Download Diabetes - nenu.edu.cn

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A chronic metabolic diseases.
Patients often need to take medicine, which costs a lot.
Patients often feel thirsty, hungry, and loss weight.
The patients were recommended to eat low fat and low
sugar food.
Diabetes and Polysacchrides
Chengxin Sun
2017/5/23
Diabetes Mellitus
Disease in which the body doesn’t
produce or properly use insulin, lead
to hyperglycemia.
Main contents
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Prevalence area and age
Diagnosis of DM
Symptoms, Effects of Long-term and
complications
Types of DM
Mechanism of DM
Drugs of anti-hyperglycimia
Polysaccharides
Prevalence
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Virtually no physician is without
patients who have the disease
Burden of Diabetes
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The development of diabetes is projected to reach
pandemic proportions over the next 10-20 years.
International Diabetes Federation (IDF) data
indicate that by the year 2025, the number of
people affected will reach 333 million, 90% of
these people will have Type 2 diabetes.
In most western societies, the overall prevalence
has reached 4-6%, and is as high as 10-12%
among 60-70-year-old people.
The annual health costs caused by diabetes and
its complications account for around 6-12% of all
health-care expenditure.
Cost of DM
Diagnosis of Diabetes Mellitus
Diagnosis of Diabetes Mellitus
A1C means a kind of glycosylated hemoglobin
Symptoms
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Diabetes mellitus may present with
characteristic symptoms such as thirst,
polyuria, blurring of vision, and weight
loss.
In its most severe forms, in absence of
effective treatment, death.
Often symptoms are not severe, or may be
absent, and consequently hyperglycaemia
sufficient to cause pathological and
functional changes may be present for a
long time before the diagnosis is made.
Effects of Long-term
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The long–term effects of diabetes mellitus
include progressive development of the
specific complications of blindness, renal
failure, foot ulcers, and features of
autonomic dysfunction, including sexual
dysfunction.
Types
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type 1 diabetes
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type 2 diabetes
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gestational diabetes mellitus (GDM)
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other specific types of diabetes
Type 1 diabetes
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It was called insulin-dependent diabetes mellitus
(IDDM) previously.
Type 1 diabetes develops when the body’s
immune system destroys pancreatic beta cells, the
only cells in the body that make the hormone
insulin that regulates blood glucose.
This form of diabetes usually strikes children and
young adults, although disease onset can occur at
any age.
Type 1 diabetes may account for 5% to 10% of all
diagnosed cases of diabetes.
Risk factors for type 1 diabetes may include
autoimmune, genetic, and environmental factors.
Type 2 diabetes
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It was previously called non-insulin-dependent diabetes
mellitus (NIDDM).
Type 2 diabetes may account for about 90% to 95% of
all diagnosed cases of diabetes.
It usually begins as insulin resistance, a disorder in
which the cells do not use insulin properly. As the need
for insulin rises, the pancreas gradually loses its ability
to produce insulin.
Type 2 diabetes is associated with older age, obesity,
family history of diabetes, history of gestational
diabetes, impaired glucose metabolism, physical
inactivity, and race/ethnicity.
African Americans, Hispanic/Latino Americans,
American Indians, and some Asian Americans and
Native Hawaiians or Other Pacific Islanders are at
particularly high risk for type 2 diabetes.
Type 2 diabetes is increasingly being diagnosed in
children and adolescents.
Gestational diabetes
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A form of glucose intolerance that is diagnosed in
some women during pregnancy.
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During pregnancy, gestational diabetes requires
treatment to normalize maternal blood glucose
levels to avoid complications in the infant.
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After pregnancy, 5% to 10% of women with
gestational diabetes are found to have type 2
diabetes.
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Women who have had gestational diabetes have a
20% to 50% chance of developing diabetes in the
next 5-10 years.
Other types of DM
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Other specific types of diabetes result from
specific genetic conditions (such as
maturity-onset diabetes of youth), surgery,
drugs, malnutrition, infections, and other
illnesses.
Such types of diabetes may account for 1%
to 5% of all diagnosed cases of diabetes.
What goes wrong in diabetes?
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Multitude of mechanisms
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Insulin
Regulation
 Secretion
 Uptake or breakdown
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Beta cells
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damage
Normal state
Insulin Secretion
Pathological state---Organic model
Cellular mechanisms
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Phosphorylation and
dephosphorylation of IRS proteins
Adiponectin
NFκB and IKK activity
Mitochondrial metabolism
β-cell dysfunction
+P and -P of IRS proteins
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Phosphotyrosine phosphatase 1B (PTP1B) is
widely expressed and negatively regulate
insulin signalling.
Serine/threonine phosphorylation of IRS1
reduces its ability to act as a substrate for
the tyrosine kinase activity of the insulin
receptor and inhibits its coupling to its
major downstream effector systems.
adipocyte
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Adiponectin signals via AMP kinase, a stressactivated signalling enzyme implicated in
various metabolic responses, including
suppression of hepatic gluconeogenesis,
glucose uptake in exercising skeletal muscle,
fatty acid oxidation, and inhibition of lipolysis,
which might explain its beneficial metabolic
effects
AMP kinase has also been implicated in the
mechanism of action of metformin, and
possibly of the thiazolidinediones, suggesting
that it has a role in clinical anti-diabetic
responses.
NFκB and IKK activity
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Nuclear factor κB (NFκB) is held in an
inactive state in resting conditions by
binding to an inhibitory partner,
Phosphorylation of IκB by its kinase (IKK)
leads to IκB degradation, releasing NFκB for
translocation to the nucleus where it can
affect the transcription of diverse genes
involved in the inflammatory response.
NFκB and IKK activity
IKK
NFκB - IκB
NFκB
IκB
Gene transcription
+Insulin resistance
Mitochondrial metabolism
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mitochondrial lipid oxidation in patients who have
impaired oxidative capacity and small mitochondria in
skeletal muscle.
PPARγ co-activator 1 (PGC1), a transcription factor for
genes involved in mitochondrial fatty acid oxidation and
ATP synthesis, was decreased in young, lean, insulinresistant offspring of parents with type 2 diabetes,
suggesting that an inherited defect in mitochondrial
oxidative phosphorylation could lead to cellular lipid
accumulation.
Decreased expression of PGC1 and related gene products
could affect mitochondrial function in people with insulinresistance
β-cell dysfunction
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Glucose toxicity
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Lipotoxicity
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Islet amyloid
Cellular model
Glucose toxicity
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In β cells, oxidative glucose metabolism will always lead
to production of reactive oxygen species, normally
detoxified by catalase and superoxide dismutase.
β cells are equipped with a low amount of these proteins
and also of the redox-regulating enzyme glutathione
peroxidase.
Hyperglycaemia has been proposed to lead to large
amounts of reactive oxygen species in β cells, with
subsequent damage to cellular components.
Loss of pancreas duodenum homeobox 1 (PDX-1), a
critical regulator of insulin promoter activity, has also
been proposed as an important mechanism leading to βcell dysfunction.
Additionally, reactive oxygen species are known to
enhance NFκB activity, which potentially induces β-cell
apoptosis.
Lipotoxicity
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in both non-diabetic and diabetic obese patients,
NEFA(“non-esterified fatty acid” or “free fatty acid”)
concentrations are raised as a result of enhanced adipocyte
lipolysis. Fatty acids lead to enhanced insulin secretion in
acute studies, but after 24 h they actually inhibit insulin
secretion.
In the presence of glucose, fatty acid oxidation in β cells is
inhibited and accumulation of long-chain acyl coenzyme-A
occurs. However, long-chain acyl coenzyme A itself can also
diminish the insulin secretory process by opening β-cell
potassium channels.
A second mechanism might be increased expression of
uncoupling protein-2, which would lead to reduced ATP
formation and, hence, decreased insulin secretion.
A third mechanism might involve apoptosis of β cells,
possibly via fatty acid or triglyceride-induced generation of
nitric oxide.
Islet amyloid
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Islet amyloid consists of deposits of islet
amyloid polypeptide, also known as amylin,
which is co-secreted with insulin at a more
than tenfold lower rate.
The physiological role of islet amyloid
polypeptide is unclear, and diverse roles
such as inhibition of insulin action,
inhibition of insulin secretion, and inhibition
of glucagon secretion have been proposed.
It has been suggested that small
aggregates are cytotoxic, possibly related
to radical production.
Melecular model
Drug of antihyperglycaemia
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Thiazolidinediones
Metformin
α-glucosidase inhibitors
Sulfonylurea derivatives
Exogenous insulin
Glucagon-like peptide 1
Experimental approaches
Summary drugs
Polysaccharides
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Polysaccharides belong to a structurally diverse and
complex class of macromolecules, in which many
monosaccharides joined together by glycosidic linkages.
They are abound in nature products, especially in plant
medicines.
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They are commonly extracted from nature products by hot
water, and can be further purified using a combination of
techniques, such as ethanol precipitation, fractional
precipitation, and acidic precipitation with acetic acid, ionexchange chromatography, gel filtration, and affinity
chromatography.
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Over 100 polysaccharides from plants have been reported
for hypoglycemic activity. Some botanical polysaccharides
are considered as important bioactive components
responsible for hypoglycemic effect.
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Investigations showed this polysaccharide administered
orally can significantly reduce blood glucose levels and
water intake, and increase the body weight of diabetic
mice compared with alloxan-induced diabetic control
group.
多糖产品
Main antiDM polysaccharides
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Astragalus polysaccharides
Lycium barbarum polysaccharides
Tea polysaccharides
Panax Ginseng polysaccharides
Ganoderma lucidum polysaccharides
Momordica charantia polysaccharides
Lycium barbarum
枸杞
Astragalus
黄芪
Ganoderma lucidum
灵芝
Ginseng
人参
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Why and How are left for us to
investigate
Referrence
1
Qi, L. W. et al. Anti-diabetic agents from natural products - An update
from 2004 to 2009. Current Topics in Medicinal Chemistry 10, 434-457,
doi:10.2174/156802610790980620 (2010 ).
2
Standards of medical care in diabetes-2010. Diabetes Care 33 (2010).
3
Dall, T. et al. Economic costs of diabetes in the U.S. in 2007. Diabetes Care
31, 596-615 (2008).
4
Stumvoll, M., Goldstein, B. J. & van Haeften, T. W. Type 2 diabetes:
principles of pathogenesis and therapy. The Lancet 365, 1333-1346,
doi:Doi: 10.1016/s0140-6736(05)61032-x (2005).
5
http://www.diabetesatlas.org/
6
http://www.healthypeople.gov/
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