Risk factors of severe hypoglycaemia in adult patients with Type I diabetes - a prospective population based study

Mühlhauser, Ingrid; Overmann, H.; Bender, Ralf; Bott, U.; Berger, Michael

doi:10.1007/s001250051065

Cited by 98 publications

(67 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In other words, although substantial insulin excess can cause hypoglycemia, the integrity of the physiological and behavioral defenses against falling plasma glucose concentrations determines if less-marked hyperinsulinemia, which must occur from time to time because of the pharmacokinetic imperfections of current insulin replacement regimens, causes an episode of hypoglycemia. Risk factors relevant to compromised glucose counterregulation that are well-established in type 1 diabetes (1,2,35,67,68) and are likely relevant to advanced type 2 diabetes include: 1) insulin deficiency; 2) history of severe hypoglycemia, hypoglycemia unawareness, or both; 3) aggressive glycemic therapy per se, as evidenced by lower HbA 1c levels, lower glycemic goals, or both. These are clinical surrogates of the key features of the pathophysiology of glucose counterregulation discussed earlier.…”

Section: Insulin Excess Plus Compromised Glucose Counterregulationmentioning

confidence: 99%

Hypoglycemia in Diabetes

2003

View full text Add to dashboard Cite

Iatrogenic hypoglycemia causes recurrent morbidity in most people with type 1 diabetes and many with type 2 diabetes, and it is sometimes fatal. The barrier of hypoglycemia generally precludes maintenance of euglycemia over a lifetime of diabetes and thus precludes full realization of euglycemia's long-term benefits. While the clinical presentation is often characteristic, particularly for the experienced individual with diabetes, the neurogenic and neuroglycopenic symptoms of hypoglycemia are nonspecific and relatively insensitive; therefore, many episodes are not recognized. Hypoglycemia can result from exogenous or endogenous insulin excess alone. However, iatrogenic hypoglycemia is typically the result of the interplay of absolute or relative insulin excess and compromised glucose counterregulation in type 1 and advanced type 2 diabetes. Decrements in insulin, increments in glucagon, and, absent the latter, increments in epinephrine stand high in the hierarchy of redundant glucose counterregulatory factors that normally prevent or rapidly correct hypoglycemia. In insulin-deficient diabetes (exogenous) insulin levels do not decrease as glucose levels fall, and the combination of deficient glucagon and epinephrine responses causes defective glucose counterregulation. Reduced sympathoadrenal responses cause hypoglycemia unawareness. The concept of hypoglycemia-associated autonomic failure in diabetes posits that recent antecedent hypoglycemia causes both defective glucose counterregulation and hypoglycemia unawareness. By shifting glycemic thresholds for the sympathoadrenal (including epinephrine) and the resulting neurogenic responses to lower plasma glucose concentrations, antecedent hypoglycemia leads to a vicious cycle of recurrent hypoglycemia and further impairment of glucose counterregulation. Thus, short-term avoidance of hypoglycemia reverses hypoglycemia unawareness in most affected patients. The clinical approach to minimizing hypoglycemia while improving glycemic control includes 1) addressing the issue, 2) applying the principles of aggressive glycemic therapy, including flexible and individualized drug regimens, and 3) considering the risk factors for iatrogenic hypoglycemia. The latter include factors that result in absolute or relative insulin excess: drug dose, timing, and type; patterns of food ingestion and exercise; interactions with alcohol and other drugs; and altered sensitivity to or clearance of insulin. They also include factors that are clinical surrogates of compromised glucose counterregulation: endogenous insulin deficiency; history of severe hypoglycemia, hypoglycemia unawareness, or both; and aggressive glycemic therapy per se, as evidenced by lower HbA 1c levels, lower glycemic goals, or both. In a patient with hypoglycemia unawareness (which implies recurrent hypoglycemia) a 2-to 3-week period of scrupulous avoidance of hypoglycemia is advisable. Pending the prevention and cure of diabetes or the development of methods that provide glucose-regulated insulin replacement or secre...

show abstract

Section: Insulin Excess Plus Compromised Glucose Counterregulationmentioning

confidence: 99%

Hypoglycemia in Diabetes

2003

View full text Add to dashboard Cite

show abstract

“…Although hypoglycaemia can, of course, result from insulin excess alone, iatrogenic hypoglycaemia is more appropriately viewed as the result of the interplay of insulin excess and compromised glucose counterregulation in Type I diabetes and advanced Type II diabetes (Table 1) [4,56]. Risk factors related to compromised glucose counterregulation that are well established in Type I diabetes [1,23,58] and are likely to be relevant in advanced Type II diabetes, include: (i) insulin deficiency; (ii) a history of severe hypoglycaemia, hypoglycaemia unawareness, or both; (iii) aggressive glycaemic therapy per se as evidenced by .. Indeed when we wish to ascribe to a physiological quality its value and true significance we must always ... draw our final conclusion only in relation to its effects in the whole."…”

Section: Clinical Risk Factors and Risk Factor Reductionmentioning

confidence: 99%

“…Obviously, because of the pharmacokinetic imperfections of all glucose-lowering therapies, iatrogenic hypoglycaemia occurs in the absence of these risk factors [56]. Nevertheless, the risk is increased considerably in their presence [1,23,58].…”

Section: Clinical Risk Factors and Risk Factor Reductionmentioning

confidence: 99%

Hypoglycaemia: The limiting factor in the glycaemic management of Type I and Type II Diabetes*

2002

Diabetologia

730

574

View full text Add to dashboard Cite

Hypoglycaemia is the limiting factor in the glycaemic management of diabetes. Iatrogenic hypoglycaemia is typically the result of the interplay of insulin excess and compromised glucose counterregulation in Type I (insulin-dependent) diabetes mellitus. Insulin concentrations do not decrease and glucagon and epinephrine concentrations do not increase normally as glucose concentrations decrease. The concept of hypoglycaemia-associated autonomic failure (HAAF) in Type I diabetes posits that recent antecedent iatrogenic hypoglycaemia causes both defective glucose counterregulation (by reducing the epinephrine response in the setting of an absent glucagon response) and hypoglycaemia unawareness (by reducing the autonomic and the resulting neurogenic symptom responses). Perhaps the most compelling support for HAAF is the finding that as little as 2 to 3 weeks of scrupulous avoidance of hypoglycaemia reverses hypoglycaemia unawareness and improves the reduced epinephrine component of defective glucose counterregulation in most affected patients. The mediator and mechanism of HAAF are not known but are under active investigation. The glucagon response to hypoglycaemia is also reduced in patients approaching the insulin deficient end of the spectrum of Type II (non-insulin-dependent) diabetes mellitus, and glycaemic thresholds for autonomic (including epinephrine) and symptomatic responses to hypoglycaemia are shifted to lower plasma glucose concentrations after hypoglycaemia in Type II diabetes. Thus, patients with advanced Type II diabetes are also at risk for HAAF. While it is possible to minimise the risk of hypoglycaemia by reducing risks -including a 2 to 3 week period of scrupulous avoidance of hypoglycaemia in patients with hypoglycaemia unawareness -methods that provide glucose-regulated insulin replacement or secretion are needed to eliminate hypoglycaemia and maintain euglycaemia over a lifetime of diabetes. [Diabetologia (2002) 45:937-948] Keywords Hypoglycaemia, glucagon, epinephrine, adrenal medulla, sympathetic nervous system, hypoglycaemia-associated autonomic failure.

show abstract

“…It is thought that the sulphonylureas, acting through their specific receptors on the beta cell, support the concentrations of insulin within the islet, the corollary being that glucagon secretion is, at least in part, secondary to a reduction in beta-cell insulin secretion. Certainly, although the data are incomplete, loss of glucagon responses to acute hypoglycaemia correlates well with loss of C-peptide secretion and is found in patients with advanced Type II (non-insulin-dependent) diabetes mellitus and Cpeptide negative Type I (insulin-dependent) diabetes mellitus within the first five years of the disease [5,6,7] and perhaps in late onset Type II diabetes [8], at the insulin requiring stage. Nevertheless, there is also evidence for central involvement in the glucagon response, via activation of the sympathetic and parasympathetic nervous systems [9].…”

Section: The Physiological Defences Against Severe Hypoglycaemia In Dmentioning

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

Risk factors of severe hypoglycaemia in adult patients with Type I diabetes - a prospective population based study

Cited by 98 publications

References 23 publications

Hypoglycemia in Diabetes

Hypoglycemia in Diabetes

Hypoglycaemia: The limiting factor in the glycaemic management of Type I and Type II Diabetes*

Hypoglycaemia unawareness and the brain

Contact Info

Product

Resources

About