New Concepts in Diabetes and Its Treatment - part 3 docx

muscles, adipose tissue and hepatocytes, while normalizing a wide range of
metabolic abnormalities associated with insulin resistance. Reported effects
include: (a) decrease in plasma triglyceride, FFA and LDL cholesterol levels
and increase in plasma HDL cholesterol; (b) increased expression of glucose
transporters GLUT-1 and GLUT-4; (c) activation of glycolysis in hepatocytes;
(d) antagonism towards some of the effects of TNF; (e) decrease in blood
pressure; (f) inhibition of vascular smooth muscle cell proliferation and
hypertrophy; (g) enhanced endothelium-dependent vasodilation, and (h) anti-
oxidant action. Finally, although thiazolidinediones do not stimulate insulin
secretion, they improve the secretory response of -cells to insulin secretagog-
ues.
Rosiglitazone (aPPARAgonist). Rosiglitazone, like other thiazolidine-
dione compounds, is a PPAR agonist, inasmuch as it potently and specifically
stimulates peroxisome proliferator-activated receptors- (PPAR) and sensi-
tizes cells to insulin. Indeed, rosiglitazone is an antidiabetic agent which en-
hances sensitivity to insulin in the liver, adipose tissue and muscle, resulting
in increased insulin-mediated glucose disposal. This compound, therefore,
improves insulin resistance, which is a key underlying metabolic abnormality
in most patients with type 2 diabetes. In contrast with troglitazone, rosiglita-
zone does not appear to be hepatotoxic, on the basis of clinical and in vitro
studies, and does not induce cytochrome P
450
3A4 metabolism. However, the
drug is contraindicated in patients with history or signs/symptoms of liver
diseases and its use requires monitoring of liver function tests. Moreover,
rosiglitazone doesnot interactsignificantly with nifedipine, oral contraceptives,
metformin, digoxin, ranitidine, or acarbose.
In clinical trials, rosiglitazone 2–12 mg/day (as single daily dose or two
divided daily doses) improved glycemic control in type 2 diabetic patients, as
shown by decrease in fasting plasma glucose and glycated hemoglobin
(HbA

1c
). Addition of rosiglitazone 2–8 mg/day to existing sulfonylurea, met-
formin or insulin therapy achieved reductions in fasting plasma glucose and
HbA
1c
.
Consistent with its mechanism of action, rosiglitazone appears to be
associated with a low risk of hypoglycemia (=2% of patients receiving mono-
therapy) and did not increase the risk of alcohol-induced hypoglycemia.
Other Compounds
The long-acting, nonsulfhydryl-containing ACE inhibitor, trandolapril,
alone and in combination with the Ca
2+
-channel blocker, verapamil, can sig-
nificantly improve whole-body glucose metabolism by acting on the insulin-
54Belfiore/Iannello
sensitive skeletal muscle glucose transport system in obese Zucker rats. Data
on the role of TNF raise the possibility that pharmacological inhibition of
this factor may provide a novel therapeutic target to treat patients with type 2
diabetes.
Suggested Reading
American Diabetes Association: Consensus Development Conference on Insulin Resistance, Nov 5–6,
1997. Diabetes Care 1998;21:310–314.
Bell PM, Hadden DR: Metformin. Endocrinol Metab Clin North Am 1997;26:523–537.
Scheen AJ: Clinical pharmacokinetics of metformin. Clin Pharmacokinet 1996;30:359–371.
Daniel JR, Hagmeyer KO: Metformin and insulin: Is there a role for combination therapy? Ann Pharma-
cother 1997;31:474–480.
Davidson MB, Peters AL: An overview of metformin in the treatment of type 2 diabetes mellitus. Am J
Med 1997;102:99–110.
DeFronzo RA, Bonadonna RC, Ferrannini E: Pathogenesis of NIDDM: A balanced overview. Diabetes

Care 1992;15:318–368.
Melchior WR, Jaber LA: Metformin: An antihyperglycemic agent for treatment of type II diabetes. Ann
Pharmacother 1996;30:158–164.
UK Prospective Diabetes Study (UKPDS) Group: Effect of intensive blood-glucose control with metformin
on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998;352:854–865.
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
55Insulin Resistance and Its Relevance to Treatment
Chapter IV
Belfiore F, Mogensen CE (eds): New Concepts in Diabetes and Its Treatment.
Basel, Karger, 2000, pp 56–71

Diet and Modification of
Nutrient Absorption
S. Iannello
Institute of Internal Medicine, University of Catania, Ospedale Garibaldi,
Catania, Italy
Diet
Introduction
In the treatment of diabetes mellitus, changes in lifestyle play a major
role, in addition to treatment with insulin or oral glucose-lowering drugs. For
most patients with type 2 diabetes, the changes in lifestyle (concerning diet
and exercise) are the cornerstone of treatment whereas the pharmacologic
intervention represents a supplementary treatment for those patients who do
not respond adequately to lifestyle changes.
Dietary caloric restriction ameliorates hyperinsulinemia and hyperglyce-
mia in obese type 2 diabetics (and improves other metabolic parameters; see
table 1) and reduces the incidence of type 2 diabetes in subjects at risk or with
impaired glucose tolerance (IGT). Glucose tolerance and insulin sensitivity

improve when normal body weight is achieved or approached. Indeed, even
a 7–10% of weight loss is enough to improve insulin resistance in all obese
type 2 diabetics. Nutritional needs are different in type 1 (lean) or type 2
(overweight or obese) diabetic patients. Diet education is crucial and requires
the participation of the patient and its family in the planning-diet process and
in the implementation of the adequate strategies to promote adherence to
dietary intervention.
Goals of dietary therapy in diabetes are to reach and maintain ideal body
weight (IBW), to maintain fasting and postprandial glycemic levels as close
as possible to normal andto achieve optimal blood lipid values, while providing
adequate caloric intake as required for the various metabolic needs.
56
Table 1. Effects of weight loss on altered
parameters in obese type 2 diabetics
Insulin resistance
Hyperglycemia
Hypertriglyceridemia
Total hypercholesterolemia
LDL cholesterol
HDL cholesterol !
Hypertension
Modern recommended diet for diabetes is relatively high in complex carbo-
hydrates (55–60% of total calories) and fibers, low in fats (25–30%) especially
saturated (=10%, to reduce dyslipidemia and atherosclerosis associated to
diabetes) and limited, but adequate, in proteins (15%).
Body Weight and Fat Distribution
Increase in body weight (related to height) or frank obesity are highly
relevant to the pathogenesis of type 2 diabetes. The ‘ideal’ body weight (actually
the weight associated with the lowest mortality) for each inch of height can
be derived from the 1983 Metropolitan Life Insurance Weights for Heights

tables, referring to 4.2 million subjects aged 20–59. For people over 55, the
tables of median weights derived from the data of the National Health and
Nutrition Examination Surveys (NHANES) may also be used. A commonly
used parameter relating weight to height is the body mass index (BMI), which
is calculated as follows: BMI>weight (kg)/height (m)
2
. In the clinical setting,
a BMI from 20 to 25 can be regarded as ‘normal’ while a BMI ?27 can be
regarded as indicative of overweight. In some studies, the following values
have been suggested for the BMI: =23.9>normal value for women; =25>
normal value for men; 23.9–28.6 (female) and 25–30 (male)>overweight;
?28.6 (female) or ?30 (male)>obesity. In 1995, the WHO established the
following BMI values: normal>18.5–24.9; overweight, 1st degree>25.0–29.9;
overweight, 2nd degree (or obesity)>30.0–39.9; overweight, 3rd degree (or
severe obesity) P40. It should be noted that the BMI associated with the
lowest mortality increases with age, ranging from =20 at age 20 to about 28
at age 70.
It should be noted that from the above values of BMI it is possible
to calculate the corresponding weight values through the formula: weight
(kg)>BMI¶height (m)
2
. Assessment of adipose tissue distribution is of para-
mount importance to distinguish between visceral (or central or abdominal
57Diet and Modification of Nutrient Absorption
or android) obesity and subcutaneous (or gynoid) obesity. A largely used
parameter is the the waist-to-hip ratio (WHR), i.e. the ratio between the
circumference at the waist and that at hip level. The cut-off value distin-
guishing normal from abnormal WHR has not yet been definitely established.
In some studies, values of WHR ?0.81 for female and ?0.92 for male
subjects were considered indicative of visceral/android obesity whereas lower

WHR values were regarded as indicative of subcutaneous/gynoid obesity.
The American Heart Association has reported that a WHR ?0.80 should
be used to indicate increased risk of cardiovascular disease in women. Other
recent data suggest an upward shift in the critical threshold for WHR to
P0.90, at which point there is an elevation in cardiovascular disease risk
factors.
It has also been shown that the simple waist circumference is a good
index of central (visceral) obesity, as is also the sagittal diameter. The values
of waist circumference indicating increased visceral fat and cardiovascular risk
were found to be ?94 cm in men and ?80 cm in women. Recently, it has
been reported that, while a waist circumference P96.5 cm is associated with
high cardiovascular risk, even a waist circumference P76.2 cm entails signifi-
cant risk. Interestingly, threshold values of waist girth corresponding to critical
amounts of visceral adipose tissue do not appear to be influenced by sex or
by the degree of obesity. It has also been estimated that a waist girth of
approximately 95 cm in both sexes, WHR values of 0.94 in men and of 0.88
in women, and sagittal diameters of 22.8 cm in men and 25.2 cm in women
correspond to a critical amount of visceral adipose tissue, equal to a fat area
of 130 cm
2
. The amount of intra-abdominal (visceral) fat may be precisely
measured with computed tomography (CT), which however is an expensive
procedure. Echography is also being used to quantify the fat tissue and its
distribution.
Total Caloric Requirement
The caloric requirement of diabetic patients is similar to that of normal
subjects and changes with age, sex and occupational daily work or physical
activity (i.e. patients engaged in a heavy activity require a larger caloric intake).
Other factors may influence dietary regimen, as the type of diabetes and
the associated diseases. In lean adult diabetic patients, caloric intake should

maintain a normal weight, while in obese diabetic patients (especially with
upper body fat distribution) a caloric restriction is required to achieve a
desirable weight. Noticeably, dietary restriction may improve metabolic control
even before weight loss is attained.
58Iannello
Sedentary normal patients need approximately 30 cal/kg IBW/day while
active normal patients need approximately 35–40 cal/kg/day. Overweight sed-
entary patients need 20–25 cal/kg/day and active obese patients need 30–35
cal/kg/day, while underweight patients need 35 cal/kg/day if sedentary and
40–50 cal/kg/day if active. In elderly sedentary diabetic patients, 20 cal/kg/day
are usually required (after 50 years of age approximately 10% less calories for
each decade is required).
A more accurate assessment of the caloric needs may be achieved by using
appropriate formulas to calculate the rest metabolic rate (RMR), such as those
of Harris & Benedict which are based on weight, height, age and sex. Since
subjects of the same weight but of different height have similar RMR, formulas
may be simplified by considering only weight, age and sex. RMR should be
increased by 30, 50 or 70% for low, medium or high levels of physical activity.
Table 2 shows the caloric requirement according sex and age for selected
weights and activity levels, based on similar formulas.
In diabetic children the caloric needs depend on the rate of growth and
activity pattern. Children 4–6 years old require 90 cal/kg/day and children
7–10 years old require 80 cal/kg/day. It is important to allow an adequate
caloric intake in juvenile diabetes. Caloric requirement in children may also
be calculated by adding to the baseline value of 1,000 cal/day the amount of
100–125 cal for every year of age up to 12 years. Youngsters should consume
3 meals daily with 2 or 3 snacks (eaten at the same time each day) to minimize
glycemic fluctuations and the risk of hypoglycemic episodes. After the caloric
content and the composition of the diet are established, the prescription of a
diet was in the past made by utilizing the data in the Exchange Lists for Meal

Planning published by the American Diabetes Association. A more useful
approach might be to use the precalculated diets (of various caloric content)
prepared by several diabetes associations or other authoritative sources. How-
ever, it is now recognized that the diet should be individualized and prepared
by taking into account the eating habits and other lifestyle factors.
It is clinically relevant that 7–35% of adolescent females with type 1
diabetes may have an eating disorder, such as anorexia or bulima nervosa.
Dietary Components
Dietary Carbohydrate
Carbohydrates are the most important source of energy and provide about
4 cal/g. The carbohydrate intake of diabetic patients should be equal to that
of nondiabetic subjects. A dietary carbohydrate content of about 50–60% of
total energy intake seems adequate in diabetic patients.
59Diet and Modification of Nutrient Absorption
Table 2. Caloric needs according to age, sex, weight
1
and physical activity
Sex and Weight Physical activity
age group kg
rest rest low low medium medium high high
kcal/kg kcal/day kcal/kg kcal/day kcal/kg kcal/day kcal/kg kcal/day
Men
18–30 years old 68 25 1,723 33 2,240 38 2,585 43 2,929
72 25 1,784 32 2,319 37 2,675 42 3,032
76 24 1,844 32 2,397 36 2,766 41 3,135
80 24 1,905 31 2,476 36 2,857 40 3,238
Average 74 24.5 1,814 31.9 2,358 36.8 2,721 41.7 3,084
31–60 years old 68 25 1,667 32 2,167 37 2,500 42 2,833
72 24 1,713 31 2,227 36 2,570 40 2,912
76 23 1,760 30 2,288 35 2,639 39 2,991

80 23 1,806 29 2,348 34 2,709 38 3,070
Average 74 23.5 1,736 30.6 2,257 35.3 2,605 40.0 2,952
Women
18–30 years old 56 24 1,323 31 1,720 35 1,985 40 2,249
60 23 1,383 30 1,798 35 2,074 39 2,351
64 23 1,442 29 1,875 34 2,164 38 2,452
68 22 1,502 29 1,953 33 2,253 38 2,553
Average 62 22.8 1,413 29.7 1,836 34.2 2,119 38.8 2,401
31–60 years old 56 23 1,309 30 1,701 35 1,963 40 2,225
60 22 1,342 29 1,744 34 2,012 38 2,281
64 21 1,374 28 1,787 32 2,062 37 2,336
68 21 1,407 27 1,829 31 2,111 35 2,392
Average 62 22.0 1,358 28.6 1,765 33.0 2,037 37.4 2,309
1
Caloric needs at rest (RMR) per day were calculated according to the following formulas (as reported
by G. Bray):
for 18- to 30-year-old men: (0.0630¶kg weight+2.8957)¶240;
for 31- to 60-year-old men: (0.0484¶kg weight+3.6534)¶240;
for 18- to 30-year-old women: (0.0621¶kg weight+2.0357)¶240;
for 31- to 60-year-old women: (0.0342¶kg weight+3.5377)¶240.
RMR was then multiplied by 1.3, 1.5 or 1.7 for low, medium or high physical activity, respectively.
Carbohydrates are available as complex or simple sugars. In diabetic
patients, complex carbohydrates or polysaccharides should be preferred. Com-
plex carbohydrates include: starches (present in large amounts in rice, cereals,
potatoes, pulses and vegetable roots), dextrins (derived from hydrolyzed
starch), glycogen (contained in liver and muscle), cellulose or pectins (indigest-
60Iannello
Table 3. Glycemic index of some foods
Bread 100% Beans 65%
Rice 83% Grapes 62%

Potatoes 81% Apples 53%
Bananas 79% Milk 49%
Spaghetti 66% Pears 47%
Oranges 66% Lentils 43%
ible complex carbohydrates contained in plant foods). In diabetics, simple
carbohydrates should be restricted. They include monosaccharides (glucose
present in oranges and carrots, fructose present in honey and ripe fruits, and
galactose derived from hydrolyzed lactose) and disaccharides (sucrose present
in beetroot and sugar cane, lactose present in milk, and maltose derived
from hydrolyzed starch). The formerly claimed diabetogenic effect of sucrose
overconsumption has not been confirmed by epidemiological or experimental
studies. However, in diabetic patients, sucrose-rich foods cause a rapid rise in
glycemic values, which can be prevented by consuming these foods as part of
a mixed meal. The recommended disaccharide (sucrose plus other glucose-
containing disaccharides) consumption by diabetic people should not exceed
5–10% of the total caloric intake. Sucrose addition as sweetener should not
exceed 20 g/day. Fructose is a natural monosaccharide, used as a sweetener.
It is converted to glucose (and stored as glycogen) or triglyceride in liver.
In diabetics with insulin deficiency and impaired hepatic glycogen synthesis,
fructose-derived glucose contributes to the hyperglycemia. Thus, the safety of
fructose use in diabetes is a debated topic. Starches are hydrolyzed to dextrins,
then to maltose and finally to glucose (through the effect of gastric acid and
intestinal enzymes). They are useful in the diabetic diet because they are
slowly digested and absorbed, inducing lower increments of the glycemic and
insulinemic values than equivalent amounts of glucose or simple sugars.
It is well established that equimolar amounts of carbohydrate in different
foods induce different glycemic postprandial excursions. Jenkins et al. [1981]
have elaborated a ‘glycemic index’, representing the incremental area under
2 h glycemic curve of food divided by the corresponding area under 2 h
glycemic curve after ingestion of a portion of white bread containing equivalent

amounts of carbohydrates, multiplied by 100 (table 3). Reference can also be
made to the glycemic response after glucose ingestion, in which instance the
glycemic index for glucose is 100. Foods containing simple sugars have a high
glycemic index, raising glycemia and insulinemia faster and to a greater extent,
and therefore are contraindicated in diabetic patients. However, several factors
can influence the food glycemic response, including: (a) type of diabetes, age,
61Diet and Modification of Nutrient Absorption
sex, body weight, physical activity and race; (b) physical form of starches, size
of food particles, food processing and preparation, fiber or fat or protein
content of food, different digestion or absorption or transit of different starch-
or sugar-containing foods, etc.
Dietary Fat
Fats are an important source of energy, providing about 9 cal/g, and
difference in the amount and type of dietary fat can have relevant metabolic
effects. In patients with IGT or type 2 diabetes or decompensated type 1
diabetes, elevated plasma levels of triglycerides and cholesterol frequently
occur. Both hypertriglyceridemia and hypercholesterolemia respond in part
to diet alterations. The recommended fat intake is O30% of total calories
(=10% of saturated fats, 6–8% of polyunsaturated fats and 14–12% of mono-
unsaturated fats given as olive oil). Low-fat diets are often high in carbohy-
drate (being the proportion of proteins relatively constant), which may favor
hypertriglyceridemia. This effect may be attenuated by supplementation with
fibers.
Saturated fats (which are solid at room temperature) are most often from
animal source (milk, butter, cheese, bacon fat, fatty meat, etc.), but they are
also contained in high concentrations in coconut and palm oils. Diets high in
saturated fat are atherogenic (increasing total and LDL cholesterol levels) and
favor insulin resistance; thus, a diet restricted in saturated fats is recommended.
Unsaturated fats (which are liquid at room temperature) derive from vegetable
source and include monounsaturated and polyunsaturated fats. A diet high

in monounsaturated fatty acids or MUFA (most often assumed as olive oil,
as it occurs with the Mediterranean diet) does not increase LDL levels, may
improve insulin sensitivity, glycemic control and HDL cholesterol levels, and
decreases plasma triglycerides. For this reason, the American Diabetes Associ-
ation (ADA) and the European Association for the Study of Diabetes (EASD)
set free the intake of monounsaturated fat in diabetic patients. On the contrary,
a diet high in polyunsaturated fatty acids or PUFA (such as corn, sunflower
and safflower oils) reduces total and LDL cholesterol but decreases HDL
cholesterol as well; moreover, some data from the literature would suggest
that they may promote carcinogenesis in experimental animals.
The intake of cholesterol should be restricted to =300 mg daily, avoiding
cholesterol-rich foods (table 4), which can produce a 15–20% reduction of
plasma cholesterol level. Excessive cholesterol intake causes increase in total
plasma cholesterol and LDL cholesterol, which can be reduced by increasing
the polyunsaturated/saturated fat ratio (which should be kept at ?0.8).
The polyunsaturated fatty acids of the omega-3 class (eicosapentaenoic
and docosahexaenoic acids), which can be formed from -linolenic acid
62Iannello
Table 4. Cholesterol content of some foods (mg/100 g)
Brain 2,000 Oysters 200
Egg yolk 1,480 Lobster 150
Lamb kidney 804 Cream 133
Chicken liver 746 Cheese, cheddar 100
Caviar 350 Whole milk 34
Butter 250 Egg white 0
(through elongation and desaturation), are contained in fish oils and are useful
to reduce the coronary risk of diabetic patients (decreasing VLDL production,
lowering arterial blood pressure, reducing platelet aggregation and prolonging
bleeding time). This explains the low prevalence of coronary heart disease in
the Greenland Eskimos (consuming 5–10 g of fish oil fatty acids daily for a

lifetime) and in the Japanese fish eaters of coastal villages. A dietary supplemen-
tation with fish or fish oil should, therefore, be recommended. It would be
advisable to replace in 2–3 meals a week the red meat with fish. However, three
considerations speak against an excessive intake of fish or fish oil: (a) fishes of
coastal waters and lakes accumulate a large quantity of mercury and chlori-
nated hydrocarbons; (b) in some type 2 diabetic patients, 3-omega fatty acids
may deteriorate glycemia (both increasing hepatic glucose production and
impairing insulin secretion), and (c) in patients with hypercholesterolemia but
without hypertriglyceridemia the metabolic effects of fish oil are uncertain.
Recently, new fat substitutes were proposed for use in the diet of diabetic
patients. One of these products is named Olestra and is made from sucrose
and long-chain fatty acids, is heat-stable, tastes like vegetable oil, promotes
cholesterol excretion and is calorie-free being not metabolized or absorbed.
Another fat substitute is named Simpless and is made from egg white or whey
protein of milk (using a process of microparticulation which confers a taste
of fat), has a low-calorie content, and is useful to make ice-cream, yogurt,
margarine, cheeses, etc.
Dietary Protein
Proteins are formed by amino acids and provide about 4 cal/g of energy.
Some amino acids cannot be synthesized by humans and must be introduced
with diet (essential amino acids). The animal proteins (contained in meat,
chicken, fish, egg, milk, etc.) are of high biological value, containing adequate
amount of essential amino acids, while vegetable proteins (peas, beans, dry
fruits, cereals, etc.) are of low biological value, laking some essential amino
acids. Leucine and arginine have important biologic effects, stimulating insulin
63Diet and Modification of Nutrient Absorption
secretion, while other amino acids are gluconeogenic and ketogenic. The
amount of proteins that should be recommended to diabetic patients depends
upon several factors, such as the patient age, the nutritional status (undernutri-
tion or malnutrition) and particular situations (growing, pregnancy, lactation,

debilitating diseases, nephropathy, uremia, hepatic diseases, etc.).
The role of dietary protein in the development and progression of diabetic
nephropathy is debated while it is clearly defined that a moderately low protein
diet is the best approach for treating renal disease of diabetic patients (see
chapter on Diabetic Nephropathy). The recommended amount of proteins in
diabetic diet is of 12–20% of total calories. In diabetic subjects a high-protein
diet can increase renal blood flow, glomerular filtration rate and intra-
glomerular pressure, accelerating glomerulosclerosis to end-stage renal failure
(Brenner’s hypothesis). It is useful to substitute, at least in part, vegetable
proteins for animal proteins, even if proteins from animal source do not seem
to significantly increase kidney workload. In subclinical or incipient stages of
diabetic nephropathy, glycemic control and low protein intake (0.8 g/kg IBW/
day) may reduce renal blood flow, restore normal glomerular hemodynamics,
decrease proteinuria and delay the progression of nephropathy. In overt diabetic
nephropathy with albumin excretion, the recommended protein restriction
should be from 0.6 to 0.8 g/kg/day. In cases of protein restriction, essential
amino acids should be supplemented. To maintain energy balance, a low
protein diet must be high in carbohydrates and fats and may exacerbate
hyperglycemia, hypertriglyceridemia or hyperinsulinemia, increasing total and
LDL cholesterol and decreasing HDL cholesterol. Moreover, in diabetic pa-
tients a low protein dietary content may favor a negative nitrogen balance and
muscle wasting.
Dietary Fibers
In normal subjects and type 2 diabetic patients, several studies demon-
strated an improvement of glucose tolerance and a reduction of insulin secre-
tion when a diet high in fiber was consumed. In type 1 diabetics, high-fiber
diet was found to decrease glycosuria, as well as basal and postprandial
glycemic levels. Moreover, high-fıber intake may improve other metabolic
parameters, and may also exert a preventive effect on cancer of bowel and
diverticular disease (diseases favored by the modern tendency to consume low-

fiber, refined foods). Dietary fibers are heterogeneous and consist of several
complex polysaccharides resistant to gastrointestinal digestive enzymes (even
if certain fibers are metabolized in the colon). Fibers can be water soluble or
insoluble and their effects are variable according to the different biochemical-
physiological characteristics. Celluloses, hemicelluloses and lignins bind water
and cations and are insoluble (wheat products and bran) whereas pectins,
64Iannello
Table 5. Foods naturally rich in fibers
Legumes Beans, peas, chickpeas, lentils
Vegetables Broccoli, artichokes, zucchini, carrots, eggplants, string beans,squash, potatoes,
tomatoes, celery, cabbage, onions, beets, fennels, turnips, radishes, asparagus,
cucumbers, cauliflower, mushrooms
Fruits Apples, blackberries, pears, strawberries, oranges, plums, bananas, grapefruit,
pineapples, peaches, cherries, apricots, kiwis, mandarins
Cereals Bran (100%), bread (rye), bread (whole-grain wheat), rice, wheat flour (whole
grain)
gums and mucilages form gels and are soluble (oats, fruits and legumes). The
foods naturally rich in fibers are legumes, roots, tubers, whole-grain cereals,
fruits and green leafy vegetables (table 5).
Usually, the soluble fibers (especially those with high viscosity) exert useful
metabolic effects, whereas insoluble fibers contribute to increase fecal bulk,
promote movements of intestinal content, being useful in constipation (which
may also result from autonomic diabetic neuropathy). The physiological effects
of fibers are influenced by osmolality or pH, mixture of fibers and foods,
water retention, fermentation by bacteria, etc. Soluble fibers would exert their
beneficial effects on carbohydrate and lipid metabolism through several mecha-
nisms, which include: (a) satiating effect; (b) delayed gastric emptying time;
(c) decreased release of gut hormones, including intestinal insulin secretagogues
(as GIP); (d) delayed small intestine transit time and altered colonic emptying
time; (e) binding of bile acids, with impaired intestinal absorption of choles-

terol; (f) formation of gels that sequester or hide nutrients (carbohydrates,
fats, cholesterol, etc.), providing a physical barrier that separates complex
carbohydrates from digestive enzymes, with reduced digestion and absorption
in small intestine; (g) increase of fecal bulk with accelerated intestinal transit,
which may reduce absorption of nutrients; (h) fermentation by the bacteria
in the colon to gases and short-chain fatty acids, which would suppress neoglu-
cogenesis, and (i) improved peripheral insulin sensitivity and increased insulin
receptor binding.
It is interesting that fibers have the best effects when naturally contained
in aliments while they have poorer effects when added as pharmaceutical
products to dietary foods. Diets useful to improve both fasting and postpran-
dial hyperglycemia in diabetic patients have been suggested, which are rich
in fibers naturally contained in foods. These diets are very rich in carbohy-
drates (up to 70%) and fibers (up to 35 g/day/1,000 kcal, both in soluble
65Diet and Modification of Nutrient Absorption
and insoluble forms). In these fiber-rich diets, fibers would mitigate the
deleterious effect of the high carbohydrate content on glucose metabolism,
and would reduce total or LDL cholesterol and triglycerides (only in dia-
betics), while lowering blood pressure and favoring weight loss in obese
patients. In hypocaloric diets, the usually recommended fiber supplementation
is in the amount of 25 g/1,000 kcal (associated with high water assumption
to induce fiber swelling).
High-fiber diets can cause (especially in the first 7–10 days) cramping,
abdominal discomfort, flatulence and diarrhea. These diets may also impair
absorption of minerals and vitamins if used for a long time (in which instance,
supplementation of calcium, trace elements and vitamins may be required).
They may also increase the risk of bezoar formation, especially when a diet
high in fibers is contraindicated (patients with gastrointestinal dysfunction,
gastroparesis or altered absorption from pancreatic enzyme deficiency). Large
amounts of dietary fibers may not be well tolerated by children, pregnant

diabetic women and elderly subjects.
Alcohol and Other Nutrients
Alcohol provides about 7 cal/g, is not a food but is another source of
energy that should be considered in a dietary plan. Interestingly, in women a
decreased risk (50%) of developing diabetes with increasing alcohol intake
was found and this effect was probably related to lower BMI linked with
alcohol consumption. Allowed intake should not exceed 10 g/day. Excessive
alcohol intake should be avoided in diabetic patients, because it inhibits glu-
coneogenesis and can favor hypoglycemic episodes in subjects treated with
insulin or drugs. In hypertriglyceridemic patients, alcohol may exacerbate
dyslipidemia and liver steatosis.
Diabetic patients may also suffer from associated diseases which require
special modified diets. In the presence of congestive heart failure, hypertension
and kidney disease, dietary sodium should be restricted. The sodium restriction
may range from 500 to 1,000 mg/day (maximum intake =3 g/day), although
the use of diuretics may reduce the need for a severe sodium restriction,
which makes foods less palatable and may provocate hypotension and fluid
or electrolyte disorders.
Sweeteners
Sweeteners can be distinguished into caloric (or natural) sweeteners and
noncaloric (or artificial) sweeteners (table 6). In both type 1 and 2 diabetic
patients, the classical sweetener, sucrose, can be allowed in the maximum
amount of 20 g/day, especially if associated to a mixed meal, because it does not
deteriorate metabolic control. An excessive sucrose intake should be avoided,
66Iannello
Table 6. Sweeteners for diabetic patients
Caloric or natural sweeteners
Sucrose
Fructose
Sugaralcohols (sorbitol, mannitol, xylitol)

Noncaloric or artificial sweeteners
Saccharin
Cyclamates
Aspartame
especially in hypertriglyceridemic or obese or severely decompensated diabetic
subjects. Sucrose is the most cariogenic of the nutritive sweeteners, and caries
is a problem in people with diabetes.
Alternative sweeteners have been proposed (sometimes as combinations
of caloric and noncaloric sweeteners). An ideal sucrose substitute for diabetic
patients should taste good and not induce hyperglycemia or elevation of plasma
lipids; it should also contain few calories, have an adequate stability and
consistency and be of low cost. Fructose is naturally found in honey and fruits
and is 1–1.8 times as sweet as sucrose. Its caloric content is about 4 cal/g
(equal to that of sucrose) but fewer calories are required to provide the same
sweetness. The ingested fructose is phosphorylated to fructose-1-P in the liver,
independently by insulin, and after splitting by aldolase it enters the glycolytic
pathway and may be converted into glucose or triglyceride. The fructose intake
does not cause side effects unless it exceeds 75 g (0.5 g/kg/day in children).
Large oral amounts (?50 g) may cause diarrhea. In doses up to 30–35 g
it does not impair glycemic control in well-compensated diabetics while in
decompensated patients it may aggravate hyperglycemia and hypertriglyceride-
mia. Xylitol is a sugar alcohol derived from xylose, which is naturally present
in fruits and vegetables. It has a sweetness equivalent to that of fructose,
produces about 4 cal/g, is slowly absorbed and does not exacerbate glycemia
or triglyceridemia (although it may induce a transient increase of uric acid
synthesis). In excessive doses it may cause osmotic diarrhea. Sorbitol (as well
as mannitol) is a sugar alcohol, obtained by reduction of glucose or fructose,
which contains about 4 cal/g. It is slowly absorbed, yet it may increase glycemia
in poorly compensated diabetic patients. Large amounts (30–50 g/day) may
induce osmotic diarrhea.

Saccharin is the most used artificial sweetener with no caloric content. It
is not metabolized and is excreted unchanged in urine. In high doses, saccharin
was reported to induce malignancy of the urinary bladder in experimental
animals, but studies in diabetic subjects indicate no relationship between sac-
67Diet and Modification of Nutrient Absorption
charin and bladder cancer. The FAO/WHO suggests a dose of 0–2.5 g/kg in
adults.
Cyclamates are 30 times as sweet as sucrose and have no caloric value;
in very high doses (2,500 mg/kg/day) they are reported to induce tumors of
the urinary bladder in rats. Although no evidence of malignancy exists in
humans, cyclamates were banned from the US market; however, they are still
available outside the USA. Aspartame is a nutritive sweetener consisting of a
synthetic dipeptide. Compared to sucrose, it has the same caloric content
(about 4 cal/g) but is 180–200 times more sweet, so that negligible calories are
required to provide the same sweetness. It has a good taste, but it is instable
in liquid solution and during heating, and is 4–5 times as expensive as sac-
charin. Some side effects were reported such as phenylketonuria in predisposed
subjects, neuroendocrine disorders and brain tumors. These data were not
confirmed by FDA, that has set 50 g/kg/day as a safe daily aspartame intake.
The alternative sweeteners with no or low caloric value are certainly useful in
the management of diabetic and obese patients that find pleasantness in sweet
foods.
Hypocaloric Diet in Overweight Type 2 Diabetes
In type 2 diabetes, caloric restriction should be correlated with the degree
of overweight or obesity, and the calculation of appropriate calories depends
upon the body weight and the physical activity of the patient. In slightly
overweight patients, a 1,600–1,800 kcal/day diet may be appropriate. In the
cases with more marked overweight, a hypocaloric diet of about 1,000–1,500
kcal/day should be prescribed. In these diets, the protein content should not
be =0.8 g/kg IBW. With weight loss, in most obese diabetic patients the

carbohydrate metabolism will improve, so that insulin or hypoglycemic drugs
may be reduced or withdrawn. Even a modest weight loss may be associated
with significant metabolic improvement, although marked individual vari-
ations occur. This improvement primarily involves fasting glycemia and is
correlated with decreased hepatic glucose output. These favorable effects may
have a positive impact on the overweight diabetic patient with regard to the
compliance to the hypocaloric diet.
The very low calorie diet (VLCD: 800–500 kcal/day, mostly derived from
high-quality proteins, with vitamin and mineral supplementation) should be
avoided in diabetic patients for the risk of severe arrhythmias or coronary
symptoms. Moreover, a long-term evaluation of VLCD (compared to conven-
tional diets) has demonstrated no significant difference on weight loss. A
VLCD should be limited to type 2 diabetic patients who are 50% or more
68Iannello
over IBW and who do not respond to conventional balanced diets, excluding
those with recent myocardial infarction, hepatic disease, renal failure or cere-
brovascular disease. Monitoring of electrocardiographic changes, urea or creat-
inine level and electrolyte disorder is required.
Diet and Exercise
Exercise is a relevant component in a program of weight loss in diabetic
patients. It improves glucose tolerance, lowers glycemia, increases peripheral
insulin sensitivity and reduces risk factors for coronary heart disease (amelio-
rating hypertension and blood lipid profile). The combination of diet plus
exercise is more effective than diet alone or exercise alone in producing long-
term weight loss, in maintaining the weight loss over time and in reducing the
dose of hypoglycemic drugs. The recommended exercise (walking or stationary
bicycle riding) should be of low or moderate intensity but of long duration,
and is especially useful in adult or older obese type 2 diabetic subjects. The
exercise should be performed at least every 2–3 days for optimum effect (ex-
amples: stationary bicycle riding or brisk walking for 30 min/day, or active

swimming for 1 h 3 times/week). Because exercise may increase the risk of
acute or delayed hypoglycemia, a prospective reduction in insulin dose for
regular exercise should be used as well as a supplementary snack of about 40 g
of carbohydrates. In decompensated diabetic patients with insulin deficiency,
exercise is contraindicated (especially if prolonged, severe or unusual) raising
glycemia and ketone levels. Alcohol may exacerbate the risk of hypoglycemia
after exercise. Diabetic patients should be encouraged to increase their physical
activity gradually, with increments of the activities within their daily lives
(walking to work, using stairs rather than elevators, etc.). However, the effects
of exercise on the caloric balance (and therefore on weight loss) may be less
than expected for several reasons. In fact, from the energy lost during exercise,
those calories should be subtracted that the patient would have lost with his
usual activity. Moreover, often the exercise stimulates the appetite, leading to
enhanced caloric assumption. Finally, in some tense individuals, exercise may
induce muscular relaxation, which means decreased isometric muscular work.
Conclusion
In conclusion, the reduction of the caloric intake in obese people may
have a relevant effect on the frequency of type 2 diabetes. On the other
hand, a proper nutritional management of obese diabetic patients is the most
69Diet and Modification of Nutrient Absorption
important factor of treatment (even if often patients are unable to lose weight
or to maintain the reduced weight). A professional consultation with the
physician or the dietician is recommended (especially for new patients) at the
beginning of diet and then at regular intervals to promote the adherence to
dieting and to verify metabolic control of diabetes and weight loss. Dietary
adherence is a serious problem in both type 1 and, especially, type 2 diabetic
patients. To improve compliance to diet, some strategies were recommended:
(a) a meal plan (adequate to the patient’s lifestyle and to the stage of the
disease) that involves long-term changes of eating and nutritional habits;
periodical reviews of meal plan are needed; (b) the education, which can

improve motivation and dietary adherence providing the patient with useful
information in an acceptable form to manage effectively nutrition and exercise;
(c) a strong feeling between physician and patient (and his relatives for young
people), and (d) an interaction afforded by group sessions, in which diabetic
patients can exchange experiences and information, providing solutions and
behavioral changes through peer example.
Modification of Nutrient Absorption
Agents capable of modifying the absorption of complex carbohydrates
or lipids, such as -glucosidase inhibitors and Orlistat, will be discussed in
Chapter VI (Overview of Diabetes Management).
Suggested Reading
American Diabetes Association: Nutritional principles for the improvement of diabetes and related com-
plications. Diabetes Care 1994;17:490–518.
American Diabetes Association: Clinical practice recommendations 1997. Diabetes Care 1997;20(suppl 1):
1–70.
Diabetes and Nutrition Study Group of the EASD: Nutritional recommendations for individuals with
diabetes mellitus. Diabetes Nutr Metab 1995;8:1–5.
Han TS, van Leer EM, Seidell JC, Lean ME: Waist circumference as a screening tool for cardiovascular
risk factors: Evaluation of receiver operating characteristics (ROC). Obes Res 1996;4:533–547.
International Diabetes Federation (IDF), 1998–1999 European Diabetes Police Group: A Desktop Guide
to Type 2 (Non-Insulin-Dependent) Diabetes mellitus. Brussels, IDF, 1999.
Jenkins DJ, Wolever TM, Taylor RH, Barker H, Fielden H, Baldwin JM, et al: Glycemic index of foods:
A physiological basis for carbohydrate exchange. Am J Clin Nutr 1981;34:362–366.
Lemieux S, Prud’homme D, Bouchard C, Tremblay A, Despres JP: A single threshold value of waist
girth identifies normal-weight and overweight subjects with excess visceral adipose tissue. Am J
Clin Nutr 1996;64:685–693.
Perry AC, Miller PC, Allison MD, Jackson ML, Applegate EB: Clinical predictability of the waist-to-
hip ratio in assessment of cardiovascular disease risk factors in overweight, premenopausal women.
Am J Clin Nutr 1998;68:1022–1027.
70Iannello

Rexrode KM, Carey VJ, Hennekens CH, Walters EE, Colditz GA, Stampfer MJ, Willett WC, Manson
JE: Abdominal adiposity and coronary heart disease in women. JAMA 1998;280:1843–1848.
Vinik A, Wing RR: Nutritional management of the person with diabetes; in Rifkin H, Porte D (eds):
Diabetes mellitus. Theory and Practice, ed 4. Amsterdam, Elsevier, 1990, pp 464–496.
WHO Expert Committee: Physical Status: The use and interpretation of anthropometry. WHO Tech Rep
Ser No 854. Geneva, WHO, 1995.
S. Iannello, 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
71Diet and Modification of Nutrient Absorption
Chapter V
Belfiore F, Mogensen CE (eds): New Concepts in Diabetes and Its Treatment.
Basel, Karger, 2000, pp 72–89

Insulin Treatment in Type 1 andType2
Diabetes: Practical Goals and Algorithms
F. Belfiore, S. Iannello
Institute of Internal Medicine, University of Catania, Ospedale Garibaldi,
Catania, Italy
Introduction
In type 1 diabetes, insulin therapy is focused on the replacement of insulin
secretion, even if lifestyle changes are required to optimize insulin treatment.
In type 2 diabetes, insulin treatment may be required when diet and oral
therapy do not suffice. A variety of highly purified preparations of human
insulin (the only form of insulin today sold in industrialized countries) are
commercially available, differing in time of onset and duration of action. These
pure human insulins result in very few problems linked to insulin antigenicity,
because human insulins are less antigenic than porcine and much less antigenic
than bovine insulins.
The production of human insulins by recombinant DNA technology has

made possible a limitless use of different insulin preparations, thus solving
the previous problem of a limited supply of animal pancreases for the large
demand of insulins. The most important indications for insulin treatment are
listed in table 1.
Types of Insulins
Insulin is formed by two peptide chains, the A and B chains (con-
sisting of 21 and 30 amino acids, respectively), joined by disulfide bridges.
Different kinds of insulin are available for clinical use, which differ accord-
ing to the species of origin, the degree of purity and the duration of
action.
72
Table 1. Indications for insulin treatment
Type 1 diabetes Diabetic vascular complications
Ketoacidosis or ketoacidotic coma Liver diseases in diabetic patients
Hyperosmolar coma Renal failure in diabetic patients
Diabetic pregnancy Secondary failure with oral hypogly-
Acute diabetes decompensation for: cemic drugs in type 2 diabetes
Severe illness or fever
Infections or sepsis
Stress or steroid treatment
Injury or surgery
Species: Bovine insulin differs from human insulin because it contains
alanine, valine and alanine at the sites A-8, A-10 and B-30, respectively,
whereas human insulin contains threonine, isoleucine and threonine at the
same sites. Porcine insulin is more similar to human insulin inasmuch as it
has the same amino acids as bovine insulin at positions A-8 and B-30 but
the same amino acid as human insulin at position A-10. Human insulin
can be obtained by modification of animal (pork) insulin (human semisyn-
thetic insulin) or can be synthesized by the recombinant DNA technique.
Human insulin is today the type of insulin most used in many countries.

Human insulin (especially the long-acting preparations – see below) is more
rapidly absorbed and has a quicker and shorter action than the porcine
insulins, perhaps because it is more soluble in subcutaneous tissues. Some
patients may have less awareness of hypoglycemia with human insulins than
with animal insulins.
Purity: In the past years, conventional insulin preparations contained a
significant amount (10,000 parts per million (ppm)) of impurities (proinsulin
and proinsulin-like compounds, insulin dimers, glucagon, somatostatin, VIP,
PP, etc). Impurity content was much less in ‘single peak’ (monocomponent)
insulins (=50 ppm) and even lower in purified insulins (1–10 ppm). Today, in
most countries, only very pure human insulin prepared by the recombinant
DNA technique is used.
Duration of Action: Three types of insulin are available which differ in
the duration of action: (a) the rapid-acting, (b) the intermediate-acting and
(c) the long-acting insulin. (a) The rapid-acting insulin preparations include
the regular insulin as well as the semilente insulin which is a suspension of
insulin and zinc in acetate buffer (with formation of zinc-insulin crystals).
(b) The intermediate-acting insulins comprise the lente insulin, which is a
30:70% mixture of semilente and ultralente (see later) insulin as well as the
73Insulin Treatment in Type 1 and Type 2 Diabetes
Neutral Protamine Hagedorn (NPH) insulin, obtained by adding the protein
protamine to insulin and adjusting the pH. (c) The long-acting insulin prepara-
tions include the ultralente insulin, obtained by modifying, during the prepara-
tion, the pH of a mixture of zinc and insulin to produce larger zinc-insulin
crystals (the larger the crystals, the slower the release of the injected insulin)
as well as the protamine-zinc insulin obtained by adding also protamine and
adjusting the pH.
After subcutaneous injection, regular insulin presents a rapid onset of
action (0.5–1 h), an early peak of activity (2–4 h) and a duration of action of
4–6 h. Thus, rapid-acting insulin, beginning to act in about 30 min, should

be given 20–30 min (perhaps 45 min) before a meal to optimize synchronization
of postprandial glycemia and circulating insulin levels. It is effective in blunting
elevations in glucose following meals and for rapid adjustments in insulin
dosage, but the pharmacokinetics of rapid-acting insulins entails that a definite
time interval is observed between insulin injection and eating. A better
synchrony between insulin peaks and meal absorption after injection of
rapid-acting insulin is observed with human insulin, which acts more rapidly
after injection and exerts shorter effects compared to previously used animal
insulins.
Intermediate-acting NPH insulin presents a delayed onset of action
(3–4 h), a delayed peak of activity (8–12 h) and a duration of action of 20–24 h;
similar activity is possessed by the lente insulin. The NPH and lente inter-
mediate-acting insulins have the same, long time-course of action, which is
useful to provide the basal level of insulin through the 24 h when given twice
per day. Intermediate-acting human insulin produces earlier peaks, that may
cause hypoglycemic events during sleep and fails to maintain an adequate
effect for a full 24-hour period.
Ultralente (long-acting) insulins present a slow onset of action (6–8 h), a
much more delayed peak of activity (14–24 h) and a duration of action of
about 32 h. The ultralente human insulin has a shorter duration of action,
compared to the animal preparations, and requires also twice-daily injections.
Table 2 summarizes the most common insulin preparations and their onset,
peak and duration of action.
Insulin Analogues
Recently, to improve the outcome of insulin therapy and to use human
insulin products with more physiological effect, a short-acting monomeric
insulin analogue, insulin lispro (Lys[B28], Pro[B29]), was developed which
was approved for clinical use and is already commercially available. It has
been used extensively in clinical practice. Reversal of the amino acids proline
and lysine at position B28 and B29 of human insulin produces an analogue

74Belfiore/Iannello
Table 2. Types of insulin
Type Preparation Onset of action Peak action Duration of action
hhh
Rapid-acting Regular 0.5–1 2–4 4–6
Intermediate-acting NPH or lente 3–4 8–12 16–24
Long-acting Ultralente
Bovine 4–6 14–24 28–36
Human 4–6 10–20 24–28
There is great variability in the onset, peak and duration of insulin action from patient
to patient, as indicated by the time intervals given. Human insulin tends to show somewhat
earlier onset and peak and shorter duration of action, compared to nonhuman insulins. This
is especially true for long-acting preparations. For this reason, different figures for the time
intervals are reported in the table for this insulin preparation.
with less tendency to self-association. Conventional insulin preparations are
prevailingly in hexameric form, which delays the absorption from subcutane-
ous injection sites, requiring the dissociation of hexamers into monomers.
The monomeric insulin lispro is rapidly absorbed from subcutaneous tissues
(so reducing the postprandial hyperglycemia) and shows a shorter duration
of action that should decrease the risk of hypoglycemia between meals and
at nighttime. Indeed, it shows early peak (1 h) (which allows a much shorter
interval between injection and eating) and a shorter duration of action
(3–4 h). The insulin lispro in appropriate dosage may result in a profile of
insulin close to the physiological one and is suitable for treating both type
1 and type 2 diabetic patients under intensive insulin therapy. Another rapid-
acting insulin analogue is currently under evaluation (B28 Asp). Longer-
acting ‘basal’ analogues are also under development such as HOE 901 that
is an insulin analogue with a lower peak of activity than NPH and a duration
of action very long (about 24 h), especially appropriate for type 1 diabetics.
Insulin Concentration

The insulin preparation available on the market today is a concentration
of 100 U/ml (U-100). In the past (and still today in some countries) a concentra-
tion of 40 U/ml (U-40) was in use. However, preparations with more concen-
trated insulin also exist (500 U/ml or U-500).
75Insulin Treatment in Type 1 and Type 2 Diabetes
Factors Influencing Insulin Concentration or Bioavailability
Pharmacokinetics of Injected Insulin
An optimal therapeutic use of insulin requires the knowledge of the factors
affecting its absorption, disposal and action. Within 5–7 min, insulin given
intravenously is concentrated in the heart, liver and kidneys and after 15 min
mainly in the latter two organs. It has been shown that, in the range of
physiological concentrations, liver extracts as much as 70% of insulin on a
single passage, and that the kidney also removes a significant percentage of
the insulin from the blood. The importance of liver and kidney in the insulin
disposal is apparent as well as the need to adjust the insulin dosage in patients
with hepatic or renal diseases.
Insulin Concentration and Dose
Insulin bioavailability is unaffected by insulin concentrations between
40 and 100 U/ml, while more diluted insulin is more rapidly absorbed. A more
concentrated regular insulin (which has a more prolonged action) can be used
for insulin-resistant patients. Increasing the dose of regular insulin delays the
time of peak serum level and prolongs the duration of action, while increasing
the dose of NPH insulin can reduce insulin absorption. It is noteworthy that,
when the dose of insulin lispro is increased, the duration of action is not
prolonged.
Insulin Mixtures
Manufactured insulin mixtures exist on the market. Biphasic premixed
insulins have been developed in various ratios of rapid-acting to NPH (30/70,
40/60, 50/50, etc.). The effect of 30/70 mixtures of regular and NPH insulins
is the same as if the components were injected separately and simultaneously,

because regular insulin retains its pharmacokinetic characteristics. When a
mixture of lente and regular insulins is used, the excess of zinc tends to bind
to regular insulin and may cause precipitation of regular insulin out of solution,
delaying its absorption and blunting its quick-acting effect. Thus, there are
some advantages in using NPH for insulin mixtures. When two types of insulin
are mixed, it is important to consider (to assure accuracy of the dose) the
variable amount of ‘dead space’ between the hypodermic syringe and the
needle. For this reason, it can be useful to always use syringes from the same
manufacturer.
Type of Administration and Site of Insulin Injection
Subcutaneous administration (with all its disadvantages) remains the only
practical method for the delivery of insulin. The peak concentration of insulin
76Belfiore/Iannello
can be influenced by the site of injection, being achieved more quickly with
abdominal injection than with injection in the anterior thigh. Absorption is
faster in an upper than in a lower limb. When insulin is injected into an
extremity, absorption increases if the extremity is subsequently involved in
exercise. Absorption also increases if the injection site is massaged or warmed.
Patients should inject insulin in the different locations at the same time each
day, i.e. in the abdomen in the morning to optimize insulin delivery and in
the leg or buttock at night to slow absorption. Rotation of sites within these
areas is very important. It is noteworthy that the absorption rate of insulin
lispro is consistent from each of the injection sites. Interestingly, it has been
shown that the patient can safely reuse the plastic insulin syringes and the
needles.
Pen injectors have been introduced for clinical use, loaded with insulin
cartridges of 1.5 ml (containing 150 U) or 3 ml (300 U). They are more prac-
tical than syringes, especially for the traveler patients, and give more accurate
dosage. Only short-acting insulin and NPH insulins can be used with pens
(lente insulins are in crystal form and crystals would be broken by the glass

marble present in the pen cartridges to help insulin stirring).
Intravenous administration (continuous or pulse) is not practical but
permits much more physiological insulin profiles. Other routes of insulin deliv-
ery have been proposed, including the intraperitoneal route (which allows
insulin to enter, at least in part, the portal vein, similarly to the endogenously
secreted insulin), as well as the subcutaneous insulin pellets, skin iontophoresis,
oral administration (insulin is degraded by gastrointestinal enzymes and there-
fore the absorption is extremely variable), nasal or pulmonary spray of insulin
(mixed with 1% deoxycholate capable to increase the mucosal insulin absorp-
tion) and rectal suppositories (unable to induce a physiological profile of
insulinemia).
It should be underlined that the physiologically secreted insulin enters
the portal vein and is taken up in substantial amount by the liver, so that
only the remaining amount reaches the general circulation and is distributed
to the peripheral tissues. In contrast, insulin given for therapeutic purposes
through the commonly used routes (subcutaneous or intravenous) enters the
general circulation and is distributed to all tissues (liver and peripheral
tissues) in approximately similar amount. Therefore, during insulin treatment,
liver is relatively hypoinsulinized and the peripheral tissues relatively hyper-
insulinized.
Depth of Injection and Massage
The depth of insulin injection is an important variable. In fact, the deeper
insulin is injected, the quicker the onset of action and the higher the peak.
77Insulin Treatment in Type 1 and Type 2 Diabetes
Usually, it is recommended to place insulin consistently into deep subcutaneous
tissue by means of a lifted flap with the injection device at a 45º angle.
Absorption is much faster when insulin is injected intramuscularly rather than
subcutaneously, and erratic intramuscular injections in thin individuals may
occur. Massage of the injection site increases insulin absorption.
Exercise and Stress

Exercise of a leg may increase absorption of the insulin injected in that
extremity; moreover, stress (by increasing epinephrine) may affect local blood
flow and absorption of insulin.
Insulin Antibodies
Insulin antibodies bind insulin and can delay the onset of action and the
duration of its effect. Among patients, the time course of a given insulin
preparation is highly variable, probably for differences in circulating insulin
antibodies. Human insulin generates lower titers of insulin antibodies and
therefore is most useful in patients who are initiating insulin therapy (and
who have not yet produced antibodies) and in patients requiring insulin inter-
mittently (intermittent use of insulin increases its antigenic effects).
Destruction of Insulin
Insulin is destroyed variably at the site of injection by some insulin-
degrading enzymes. An unusual cause of altered insulin pharmacokinetics
may be the local degradation of insulin by proteases, at the site of injection.
This mechanism, however, has not been established in patients with poorly
controlled diabetes either at the injection site or by in vitro studies with patient’s
fat incubated with insulin.
Storage of Insulin
Insulin can be kept at room temperature (=25 ºC) for 1–2 months without
losing activity, whereas for longer conservation it should be stored in the
refrigerator (between 4 and 8 ºC). Insulin does not withstand temperatures
=2 ºC and freezing must therefore be avoided.
Insulin Requirement
Insulin dose depends on the patterns of food intake and physical activity,
on diurnal variations in insulin requirement, on experience of hypoglycemia,
on the state of injection sites and on the type of diabetes. Insulin requirement
of young, adolescent diabetic patients is sometimes high and changing. As a
78Belfiore/Iannello