- •
Hypoglycemia is a frequent occurrence for many patients with type 1 or type 2 diabetes treated with insulin or insulin secretagogues and those with renal insufficiency.
- •
Episodes of hypoglycemia have significant morbidity and mortality and are the main limiting factor for achieving near optimal glycemic control.
- •
Impaired glucose counterregulation and hypoglycemia unawareness are the major risk factors for severe hypoglycemia.
- •
Risk factors, including impaired glucose counterregulation and
Endocrinology and Metabolism Clinics of North America
Hypoglycemia
Section snippets
Key points
General considerations
Normally, plasma glucose concentrations are maintained within a relatively narrow range throughout the day (usually between 55 and 165 mg/dL, ∼3.0 and 9.0 mM/L) despite wide fluctuations in the delivery (eg, meals) and removal (eg, exercise) of glucose from the circulation. This is accomplished by a tightly linked balance between glucose production and glucose utilization regulated by complex mechanisms.
Hypoglycemia is to be avoided to protect the brain and prevent cognitive dysfunction.
Epidemiology of hypoglycemia
The reported incidence of hypoglycemia varies considerably among studies. For the purpose of reporting hypoglycemia in clinical trials, the American Diabetes Association and the Endocrine Society have developed 5 categories, as outlined in Table 1.3 The incidence of one category, severe hypoglycemia, has been determined more precisely, as it is defined as that associated with unconsciousness or requiring external assistance. The complete detection of chemical hypoglycemia (commonly defined as a
Risk factors for hypoglycemia
Risk factors for hypoglycemia are summarized in Box 1. Conventional risk factors relate to absolute or relative insulin excess. These include insulin doses that are excessive or ill-timed, missed meals or snacks, lack of compensation for increased exercise, alcohol ingestion, or mistaken insulin administration. However, a thorough analysis of a large number of episodes of severe hypoglycemia in the DCCT has indicated that such conventional risk factors explained only a minority of the episodes17
Normal Hypoglycemia Counterregulation and Hypoglycemia Awareness
Glucose counterregulation refers to the sum of the body’s defense mechanisms that prevent hypoglycemia from occurring and that restore euglycemia. Hypoglycemia awareness refers to the symptomatic responses of hypoglycemia that alert the patient of declining blood glucose levels.
In healthy postabsorptive humans (ie, after an overnight fast), the sum of glucose release by liver and kidney nearly equals systemic glucose utilization so that plasma glucose concentrations remain relatively stable.
Manifestations of hypoglycemia
Manifestations of hypoglycemia are nonspecific and can sometimes be noted by observers rather than patients themselves. They can be categorized as neurogenic (mostly due to sympathetic neural activation) and neuroglycopenic (due to brain glucose deprivation) (Box 2). Neurogenic manifestations, also called autonomic or sympathoadrenal, precede neuroglycopenic symptoms and allow patients to recognize and self-treat hypoglycemia. Patients with hypoglycemia unawareness are likely to have
Complications of hypoglycemia
An episode of severe hypoglycemia can be detrimental or even fatal mostly due to its effects on the central nervous system. At plasma glucose concentration of approximately 55 mg/dL (∼3 mM/L), cognitive impairment and electroencephalogram changes are demonstrable. Decreases below 40 mg/dL (∼2.5 mM/L) result in sleepiness and gross behavioral (eg, combativeness) abnormalities. Further decreases can produce coma, and values less than 30 mg/dL (∼1.6 mM/L), if prolonged, can cause seizures,
Treatment
Treatment is aimed at restoring euglycemia, preventing recurrences, and, if possible, alleviating the underlying cause.
In an insulin-taking diabetic patient with mild hypoglycemia due to a skipped meal, 15 to 20 g of oral carbohydrate every 15 to 20 minutes until the blood glucose is above 80 mg/dL (4.5 mM/L) constitutes adequate treatment (Box 3).97, 98 Examples for oral carbohydrate source are presented in Box 4. In a patient with more severe hypoglycemia resulting in obtundation, in whom
References (134)
- et al.
Nocturnal hypoglycaemias in type 1 diabetic patients: what can we learn with continuous glucose monitoring?
Diabetes Metab
(2007) - et al.
Frequency and risk factors of severe hypoglycemia in insulin-treated type 2 diabetes: a literature survey
J Diabet Complications
(2006) - et al.
Rates of hypoglycemia in users of sulfonylureas
J Clin Epidemiol
(1997) - et al.
Economic and clinical impact of inpatient diabetic hypoglycemia
Endocr Pract
(2009) - et al.
Brain metabolism during fasting
J Clin Invest
(1967) Banting lecture: hypoglycemia, the limiting factor in the management of IDDM
Diabetes
(1994)- et al.
Hypoglycemia and diabetes: a report of a Workgroup of the American Diabetes Association and The Endocrine Society
Diabetes Care
(2013) - et al.
Hypoglycemia
- et al.
Nocturnal hypoglycaemia in Type 1 diabetic patients, assessed with continuous glucose monitoring: frequency, duration and associations
Diabet Med
(2007) - et al.
Frequency of severe hypoglycemia requiring emergency treatment in type 1 and type 2 diabetes: a population-based study of health service resource use
Diabetes Care
(2003)
Risk of hypoglycemia in types 1 and 2 diabetes: effects of treatment modalities and their duration
Diabetologia
Hypoglycemia in type 2 diabetes
Diabet Med
Hypoglycemia and counterregulation in type 2 diabetes
Lancet
DCCT Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin dependent diabetes mellitus
N Engl J Med
A systematic review and meta-analysis of hypoglycemia and cardiovascular events: a comparison of glyburide with other secretagogues and with insulin
Diabetes Care
Three-year efficacy of complex insulin regimens in type 2 diabetes
N Engl J Med
Hypoglycemia in type 2 diabetes
Diabetes Care
DCCT Research Group. Epidemiology of severe hypoglycemia in the diabetes control and complications trial
Am J Med
Incidence of severe hypoglycemia and its causes in insulin- treated diabetics
Acta Med Scand
R.D. Lawrence Lecture 1994. Limits of normality: the mechanisms of hypoglycemia unawareness
Diabet Med
Hypoglycemia unawareness in IDDM
Diabetes Care
Abnormal glucose counterregulation in insulin-dependent diabetes mellitus: interaction of anti-insulin antibodies and impaired glucagon and epinephrine secretion
Diabetes
Defective glucose counterregulation after strict control of insulin-dependent diabetes mellitus
N Engl J Med
Intensive insulin therapy reduces counterregulatory responses to hypoglycemia in type I diabetes
Ann Intern Med
Further defects in counterregulatory responses induced by recurrent hypoglycemia in IDDM
Diabetes
Compromised hormonal counterregulation, symptom awareness, and neurophysiologic function after recurrent short-term episodes of insulin-induced hypoglycemia in IDDM patients
Diabetes
Effects of autonomic neuropathy on counterregulation and awareness of hypoglycemia in type 1 diabetic patients
Diabetes Care
Decreased response of epinephrine and norepinephrine to insulin-induced hypoglycemia in diabetic autonomic neuropathy
Horm Metab Res
Reduced epinephrine secretion and hypoglycemic unawareness in diabetic autonomic neuropathy
Ann Intern Med
Higher glycemic thresholds for symptoms during beta-adrenergic blockade in IDDM
Diabetes
Identification of type I diabetic patients at increased risk for hypoglycemia during intensive therapy
N Engl J Med
Frequency of severe hypoglycemia in patients with type 1 diabetes with impaired awareness of hypoglycemia
Diabetes Care
Hypoglycemia
Presence of macroalbuminuria predicts severe hypoglycemia in patients with type 2 diabetes mellitus
Diabetes Care
Emptying of the gastric substitute, glucagon-like peptide-1 (GLP-1), and reactive hypoglycemia after total gastrectomy
Dig Dis Sci
Changes in glucose tolerance and serum insulin following partial gastrectomy and intestinal resection
Gut
Effect of adrenergic agents on postgastrectomy hypoglycemia
Diabetes
Mechanism of postgastrectomy hypoglycemia
Arch Intern Med
Mechanisms of recovery from type 2 diabetes after malabsorptive bariatric surgery
Diabetes
Changes in insulin resistance following bariatric surgery: role of caloric restriction and weight loss
Obes Surg
Meta-analysis: surgical treatment of obesity
Ann Intern Med
Postprandial GLP-1, norepinephrine, and reactive hypoglycemia in dumping syndrome
Dig Dis Sci
Gut hormone profile and gastric emptying in the dumping syndrome. A hypothesis concerning the pathogenesis
Scand J Gastroenterol
Nutrient, neural and endocrine control of glucagon-like peptide secretion
Horm Metab Res
Gastrointestinal hormone responses to meals before and after gastric bypass and vertical banded gastroplasty
Ann Surg
Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery
N Engl J Med
Severe hypoglycaemia post-gastric bypass requiring partial pancreatectomy: evidence for inappropriate insulin secretion and pancreatic islet hyperplasia
Diabetologia
Hyperinsulinemic hypoglycemia with nesidioblastosis after gastric-bypass surgery
N Engl J Med
Clinical features and morphological characterization of 10 patients with noninsulinoma pancreatogenous hypoglycaemia syndrome (NIPHS)
Clin Endocrinol (Oxf)
Hyperinsulinemic hypoglycemia after gastric bypass surgery is not accompanied by islet hyperplasia or increased beta-cell turnover
Diabetes Care
Cited by (34)
Gastrointestinal autonomic neuropathy in diabetes
2020, Autonomic Neuroscience: Basic and ClinicalCitation Excerpt :Hypoglycemia is appropriately feared by patients with diabetes, and is often the limiting factor in achieving optimal glycemic control using insulin or sulfonylureas (Frier, 2014). In health, a hierarchy of protective responses is triggered by falling blood glucose levels, including the ‘early’ (glucagon and catecholamines) and ‘late’ (cortisol and growth hormone) counter-regulatory hormone responses (Alsahli and Gerich, 2013). It is not widely appreciated that gastric emptying is accelerated markedly in response to insulin-induced hypoglycemia, allowing for more rapid intestinal absorption of ingested nutrients (Russo et al., 2005; Marathe et al., 2019).
Multiple predictively equivalent risk models for handling missing data at time of prediction: With an application in severe hypoglycemia risk prediction for type 2 diabetes
2020, Journal of Biomedical InformaticsCitation Excerpt :Many clinical risk factors for hypoglycemia have been identified. These include older age, diabetes duration, burden of co-morbidities, glycemic treatment intensification, current insulin treatment, duration of insulin treatment and use of other T2DM medications [37–42]. Risk models predicting short-term (2–12 months) [43–48] and long-term (5 years) [49] hypoglycemia have been developed.
High glycemic index and glycemic load diets as risk factors for insomnia: Analyses from the Women's Health Initiative
2020, American Journal of Clinical NutritionRenal glucose metabolism in normal physiological conditions and in diabetes
2017, Diabetes Research and Clinical PracticeCitation Excerpt :In respiratory acidosis patients, an increase in net renal glucose release has been demonstrated to be inversely proportional to blood pH [65]. ( C) Glucose counterregulation in diabetes: Patients with type 1 diabetes mellitus (T1DM) and prolonged type 2 diabetes mellitus (T2DM) lose their glucagon response and become dependent on catecholamine responses [66]. When glucagon response is lost, catecholamines become the major counterregulatory hormonal factor by increasing renal glucose release during hypoglycemia [67].
Social vulnerability and hypoglycemia among patients with diabetes
2017, Endocrinologia, Diabetes y NutricionCitation Excerpt :In fact, low socioeconomic status confers a risk of hypoglycemia similar to that attributed to insulin use.11 The global frequency of hypoglycemia varies considerably among studies, being greater in patients with type 1 diabetes (T1D) than in patients with type 2 diabetes (T2D).12–14 In the Diabetes Control and Complications Trial (DCCT), patients in the intensive arm had a 65% incidence of severe hypoglycemia, compared with 35% in the conventional group.
Fucoidan from sea cucumber Cucumaria frondosa exhibits anti-hyperglycemic effects in insulin resistant mice via activating the PI3K/PKB pathway and GLUT4
2016, Journal of Bioscience and Bioengineering
Disclosures: Dr Alsahli has nothing to disclose.
Funding Sources: Dr Gerich: University of Rochester Senior Faculty Associates Program.
Conflict of Interest: Dr Gerich: Consultant: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Merck, Sanofi-Aventis, and Janssen Pharmaceuticals.
Speakers' Bureau: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Merck, Sanofi-Aventis, and Janssen Pharmaceuticals.