Insulin formulations and delivery methods by fdjerue7eeu

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									Insulin formulations and delivery methods

First, the development of insulin ª¥

Since 1921, insulin extracted from bovine pancreas for diabetes
treatment success so far, nearly 80 years of history. The initial
extraction of insulin the pancreas is broken up, with acid ethanol
extraction, the extract and after vacuum evaporation, and then NaCl
salting out, precipitation by insulin "salt cake", the salt
cake dissolved in water, adjust pH to the isoelectric point of insulin
pH5.0 ~ 5.5, so settle down insulin, namely as "amorphous
insulin." The content of 50% to 60% efficiency value of about
10U/mg. Although the initial amorphous insulin treatment that many
patients, but its side effects, many systemic and local allergic
reactions. Available in 1926 that further strengthen the
recrystallization of amorphous insulin, reported in 1934 to promote
insulin re-crystallization of zinc, was developed to repeatedly
re-crystallization, thus making a significant increase in the purity
of insulin. 97% of its content, to titers 25U/mg. 40 years is the
widespread use of "re-crystallization of insulin."
Application of this systemic allergic reaction to insulin disappeared,
local allergy and lipoatrophy than rare. However, since 1956, RIA
technology development, testing using the serum of patients with
recrystallized insulin, found that 90% of the insulin antibody, and
found that also contain a small amount of impurities. Insulin is made
up of 51 amino acids, molecular weight of 5734, found by
radioimmunoassay, and recrystallization of insulin in the molecular
weight of 9,000 ~ 15,000 with pig insulin and intermediate metabolites
and pancreatic protein complex, to further reduce their
immunogenicity, 60 Since people were further purified insulin crystals
refined by adding zeolite anion-exchange chromatography in the regular
insulin molecules of impurities removed, get a more pure "single
peak of insulin", a single peak of insulin available after
repeated chromatography "High purity of insulin" - one
component of insulin (purity 99.9%, proinsulin <1 / 10 million).
Single peak insulin or through the clinical application of
single-component insulin, the antibody detection rate decreases with
increasing purity, dosage will be reduced accordingly. Although with
the increase in insulin purity, improved clinical efficacy, but the
animal insulin to human insulin composition is different. Human
insulin containing 21 amino acids from the A chain and contains 30
amino acids of the B chains, two peptide chains linked by disulfide
bonds. Commonly used porcine insulin B chain on the first 30 amino
acids are alanine, and human insulin are threonine, and therefore
proposed the application of the superiority of human insulin. But the
body of insulin extraction and chemical synthesis of human insulin,
insulin-expensive limited clinical application. Gene technology to
promote the early 80s the development of the pharmaceutical industry
in 1978, the first fermentation with E. coli E, the first synthetic
human insulin, respectively, A chain and B chain, and then the two
chains by disulfide bond together to become insulin molecules. 1986
developed another way, the first biosynthetic insulin, and then
digested with trypsin and carboxypeptidase to be human insulin C
peptide. This approach is similar to the secretion of human islet B
cells than the A, B-chain synthesis is more convenient. The late 20th
century, 70, Denmark Novo Nordisk (Novo Nordisk) company was the first
production of semi-synthetic insulin. In China in 1992, the company
officially listed NoVo human insulin of insulin that is, all its
applications is the yeast fermentation substrate. 1982 United States
Lilly (Eli Lilly) Company first synthesized by recombinant DNA human
insulin, marking the beginning of era of biotechnology drugs in 1996,
they developed the first insulin analogue lispro 1 insulin (lispro).
There are currently more than 300 insulin analogues have been prepared
in the laboratory out, and some have entered the market. If available
for insulin lispro (lispro) and insulin aspart (aspart), long-acting
insulin glargine (glargine) and to special insulin (determir). The
good news is, China's Tonghua Li Dongbao companies and companies
willing to develop and produce a short-acting human insulin and
long-acting insulin analogues.

Second, classification and characteristics of commonly used insulin ª¥

There are several ways the classification of insulin from the
production process can be divided into non-genetic engineering,
genetic engineering of insulin and insulin; from the effect of the
length of time and the speed of onset can be divided into quick (or
short effect), short-acting, in effect and long-acting insulin;
different from the amino acid sequence can be divided into animal
insulin, human insulin and insulin analogues. In the clinical
classification of the latter two often combined.

(A) in accordance with the amino acid sequence classification

Animal Insulin: The animal pancreatic extract and the appropriate
purified porcine or bovine insulin. Structure of porcine insulin and
human insulin is similar to only one amino acid different from that of
the B chain of 30 amino acids different from human insulin B30-bit is
on the alanine replaced threonine. Bovine insulin and human insulin
has three amino acids different, first and foremost on the human
insulin-B30-bit alanine replaced threonine, in addition also on the A8
and A10 bit threonine and isoleucine for into alanine and valine.
Because the molecular structure of animal insulin and human insulin
differ in part, and contains impurities, so there are some
immunogenicity, probably in the human body to produce antibodies in
some patients after injection of skin allergies. In addition, the
effectiveness of the lowest animal insulin, insulin from animal
insulin for employment, increased risk of hypoglycemia, so the dose
should be reduced by 15% to 20%. Currently animal insulin has been
gradually phased out, very little clinical application.

Human insulin: a molecular weight of 5734, is a small molecule
protein, human insulin from proinsulin cleavage, the A, B two chains,
one chain contains 21 amino acids A, B chain containing 30 amino
acids, two chain disulfide bonds between the two connections within
the A chain and a disulfide bond, the 6 and 11 amino acids connected.
Currently, many major hospitals at home and abroad by recombinant DNA
technology with the production of neutral human insulin products,
including Novo Nordisk's Novolin, Eli Lilly's Humulin and produced by
domestic Tonghua Dongbao Gan Shulin series, there are short-acting, in
effect, in effect short-premixed preparations (30% short-acting
premixed insulin preparations are Novolin 30R and Humulin 70/30, in
effect short-acting and 50% each preparations have Novolin 50R, etc.).

Insulin analogue: human insulin as a hexamer, subcutaneous injection
can not be directly absorbed into the bloodstream, to be depolymerized
into monomers or dimers to enter the blood circulation through the
capillaries to play a role, and different decomposition and absorption
between individuals very different,
And the final concentration of insulin into the circulation decline.
The late 20th century, 90 in the structure and composition of
insulin-depth study found that modification of the peptide chain may
change its chemical and biological characteristics, developed more
suitable for human physiological needs of the insulin analogues. Or
absorb faster, absorb more slowly or gently, but do not alter the main
biological function of human insulin and recombinant human insulin
compared to better simulate endogenous insulin secretion. Among them,
rapid-acting insulin analogue insulin molecules through the
modification of the role of between and within the important region to
the onset, peak and duration shorter than human insulin, more
physiological postprandial insulin spectrum, clinical use of blood
glucose after the meal can be more stable, generally do not cause low
blood sugar at night; and long-acting insulin analogue insulin by
changing the isoelectric point or molecular weight increase of the
methods of insulin to break down, extend the absorption, the
absorption variability is small and no peak, to better simulate
physiological basis of insulin secretion, after the application of
clinical practice to prove the risk of hypoglycemia compared with
human insulin in a small effect. The characteristics of several
insulin analogues:

(1), insulin lispro (lispro) brand name, excellent bleeding music
(Humalog), the product is the United States in 1996, Lilly Company
developed the world's first 1 and insulin analogues, have been in the
United States and European countries approved for clinical , May 2005
to enter the Chinese market. U.S. Food and Drug Administration (FDA)
has approved its use of type 1 and type 2 diabetes. Insulin lispro is
Escherichia coli (E coli) strains using recombinant DNA technology for
the synthesis of the host's acting insulin analogues, human insulin
with different structures is that the B chain C terminal proline and
29 of 28 sequential exchange of lysine, thus weakening the interaction
between the monomers so difficult to form a hexamer, after
subcutaneous injection in monomeric form. Its main features are:
soluble, low self-binding, subcutaneous absorption of local fast onset
and short duration peak (see Table 1). The pharmacokinetic
characteristics more in line with changes in human physiological
insulin and glucose spectrum. Insulin lispro compared with human
insulin, insulin receptor affinity rather, while the insulin-like
growth -1 (IGF-1) receptor affinity is higher than 50% of human

Clinically, the rapid-acting insulin analogue insulin lispro with both
long-term and long-acting insulin analogues in the joint for multiple
daily injections (MDII), can also be used in insulin pump (CSII), you
can immediately prior to meals injection, and even meal, postprandial
injection. Studies have shown that when the maternal serum
concentration of insulin lispro (100 ~ 200) mU / mL, it will not cross
the placenta. Existing applications, excellent clinical data show that
secretion of music: not found to cause fetal abnormalities; without
increasing complications of diabetes and fetal adverse events; to
better control blood sugar gestational diabetes. Produced by domestic
Gan Li insulin lispro (brand name, Sau Lin-speed), ¢ò clinical trial
showed superior efficacy and similar bleeding music.
(2) insulin aspart (aspart) trade name aspart (Novolog), developed by
the Danish company Novo Nordisk in 1999 in Germany, Sweden and the UK
the first market, in December 2002 to enter China. Currently, FDA has
approved it for type 1 and type 2 diabetes.

Insulin aspart is saccharomycescerevisiae (baker yeast) host using
recombinant DNA technology for the synthesis of human insulin
analogues available. And the difference between human insulin is
negatively charged will replace the B chain of aspartate 28 of the
proline, which hinders the charge repulsion between the
self-aggregation of insulin monomers. In solution, the analogue to a
mixture of monomer and dimer form, so when the subcutaneous insulin
absorption faster than normal. Insulin aspart and human insulin
receptor affinity was 88%, and IGF-1 binding capacity similar to
natural insulin.

Available human insulin analogue insulin aspart pharmacokinetics and
insulin lispro are similar can be used for MDII and CSII, insulin pump
therapy is used, the incidence of hypoglycemia than regular insulin
(RI) MDII low, HbA1c standard time shortened. Studies have
demonstrated that in children with type 1 diabetes, insulin aspart can
be safely and effectively reduces postprandial blood glucose, has been
approved in Europe for 2 to 6 years old children. Currently, insulin
aspart for patients with diabetes in pregnancy Clinical study was
relatively small.

(3) insulin glargine (glargine) trade name Lantus (lantus), by the
French Sanofi-Aventis (Sanofi - Aventis) developed long-acting basal
insulin analogue, for the first time in the German market in 2000 ,
April 2004 FDA approved the use of adult type 1 and type 2 diabetes
and children with type 1 diabetes, the same year in June, EMEA
approved the use of type 1 and type 2 diabetes. June 2005 in China
market. Li Gan company of development and production of insulin
glargine, the trade name long show lin, has also been listed in China.

Insulin glargine is a non-pathogenic strains as host Ecoli synthesis
of recombinant human insulin analogues, human insulin with the
difference lies in the A chain of 21 amino acids are glycine replaced
by aspartate, and increased terminal B-chain C 2 arginine, so that the
isoelectric point of from 5 to 6 to 7, the hexamer structure is more
stable. Insulin glargine in acidic solution (pH = 4.0) was dissolved,
after subcutaneous injection of 7.4 pH (neutral environment) can form
micro-precipitates, these micro-deposits in the longer time to release
a steady insulin monomer, which makes the decomposition of insulin
absorption and action time to play a long-lasting effect sustained
release, and its hypoglycemic effect sustainable 24h, and no obvious
peak, can simulate the normal basis for human insulin secretion. Due
to structural changes in the last two positions are not involved in
insulin receptor binding, it will not affect the biological activity
of insulin. Number of major clinical studies showed that the
combination with RI, insulin glargine treatment (can not mix and can
not diluted) group was significantly lower than the mean fasting blood
glucose in patients with NPH group. However, one study showed that two
groups of patients in the treatment of end point HbA1c levels were not
significantly different. Compared with bedtime injection of NPH,
bedtime injection of insulin glargine lower incidence of nocturnal
hypoglycemia. Failure of oral hypoglycemic drug therapy can be added
with insulin glargine treatment.

(4) to special insulin (determir) brand name Novo Peace (levemir),
developed by the Danish company Novo Nordisk. This product in June
2004 approved in the EU market. June 2005 FDA approval of its
treatment for type 2 diabetes, type 1 diabetes research is still in
phase ¢ó clinical trial.

In particular insulin is a soluble long-acting insulin analogues in
preparations of insulin, compared with the ordinary people, and its B
chain, in addition to 30 amino acids, and 29 in the B chain of lysine
added a 14-C fatty acids side chain, thus increasing its molecular
weight, where the presence of zinc ions, insulin hexamer molecules
still exist in the form. The absorption after subcutaneous injection
of slow diffusion, in the plasma ~ 99% and 98% albumin binding,
release of an extremely slow speed into the blood, plasma
concentrations of stable curves of a small valley, the role of long
duration. Similar with insulin glargine, especially in the long-acting
insulin analogues in daily injections of insulin can be 1, to provide
a basis for the insulin levels in diabetic patients, fasting blood
glucose control, with RI or short-acting insulin analogues such as MS,
is also with daily injections of 2 reported. T1DM patients abroad
study found that 1000 cases, in particular the effect of insulin
reduced HbA1c than NPH, less chance of hypoglycemia at night NPH.
Present to insulin in children and pregnant women, particularly the
application of the safety, efficacy, lack of adequate clinical

(5) Apidra (glulisine) trade name Apidra (no Chinese name), developed
by the French Sanofi-Aventis. FDA has approved the April 2004 for
adults with type 1 and type 2 diabetes, the European Committee for
Medicinal Products for human use (CHMP) has approved the listing. This
product is not yet in the domestic market.

Apidra to insulin rDNA origin Glulisine, is a recombinant DNA human
insulin available analogues. This product usually before meals or
after meals 20min 15min injection, 10 ~ 20min onset, 1h after the
peak, the role can be maintained 4h, lower postprandial glucose peak.
It can be coupled with long-acting insulin preparations. Current
clinical research on the products is relatively small, particularly in
children, pregnant women in the application of the safety,
effectiveness, and its teratogenic, mutagenic and other side effects
in clinical studies were still ongoing. But there are some trials have
demonstrated the application in the safety of children and good

(B) the effect of the duration of classification

1. Acting insulin are insulin analogues. Including insulin aspart and
lispro insulin. Available short-acting insulin analogue of human
insulin to avoid the shortcomings. Its rapid onset, peak fast,
half-life is short, clear fast, and postprandial hyperglycemia state
synchronization, restoration of basic state quickly, more in line with
the physiological requirements, which can make patients with diabetes
can control the level of glycated hemoglobin in the ideal range, more
better control of postprandial blood glucose, to obtain a lower
incidence of hypoglycemia, and more flexible way of life and
treatment. Usually within 15min in the fasting or postprandial
injection immediately, starting the reaction time was 10 ~ 20min, the
maximum reaction time was 40min, the duration of action for the 3 ~
5h. When using rapid-acting insulin analogues should be noted, for
patients with type 1 diabetes or poor islet function in patients with
type 2 diabetes, insulin secretion as the basis of very little, but
lost the role of insulin analogues available soon, so similar in use
of insulin lispro material should be appropriately increased basal
insulin dose.

2. Short-acting insulin of animal origin, including normal insulin
injection, neutral insulin injection, including human insulin
injection or Novolin R refills or special charge, Humulin R injection
or refills or special charge, Ganshu Lin R injection fluid or

Short-acting insulin in solution was not retained by the modified
insulin, whose appearance is brighter. Their relatively rapid onset,
after subcutaneous administration, the initial reaction time was
30min, the maximum reaction time was 3h, maintaining the reaction time
was 8h. Short-acting insulin is used to cover the meal insulin
requirements, the main control postprandial blood glucose, in order to
have time to absorb, it should be 20 ~ 30min before the injection of a
meal, if lower fasting blood glucose, can be injected immediately
before meals. Current clinical use of short-acting human insulin has
some shortcomings) the slow onset, due to the onset 30min after the
injection, which requires patients injected 30min before a meal,
postprandial blood glucose can not be effectively controlled. Injected
30min before a meal, and the lives of patients with great
inconvenience. (2) the role of peak slow to reach peak 90min after
injection, the body can not synchronize physiological blood glucose
peak, and thus on the postprandial glycemic control. And if you want
better control of postprandial glucose, insulin dose required is
relatively large, it is very easy to hypoglycemia the next meal
phenomenon. Diabetic patients increased concerns on insulin

3. The effect of insulin: The most common preparation is a
low-protamine zinc insulin, insulin with protamine and zinc ions to
form complexes, and insulin protamine molecule ratio of 1:1, a white
suspension, only the subcutaneous injection, the initial reaction time
is 1 ~ 2h, the maximum reaction time was 12h, to maintain the role of
time was 24h, usually used in conjunction with short-acting insulin to
provide the basis of the amount of insulin the day, with long-acting
insulin release profile compared to Variation small. Most commonly
used to control the next morning fasting blood glucose injection
before going to bed. The main varieties of animal origin, including
low-protamine zinc insulin injection million Surin, recombinant human
insulin Novolin N or refills or special charge, Humulin NPH or refills
or special charge, Ganshu Lin N, or cartridge.

4. Animal origin for the long-acting insulin protamine zinc insulin
(PZI), and insulin glargine and insulin in particular.

PZI protamine zinc insulin protamine zinc in the low increase on the
basis of the ratio of protamine, is more close to human body fluids
PH, lower solubility, effect lasts longer. Usually injected once a
day, and with the use of short-acting insulin to provide basal insulin
requirements. 3-4 hours after subcutaneous injection 20 hours of
onset, 12-peak, the role of maintenance of 24-36 hours. Because
long-acting preparations are mostly suspension dosage form, may cause
instability in the absorption and efficacy.

Long-acting insulin analogue was dissolved in the acidic environment
of the state, to clarify the solution. The onset time of subcutaneous
injection of 1.5 hours, and its role for sustainable 24h, day 1, to
overcome the current peak in the efficiency of insulin uptake and
disadvantages of short half-life is the ideal supplement basal insulin

5. Premixed insulin, also known as dual-phase insulin, is a mixture
containing the two insulin, which can have a short-acting and
intermediate-acting insulin effect. There is currently commercially
available with Novolin 30R is 30% of the short-acting and 70% of R N
in the effect of insulin; Novolin 50R is 50% with short-acting and 50%
of R N in the effect of insulin; Humulin 70/30 is 30% with
short-acting and 70% of R N in the effect of insulin; excellent music
secretion 75/25 (equivalent to 25% of the optimal secretion of music,
in effect the equivalent of more than role) and aspart 30, Connaught
and the sharp 30 Special charge is a soluble insulin aspart protamine
binding and crystallization of insulin aspart biphasic mixture.
Short-acting preparations in the rapid onset component, you can better
control postprandial blood glucose, in effect slow release of the main
ingredients from sustainable alternative basal insulin secretion. Easy
to use premixed insulin, a relatively small number of injections,
patient compliance is good, but because of limited mixing program for
some special cases, it is difficult to ideal blood sugar control.

Third, the insulin drug delivery

(A) subcutaneous injection (pen insulin syringes): The oral insulin in
the gastrointestinal tract vulnerable to low pH value and the
enzymatic destruction, and it's small intestine through the rate, it
is still currently used insulin injections, usually by subcutaneous
administration. After half a century of development, mode of
administration of insulin has also been updated, in addition to
ordinary syringes for injection of insulin, the widely used clinically
for the pen insulin syringes, refills will be made into the form of
insulin, with a dedicated injection pen, you can simplify the
operation, the injected dose is more accurate, easy to carry, reducing
pain, by patients are welcome. Disadvantage is that flexibility can
not be mixed insulin as needed. Special filling device is a 3ml
pre-filled disposable insulin injection device, designed as a pen
shape, out of direct discarded. Avoid the potential replacement
cartridge error dose or species, but the cost is higher, the
affordability of patients is limited.

(B) Intravenous infusion: only short-acting insulin.

(C) of the insulin pump: continuous subcutaneous insulin infusion
(CSII) of the mode of administration of insulin-dependent patients,
especially for patients with brittle diabetes, has brought great
convenience. The wider is the current open-loop insulin pump, which is
short-acting insulin by the placing storage needle through the
catheter and infusion pump were connected with the use of adjustable
micro-computer control of insulin infusion to simulate the
physiological secretion of insulin on an ongoing basis and meals
pulsatile-release, and with self-blood glucose monitoring, blood
glucose control can close to normal physiological levels, adjust the
dose of a more flexible, reducing the pain of repeated injections.
Continuous improvement by insulin pump, and its shape is like an
ordinary pager and portable, the current major clinical use of
intensive insulin therapy and insulin-dependent brittle diabetic
patients. But because of its more expensive, limiting its application.
Adverse reactions are infusion site infection due to pump failure or
human error led to disruption or excessive infusion of insulin

(D) jet injection system is a needle-free subcutaneous injection of
insulin which enables patients to receive the system, the device
expensive and cumbersome application is currently limited.

(E) non-injection drug delivery: long-term administration of insulin
to patients has brought unimaginable pain and trouble, non-injection
drug delivery become a research hotspot. Current research mainly in
the following ways:

1. Inhalation preparation
(1) absorption by the lung bioavailability of inhaled insulin is
approximately 10% -15%, equivalent dose equivalent to insulin
injections 3 times. Pharmacokinetics showed rapid onset of its role
and subcutaneous injection of ultra-short acting insulin analogues
similar. Currently there are two kinds of inhaled insulin
formulations, dry powder insulin and insulin-soluble liquid, aerosol
is required when using the diameter of alveolar easily absorbed 1 ~
3¦Ìm particles. A number of studies show that inhaled insulin aerosol
can significantly lower fasting and postprandial blood glucose, oral
hypoglycemic agents in patients with poor efficacy of insulin aerosol
can be combined with significantly improved blood sugar. Some
potential problems with inhaled insulin, the bioavailability of his
state by the impact of lung function. At present the main products are
Pfizer's inhaled insulin powder formulations of insulin Exubera, Novo
Nordisk's inhaled formulations of liquid formulations NN1998
(AERxiDMS) and Eli Lilly's inhaled powder preparations and so on.

(2) has been reported by the nasal mucosa of nasal absorption of
inhaled insulin can significantly lower blood glucose, but smaller
nasal absorption, nasal ciliary clearance is stronger, so the
absorption efficiency is low. For increasing the absorption efficiency
will be increased by adding surfactant irritation caused by nasal
mucosa, so few studies.

(3) the oral mucosa absorption of insulin by the oral mucosa of the
method is called "ORALIN". Found, T2DM patients with ORALIN
15min before a meal to give insulin, and subcutaneous injection of
insulin similar effect.

2. Oral Insulin

The small intestine in humans and animals there are certain specific
areas, accounting for about 25% of intestinal mucosa, allowing some
particles into the lymph factor and circulatory system. Using this
feature can be included into the insulin microspheres made of
different materials (vesicles, nano-ball), to carry insulin into the
circulatory system. Steric vector of insulin and to prevent contact
with the gastrointestinal tract enzymes, and the trypsin inhibitor and
insulin were encapsulated in microspheres system, could increase drug
bioavailability. Development of oral insulin in recent years, can
simulate the physiological insulin secretion, has proved to have lower
blood glucose, plasma insulin increased the role of the more promising
drugs. Formulations of the present study are capsules, capsules,
microcapsules and the compound encapsulated emulsion. The main
disadvantage is affected by many factors dose is difficult to
accurately calculate, on the gastrointestinal mucosa may have side
effects. Existing products are developed by Generex oral tablet
Oralin, Lilly's U.S. AI-401 and other oral dosage forms.

3. There are also eye drops and Insulin penetrant through the skin,
are in the study.

Fourth, insulin and other drugs and the interaction of factors

(A) against the drug insulin

1. Glucocorticoids, adrenocorticotropic hormone, glucagon, estrogen,
oral contraceptives, thyroxine, epinephrine, thiazide diuretics,
phenytoin, phenyl alanyl blood glucose levels can be increased

2. Calcium channel blocker, clonidine, danazol, diazoxide, growth
hormone, heparin, H2 receptor antagonists, marijuana, morphine,
nicotine and other changes in glucose metabolism can make blood sugar.

3. Smoking can be antagonized by the release of catecholamines and the
hypoglycemic effect of insulin.

(B) synergistic effect of the drug insulin

1. Salicylates, anti-clotting drugs, sulfa drugs, and anticancer drugs
methotrexate competition with insulin and plasma protein binding of
free insulin in the blood increased.

2. Oral hypoglycemic agents and insulin have synergistic hypoglycemic
effect. Anabolic steroid, androgen, or monoamine oxidase inhibitors,
non-steroidal anti-inflammatory analgesic drugs may enhance the
hypoglycemic effect of insulin.

3. ¦Â-receptor blockers such as propranolol combination with insulin
can increase the risk of low blood sugar, hypoglycemia can cover up to
extend the time low blood sugar.

4, and a lot of moderate ethanol can enhance the role of
insulin-induced hypoglycemia.

5. Chloroquine, quinidine, quinine can delay the degradation of
insulin to enhance its hypoglycemic effect.

6. Angiotensin-converting enzyme inhibitors, bromocriptine, fibrate,
ketoconazole, lithium, mebendazole, or theophylline may increase the
hypoglycemic effect of insulin that may cause lower blood sugar.

(C) Other factors

1. ª¥ long-term use of insulin antibody production animal insulin,
insulin-producing antibodies, can significantly reduce the insulin

2. Post-receptor defect of insulin receptor or
Can cause insulin dosage increased, but the hypoglycemic effect is not
obvious. ª¥

3. ª¥ liver disease cirrhosis, the liver of insulin, glucagon, growth
hormone inactivation reduced degradation, may have hyperinsulinemia,
hyperlipidemia high glucagon, etc. occur, the number of insulin
receptors on target cells to reduce , expressed as insulin resistance,
blood glucose fluctuations at this time, the application of insulin
than the large number of very difficult to get good control of blood
glucose. ª¥

4. ª¥ hyperglycemia and glucose toxicity

Blood glucose not only its own role by promoting their absorption, can
also affect the secretory function of islet B cells. Under normal
conditions in the body, acute hyperglycemia can promote their own
insulin secretion and glucose utilization in chronic hyperglycemia,
the suppression of insulin secretion and glucose metabolism, a
phenomenon known as glucose toxicity, which led to decreased blood
glucose increase in insulin effect, as well as reduce the dose of

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