New Concepts in Diabetes and Its Treatment - part 4 ppsx

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 differ-
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) Regular and intermediate-acting insulin before breakfast, regular insu-
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.
81Insulin Treatment in Type 1 and Type 2 Diabetes
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 effects 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 -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 -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 -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 efforts aimed at glycemic control, because optimized insulin therapy
may help to preserve -cell function. It is recommended to continue insulin
treatment even at low doses (even 1–4 U/day), since this can preserve -cell
function and may favor the remission.
Continuous Subcutaneous Insulin Infusion (CSII)
In sufficiently 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,
82Belfiore/Iannello
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 different 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
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.
83Insulin Treatment in Type 1 and Type 2 Diabetes
(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
glucose self-monitoring is perceived as too difficult or intrusive into individual’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, to define the desired glycemic range to be achieved, and to provide
all the appropriate technical instructions, including the comparison of meter-
obtained results with laboratory values.
Glycated Hemoglobin (HbA
1c
)
The patient with diabetes should have a periodic determination of HbA
1c
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 HBA
1c
reflect the mean glycemia over the
2–3 months prior to the test.
Serum Fructosamine Test
This test has been suggested as a less difficult to perform and less costly
alternative to HBA
1c

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. HBA
1c
, compared to fructosamine test, should be considered as the
preferable test for monitoring diabetic control.
84Belfiore/Iannello
Complications of Insulin Treatment
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.
Insulin Edema
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 effect 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)
Insulin Lipoatrophy
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-
ary to insulin degradation or aggregation products. Indeed,inbiopsyspecimens
of lipoatrophic areas, antigen-antibody reactions were not seen. Local reactions
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
85Insulin Treatment in Type 1 and Type 2 Diabetes
still occasionally occurs is unknown. Injecting the purified insulin at the edges
and center of the affected atrophic area improves lipoatrophy (due to the
lipogenic effect of insulin). Addition of dexamethasone to the insulin in the
syringe (4 g/U, total daily dose not exceeding 0.75 mg) has also been sug-
gested. In a recent case of severe well-circumscribed lipoatrophy, good results
were obtained by treating the area with a fatty acid mixture while the patient
was instructed to avoid this area for insulin injection.
Insulin Lipohypertrophy
It consists of visible or palpable increase of localized subcutaneous fat
(most prevailingly in the anterior or lateral part of thighs) at the site of insulin
injection, sometimes coexisting with lipoatrophy. Repeated and prolonged use
of the same site for insulin injection is a main determinant in the development
of lipohypertrophy. Often the affected patients report that injection into lipohy-

pertrophic areas is less painful, perhaps because the subcutaneous tissue tends
to be fibrous. Lipohypertrophy is due to a possible growth factor effect of
insulin on cellular elements of subcutaneous tissue, and may alter the absorp-
tion rate of insulin, thus possibly affecting metabolic control. Prevalence rates
of lipohypertrophy vary between 20–45% in type 1 and 3–6% in type 2 diabetic
patients. Independent risk factors which contribute to the presence of lipohy-
pertrophy are female sex, type 1 diabetes, higher BMI and missing rotation
of insulin injections. The most severe cases of insulin lipohypertrophy can be
treated with liposuction, but prevention is important, primarily by systemat-
ized rotation of injection sites within the recommended areas. An important
role is played by educational interventions to establish an organized rotation
system for insulin injection sites, to self-recognize lipohypertrophy and to
normalize the high BMI.
Syndrome of Immunologic Insulin Resistance
All patients who receive insulin develop circulating antibodies, whose
production can be influenced by several factors (table 5). Patients never treated
with exogenous insulin may have circulating insulin antibodies, probably in-
volved in the autoimmune reactions of type 1 diabetes. The high level of insulin
antibodies may function as a reservoir from which insulin may be released
unpredictably (thus inducing delayed hypoglycemia), or may bind insulin (thus
causing hyperglycemia), or may form immune complexes (thus sequestering
insulin in the reticuloendothelial system or stimulating procoagulant activity
and favoring diabetic complications). In diabetic patients, this syndrome may
result in an excessive insulin requirement (100–200 U/day in adults and up to
2.5 U/kg in children). In the most severe cases, steroids even at high doses for
3–4 weeks should be used. It is noteworthy that the immunogenicity of insulin
86Belfiore/Iannello
Table 5. Factors influencing the formation of insulin antibodies
Insulin species (human insulin is less immunogenic than animal insulins)
Insulin purity (monocomponent insulins are less immunogenic)

Insulin pharmaceutical form (regular insulin is less immunogenic than modified insulins)
Pattern of insulin treatment (episodic therapy and CSII may increase insulin immunogenicity)
Genetic factors (HLA-A2-B44 and HLA-B44-DR7 predispose to immune complications of
insulin therapy)
Residual insulin secretion (when present, it reduces immune response to insulin)
lispro has been found to be similar to that of human insulin in both type 1
and type 2 diabetic patients.
Insulin Allergy
It includes different forms:
(a) Local allergycomprisesimmediate orbiphasicordelayedreactionsand
consists of erythematous and pruritic indurated lesions or more severe reactions
in subcutaneousareasinjectedwith insulin preparations. Protamineorzinc have
beenimplicated. ThesereactionsareIgE-dependentandmayoccurwithconven-
tional insulin treatment or CSII in subjects with intermittent insulin treatment
or with allergy to other drugs (such as penicillin) or with obesity. The affected
patients will improve within 30–60 days continuing the use of insulin (probably
because ofaspontaneous desensitization),whereasinthe mostseverecaseslocal
steroids in low doses or oral antihistaminics may be considered.
(b) Generalized allergy ranges from a simple urticaria to more severe
reactions such as anaphylaxis with angioedema, bronchospasm, pharyngeal
edema and collapse. These generalized reactions are due to the interaction of
insulin (acting as an antigen) with specific IgE bound to mast cells or blood
basophils and are very uncommon (=0.05%). No deaths for insulin allergy
are reported. Human insulins are efficacious in the majority of allergic patients
for the treatment of this systemic allergy, while in the remainder desensitization
is successful (about half of patients who cannot be desensitized are overweight).
Immunologic insulin resistance may coexist with or following insulin allergy.
Insulin allergy is different from stress-induced urticaria, in which the central
nervous system is important in the generation of immune response.
Conditions of Altered Insulin Responses

Conditions of altered insulin responses include: (a) insulin resistance
linked to occult infections; (b) iatrogenic hypoglycemia or factitious inten-
87Insulin Treatment in Type 1 and Type 2 Diabetes
tional insulin overdosing (see chapter VIII on Clinical Emergencies in Dia-
betes. 2: Hypoglycemia); (c) labile or ‘brittle’ diabetes, which can be idiopathic
or secondary and includes a group of insulin-dependent diabetic patients
(about 2–10%) characterized by unexplainable and extreme glycemic short-
term and long-term fluctuations with frequent ketosis proneness or hypogly-
cemic crises, or both. Brittle diabetes can depend on altered insulin absorp-
tion, or poor residual insulin secretion, or excess of counter-hormone
regulation, or emotional stress. Some of these patients are adolescent women
who distort their insulin treatment to prolong the stay in the hospital for
psychosocial problems. In these instances, the treatment of brittle diabetes
requires a strong effort by the patient’s family and the medical and psycholog-
ical team.
Role of Education
A successful insulin management requires actively applied systems of
patient education. The aim of education and training is to provide adequate
information in a simple form suitable to the ability of the subject, in order to
allow the diabetic patients to develop the required knowledge to self-manage
their disease and to ensure an optimal and appropriate use of insulin therapy
(and other therapeutical measures). Behavioral changes and insulin treatment
adjustments may be made in a graduated manner (step-by-step), and a system-
atic reinforcement is critical after the goals are achieved. Nutritional manage-
ment is also an integral part of initial and following programs of education.
The provision of a diabetes professional team (doctors, educators or diabetes
nurse specialists, nutritionists or dieticians, and podiatrists or chiropodists) is
also necessary as well as a continuing education for the professional staff.
Several factors should be considered for a good therapy, including patient’s
lifestyle, physical activity, dietary habits, glucose self-monitoring, correct time

to injection (some patients may take regular insulin 5–15 min before the meal,
instead of 30 min before), insulin dosage adjustments, usual injection sites
and, finally, possible interactions with otherdrugs. How to avoid hypoglycemia,
what to do during an episode of hypoglycemia or the correct behavior during
acute illness or stress must be included in the education program. Each visit
should be an opportunity to assess the current level of self-management, the
behavioral change and goal achievement. Overall glycemic control is optimized
when education and motivation are emphasized. In this approach, every dia-
betic patient should be considered unique.
88Belfiore/Iannello
Suggested Reading
Anderson JH, Brunelle R, Koivisto VA: Reduction of post-prandial hyperglycemia and frequency of
hypoglycemia in IDDM patients on insulin analog treatment. Diabetes 1997;46:265–270.
Campbell PJ, May ME: A practical guide to intensive insulin therapy. Am J Med Sci 1995;310:24–30.
Diabetes Control and Complications Trial Research Group: The effect of intensive treatment of diabetes
on the development and progression of long-term complications in insulin-dependent diabetes
mellitus. N Engl J Med 1993;329:977–986.
Dimitriadis G, Gerich J: Importance of timing of preprandial subcutaneous insulin administration in the
management of diabetes mellitus. Diabetes Care 1983;6:374–377.
Galloway JA, deShazo RD: Insulin chemistry and pharmacology; insulin allergy, resistance, and lipodys-
trophy; in Rifkin H, Porte D (eds): Diabetes mellitus. Theory and Practice, ed 4. Amsterdam,
Elsevier, 1990, pp 497–512.
Sane T, Helve E, Yki-Jarvinen H: One year’s response to evening insulin therapy in non-insulin-dependent
diabetes. J Intern Med 1992;231:253–260.
Strowing S, Raskin P: Insulin treatment and patient management; in Rifkin H, Porte D (eds): Diabetes
mellitus. Theory and Practice, ed 4. Amsterdam, Elsevier, 1990, pp 514–525.
F. Belfiore, Institute of Internal Medicine, University of Catania, Ospedale Garibaldi,
I–95123 Catania (Italy)
Tel. +39 095 330981, Fax +39 095 310899, E-Mail francesco.belfi
89Insulin Treatment in Type 1 and Type 2 Diabetes

Chapter VI
Belfiore F, Mogensen CE (eds): New Concepts in Diabetes and Its Treatment.
Basel, Karger, 2000, pp 90–102

Overview of Diabetes Management:
‘Combined’ Treatment and
Therapeutic Additions
F. Belfiore, S. Iannello
Institute of Internal Medicine, University of Catania, Ospedale Garibaldi,
Catania, Italy
Lessons from Recent Large Trials on Diabetes Treatment
The Diabetes Control and Complication Trial (DCCT), a large multicenter
study conducted on more than 1,400 type 1 diabetics (aged 12–39 years) for
a period of 7–10 years, has established that close blood glucose control (even
if complete normalization of glycemic level was not obtained) reduces the
frequency of late diabetic complications. Patients were assigned randomly to
either intensive insulin therapy (3 or more daily injections or insulin pump,
glucose self-monitoring 4 or more times per day, and frequent contact with
a diabetes health-care team) or conventional therapy (1 or 2 injections of
insulin mixtures per day, less frequent monitoring and medical contacts). The
target goals of therapy were markedly different. Compared to the conventional
care group, the intensive care group showed lower glycated hemoglobin (by
1.5–2.0%) and mean glucose level (by 60–80 mg/dl), yet most of the intensive
care patients group failed to achieve normal glycemic levels. However, intensive
care reduced the development of retinopathy by 76% (and its progression by
54%), the risk of microalbuminuria by 39%, frank proteinuria by 54%, and
clinical neuropathy by 60%. Major cardiovascular events were also reduced,
although statistical significance was not reached, in any case excluding that
intensive insulin therapy may entail risk for macrovascular complications.
The correlation of mean blood glucose with the frequency of retinopathy

progression was linear, suggesting that there is no threshold glycemic level at
which complications occur, so that any degree of improvement in glycemic
control exerts beneficial effects on the progression of complications. These
90
beneficial effects, however, were obtained at the expense of a more common
weight gain and, especially, of an increased (3-fold) risk of severe hypoglycemic
episodes, often not accompanied by the classical symptoms (intensive treat-
ment reduces the adrenergic response to hypoglycemia), which makes intensive
treatment less appropriate for some people (hypoglycemia unawareness, special
occupations, children, old people, etc.). Finally, it should be noted that the
DCCT results were obtained through a close cooperation between the patients
themselves and an expert team, primarily nurse educators and dieticians. There-
fore, it may not be easy to follow the DCCT criteria in everyday clinical
practice.
The data from DCCT conclusively demonstrate that in type 1 diabetes
the control of blood glucose really matters to prevent late complications. A
recently concluded multicenter investigation on a very large study population
(?5,000 patients), the United Kingdom Prospective Diabetes Study (UKPDS),
whose results were presented at the European Association for the Study of
Diabetes in Barcelona, September 1998, has obtained similar results in type
2 diabetic patients. As summarized by Laakso [1999], this study has shown
that, compared to ‘dietalone’, the intensive control of blood glucose (regardless
of the treatment used – sulfonylureas, metformin or insulin) reduced retinopa-
thy or nephropathy by 25%, myocardial infarction by 16% and any diabetes-
related endpoint by 12%. For every one percentage point reduction in HbA
1c
,
there is a 35% reduction in retinopathy, nephropathy or neuropathy, and a
25% reduction in diabetes-related deaths (stroke frequency was not affected).
As observed in the DCCT, there was no evidence of any glycemic threshold

for micro- or macrovascular complications. With strict metabolic control, the
risk of hypoglycemic episodes increased. Obese type 2 diabetic patients treated
with metformin, compared with diet treatment, had even more pronounced
benefits, showing reduction of 32 and 42% of diabetes-related endpoints and
diabetes-related deaths, respectively, as well as a 36% reduction of all-cause
mortality. In addition, they gained less weight and had fewer hypoglycemic
episodes compared to the insulin- or sulfonylurea-treated patients.
The UKPDS also pointed out that type 2 diabetic patients with tight
control of blood pressure (mean 144/82 mm Hg), obtained either by ACE
inhibitors or -blockers, compared to the untreated group (154/87 mm Hg),
showed reduction of any diabetes-related endpoint (by 24%), diabetes-related
deaths (by 32%), stroke (by 44%) and microvascular complications (by 37%).
Reduction of myocardial infarction of 21% occurred but did not reach statis-
tical significance.
It should be noted that in the UKPDS the treatment goal of maintaining
fasting glycemia below 6 mmol/l (108 mg/dl) was not achieved. Strict metabolic
control would consist of keeping glycemia below 10 mmol/l or 180 mg/dl at
91Overview of Diabetes Management
all times during the day. The UKPDS conclusively demonstrated that strict
control of blood glucose and of blood pressure are greatly beneficial in type
2 diabetes for preventing micro- and macrovascular complications. UKPDS
also has evidenced that about 50% of newly diagnosed type 2 diabetic patients
already show early signs of complications. This study has also showed that
treatment with insulin or sulfonylureas is not harmful. However, this study
did not demonstrate that this is also the case for elderly diabetic patients.
Moreover, metformin was compared with other intensive treatments combined,
not separately, with insulin and sulfonylureas. Concerning the possible negative
effects of the association sulfonylurea-metformin, UKPDS did not provide
sufficient evidence to suggest that this combination should not be used. Not
all possible therapeutical combinations were tested, as, for instance, the com-

bination insulin-metformin, which might bear the advantage that weight gain
is prevented. Finally, it should be noted that the glucose levels fixed as thera-
peutical goal in the UKPDS may not be achievable in all patients; individual
patient targets should be defined in relation to age and other risk factors.
On the basis of the UKPDS data, the British Diabetic Association recom-
mends that the treatment should be aimed at the following goals: blood pressure
levels of 140/80 mm Hg or below; HbA
1c
levels of 7.0% (or within 1% of the
upper end of the laboratory’s normal range); fasting blood glucose levels of
4–7 mmol/l (72–126 mg/dl), and self-monitored blood glucose levels before
meals of 4–7 mmol/l (72–126 mg/dl).
According to the IDF guidelines [1999] for type 2 diabetes, the risk for
vascular complications as related to metabolic compensation (blood glucose
and HbA
1c
) is as follows:
‘Low risk’: HbA
1c
(DCCT standardized) O6.5%; fasting/preprandial ve-
nous plasma glucose (VPG) =100 mg/dl (6.0 mmol/l); fasting/preprandial self-
monitored blood glucose (SMBG) =100 mg/dl (O5.5 mmol/l); postprandial
SMBG =135 mg/dl (=7.5 mmol/l).
‘Arterial risk’: HbA
1c
>6.6–7.5%; fasting/preprandial VPG>110–125 mg/dl
(6.1–6.9 mmol/l); fasting/preprandial SMBG>100–109 mg/dl (5.6–6.0 mmol/l);
postprandial SMBG>135–160 mg/dl (7.5–9.0 mmol/l).
‘Microvascular risk’: HbA
1c

?7.5%; fasting/preprandial VPG?125 mg/dl
(?7 mmol/l); fasting/preprandial SMBG P110 mg/dl (P6.0 mmol/l); post-
prandial SMBG ?160 mg/dl (?9.0 mmol/l).
Type 2 Diabetes
In those patients with type 2 diabetes in whom good metabolic control
cannot be achieved with diet and physical exercise, pharmacological treat-
92Belfiore/Iannello
ment should be introduced, based on sulfonylureas (to stimulate insulin
secretion) or metformin (to ameliorate insulin action), as discussed in chapter
II on Insulin Secretion and Its Pharmacological Stimulation and chapter
III on Insulin Resistance and Its Relevance to Treatment. Further aspects
of treatment will be considered in this chapter. According to the IDF
guidelines [1999] to type 2 diabetes, oral therapy should be started when,
despite an adequate trial of lifestyle intervention/education, HbA
1c
is ?6.5%
and fasting VPG is ?110 mg/dl (?6.0 mmol/l), or (in thin subjects without
arterial risk factors) HbA
1c
is ?7.5% and fasting VPG is ?125 mg/dl (P7.0
mmol/l).
Sulfonylurea Failure
In type 2patients treated with sulfonylureas, the phenomenon of sulfonylu-
rea failure, either primary or secondary, may occur.
Primary Sulfonylurea Failure. It is the failure to show any significant
response to therapy and it occurs in about 5% of the patients treated with
sulfonylureas. It has been suggested that probably some of these patients are
unrecognized type 1 diabetics. The cause of this failure is uncertain. Primary
failure occurs with greater frequency in underweight diabetic patients, in those
with diabetes duration longer than 5 years, or in diabetic patients previously

treated with insulin.
Secondary Sulfonylurea Failure. It is defined as a persistent hyperglycemia
in spite of maximal doses of drug after an initial successful response for at
least 6 months, and may occur in about 5–10% of type 2 diabetic patients,
although this percentage varies with the populations studied. The majority of
secondary failures occurs during the first 3 years of oral therapy. Most likely,
secondary failure is caused by increased insulin resistance consequent to in-
creased dietary intake and body weight, or to intercurrent illness and, usually,
the correction of these causes restores sulfonylurea responsiveness. In other
instances, a further deterioration of -cell function may be the responsible
factor (as revealed by decreased C-peptide response to intravenous glucagon).
It is noteworthy that about 33% of the diabetic patients with sulfonylurea failure
show islet cell antibodies (ICA or GAD antibodies), or multiple autoantibodies
(islet cell, thyroid antimicrosomal, gastric parietal cell, etc.), or possess the
HLA phenotype DR3/DR4, characteristics which suggest that these diabetic
patients may actually be affected by late-onset type 1 diabetes. Among the first-
generation sulfonylureas, failure was less often observed with chlorpropamide.
With the indroduction of second-generation drugs the incidence of failure has
become very low (about 0.3%). In theevent that a complicating illness is causing
a secondary failure, the patient can usually be treated with sulfonylureas again
after the intercurrent problem has cleared.
93Overview of Diabetes Management
For the patients who show secondary failure of sulfonylureas or respond
only partially to maximum doses of oral sulfonylureas, various combined
therapies can be employed. In the IDF guidelines [1999] to type 2 diabetes,
the following combination therapy is suggested: (a) metformin with sulfonylu-
reas; (b) sulfonylureas with -glucosidase inhibitors, and (c) sulfonylureas with
PPAR agonists.
Combined Sulfonylurea-Metformin Therapy
The oral hypoglycemic drugs, sulfonylureas and metformin, are largely

used in combination in the treatment of type 2 diabetic patients, inasmuch as
they exert different and complementary effects. Sulfonylureas stimulate insulin
secretion whereas metformin ameliorates insulin action by enhancing periph-
eral glucose utilization and repressing hepatic glucose production.
Recent in vitro studies reported that metformin may potentiate glucose-
stimulated insulin release from human pancreatic islets. Not enough evidence
exists to support the suggestion that the association sulfonylureas-metformin
entails a risk for diabetes-related deaths. In some countries, tablets containing
a mixture of metformin and sulfonylureas (examples: 400 or 500 mg of metfor-
min and 2.5 mg of glibenclamide) are available on the market.
Combined Sulfonylurea-Insulin Therapy
This combined therapy may be successful in type 2 insulin-resistant dia-
betic patients who are no longer responsive to oral drugs. Sulfonylureas de-
crease the exogenous insulin doses required to achieve a good glycemic control.
Many studies have tested this therapeutic combination and have shown that
about 30–40% of patients require significantly less insulin or sulfonylureas
when treated this way. Thesepatients, usually, show higher basal and stimulated
serum C-peptide levels and increased insulin-mediated glucose disposal. The
beneficial effects of the combination sulfonylurea-insulin can depend on an
increase of endogenous insulin secretion or on a reduction of liver and periph-
eral insulin resistance, and may be transient or prolonged. The recommended
regimen is a dose of intermediate-acting insulin at night (to control overnight
glucose production) and oral sulfonylureas during the day at meals (to reduce
postprandial hyperglycemia).
Therapy with Other Drugs
Repaglinide. This is a nonsulfonylurea insulinotropic hypoglycemic agent
of the meglitinide family (meglitinide is a compound with a poorly efficient
insulinotropic activity), and shows a common conformation with the hypogly-
cemic sulfonylureas glibenclamide and glimepiride (see chapter II on Insulin
Secretion and Its Pharmacological Stimulation).

94Belfiore/Iannello
Orlistat. In obese-diabetic patients who need to lose weight, a new nonsys-
temically acting antiobesity drug, orlistat, may be a useful add-on. It possesses
an inhibitory activity against gastrointestinal lipase A, thus selectively reducing
the absorption of dietary fat in the gastrointestinal tract. After drug with-
drawal, the lipase activity is rapidly restored, due to the continuous enzyme
secretion. Orlistat has little or no effect on gastrointestinal enzymes other than
lipase A such as amylase, trypsin, chymotrypsin and phospholipases. About
30% of dietary triglycerides remain undigested and is not absorbed, producing
an additional caloric deficit compared to diet alone. Orlistat treatment also
decreases the solubility and subsequent absorption of cholesterol, so improving
lipid levels (both total and LDL cholesterol levels are reduced). More than
4,800 patients have received orlistat in clinical trials (the recommended dosage
is 120 mg t.i.d. taken during meals), and the results demonstrate the efficacy
(weight loss was 70% greater than with placebo plus diet), safety and toler-
ability of the drug for long-term use. Orlistat-treated obese-diabetic patients
present a best compliance with dietary restriction (because a severe dietary
fat restriction is unnecessary) and a metabolic improvement (lowering of fasting
blood glucose or HbA
1c
and reduction of sulfonylurea dosage requirement).
This drug is free of systemic side effects, and gastrointestinal symptoms (related
to the increased fecal fat excretion) are mild and self-limited. Orlistat treatment
does not seem to increase the risk of gallstone formation (which can be favored
by weight loss).
Other Drugs. The possible use of some thiazolidinedione derivatives, such
as pioglitazone, troglitazone, and rosiglitazone, has been discussed in chap-
ter III (Insulin Resistance and Its Relevance to Treatment). Since fasting
hyperglycemia in diabetes is correlated with high hepatic glucose production,
which is determined by an elevated gluconeogenesis favored by FFA, inhibition

of both FFA release (from adipose tissue) and oxidation (in the liver) may be
an efficient modality to treat fasting hyperglycemia. Several drugs have been
developed which inhibit FFA release from adipose tissue (acipimox, a nicotinic
acid derivative) or hepatic FFA oxidation (etomoxir, a mitochondrial inhibitor
of the carnitine palmitoyl transferase-1, the rate-limiting step in FFA oxida-
tion). Severe fasting hypoglycemia and other side effects may occur with these
drugs and limit their clinical use.
Somatostatin or somatostatin analogues improve glucose metabolism in
diabetic patients, especially under stress, selectively inhibiting the secretion of
glucagon and GH without influencing insulin secretion. A role of somatostatin
was also suggested in late diabetic vascular complications, but it remains to
be elucidated.
Amylin is a recently discovered 37-amino-acid peptide, that is cosecreted
with insulin by pancreatic -cells (it is regarded as the second -cell hormone)
95Overview of Diabetes Management
Table 1. Physiological actions of amylin or pramlintide
Inhibition of food intake (through a central mechanism)
Slowing of gastric motility and inhibition of gastric emptying
Inhibition of postprandial glucagon secretion
Suppression of postprandial hepatic glucose production
Suppression of arginine-stimulated glucagon secretion
Preservation of the glucagon increase in response to hypoglycemia
Inhibition of insulin secretion in response to a variety of secretagogues
Renal effects (stimulation of the renin-angiotensin-aldosterone system in rats
and humans with possible induction of hypertension)
Inhibition of gastric acid secretion, and gastroprotection
in response to nutrient stimuli. It has been isolated and characterized as the
major component of pancreatic amyloid deposits present in type 2 diabetic
patients. In normal humans, plasma amylin concentrations vary in response
to blood glucose levels, whereas in type 1 diabetic subjects and in late-stage

type 2 diabetics it is reduced (being often almost undetectable) and do not
increase in response to glucose load. Amylin secretion appears to be delayed
and diminished in these populations. Human amylin tends to aggregate or
forms insoluble particles and is not suitable for therapeutical use. A synthetic
analog of human amylin, pramlintide, was developed, which is readily soluble
in water and which possesses the same biological activities as amylin. The
physiologic actions of human amylin or pramlintide are shown in table 1.
Amylin appears to complement the glucose disposal actions of insulin and
improves glucose regulation in type 1 or type 2 diabetic patients, who are
absolutely or relatively deficient in amylin. This peptide, administered subcuta-
neously at 10–100 g 4 times/day, was able in a multicenter trial to effectively
reduce the 24-hour plasma glucose profile in type 1 diabetic patients, without
important side effects (only transient, dose-related, upper gastrointestinal
symptoms such as nausea were observed). In type 2 diabetics treated with
exogenous insulin, pramlintide improved metabolic control and produced sta-
tistically significant reduction of serum fructosamine, HbA
1c
and total choles-
terol as well as a trend towards decreased body weight.
Ty p e 1 Diabetes
The treatment of type 1 diabetes with diet and insulin has been discussed
in chapter IV on Diet and Modification of Nutrient Absorption and chapter
96Belfiore/Iannello
Table 2. Immunoregulation therapies in
animal models
IL-2, IL-4, IL-10 and TNF-
Anticytokine and anti-IFN- antibodies
AntiT-cellantibodies,anti-CD3, -CD4,-CD8
Anti T-cell-receptor antibodies
Anti-MHC class I and class II antibodies

Immunosuppressive drugs (cyclosporine)
Immunomodulating agents
Adjuvants (BCG vaccine and CFA)
Nicotinamide
Treatment with autoantigen:
Insulin
GAD
Heat-shock protein
Table 3. Immunoregulation treatments in diabetic humans
Cyclosporine treatment (low benefit, several toxic side effects and recurrence of disease limit
its clinical use)
Preventive treatment with intravenous or subcutaneous insulin (with a moderate protective
effect in 60% of high-risk individuals, compared to 0% in controls)
Daily oral insulin (7.5 mg/day)
Low doses (nonhypoglycemic) of subcutaneous insulin (capable to prevent or delay type 1
diabetes in prediabetic subjects)
Daily oral nicotinamide (3 g/day) (useful to prevent type 1 diabetes)
V on Insulin Treatment in Type 1 and Type 2 Diabetes. Here, additional
aspects will be considered.
Immunologic Treatment
Immunoregulatory Therapy. This intervention is suggested in the predia-
betic state (before the autoimmune -cell destruction) and is directed to the
following goals: to prevent the induction of diabetogenic T lymphocytes (or
to delete these cells), to induce regulatory cells which inhibit these diabetogenic
lymphocytes, and to induce immunological tolerance to autoantigens. Two
animal models of autoimmune juvenile diabetes provide a very useful system
to evaluate efficacy of the various proposed therapies, i.e. NOD (nonobese-
diabetic) mice and BB mice. In these animals, several immunoregulation strat-
egies appeared capable to prevent type 1 diabetes (table 2). Only few of these
therapies can be applicable to human diabetes. In high-risk prediabetic subjects,

clinical trials are in progress with different treatments (table 3).
97Overview of Diabetes Management
Immunosuppression Therapy. This form of therapy is directed to prevent
the action of diabetogenic T cells (in the early stage of insulitis) in order
to preserve insulin secretion, at least in the short term. In a study, BCG
antituberculosis vaccination was reported to be effective, with a 66% remission
in the newly diagnosed treated patients as compared to 7% in the controls.
Two other clinical trials with BCG vaccine in newly diagnosed type 1 diabetics
have found no beneficial effects.
Autoantigen Therapy. It is a new promising approach to prevent type 1
diabetes, explored in animal models but whose applicability in humans has
not yet been established. It includes: nasal immunization or oral feeding with
insulin (which is a -autoantigen in susceptible subjects), and nasal immuniza-
tion or oral feeding with GAD, IA-2, ICAp69 and heat-shock protein.
Gene Therapy
It is the frontier of immunological therapy in diabetes mellitus and is
directed to express regulatory cytokines (such as IL-4, IL-10 and TGF-)or
autoantigens in the thymus (selection of T cells in the thymus results in deletion
of cells that cause autoimmunity), thus preventing or delaying type 1 diabetes.
In overt clinical diabetes, both immunoregulatory and immunosuppressive
therapy are unsuccessful. However, it is useful to identify the appearance
of antibodies already in the preclinical period in order to preventively treat
susceptible people (who will develop type 1 diabetes).
Pancreas or Islet Transplantation
Pancreas Transplantation. Pancreas transplantation (total or segmental)
is most often performed together with kidney transplantation, when the latter
is needed. This requires immunosuppression treatment. Transplant of the
pancreas alone is perhaps not advisable, because the advantage of good meta-
bolic control should be evaluated against the risks of the immunosuppression
therapy. However, successful pancreas transplantation, until rejection occurs,

is able to normalize blood glucose. Pancreas transplantation is the only treat-
ment of type 1 diabetes that consistently establishes an insulin-independent,
normoglycemic state. Currently, long-term (?1 year) insulin independence is
achieved in ?80% of recipients of pancreas grafts placed simultaneously with
the kidney and ?70% in recipients of a pancreas after a kidney, and ?60% of
nonuremic recipients of a pancreas alone. The penalty is immunosuppression,
already obligatory for a kidney recipient, but the benefits are improvement in
quality of life and the effect that perfect control of glycemia can have on
secondary complications. Pancreas grafts may function for a long time and
-cell ‘exhaustion’ does not occur in patients with high preoperative C-peptide
(?1.37 ng/ml) levels. Pancreas transplantation can reverse the lesions of dia-
98Belfiore/Iannello
betic nephropathy, but reversal requires more than 5 years of normoglycemia.
Moreover, with the improvement of metabolic control, reduction of hyperten-
sion is often observed. However, pancreas-kidney transplantation provokes
proportional hyperproinsulinemia, which is closely associated with reduced
clearance in the kidneys. Long-term follow-up after transplantation indicates
that GAD antibodies persist and ICA reappear despite immunosuppressive
therapy in patients with functioning pancreas transplants, which may entail
a risk for diabetes recurrence.
Islet Transplantation. Transplantation of isolated islets has not yet yielded
fully satisfactory results. The same is true for the implantation of nonislet
cells engineered to produce human insulin. Yet, islet transplantation could
become an attractive alternative to whole organ transplantation, since it is a
simpler and safer procedure. However, the requirement for long-term immuno-
suppression has limited the indication of islet transplantation to patients re-
ceiving a simultaneous kidney transplant or already bearing one. Although
the majority ofrecipients of islet allografts did notbecome insulin independent,
the long-term results inpatients with even partial graft function are comparable
or better than those achievable with intensive insulin therapy. Indeed, successful

islet transplantation is a difficult challenge, but current achievements with
human islet allografts may greatly improve glycemic control. In some studies,
serum C-peptide levels diminished after a few months, and after 6–10 months
were undetectable. Islet function loss is probably to be explained by rejection
or cytomegalovirus infection. Moreover, trials of donor bone marrow infusions
combined with solid organ transplants are in progress to determine whether
donor-specific tolerance can be achieved with the potential to expand the
future indications of islet transplantation in diabetes.
Drugs Suggested for Both Type 1 and 2 Diabetes
-Glucosidase Inhibitors. These include acarbose (an insoluble -glucosi-
dase inhibitor) and miglitol (a soluble short-term -glucosidase inhibitor).
Both are alternative drugs, orally active, that act at the brush border of the
small intestine by inhibiting -glucosidase, thus interfering with the conversion
of disaccharides to monosaccharides. Therefore, they delay the digestion of
complex carbohydrates and disaccharides by reducing absorption of glucose
and flattening the postprandial glucose level. Acarbose is an antihyperglycemic
agent which has been proposed as add-on therapy in type 2 diabetic patients
not well controlled with diet alone, sulfonylureas, metformin or insulin, and
in type 1 diabetic patients with large meal-related plasma glucose excursions.
Treatment with acarbose has several effects (table 4). The efficacy and side
99Overview of Diabetes Management
Table 4. Eff ects of acarbose treatment
Delay in digestion of complex carbohydrates Increase in breath hydrogen
Reduction in glucose absorption Decrease in nutrient-stimulated insulin
Decrease in postprandial glycemia secretion
Decrease in postprandial insulinemia Decrease in nutrient-stimulated GIP secretion
Decrease in postprandial C-peptide level Decrease in fasting serum triglycerides
Decrease in fasting glycemia Decrease in fasting serum cholesterol
(only in some diabetic patients)
effects of this drug seem to depend on national nutrition habits. Numerous

controlled studies in type 2 diabetes have demonstrated the usefulness of
acarbose, at a dose of 150–600 mg/day, in decreasing fasting and postprandial
glucose levels as well as HbA
1c
concentrations (mean decrease of 0.7%), whether
acarbose was given as first-line therapy in diet-treated diabetic patients or in
combination in individuals already receiving a sulfonylurea, metformin or
insulin. Only a few controlled studies have compared the effects of acarbose
with those of either sulfonylurea or metformin, yielding controversial results.
In type 1 diabetic patients, a small reduction of HbA
1c
levels was also reported
after addition of acarbose to insulin therapy, which in some cases allowed a
slight reduction of daily insulin needs. All these favorable biological effects
occurred without exposing the patient to hypoglycemia or weight gain. A few
studies have also reported favorable effects on postprandial lipid profile and
some other vascular risk factors.
In a recent study, acarbose was suggested as a first-line drug in the treat-
ment of either type 2 diabetic patients with mild elevation of glycemia, alone
or as an adjunct to sulfonylureas, or in type 1 patients associated with insulin
therapy. Acarbose was reported to reduce HbA
1c
by 0.4–1.5% with a maximum
effect at 3 months, which was further well maintained.
In the UKPDS, glibenclamide as well as insulin therapy induced a weight
gain of 4.8 kg, whereas the intake of acarbose (probably through reduction
of hyperinsulinemia) was associated with a mild weight loss (0.7 kg after
1 year follow-up). Acarbose also has the advantage that it does not cause
hypoglycemia, being an antidiabetic rather than a hypoglycemic agent. It is
well tolerated in the dose range of 25–250 mg t.i.d., but small doses (from 25

to 50 mg t.i.d.) can also be effective and cause only fewer gastrointestinal side
effects. Thelatter include meteorism, flatulence, nausea, borborygmus, diarrhea
and abdominal cramps or distension. The frequency of gastrointestinal com-
plaints is not related to the acarbose dose and decreases over time. Adaptation
of intestinal enzyme activity may account for the diminution of intestinal side
100Belfiore/Iannello
effects. The drug was shown to be safe and well tolerated. It may also improve
hyperlipoproteinemia. However, it is not clear whether the extra cost of acar-
bose, when compared to that of older oral antidiabetic agents, is justified since
no study has yet demonstrated its potential benefit on the complications and
long-term prognosis of diabetic patients.
Insulin-Like Growth Factor I (IGF-I). IGF-I (or somatomedin C) is one
of the major components of nonsuppressible insulin-like activity. IGF-I and
insulin share common steps in signal transduction, and the action of IGF-I
on carbohydrate metabolism is preserved in certain insulin-resistant states.
GH hypersecretion and reduced circulating IGF-I levels are prevalent in poor-
controlled insulin-dependent diabetes. Recently, both bacteria and fungi have
been engineered to produce sufficient quantities of recombinant human IGF-I
(rhIGF-I), so that rhIGF-I has been proposed as a potential therapeutic agent
in the treatment of both type 1 and type 2 diabetic patients. rhIGF-I not only
improves glucose tolerance and increases insulin sensitivity, but also improves
insulin secretion in response to intravenous glucose. It is uncertain whether
this is a direct effect of rhIGF-I on the pancreatic -cell or an effect secondary
to improved glycemic control (reduced glucose toxicity). The most appropriate
dose to achieve efficacy and safety remains to be defined.
Nicotinamide. This soluble vitamin of the B group, alone or with sulfonylu-
reas, increases serum C-peptide release in type 1 patients as well as in type 2
diabetic patients with sulfonylurea failure, improving glycemic control.
Suggested Reading
Alejandro R, Ricordi C: Current indications and limits of pancreatic islet transplantation in diabetic

nephropathy. J Nephrol 1997;10:245–252.
Bailey CJ, Turner RC: Metformin. N Engl J Med 1996;334:574–579.
Fischer S, Hanefeld M, Spengler M, Boehme K, Temelkova Kurktschiev T: European study on dose-
response relationships of acarbose as a first-line drug in non-insulin-dependent diabetes mellitus:
Efficacy and safety of low and high doses. Acta Diabetol 1998;35:34–40.
Genuth S: Management of adult onset diabetes with sulfonylurea drug failure: Diabetes mellitus, perspec-
tive on therapy. Endocrinol Metab Clin North Am 1992;21:351–369.
International Diabetes Federation (IDF), 1998–1999 European Diabetes Police Group: A Desktop Guide
to Type 2 (Non-Insulin-Dependent) Diabetes mellitus. Brussels, IDF, 1999.
Laakso M: Benefits of strict glucose and blood pressure control in type 2 diabetes. Lessons from the UK
Prospective Diabetes Study. Circulation 1999;99:461–462.
Lebovitz HE: Oral hypoglycemic agents; in Rifkin H, Porte D (eds): Diabetes mellitus. Theory and
Practice, ed 4. New York, Elsevier, 1990, pp 554–574.
Linse L, Brasseur R, Malaisse WJ: Conformational analysis of non-sulfonylurea hypoglycemic agents of
the meglitinide family. Biochem Pharmacol 1995;50:1879–1884.
Masetti M, Inverardi L, Ranuncoli A, Iaria G, Lupo F, Vizzardelli C, Kenyon NS, Sutherland DE:
Pancreas transplantation as a treatment for diabetes: Indications and outcome. Curr Ther Endocrinol
Metab 1997;6:496–499.
101Overview of Diabetes Management
Moses AC, Morrow LA, O’Brien M, Moller DE, Flier JS: Insulin-like growth factor I as a therapeutic
agent forhyperinsulinemic insulin-resistant diabetes mellitus. Diabetes Res Clin Pract 1995;28(suppl):
185–194.
Singh B: Possible immunological treatment for type 1 diabetes in the 21st century. Pract Diabetes 1997;
14:197–200.
Thomson RG, Pearson L, Schoenfeld SL, Kolterman OG, and the Pramlintide in Type 2 Diabetes Group:
Pramlintide, a synthetic analog of human amylin, improves the metabolic profile of patients with
type 2 diabetes using insulin. Diabetes Care 1998;21:987– 993.
F. Belfiore, Institute of Internal Medicine, University of Catania, Ospedale Garibaldi,
I–95123 Catania (Italy)
Tel. +39 095 330981, Fax +39 095 310899, E-Mail francesco.belfi

102Belfiore/Iannello
Chapter VII
Belfiore F, Mogensen CE (eds): New Concepts in Diabetes and Its Treatment.
Basel, Karger, 2000, pp 103–110

Clinical Emergencies in Diabetes.
1: Diabetic Ketoacidosis and
Hyperosmolar Nonketotic Syndrome
F. Belfiore, S. Iannello
Institute of Internal Medicine, University of Catania, Ospedale Garibaldi,
Catania, Italy
Diabetic Ketoacidosis
Diabetic ketoacidosis (DKA) is the classical acute metabolic complication
of type 1 diabetes, although it may also occur much less commonly in type 2
diabetes, being primarily due to severe insulin deficiency.
The hormonal pattern favoring DKA is represented by severe insulin defi-
ciency and/or excessofcounterregulatoryhormones (or stress hormones) which
include glucagon, catecholamines, cortisol and GH. Among counterregulatory
hormones, however, glucagon plays the major role, so that the key hormonal
condition favoring DKA is depression of the insulin/glucagon ratio. Insulin de-
ficiency may occur because ofinterruption or inadequacy of insulin administra-
tion or in the setting of the first manifestation of type 1 diabetes. Counter-
regulatory hormones may increase following physical (infections, surgery,
trauma) or emotional stresses, and oppose insulin action. In addition, epineph-
rine may also stimulate glucagonrelease,which is also favored bylackofinsulin.
The deficiency of insulin reduces peripheral glucose utilization, while the
low insulin/glucagon ratio stimulates hepatic gluconeogenesis (and therefore
hepatic glucose production) by inducing a decrease of the key regulatory
compound fructose-2,6-P (which stimulates glycolysis and depresses glucone-
ogenesis). Gluconeogenesis utilizes the gluconeogenic precursors which come

from muscle (pyruvate and lactate derived from glucose, alanine derived from
proteolysis as well as from amination of pyruvate, and other amino acids
derived from proteolysis) and to a minor extent from adipose tissue (glycerol,
released together with FFA during lipolysis). These changes result in marked
103
hyperglycemia. The lack of insulin will also produce a high rate of lipolysis
(insulin exerts an antilipolytic action by inhibiting the hormone-sensitive li-
pase), so that the adipose tissue releases large amounts of FFA with consequent
hyperafflux of FFA to the liver. As outlined in figure 2 and its legend in
chapter I, in the liver the FFA may be reesterified to triglycerides (in the
cytosol) or -oxidized to acetyl-CoA. Triglycerides so formed may be deposited
in the hepatocytes (causing steatosis) or may be incorporated into VLDL
which are secreted into the circulation. The -oxidation of FFA to acetyl-
CoA occurs after the transport of FFA into the mitochondria, effected by the
enzyme CPT-1. Glucagon activates the latter mechanism (ketogenesis) both
by enhancing the availability of carnitine (a metabolite required for the CPT-1
reaction) and, especially, by lowering the concentration of malonyl-CoA, a
key regulatory compound which inhibits CPT–1. Glucagon lowers the malonyl-
CoA level by two mechanisms: (a) by inhibiting glycolysis (through the diminu-
tion of the regulatory compound fructose-2,6-P – see above) and therefore
the concentration of pyruvate, through the sequence pyruvate (cytoplasm) K
acetyl-CoA (mitochondria) K citrate (mitochondria) K citrate (cytoplasm)
K acetyl-CoA (cytoplasm) K malonyl-CoA (cytoplasm), and (b) by inhibiting
the enzyme acetyl-CoA carboxylase that catalyzes the latter step (conversion
of acetyl-CoA to malonyl-CoA). The resulting activation of -oxidation of
FFA leads to formation of excessive amounts of acetyl-CoA which is then
condensed to form -hydroxybutyrate (two molecules of acetyl-CoA are con-
verted into acetoacetate, which can then be converted to -hydroxybutyrate).
Thus, in DKA the liver exerts two main functions: (a) as concerns carbohy-
drate metabolism, it takes up gluconeogenic precursors and releases glucose

(producing hyperglycemia, osmotic diuresis and dehydratation, with osmolality
in the 310–330 mosm/l range) and (b) concerning lipid metabolism, it takes
up FFA and releases VLDL and ketone bodies (which results inhypertriglyceri-
demia and acidosis).
Clinical Picture
Preceded by polyuria (due to osmotic diuresis), the clinical picture begins
with anorexia, nausea, vomiting (which precludes oral fluid intake) and, often,
abdominal pain (periumbilical and constant) which can mimic a surgical emer-
gency. If treatment is not started, alterations in consciousness ensue, which
may evolve to frank coma. Physical signs are due to dehydration and acidosis
and include: sweet, sickly smell of the patient’s breath, deep and rapid respira-
tion (Kussmaul respiration), low jugular venous pressure and tachycardia. In
most severe cases, vascular collapse and acute renal failure may develop. White
blood cell count may be markedly elevated, even in the absence of infection.
Body temperature is normal or tendencially low, unless infections develop.
104Belfiore/Iannello
Laboratory Data
Laboratory data show increase of the anion gap, and abnormalities in
potassium, sodium, triglycerides, azotemia and amylase. The anion gap is the
difference between the routinely measured cations and anions. Normally, to
maintain a pH close to neutrality (7.35–7.45), the sum of cations, including
sodium, potassium, calcium and magnesium, should be approximately equal
to the sum of anions, such as chloride, bicarbonate, and other routinely not
measured anions comprising some organic acids (lactic acid, pyruvic acid,
FFA, etc.) and inorganic acids (phosphates, sulfates) as well as anionic proteins
(albumin and others). When, in pathologic conditions, an acidic compound
enters or increases in the blood (ketone bodies in the case of DKA), it is
neutralized with the sodium (and potassium) subtracted from bicarbonates.
The latter in this way become carbonic acid which rapidly dissociates into
CO

2
(which will be lost with the breath) and H
2
O (which will be eliminated
by the kidneys). As result of this process, the concentration of blood bicarbo-
nates falls to an extent proportional to the amount of the acidic compounds
which originate from the perturbation. In the clinical setting, the cations and
anions measured as routine are Na
+
,K
+
,Cl
Ö
and HCO
Ö
3
whereas other
cations and anions remain unmeasured. Therefore, considering only the rou-
tinely measured cations and anions there is, already in the normal state, an
anion gap which can be calculated as follows: Serum anion gap>
([Na
+
]+[K
+
])Ö([Cl
Ö
]+[HCO
Ö
3
]), with normal values of about 14–16 mmol/

l or, in a simpler way: Serum anion gap>[Na
+
]Ö([Cl
Ö
]+[HCO
Ö
3
]), with nor-
mal values of about 10–12 mmol/l. About half of the normal anion gap is
accounted for by albumin and the other by anionic proteins. With the technical
procedures in use in recent years, which yield higher values for Cl
Ö
, the normal
anion gap may be remarkably lower. It is therefore useful to refer to the normal
values of the local laboratory. In DKA, the increased anion gap is due to the
fall in bicarbonate (6–10 mmol/l) caused by the accumulation in the blood of
the ketone bodies (acetoacetate and -hydroxybutyrate), with minimal contri-
bution of lactate and FFA.
Potassium content of total body decreases markely, although serum K
+
levels may be initially normal due to the cell buffering mechanism (exchange
of intracellular K
+
for extracellular H
+
), before diminishing as a consequence
of the osmotic diuresis (together with other electrolytes such as magnesium
and phosphates). Sodium concentration tends to be moderately lowered (in
the 130–132 range) due to the osmotic shift of water into the plasma space,
and may become severe if prolonged vomiting plus water drinking occur.

Triglycerides are elevated, sometimes to very high values, due to both
enhanced hepatic prodution of VLDL (stimulated by the hyperafflux of FFA to
the liver) and diminished VLDL disposal due to reduced activity of lipoprotein
105Clinical Emergencies in Diabetes