Diabetic Emergencies: Hypoglycemia Caused by Insulin

Stavros Liatis, Nikolaos Katsilambros

Hypoglycemia is defined as blood glucose concentration below the normal range, the lower level of normality being equivocal.

From a physiological point of view, a detectable impairment of higher cerebral function has been demonstrated at plasma glucose levels of 54 mg/dl (3 mmol/L) or less.¹ Counter-regulatory responses to hypoglycemia have been described at plasma levels between 65-70 mg/dl (3.6-3.9 mmol/L).²

Physiology of blood glucose regulation 

In normal individuals, blood glucose levels remain under strict regulation, coordinated by complex neuroendocrine mechanisms. This happens because glucose is an obligate metabolic fuel for the brain, which, due to its very limited fuel-storing capacity, is dependent on the continuous supply of glucose from the blood stream. Therefore, in cases where blood glucose falls, or tends to fall, below normal range, several counter-regulatory responses are elicited² (Figure 4.1). The key components of this counter-regulatory mechanism are:

1. Suppression of insulin secretion from the pancreatic β-cells. This happens even when plasma glucose is within the normal range, if there is a tendency for plasma glucose to decline (below 80 mg/dl [4.4 mmol/L]).
2. Increase in glucagon secretion from the pancreatic α-cells, when plasma glucose is in the range of 65-70 mg/dl (3.6-3.9 mmol/L).
3. Increase in adrenomedullary epinephrine secretion when plasma glucose falls below the normal range (65-70 mg/dl [3.6-3.9 mmol/L]).
4. Increased growth hormone and adrenocorticotropin secretion from the anterior pituitary.

This battery of neuroendocrine responses results in increased endogenous glucose production, reduction in peripheral glucose utilization, increased lipolysis, and increased proteolysis, all combining to "push" plasma glucose concentration to increase. It has to be emphasized, however, that insulin, glucagon, and epinephrine play the most critical role among the glucose counter-regulatory factors, acting within a few minutes.

The defense mechanism against falling blood glucose is so effective that hypoglycemia is a very uncommon condition in non-diabetic individuals.

Hypoglycemia in diabetes

Pathophysiology of low blood glucose counter-regulation

Hypoglycemia in diabetes usually results as a consequence of treatment aimed at correction of hyperglycemia. Iatrogenic hypoglycemia is considered the major obstacle preventing good glycemic control in patients with diabetes. The problem appears when insulin deficiency, which is a hallmark of the disease, is overcorrected. Nevertheless, hypoglycemia is a much more common problem in Type 1 than in Type 2 diabetes, the first of which is characterized by absolute insulin deficiency, whereas the latter is characterized by relative deficiency which, however, deteriorates with time.

Hypoglycemic thresholds (i.e., the plasma glucose values at which counter-regulatory mechanisms are activated) may be altered in patients with diabetes, depending on glucose control. A higher threshold is often associated with poor glycemic control while, in tightly-controlled individuals or those with frequent episodes of hypoglycemia, a shift toward lower levels is often observed. ^3,4

In Type 1 diabetes, complete lack of insulin secretion results in impairment of the first counter-regulatory defensive mechanism against hypoglycemia, that is, reduction of insulin secretion. In these patients, plasma insulin levels are directly related to the passive absorption of exogenously administered insulin and its pharmacokinetic profile. In addition, endogenous insulin deficiency is considered responsible for a blunted glucagon response to hypoglycemia. This is probably a signaling defect, since glucagon-secreting cells and secretion of glucagon induced by stimuli other than hypoglycemia are intact in such patients.⁵ Finally, even the epinephrine response to hypoglycemia is attenuated in Type 1 diabetes, mainly due to the shift of its counter-regulatory threshold toward lower plasma glucose levels.⁴ The latter is believed to be the result of frequent iatrogenic hypoglycemic events, although sleep, and to some extent prior exercise, may similarly influence epinephrine response.⁶

In patients with Type 2 diabetes, the counter-regulatory response has been reported to be relatively intact in the early stages of the disease but the frequency of iatrogenic hypoglycemia typically increases as the insulin deficiency progresses and insulin therapy is introduced. The potential effects of aging on counter-regulation should also be taken into account, as people with Type 2 diabetes are often elderly and are hence more susceptible to the clinical consequences of hypoglycemia. It has been reported that the magnitude of the counter-regulatory response is reduced in the elderly (≥ 65 years) when blood glucose falls below 60 mg/dl (3.3 mmol/L), while it is preserved at more profound hypoglycemic levels (blood glucose < 50 mg/dl [2.8 mmol/L]). ⁷ 

Hypoglycemia unawareness is due to the attenuated epinephrine response observed in patients with diabetes and frequent hypoglycemic episodes. It has been shown that recent antecedent iatrogenic hypoglycemia leads to defective glucose counter-regulation and, consequently, to hypoglycemia unawareness, which in turn predisposes to further episodes of iatrogenic hypoglycemia.⁸ This vicious circle has been recently described as hypoglycemia-associated autonomic failure (HAAF). That concept has been extended to include exercise-and sleep-related HAAF.⁶ HAAF is reversible, however, since it has been shown that the sympathoadrenal response to hypoglycemia is a dynamic process.⁹ Reversal of HAAF is mainly based on strict avoidance of low blood glucose levels over a period of 2-4 weeks.⁹

References

1. Maran A, Lomas J, Macdonald IA, et al. Lack of preservation of higher brain function during hypoglycaemia in patients with intensively-treated IDDM. Diabetologia 1995; 38: 1412-8.
2. Mitrakou A, Ryan C, Veneman T, et al. Hierarchy of glycemic thresholds for counterregulatory hormone secretion, symptoms, and cerebral dysfunction. Am J Physiol 1991; 260: E67-74.
3. Boyle PJ, Schwartz NS, Shah SD, et al. Plasma glucose concentrations at the onset of hypoglycemic symptoms in patients with poorly controlled diabetes and in nondiabetics. N Engl J Med 1988; 318: 1487-92.
4. Amiel SA, Sherwin RS, Simonson DC, et al. Effect of intensive insulin therapy on glycemic thresholds for counterregulatory hormone release. Diabetes 1988; 37: 901-7.
5. Banarer S, McGregor VP, Cryer PE. Intraislet hyperinsulinemia prevents the glucagon response to hypoglycemia despite an intact autonomic response. Diabetes 2002; 51: 958-65.
6. Cryer PE. Diverse causes of hypoglycemia-associated autonomic failure in diabetes. N Engl J Med 2004; 350: 2272-9.
7. Ortiz-Alonso FJ, Galecki A, Herman WH et al. Hypoglycemia counterregulation in elderly humans: relationship to glucose levels. Am J Physiol 1994; 267: E497-506.
8. Cryer PE. Mechanisms of hypoglycemia-associated autonomic failure and its component syndromes in diabetes. Diabetes 2005; 54: 3592-601.
9. Fanelli CG, Epifano L, Rambotti AM, et al. Meticulous prevention of hypoglycemia normalizes the glycemic thresholds and magnitude of most of neuroendocrine responses to, symptoms of, and cognitive function during hypoglycemia in intensively treated patients with short-term IDDM. Diabetes 1993; 42: 1683-9.

Christina Kanaka-Gantenbein, MD, PhD
Associate Professor of Pediatric Endocrinology and Diabetology
First Department of Pediatrics, University of Athens
Agia Sofia Children’s Hospital
Athens, Greece

Stavros Liatis, MD
Consultant in Internal Medicine and Diabetology
Laiko General Hospital

Konstantinos Makrilakis, MD, MPH, PhD
Assistant Professor of Internal Medicine and Diabetology
Athens University Medical School
Laiko General Hospital
Athens, Greece

Nikolaos Tentolouris, MD, PhD
Assistant Professor of Internal Medicine and Diabetology
University of Athens
Laiko General Hospital
Athens, Greece

A John Wiley & Sons, Ltd., Publication This edition first published 2011 © 2011 by John Wiley & Sons, Ltd.

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Diabetic Emergencies: Diagnosis and Clinical Management provides emergency room staff, diabetes specialists and endocrinologists with highly practical, clear-cut clinical guidance on both the presentation of serious diabetic emergencies like ketoacidosis, hyperosmolar coma and severe hyper- and hypoglycemia, and the best methods of both managing the emergencies and administering appropriate follow-up care.

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