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Approach to the adult with brittle diabetes or high glucose variability

Approach to the adult with brittle diabetes or high glucose variability
Author:
Ruth S Weinstock, MD, PhD
Section Editor:
Irl B Hirsch, MD
Deputy Editor:
Katya Rubinow, MD
Literature review current through: Dec 2022. | This topic last updated: Nov 11, 2021.

INTRODUCTION — Almost all adults with diabetes experience glycemic excursions that are larger and less predictable than in people without diabetes (ie, glucose variability). The magnitude of this glycemic variability differs among adults with diabetes, but it is generally greater in type 1 than in type 2 diabetes. When the fluctuations in blood sugar are frequent and cause unpredictable episodes of diabetic ketoacidosis (DKA) and/or serious hyperglycemia or hypoglycemia, they adversely affect quality of life and cause a considerable burden on hospital, social, and caregiver resources due, at least in part, to multiple hospital admissions or emergency department visits.

The clinical characteristics, evaluation, and management of adults with high glucose variability, and in particular unpredictable episodes of DKA and/or serious hyperglycemia or hypoglycemia that interfere with daily activities ("brittle diabetes"), will be reviewed here. The management of diabetes mellitus in general, including blood glucose monitoring (BGM) and insulin pump therapy, are reviewed elsewhere. (See "Management of blood glucose in adults with type 1 diabetes mellitus" and "Insulin therapy in type 2 diabetes mellitus" and "Glucose monitoring in the ambulatory management of nonpregnant adults with diabetes mellitus".)

DEFINITIONS

High glucose variability – High glucose variability refers to wide glycemic excursions that occur within the same day, including fluctuations between hyperglycemia (typically postprandial) and hypoglycemia, as well as fluctuations that occur at the same time on different days [1]. With the increasing use of continuous glucose monitoring (CGM) devices, there is a greater understanding of how glucose levels change throughout the day and wide fluctuations in glucose levels are known to be common [2-5]. Glucose variability is important in patients with type 1 diabetes who have an absolute insulin deficiency, incomplete suppression of hepatic glucose production, and compromised counterregulatory responses (see "Physiologic response to hypoglycemia in healthy individuals and patients with diabetes mellitus"). Some patients with longstanding, insulin-treated type 2 diabetes may also have high glucose variability [6,7].

Some glucose variability is a normal aspect of glucose physiology. There is not a well-established glycemic threshold for high glucose variability. It has been measured historically with a variety of measurements, such as mean amplitude of glucose excursions (MAGE), continuous overall net glycemic action (CONGA), and standard deviation (SD) [8]. CGM device downloads routinely display three measures of glucose variability: interquartile range, SD around the mean, and coefficient of variation (CV) (figure 1) [9]. In one report of 376 people with diabetes, CV >36 percent (based upon two 24-hour day validated CGM profiles) correlated with increased frequency of hypoglycemia [10]. Many other measures of glucose variability have been proposed and studied as well, but these are not routinely reported or used in clinical practice [11,12].

Brittle diabetes – Brittle diabetes represents the most severe phenotype of high glucose variability. Historically, brittle diabetes was defined as severe glycemic instability of blood glucose levels with frequent and unpredictable episodes of hypoglycemia and/or diabetic ketoacidosis (DKA) that disrupt life activities, often requiring frequent and/or prolonged hospitalizations [13,14]. Given the imprecision of the term "brittle" diabetes, it is no longer commonly used, and instead, clinicians focus on the individual problem, recurrent DKA, wide glycemic excursions, serious hyperglycemia, or severe hypoglycemia.

Brittle diabetes predominantly occurs in the setting of absolute insulin deficiency (undetectable or very low levels of C-peptide), as occurs in type 1 diabetes or pancreatic diabetes (eg, post-pancreatectomy). Such patients are treated with multiple daily insulin injections or continuous subcutaneous insulin infusion therapy with an insulin pump.

The following subgroups of individuals are prone to severe glycemic dysregulation or "brittle diabetes" [15]:

Adolescents and young adults with type 1 diabetes and psychological challenges including eating disorders, depression, and alcohol and drug use.

People with coexisting conditions that result in severe glucose variability such as erratic insulin absorption due to the presence of lipohypertrophy; poorly functioning insulin infusion sites (for insulin pump users) or rare lipodystrophies; and gastroparesis, advanced chronic kidney disease, or infections.

Older adults with severe insulin deficiency including geriatric type 1 diabetes, particularly in the presence of cognitive impairment.

Individuals with severe insulin deficiency and poor access to insulin, monitoring supplies and devices, and food.

CLINICAL PRESENTATIONS AND RISK FACTORS — Classically, two clinical presentations of brittle diabetes have been described, predominant hypoglycemia with recurrent severe hypoglycemia and predominant hyperglycemia with recurrent diabetic ketoacidosis (DKA), but it is now well recognized that there are many individuals who have wide glycemic fluctuations spanning both severe hypoglycemia and hyperglycemia. High glucose variability is most concerning when it is associated with frequent episodes of severe hypoglycemia or DKA.

Predominant hypoglycemia with recurrent severe hypoglycemia — With the increasing availability of continuous glucose monitoring (CGM), it is apparent that unrecognized biochemical hypoglycemia is more widespread than previously appreciated [16-19]. Frequent hypoglycemia, even if asymptomatic, causes defective glucose counterregulation and a vicious cycle of recurrent hypoglycemia, increasing the risk for severe hypoglycemia. (See "Physiologic response to hypoglycemia in healthy individuals and patients with diabetes mellitus", section on 'Hypoglycemia-associated autonomic failure'.)

For adults with type 1 diabetes, in general, severe hypoglycemia, defined by consensus as episodes requiring assistance from another person to treat, is a more frequent problem than DKA [20]. Similarly, among Medicare beneficiaries with type 2 diabetes, hospitalizations for severe hypoglycemia have increased, while hospitalizations for hyperglycemia have decreased, particularly in older patients (≥75 years) and in Black individuals [21]. Risk factors for hypoglycemia include older age and longer duration of diabetes, dementia, recent hypoglycemia, alcohol ingestion, and advanced chronic kidney disease [20,22-27]. (See "Hypoglycemia in adults with diabetes mellitus", section on 'Risk factors for hypoglycemia'.)

Predominant hyperglycemia with recurrent diabetic ketoacidosis — DKA is due to underdosing or omitting insulin, which may be due to cost, behavioral/psychological problems, educational factors (eg, lack of sick day rule knowledge), infections, and medical illnesses [28,29]. It is more common at younger ages, particularly in the pediatric type 1 diabetes population and in lower socioeconomic levels [14,20].

In youth and young adults, especially female adolescents and young adults with type 1 diabetes, disordered eating behaviors and insulin omission or underdosing to promote weight loss are common risk factors for DKA. Such individuals have more frequent DKA hospitalizations and higher mortality [30-32]. (See "Complications and screening in children and adolescents with type 1 diabetes mellitus", section on 'Eating disorders'.)

Presence of both serious hyperglycemia and hypoglycemia — With increasing use of CGM, it has become apparent that wide glycemic excursions, with both serious hypoglycemia and hyperglycemia, are more common than previously recognized [15]. For these individuals, both medical and psychosocial contributing factors should be considered.

ETIOLOGY — There are three major etiologic categories for brittle diabetes (and for high glucose variability, in general): physiologic, behavioral, and psychosocial. After improving the physiologic match between insulin delivery and insulin requirements and addressing the behavioral and psychosocial aspects that may be contributing, there are still a small number of patients with type 1 diabetes with inexplicable brittle diabetes.

Physiologic — The most common biologic cause of brittle diabetes and high glucose variability is the nonphysiologic matching of meals/snacks and exercise with the absorption of the needed amount of subcutaneous insulin. With the availability of basal and bolus insulin regimens, using long-acting and rapid-acting insulin analogs, or insulin pump therapy, there has been substantial improvement in the ability to treat most patients with type 1 diabetes effectively [16,33], but the treatment remains imperfect. Adequate control of postprandial hyperglycemia and exercise-related hypoglycemia remains a challenge. In addition, inadvertent discontinuation of insulin infusions from insulin pump failure or dislodged or blocked insulin infusion sets, can contribute to the development of DKA.

Other physiologic causes of high glucose variability (high and low glucose levels) include poorly timed insulin injections that are supposed to be given preprandially but are delayed, delayed gastric emptying as well as other conditions associated with abnormal/erratic food absorption, renal failure, stress, abnormal or erratic insulin absorption from areas of lipohypertrophy, untreated celiac disease, and adrenal insufficiency [13,34,35].

Behavioral and psychosocial — Patient-centered behavioral issues have often been considered to underlie poor glycemic control. Especially in adolescents and young adults [14,36-39], some of these problems may be short-lived and related to a stressful situation (unhappiness at school or home), which causes the patient to neglect their diabetes care [37]. When these young "brittle" diabetes patients were studied in a controlled environment with regimented meals and exercise and insulin dosing choices made by and administered by the health care team, their labile glycemic state often improved [37].

In adults with hypoglycemic "brittle" diabetes, identified psychosocial factors included poor adherence, family dysfunction, "obsessional control," "life chaos," factitious insulin overdose, anorexia nervosa, and other psychological problems [34]. In a case-control study from Italy, "brittle" diabetes was associated with a higher likelihood of borderline, histrionic, and narcissistic personality disorder [39]. Additional contributory factors can include excessive use of alcohol, drug abuse, and other conditions that limit the ability to self-manage the disease such as dementia/severe cognitive impairment, lack of resources and financial constraints including food and housing insecurity, lack of health insurance, and inability to pay for medications.

The role of depression is controversial. Adults with diabetes may not have a higher prevalence of depression than the general population, but in cross-sectional studies, it has been reported that those who are depressed can have worse diabetes self-care and glycemic control, as well as more DKA and severe hypoglycemia [29,40,41]. In other studies, attention has also been focused on diabetes-related distress in adults with type 1 and type 2 diabetes, with reports of an association between greater diabetes distress and higher glycated hemoglobin (A1C), more hypoglycemia, and insulin omission [42-44].

Financial problems are increasingly a cause of hyperglycemia, with some patients rationing their insulin (underdosing or omitting injections) due to the high cost of insulin [29]. Unreliable access to food and inability to purchase monitoring devices, supplies, and other needed medications are additional contributing factors.

EVALUATION

Initial — A careful evaluation should be performed in patients with brittle diabetes/high glucose variability to identify risk factors and to differentiate physiologic from potential behavioral/psychosocial causes [33,45]. For all patients, a diabetes educational assessment is useful to evaluate whether the patient knows how to manage diabetes, is injecting insulin properly, and whether the current insulin regimen is reasonable. Use of continuous glucose monitoring (CGM; professional or personal) can be helpful to elucidate glycemic patterns that have been previously unrecognized. (See "Management of blood glucose in adults with type 1 diabetes mellitus" and "Insulin therapy in type 2 diabetes mellitus" and "Glucose monitoring in the ambulatory management of nonpregnant adults with diabetes mellitus".)

History – The detailed history should include several specific points, including:

Duration of diabetes

Description of all episodes of diabetic ketoacidosis (DKA) and severe hypoglycemia

Presence of diabetes complications and comorbidities that may increase the risk of glucose variability (particularly autonomic neuropathy [gastroparesis], cognitive impairment, renal and cardiovascular disease, celiac disease)

Recent illness or infection

Prescribed insulin regimens and any recent medication change

Frequency of blood glucose monitoring (BGM) and use of CGM

Presence of depression, psychiatric illness, or cognitive impairment

Presence of medication or food insecurity

Whether a period of "stable" diabetes preceded the variability and if there were changes in the patient's life circumstances coincident with its onset should be determined.

Glycemic profile – In addition to BGM, the use of a professional or personal CGM, with a log of food intake, physical activity, and insulin administration, is particularly helpful to better understand the person's glycemic profile.

To discover the causes of recurrent DKA, the frequency and reasons for missed insulin injections or lower than required insulin administration need to be determined. Ascertain whether BGM or CGM is being used consistently and whether the patient has responded appropriately. If not, determine the reason for the inadequate use or inappropriate response.

To discover the causes of severe hypoglycemia, the source of mismatched insulin requirements and insulin delivery (which often involves poor coordination of eating behavior, exercise, and insulin delivery) needs to be determined. The patient may be overcorrecting with insulin for hyperglycemia, related to fear of hyperglycemia and/or "stacking" of insulin doses (multiple doses close together in time). (See "Hypoglycemia in adults with diabetes mellitus", section on 'Risk factors for hypoglycemia'.)

Unexplained hyperglycemia — For patients with recurrent episodes of DKA, a possible undiagnosed infection (such as sinusitis, osteomyelitis, renal, perinephric or perirectal abscess, lung abscess) should be excluded. These problems are more likely in a patient using intravenous drugs. A urinary drug screen may be helpful if drug use is suspected. Poor dentition with dental abscesses should also be considered.

Unexplained hypoglycemia — For patients with persistent unexplained hypoglycemia, further evaluation for less common causes may be warranted:

Hypothyroidism and adrenal insufficiency – Thyroid function tests (thyroid-stimulating hormone [TSH], free thyroxine [T4]) and a corticotropin (ACTH) stimulation test should be performed if the clinical history is suggestive of hypothyroidism or glucocorticoid deficiency. (See "Diagnosis of and screening for hypothyroidism in nonpregnant adults" and "Diagnosis of adrenal insufficiency in adults".)

Insulin autoimmune hypoglycemia – Autoimmune hypoglycemia is a rare cause. It occurs in patients who have antibodies directed to endogenous insulin or to the insulin receptor. Symptoms can occur postprandially, fasting, or in both states. In patients with insulin autoantibodies, insulin secreted in response to a meal binds to the antibody and then disassociates in an unregulated fashion causing hyperinsulinemia and hypoglycemia. In patients with antibodies to the insulin receptor (also extremely rare), hypoglycemia occurs as a result of antibody activation of the receptor. Measurement of insulin and insulin receptor antibodies is necessary to confirm the diagnosis [33]. (See "Hypoglycemia in adults without diabetes mellitus: Diagnostic approach", section on 'Determining the cause of hypoglycemia'.)

MANAGEMENT — The approach to management will vary depending on the specific problem for the individual patient (eg, recurrent diabetic ketoacidosis [DKA], recurrent severe hypoglycemia, or both). If an underlying condition has been identified during the course of the evaluation, treatment may improve glycemic variability. (See "Management of celiac disease in adults" and "Treatment of gastroparesis" and "Treatment of primary hypothyroidism in adults" and "Treatment of adrenal insufficiency in adults".)

However, for many patients, high glycemic variability is difficult to treat.

General principles

Education – Diabetes self-management education and support is important for the patient who is struggling with insulin dosing and dietary prescriptions. Patients need to be instructed on how to match the insulin dose to the amount of carbohydrates ingested at each meal. If carbohydrate counting is not possible, carbohydrate consistency in each meal should be discussed. In addition, insulin regimens should be individually tailored to reduce the risk of hypoglycemia, while maintaining or improving glycemic control. If there is a history of hypoglycemia unawareness, a two- to three-week period of scrupulous avoidance of hypoglycemia is advisable since that often restores awareness. (See "Nutritional considerations in type 1 diabetes mellitus", section on 'Carbohydrate consistency' and "Management of blood glucose in adults with type 1 diabetes mellitus", section on 'Choice of insulin delivery' and "Hypoglycemia in adults with diabetes mellitus", section on 'Strategies to manage hypoglycemia'.)

Health care professionals who educate and treat patients with insulin-requiring diabetes should have expertise in the principles of insulin management. Patient education and empowerment, frequent blood glucose monitoring (BGM) or use of continuous glucose monitoring (CGM), flexible and rational insulin (and other drug) regimens, proper insulin administration, recognition and treatment of hypoglycemia, individualized glycemic goals, and ongoing professional guidance and support are required to meet these goals.

BGM – Regular BGM is critical to the glycemic management of type 1 and intensively treated (basal/bolus insulin) type 2 diabetes. CGM (compared with sole use of BGM) can further facilitate glycemic control or at least provide a clearer understanding of the time periods when glucose control is problematic. (See "Glucose monitoring in the ambulatory management of nonpregnant adults with diabetes mellitus", section on 'CGM systems'.)

Insulin pumps – Continuous subcutaneous insulin infusion (insulin pump therapy) has been used in conjunction with a CGM device to give patients more information about their blood glucose levels and allow them to make better informed decisions about insulin dosing. With some systems, insulin infusion automatically suspends when hypoglycemia is predicted to occur ("low glucose suspend"). This approach may improve glycemic control without an increase in the rate of severe hypoglycemia and can reduce time in hypoglycemia. Hybrid closed-loop systems ("artificial pancreas") use automated insulin delivery technology that significantly improves time spent in the glycemic target range and reduce time spent in hypoglycemia. (See "Continuous subcutaneous insulin infusion (insulin pump)", section on 'Types of insulin pumps'.)

Psychosocial — In patients with a clear psychological component to diabetes instability, a psychological evaluation and referral are warranted since psychotherapy has been shown to be effective in selected patients [46]. An evaluation addressing social determinants of health with referral to appropriate community resources is also important for patients with financial and other social barriers.

If deliberate mismanagement by a patient is suspected, in-hospital assessment and management of blood sugars are often necessary [47]. During the initial period, the patient has to stay on the treatment unit at all times, where they can be closely monitored and observed, with all blood glucose testing, food, and insulin being administered by the staff. Subsequently, the patient may be allowed to become involved in his or her management, provided that blood glucose control and behavior remain reasonable. Some patients with so-called "brittle" diabetes will have relatively easy-to-control diabetes in this setting, clearly suggesting that behavioral or regimen-based problems underlie their glycemic variability as an outpatient.

Many patients with brittle diabetes continue to be admitted with recurrent problems until their general life situation improves. Referral to a specialty center may be indicated in severe cases. This is particularly important if there is a possibility that the clinician (or another team member) is becoming so involved with the patient's case that they may lose objectivity or be manipulated by the patient. Patients who are using their severe glycemic instability to escape from an unhappy situation in the outside world may use the hospital as a sanctuary, become very familiar with all the staff, bend the rules for their own convenience, and interfere with their management in bizarre ways to ensure that they need to remain hospitalized. Fortunately, this is rare.

Other — Pancreas transplantation or pancreatic islet cell transplantation are options for the small minority of patients with a history of severe and frequent metabolic complications (hypoglycemia, DKA) and a consistent failure of insulin-based management to prevent these complications [33]. (See "Pancreas and islet transplantation in diabetes mellitus", section on 'Indications for transplantation'.)

OUTCOMES — In older reports, the overall mortality rate for patients with brittle diabetes was high, ranging from 20 to 50 percent in series from specialist centers [36-38,48]. In one series, the causes of death were chronic renal failure, diabetic ketoacidosis (DKA), hypoglycemia, and subarachnoid hemorrhage [48]. The age at death ranged from 27 to 45 years.

Although most clinical experts in the management of type 1 diabetes continue to see patients with frequent severe hypoglycemia and/or DKA, many of whom have a substantial behavioral or iatrogenic contribution to their brittle state, there are few modern-day descriptions of brittle diabetes encompassing the era of intensive insulin therapy and use of continuous glucose monitoring (CGM). There is a growing literature on severe hypoglycemia in adults with type 1 and type 2 diabetes, relating a history of severe hypoglycemia with increased risk of adverse consequences (see "Hypoglycemia in adults with diabetes mellitus", section on 'Consequences'). For many, if not most, of these insulin-requiring adults, use of CGM and sensor-augmented insulin pump therapy or hybrid closed-loop systems helps reduce time in hypoglycemia. In the future, the "closed loop," or artificial pancreas, should be of great benefit. (See "Continuous subcutaneous insulin infusion (insulin pump)", section on 'Insulin only, partially automated system'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diabetes mellitus in adults".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Type 1 diabetes (The Basics)" and "Patient education: Using insulin (The Basics)")

Beyond the Basics topics (see "Patient education: Type 1 diabetes: Overview (Beyond the Basics)" and "Patient education: Blood glucose monitoring in diabetes (Beyond the Basics)" and "Patient education: Type 1 diabetes: Insulin treatment (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

High glucose variability refers to wide glycemic excursions that occur within the same day, including fluctuations between hyperglycemia (typically postprandial) and hypoglycemia, as well as fluctuations that occur at the same time on different days. With the increasing use of continuous glucose monitoring (CGM) devices, there is a greater understanding of how glucose levels change throughout the day and wide fluctuations in glucose levels are known to be common (figure 1). There is not a well-established glycemic threshold for high glucose variability. (See 'Definitions' above.)

Brittle diabetes represents the most severe phenotype of high glucose variability. Historically, brittle diabetes was described as severe glycemic instability of blood glucose levels with frequent and unpredictable episodes of hypoglycemia and/or diabetic ketoacidosis (DKA) that disrupt life activities, often requiring frequent and/or prolonged hospitalizations. The term "brittle" diabetes is no longer commonly used, and instead, clinicians focus on the individual problem, recurrent DKA, wide glycemic excursions, serious hyperglycemia, or severe hypoglycemia. (See 'Definitions' above.)

Brittle diabetes is commonly observed in adults with absolute insulin deficiency (undetectable C-peptide levels) requiring treatment with multiple daily insulin injections or continuous subcutaneous insulin infusion therapy with an insulin pump. These patients usually have type 1 diabetes or pancreatic diabetes (eg, post-pancreatectomy). Risk factors include duration of diabetes, behavioral/psychological problems, educational and social factors, and medical comorbidities (eg, cognitive impairment, advanced renal disease). (See 'Clinical presentations and risk factors' above.)

There are three major etiologic categories for brittle diabetes (and for high glucose variability, in general): physiologic, behavioral, and psychosocial. After improving the physiologic match between insulin delivery and insulin requirements and addressing the behavioral, psychological, and social aspects that may be contributing, there are still a small number of patients with type 1 diabetes with inexplicable brittle diabetes. (See 'Etiology' above.)

A careful evaluation should be performed in patients with brittle diabetes/high glucose variability to differentiate among the various causes. It is important to take a detailed history to include several specific points, such as the duration of diabetes, a description of all episodes of DKA and severe hypoglycemia, prescribed insulin regimens, and the presence of diabetes complications (particularly autonomic neuropathy, which may be indicative of gastroparesis, chronic kidney disease, and cardiovascular disease). Because psychosocial factors are important contributors to disease instability, a psychosocial assessment is an important component of the evaluation. For patients with unexplained severe hypoglycemia or DKA, further evaluation for less common causes may be warranted. (See 'Evaluation' above.)

The management of brittle diabetes includes diabetes education, intensive insulin therapy (multiple daily injections or insulin pump) with CGM, and frequent interaction between patient and clinician. Health care professionals who educate and treat patients with insulin-requiring diabetes should have expertise in the principles of insulin management. In patients with a clear psychosocial component to diabetes instability, a psychological and/or social intervention is warranted since psychotherapy and addressing social determinants of health have been shown to be effective in selected patients. For the small minority of patients who comply with intensive insulin therapy and educational programs but have persistent, recurrent, and disabling hypoglycemia and/or DKA, pancreas or islet cell transplantation may be effective. (See 'Management' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges David McCulloch, MD, who contributed to an earlier version of this topic review.

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