Diabetes mellitus - (Part-3) -- Laboratory diagnosis and management

Diabetes Mellitus- Laboratory
Diagnosis and Treatment

(Part-3)
Biochemistry for medics
www.namrata.co

Contents
1) Laboratory Diagnosis
o Urine Analysis
o Blood Biochemistry
o Immunological Assays
2) Management
o Management of type 1 DM
o Management of type 2 DM
3) Summary

URINE ANALYSIS
a) Detection of urinary glucose (Glucosuria)
o First-line screening test for diabetes
mellitus
o Normally glucose does not appear in urine
until the plasma glucose rises above 160180 mg/dl.
o In certain individuals due to low renal
threshold glucose may be present despite
normal blood glucose levels.
o Conversely renal threshold increases with
age so many diabetics may not have
Glycosuria despite high blood sugar levels.

Positive
Benedict’s test

URINE ANALYSIS (Contd.)
o Detection of Glucosuria- A specific and convenient
method to detect glucosuria is the paper strip
impregnated with glucose oxidase and a chromogen
system (Clinistix, Diastix), which is sensitive to as little
as 0.1% glucose in urine.
o Diastix can be directly applied to the urinary stream,
and differing color responses of the indicator strip
reflect glucose concentration.
o Benedict’s and Fehling’s test can also detect
glucosuria.
DiastixReagent strips

b) Ketonuria
o Qualitative detection of
ketone bodies can be
accomplished by nitroprusside
tests (Acetest or Ketostix),
Rothera’s test etc.
oThese tests do not detect
Beta-hydroxy butyric acid,
which lacks a ketone group
o Ketone bodies may be
present in a normal subject as
a result of simple prolonged
fasting.

Positive
Rothera’s
test
KetostixReagent
strips

c) Microalbuminuria
o May be defined as an
albumin excretion rate
intermediate between
normality (2.5-25 mg/day)
and macroalbuminuria
(250mg/day).
oThe small increase in
urinary albumin excretion
is not detected by simple
albumin stick tests and
requires confirmation by
careful quantization in a
24 hr urine specimen.

o The importance of microalbuminuria in the diabetic
patient is that it is a signal
of early reversible renal
damage.
o Performing an albumin-tocreatinine ratio is probably
easiest.
o Microalbuminuria is a
common finding (even at
Gradation of turbidity is linked to
diagnosis) in type 2
protein concentration
diabetes mellitus and is a
risk factor for macro
vascular (especially
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coronary heart) disease. Biochemistry For Medics

7

BLOOD BIOCHEMISTRY
1) Blood Glucose Estimation
Choice of sample
• Plasma or serum from venous blood
samples has the advantage over
whole blood of providing values for
glucose that are independent of
Haemtocrit and that reflect the
glucose concentration to which body
tissues are exposed.
• Plasma and serum are more readily
measured on automated equipment,
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Biochemistry For Medics
they are used in most laboratories.

8

BLOOD BIOCHEMISTRY
Choice of sample (contd.)
• If serum is used or if plasma is collected from
tubes that lack an agent to block glucose
metabolism (such as fluoride), samples should be
refrigerated and separated within 1 hour after
collection.
• The glucose concentration is 10–15% higher in
plasma or serum than in whole blood because
structural components of blood cells are absent.
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BLOOD BIOCHEMISTRY
Fasting blood Glucose
o Fasting blood glucose is
measured after an overnight fast
of 10 hrs.
o Fasting blood glucose estimation
is better than random blood
glucose.
o FPG < 5.6 mmol/L (100 mg/dL) is considered normal;
o FPG = 5.6–6.9 mmol/L (100–125 mg/dL) is defined as IFG;
and
o FPG >7.0 mmol/L (126 mg/dL) warrants the diagnosis of DM.

BLOOD BIOCHEMISTRY(contd.)
Random blood Glucose
o Random is defined as without regard to time since the
last meal.
o RBG measurement is required only during emergency.
oThe current criteria for the diagnosis of DM emphasize
that the FPG is the most reliable and convenient test for
identifying DM in asymptomatic individuals.
o A random plasma glucose concentration >11.1 mmol/L
(200 mg/dL) accompanied by classic symptoms of DM
(polyuria, polydipsia, weight loss) is sufficient for the
diagnosis of DM

Glucose tolerance test
o When the fasting plasma glucose level is 126 mg/dL
or higher on more than one occasion, further
evaluation of the patient with a glucose challenge is
unnecessary.
oHowever, when fasting plasma glucose is less than
126 mg/dL in suspected cases, a standardized oral
glucose tolerance test may be done .

Glucose tolerance test
Methodology
75 g of glucose dissolved in 300 mL of
water is given after an overnight fast to a
person who has been receiving at least
150–200 g of carbohydrate daily for 3 days
before the test.

Glucose tolerance test- Data InterpretationThe Diabetes Expert Committee criteria for evaluating
the standard oral glucose tolerance test.
Normal
Glucose
Tolerance

Impaired
Glucose
Tolerance

Diabetes
Mellitus

Fasting plasma < 110
glucose (mg/dL)

110–125

>126

Two hours after < 140

140–199

>200

glucose load

Concentration in mg/dl

Glucose Tolerance Test

(mg/dl)

Time in minutes

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Normal Glucose tolerance curve

15

b) Glycated hemoglobin (Hb1C) measurements
o HbA1c comprises 4–6% of total hemoglobin A 1.
o Since glycohemoglobins circulate within 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.
o Any condition that shortens erythrocyte survival
or decreases mean erythrocyte age (eg, recovery
from acute blood loss, hemolytic anemia) will falsely
lower HbA1c irrespective of the assay method used.

Glycated hemoglobin (Hb1C) measurements

Methods for measuring HbA1c include electrophoresis, cationexchange chromatography, boronate affinity chromatography,
and immunoassays.
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c) Serum fructosamine
estimation
oSerum fructosamine is formed by
nonenzymatic glycosylation of
serum proteins (predominantly
albumin).
oSerum albumin has a much
shorter half-life than hemoglobin,
serum fructosamine generally
reflects the state of glycemic
control for only the preceding 1–2
weeks.

Serum fructosamine Estimation
o Normal values vary in relation to

the serum albumin concentration are
1.5–2.4 mmol/L when the serum
albumin level is 5 g/dL.
o When abnormal hemoglobins or
hemolytic states affect the
interpretation of glycohemoglobins
or when a narrower time frame is
required, such as for ascertaining
glycemic control at the time of
conception in a diabetic woman who
has recently become pregnant, serum
fructosamine assays offer some
advantage.
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Self-monitoring of blood glucose
o Capillary blood glucose
measurements performed by
patients themselves, as
outpatients, are extremely useful.
o In type 1 patients in whom
"tight" metabolic control is
attempted, they are
indispensable.
oThere are several paper strip
(glucose oxidase, glucose
dehydrogenase, or hexokinase)
methods for measuring glucose on
capillary blood samples.

A reflectance photometer
or an amperometric
system is then used to
measure the reaction
that takes place on the
reagent strip.

Lipid profile
o Serum Total cholesterol is elevated
o Serum triglycerides are high
o Serum HDLc is low
o Qualitative change in LDL particles,
producing a smaller dense particle
whose membrane carries
supranormal amounts of free
cholesterol.
oThese smaller dense LDL particles
are more susceptible to oxidation,
which renders them more
atherogenic

Additional Tests
o The patient should be screened for DMassociated conditions (e.g., kidney, liver and
thyroid dysfunction).
o Individuals at high risk for cardiovascular disease
should be screened for asymptomatic CAD by
appropriate cardiac stress testing, when indicated.
oThe classification of the type of DM may be
facilitated by laboratory assessments.


Insulin Luminescence assay kit

C-Peptide Luminescence assay kit

Serum insulin or C-peptide measurements do not
always distinguish type 1 from type 2 DM, but a low Cpeptide level confirms a patient's need for insulin.
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IMMUNOLOGICAL ASSAYS
o Antibodies to insulin, islet cells, or Glutamic
acid decarboxylase (GAD) can be estimated to
differentiate between the types of diabetes
mellitus
oThey are absent in type 2 diabetes mellitus.
o Latent autoimmune diabetes of adults, or
LADA, is a form of slow-onset type 1 diabetes
that occurs in middle-aged (usually white)
adults.
oIt can be differentiated from type 2 diabetes
by measuring anti-GAD65 antibodies.

Management of Diabetes Mellitus
The goals of therapy for type 1 or type 2 DM
are to:
(1)eliminate symptoms related to
hyperglycemia,
(2)reduce or eliminate the long-term micro
vascular and macro vascular complications
of DM, and
(3)allow the patient to achieve as normal a
lifestyle as possible.

Management of Type 1 Diabetes
Mellitus
o Because individuals with type 1 DM partially or
completely lack endogenous insulin production,
administration of basal, exogenous insulin is
essential for regulating glycogen breakdown,
gluconeogenesis, lipolysis, and ketogenesis.
o Likewise, insulin replacement for meals should
be appropriate for the carbohydrate intake and
promote normal glucose utilization and storage.

Mellitus
Insulin Preparations
oInsulin is indicated for type 1 diabetes as well as
for type 2 diabetic patients with insulinopenia
whose hyperglycemia does not respond to diet
therapy either alone or combined with other
hypoglycemic drugs.
oWith the development of highly purified human
insulin preparations, immunogenicity has been
markedly reduced, thereby decreasing the
incidence of insulin allergy, immune insulin
resistance, and localized lipoatrophy at the
injection site.

Mellitus
oInsulins can be classified as short-acting or long-acting
oThe short-acting preparations are regular insulin and the
rapidly acting insulin analogs .
oThey are dispensed as clear solutions at neutral pH and
contain small amounts of zinc to improve their stability and
shelf life.
oThe long-acting preparations are NPH insulin and the
long-acting insulin analogs.
oNPH insulin is dispensed as a turbid suspension at neutral
pH with protamine in phosphate buffer.
oThe long-acting insulin analogs are also dispensed as clear
solutions.

Mellitus
Mixed insulin preparations
oSince intermediate insulins require several
hours to reach adequate therapeutic levels,
their use in patients with type 1 diabetes
requires supplements of regular or rapidly
acting insulin analogs preprandially.
oFor convenience, regular or rapidly acting
insulin analogs and NPH insulin may be mixed
together in the same syringe and injected
subcutaneously in split dosage before
breakfast and supper.

Mellitus
Methods of insulin administration
1) Insulin syringes and needles-Plastic disposable
syringes are available in 1-mL, 0.5-mL, and 0.3-mL
sizes.
2) Insulin pen injector devices-Insulin pens eliminate
the need for carrying insulin vials and syringes.
3) Insulin pumps-Insulin infusion pumps are used for
subcutaneous delivery of insulin. These pumps are
small (about the size of a pager) and very easy to
program.
4) Inhaled insulin-A novel method for delivering a
pre-prandial powdered form of insulin by inhalation
(Exubera) has been approved by the FDA.

Mellitus
Methods of insulin administration

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Mellitus

An insulin pump is an alternative to
Inhaled Insulin-The FDA
multiple daily injections of insulin by
approved the first inhaled
insulin syringe or an insulin pen and
version of insulin
allows for intensive insulin therapy
when used in conjunction with blood
called Exubera from Pfizer
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glucose
Inc.

32

Mellitus
o Complications of Insulin
Therapy
Hypoglycemia, Insulin allergy,
immune insulin resistance
and lipodystrophy at the
injection site are some of the
complications of insulin
therapy.
o Besides insulin therapy,
life long dietary and life style
modifications are required
to be done to achieve
euglycemia.

Injection site Lipodystrophy

Mellitus
o Islet cell transplantation is
a minimally invasive
procedure, wide application
of this procedure for the
treatment of type 1 diabetes
is limited by the dependence
on multiple donors and the
requirement for potent longterm immunotherapy.

Islet cell transplantation

Mellitus
Stem cell therapyStem cell therapy
is one of the most
promising
treatments for the
near future. It is
expected that this
kind of therapy can
ameliorate or even
reverse some
diseases.
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35

Mellitus
oThe goals of therapy for type 2 DM are similar
to those in type 1.
oThe care of individuals with type 2 DM must
also include attention to the treatment of
conditions associated with type 2 DM (obesity,
hypertension, dyslipidemia, cardiovascular
disease) and
oDetection/management of DM-related
complications.

Mellitus
a) Weight reduction
o Treatment is directed toward achieving weight
reduction, and prescribing a diet is only one means
to this end.
o Behavior modification to achieve adherence to the
diet
o Increased physical activity to expend energy—is also
required.

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Mellitus
b) Hypoglycemic agents
• If the patient is not able to achieve target glycemic
control with weight management and exercise, then
pharmacologic therapy is indicated.
• Based on their mechanisms of action, glucoselowering agents are subdivided into agents that
increase insulin secretion, reduce glucose production
and increase insulin sensitivity

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Mellitus
1) Insulin Secretagogues
o Insulin Secretagogues stimulate insulin
secretion by interacting with the ATPsensitive potassium channel on the beta cells.
o These drugs are most effective in individuals
with type 2 DM of relatively recent onset (<5
years), who have residual endogenous insulin
production.

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Mellitus
a) Sulfonylurea—first b) Sulfonylurea—
generation
second generation
  Chlorpropamide
  Glimepiride

c) Non sulfonylureas
  Repaglinide

  Tolazamide

  Glipizide

  Nateglinide

  Tolbutamide

  Glipizide (extended
release)
  Glyburide
Glyburide (micronized)

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Mellitus
• Insulin Secretagogues are generally well tolerated.
• All of these agents, however, have the potential to
cause profound and persistent hypoglycemia, especially
in elderly individuals.
• Hypoglycemia is usually related to delayed meals,
increased physical activity, alcohol intake, or renal
insufficiency.

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Mellitus
2) Biguanides
• Metformin is representative of this
class of agents.
• It reduces hepatic glucose production
through an undefined mechanism and
improves peripheral glucose utilization
slightly.
• Metformin reduces fasting plasma
glucose and insulin levels, improves the
lipid profile, and promotes modest
weight loss.
• The major toxicity of metformin, lactic
acidosis, can be prevented by careful
patient selection.

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Mellitus
3) α-Glycosidase Inhibitors
o α -Glycosidase inhibitors (acarbose
and miglitol) reduce postprandial
hyperglycemia by delaying glucose
absorption; they do not affect
glucose utilization or insulin
secretion.
o These drugs, taken just before each
meal, reduce glucose absorption by
inhibiting the enzyme that cleaves
oligosaccharides into simple sugars
in the intestinal lumen.
o The major side effects (diarrhea,
flatulence, abdominal distention)
are related to increased delivery of
oligosaccharides to the large bowel
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Mellitus
4) Thiazolidinediones
•Thiazolidinediones reduce insulin
resistance.
•Rosiglitazone, Pioglitazone belong
to this category.
•Thiazolidinediones promote a
redistribution of fat from central to
peripheral locations.
•Circulating insulin levels decrease
with use of the thiazolidinediones,
indicating a reduction in insulin
resistance
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Mellitus
5) Insulin Therapy in Type 2 DM
o Insulin should be considered as the initial therapy in
type 2 DM, particularly in lean individuals or those with
severe weight loss, in individuals with underlying renal
or hepatic disease that precludes oral glucose-lowering
agents, or in individuals who are hospitalized or
acutely ill.
o Insulin therapy is ultimately required by a substantial
number of individuals with type 2 DM because of the
progressive nature of the disorder and the relative
insulin deficiency that develops in patients with longstanding diabetes.
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Summary Of Type 1 DM
1) Diabetes mellitus type 1 (Type 1 diabetes, IDDM, or juvenile
diabetes) is a form of diabetes mellitus that results from
autoimmune destruction of insulin producing beta cells of the
pancreas.
2) The classical symptoms of Type 1 diabetes are polyuria,
polydipsia, polyphagia and weight loss.
3) Type 1 diabetes is fatal unless treated with insulin.
4) Injection is the most common method of administering
insulin; insulin pumps and inhaled insulin has been available
at various times.
5) Diabetic keto acidosis is the commonest complication of
Type 1 DM.

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Summary of Type 2 DM
1)Type 2 DM is characterized by impaired insulin secretion,
insulin resistance, excessive hepatic glucose production,
and abnormal fat metabolism.
2) While many patients with type 2 diabetes present with
increased urination and thirst, many others have an
insidious onset of hyperglycemia and are asymptomatic
initially.
3) Hyperglycemic hyperosmolar state (HHS) is an acute
complication of Type 2 diabetes. Chronic complications are
micro and macro vascular involving small and large blood
vessels respectively.
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Summary of Type 2 DM(contd.)
4) Glucose lowering agents that either increase insulin
secretion, reduce glucose production, increase insulin
sensitivity, and enhance GLP-1 (Glucagon like peptide)
action are used to treat hyperglycemia.
5) The care of individuals with type 2 DM must also
include attention to the treatment of conditions
associated with type 2 DM (obesity, hypertension,
dyslipidemia, cardiovascular disease) and
detection/management of DM-related complications.
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For further details
•Refer

A Case oriented Approach Towards
Biochemistry
•A Book Of Clinical BiochemistryJay pee Brothers Medical
Publishers.
•http://www.jaypeebrothers.com/pgDetails.aspx?cat=s&book_id=978

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Diabetes mellitus - (Part-3) -- Laboratory diagnosis and management

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Diabetes mellitus - (Part-3) -- Laboratory diagnosis and management