General principles of insulin therapy in diabetes mellitus

INTRODUCTION — Insulin is used in the treatment of patients

with diabetes of all types. The need for insulin depends upon the balance between :

o insulin secretion ando insulin resistance

All patients with type 1 diabetes need insulin treatment permanently, unless they receive an islet or whole organ pancreas transplant

many patients with type 2 diabetes will require insulin as their beta cell function declines over time

WHICH PATIENTS NEED INSULIN —

o all patients with type 1 diabeteso patients with secondary diabetes due to pancreatic

insufficiencyo many patients with type 2 diabetes to manage hyperglycemia

The peak incidence of type 1 diabetes is around the time of puberty, but about 25 percent of cases present after 35 years of age [1]

Clinical features which, if present in a patient with diabetes at any age, suggest the need for insulin therapy include :

o marked and otherwise unexplained recent weight loss (irrespective of the initial weight),

o a short history with severe symptoms, and o the presence of moderate to heavy ketonuria

Diabetic ketoacidosis at first presentation usually indicates that the patient has type 1 diabetes and will require lifelong insulin treatment.

However, some patients with type 2 diabetes, especially in the Afro-Caribbean populations (so-called "Flatbush diabetes"), may present with ketoacidosis [2] .

A more difficult question is when to use insulin in patients with type 2 diabetes.

This disorder is characterized by both :

o insulin resistance and o relative insulin deficiency

Therapy should begin with diet, weight reduction, and exercise, which can frequently induce normoglycemia if compliance is optimal.

Patients with persistent hyperglycemia are often started on one or more oral hypoglycemic drugs.

Metformin is a good early choice, based on its safety profile, neutral effect with regard to weight gain, and ability to lower glycemia.

Insulin is added if goal glycemic control is not attained.

Initiation of insulin therapy, however, is often unnecessarily delayed, owing to physician or patient reluctance and other factors, thus exposing patients to the physiological consequences of prolonged hyperglycemia.

Patient preconceptions about use of insulin need to be addressed [3] . Patients should be made aware that initiating insulin does not represent a personal "failure" and that most patients with type 2 diabetes will eventually require exogenous insulin, due to decline in endogenous insulin production.

INSULIN PREPARATIONS

Standard preparations —

divided into two basic categories:

Intermediate- to long-acting preparations

(NPH, neutral protamine lispro [NPL], detemir, or glargine)

are typically administered once or twice daily to provide basal insulin levels that suppress hepatic glucose production and maintain near normoglycemia in the fasting state.

Intermediate-acting insulin

(NPH)

also provides some peak coverage for breakfast and lunch intake, although not as physiologic as replacement with faster-acting insulin given at mealtimes.

Basal insulin levels can also be achieved by continuous infusion of regular insulin via an insulin pump, used almost exclusively in type 1 diabetes.

Short acting

o (regular) or o rapid-acting (lispro, aspart, or glulisine) insulin

are typically provided as a premeal bolus to cover the extra requirements after food is absorbed.

To produce an insulin preparation with :

o a faster onset and o shorter duration than regular insulin (clear zinc

insulin, CZI)

modifications have been made in the insulin molecule to prevent it from forming hexamers or polymers that slow absorption and delay action [4] .

These rapid-acting insulins :

(insulin lispro, aspart, and glulisine)

Have :

o an onset of action within 5 to 15 minutes, o peak action at 30 to 90 minutes, and o a duration of action of two to four hours [5-8]

conventional insulin therapy =

simpler insulin regimens, such as single daily injections, or two injections per day of regular and NPH insulin, mixed together in the same syringe and given in fixed amounts before breakfast and dinner.

intensive insulin therapy =

more complex regimens that separate basal insulin delivery (given as one to two daily injections of intermediate- or long-acting insulin)

with superimposed doses of short acting or rapid acting insulins three or more times daily.

While intensive regimens were initially used for patients with type 1 diabetes, they are now frequently used for patients with type 2 diabetes as well.

Conventional insulin therapy is unlikely to achieve target A1C levels in patients with type 1 diabetes, and may provide suboptimal glycemic control for patients with type 2 diabetes as beta cell function declines.

Both glucose and insulin metabolism are altered in patients who have chronic renal failure. The changes in the insulin regimen that must be made in these patients are discussed separately.

Premixed insulins —

The use of premixed insulins is not recommended for patients with type 1 diabetes, as intensive regimens require frequent adjustments of the premeal bolus of short acting or rapid acting insulin.

Premixed Lispro/NPH in type 1 diabetes may be of some benefit for patients who will not comply with an intensive regimen [9] .

o Some patients with type 2 diabetes who require premeal insulin in addition to basal insulin prefer premixed insulins for convenience.

o Some premixed (biphasic) insulin preparations are commercially available, but patients may also draw up their premeal and basal insulins in the same syringe prior to injection.

However, there are problems with mixing different insulin preparations:

1..When drawing up both insulin preparations in the same syringe, serum insulin concentrations tend to approach a single peak.

This is less of a problem when a rapid-acting insulin rather than regular insulin is mixed with NPH and injected immediately after mixing [10] .

It is also less of a problem with premixed insulins, such as Lispro Mix25 (25 percent insulin lispro and 75 percent of an intermediate-acting insulin) [11] .

2..The peak action also varies directly with the proportion of regular insulin in the combination.

One study, as an example, compared the time course of serum insulin concentrations with two mixtures of different NPH-to-regular insulin ratios: 50/50 (equivalent to 10.5 units of each preparation in a 70 kg patient) and 70/30 (equivalent to 14.7 units of NPH and 6.3 units of regular insulin) [12] .

The former, which contained more regular insulin, resulted in higher serum insulin concentrations in the first six hours

Changes in the proportion of NPH-to-regular insulin in these premixed combinations are often not sufficient to improve postprandial glycemic control [13] .

In addition, because of the variability in peak effect, it may be more difficult to achieve excellent glycemic control with premixed insulins even though they are easier to use [14] .

Many patients with type 2 diabetes can use pre-mixed

preparations with reasonable effect. However, if the aim is to truly vary the dose of fast-acting insulin before a meal, patients would do best to give the fast-

acting and intermediate-acting insulins as separate injections.

If near normoglycemia is the goal, it is preferable to

keep basal and premeal insulin injections separate and to adjust them independently.

ADA guidelines for mixed-insulin —

We almost never recommend commercially premixed insulins in the treatment of type 1 diabetes.

When commercially or self-mixed insulins are used for patients with type 2 diabetes, the following guidelines adapted from the American Diabetes Association (ADA) should be followed [15] .

1..Patients who are well-controlled on a self-mixed regimen should continue the same procedure for preparing their dose.

2..Insulin glargine and insulin detemir should not be mixed with other insulins due to the low pH of the diluents.

3..After mixing NPH with regular insulin, the formulation should be used immediately

4..Rapid-acting insulin can be mixed with NPH. When this is done, the mixture should be injected within 15 minutes prior to a meal.

Inhaled insulin —

An inhaled form of rapid-acting insulin was available for a short time but was discontinued in 2007.

Other inhaled insulin preparations are in clinical trials but are not currently available.

Studies have shown that inhaled insulin causes a very rapid rise in serum insulin concentration (similar to that after subcutaneous insulin lispro and aspart, and faster than that after subcutaneous regular insulin) [16,17] .

However, due to its inefficient absorption, higher doses of insulin must be administered to achieve a therapeutic response.

DETERMINANTS OF INSULIN EFFICACY —

Effective use of insulin requires an understanding of the major

variables that affect the degree of glycemic control.

These include :

o the insulin preparation, o the size of the subcutaneous depot,o injection technique, o the site of injection, and o subcutaneous blood flow

Type of insulin —

o The time of onset, o peak activity, and o duration of action

of subcutaneous insulin preparations :

can only be approximated, since the usually quoted data are based upon the administration of small amounts of insulin to a few normal subjects

Furthermore, the degree of absorption of any dose, both among

patients and in the same patient, can vary from day to day by as much as 25 to 50 percent, leading to unexplained

fluctuations in glycemic control [18,19] .

This effect is greatest with longer-acting insulins and least with regular, lispro, aspart, and glulisine insulin.

Thus, a dose of NPH insulin given before the evening meal may be sufficient to last through the night in one patient but may dissipate in another, resulting in fasting hyperglycemia.

Part of the day-to-day variability in the absorption of NPH insulin may be due to incomplete mixing of the suspensions of insulin and protamine or zinc. However, the absorption of long-acting insulin analogs such as insulin glargine also seems to vary [20] . There is some suggestion that day to day variability of absorption is less with insulin detemir, but the clinical significance of this has not been established [21] .

Size of subcutaneous depot —

The variability in absorption is increased and net absorption is reduced with increasing size of the subcutaneous depot [18] .

This can become a limiting factor in patients who are insulin resistant and require large doses given several times per day.

Conversely, one of the reasons why continuous subcutaneous insulin infusions may serve to smooth blood glucose control is that only regular insulin is used and the size of the subcutaneous depot is very small (since the reservoir is held in a syringe or other chamber, outside the body) [22] .

Another approach to reduce the size of the subcutaneous depot and thereby increase insulin absorption is to use high pressure jet injectors [23] .

These devices lead to a more rapid fall in blood glucose concentrations and a shorter duration of insulin action [24] , although there is no evidence that the variability in insulin absorption is improved.

Jet injectors may also cause less pain than traditional needles and syringes. However, they are expensive, difficult to maintain, and are not recommended for routine use.

A variety of pen injectors, used with pre-filled cartridges, are now available which are more convenient than conventional syringes and bottles, but are more expensive. When small doses of regular insulin (less than five units) are being given, the error in measuring the dosage is almost 50 percent less when using pen injectors than with conventional insulin syringes [25] .

Injection technique —

Injection technique is the same with insulin syringes and with pen injectors. Both the angle of needle entry and the depth of penetration affect the rate of insulin absorption.

Very shallow insertion can cause a painful intradermal injection that is not well absorbed.

In comparison, a perpendicular injection in a lean area may result in an intramuscular injection, from which absorption is more rapid [26,27] .

Patients should be referred to a certified diabetes educator to be taught proper insulin injection technique. The recommended technique is to use an area of the body in which about 2.5 cm (one inch) of subcutaneous fat can be pinched between two fingers.

The syringe, with a 0.5 inch microfine (27G) or ultrafine (29G) needle, is inserted perpendicular to the pinched skin up to the hilt and the insulin is then injected.

The syringe barrel should not be pulled back before injection or the needle removed if blood is obtained. The needle should be held in place for several seconds before being withdrawn. This is especially important when using pen injectors, to avoid insulin leakage after withdrawal of the needle.

The common practice of cleaning the skin with an alcohol swab before injection may not be necessary.

In a crossover study of 50 patients who received over 13,000 injections, there was no difference when the usual manner of injection was compared with injections through clothing [28] .

The only problem with the latter was an occasional blood stain on the clothing.

Site of injection —

Potential sites for insulin injection are the :

o upper arms, o abdominal wall, o upper legs ando buttocks

A common cause of day-to-day variability in insulin action is the random rotation of injection sites from one region of the body to another.

Insulin is absorbed :

o fastest from the abdominal wall, o slowest from the leg and buttock, ando at an intermediate rate from the arm

at any of these sites, the rapidity of insulin absorption varies inversely with subcutaneous fat thickness [19,29] .

In a study using radiolabeled regular insulin, the percent of the dose that disappeared at two hours was approximately 49 percent in the abdomen, 37 percent in the arm, and 26 percent in the leg [29] .

The postprandial rise in plasma glucose concentration varied inversely with the rate of insulin absorption, being 30 to 50 mg/dL (1.7 to 2.8 mmol/L) less after abdominal than after leg injection; the values after arm injection were intermediate between these responses.

These differences can be useful clinically.

Premeal regular or rapid-acting insulin should be rapidly absorbed, and injection into the abdominal wall may therefore be preferable.

On the other hand, slower absorption from the leg or buttock may be desirable with the pre-evening meal dose of intermediate-acting insulin to ensure a duration of action that lasts through the night.

Alterations in subcutaneous blood flow —

The degree of insulin absorption is also determined by the rate of subcutaneous blood flow.

Thus, insulin absorption is :

o reduced by smoking [30] ando increased by any increases in skin temperature [31] induced

by exercise, saunas or hot baths, and local massage [32-35] .

These variations are more marked with regular and rapid-acting insulins than with longer-acting insulins [34] .

SUMMARY AND RECOMMENDATIONS

Insulin therapy is essential in all patients with type 1 diabetes, and

is also often used in patients with type 2 diabetes.

Although initial treatment for type 2 diabetes should be diet modification and exercise, followed by oral agents if normoglycemia is not achieved, insulin therapy is often indicated and its use should not be delayed when it becomes necessary.

While intensive insulin therapy, utilizing a basal insulin with multiple premeal injections of a very rapidly acting insulin, has become standard therapy in type 1 diabetes, simpler regimens are often used in type 2 diabetes.

We suggest not prescribing premixed insulin for type 1 diabetes (Grade 2C).

Premixed insulin may be considered in some patients with type 2 diabetes for convenience.

Specific guidelines should be followed for premixing to avoid changes in speed of absorption and peak action.

Commercially available premixed insulins are a reasonable choice if the insulin ratio is appropriate to the patient's insulin requirement.

Effective use of insulin requires an understanding of the major variables that affect the degree of glycemic control: the insulin preparation, the size of the subcutaneous depot, injection technique, the site of injection, and subcutaneous blood flow

Insulin absorption is variable between patients and in the same patient, especially for longer acting preparations.

Variability is greater with larger injection doses

Injections should be given into an area of pinched skin, with needle inserted perpendicular and up to the hilt; the barrel should not be pulled back.

Precleaning skin with alcohol is unnecessary and mayincrease the pain of an injection.

Absorption is fastest from injections into the abdominal wall, which may be a preferable site for premeal insulin.

Slower absorption from the leg or buttock may be appropriate for evening doses of intermediate-acting insulin.

Addressing patient resistance to insulin therapy for patients with type 2 diabetes Patient concerned with pain from injection

o Minimal with thinner, smaller needles o Use of insulin pens

Patient worried that starting insulin signifies worsening diabetes

o Diabetes is a progressive disease o Taking insulin will control blood glucose and help prevent

complications o Taking insulin may slow down the rate of beta cell failure

Patient believes that need for insulin signifies patient failure to follow treatment regimen

o Diabetes is a progressive disease; beta cell activity declines over time

o Not related to patient compliance o Patient fears low blood sugar reactions o Explain that severe hypoglycemia is rare in type 2

diabetes o Self-monitoring glucose levels o Explain how to avoid and how to treat hypoglycemia

Patient concerned that taking insulin will upset daily routine

o Address specific concerns o Taking insulin may be less intrusive than complicated

drug regimens

Patient believes that insulin will decrease his/her quality of life

o Benefits from glucose control: more energy, better sleep, overall well-being

o Patient thinks insulin will lead to diabetic complications o Discuss role of insulin in reducing risk of diabetic

complications

Patient concerned that he/she will be treated differently by friends and family

o Educate friends and family: offer reading materials on diabetes, support groups for family

o Patient has heard insulin causes weight gain o Role of diet and exercise

Patient wants a more natural alternative therapy

o Insulin is the most natural therapy for diabetes. It is replacing the hormone that the patient does not make enough of.