Cases illustrating problems with insulin therapy for type 1 diabetes mellitus

INTRODUCTION — The following cases illustrate some of the common problems that may arise during intensive insulin therapy in people with type 1 diabetes mellitus. The management of type 1 diabetes is reviewed in detail separately. (See "Management of blood glucose in adults with type 1 diabetes mellitus" and "Overview of general medical care in nonpregnant adults with diabetes mellitus".)

CASE 1: GLYCEMIC VARIABILITY DUE TO DIET — A 57-year-old hospital administrator who has had type 1 diabetes for 15 years is trying very hard to improve her glycemic control. She does not "count" carbohydrates (does not estimate her carbohydrate intake or use an insulin-to-carbohydrate ratio) and does not use an insulin sensitivity factor for correction doses. Instead, she adjusts her insulin dose, her food intake, and exercise pattern in response to how she feels. Her work hours vary, and she frequently needs to attend business lunches and dinners.

Her usual insulin doses are:

●Before breakfast – 6 units regular insulin and 26 units NPH insulin

●Before lunch – 4 units regular insulin

●Before evening meal – 4 units regular insulin

●Before bedtime – 26 units NPH insulin

She is frustrated at the unpredictability of her blood glucose values, as shown in the table (table 1).

Interpretation and approach — When a person continually adjusts insulin doses using an approach that is not consistent and also varies food intake and exercise routines, it is difficult to identify glycemic patterns. In this setting, keeping a three-day record of food intake, insulin doses, and exercise can be helpful in understanding the basis for the wide glycemic excursions (figure 1). As can be seen, the woman's total carbohydrate intake and its distribution are markedly different each day. This variability prevents the attainment of glycemic control with a fixed-dose insulin regimen. In general, the use of fixed doses of preprandial short-acting insulin in a person who does not eat the same amount of food or eat at the same times each day does not work well.

A consultation with a registered dietitian or diabetes educator to learn carbohydrate counting (usually more realistic than trying to eat a similar amount of carbohydrates from day to day) can be helpful. She should be taught to calculate her mealtime insulin dose using an insulin-to-carbohydrate ratio and to use an insulin sensitivity (correction) factor to supplement the pre-breakfast and pre-dinner insulin dose. She should not use the same correction factor for the pre-lunch insulin dose, as a lesser amount of regular insulin is needed since NPH insulin given in the morning has its greatest glucose-lowering effect in the late morning and early afternoon. (See "Nutritional considerations in type 1 diabetes mellitus", section on 'Advanced carbohydrate counting'.)

●If her insulin-to-carbohydrate ratio is 1:15 (ie, she needs 1 unit of regular insulin to cover 15 g of carbohydrate) and she eats 90 g of carbohydrate for breakfast, she would take 6 units of regular insulin. If she eats only 30 g of carbohydrates one morning, she would take 2 units of regular insulin.

●If her correction factor is 30 (1 unit lowers glucose concentration by 30 mg/dL [1.7 mmol/L]), she then adjusts the pre-breakfast or pre-dinner insulin based upon her pre-meal glucose and her target glucose. If the target glucose is 120 mg/dL (6.7 mmol/L) and the pre-meal glucose is 210 mg/dL, she would give herself an extra 3 units of "correction" insulin (subtract 120 mg/dL from the pre-meal glucose and divide by 30 to calculate the correction insulin).

The timing of the administration of the regular insulin in relation to the meal is also important. Due to the relatively slow absorption of regular insulin (compared with the rapid-acting insulin analogs), it is best taken 30 to 45 minutes before eating. Given her busy and unpredictable schedule, including the challenge of testing her blood glucose and administering her pre-meal dose 30 to 45 minutes before meals, she may prefer a rapid-acting insulin analog, which can be taken immediately before the meal to allow her greater flexibility in her variable lifestyle. The rapid-acting analogs also have a shorter duration of action than regular insulin and may reduce the occurrence of hypoglycemia before the next meal. However, if hypoglycemia in the late morning persists, changing from NPH insulin to a basal insulin with a longer, flatter insulin profile may be helpful. If NPH insulin is continued and late morning hypoglycemia persists, a mid-morning snack will be needed, but this may be difficult for her to do at work and can contribute to unwanted weight gain.

If she cannot or is unwilling to learn to use an insulin-to-carbohydrate ratio, the registered dietitian can assist her in developing a carbohydrate-consistent diet (approximately the same amount of carbohydrate for each breakfast, for each lunch, and for each dinner). Based on the agreed upon carbohydrate content of each meal, a fixed dose of insulin can be used, and an algorithm can be provided that incorporates a correction dose for elevated glucose readings. In addition, providing instructions for increasing regular insulin for high carbohydrate meals (eg, pizza), reducing regular insulin for the meal preceding exercise, and/or eating a carbohydrate snack before and/or during exercise is important.

CASE 2: BEDTIME HYPERGLYCEMIA AND UNSUSPECTED LATE MORNING HYPERGLYCEMIA — A 27-year-old woman with type 1 diabetes is treated with the following regimen:

●Before brunch – 8 units insulin aspart and 20 units insulin detemir

●Before evening meal – 4 units aspart

●Before bedtime – 12 units detemir

Her blood glucose values before meals and before bedtime are as shown in the table (table 2). She also recently started to use a continuous glucose monitor (CGM). Her CGM glucose levels on a recent day are shown in the figure (figure 2). On this day (and most days), she eats two meals: brunch and dinner.

Interpretation and approach — After examining the available blood glucose readings (table 2), it appears that the main problem with her current level of glycemic control is hyperglycemia before bedtime. However, the CGM data reveal hyperglycemia after brunch as well.

You suggest that the hyperglycemia can be improved by increasing the dose of insulin aspart before her brunch and evening meal. It is also prudent to consider some other aspects of her lifestyle. As an example, she may be snacking after dinner, including close to bedtime. Furthermore, the evening meal may be her biggest and most variable meal of the day. It would therefore be helpful for her to learn carbohydrate counting and to use an insulin-to-carbohydrate ratio when calculating her mealtime insulin aspart doses (see "Nutritional considerations in type 1 diabetes mellitus", section on 'Advanced carbohydrate counting'). Exercise in the afternoon may also be lowering her late afternoon glucose levels.

Her lowest glucose reading before dinner was 72 mg/dL. Overnight, her glucose readings fell to 80 mg/dL (after being hyperglycemic at bedtime). In addition to needing more insulin aspart to cover her meals, lower doses of insulin detemir will be needed to prevent overnight and late afternoon/early evening hypoglycemia.

CASE 3: MORNING HYPERGLYCEMIA — A 24-year-old insurance salesman with type 1 diabetes for two years feels stressed and tired at work and has early morning headaches. His glycated hemoglobin (A1C) value is 9.6 percent. Until fairly recently, he thought that his diabetes was well controlled. His current regimen is:

●Before breakfast – 6 units regular insulin and 28 units NPH insulin

●Before evening meal – 4 units regular insulin and 16 units NPH insulin

Blood glucose values are as shown in the table (table 3).

Interpretation and approach — The increasing difficulty in maintaining glycemic control in this patient with recent-onset diabetes is probably due in part to a progressive decline in endogenous insulin secretion. In addition, his insulin regimen is not ideal, as he is taking too little regular insulin, and he is taking NPH insulin too early in the evening. As an example, his high blood glucose values at 1:30 PM suggest that he needs to take regular insulin before lunch.

The triad of reasonable blood glucose values before bedtime, very high fasting values before breakfast, and a history of tiredness and early morning headache suggest a problem with the NPH insulin dose that he is taking before his evening meal. The action of the NPH insulin may be maximal in the late evening and middle of the night (causing both normoglycemia at bedtime and nocturnal hypoglycemia) and then dissipating in the early morning (causing hyperglycemia before breakfast). The presence of nocturnal hypoglycemia followed by early morning hyperglycemia (or hypoglycemia) can be confirmed by measuring blood glucose at 3 AM or by using continuous glucose monitoring (CGM).

One solution is to move his evening dose of NPH insulin from before the evening meal to before bedtime. In addition, both of his NPH insulin doses are likely to be too high. When using NPH insulin at night, a bedtime snack may be needed to prevent hypoglycemia during the night. When using NPH and regular insulins in the morning, a mid-morning snack may be needed. These snacks can contribute to weight gain.

Another approach would be to switch from NPH insulin to a basal insulin with a longer, flatter profile (such as insulin glargine or degludec), and to change from regular insulin to a rapid-acting insulin analog to control mealtime glycemic excursions and to use for correction of hyperglycemia. (See "Management of blood glucose in adults with type 1 diabetes mellitus", section on 'Multiple daily injections'.)

A review of his exercise patterns in the evening may also be helpful. Vigorous evening exercise makes it more likely that his blood glucose concentration will fall to low values during the night. (See "Cases illustrating the effects of exercise in intensive insulin therapy for type 1 diabetes mellitus".)

The following changes in his insulin regimen lead to marked improvement in his glycemic control:

●8 units insulin glulisine and 30 units U-300 insulin glargine before breakfast

●6 units glulisine before lunch

●8 units glulisine before the evening meal

Three months later, his blood glucose values are as shown in the table (table 4).

His A1C value is now 7.8 percent. He has more energy, the headaches are gone, he is eating and exercising consistently, and has just been promoted because of his improved productivity. To reduce his A1C value further (goal is below 7 percent), he should be taught carbohydrate counting so that he can use an insulin-to-carbohydrate ratio. If this is not possible, a pre-meal insulin algorithm should be provided. The use of CGM may also be helpful. (See 'Case 1: Glycemic variability due to diet' above and "Management of blood glucose in adults with type 1 diabetes mellitus", section on 'Designing an MDI insulin regimen' and "Management of blood glucose in adults with type 1 diabetes mellitus", section on 'Follow-up'.)

CASE 4: UNPREDICTABLE GLUCOSE PATTERN — A 19-year-old college freshman has had type 1 diabetes since age 9. His A1C in his senior year of high school was 7.5 percent, but the most recent one was 9.4 percent. He is taking a full course load, is getting decent grades, and is involved in lots of intramural sports, drama, and campus politics. He takes 32 units of insulin U-100 glargine in the morning, plus 4 to 8 units of lispro insulin before his meals. He is frustrated with his blood glucose values, which are shown in the table (table 5).

Interpretation and approach — Despite testing his blood glucose at least five times daily, there is no discernable pattern. In this situation, it is important to take a more detailed history of exactly what his day-to-day life is like and exactly how and where he is giving his insulin injections. Some days he is up at 7 AM, and on other days he does not get up until 1 PM. The timing of his "morning" dose of insulin glargine therefore varies by six hours from day to day. He has been rotating his glargine and lispro shots from his arm, leg, buttock, or abdomen just like he was told to do when he was first diagnosed at age 9. One day he went for a three-hour bike ride just after giving his morning glargine insulin in his thigh. He was severely hypoglycemic two hours into the ride. He sometimes forgets to check his blood glucose or take his lispro before he eats so then takes a dose of lispro immediately after the meal based on how much carbohydrate he thinks he just ate. He then checks his blood glucose one to two hours later and gives himself a "correction dose" of lispro at that time if his blood glucose is too high.

Unpredictable blood glucose patterns commonly indicate variability in eating, exercise, timing of insulin administration, and/or physical or emotional stress. You can attempt to help the patient reduce sources of variability:

●Help him find a consistent time of day to give his glargine insulin in the afternoon or evening so that it is given at more or less the same time every day.

●Help him come up with strategies to remind him to check his blood glucose levels before his meals and to take the dose of lispro insulin based on the blood glucose and the estimated amount of carbohydrate he is about to eat.

●Ask him not to exercise a leg or arm within two hours of giving an insulin injection into that limb.

●Try giving the glargine insulin in the buttock or thigh and lispro into the abdomen.

●Try changing the basal insulin from glargine to insulin degludec or U-300 insulin glargine.

U-300 insulin glargine has a longer duration of action than U-100 glargine. Insulin degludec has the longest duration of action of the available basal insulins, and it might better suit his lifestyle, especially his inability to take his basal insulin at the exact same time each day. Alternatively, insulin pump therapy can be considered, but even with insulin pump therapy, he will need to bolus appropriately for meals.

He may also do better when using a continuous glucose monitor (CGM). Use of a CGM can show him in close to real time what his blood glucose levels are doing, alarm for hypoglycemia and hyperglycemia, and help him make better self-management decisions. (See "Glucose monitoring in the ambulatory management of nonpregnant adults with diabetes mellitus", section on 'Benefits of CGM'.)

CASE 5: SOME CONSISTENCY IN GLUCOSE PATTERN — A 32-year-old executive has a busy office job that is unpredictable in terms of physical activity, time of meals, and/or the length of the workday. Her current insulin regimen is:

●Before breakfast – 4 units regular insulin and 10 units NPH insulin

●Before evening meal – 8 units regular insulin and 14 units NPH insulin

Her blood glucose records for one week are shown in the table (table 6).

Interpretation and approach — Evaluation of the records can be best approached by considering each time period separately:

●Before breakfast – Her average blood glucose value before breakfast is too high at 181 mg/dL (10.1 mmol/L). The individual values are also fairly consistent (from 147 to 191 mg/dL [8.2 to 10.6 mmol/L]), apart from one high value (246 mg/dL [13.7 mmol/L]) on day 5, which can probably be explained by her late-night pizza the preceding day.

Although she could slowly increase her NPH insulin dose before the evening meal, this would be dangerous since this is the insulin that is working during the night, and the two 3 AM values are in the normal/low normal range. Increasing her evening NPH insulin dose will increase the risk of nocturnal hypoglycemia. This risk can be reduced by having her take her evening dose of NPH insulin at bedtime, instead of before the evening meal, and increasing the dose in small increments while continuing to measure blood glucose both at 3 AM and before breakfast. Another approach is to switch her basal insulin to insulin detemir, insulin glargine, or insulin degludec. Alternatively, insulin pump therapy can be initiated.

●Before lunch – Her before-lunch blood glucose values are consistent and average 106 mg/dL (5.9 mmol/L). This is very good control, suggesting that her morning dose of regular insulin and her breakfast and mid-morning snacks are appropriate and consistent from day to day and that her exercise and work schedule for the morning are relatively constant. However, she may be in danger of hypoglycemia before lunch once her before-breakfast glucose values are lowered as recommended above. It might therefore be wise to slightly decrease her morning regular insulin dose as the bedtime NPH insulin dose is increased.

●Before evening meal – Her before evening meal blood glucose values are too low, with an average value of 78 mg/dL (4.3 mmol/L) and three hypoglycemic episodes during the week. These findings suggest that she may be taking too much NPH insulin before breakfast, since this is the insulin that is acting during the afternoon. Other possible explanations might be that she goes to the gym in the afternoon, her lunch is too early or too light, or that she does not eat an adequate mid-afternoon snack. Since she does not want to eat more because she does not want to gain weight, reducing her morning NPH insulin dose is recommended. Alternatively, as suggested above, changing her basal insulin preparation or switching to insulin pump therapy could be considered.

●Before bedtime – Her before bedtime blood glucose values average 138 mg/dL (7.7 mmol/L). While this average is close to ideal, the individual values vary widely from 57 to 301 mg/dL (3.2 to 16.7 mmol/L). This suggests that some variable aspect of her lifestyle is creating the fluctuations in the bedtime glucose values. Possible problems include variation in the time or content of her evening meal or snacks, or in evening exercise. As an example, the blood glucose value of 301 mg/dL (16.7 mmol/L) before bedtime on day 2 may have resulted from dietary overcompensation for her hypoglycemic episode before the evening meal.

Reducing the pre-dinner regular insulin dose when planning to engage in evening exercise (and increasing the pre-dinner regular insulin when eating higher carbohydrate/fat meals such as pizza) are recommended. Use of a mealtime insulin-to-carbohydrate ratio and insulin sensitivity (correction) factor would also be helpful. If correction is needed near bedtime, dosing should be conservative to avoid nocturnal hypoglycemia.

In summary, the record-keeping is excellent. Nevertheless, it is not sufficient to permit complete assessment of her problems before the evening meal and before bedtime. It would be helpful to know the exact times when her blood glucose is measured, exactly when she is physically active, and when she eats and the content of each meal. Use of a continuous glucose monitor (CGM) would provide a more complete picture of her glycemic excursions and permit her to use glucose trends to better self-manage her diabetes. (See "Glucose monitoring in the ambulatory management of nonpregnant adults with diabetes mellitus".)

CASE 6: LATE AFTERNOON HYPOGLYCEMIA — A 42-year-old garage mechanic is treated with the following insulin regimen:

●Before breakfast – 8 units insulin lispro and 16 units insulin glargine

●Before lunch – 4 units lispro

●Before evening meal – 10 units lispro and 22 units glargine

He uses an algorithm (table 7) to adjust pre-meal doses of lispro insulin. Blood glucose values for one week are shown in the table (table 8).

Interpretation and approach — The blood glucose record is quite complete, but there is no information about the quantity of food eaten and periods of exercise. He is consistent about the timing of blood glucose testing and meals and has adjusted his insulin doses correctly using the algorithm. His blood glucose was measured between 7:05 and 7:15 AM every day, except for day 7 when he slept late and the test was done at 9:55 AM. Several patterns can be detected:

●On day 7, the fasting blood glucose was 158 mg/dL (8.8 mmol/L). According to the algorithm, he should have increased the dose of lispro insulin by 2 units (for a total dose of 10 units lispro). He did not do this, and it turned out to be the correct decision since his pre-lunch glucose reading was at target.

●On day 1, when his fasting glucose was 100 mg/dL (5.6 mmol/L), he took the same dose of lispro as on day 7 and was hyperglycemic before lunch.

●This suggests that either the carbohydrate content of breakfast varies on different days, or that hyperglycemia before lunch is related to eating a mid-late morning snack. He would benefit from either using an insulin-to-carbohydrate ratio (preferred), or an algorithm that contains a different amount of insulin for small, medium, and large carbohydrate meals.

●His average blood glucose value is too low (83 mg/dL [4.6 mmol/L]) before the evening meal, with hypoglycemia occurring on days 2 and 4. On these days, he increased his pre-lunch insulin lispro dose per the algorithm. This suggests that the algorithm is too aggressive (gives too much "correction" insulin) for the mid-day meal. Additional possible explanations include a morning dose of insulin glargine that is too high, a lunchtime dose of lispro insulin that needs to be adjusted for the carbohydrate content of the meal, or engaging in exercise in the afternoon.

CASE 7: USE OF HYBRID CLOSED-LOOP SYSTEM — A 42-year-old man with type 1 diabetes since age 20 has been using an insulin pump for the past 19 years. His basal rate is 1.15 units/hour from 6 AM to 2 AM and 1.5 units/hour from 2 AM to 6 AM. He uses an insulin-to-carbohydrate ratio of 1:7.5 for breakfast and lunch and 1:7 for dinner. His insulin sensitivity factor (correction factor) is 45. After beginning a hybrid closed-loop system (hybrid artificial pancreas) in the automatic ("Auto") mode, his glucose readings are as shown in the figure in period "B" (figure 3). (See "Management of blood glucose in adults with type 1 diabetes mellitus".)

Interpretation and approach — During period "B," he consistently is hyperglycemic after lunch whereas evening readings are variable (figure 3). He is advised to change his insulin-to-carbohydrate ratio to 1:7 (from 1:7.5) for lunch, resulting in slightly more insulin coverage, and he reviewed his carbohydrate counting skills with a registered dietitian. In addition, he should take mealtime insulin boluses before he starts to eat the meal. When using Auto mode, if the mealtime bolus is taken after starting to eat (after the glucose levels start to rise), the automatic feature will give more basal insulin in response to the rising glucose concentrations, resulting in more insulin on board and a higher risk of hypoglycemia after the meal.

After making these changes, his time in range improved from 56 to 72 percent (period "A" in the figure) (figure 3). The greatest variability remains in the late afternoon and evening, when his physical activity and the composition of meals are the most unpredictable. Cases illustrating approaches to the management of exercise with intensive insulin therapy are discussed separately. (See "Cases illustrating the effects of exercise in intensive insulin therapy for type 1 diabetes mellitus".)

CASE 8: EVENING HYPERGLYCEMIA — A 34-year-old teacher is striving for excellent glycemic control. He eats a healthy diet, counts carbohydrates, exercises at a consistent time each day, and has been taking the following regimen:

●Before breakfast (6 AM) – 4 units insulin aspart

●Before lunch – 4 units insulin aspart

●Before evening meal (6 PM) – 6 units insulin aspart

●Before bedtime (10 PM) – 28 units insulin glargine

Doses of insulin aspart are also adjusted using an insulin algorithm.

Typical blood glucose concentrations are shown in the table (table 9).

Interpretation and approach — Blood glucose values are ideal before breakfast and lunch, but are somewhat high before the evening meal and are much too high before bedtime. It is likely that the effect of the insulin glargine is waning after 20 hours. He could try splitting the insulin glargine dose into two equal doses taken approximately 12 hours apart. Alternatively, if he wants to take only one injection of basal insulin daily, he could change from U-100 insulin glargine to the longer-acting insulin degludec or U-300 insulin glargine. He may also require a higher dose of insulin aspart before lunch and likely requires a higher dose of insulin aspart before the evening meal.

CASE 9: SWITCHING FROM NPH INSULIN TO INSULIN DETEMIR — A 33-year-old man with type 1 diabetes is treated with the following regimen:

●Before breakfast – 28 units NPH insulin

●Before bedtime – 12 units NPH insulin

He also administers insulin aspart by an algorithm before each meal.

Despite being extremely consistent from day-to-day in his activity level and in the timing and carbohydrate content of his meals, he is having unpredictable swings in blood glucose concentrations with occasional episodes of hypoglycemia in the late morning or early afternoon.

Blood glucose values are shown in the table (table 10). In order to change from NPH to insulin detemir, his total daily dose of NPH is calculated (28 + 12 = 40), decreased by 10 percent (4 units), and is given as a single injection of 36 units of detemir insulin at bedtime.

One week later, his blood glucose values are as shown in the table (table 11).

Interpretation and approach — The episode of hypoglycemia at 4 AM suggests that 36 units of insulin detemir at bedtime is too much for him. The blood glucose values before lunch are ideal, but they are too high before dinner and even higher before bedtime. This suggests that insulin detemir is not lasting 24 hours. After switching to 20 units insulin detemir twice daily (at approximately 8 AM and 8 PM), his blood glucose values became stable throughout the day.

While many individuals with type 2 diabetes do well with a single dose of insulin detemir at bedtime, this case illustrates two practical points. Although its peak action is less than that of NPH insulin, it can have a slight peak in some patients, which may result in hypoglycemia during the night (figure 4). Importantly, most individuals with type 1 diabetes require two daily injections of detemir to provide 24-hour basal insulin coverage.

CASE 10: HYPERGLYCEMIA RELATED TO FEAR OF HYPOGLYCEMIA — A 57-year-old woman who lives alone has had type 1 diabetes for 41 years. She has hypoglycemia unawareness, a history of severe hypoglycemia (including automobile accidents in the past), and a fear of hypoglycemia. Her diabetes is also complicated by nephropathy, neuropathy, nonproliferative retinopathy, and hypothyroidism. She takes insulin glargine 32 units each morning. Her insulin-to-carbohydrate ratio is 1:10 and insulin sensitivity (correction) factor is 45 with a target glucose of 120 mg/dL (6.7 mmol/L), but she usually takes less insulin aspart than prescribed because of fear of hypoglycemia (on average, 12 units of insulin aspart daily).

Over the past year, her A1C range has been 7.3 to 7.6 percent, most recently 7.3 percent. Her weight is 258 lbs (117 kg) and body mass index (BMI) 42.5 kg/m². She recently started using a continuous glucose monitoring (CGM) device, which was downloaded at this visit (figure 5). Her time in target range is only 46.3 percent, and she has wide glycemic excursions. Her high glucose variability is also reflected by the high coefficient of variation (38.1 percent).

Interpretation and approach — This patient is taking too much basal insulin (glargine) in the morning and not enough mealtime insulin, especially with her evening meal. The afternoon hypoglycemia is related to her morning insulin glargine dose. It is also likely that the glucose-lowering effects of her insulin glargine are waning overnight, contributing to nocturnal hyperglycemia. She would benefit from splitting her glargine dose to twice daily. She was reluctant to change her insulin regimen due to her fear of nocturnal hypoglycemia, but she agreed to change her insulin glargine to 18 units each morning and 12 units each evening. These changes were agreed upon using shared decision-making. She was also encouraged to take more insulin aspart, using her insulin-to-carbohydrate ratio for evening meals and to reduce her nighttime snacks.

ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledge David McCulloch, MD, who contributed to earlier versions of this topic review.