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Transcript
‫الدكتور الصيدالني‬
‫احمد يحيى دالل باشي‬
‫أستاذ في الكيمياء الحياتية الطبية‬
‫رئيس فرع الكيمياء الحياتية‬
‫كلية الطب‪/‬جامعة الموصل‬
‫مدير وحدة التعليم الطبي في زاخو‬
Disorders of Carbohydrates metabolism,
Hyperglycemia, Diabetes Mellitus & Hypoglycemia
PATHWAYS IN GLUCOSE METABOLISM
The
major energy pathways involved with glucose metabolism in
the body includes the followings:.
Glycolysis: Metabolism of glucose molecule to pyruvate or
lactate for production of energy.
Gluconeogenesis: Formation of glucose-6-phosphate from
non carbohydrate sources.
Glycogenolysis: Breakdown of glycogen to glucose for use
as energy.
Glycogenesis: Conversion of glucose to glycogen for
storage.
Lipogenesis: Conversion of carbohydrates to fatty acids.
Lipolysis: Decomposition of fat.
Regulation of Carbohydrate Metabolism
The liver, pancreas, and other endocrine glands are all involved in
controlling the blood glucose concentrations within a narrow range.
Control of blood glucose is under two major hormones: insulin
and glucagon both produced by the pancreas. Their actions oppose
each other. Other hormones also exert some control over blood glucose
concentrations. Insulin is the primary hormone responsible for the
entry of glucose into the cell. It is synthesized by the cells of islets of
Langerhans in the pancreas.
When these cells detect an increase in body glucose, they release
insulin. The release of insulin causes an increased movement of glucose
into the cells and increased glucose metabolism. Insulin is normally
released when glucose levels are high and is not released when glucose
levels are decreased. It decreases plasma glucose levels by increasing
the entry of glucose in muscle and adipose tissue. It also regulates
glucose by increasing glycogenesis, lipogenesis, and glycolysis
and inhibiting glycogenolysis. Insulin is the only hormone that
decreases glucose levels and can be referred to as a hypoglycemic
agent .
Glucagon is the primary hormone responsible for increasing
glucose levels. It is synthesized by the β cells of islets of
Langerhans in the pancreas and released during stress and fasting
states. When these cells detect a decrease in body glucose, they
release glucagon. Glucagon acts by increasing plasma glucose
levels by glycogenolysis in the liver and an increase in
gluconeogenesis. It can be referred to as a hyperglycemic
agent
Two hormones produced by the adrenal gland affect
carbohydrate metabolism.
Epinephrine, produced by the adrenal medulla, increases plasma
glucose by inhibiting insulin secretion, increasing glycogenolysis,
and promoting lipolysis. Epinephrine is released during times of
stress.
Glucocorticoids, primarily cortisol, are released from the adrenal
cortex on stimulation by adrenocorticotropic hormone (ACTH). Cortisol
increases plasma glucose by decreasing intestinal entry into the cell and
increasing gluconeogenesis, glycogenolysis, and lipolysis.
Two anterior pituitary hormones, growth hormone and ACTH,
promote increased plasma glucose. Growth hormone increases
plasma glucose by decreasing the entry of glucose into the cells
and decreasing glycolysis. Its release from the pituitary is
stimulated by decreased glucose levels and inhibited by increased
glucose. Decreased levels of cortisol stimulate the anterior
pituitary to release ACTH. ACTH, in turn, stimulates the adrenal
cortex to release cortisol and increases plasma glucose levels by
converting liver glycogen to glucose and promoting
gluconeogenesis.
Two other hormones affect glucose levels: Thyroxine and
somatostatin. The thyroid gland is stimulated by the production
of thyroid-stimulating hormone (TSH) to release thyroxine that
increases plasma glucose levels by increasing glycogenolysis,
gluconeogenesis, and intestinal absorption of glucose.
Somatostatin, produced by the β cells of the islets of Langerhans of the
pancreas, increases plasma glucose levels by the inhibition of insulin,
glucagon, growth hormone, and other endocrine hormones.
HYPERGLYCEMIA
Hyperglycemia is an increase in plasma glucose levels. In
healthy patients, during a hyperglycemia state, insulin is secreted
by the β cells of the pancreatic islets of Langerhans. Insulin
enhances membrane permeability to cells in the liver, muscle, and
adipose tissue.
Diabetes Mellitus
Diabetes mellitus is actually a group of metabolic diseases
characterized by hyperglycemia resulting from defects in insulin
secretion, insulin action, or both. In 1979, the National
Diabetes Data Group developed a classification and diagnosis
scheme for diabetes mellitus. This scheme included dividing
diabetes into two broad categories: type 1, insulin-dependent
diabetes mellitus (IDDM); and type 2, non–insulin-dependent
diabetes mellitus (NIDDM).
In 1995, the International Expert Committee and the
American Diabetes Association, describe the classification as
follow (Table 13-3).
Therefore, the ADA/World Health Organization (WHO) guidelines
recommend the following categories of diabetes:
■ Type 1 diabetes
■ Type 2 diabetes
■ Other specific types of diabetes
■ Gestational diabetes mellitus (GDM)
Type 1 diabetes is characterized by inappropriate hyperglycemia
primarily a result of pancreatic islet β-cell destruction and cellularmediated autoimmune destruction of the β cells of the pancreas,
causing an absolute deficiency of insulin secretion and a tendency to
ketoacidosis.
Type 2 diabetes, in contrast, includes hyperglycemia cases that result
from insulin resistance with an insulin secretory defect.
An intermediate stage, in which the fasting glucose is increased abovenormal limits but not to the level of diabetes has been named,
impaired fasting glucose. Use of the term impaired glucose
tolerance to indicate glucose tolerance values above normal but below
diabetes levels was retained. Also, the term gestational diabetes
mellitus was retained for women who develop glucose intolerance
during pregnancy.
Upper limit of 110 mg/dL on the fasting plasma glucose is
designated as the upper limit of normal blood glucose.
Type 1 constitutes only 10 - 20% of all cases of diabetes and
commonly occurs in childhood and adolescence. Characteristics of
type 1 diabetes include abrupt onset, insulin dependence, and ketosis
tendency.
Signs and symptoms include polydipsia (excessive thirst), polyphagia
(increased food intake), polyuria (excessive urine production), rapid
weight loss, hyperventilation, mental confusion, and possible loss of
consciousness (due to increased glucose to brain).
Complications include microvascular problems such as nephropathy,
neuropathy, and retinopathy. Increased heart disease is also found in
patients with diabetes.
Type 2 DM is characterized by hyperglycemia as a result of an
individual’s resistance to insulin with an insulin secretory defect. This
resistance results in a relative, not an absolute, insulin deficiency. Type
2 constitutes the majority of the diabetes cases. Most patients in this
type are obese or have an increased percentage of body fat distribution
in the abdominal region. This type of diabetes often goes undiagnosed
for many years and at increased risk with an increase in age, obesity,
and lack of physical exercise. Characteristics usually include adult onset
of the disease and milder symptoms than in type 1, with ketoacidosis
seldom occurring. However, these patients are more likely to go into a
hyperosmolar coma and are at an increased risk of developing
macrovascular and microvascular complications.
Other specific types of diabetes are associated with certain
conditions (secondary), including genetic defects of β-cell function or
insulin action, pancreatic disease, diseases of endocrine origin, drug- or
chemical-induced insulin receptor abnormalities, and certain genetic
syndromes. The characteristics and prognosis of this form of diabetes
depend on the primary disorder.
GDM is “any degree of glucose intolerance with onset or first
recognition during pregnancy.” Causes of GDM include metabolic
and hormonal changes. Patients with GDM frequently return to
normal postpartum.
However, this disease is associated with increased perinatal
complications and an increased risk for development of diabetes
in later years.
Infants born to mothers with diabetes are at increased risk
for respiratory distress syndrome, hypocalcemia, and
hyperbilirubinemia.
Pathophysiology of Diabetes Mellitus
In both type 1 and type 2 diabetes, the individual will be
hyperglycemic, which can be severe. Glucosuria can also occur after the
renal tubular transporter system for glucose becomes saturated. This
happens when the glucose concentration of plasma exceeds roughly
180 mg/dL in an individual with normal renal function and urine
output.
As hepatic glucose overproduction continues, the plasma glucose
concentration reaches around 300 to 500 mg/dL (17–28 mmol/L).
The difference in glucagon and insulin concentrations in these two
groups appears to be responsible for the generation of ketones through
increased β-oxidation. In type 1, there is an absence of insulin with an
excess of glucagon. This permits gluconeogenesis and lipolysis to occur.
The laboratory findings of a patient with diabetes with ketoacidosis
tend to reflect dehydration, electrolyte disturbances, and
acidosis. Acetoacetate, β-hydroxybutyrate, and acetone are produced
from the oxidation of fatty acids. The two former ketone bodies
contribute to the acidosis, normal or elevated plasma sodium and
potassium, slightly decreased bicarbonate, elevated blood urea nitrogen
(BUN) and creatinine.
Criteria for Testing Prediabetes and Diabetes
The testing criteria for asymptomatic adults for type 2 diabetes
mellitus were modified by the ADA Expert Committee to allow for earlier
detection of the disease.
According to ADA recommendations, all adults older than 45 years
should have a measurement of fasting blood glucose every 3 years.
Testing should be carried out at an earlier age or more frequently in
individuals who display overweight tendencies (i.e., body mass index
[BMI] ≥25 kg/m2) and have additional risk factors, as follows:
■ Habitually physically inactive
■ Family history of diabetes in a first-degree relative
■ History of GDM
■ Hypertension (blood pressure ≥140/90 mm Hg)
■ Low (HDL) high-density lipoprotein cholesterol concentrations (<35 mg/dL
[0.90 mmol/L])
■ Elevated triglyceride concentrations >250 mg/dL (2.82 mmol/L)
■ History of impaired fasting glucose/impaired glucose tolerance
■ Women with polycystic ovarian syndrome (PCOS)
■ Other clinical conditions associated with insulin resistance (e.g., severe
obesity)
■ History of cardiovascular disease
In the absence of the above criteria, testing for prediabetes and
diabetes should begin at age 45 years. If results are normal,
testing should be repeated at least at 3-years intervals.
As the incidence of adolescent type 2 diabetes has raised
dramatically in the past few years, criteria for the testing for type
2 diabetes in asymptomatic children have been developed. These
criteria include initiation of testing at the age 10 years or at onset
of puberty, with follow-up testing every 2 years for,
overweight plus any two of the following risk factors:
■ Family history of type 2 diabetes in first or second degree
relative
■ Race/ethnicity (e.g., Native American, African American, Latino,
Asian American, and Pacific Islander)
■ Signs of insulin resistance or conditions associated with insulin
resistance (e.g., hypertension, dyslipidemia)
■ Maternal history of diabetes or GDM
Criteria for the Diagnosis of Diabetes Mellitus
Three methods of diagnosis are suggested: (1) symptoms of
diabetes plus a random plasma glucose level of ≥200 mg/dL, (2) a
fasting plasma glucose of ≥126 mg/dL, or (3) an oral glucose tolerance
test (OGTT) with a 2-hour postload (75-g glucose load) level ≥200
mg/dL, each of which must be confirmed on a subsequent day by any
one of the three methods.
An intermediate group who did not meet the criteria of
diabetes mellitus but who had glucose levels above
normal was defined by two methods.
First, those patients with fasting glucose levels ≥100
mg/dL but <126 mg/dL were called the impaired
fasting glucose group.
Another set of patients who had 2-hour OGTT levels of
≥140 mg/dL but <200 mg/dL was defined as having
impaired glucose tolerance.
Patients with impaired fasting glucose and/or impaired
glucose tolerance are referred to as having
“prediabetes,” indicating the relatively high risk for the
development of diabetes in these patients.
The preferred test for diagnosing diabetes is measurement of the
fasting plasma glucose level.
HYPOGLYCEMIA
Hypoglycemia involves decreased plasma glucose levels and can
have many causes—some are transient and relatively insignificant, but
others can be life threatening. The plasma glucose concentration in
Hypoglycemia is usully less than 65 mg/dL (3.6 mmol/L); at about 50 to
55 mg/dL (2.8–3.0 mmol/L), observable symptoms of hypoglycemia
appear. The warning signs and symptoms of hypoglycemia are all
related to the central nervous system. The release of epinephrine into
the systemic circulation and of norepinephrine at nerve endings of
specific neurons act with glucagon to increase plasma glucose.
Symptoms of hypoglycemia are increased hunger, sweating,
nausea and vomiting, dizziness, nervousness and shaking, blurring of
speech and sight, and mental confusion.
Laboratory findings include decreased plasma glucose levels during
hypoglycemic episode . Extremely elevated insulin levels may be found
in patients with pancreatic β-cell tumors (insulinoma).
Genetic Defects in Carbohydrate Metabolism
Glycogen storage diseases are result of the deficiency of a
specific enzyme that causes an alternation of glycogen metabolism. The
most common congenital form of glycogen storage disease is glucose6-phosphatase deficiency type 1, which is also called von Gierke
disease, an autosomal recessive disease. This disease is characterized
by severe hypoglycemia that coincides with metabolic acidosis,
ketonemia, and elevated lactate and alanine. Hypoglycemia occurs
because glycogen cannot be converted back to glucose by way of
hepatic glycogenolysis.
A glycogen buildup is found in the liver; causing hepatomegaly. The
patients usually have severe hypoglycemia, hyperlipidemia, uricemia,
and growth retardation. A liver biopsy will show a positive glycogen
stain. Although the glycogen accumulation is irreversible, the disease
can be kept under control by avoiding the development of
hypoglycemia. Liver transplantation corrects the hypoglycemic condition.
Other enzyme defects or deficiencies that cause hypoglycemia include
glycogen synthase, fructose-1,6-bisphosphatase,
phosphoenolpyruvate carboxykinase, and pyruvate carboxylase.
.
Galactosemia, a cause of failure to thrive syndrome in infants, is a
congenital deficiency of one of two enzymes involved in galactose
metabolism, resulting in increased levels of galactose in plasma. The
most common enzyme deficiency is galactose-1-phosphate uridyl
transferase. Galactosemia occurs because of the inhibition of
glycogenolysis and is accompanied by diarrhea and vomiting.
Galactose must be removed from the diet to prevent the development
of irreversible complications. If left untreated, the patient will develop
mental retardation and cataracts. The disorder can be identified by
measuring erythrocyte galactose-1-phosphate uridyltransferase activity.
Laboratory findings include hypoglycemia, hyperbilirubinemia, and
galactose accumulation in the blood, tissue, and urine following milk
ingestion.
Another enzyme deficiency, fructose-1-phosphate aldolase
deficiency, causes nausea and hypoglycemia after fructose ingestion.
There are also alimentary hypoglycemias, appears to be caused by
an increase in the release of insulin in response to rapid absorption of
nutrients after a meal
ROLE OF LABORATORY IN DIFFERENTIAL DIAGNOSIS AND
MANAGEMENT OF PATIENTS WITH GLUCOSE METABOLIC
ALTERATIONS
Laboratory tests are used for demonstration of hyperglycemia or
hypoglycemia to diagnose diabetes mellitus and hypoglycemic conditions.
Other laboratory tests have been developed to identify insulinomas and to
monitor glycemic control and the development of renal complications.
Methods of Glucose Measurement
Glucose can be measured from serum, plasma, or whole blood. Today,
most glucose measurements are performed on serum or plasma. The
glucose concentration in whole blood is approximately 11% lower than the
glucose concentration plasma.
Serum or plasma must be separated from the cells within 1 h to prevent
substantial loss of glucose by the cellular fraction and can be refrigerated.
Sodium fluoride (gray-top tubes) are often used as an anticoagulant and
preservative of whole blood. The fluoride inhibits glycolytic enzymes.
However, although fluoride maintains long-term glucose stability, the rates
of decline of glucose in the first hour after sample collection in tubes with
and without fluoride are virtually identical.
Therefore, the plasma should be separated from the cells as soon as
possible.
Fasting blood glucose (FBG) should be obtained in the morning after an
approximately 8- to 10-hours fast (not longer than 16 hours). Fasting
plasma glucose values have a diurnal variation with the mean FBG
higher in the morning than in the afternoon. Diabetes in patients tested
in the afternoon may be missed because of this variation. Cerebrospinal
fluid and urine can also be analyzed.
Urine glucose measurement is not used in diabetes diagnosis;
however, some patients use this measurement for monitoring purposes.
Self-Monitoring of Blood Glucose
The ADA has recommended that individuals with diabetes monitor
their blood glucose levels in an effort to maintain levels as close to
normal as possible. For persons with type 1 diabetes, the
recommendation is 3 to 4 times/day.
It is important that patients be learned how to use the testing
instrument to ensure the accuracy of their results.
Urine glucose testing should be replaced by self-monitoring of blood
glucose; however, urine ketone testing will remain for type 1 and
gestational diabetes.
Glucose Tolerance and 2-Hour Postprandial Tests
A solution containing 75 g of glucose is administered, and a
specimen for plasma glucose measurement is drawn 2 hours later.
Children receive 1.75 g/kg of glucose to a maximum dose of 75 g.
The oral glucose tolerance test (OGTT) is not recommended for
routine use under the ADA guidelines. This procedure is inconvenient to
patients and is not being used by physicians for diagnosing diabetes.
However, if the OGTT is used, WHO recommends the criteria listed in
Table 13-7.
It is important that proper patient preparation be given before
this test is performed. The patient should be ambulatory and on a
normal-to high carbohydrate intake for 3 days before the test.
The patient should be fasting for at least 10 hours and not longer than
16 hours, and the test should be performed in the morning because of
the hormonal diurnal effect on glucose.
Just before tolerance and while the test is in progress, patients should be
prevented from exercise, eating, drinking (except that the patient may
drink water), and smoking.
Factors that affect the tolerance results include medications such as
large doses of salicylates, diuretics, anticonvulsants, oral contraceptives,
and corticosteroids. Also, gastrointestinal problems, including
malabsorption problems, gastrointestinal surgery, vomiting and
endocrine dysfunctions, can affect the OGTT results.
Glycosylated Hemoglobin/Hemoglobin A1c
Glycosylated hemoglobin is the term used to describe the
formation of a hemoglobin compound produced when glucose (a
reducing sugar) reacts with the amino group of hemoglobin (a protein).
The glucose molecule attaches non-enzymatically to the hemoglobin
molecule to form a ketoamine. The rate of formation is directly
proportional to the plasma glucose concentrations. Because the average
red blood cell lives approximately 120 days, the glycosylated
hemoglobin level at any one time reflects the average blood glucose
level over the previous 2 to 3 months.
Therefore, measuring the glycosylated hemoglobin provides the clinician
with a time-averaged picture of the patient’s blood glucose
concentration over the past 3 months.
Hemoglobin A1c (HbA1c), the most commonly detected
glycosylated hemoglobin, is a glucose molecule attached to one or both
N-terminal valines of the β-polypeptide chains of normal adult
hemoglobin. HbA1c is a more reliable method of monitoring long-term
diabetes control than random plasma glucose. Normal values range
from 4.5 to 8.0. It is determined that for every 1% change in the HbA1c
value, there is a 35 mg/dL (2 mmol/L) change in the mean plasma
glucose (Table 13-10).
It is important to remember that two factors determine the
glycosylated hemoglobin levels: (1) the average glucose concentration
and (2) the red blood cell life span. If the red blood cell life span is
decreased because of another disease state such as
hemoglobinopathies, the hemoglobin will have less time to become
glycosylated and the glycosylated hemoglobin level will be lower. Current
ADA guidelines recommend that an HbA1c test be performed at least two times
a year with patients who are meeting treatment goals and who have stable
glycemic control. For patients whose therapy has changed or who are not
meeting glycemic goals, a quarterly HbA1c test is recommend.
Lowering HbA1c to an average of less than 7% has clearly been shown to
reduce the microvascular, retinopathic, and neuropathic complications of
diabetes.
Ketones
The ketone bodies are produced by the liver through metabolism
of fatty acids to provide a ready energy source from stored lipids at
times of low carbohydrate availability. The three ketone bodies are
acetone (2%), acetoacetic acid (20%), and β-hydroxybutyric acid
(78%). A low level of ketone bodies are present in the body at all times.
However, in cases of carbohydrate deprivation or decreased
carbohydrate use such as diabetes mellitus, starvation/fasting, high-fat
diets, prolonged vomiting, and glycogen storage disease, blood levels of
ketone bodies increase due to lincreased lipolysis to meet energy
needs.
The term ketonemia refers to the accumulation of ketones in blood,
and the term ketonuria refers to accumulation of ketones in urine.
The measurement of ketones is recommended for patients with
type1 diabetes during acute illness, stress, pregnancy, or elevated blood
glucose levels above 300 mg/dL or when the patient has signs of
ketoacidosis. The specimen requirement is fresh serum or urine; the
sample should be tightly stoppered and analyzed immediately.
Microalbuminuria
Diabetes mellitus causes progressive changes to the kidneys and
ultimately results in diabetic renal nephropathy. This complication
progresses over years and may be delayed by aggressive glycemic
control. An early sign that nephropathy is occurring is an increase in
urinary albumin. Microalbumin measurements are useful to assist in
diagnosis at an early stage and before the development of proteinuria.
An annual assessment of kidney function by the determination of
urinary albumin excretion is recommended for diabetic patients.
Microalbuminuria is defined as persistent albuminuria in the range of
30 to 299 mg/24 h or an albumin-creatinine ratio of 30 to 300 g/mg.
Clinical proteinuria or macroalbuminuria is established with an
albuminuria ≥300 mg/24 h or an albumin-creatinine ratio of ≥300 g/mg.
Insulin measurements are not required for the diagnosis of
diabetes mellitus, but in certain hypoglycemic states, it is important to
know the concentration of insulin in relation to the plasma glucose
concentration.