secretion (throughout the day and night) and acute increases of insulin levels connected to ingestion of meals. This regimen improves diabetic control, re-duces excursions in glycemic levels and provides a good ﬂexibility. Four diVer-ent regimens may be used:
(a) The simplest intensive regimen entails the use of three injections, regular and intermediate-acting insulin before breakfast, regular insulin before supper and intermediate-acting insulin at bedtime. This 3 times daily insulin dose regimen is useful in diabetic patients with frequent nocturnal hypoglyce-mia and pre-breakfast hyperglycemia. The primary disadvantage of this approach is that meal schedules must be ﬁxed rather rigidly.
(b) Regular insulin before each meal and intermediate-acting insulin at bedtime (4 daily insulin doses). This regimen provides the greatest ﬂexibility because regular insulin can be adjusted to cover each meal, avoiding postpran-dial hyperglycemia.
(c) Regularandintermediate-actinginsulinbeforebreakfast,regularinsu-lin before lunch and supper, and intermediate-acting insulin at bedtime (4 daily insulin doses).
(d) Regular insulin before each meal and ultralente insulin in the morning (to replace basal insulin secretion) or subdivided before breakfast and before supper (4 daily insulin doses). It is less preferable to the (b) regimen because ultralente presents unexpected small peaks 15–24 h after injection.
Human insulin lispro is very appropriate for multiple injection therapy, especially in patients with marked postprandial hyperglycemia and nocturnal hypoglycemia or with a variable lifestyle. Patients on insulin lispro had signiﬁcantly lower glucose levels following meals (however with the potentially unwanted result of a rise in preprandial glucose) and showed a reduction in the incidence of severe hypoglycemia by 30% (compared to regular human insulin). In patients treated with insulin lispro (compared to those treated with human regular insulin) there should be less need for snacks. The majority of patients on insulin lispro reported an improved quality of life. However, there are some ‘failures’ with this type of insulin, as a number of patients may appear unable to control their diabetes with insulin lispro. At present, insulin lispro should be used with caution in children under the age of 12 as well as in gestational diabetes or pregnancy, because of lack of experience.
Other, far too complex, multiple-injection regimens have also been sug-gested. Certainly, the adherence to therapy is less likely to occur when the program of treatment is far too complicated. Some patients object to such frequent needle injections and ask for changing from this insulin regimen to a simpler program. Pen devices or jet injectors ﬁlled with insulin (that are easy to carry) make the multiple daily insulin regimens better accepted.
Insulin Treatment in Type 1 and Type 2 Diabetes 81
It is advisable to use no more than two types of insulin. It is noteworthy that in some patients a morning fasting hyperglycemia (the dawn phenom-enon) occurs, that depends on the hepatic glucose overproduction activated in the morning due to inadequate overnight delivery of insulin and a sleep-associated GH release. This phenomenon is most pronounced in type 1 diabetic patients for their inability to compensate by raising endogenous insulin secretion. The magnitude of the dawn phenomenon can be attenuated by designing insulin regimens which ensure that the eVects of exogenous insulin do not peak in the middle of the night and then become dissipated by morning.
Some patients (about 1/3 of type 1 diabetic patients) may experience early in the course of disease a brief honeymoon period, during which there is a partial recovery of b-cell function and a transient or a prolonged fall in the exogenous insulin requirement (=0.5 U/kg/day). The honeymoon phenom-enon may be due to the termination of a ‘stress’ episode (infections, etc.) that has anticipated the manifestation of diabetes in a subject with ongoing b-cell destruction process. Spontaneous remission is less frequent in children and adolescent or pubertal patients, and more frequent in adult postpubertal pa-tients. A low residual insulin secretion (probably linked to a more aggressive destruction of b-cells) can be implicated in children while a low insulin sensitiv-ity (probably linked to the increased secretion of GH hormone) may be impor-tant in pubertal patients. The honeymoon should not be regarded as a signal to reduce eVorts aimed at glycemic control, because optimized insulin therapy may help to preserve b-cell function. It is recommended to continue insulin treatment even at low doses (even 1–4 U/day), since this can preserve b-cell function and may favor the remission.
Continuous Subcutaneous Insulin Infusion (CSII)
In suYciently motivated diabetic patients, an alternative that provides a greater ﬂexibility of insulin treatment (minimizing variations in its absorp-tion) is CSII, with which insulin delivery may somewhat mimic that occurring in nondiabetic individuals. Insulin delivery pumps may be implantable or portable (with ‘closed loop’ or ‘open loop’ insulin infusion systems). The CSII method administers rapid-acting insulin around the clock using a battery-powered (externally worn) infusion pump, that delivers basal rates continuously (usually 0.5–2.0 U/h) and can be programmed to vary the ﬂow rate automatically, reducing the ﬂow rate at 1.0–4.0 a.m. and increasing it to compensate for increased insulin requirements early in the morning. Before meals, insulin boluses are given by manually activating the pump, in amounts based on frequent blood glucose self-monitoring determinations. Usually, a 3- to 5-day hospital stay is required for learning to use the insulin pump,
Table 3. Problems limiting the use of CSII
Interruption of insulin delivery (commonly due to insulin precipitation within the catheter) that leads to rapid severe hyperglycemia and ketoacidosis (because there is no depot insulin and all insulin being used is short-acting)
Pump malfunction (a pump malfunction with insulin overdose can produce severe and even fatal hypoglycemia)
Loss of battery charge Leakage from the catheter Empty insulin reservoir Needle displacement
Local infections (such as abscesses at the catheter site, only occasionally reported)
and successively a health-care professional should be available 24 h/day to assist the patient. Most pumps contain a syringe or a reservoir ﬁlled with insulin attached to an infusion set consisting of a catheter and a 27-gauge needle which is inserted into subcutaneous tissue (preferably in the abdomen). Unfortunately, the CSII presents several problems that limit its use (table 3), and the patients with brittle diabetes (see below) may not be the best candidates for a successful use of CSII. Most modern pumps present alarm systems for the diVerent pump problems. Some diabetic patients are absolutely incapable to safely employ the insulin pump and to use the appropriate infusion rates. The high cost is another relevant disadvantage of CSII.
Self-monitoring is an important component of diabetes management, which helps to achieve a good glycemic control and therefore to prevent complications (especially microangiopathy). Several factors may inﬂuence the method and frequency of self-monitoring, such as the type of insulin regimen prescribed, glycemic goals of therapy, capabilities of diabetic patient, etc. Self-monitoring includes the following tests:
(a) Urine testing for glucose (2 or 4 times/day) is the less reliable option for self-monitoring, inasmuch as it allows only a coarse estimation of glycemia. It might be used for insulin or dietary adjustments in patients with stable diabetes.
(b) Urine testing for ketones is a component of self-monitoring routines of type 1 diabetic patients, especially in presence of unexplained hyperglycemia or to manage acute events of metabolic decompensation.
Insulin Treatment in Type 1 and Type 2 Diabetes 83
(c) Blood glucose self-monitoring is the most important advance in dia-betes care. It requires the use of devices or meters that read blood glucose testing strips. All the modern meters can store and recall obtained blood glucose readings. These glucose determinations provide an estimation of gly-cemic control at any given moment, from day to day, and may be especially useful for speciﬁc problems (hypoglycemia, acute illness, ketonuria, periods of unstable diabetes, etc.). Several factors may limit the use of this method, such as a low level of motivation, a poor accuracy of determination, technical errors, intellectual inability to use the glycemic results, low visual or physical abilities, lack of education, high costs, etc. For some diabetic patients, blood glucoseself-monitoringisperceivedastoodiYcultorintrusiveintoindividual’s routine, while other patients who desire to improve their glycemic control may accept to perform blood glucose tests several times a day on a regular basis. In these motivated patients, it is very important to monitor their technical competence, todeﬁne the desiredglycemic range tobe achieved, andto provide all the appropriate technical instructions, including the comparison of meter-obtained results with laboratory values.
The patient with diabetes should have a periodic determination of HbA1c because this measurement is the most objective method of glucose control measurement over a long period. HbA is glycated in an irreversible and non-enzymatic fashion, and the levels of HBA1c reﬂect the mean glycemia over the 2–3 months prior to the test.
This test has been suggested as a less diYcult to perform and less costly alternative to HBA1c determination, with which shows a good correlation. This test measures the level of glycosylated proteins in the blood (mainly albumin), and reﬂects the mean glycemic control during a 2- to 3-week period. Its validity is uncertain when interfering substances (bilirubin, hemolysis, etc.) are present or serum albumin concentration is abnormal. The test accuracy can be improved by correcting the fructosamine result for variations in serum albumin. HBA1c, compared to fructosamine test, should be considered as the preferable test for monitoring diabetic control.
The most important complication of insulin therapy is hypoglycemia, which is discussed in chapter VIII (Clinical Emergencies in Diabetes. 2: Hy-poglycemia). The other complications are listed below.
In poorly controlled diabetic patients, insulin therapy can result in a marked accumulation of ﬂuid, with localized (periorbital, pretibial or presa-cral) or generalized edema. The causes are probably multiple (table 4). A dietary restriction of salt and a temporary use of diuretics can be recom-mended. Edema will most often subside within 3–5 days.
Table 4. Causes of insulin edema
ADH increase (ascribed to hypovolemia resulting from osmotic diuresis) Cessation of natriuretic eVect of hyperglucagonemia
Increased plasma volume and transcapillary escape of albumin (with reduced colloid osmotic pressure)
Excessive infusion of isotonic saline
Na retention (induced by excess of insulin infused or injected)
It was a common complication prior to the introduction of monocompo-nent insulins, consisting of a loss of fat at the site of insulin injection or, occasionally, at distant sites. In 25% of lipoatrophic patients, local allergy coexists. Lipoatrophy is frequently observed in young children (50%) or in young women (20%), compared to male adults (5%). Lipoatrophy, moreover, may occur after repeated injections of other substances such as narcotics or GH preparations. Thus, atrophy might be the result of a repeated mechanical trauma, even if insulin impurities can stimulate immune factors or immune complex formation which lead to local release of lipolytic substances. These reactions occur without overt inﬂammation and were considered also second-arytoinsulindegradationoraggregationproducts.Indeed,inbiopsyspecimens oflipoatrophicareas,antigen-antibodyreactionswerenotseen.Localreactions to protamine (a constituent of insulin preparations) and to silicone oil (the lubriﬁcant in disposable syringes) may play a role in some patients. Switching to puriﬁed or human insulins and rotating the site of injections result in improvement of skin alterations in 97% of lipoatrophic patients. Very few cases were reported with recombinant human insulins, and the reason why it
Insulin Treatment in Type 1 and Type 2 Diabetes 85
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