Transcript Chapter18 Diabetes Mellitus

Diabetes Mellitus
Diabetes Mellitus epidemiology
• World WHO 2004 > 150 million
• China at present > 40million
• The second in the word
• annual gain >10%
concept
• Diabetes Mellitus is a syndrome with
chronic hyperglycemia due to either a
deficiency of insulin secretion or to a
combination of insulin resistance and
inadequate insulin secretion to
compensate and leads to dysmetabolism
of proteins, lipid as well as many other
metabolites and elements.
• Type 1 diabetes is due to pancreatic
islet B cell destruction predominantly
by an autoimmune process , and these
patients are prone to ketoacidosis.
• Type 2 diabetes is the more prevalent
form and results from insulin
resistance with a defect in
compensatory insulin secretion.
• CLASSIFICATION AND PATHOGENESIS
• Clinical findings
• Differential Diagnosis
• Treatment : Diabetes Mellitus Diet
CLASSIFICATION AND
PATHOGENESIS
• Diabetes is now classified according to
its etiology recommended by the
American Diabetes Association (ADA)
in 1997 and revised by WORLD Health
Organization in 1999(usually referred to
WHO/1999 Recommendation
TYPE 1 DIABETES MELLITUS
• The form of diabetes is immune –
mediated in over 90% of cases and
idiopathic in less than 10% .The rate of
pancreatic B cell destruction is quite
variable ,being rapid in some
individuals and slow in others
TYPE 1 DIABETES MELLITUS
• It can occur at any age but most
commonly arises in children and young
adults with a peak incidence before
school age and again at around puberty
before last century
TYPE 1 DIABETES MELLITUS
• It is a catabolic disorder in which
circulating insulin is very low or
virtually absent .
• The insulin secretion, due to the
pancreatic B cell destruction ,fails to
meet the requirement of nutrient
absorption.
TYPE 1 DIABETES MELLITUS
• Exogenous insulin is therefore
required to reverse the metabolic state,
prevent ketosis, reduce the
hyperglucagonemia ,and maintain
glucose homeostasis.
TYPE 1 DIABETES MELLITUS
• Certain human leukocyte antigens
(HLA) are strongly associated with the
development of type 1 diabetes.
• About 95% of type 1 patients possess
either HLA-DR3 or HLA-DR4, compared
with 45%-50% of white controls
TYPE 1 DIABETES MELLITUS
• HLA-DQ genes with even more
specific ,markers of type 1
susceptibility, since a particular variety
(HLA-DQB1*0302 )is found in the DR4
patients with type 1,while a
“protective ”gene (HLADQB1*0602) is
often present in the DR4 controls.
TYPE 1 DIABETES MELLITUS
• Recently it was found the freqency of
“susceptible” genotype decreases and
the frequency of “protective ”genotype
increased as the onset age of a subject
becomes older.
TYPE 1 DIABETES MELLITUS
• In addition , most patients with type 1
diabetes at diagnosis have circulating
antibodies to islets (islet cell antibodies,
ICA), insulin antibodies(IAA) ,glutamic
acid decarboxylase (GAD 65),and to
tyrosine phosphatases(IA-2 and IA2-b,
IA is the abbreviation for insulinoma
associated antigen).
TYPE 1 DIABETES MELLITUS
• The antibody levels decline with
increasing duration of the disease.
• Also, once patients are treated with
insulin ,low levels of anti-bodies
develop.
TYPE 1 DIABETES MELLITUS
• More recently regulatory T cell and
cytotoxic T cell abnormality were
considered to be critical in the
development of isletitis and b cell
destruction.
TYPE 1 DIABETES MELLITUS
• The polymorphism in gene encoding
cytotoxic lymphocyte antigeng4 (CTLA4) was found related to development of
autoimmune diabetes as well as
autoimmune thyroiditis.
• B-cell reactive T cell avidity was
proposed at the beginning of isletitis.
TYPE 1 DIABETES MELLITUS
• Certain unrecognized patients with a
milder expression of type 1 diabetes
initially retain enough b cell function to
avoid ketosis but later in life develop
increasing dependency on insulin
therapy as b cell mass diminishes
(usually 6 years after dignosis).
TYPE 1 DIABETES MELLITUS
• Islet cell antibody survey among
northern Europeans indicate that up to
15% of “type 2”patients may actually
have this mild form of type 1 diabetes
(latent autoimmue diabetes of
adulthood, LADA)
TYPE 2 DIABETES MELLITUS
• This presents a heterogeneous group
comprising milder forms of diabetes
that occur predominantly in adults but
occasionally in juveniles.
• More than 90% of all diabetes in the
United States and China are included
under this classification .
• In most cases of this type of diabetes,
this cause is unkown.
TYPE 2 DIABETES MELLITUS
• The pathogenesis currently received is
illustrated in (Figure 6-18-1 )
• Tissue insensitivity to insulin has been
noted in most type 2 patients
irrespective of weight and has been
attributed to several interrelated factors
Figure 6-18-1 pathogenesis of type 2
diabetes mellitus
TYPE 2 DIABETES MELLITUS
• These include a putative(and as yet
undefined ) genetic factor ,which is
aggravated in time by additioal
enhancers of insulin resistance such as
aging ,a sedentary lifestyle, and
abdominal –visceral obesity .
• In addition ,there is an accompanying
deficiency in the response of
pancreatic b cells to glucose .
TYPE 2 DIABETES MELLITUS
• Both the tissue resistance to insulin
and the impaired b cell response to
glucose appear to be further
aggravated by increased
hyperglycemia (glucose toxicity), and
both defects are ameliorated by
treatment that reduces the
hyperglycemia toward normal
TYPE 2 DIABETES MELLITUS
• Most epidemiologic data indicate
strong genetic influences.
• Attempts to identify genetic markers for
type 2 have as yet been unsuccessful.
Other specific types of diabetes mellitus
• Other specific types of diabetes mellitus
is relatively rare
• Maturity –onset diabetes of the young
(MODY) is a subgroup due to monogenic
disorder characterized by non-insulin –
dependent diabetes with autosomal
dominant inhenritantance and an age at
onset of 25 years or younger.
Other specific types of diabetes mellitus
• Diabetes due to mutant insulin is a very
rare subtype of nonobese type 2
diabetes ,with no more than ten
families having been described.
Other specific types of diabetes mellitus
• Diabetes duo to a mutation of
mitochondrial DNA that impairs the
transfer of leucine or lysine into
mitochondrial , proteins has been
described.
Other specific types of diabetes mellitus
• Since sperm do not contain
mitochondria, only the mother
transmits mitochondrial genes to her
offspring.
Gestational diabetes mellitus (GDM)
• GDM is defined as any degree of
glucose intolerance with onset or first
reconition during pregnancy.
• The definition appleies regardless of
whether insulin or only diet
modification is used for treatment or
whether the condition persists after
pregnancy.
Gestational diabetes mellitus (GDM)
• It does not exclude the possibility that
unrecognized glucose intolerance may
have antedated or begun concomitantly
with the pregnancies.
• The prevalence may range from 1%14%of pregnancies, depending on the
population studied
Gestational diabetes mellitus (GDM)
• GDM represents nearly 90% of all
pregnancies complicated by diabetes.
• Insulin is recommended as the only
modality of treatment even trial of oral
agents that are undertaken showed
safe.
Gestational diabetes mellitus (GDM)
• Deterioration of glucose tolerance
occurs normally during pregnancy ,
particularlyi n the 3rd trimester.
Clinical findings
• Symptoms and signs
• Laboratory findings
Clinical findings
• Symptoms and signs
• The principal clinical features of the
two major types of diabetes mellitus
are listed for comparison in (Table 6-183)
Diabetes Mellitus: Signs &
Symptoms
Three
polys:
polyphagia,
polyuria, &
polydipsia
Weight loss
Fatigue
Hyperglycemia
Clinical findings
• Symptoms and signs
• Patients with type 1 diabetes present
with a characteristic symptom complex.
• An absolute deficiency of insulin
results in accumulation of circulating
glucose and fat acids,with conseqent
hyperosmolality and hyperketonemia.
Clinical findings
• Symptoms and signs
• Patients with type 2 diabetes may or
may not present with characteristic
features.
• The presence of obesity or a strongly
positive family history for mild diabetes
suggests a high risk for the
development of type 2 diabetes.
Laboratory findings
•
•
•
•
•
Urinary analysis
Blood test procedures
B cell Reserve Evaluation
Autoantibodies
Lipoprotein Abormalities in Diabetes
Clinical findings
• Laboratory findings
• Urinary analysis
• Glycosuria and ketonuria can be found
in diabetic patients.
Clinical findings
•
Laboratory findings
•
Blood test procedures
•
•
A. Glucose Tolerance Test
B. Glycated Hemoglobin (Hemoglobin A1)
measurements
C. Serum Fructosamine
D. Self –Monitoring of Blood Glucose
E.Continuous Glucose Monitoring Systems
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•
•
Blood test procedures
• A. Glucose Tolerance Test
• Criteria for laboratory confirmation of
diabetes mellitus if the fasting plasma
glucose level is 7.0 mmol/L(126mg/dL)
or higher on more than one occasion ,
further evaluation of the patient with a
glucose challenge is unnecessary .
Blood test procedures
• A. Glucose Tolerance Test
• However ,when fasting plasma glucose
is less than 7.0 mmol/L(126mg/dL) in
suspected cases ,a standardized oral
glucose tolerance test may be ordered .
Blood test procedures
B. Glycated Hemoglobin(HemoglobinA1)
measurements
Glycated hemoglobin is abnormally high in
diabetics with chronic hyperglycemia and
reflects their metabolic control.
It is produced by nonenzymatic condensation
of glucose molecules with free amino groups
on the globin component of hemoglobin.
Blood test procedures
B. Glycated Hemoglobin(HemoglobinA1)
measurements
The higher the prevailing ambient levels of
blood glucose, the higher will be the level of
glycated hemoglobin.
The major form of glycohemoglobin is termed
hemoglobin A1c,which normally comprises
only 4%-6% of the total hemoglobin
Blood test procedures
B. Glycated Hemoglobin(HemoglobinA1)
measurements
• Since glycohemoglobins circulate with
in red blood cells whose life span lasts
up to 120 days, they generally reflect
the state of glycemia over the
preceding 8-12 weeks, thereby
providing an improved method of
assessing diabetic control.
Blood test procedures
B. Glycated Hemoglobin(HemoglobinA1)
measurements
• Measurements should be made in patients
with either type of diabetes mellitus at 3-to 4
month intervals so that adjustment in
therapy can be made if glycohemoglobin is
either subnormal or if it is more than 2%
above the upper limits of normal for a
particular laboratory.
Blood test procedures
•
•
C. Serum Fructosamine
Serum fructosamine is formed by
nonenzymatic glycosylation of serum
proteins (predominantly albumin).
Blood test procedures
• C. Serum Fructosamine
• Since serum albumin has a much
shorter half-life than hemoglobin,
serum fructosamine generally reflects
the state of glycemic control for only
the preceding 2 weeks.
Blood test procedures
• C. Serum Fructosamine
• Normal values vary in relation to the
serum albumin concentration and are
1.5-2.4mmol/L when the serum albumin
level is 5 g/dL
Blood test procedures
•
•
D.Self –Monitoring of Blood Glucose
Capillary blood glucose
measurements performed by patients
themselves, as outpatients, are
extremely useful.
Blood test procedures
E. Continuous Glucose Monitor
Systems
The main value of these systems
appears to be in identifying
episodes of asymptomatic
hypoglycemia, especially at night.
B cell Reserve Evaluation
• It is estimated more than 50% of b cell
were lost at the onset of diabetes.
• The b cell reserve is usually measured
in its secreted functional proteinsinsulin.
B cell Reserve Evalution
• Measurement of insulin is usually used for
functional evaluation in those not on insulin,
and C-peptide can be used as an alternative
toolin those on insulin.
• Fasting and 2-hour after stimulator insulin or
C-peptide are usually measured .
• The stimulator can be glucose , arginine,
glucagons.
B cell Reserve Evalution
• Glucose is often replaced by standard meal
equivalent to 75g glucose.
• Reference values should be setup in each
laboratory and should be interpreted
according to adiposity, or insulin resistance
• The evaluation is not a routine practice in
clinics, but is used in research protocol.
Autoantibodies
• It is gradually acccepted that determination of
islet b cell autoimmunity is usual in typing of
diabetes
• Insulin autoantibody (IAA), glutamic acid
decarboxylase (GADA), islet cell antibodies
( ICA) ,-now replaced by tyrosine phosphatase
autoantibodies (IA-2,IA2-b) are the most
commonly used tests
Autoantibodies
• Several other antibodies were studied
for their utility in predicting type 1
diabetes.
• One is carboxypeptidase antibody
(CPH) that is thoroughly studied a
Chinese group.
• IAA is more frequently detected in very
young child diabetes.
Autoantibodies
• ICA, in juvenile diabetes.
• GADA, in elder diabetes.
• The autoantibodies profile can change
during the progression of disease.
• GADA appears relatively late.
• A positive result predicts the need for
insulin in 6 years.
Lipoprotein Abnormalities in
Diabetes
• Circulating lipoprotein are just as dependent
on insulin as the plasm glucose .
• In type 1 diabetes , moderately deficient
control of hyperglycemia is associated with
only a slight elevation of LDL cholesterol and
serum triglycerides and little if any change in
HDL cholesterol
Lipoprotein Abormalities in Diabetes
• Once the hyperglycemia is corrected,
lipoprotein levels are generally normal.
• However ,in obese patients with type 2
diabetes, a distict “diabetic dyslipidemia” is
characteristic of the insulin resistence
syndrome.
Lipoprotein Abormalities in Diabetes
• Its feathers are a high serum
triglyceride level(300-400mg/L), a low
HDl cholesterol (less than 30mg/dL),
and a qualitative change in LDL
particles, producing a smaller dense
particle whose membrane carries
supro-normal amountes of free
cholesterol.
Lipoprotein Abormalities in Diabetes
• These small dense LDL particles are more
susceptible to oxidation, which renders them
more atherogenic.
• Since primary disorders of lipid metabolism
may coexist with diabetes, persistence of
lipid abnormalities after restoration of normal
weight and blood glucose should prompt a
diagnostic workup and possible
pharmacotherapy of the lipid disorder.
Differential Diagnosis
• Hyperglycemia secondary to other
sources
• Secondary hyperglycemia has been
associated with various disorders of
insulin target tissues (liver, muscle , and
adipose tissue)(Table 6-18-5).
Differential Diagnosis
• Other secondary cause of carbohydrate
intolerance include endocrine
disorders-often specific endocrine
tumors-accociated with excess
production of growth hormone,
glucocorticoids, catecholamines,
glucagon , or somatostatin.
Differential Diagnosis
• A rare syndrome of extreme insulin
resistance associated with acanthosis
nigricans afflicts either young women with
androgenic features as well as insulin
receptor mutations or older people ,
mostly women , in whom a circulating
immunoglobulin binds to insulin receptors
and reduces their affinity to insulin.
Differential Diagnosis
• Medications such as diuretics ,
phenytoin , niacin, and high-dose
glucocorticoids can produce
hyperglycemia that is reversible once
the drugs are discontinued or when
diuretic-induced hypokalemia is
corrected
Differential Diagnosis
• Chronic pancrearitis or subtotal
pancreatectomy reduces the number of
functioning b cells and can result in
metabolic derangement very similar to
that of genetic type 1 diabetes except
that a concomitant reduction in
pancreatic a cells may reduce glucagon
secretion so that relatively lower doses
of insulin replacement are needed.
Differential Diagnosis
• Insulin-dependent diabetes is
occassionally associated with
Addison’s disease and autoimmune
thyroiditis (Schimidt’s syndrome, or
polyglandular failure syndrome).
Differential Diagnosis
• This occurs more commonly in women
and represents an autoimmune
disorder in which there are circulating
antibodies to adrenocortical and
thyroid tissue, thyroglobulin,and
gastric parietal cells.
Nondiabetic Glycosuria
• Nondiabetic glycosuria(renal
glycosuria) is a benign asymptomatic
condition wherein glucose appears in
urine despite a normal amount of
glucose in blood , either basally or
during a glucose tolerance test.
Nondiadetic Glycosuria
• Its cause may vary from an autosomally
transmitted genetic disorder to one
associated with dysfunction of the proximal
renal tubule (Fanconi’s syndrome ,chronic
renal failure), or it may merely be a
consequence of the increasd load of glucose
presented to the tubules by the elevated
glomerular filtration rate during pregnancy.
Nondiabetic Glycosuria
• As many as 50% of pregnant women
normally have demonstrable sugar in
the urine, especially during the third
and fourth months.
• This sugar is practically always
glucose except during the late weeks of
pregnancy , when lactose may be
present.
Treatment
• Diabetes mellitus requires ongoing
medical care as well as patient and
family education both to prevent acute
illness and to reduce the risk of longterm complications.
Treatment
• Diet
• A well-balanced，nutritious diet remains a
fundamental element of therapy.
• However, In more than half of case ,diabetic
patients fail to follow their diet .
• In prescribing a diet, it is important to relate
dietary objectives to the type of diabetes.
Treatment
• Diet
• In obese patients with mild hyperglycemia,
the major goal of diet therapy is weight
reduction by caloric restriction.
• Thus ,there is less need for exchange lists,
emphasis on timing of meals ,or periodic
snacks, all of which are so essential in the
treatment of insulin – requiring nonbese
diabetics.
Treatment
• ADA Recommendations
• The American Diabetes Association release
an annual position statement on medical
nutrition therapy that replaces the calculated
ADA diet formula of the past with
suggestions for an individully tailored dietary
prescription based on metabolic , nutritional,
and life style requirements .
Treatment
• ADA Recommendations
• They contend that the concept of one diet for
“diabetes” and the prescription of an “ADA
diet” no longer can apply to both major type
of diabetes.
• In their recommendations for persons with
type 2 diabetes, the 55%-60% carbohydrate
content of previous diets has been reduce
considerably because of the tendency of
high carbohydrate intake to cause
hyperglycemia, hypertriglyceridemia, and a
lowered HDL cholesterol
Treatment
• ADA Recommendations
• .In obese type 2 patients, glucose and lipid
goals join weight loss as the focus of
therapy .
• These patients are advised to limit their
carbohydrate content by substituting
noncholesterologenic monounstaturated oils
such as olive oil ,rapeseed (canola) oil, or the
oil in nuts and avocados.
Treatment
• ADA Recommendations
• This maneuver is also indicated in type
1 patients on intensive insulin
regimens in whom near-normoglycemic
control is less achievable on higher
carbohydrate diets.
Treatment
• ADA Recommendations
• They can administer 1 unit of regular insulin
or insulin lispro for each 10 or 15 g of
carbohydrate eaten at a meal .
• In these patients , the ratio of carbohydate to
fat will vary among individuals in relation to
their glycemic responses ,insulin regiments,
and exercise pattern.
Treatment
• ADA Recommendations
• The current recommendations for both
types of diabetes continue to limit
cholesterol to 300 mg dairly and advise
a daily protein intake of 10%-20% of
total calories
Treatment
• ADA Recommendations
• They suggest that saturated fat be no
higher than 8%-9% of total calories with
a similar proportion of polyunsaturated
fat and that the remainder of caloric
needs be made up of an individualized
ratio of monounsaturated fat and of
carbohydrate containing 20-35 g of
dietary fiber .
Treatment
• ADA Recommendations
• Poultry ,veal, and fish continue to be
recommended as a substitute for red meats
for keeping saturated fat content low.
• The present ADA position statement proffers
no evidence that reducing protein intake
below 10% of intake (about 0.8 g/kg/d) is of
any benefit in patients with nephropathy and
renal impairment ,and doing so may be
detrimental.
Treatment
• Dietary Fiber
• Plant components’ such as cellulose ,gum,
and pectin are indigestible by humans and
termed dietary “fiber”.
• The ADA recommends food such as oatmeal ,
cereals, and beans with relatively high
soluble fiber content as staple components
of the diet in diabetics.
Treatment
• Dietary Fiber
• High soluble fiber content in the diet
may also have a favorable effect on
blood cholesterol levels.
Treatment
• Artifficial Sweeteners
• The latest position statement of ADA
concludes that all nonnutritive
sweeteners that have been approved by
the FDA (such as aspartame and
saccharin) are safe for consumption by
all people with diabetes.
Treatment
• Artifficial Sweeteners
• Two other nonnutritive sweeteners
have been approved by the FDA as safe
for general use: sucralose(Splenda)
and acesulfame potassium
(Sunett ,Sweet one, DiabetiSweet)
Treatment
• Artifficial Sweeteners
• Nutritive sweeteners such as sorbitol
and fructose have increased in
popularity .
• Except for acute diarrhea induce by
ingestion of large amounts of sorbitol –
containing foods, their relative risk has
yet to be established.
Treatment
• Artifficial Sweeteners
• Fructose represents a “natural ”sugar
substance that is a highly effective
sweetener which induces only slight
increases potential adverse effects of large
amounts of fructose (up to 20% of total
calories) on raising serum cholesterol and
LDL cholesterol , the ADA feels it may have
no overall advantage as a sweetening agent
in the diabetic diet.