: Clinical Measures Of Alpha Cell Functionmentioning

confidence: 99%

See 1 more Smart Citation

Alpha cell function in health and disease: influence of glucagon-like peptide-1

Dunning¹,

2005

View full text Add to dashboard Cite

Although there is abundant evidence that hyperglucagonaemia plays a key role in the development of hyperglycaemia in type 2 diabetes, efforts to understand and correct this abnormality have been overshadowed by the emphasis on insulin secretion and action. However, recognition that the incretin hormone glucagon-like peptide-1 (GLP-1) exerts opposing effects on glucagon and insulin secretion has revived interest in glucagon, the neglected partner of insulin, in the bihormonal hypothesis. In healthy subjects, glucagon secretion is regulated by a variety of nutrient, neural and hormonal factors, the most important of which is glucose. The defect in alpha cell function that occurs in type 2 diabetes reflects impaired glucose sensing. GLP-1 inhibits glucagon secretion in vitro and in vivo in experimental animals, and suppresses glucagon release in a glucose-dependent manner in healthy subjects. This effect is also evident in diabetic patients, but GLP-1 does not inhibit glucagon release in response to hypoglycaemia, and may even enhance it. Early clinical studies with agents acting through GLP-1 signalling mechanisms (e.g. exenatide, liraglutide and vildagliptin) suggest that GLP-1 can improve alpha cell glucose sensing in patients with type 2 diabetes. Therapeutic approaches based around GLP-1 have the potential to improve both alpha cell and beta cell function, and could be of benefit in patients with a broad range of metabolic disorders.

show abstract

Section: Normal Alpha Cell Functionmentioning

confidence: 99%

Section: Clinical Measures Of Alpha Cell Functionmentioning

confidence: 99%

Alpha cell function in health and disease: influence of glucagon-like peptide-1

Dunning¹,

2005

View full text Add to dashboard Cite

show abstract

“…Memory is one the of the most important cognitive domains with respect to everyday function. Previous studies applied memory tests as part of a larger battery of cognitive tests during hypoglycaemia [3][4][5][6][7][8], and the variability of reported results may relate to the use of different memory tests. Methodological variation in hypoglycaemia studies has been reviewed elsewhere [9]; particularly pertinent issues include sample size and statistical power, the method of measurement of blood glucose, and the target level for, and the duration of, hypoglycaemia.…”

Section: Introductionmentioning

confidence: 99%

The effects of acute hypoglycaemia on memory acquisition and recall and prospective memory in type 1 diabetes

et al. 2006

View full text Add to dashboard Cite

Aims/hypothesis Global memory performance is impaired during acute hypoglycaemia. This study assessed whether moderate hypoglycaemia disrupts learning and recall in isolation, and utilised a novel test of prospective memory which may better reflect the role of memory in daily life than conventional tests. Subjects and methods Thirty-six subjects with type 1 diabetes participated, 20 with normal hypoglycaemia awareness (NHA) and 16 with impaired hypoglycaemia awareness (IHA). Each underwent a hypoglycaemic clamp with target blood glucose 2.5 mmol/l. Prior to hypoglycaemia, subjects attempted to memorise instructions for a prospective memory task, and recall was assessed during hypoglycaemia. Subjects then completed the learning and immediate recall stages of three conventional memory tasks (word recall, story recall, visual recall) during hypoglycaemia. Euglycaemia was restored and delayed memory for the conventional tasks was tested. The same procedures were completed in euglycaemic control studies (blood glucose 4.5 mmol/l). Results Hypoglycaemia impaired performance significantly on the prospective memory task (p=0.004). Hypoglycaemia also significantly impaired both immediate and delayed recall for the word and story recall tasks (p<0.01 in each case). There was no significant deterioration of performance on the visual memory task. The effect of hypoglycaemia did not differ significantly between subjects with NHA and IHA. Conclusions/interpretation Impaired performance on the prospective memory task during hypoglycaemia demonstrates that recall is disrupted by hypoglycaemia. Impaired performance on the conventional memory tasks demonstrates that learning is also disrupted by hypoglycaemia. Results of the prospective memory task support the relevance of these findings to the everyday lives of people with diabetes.

show abstract

“…Different brain functions have different sensitivities to hypoglycaemia. As described above, the activation of the various parts of the hypothalamic and sympathetic centres occur at plasma glucose concentrations ranging from 3.0 and 3.6 mmol/l [57, 88,89], and different parts of the cerebral cortex, investigated as performance of different cognitive function tasks, also show detectable evidence of dysfunction at different glucose concentrations during progressive hypoglycaemia [8,65,84,85]. In addition to being differently sensitive to hypoglycaemia per se, different brain tasks have a different ability to alter their sensitivity to hypoglycaemia in hypoglycaemia unaware states.…”

Section: Potential Mechanisms Of Failure Of Central Glucose Counterrementioning

confidence: 99%

Hypoglycaemia unawareness and the brain

Smith

Amiel

2002

Diabetologia

View full text Add to dashboard Cite

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

show abstract

Hierarchy of glycemic thresholds for counterregulatory hormone secretion, symptoms, and cerebral dysfunction

Cited by 368 publications

References 25 publications

Alpha cell function in health and disease: influence of glucagon-like peptide-1

Alpha cell function in health and disease: influence of glucagon-like peptide-1

The effects of acute hypoglycaemia on memory acquisition and recall and prospective memory in type 1 diabetes

Hypoglycaemia unawareness and the brain

Contact Info

Product

Resources

About