Diabetes mellitus part-1

Diabetes Mellitus

(Part-1)
Biochemistry for medics
www.namrata.co

Contents
• General Introduction
• Classification
• Gross differences between Type 1 and Type 2
Diabetes Mellitus
• Etiology and pathophysiology
• Genetic considerations
• Metabolic alterations
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Diabetes mellitus

Diabetes mellitus is a syndrome with
disordered metabolism and inappropriate
hyperglycemia due to either a deficiency of
insulin secretion or a combination of
insulin resistance and inadequate insulin
secretion to compensate.

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Classification of Diabetes Mellitus
DM is classified on the basis of the
pathogenic process that leads to
hyperglycemia, as opposed to earlier criteria
such as age of onset or type of therapy .
The two broad categories of DM are
designated type 1 and type 2.
Both types of diabetes are preceded by a
phase of abnormal glucose homeostasis as the
pathogenic processes progresses.

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Diabetes Mellitus
The terms insulin-dependent diabetes mellitus (IDDM)
and noninsulin-dependent diabetes mellitus (NIDDM) are
obsolete.
Since many individuals with type 2 DM eventually
require insulin treatment for control of glycemia.
Age is not a criterion in the classification system.
Although type 1 DM most commonly develops before the
age of 30, an autoimmune beta cell destructive process
can develop at any age.
It is estimated that between 5 and 10% of individuals
who develop DM after age 30 have type 1 DM.
 Likewise, type 2 DM more typically develops with
increasing age but is now being diagnosed more
frequently in children and young adults, particularly in
obese adolescents.
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Etiological Classification of Diabetes
Mellitus
I. Type 1 diabetes (β-cell
destruction, usually leading to
absolute insulin deficiency)
A. Immune-mediated
B. Idiopathic
II. Type 2 diabetes (may range from
predominantly insulin resistance
with relative insulin deficiency to
a predominantly insulin secretory
defect with insulin resistance)
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Mellitus (contd.)
III. Other specific types of diabetes
A. Genetic defects of β cell function (MODY 1-6)
B. Genetic defects in insulin action
(Characterized by Insulin resistance)
C. Diseases of the exocrine pancreas
o Pancreatitis
o Pancreatectomy
o Neoplasia
o Cystic fibrosis
o Hemochromatosis
o Fibrocalculous pancreatopathy
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Mellitus (contd.)
F. Infections
o Congenital rubella
o Cytomegalovirus
o Coxsackie
G. Uncommon forms of immune-mediated diabetes
o “Stiff-person" syndrome
o Anti-insulin receptor antibodies
H. Other genetic syndromes sometimes associated with diabetes
o Down's syndrome
o Klinefelter's syndrome
o Turner's syndrome,
o Laurence-Moon-Biedl syndrome
o Porphyria
IV. Gestational diabetes mellitus (GDM)
[MODY, maturity onset of diabetes of the young].
Source: Adapted from American Diabetes Association, 2007.

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Gross differences between Type 1
and Type 2 Diabetes mellitus
S.N.

Feature

Type 1 DM

Type 2 DM

1

Previous names

Insulin Dependent diabetes
mellitus(IDDM) , also called
Juvenile onset DM

Non insulin dependent
Diabetes mellitus (NIDDM),
also called Maturity onset
diabetes mellitus

2.

Age of Onset

Usually during childhood or
puberty (Exception- LADALatent auto immune Diabetes
mellitus of adults )

Frequently after the age of
35( Exceptions- can be
observed in children and
adolescents , MODYMaturity onset diabetes of
young )

3.

Pattern of onset

Abrupt- Symptoms develop
rapidly

Slow – Symptoms appear
gradually

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Gross differences between Type 1 and
Type 2 Diabetes mellitus (contd.)
S.N.

Feature

Type 1 DM

Type 2 DM

4.

Prevalence

10% of the diagnosed
cases

90 % of the diagnosed
cases

5.

Genetic
predisposition

Moderate

Very strong

6.

Nutritional state at
the time of onset

Undernourished

Mostly obese

7.

Biochemical defect

Auto immune destruction
of β cells in 90 % of the
cases, in remaining 10%
cause is not known. Thus
there is impaired
production of insulin

Insulin resistance
combined with inability
of β cells to produce
appropriate amount of
insulin

8.

Plasma insulin

Low to absent

High in the early stage,
low in the disease of
10
long duration

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Gross differences between Type 1 and
Type 2 Diabetes mellitus (contd.)
S.N.

Feature

Type 1 DM

Type 2 DM

9.

Acute Complications

Hypoglycemia and
ketoacidosis

Hyperosmolar non
ketotic coma

10.

Frequency of ketosis

Very common

Rare

11.

Treatment

Insulin is always needed,
oral hypoglycemic drugs
are ineffective.

Diet, exercise, oral
hypoglycemic drugs
and insulin in severe
cases

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Etiology of Type 1 Diabetes
This form of diabetes is immune-mediated in over 90% of
cases and idiopathic in less than 10%.
Immune-mediated
o The rate of pancreatic B cell destruction is quite variable,
being rapid in some individuals and slow in others.
o Approximately one-third of the disease susceptibility in
immune mediated type is due to genes and two-thirds to
environmental factors.
Idiopathic
o Less than 10% of subjects have no evidence of pancreatic
B cell autoimmunity to explain their insulinopenia and
ketoacidosis.
o This subgroup has been classified as "idiopathic type 1
diabetes" and designated as "type 1B."
o Although only a minority of patients with type 1 diabetes
fall into this group, most of these are of Asian or African
origin.
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Pathophysiology of Type 1 Diabetes
o Auto Immune destruction
Pathologically, the pancreatic
islets are infiltrated with
lymphocytes (in a process
termed insulitis).
o After all beta cells are
destroyed, the inflammatory
process abates, the islets
become atrophic
oThe autoimmune destruction of
pancreatic β-cells leads to a
deficiency of insulin secretion.
oIt is this loss of insulin secretion
that leads to the metabolic
derangements associated with
IDDM.
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Mellitus (contd.)
oIn addition to the loss of insulin secretion, the function
of pancreatic α-cells is also abnormal.
oThere is excessive secretion of glucagon in IDDM
patients. Normally, hyperglycemia leads to reduced
glucagon secretion.
oHowever, in patients with IDDM, glucagon secretion is
not suppressed by hyperglycemia.
oThe resultant inappropriately elevated glucagon levels
exacerbate the metabolic defects due to insulin
deficiency .
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Genetic considerations in Type 1 DM
o Children of diabetic parents are at increased lifetime
risk for developing type 1 diabetes.
o A child whose mother has type 1 diabetes has a 3% risk
of developing the disease and a 6% risk if the child's
father has it.
oThe risk in siblings is related to the number of HLA
haplotypes that the sibling shares with the diabetic
parent.
o If one haplotype is shared, the risk is 6% and if two
haplotypes are shared, the risk increases to 12–25%
oThe highest risk is for identical twins, where the
concordance rate is 25–50%.
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Type 1 Diabetes Mellitus- An
Overview of Etiology

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Etiology of Type 2 Diabetes Mellitus
Type 2 Diabetes mellitus (formerly called non - insulin dependent diabetes mellitus (NIDDM) or adult - onset diabetes
mellitus) is a disorder that is characterized by high blood glucose in
the context of insulin resistance and relative insulin deficiency.
Circulating endogenous insulin is sufficient to prevent ketoacidosis
but is inadequate to prevent hyperglycemia in the face of increased
needs owing to tissue insensitivity (insulin resistance).
Genetic and environmental factors combine to cause both the
insulin resistance and the beta cell loss.
The disease is polygenic and multifactorial since in addition to
genetic susceptibility, environmental factors (such as obesity,
nutrition, and physical activity) modulate the phenotype.
The mechanisms by which these genetic alterations increase the
susceptibility to type 2 diabetes are not clear.
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Mellitus
• Type 2 DM is characterized by impaired insulin secretion,
insulin resistance, excessive hepatic glucose production, and
abnormal fat metabolism.
• In the early stages of the disorder, glucose tolerance remains
near-normal, despite insulin resistance, because the pancreatic
beta cells compensate by increasing insulin output .
• As insulin resistance and compensatory hyperinsulinemia
progress, the pancreatic islets in certain individuals are unable
to sustain the hyperinsulinemia state.
• IGT, characterized by elevations in postprandial glucose, then
develops.
• A further decline in insulin secretion and an increase in hepatic
glucose production lead to overt diabetes with fasting
hyperglycemia.
• Ultimately, beta cell failure may ensue.

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Pathophysiology of Type 2 DM

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Insulin resistance
oInsulin resistance is a state in which a
given concentration of insulin produces a
less-than-expected biological effect.
oInsulin resistance has also been arbitrarily
defined as the requirement of 200 or more
units of insulin per day to attain glycemic
control and to prevent ketosis.
oInsulin resistance results from inherited
and acquired influences.
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Causes of Insulin resistance
•

Pre receptor
– Abnormal insulin (mutations)
– Anti-insulin antibodies

•

Receptor
– Decreased number of receptors (mainly, failure to activate tyrosine
kinase)
– Reduced binding of insulin
– Insulin receptor mutations
– Insulin receptor – blocking antibodies
Postreceptor
– Defective signal transduction
– Mutations of GLUT4 (In theory, these mutations could cause insulin
resistance, but polymorphisms in the GLUT4 gene are rare.)

•

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Causes of Insulin resistance(contd.)
• Combinations of defects Obesity is
associated mainly with post receptor
abnormality and is also associated with a
decreased number of insulin receptors.
Obesity is the most common cause of
insulin resistance.
• Aging - This may cause insulin resistance
through a decreased production of GLUT4 transporters
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(contd.)
Increased production of insulin
antagonists - A number of disorders are
associated with increased production of
insulin antagonists, such as oCushing syndrome
oAcromegaly
oStress states, such as trauma, surgery,
diabetes ketoacidosis, severe infection,
uremia, and liver cirrhosis.
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(contd.)

•Medications include glucocorticoids
(Cushing syndrome), cyclosporine, niacin,
and protease inhibitors.
•Human immunodeficiency virus
(HIV)- Protease inhibitor – associated
lipodystrophy is a recognized entity.
Nucleoside analogues have also been
implicated in the development of insulin
resistance.

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Causes of Insulin
resistance(contd.)

Insulin treatment
oLow titer IgG anti-insulin antibody levels are present in most
patients who receive insulin.
oEnhanced destruction of insulin at the site of subcutaneous
injection has also been implicated.
Other conditions that are categorized as receptor or post
receptor insulin-resistant state
o Leprechaunism
o Lipodystrophic states
o Ataxia-telangiectasia
o Werner syndrome
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Risk factors for type 2 Diabetes
mellitus

• Family history of diabetes (i.e., parent or sibling with type 2
diabetes)
• Obesity (BMI >25 kg/m2)
• Habitual physical inactivity
• Race/ethnicity (e.g., African American, Latino, Native American,
Asian American, Pacific Islander)
• Previously identified IFG or IGT
• History of GDM or delivery of baby >4 kg (>9 lb)
• Hypertension (blood pressure >140/90 mmHg)
• HDL cholesterol level <35 mg/dL (0.90 mmol/L) and/or a
triglyceride level >250 mg/dL (2.82 mmol/L)
• Polycystic ovary syndrome or acanthosis nigricans
• History of vascular disease
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Obesity and Type 2 Diabetes Mellitus
•The increased adipocyte mass leads to increased
levels of circulating free fatty acids and other fat
cell products
•The increased production of free fatty acids and
some adipokines may cause insulin resistance in
skeletal muscle and liver.
•For example, free fatty acids impair glucose
utilization in skeletal muscle, promote glucose
production by the liver, and impair beta cell
function.
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Obesity and Type 2 Diabetes
Mellitus (contd.)
• Adipocytes secrete a number of biologic products
(nonesterified free fatty acids, retinol-binding protein 4,
leptin, TNF-α, resistin, and adiponectin). In addition to
regulating body weight, appetite, and energy expenditure,
adipokines also modulate insulin sensitivity.
• The production by adipocytes of adiponectin, an insulinsensitizing peptide, is reduced in obesity and this may
contribute to hepatic insulin resistance.
• Adipocyte products and adipokines also produce an
inflammatory state and may explain why markers of
inflammation such as IL-6 and C-reactive protein are often
elevated in type 2 DM.
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Genetic considerations in Type 2 DM
• Genetic and environmental factors combine to cause both
the insulin resistance and the beta cell loss.
• In monozygotic twins over 40 years of age, concordance
develops in over 70% of cases within a year whenever type 2
diabetes develops in one twin.
• Individuals with a parent with type 2 DM have an increased
risk of diabetes; if both parents have type 2 DM, the risk
approaches 40%.
• The disease is polygenic and multifactorial since in addition
to genetic susceptibility, environmental factors (such as
obesity, nutrition, and physical activity) modulate the
phenotype.
• The mechanisms by which genetic alterations increase the
susceptibility to type 2 diabetes are not clear.
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Metabolic alterations in Diabetes
Mellitus
A) Glucose metabolism- Increased hepatic output and
decreased glucose utilization
o Peripheral uptake- Reduced uptake of glucose in skeletal
muscle, cardiac muscle and adipose tissue (GLUT- 4 receptors
are insulin dependent)
oGlycolysis
 Reduced rate of phosphorylation in liver cells (Glucokinase
is insulin dependent)
Glycolytic enzymes are covalently modified by glucagon
mediated c AMP cascade.
Reduced availability of Fr 2,6 bisphosphate, reduced activity
of PFK-1
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Reduced rate of glycolysis

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Glucose metabolism in diabetes
mellitus (contd.)
Gluconeogenesis- Increased rate of gluconeogenesis due to o Increased availability of substrates
o Increased activity and concentration of enzymes of pathway
of gluconeogenesis under the effect of glucagon
Glycogen Metabolism- Enzyme activities are altered by
glucagon triggered phosphorylation cascade
Glycogenesis- Inhibited due to reduced activity of glycogen
synthase (Phosphorylated form is inactive form)
Glycogenolysis- Stimulated due to increased activity of
phosphorylase (Phosphorylated form is active form)
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Glucose metabolism in diabetes
mellitus (contd.)
TCA cycle- suppressed due to non availability of
oxaloacetate as it is channeled towards glucose
production
HMP Pathway- Suppressed due to reduced activity of
glucose-6-P dehydrogenase enzyme as that is under the
influence of insulin.
Net effect-The combination of increased hepatic glucose
production and reduced peripheral tissues metabolism
leads to elevated plasma glucose levels.

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Implications of altered
carbohydrate metabolism
• The net effect of altered carbohydrate metabolism is
hyperglycemia
• When the capacity of the kidneys to absorb glucose is
surpassed, Glycosuria ensues.
• Glucose is an osmotic diuretic and an increase in renal
loss of glucose is accompanied by loss of water and
electrolytes, termed polyuria.
• The result of the loss of water (and overall volume)
leads to the activation of the thirst mechanism
(polydipsia).
• The negative caloric balance which results from the
glucosuria and tissue catabolism leads to an increase in
appetite and food intake (polyphagia).
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Lipid metabolism in Diabetes
Mellitus
A) Adipolysis
•There is a rapid mobilization of triglycerides
from adipose tissue leading to increased levels
of plasma free fatty acids.
•The free fatty acids are taken up by numerous
tissues (however, not the brain) and
metabolized to provide energy.
•Free fatty acids are also taken up by the liver.
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Mellitus (contd.)
B) Fatty acid oxidation- Increased
Biochemical Basis
o Normally, the levels of malonyl-CoA are high in the presence
of insulin.
oThese high levels of malonyl-CoA inhibit carnitine palmitoyl
Transferase I, the enzyme required for the transport of fatty
acyl-Co A's into the mitochondria where they are subject to
oxidation for energy production.
oThus, in the absence of insulin, malonyl-CoA levels fall and
transport of fatty acyl-Co A's into the mitochondria increases.
oMitochondrial oxidation of fatty acids generates acetyl-CoA
which can be further oxidized in the TCA cycle.
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Mellitus (contd.)

Implication of high rate of fatty acid oxidation
1) Ketosis
oIn hepatocytes the majority of the acetyl-CoA is not oxidized by the TCA
cycle but is metabolized into the ketone bodies, Acetone, Acetoacetate and βhydroxybutyrate.
oThese ketone bodies leave the liver and are used for energy production by
the brain, heart and skeletal muscle.
o In IDDM, the increased availability of free fatty acids and ketone bodies
exacerbates the reduced utilization of glucose furthering the ensuing
hyperglycemia.
oProduction of ketone bodies, in excess of the body’s ability to utilize them
leads to ketoacidosis.
oIn diabetics, this can be easily diagnosed by smelling the breath. A
spontaneous breakdown product of acetoacetate is acetone which is
36
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volatilized by the lungs producing a distinctive odor.

Mellitus (contd.)
Implication of high rate of fatty acid
oxidation

2) Hypercholesterolemia- Excess Acetyl co
A, the end product of fatty acid oxidation
can enter the pathway of Cholesterol
biosynthesis causing hypercholesterolemia,
increasing the risk for atherosclerosis.

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Mellitus (contd.)
Serum Triglyceride levels
o Normally, plasma triglycerides are acted upon
by lipoprotein lipase (LPL), an enzyme on the
surface of the endothelial cells lining the
vessels.
o In particular, LPL activity allows fatty acids to
be taken from circulating triglycerides for
storage in adipocytes.
o The activity of LPL requires insulin and in its
absence a hypertriglyceridemia results.
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Mellitus (contd.)
Net effect- Dyslipidemia (Atherogenic profile)
oIncreased level of circulating free fatty acids
oKetoacidosis
oHypercholesterolemia
oHypertriglyceridemia
oVLDL c and LDLC High
oHDLc low (Inverse relation with triglycerides)

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Protein metabolism in Diabetes
Mellitus
• Insulin regulates the synthesis of many genes, either
positively or negatively that then affect overall
metabolism.
• Insulin has a global effect on protein metabolism,
increasing the rate of protein synthesis and
decreasing the rate of protein degradation.
• Thus, insulin deficiency will lead to increased
catabolism of protein.

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Protein metabolism in Diabetes
Mellitus (Net effect)
• The increased rate of proteolysis leads to
elevated concentrations in plasma amino
acids.
• These amino acids serve as precursors for
hepatic and renal gluconeogenesis.
• In liver, the increased gluconeogenesis
further contributes to the hyperglycemia
seen in IDDM.
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Advanced Glycosylation End Products
o Increased intracellular glucose leads to the formation of
advanced glycosylation end products (AGEs) via the
nonenzymatic glycosylation of intra- and extra cellular
proteins.
oNonenzymatic glycosylation results from the interaction of
glucose with amino groups on proteins.
o AGEs have been shown to cross-link proteins (e.g., collagen,
extracellular matrix proteins), accelerate atherosclerosis,
promote glomerular dysfunction, reduce nitric oxide synthesis,
induce endothelial dysfunction, and alter extracellular matrix
composition and structure.
oThe serum level of AGEs correlates with the level of glycemia,
and these products accumulate as glomerular filtration rate
declines.
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Glycated hemoglobin (HbA1C)
• Hemoglobin becomes glycated by ketoamine reactions between
glucose and other sugars and the free amino groups on the alpha
and beta chains.
• Only glycation of the N-terminal valine of the beta chain imparts
sufficient negative charge to the hemoglobin molecule to allow
separation by charge dependent techniques.
• These charge separated hemoglobin are collectively referred to as
hemoglobin A1 (HbA1).
• The major form of HbA1 is hemoglobin A1c (HbA1c) where glucose is
the carbohydrate. HbA1c comprises 4–6% of total hemoglobin A1.
• The remaining HbA1 species contain fructose-1, 6 bisphosphate
(HbA1a1); glucose-6-phosphate (HbA1a2); and unknown carbohydrate
moiety (HbA1b).
• The hemoglobin A1c fraction is abnormally elevated in diabetic 43

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Sorbitol Pathway
• Hyperglycemia increases glucose metabolism via the
Sorbitol pathway.
• Intracellular glucose is predominantly metabolized by
phosphorylation and subsequent glycolysis, but when
increased, some glucose is converted to sorbitol by the
enzyme aldose reductase.
• Increased sorbitol concentration alters redox
potential, increases cellular osmolality, generates
reactive oxygen species, and likely leads to other types
of cellular dysfunction.
• Diabetic cataract is the result of osmolysis by sorbitol
44
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accumulation

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Water and Electrolyte imbalance
in Diabetes mellitus
• Dehydration is a frequent finding ,
Polyuria is responsible for dehydration.
• Hypokalemia- total body K is low, but
there be false hyperkalemia due to non
functioning of Sodium Potassium ATPase
pump. Caution is needed during Insulin
administration.
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Diabetes mellitus part-1

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