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The Management of Type 1 Diabetes

Page history last edited by Robert Rushakoff, MD 11 years, 2 months ago

 

The Web diabetesmanager

 

 

The Management of Type 1 Diabetes

 

Irl B Hirsch, MD

Jay S Skyler, MD

 

The discovery of insulin in 1921 was one of the greatest medical breakthroughs in history. Individuals, mostly children with type 1 diabetes, whose life expectancies were measured in months were now able to prevent fatal ketoacidosis by taking injections of crude “soluble” (later known as regular) insulin. Of course, new problems were soon noted. Hypoglycemia, occasionally life-threatening, was encountered as diabetes monitoring by urine testing for glycosuria was crude at best during those first years after the discovery of insulin. The insulin itself was often impure and varied in potency from lot to lot. Allergic reactions were common and occasionally anaphylaxis would occur. Even more concerning was the appreciation that these patients often succumbed to chronic vascular complications which either dramatically reduced quality of life or resulted in a fatal cardiovascular event.

 

The tools to manage individuals with type 1 diabetes improved over the decades since the discovery of insulin. These initial insulins were all manufactured from bovine or porcine pancreata and production techniques also became more efficient. Insulins with longer durations of action were first introduced in the 1930s, and over time these insulins improved in their purity and consistency of potency. Nevertheless, “standard” animal insulins prior to 1972 contained 80,000 parts per million (8%) impurities, enough to elicit local reactions when injected as well as systemic effects. By way of comparison, all insulins sold in the United States today contain less than 10 parts per million impurities.

 

Major improvements in the tools to manage type 1 diabetes were developed in the late 1970s and early 1980s. First, not only was “purified” insulin introduced, but in 1982 the first insulins of human amino-acid sequence were marketed both by Eli Lilly and Company using a human insulin made by recombinant DNA technology and by Novo A/S using a human insulin made by a semi-synthetic methodology. These insulins were available as short-acting (regular) and longer-acting [Neutral Protamine Hagedorn (NPH), lente, and ultralente] preparations. The other major advance with insulin therapy was delivery by continuous subcutaneous insulin infusion (CSII) pumps. While pumps were initially touted as providing less variable insulin absorption since only regular insulin was used, the use of CSII had a greater impact: both patients and clinicians used this tool to teach themselves how to best use “basal bolus” therapy, a strategy that would become a standard of care after the beginning of the next century with the development of insulin analogues.

 

Better Monitoring Tools

At the same time as the development of human insulin and insulin pumps, improvements in glucose monitoring were introduced. Although there was initial skepticism if home blood glucose monitoring would be accepted by patients with diabetes, history would confirm that this technology would revolutionize diabetes management and allow patients to titrate blood glucose to normal or near-normal levels. While self monitoring of blood glucose (SMBG) allowed immediate evaluation of diabetes management, the introduction of hemoglobin A1c (A1c, or glycated hemoglobin) around the same time was used as a marker of objective longer-term (about 90 days) glucose control. When hemoglobin is exposed to glucose in the bloodstream, the glucose slowly becomes nonenzymatically bound to the hemogobin in a concentration-dependent fashion. The percentage of hemoglobin molecules that are glycated (bound to glucose) indicates what the average blood glucose concentration has been over the life of the cell. Perhaps as importantly, A1c made it possible for researchers to study the effects of long-term glucose control and the development of vascular complications. New students of diabetes may now find it difficult to appreciate that one of the greatest medical controversies between the discovery of insulin and the early 1990s was the relationship between glucose control and diabetes complications. Improved insulins, pumps, SMBG, and A1c finally allowed this question to be properly studied.

 

The Diabetes Control and Complications Trial

([5][6][7][8][9][10][11][12][13][14])

All of the controversy about the impact of glucose control and vascular complications was dramatically answered with the publication of the Diabetes Control and Complications Trial (DCCT) in 1993. The trial showed definitively that stringent blood glucose control could postpone, prevent, or slow the progression of retinal, renal, and neurological complications in individuals with type 1 diabetes. In patients treated with “intensive therapy”—that is, therapy aimed at maintaining blood glucose levels as close to normal as possible—the risk of developing diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy were dramatically reduced compared to conventionally treated patients (figure 1). Moreover, the risk was continuous across the range of A1c – the higher the A1c, the greater the risk (figure 2). Other benefits of intensive diabetes management include improved lipid profiles, reduced risk factors for macrovascular disease, and better maternal and fetal health.

 

Figure 1a. [A] Cumulative incidence and risk reduction of retinopathy (three-step progression) in the primary prevention and secondary intervention cohorts of the Diabetes Control and Complications Trial (DCCT), and overall cumulative incidence and risk reduction for the need for laser photocoagulation.

 

Figure 1b. [B] Cumulative incidence and risk reduction of microalbuminuria, nephropathy, and clinical neuropathy in the DCCT. Adapted from: The Diabetes Control and Complications Trial Research Group: Progression Of Retinopathy With Intensive Versus Conventional Treatment In The Diabetes Control And Complications Trial. Ophthalmology 1995; 102:647-661. The Diabetes Control and Complications Trial Research Group. Effect of intensive therapy on the development and progression of diabetic nephropathy in the Diabetes Control and Complications Trial. Kidney International 1995;47:1703-1720. and The Diabetes Control and Complications Trial Research Group. The effect of intensive diabetes therapy on the development and progression of neuropathy. Annals of Internal Medicine 1995;122:561-568.

 

 

Figure 2. Relationship between microvascular complications and A1c in type 1 diabetes. Stylized relative risks for development of various complications as a function of mean A1c during follow-up in the DCCT. For the purposes of illustration, the relative risk of various complications is set to 1 at A1c of 6%. The lines depict a stylized relationship for risk of: (A) sustained progression of retinopathy (), (B) progression to clinical nephropathy (urinary albumin excretion > 300 mg/24 hrs) (), (C) progression to severe non-proliferative or proliferative retinopathy (), (D) progression to clinical neuropathy (), and (E) progression to microalbuminuria (urinary albumin excretion > 40 mg/24 hrs) (). Adapted from: Skyler JS: Diabetic Complications: Glucose Control Is Important. Endocrinology and Metabolism Clinics of North America 1996; 25:243-254.

 

 

Since the DCCT was completed in 1993, subjects have been followed in an observational study called Epidemiology of Diabetes Interventions and Complications (EDIC). It was soon observed that the impact of this improved diabetes therapy for an average of 6.5 years (maintaining an A1c of approximately 7% with multiple injections or CSII compared to once or twice daily insulin and an A1c of approximately 9%) had long-lasting effects. Termed “metabolic memory”, there continued to be improvements in microvascular complications eight years after the DCCT ended (figure 3). Despite the fact that A1c levels remained about 8% for both groups after the DCCT, there was reduced risk of progression of retinopathy and nephropathy. Moreover, 11 years after the conclusion of the formal DCCT study, with as long as 20 years of total follow-up, there was demonstrated a risk reduction of 57% for nonfatal myocardial infarction, stroke, or death and a risk reduction of 42% for first of any of the predefined cardiovascular disease outcomes (figure 4). That it took this long for sufficient cardiovascular events to accumulate is not surprising since the mean age of DCCT participants at study entry was only 27 years. The conclusions of this are profound since this was the first study to report a reduction of macrovascular disease with glucose control. Furthermore, these data confirmed the need to control blood glucose as meticulously as possible early in the course of the disease.

 

Even more recent observations from the DCCT/EDIC database speak to the tremendous change in the epidemiology of the vascular and neuropathic complications once common in type 1 diabetes[15].  After 30 years of diabetes, those individuals randomized to intensive therapy in the DCCT had a cumulative incidence of retinopathy, nephropathy, and cardiovascular disease of 21%, 9%, and 9% respectively. Furthermore, fewer than 1% became blind, required renal replacement therapy, or had an amputation.

 

 

Figure 3. Cumulative incidence over 8 years of further progression of retinopathy in the former DCCT conventional-therapy and intensive-therapy groups.. Adapted from: The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Effect of intensive therapy on the microvascular complications of type 1 diabetes mellitus. JAMA 2002; 287: 2563-2569.

 

 

Figure 4a. [A] Cumulative incidence of first occurrence of nonfatal myocardial infarction, stroke, or death from cardiovascular disease in the former DCCT conventional-therapy and intensive-therapy groups.

 

 

Figure 4b. [B] Cumulative incidence of the first of any of the predefined cardiovascular disease outcomes in the former DCCT conventional-therapy and intensive-therapy groups. Adapted from: The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 2005; 353:2643-2653.

 
 
 

Current Targets

Current glycemic targets from the American Diabetes Association (ADA) (Table 1) include a target A1c of <7%. However, it should be noted that this recommendation is a general target and the goal for the individual patient is as close to normal as possible (A1c of < 6%) without significant hypoglycemia. Indeed, to obtain an A1c for a group of individuals of 7% one needs to aim for 6% for each individual as not all persons will achieve the stated goal. In fact, the operational goal in the DCCT intensive group was an A1c of < 6.05% while the overall achieved A1c was 7.2%. On the other hand, A1c targets appropriately may be set higher in patients with type 1 diabetes and hypoglycemia unawareness, those with limited life expectancies, in very young children, or those with co-morbid conditions that could be aggravated by hypoglycemia (e.g known cerebrovascular disease and a history of transient ischemic attacks).

 

 

Table 1. Summary of American Diabetes Association Recommendations for Adults with Diabetes

Glycemic control

  1. A1C <7.0%* for patients in general

  2. A1C <6.0% (as close to normal as possible without significant hypoglycemia) for the individual patient

  3. Preprandial capillary plasma glucose 90–130 mg/dl

  4. Peak postprandial capillary plasma glucose (1-2 h after the beginning of the meal) <180 mg/dl

Blood pressure

  1. <130/80 mmHg

Lipids

  1. LDL <100 mg/dl (ideally <70 mg/dl)

  2. Triglycerides <150 mg/dl

  3. HDL >40 mg/dl in men, >50 mg/dl in women

*Referenced to a nondiabetic range of 4.0–6.0% using a DCCT-based assay.

 

 

SMBG is an important tool to reach this target. Currently, the ADA suggests 3 or more home glucose tests each day for patients receiving insulin. However, many patients with type 1 diabetes will require more testing to reach these targets safely, without significant hypoglycemia. Indeed, the ADA also suggests more frequent testing to achieve the postprandial target which is < 180 mg/dL 1 to 2 hours after eating. To safely achieve an A1C level below 7%, most patients require a minimum of 4 to 6 tests daily.

 

It should also be pointed out that specific non-glycemic targets have also been recommended (Table 1). For blood pressure, all patients with diabetes should maintain blood pressures at least below 130/80, and even lower targets should be considered if albuminuria is present. Second, the primary goal for LDL-cholesterol is below 100 mg/dL, and for those over 40 years old statin therapy to achieve an LDL-cholesterol reduction of 30-40% regardless of baseline LDL is recommended. For those with known cardiovascular disease, it is suggested an LDL-cholesterol reduction with a statin to achieve an LDL reduction of 30-40% for all patients but with a primary LDL target of 70 mg/dL.

 

Multiple-Component Insulin Therapy

([16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32])

The introduction of SMBG, insulin analogues, insulin pumps, and more recently continuous glucose monitoring (CGM) has made it possible for people with type 1 diabetes to manage blood glucose more effectively. Whereas the initial goal of therapy after the discovery of insulin was simply avoidance of ketoacidosis, by the 1980s and certainly after the report of the DCCT the new targets were meticulous glycemic control, avoidance of hypoglycemia, and improving the quality and duration of life so that ideally it was similar to those without diabetes. While our tools have dramatically improved patient's ability to control glycemia, large swings in blood glucose and at least some hypoglycemia will still be seen frequently even with normal or near-normal A1C levels.

 

The insulin regimens used in the “intensive therapy” group in the DCCT were the use of multiple daily injections (MDI) or CSII. These regimens, administering regular insulin with meals, at the time were the best mimics of normal insulin secretion. Also called “physiologic insulin replacement”, two types of insulin were provided. The first, “basal” insulin, is the background insulin required to modulate basal hepatic glucose production overnight and between meals. The other, “prandial” (also called “bolus” or simply “meal-time”) insulin replacement, provides enough insulin to dispose of glucose in the muscle after eating. Physiologic insulin regimens with both basal and bolus insulin components provide flexibility not possible with older twice-daily NPH and regular regimens (figure 5). Unfortunately, as we approach two decades after the announcement of the results of the DCCT, many individuals both in the United States and around the world still use the older therapies which make it difficult if not impossible to attain near-normal glycemic control safely in type 1 diabetes. It should be pointed out that once- or twice-daily basal injections are sometimes adequate for newly diagnosed patients with type 1 diabetes or those with latent autoimmune diabetes mellitus of adults (LADA) who are still producing endogenous insulin. [LADA is the term used for a slowly progressive form of type 1 diabetes in adults. These individuals are positive for one of the immune markers of type 1 diabetes such as antibodies to glutamic acid decarboxylase (GAD) or insulin autoantibody 2 (IA-2) and are found to secrete endogenous insulin for several years after their diagnosis]. However, given the inflammatory response seen with postprandial hyperglycemia, although currently speculative it is certainly possible that part of the preservation of c-peptide response seen in the DCCT subjects was due to the more physiological insulin regimen used by the intensive therapy subjects[33]

 

Figure 5. Blood glucose levels over 11 days in a patient with type 1 diabetes receiving twice daily NPH insulin. Note that using the NPH to contribute to both prandial and basal need blood glucose results in extremely variable glycemia. In this study blood glucose measurements were obtained 8 times each day. Adapted from: Lauritzen T, Faber OK, Binder C. Variation in 125I-insulin absorption and blood glucose concentration. Diabetologia 1979;17:291-295

 

 

The main reason the twice daily regimens of NPH and regular are generally ineffective is due the fact the time-action profile of these two standard insulins do not readily allow for the clear separation of basal and prandial insulin action. Due to the overlapping pharmacokinetics and pharmacodynamics of these insulins, in the classic “split-mix” regimen each insulin component has both prandial and basal action rather than clear separation. Although the regular insulin components are nominally responsible for meal glucose disposal after breakfast and dinner, the effective duration of action of the morning regular insulin (approximately 6 to 8 hours) extends through lunch, making it a prandial insulin for that meal as well (figure 6), and letting it serve as a basal insulin between breakfast and lunch. At the same time, the morning NPH insulin, with an effective duration of 10-16 hours, functions as a basal insulin after absorption of breakfast and lunch, but because of its relatively rapid onset, also serves as part of the prandial insulin component at breakfast and as the primary prandial insulin at lunch. Compensating for the inherent variability of this overlapping action requires strict and consistent coordination as to the timing of injections and meals, especially in patients aiming for stringent glycemic control for whom delaying lunch or skipping a mid-morning snack may result in hypoglycemia.

 

Figure 6. These Idealized insulin action curves for morning regular insulin plus NPH insulin demonstrate the problem with these conventional insulins, namely that each insulin has both a prandial component and a basal component, thus neither provides physiologic insulin replacement. B=breakfast; L=lunch.

 

A simpler conceptual approach – preferred by most patients with type 1 diabetes – is to use a distinct prandial insulin for each meal (e.g., regular insulin, insulin lispro, insulin aspart, or insulin glulisine) and a separate basal insulin (e.g., NPH, insulin glargine, or insulin detemir). Although these true basal-prandial regimens require more shots than conventional twice-daily regimens, they are considerably more flexible, allowing greater freedom to skip meals or change mealtimes. Moreover, use of the long-acting basal insulin analogues – insulin glargine or detemir – and the rapid-acting insulin analogues, – insulin lispro, insulin aspart, or insulin glulisine, – facilitates achievement of individual, defined blood glucose targets. Strategies used for attaining that control include changing the timing of insulin injections in relation to meals, changing the portions or content of food to be consumed, or adjusting insulin doses or supplements for premeal hyperglycemia.

 

Types of Insulin

Selecting the appropriate insulin depends largely on the desired time course of insulin action. Table 2 summarizes the pharmacodynamic characteristics—time to onset of action, time of peak action, effective duration of action, and maximum duration of action—of currently available insulins; however, these can vary considerably amongst individuals.

  

Table 2. Currently Available Insulin Preparations

Insulin Preparation

Onset of Action (h)

Peak action (h)

Effective duration of action (h)

Maximum duration (h)

Rapid-acting analogues

Insulin lispro (Humalog)

¼ - ½

½- 1 ¼

3-4

4-6

Insulin aspart (NovoLog)

¼ - ½

½ -1 ¼

3-4

4-6

Insulin glulisine (Apidra)

¼ - ½

½ -1 ¼

3-4

4-6

Short-acting

Regular (soluble)

½ - 1

2-3

3-6

6-8

Intermediate-acting

NPH (isophane)

2-4

6-10

10-16

14-18

Long-acting analogue

Insulin glargine (Lantus)

3-4

8-16

18-20

20-24

Insulin detemir (Levemir)

3-4

6-8 (though relatively flat)

14

up to 20 to 24 

 

 

Insulin products are categorized according to their putative action profiles:

  1. Rapid-acting: insulin lispro, insulin aspart, and insulin glulisine

  2. Short-acting: regular (soluble) insulin

  3. Intermediate-acting: NPH (isophane) insulin

  4. Long-acting: insulin glargine and insulin detemir

A general principle to bear in mind is the longer the time to peak, the broader the peak and the longer the duration of action. Additionally, the breadth of the peak and the duration of action will be extended with increasing dose. Figure 7 should therefore be considered a conceptual representation of insulin action curves.

 

Figure 7. Idealized insulin time-action profiles after subcutaneous injection of insulin aspart, insulin lispro, insulin glulisine, regular insulin, NPH insulin, insulin detemir, and insulin glargine.

 

 

Rapid-Acting Insulin

The rapid acting insulin analogues have an onset of action about 15-30 minutes after injection, with peak action around 30-90 minutes after injection, and have an effective duration of action of 4 to 5 hours when injected subcutaneously because they are rapidly converted from hexameric crystals to insulin monomers after injection resulting in more rapid absorption, something which is not the case with regular insulin. These insulins have been genetically engineered via site-specific mutagenesis of the insulin sequence so that insulin lispro differs from human insulin by inversion of the amino acids lysine and proline at positions 28 and 29 of the insulin B-chain; the substitution of aspartic acid for proline at position 28 of the insulin B-chain for insulin aspart and for insulin glulisine the substitution of lysine for asparagine at position B3 of the insulin B-chain as well as the substitution of glutamic acid for lysine at position 29 of the insulin B-chain. These rapid-acting insulin analogues are most suitable as mealtime prandial insulin injections (figure 8) or in insulin pumps for CSII (figure 9).

  

Figure 8. Idealized insulin curves for morning regular insulin (magenta) and insulins lispro, aspart/, or glulisine (blue). The rapid-acting analogues only provide prandial insulin while regular insulin contributes to both prandial and basal insulinemia. B=breakfast; L=lunch.

 

 

Figure 9. Idealized insulin curves for CSII with either insulin lispro, aspart, or glulisine, with a gray background of physiologic insulin levels seen in healthy individuals. Note the basal insulin component can be altered based on changing basal insulin requirements. Typically, insulin rates need to be lowered between midnight and 0400 h (to prevent the “predawn phenomenon” of “sleep-realted hypoglycemia”) and raised between 0400 h and 0800 h (to prevent the hyperglycemia of the “dawn phenomenon”). The basal rate the rest of the day is usually intermediate to the other two. Modern-day pumps can calculate prandial insulin dose by the patient entering into the pump the blood glucose concentration and the anticipated amount of carbohydrate to be consumed. The pump calculates how much previous prandial insulin is still active, and provides the patient a final suggested dose which the patient may activate or override. B=breakfast; L=lunch; S=supper; HS=bedtime.

 

 

 

Short-Acting Insulin

Regular insulin has an onset of action 30 to 60 minutes after subcutaneous injection, a peak effect around 2 to 3 hours after injection, and an effective duration of action of 6 to 8 hours. Recommended use is for injection to be at least 20 to 30 minutes prior to meals in an attempt to better match insulin action with carbohydrate absorption. In contract to subcutaneous administration, regular insulin acts almost instantly when injected intravenously, with a half-life of approximately 6 minutes.

Intermediate-Acting Insulin

There is retarded absorption of NPH ( or isophane) insulin due to the addition of protamine to regular insulin during its manufacture. The onset of action of NPH insulin occurs about 2 to 4 hours from the time of its subcutaneous injection, with a peak effect around 6 to 10 hours after injection, and an effective duration of action of 10 to 16 hours. NPH is commonly used as a twice-daily basal insulin. NPH insulin comes as a suspension rather than a solution, and must be appropriately handled to assure uniformity of the suspension.

Long-Acting Insulin

The currently available long acting insulin analogues are insulin glargine and insulin detemir, both of which have been re-engineered to create insulins with prolonged biological activity. Insulin glargine differs from human insulin by the substitution of glycine for alanine at position 21 of the insulin A-chain plus the addition of two extra amino acids – both arginines – at the end of the insulin B-chain, extending it from its usual length of 30 amino acids to 32 amino acids. Insulin glargine is soluble at acid pH, and forms a microprecipitate in the subcutaneous tissue which is at neutral pH; this microprecipitate is slowly released with near linear kinetics over a period of 20 to 24 hours in most patients. Insulin detemir differs from human insulin by having the terminal amino acid (threonine) removed from the insulin B-chain (position 30) thus shortening this chain to 29 amino acids; in addition, the epsilon amino group of the now terminal lysine at position 29 is covalently acylated with a 14 carbon fatty acid (myristic acid), which binds to albumin both in subcutaneous tissue and in the circulation and thus prolongs its action.

 

Factors Influencing Insulin Absorption

Variability of insulin absorption is perhaps the greatest obstacle to replicating physiologic insulin secretion. Among the many factors that affect insulin absorption and availability (Table 3) are injection site; the timing, type, or dose of insulin used; and physical activity. Day-to-day intraindividual variation in insulin absorption is approximately 25%, and the variation between individuals may be as high as 50%. One reason for this is that large doses of human insulin form an insulin depot, which can unpredictably prolong duration of action; this is less of an issue with rapid-acting insulin analogues, however. Patients injecting 40 U of NPH insulin into their abdomen before breakfast, for example, may have a markedly different onset and peak of action than the same patients injecting 20 U of NPH in their thigh in the evening; mixing insulin lispro with the morning NPH dose and regular insulin with the evening dose would also lead to further variation, especially if the NPH is not resuspended properly. In general, any strategy that increases the consistency of delivery should decrease glucose fluctuations; and insulin regimens that emphasize shorter-acting insulins are more reproducible in their effects on blood glucose levels.

 

 

Table 3. Factors Affecting the Bioavailability and Absorption Rate of Subcutaneously Injected Insulin

Factor

Effects

Site of injection

Abdominal injection (particularly if above the umbilicus) results in the quickest absorption; arm injection results in quicker absorption than thigh or hip injection.

Depth of injection

Intramuscular injections are absorbed more rapidly than subcutaneous injections.

Insulin concentration

U-40 insulin (40 units per mL) is absorbed more rapid than U-100 insulin (100 units per mL).

Insulin dose

Higher doses have prolonged durations of action compared with lower doses.

Insulin mixing

Regular insulin maintains its potency and time-action profile when it is mixed with NPH insulin; no insulin should be mixed with insulin glargine or insulin detemir

Exercise

Exercising a muscle group before injecting insulin into that area increases the rate of insulin absorption.

Heat application or Massage

Local application of heat or massage after an insulin injection increases the rate of insulin absorption.

Insulin pens are convenient and their use may avert some insulin errors, but insulin cartridges for pens and disposable pens are more costly than insulin in vials. An insulin pump using only a rapid-acting insulin analogue significantly reduces variability. Like multiple-injection regimens, use of an insulin pump requires frequent blood glucose monitoring, as well as a back-up method of insulin administration, and attention to mechanical and injection site issues.

 

Timing of Premeal Injections

Gauging the appropriate interval between preprandial injections and eating, known as the “lag time,” is essential for coordinating insulin availability with glycemic excursions following meals. The timing of the injections should also be adapted to the level of premeal glycemia. Insulin lispro, insulin aspart, and insulin glulisine have rapid onset of action and, ideally, should be given within 10 minutes before mealtime when blood glucose is in the target range; however, provided there is no hyper- or hypoglycemia present, these insulins may be administered at any time from 10 minutes prior to meal consumption to just prior to eating, or even immediately after eating if one is not sure that the planned meal will be consumed (e.g., in finicky eaters, babies, or the elderly). Regular insulin administered subcutaneously is best administered at least 20 to 30 minutes before eating if blood glucose levels are within target, keeping in mind that if the meal is delayed hypoglycemia may ensue. When blood glucose levels are above a patient’s target range, the lag time should be increased to permit the insulin to begin to have an effect sooner so that the hyperglycemia may be partly reduced before meal carbohydrate elevates blood glucose further. In this case, rapid-acting acting insulin analogues can be given perhaps 15 minutes and regular insulin perhaps 30 to 60 minutes before the meal. On the other hand, when premeal blood glucose levels are below target range, administration of regular insulin should be delayed until immediately before eating, and injections of rapid-acting insulin should be postponed until after some carbohydrates have been consumed.

 

It should also be mentioned that patients who test their blood glucose frequently or use real-time continuous glucose monitoring (see below) are best able to gauge best possible lag times by knowing the glycemic trend when the meal is about to be consumed. For example, someone with a blood glucose level of 130 mg/dL but a steep trend upwards would ideally like to use a longer lag time than someone with the same blood glucose but a steep trend downward. It becomes easy to see why frequent SMBG (or continuous monitoring) assists in determining lag times better than simply measuring glucose levels before meals.

 

Role of Insulin Analogues

Most of the problems of insulin replacement in type 1 diabetes arise from the fact that subcutaneous injection or pump infusion remains is a non-physiologic route of administration. From the subcutaneous site of injection, insulin is absorbed into the systemic rather than the hepatic portal circulation. More importantly, as noted, there is considerable variability of absorption of subcutaneous insulin from one injection to another. Insulin analogues in large part overcome this problem.

 

As noted, there are now three rapid-acting insulin analogues: insulin lispro, insulin aspart, and insulin glulisine. All three have a rapid onset of action and peak as noted above, thereby improving 1- to 2-hour postprandial blood glucose control compared with regular insulin. These rapid-acting analogues must be used in conjunction with a basal insulin to improve overall glycemic control (figure 10). Importantly, the rapid-acting analogues have consistently outperformed regular insulin in having less late post-prandial hypoglycemia. This finding should not be surprising since the long duration of regular insulin is much longer than the gut absorption of a typical mixed meal.

 

Figure 10. Idealized insulin curves for prandial insulin with a rapid-acting analogue (insulin aspart, insulin lispro, or insulin glulisine) with basal insulin given as insulin glargine or insulin detemir. Each insulin preparation is responsible for either the prandial or basal component. Many patients find the basal insulins do not last the entire 24 hours and they give the insulin twice daily. B=breakfast; L=lunch; S=supper; HS=bedtime.

 

 

Regarding long acting insulin analogues, clinical trials have demonstrated lower fasting glucose levels and less nocturnal hypoglycemia with insulin glargine than with NPH insulin, advantages that are especially relevant in patients aiming for meticulous control (A1c <7%) or those with hypoglycemia unawareness. Trials with type 1 diabetes have shown similar results with insulin detemir, which, compared with NPH insulin, was equally effective in maintaining glycemic control. In general, hypoglycemia is reduced with both long-acting insulin analogues compared to NPH insulin. Since hypoglycemia is clearly one of the treatment-limiting aspects of type 1 diabetes therapy, the use of these analogues has gained wide-spread acceptance.

Patients with type 1 diabetes derive the greatest therapeutic benefit when basal and prandial analogues are used together, because the physiologic pharmacokinetics and pharmacodynamics of these analogues make separating the basal and prandial components of insulin replacement easier. As a general rule of thumb, about half of the total daily dose of insulin is given as basal insulin, while the other half is given as prandial insulin. The amount of prandial insulin can initially be determined by approximating the percentage of calories consumed at each meal. As patients become more educated, however, they may alter the prandial dose by estimating the carbohydrate component of each meal or snack and taking a unit of insulin for a defined number of grams of carbohydrate (e.g., one unit for each 8, 10, or 12 grams of carbohydrate).

 

Practical Use of Modern-Day Insulin Regimens For Type 1 Diabetes

Multiple Daily Injections (MDI)

In practice with the use of insulin analogues, it is common to find many patients requiring as little as 40% of their insulin requirements as basal insulin. Perhaps the most frequent mistake in the use of insulin therapy is providing the majority of insulin as basal insulin. The reasons for this are multiple, but this evolves over time as patients and clinicians observe hyperglycemia and assume the problem requires more basal insulin.

 

Most patients with type 1 diabetes will require 0.4 to 0.8 units of insulin/kg/day. This may vary based on numerous factors, including family history of type 2 diabetes, lifestyle (sedentary vs. active), adiposity, gender (males usually require more than females), concomitant illness, and any remaining endogenous insulin secretion. For a typical 75 kg man, a usual total daily insulin dose would be between 30 and 60 units/day [calculated as: 0.4 units/kg x 75 kg = 30 units/day to 0.8 units/kg x 75 kg = 60 units/day]. Let’s say that this person is using 0.7 units/kg, this would be 0.7 units/kg x 75 kg = 52 units/day, and thus the usual basal insulin dose would be 40 to 50% of that, or 21 to 26 units.

Both long-acting insulin analogues – insulin glargine and insulin detemir – can be administered once or twice daily. In general, the lower the dose of insulin, the shorter the duration of action. If it is decided to start with once daily basal insulin, it is usually administered at bedtime. That way, basal insulin deficiency late the following day can be compensated by the use of prandial insulin at dinner time. Insulin detemir will often require larger doses of insulin compared to NPH insulin.

 

Titration of basal insulin is generally accomplished by observing glucose trends during periods of fasting. The most common way this is done is observing glucose swings overnight when glycemia is not contaminated by food or prandial insulin. Ideally, glucose levels within target (90-130 mg/dL) at bedtime remain stable until the next morning. To confirm stability, it may be beneficial to measure a middle-of-the night glucose reading. Skipping breakfast to confirm stability through the morning will further allow the ability to review basal insulin effectiveness. However, problems with morning insulin resistance (the dawn phenomenon) or insulin waning, particularly into the afternoon with low doses of basal insulin, convince many patients and their physicians to add a second injection of basal insulin in the morning (or proceed to insulin pump therapy). Most often, if two injections of basal insulin are administered, it is given in two equal doses, but this detail has not been studied. One school of thought (championed by IBH) is that if the basal insulin is given once or twice daily, the timing of the injections should be consistent from day-to-day to minimize variable insulinemia. Another school of thought (championed by JSS) is that with a peakless basal insulin (e.g., insulin glargine) the timing of the two injections is less important, and that having the patient administer half of the basal dose before retiring and the other half upon arising offers substantial convenience and flexibility in lifestyle without either sacrificing glycemic control or creating substantial variability in insulinemia.

 

Practical aspects of prandial insulin include lag times as noted above, and the incorporation of either carbohydrate counting or some mechanism to best match an appropriate dose of insulin with the calorie content of that meal. Typical doses of rapid-acting analogue for type 1 diabetes would be 1 unit per 10 to 15 grams of carbohydrate, but there are many exceptions to this. Obese patients with type 1 diabetes may require as much as 1 unit per 5 grams of carbohydrate while thin insulin sensitive patients may require doses no higher than 1 unit per 20 grams of carbohydrate.

 

Similarly, patients require pre-determined algorithms for premeal hyperglycemia. These “correction doses”, or supplements, are added to the prandial dose. Typical doses of a rapid-acting analogue for the correction dose are 1 unit per 30 to 50 mg/dL, with targets that need to be individualized for each patient. For example, a common scenario would be to have a correction dose of 1 unit per 40 mg/dL above 130 mg/dL. The other term for correction dose is “insulin sensitivity factor”. Thus, if this individual had a premeal glucose of 250 mg/dL, the correction dose would be (250-130)/40 = 3 units. In addition, for this degree of hyperglycemia a greater lag time, typically 20 minutes would be recommended.

 

Perhaps the most important practical advice is the use of between-meal SMBG, particularly if there is premeal hyperglycemia or if the carbohydrate content of the meal is unknown, particularly common when meals are not prepared by the patient or family member. Between-meal hyperglycemia can be treated with additional correction dose insulin. While the ADA suggests a 1 to 2-hour postprandial target of less than 180 mg/dL and the American Association of Clinical Endocrinologists recommends even a more stringent target of 140 mg/dL, in actuality these targets are difficult to achieve unless the carbohydrate content of the meal is quite low and the insulin is matched perfectly. Therefore, to understand how to safely correct between-meal hyperglycemia, the patient needs to appreciate insulin-action times, i.e., the pharmacodynamics of insulin after injection (figure 11). Modern-day insulin pumps do these calculations for the patient, but the MDI patient needs to understand this concept without any assistance from computer software. After injection of a rapid-acting insulin analogue, insulin activity will typically last 5 to 6 hours in adults. Additional insulin injected within this timeframe without taking into consideration how much “insulin-on-board” is available risks “insulin stacking” and hypoglycemia. Therefore, the insulin dose for between-meal hyperglycemia needs to be calculated by the patient by the formula:

 

Figure 11. The appearance of insulin into the blood stream (pharmacokinetic) is different than the measurement of insulin action (pharmacodynamic). This figure is a representation of timing of insulin action for insulin aspart from euglycemic clamp (0.2 U/kg into the abdomen). Using this graph assists patients to avoid “insulin stacking”. For example, 3 hours after administration of 10 units of insulin aspart, one can estimate that there is still 40% of the 10 units, or 4 units of insulin remaining. By way of comparison, the pharmacodynamic duration of action of regular insulin is approximately twice that of insulin aspart or insulin lispro. Currently used insulin pumps keep track of this “insulin-on-board” to avoid insulin stacking. Adapted Mudaliar S, Lindberg FA, Joyce M, Beerdsen P, Strange P, Lin A, Henry RR: Insulin aspart (B28 Asp-insulin): a fast-acting analog of human insulin. Diabetes Care 1999; 22:1501-1506.

 

Total Correction Dose – Insulin-On-Board = Suggested Correction Dose

Patients monitoring frequent between-meal glucose levels often learn quickly that if this concept is not appreciated hypoglycemia will result from overly aggressive insulin dosing from the stacking of the insulin. The fundamental problem with this entire strategy of between-meal adjustments from SMBG data is that even if one knows the amount of insulin-on-board, the direction of the glucose (glycemic trend) is not necessarily appreciated. As an example, a patient with a target of 100 mg/dL, an insulin sensitivity factor of 30 (i.e.. 1 unit for every mg/dL above target [in this case 100 mg/dL] and a blood glucose of 250 mg/dL gave 6 units of insulin aspart 2 hours previously. The patient needs to appreciate that well over 3 units of insulin are still active. However, if the meal happened to be a high carbohydrate, low protein/low fat meal, the glycemic trend two hours later is moving quickly downward, and giving the normal correction dose [(250-100)/30]- 3 = 2 units will likely be too much insulin since the glucose is trending down anyway. Often, the actual glycemic trend is not known, making any correction dose insulin difficult to estimate. This is the main advantage of the use of continuous glucose monitors (CGM). By knowing the glycemic trend, it is possible to much more safely add appropriate doses of correction dose insulin between meals.

 

Practical Use of CSII for Type 1 Diabetes

([34][35][36][37][38][39][40][41][42])

While not a new tool, insulin pump therapy remains the gold standard of insulin delivery for type 1 diabetes (figure 9). CSII is the most precise way to mimic normal insulin secretion because basal rates can be programmed in half-hour segments throughout a 24-hour period. Essentially, the CSII pump may be thought of as a computerized mechanical syringe automatically delivering insulin in physiologic fashion. Patients can accommodate metabolic changes related to eating, exercise, illness, or varying work and travel schedules by modifying insulin availability on an hour-to-hour basis. Basal rates can also be adjusted to match lower insulin demands at night (e.g., between approximately 11 PM and 3 to 4 AM) and higher requirements between 3 to 4 AM and 9 AM. Although hour-to-hour variability is possible, most patients use only 1 to 3 basal rates per day. On the other hand, they may use totally different basal rates on weekends versus weekdays, summer versus winter, or while on vacation.Various studies comparing glycemic control during CSII versus intensive insulin injection regimens have been published. A meta-analysis of 12 randomized controlled trials of CSII versus multiple injection regimens showed a weighted mean difference in blood glucose concentration of 16 mg/dL (95% CI 9-22) and a difference in A1C of 0.5% (95% CI 0.2-0.7) favoring CSII. The slightly but significantly better control in patients on CSII was accomplished with a 14% average reduction in daily insulin dose.

 

Interestingly, a widely perceived disadvantage of CSII—i.e., that it predisposes patients to hypoglycemia—is one of the most common misconceptions about its use. In fact, a large body of evidence suggests that hypoglycemia is significantly less common in CSII than injection therapy, even when the injection regimen is not intensive.

Modern insulin pumps are much smaller and easier to use than the pumps of a decade ago. Most weigh around 115 grams (4 oz), and are approximately the size of a small cellular phone (figure 12). Each houses an insulin-filled cartridge or syringe connected to a 23- to 24-inch, 31-inch, or 42- 43-inch length of plastic tubing. At the end of the tubing is a 25- or 27-gauge needle or a soft Teflon cannula that can be inserted into the subcutaneous tissue at a 30- to 45- or 90-degree angle, depending on the type of infusion set used. The abdomen is the preferred infusion site because placement of the catheter there is convenient and comfortable and insulin absorption is most consistent in this region. However, the upper outer quadrant of the buttocks, upper thighs, and triceps fat pad of the arms may also be used.

 

Figure 12. Examples of four modern-day insulin pumps. Upper left is the Medtronic MiniMed Paradigm 722 pump; upper right is the Animas Ping insulin pump; lower left is the Insulet Omnipod insulin pump; – the insulin delivery piece (right) is disposable and operated by the controller (left); the lower right is the Roche Spirit. 

 

 

 

 

 

 

Many infusion sets allow removal of the insertion needle, leaving only the soft cannula in place subcutaneously (figure 13). Early adapters of CSII were required to use straight or bent needles but those for the most part have disappeared. After the syringe is placed in the pump, a lever mechanically pushes down the plunger of the syringe, and the insulin travels through the infusion tube, entering the subcutaneous tissue through the soft, flexible catheter. In current models, infusion lines have a “quick-release” mechanism, allowing the pump to be temporarily disconnected from the tubing going to the insertion site. This quick-release feature makes dressing, swimming, showering, and other activities more convenient. A newer version of CSII involves a disposable “pod” which is discarded every three days (figure 12). The insulin is infused directly from the pod through a catheter without the use of any tubing. Both basal and bolus insulin dosing is communicated to the pod though radio frequency via a separate “personal diabetes manager”. It is clear that choices of CSII continue to grow for patients with type 1 diabetes.

Figure 13. Examples of modern-day insulin pump infusion sets.

 

With the introduction of rapid-acting analogues, there is no reason to use regular insulin with CSII. Indeed, all three rapid-acting analogues are approved in the United States for use in insulin pumps. The basal rate of the insulin pump provides continuous delivery of microliter amounts of insulin thus providing basal insulinemia and replacing the need for separate basal insulin such as NPH insulin, insulin glargine, or insulin detemir. The boluses activated before each meal ideally provide the incremental prandial insulin, just as would be done with separate subcutaneous injections of insulin lispro, insulin aspart, or insulin glulisine. Although this is generally an improvement compared to regular insulin, in fact the pharmacodynamics of the rapid-acting analogues (table 2), particularly when used with a low-fat/low protein-containing meal has resulted in a new research goal for finding an even faster-acting mealtime insulin. For many patients, the real advantages of pump therapy is that it allows programming of many different basal infusion rates (usually ranging from 0.4 to 2.0 units/hour) to meet non-prandial insulin requirements, though it is unlikely that the average patient will require more than 3 different rates. As with MDI, correction doses can be provided before or between meals.

 

However, there are many fundamental differences between CSII and MDI. First, as noted above, the basal dose can be titrated for each individual throughout the day. There are various recommendations for how to best do this, but we prefer to perform “basal checks”. This is accomplished on a night the patient has a bedtime glucose level within target (e.g., 90 to 130 mg/dL). The patient then measures at least one but preferably two glucose levels throughout the night. The next morning breakfast is skipped and glucose is measured every hour, if possible until early afternoon. If hypoglycemia occurs at any time during this time period, food is consumed and the experiment is completed. An insulin adjustment can then be made. Alternatively, if glucose levels tend to rise at any time during this period, basal rates need to be increased. It is important to appreciate the insulin action times with basal rates, just as with correction doses noted above. For example, if glucose levels are found to increase around 5 AM, it would be appropriate to increase the basal dose around 4 AM. For many patients, even earlier changes in basal rates will be required.

 

Another major difference between CSII and MDI is that most current pumps can accurately track the insulin-on-board for safer use of correction doses (figure 11). As noted above, doing this accurately can have a major impact in preventing insulin stacking. Modern-day pumps also calculate insulin required based on carbohydrates anticipated to be consumed. The other piece of information included in the insulin dose calculation by the pump is the fingerstick blood glucose measurement at the time. So the seemingly complicated mathematics to best utilize MDI are done automatically with CSII.  Finally, pumps can be programmed for individual boluses to be administered over an extended period of time (“extended” or “square wave” bolus). This feature may be particularly helpful for very high-fat meals, or those patients with delayed gastric emptying, seen with gastroparesis or those receiving pramlintide (see below). It needs to be emphasized that as the technology for continuous glucose monitoring improves, insulin dosing decisions can be made with more certainty.

 

From a practical point of view, the first and most important insulin dose to provide in a correct amount is the basal rate. If the basal dose is set incorrectly, neither the bolus doses nor the correction doses will be appropriate. The most common mistake we see (as with MDI) is the basal dose set too high, making even small correction doses cause hypoglycemia. The greatest advantage of CSII is it allows more flexibility and titration of the basal doses. The other major advantage of CSII is it allows the use of “temporary basal rates”, i.e., an insulin dose increase (such as during intercurrent illness) or an insulin dose decrease (such as during exercise) for a specific period of time. Again, due to the time action of the rapid-acting analogues, sufficient time must be incorporated when using a temporary basal rate. For example, we find that for exercise, the insulin rate must be decreased one to two hours prior to the activity.

 

There are several risks with CSII. The first is an abrupt stoppage of insulin delivery either from an occlusion or dislodging of the catheter. For most patients who measure glucose levels at least 4 times daily (or use continuous glucose monitoring) the problem can be discovered and rectified quickly. However, for the occasional patient who tests infrequently or misses several glucose tests the discontinuation of the insulin infusion can result in ketoacidosis. Fortunately, this is rare. When glucose levels are found to be elevated for no apparent reason, it is appropriate to bolus the appropriate correction dose and if after 1 to 2 hours glucose levels are not improved, a separate subcutaneous injection of a rapid-acting insulin analogue is recommended; the pump infusion site also should be changed.

 

Another potential complication is infection, sometimes even abscess formation, at the infusion site. This is also rare and can be minimized by meticulously cleaning the pump site prior to catheter or needle insertion. Although not as severe, inflammation at pump sites can be problematic. This can be minimized by changing the infusion set every 24 to 72 hours and rotating pump sites. Similarly, some patients develop lipohypertrophy from repetitively infusing the insulin in the same area. This can result in extreme variability in insulin absorption. Again, frequent rotation of pump sites can alleviate this problem which is under-reported. Clinicians should therefore make site observation part of every clinic visit.

 

Pramlintide 

[43][44][45][46][47][48])

In 2005 pramlintide was approved for use in type 1 diabetes. This agent is an analogue of the hormone amylin, a peptide normally co-secreted with insulin. The primary function of amylin is to reduce postprandial hyperglycemia and this is accomplished by three mechanisms: a reduction of mealtime glucagon secretion, a delay of gastric emptying, and a primary effect to reduce satiety. This latter effect is likely related to the fact that amylin receptors have been found in the brain, thus also classifying the peptide as a “neurohormone”. Although the pharmacokinetics and pharmacodynamics of pramlintide are similar to human amylin (the half-life is about 48 minutes with an effect on blood glucose lasting about 3 hours), pramlintide the analogue does not aggregate, form insoluble particles, or adhere to surfaces, as does preparations of amylin itself. Mean A1c reductions of about 0.5-0.7% have been noted in clinical trials.

 

Pramlintide is injected just prior to meals at an initial dose of 15 mcg per meal and increased as tolerated every three days to a final dose of 60 mcg per meal. It is now available in a pen and it is important to note there are two different pens available: one developed specifically for type 1 diabetes where doses can be given in 15 mcg increments up to a dose of 60 mcg, and a pen for type 2 diabetes with 60 mcg and 120 mcg doses. It is recommended the drug be administered only prior to major meals consisting of 250 calories or 30 grams of carbohydrate. Prandial insulin doses both for those receiving their insulin as MDI or CSII need to be reduced due to a reduction of food intake and the delay in gastric emptying. For those receiving insulin via a pump, most clinicians have found using an “extended bolus” (see above) works best to avoid postprandial hypoglycemia. For those using MDI, some patients administer their insulin just prior to eating (without a lag time) or after eating. Others have found smoother postprandial glycemia using preprandial regular insulin in place of a rapid-acting analogue. Although the package insert suggests reducing the dose by 50%, many have found this too large of a reduction for those receiving appropriate basal insulin and a 25% reduction works well for most. Alternatively, the initial insulin dose reduction might be 25%, increasing to 40 or 50% reduction as the pramlintide dose increases from 15 mcg to 60 mcg before each meal. Due to the mechanism of action of pramlintide noted above, weight loss is common and mean weight loss after 6 months of 1 to 2 kg is the norm. However, this effect is quite variable and weight losses of 5 to 10 kg have been reported.

 

The major side effect of pramlintide is nausea, or more accurately, a post-prandial feeling of abdominal fullness. In the registration studies, where nausea was routinely questioned for, some nausea was noted in 30 to 40% of patients. The nausea is most often mild and self-limited. The most important practical point is that if nausea occurs one should not titrate the dose upwards until the nausea resolves. Some patients require extremely slow titration, no more than 6 mcg dose increments per week (1 unit on an insulin syringe).

 

Severe hypoglycemia has also been noted with the use of pramlintide. In the open-label clinical trials with prandial insulin reduction, severe hypoglycemia was reported in 2.3% and 0.9% of patients in the first three and subsequent three months respectively. However, this can be minimized by ensuring proper basal insulin dosing (both CSII and MDI) prior to initiation. Frequent post-meal glucose testing will also reduce the frequency of post-meal hypoglycemia.

 

Continuous Glucose Monitoring

([49][50][51][52][53][54])

Perhaps the most innovative technology for the treatment of type 1 diabetes is the introduction of real-time continuous glucose sensors introduced in 2006 (figure 13). Retrospective 72-hour continuous glucose monitors (CGM) have been available since 1999. Both real-time and retrospective sensors measure interstitial fluid (ISF) glucose with glucose oxidase. A current is generated which is then transmitted to a receiver as a glucose measurement, which is in essence a mean ISF glucose value over the previous few minutes. Due to the time it takes to measure the glucose, there is a lag in the glucose reading when comparing blood glucose and CGM values. This is particularly relevant when glucose levels are trending up or down quickly. Due to this, these initial devices are labeled for use as adjunctive therapy with routine SMBG. Patients can customize alarms to activate for hypoglycemia or hyperglycemia. Understanding the trend allows patients to use another parameter to increase or decrease the mealtime insulin dose. It also allows patients to intercept hypoglycemia (or hyperglycemia) prior to its occurrence. As noted in figure 13, one sensor is integrated with an insulin pump (a “sensor-augmented pump”) so that the pump and receiver is the same device. Even after short periods of time, many patients can learn how to best use this technology to improve both mean glucose and glycemic variability (figure 14).

 

Figure 13. Examples of real-time continuous glucose monitoring systems. Left: the Medtronic MiniMed Sensor Augmented Pump (top shows patient wearing it, bottom shows schematic of concept). Center: the DexCom STS continuous glucose sensor (top shows patient wearing it, bottom shows receiver). Right: Abbott Diabetes Care Navigator continuous glucose sensor (top shows patient wearing it, bottom shows receiver).

 

 

Figure 14. Example of a download from a patient using a sensor-augmented pump showing (upper) first week on device and (lower) improved control during second week on the device.

 

 

It would be a mistake to consider these first-generation glucose sensors as a final chapter in the improvements in technology of type 1 diabetes. Rather, this is actually a beginning of much more sophisticated technology which should in the future lead to a true artificial pancreas.

 

Conclusions

No disease has had such an evolution of therapy in the past 80 years as type 1 diabetes. From certain death to the discovery of insulin, from impure animal insulin preparations to purified human insulins, from once daily long-acting insulin to CSII, from urine glucose testing to real-time continuous glucose sensors, treatments continue to emerge that improve the lives of people with type 1 diabetes. Our current challenges remain teaching the providers how to best use these new tools, directing our medical systems to allow us to best utilize these therapies, and perhaps most importantly, transferring these new technologies to the patients who can best apply them. Although the future is exciting, we need to first master the use of our current tools before we can successfully move forward. Hopefully, in the near future the successful management of type 1 diabetes will become a reality for all with this disease.

 

 

 

Footnotes

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