Classification and pathogenesis of DM

1. 1
Diabetes Mellitus
A.INTRODUCTION
Diabetes has been known for a very long time. Infact the word ‘diabetes’ was
derived from the greek diabainein, meaning "a siphon," referring to the
excessive urination associated with the disease. It was first recorded in 1425,
and in 1675, the Greek mellitus, “like honey,” was added, to reflect the sweet
smell and taste of the patient’s urine.
It should be noted that an unrelated and rare disorder, diabetes insipidus, is
usually caused by ADH deficiency.(insipidus reflect the fact that in this
disorder, the urine is tasteless; ancient physicians used to notice if ants are
attracted to the urine of a patient that present with polyuria to determine if
he/she has mellitus or insipidus diabetes)
B. Definition
Diabetes mellitus is a clinical syndrome characterised by hyperglycaemia,
polyuria, polydipsia polyphagia and glycosuria.
Even though alot of glucose is present in the blood, resistance to or absence
of insulin makes glucose unavailable to the body cells and they starve for
energy thus leaving the patients hungry leading to polyphagia. In the
hyperglycaemic state of DM, the renal threshold for glucose reabsorption is
exceeded so glucose appears in the urine. Water which is osmotically active
follows glucose and there is polyuria which leads to dehydration and
consequently polydipsia.
Classification
There are two main types of diabetes mellitus
Type 1
Type2
OTHER SPECIFIC TYPES

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 GENETIC DEFECTS OF beta CELL FUNCTION
 GENETIC DEFECTS IN INSULIN ACTION
 OTHER GENETIC SYNDROMES ASSOCIATED WITH DIABETES
 DISEASES OF THE PANCREAS cystic fibrosis, haemochromatosis, neoplasia,
pancreatitis, pancreatectomy
 ENDOCRINOPATHIES acromegaly, Cushing’s syndrome, glucagonoma,
hyperthyroidism, pheochromocytoma
 INFECTIONS
 UNCOMMON FORMS OF IMMUNE-MEDIATED DIABETES
 DRUG OR CHEMICAL INDUCED atypical antipsychotics, corticosteroids,
nicotinic acid, pentamidine,phenytoin, protease inhibitors, thiazides.
C. Normal physiology of insulin metabolism
Insulin and glucagon are two principal hormones involved in glucose
metabolism. Both hormones are secreted from the endocrine pancreas; the
islet of langerhans with beta cells producing insulin and alpha cells glucagon.
The principal metabolic function of insulin is to increase the rate of glucose
transport into certain cells in the body.
It also;

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 reduces the production of glucose from the liver.
 promotes lipogenesis and inhibits lipolysis in adipocytes
 promotes amino acid uptake and protein synthesis while inhibiting protein
degradation.
Thus, the metabolic effects of insulin can be summarized as anabolic, with
increased synthesis and reduced degradation of glycogen, lipid, and protein.
In addition to these metabolic effects, insulin has several mitogenic
functions, including initiation of DNA synthesis in certain cells and
stimulation of their growth and differentiation.
While insulin act to lower blood glucose level by mechanisms stated above,
Glucagon on the other hand is a blood glucose rising hormone.
During fasting states, low insulin and high glucagon levels facilitate hepatic
gluconeogenesis and glycogenolysis while decreasing glycogen synthesis,
thereby preventing hypoglycaemia. Thus, fasting plasma glucose levels are
determined primarily by hepatic glucose output. After a meal, insulin levels
rise and glucagon levels fall in response to the large glucose load. The most
important stimulus that triggers insulin release is glucose itself, which initiates
insulin synthesis in the pancreatic beta cells.
D. Classification and pathogenesis
In both of the common types of diabetes, environmental factors interact
with genetic predisposition to determine which people develop the clinical
syndrome.

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Type 1 diabetes (T1D)
This type of diabetes starts when patients are young. Patients are usually not
obese. it is characterized by an absolute deficiency of insulin secretion. Type 1
diabetes accounts for approximately 10% of all cases of diabetes.
Mechanism
Type 1 diabetes is an autoimmune disease in which islet destruction is caused
primarily by immune effector cells reacting against endogenous beta cell
antigens. It is a type IV hypersensitivity which most commonly develops in
childhood, becomes manifest at puberty, and progresses with age.

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Most patients with type 1 diabetes depend on exogenous insulin for survival;
without which they develop serious metabolic complications such as
ketoacidosis and coma. This autoimmune attack is progressive and the classic
manifestations of the disease (hyperglycaemia and ketosis) occur late in its
course, after more than 90% of the beta cells have been destroyed. What
usually trigger this autoimmune attack in type 1 is lost self-tolerance in T cells.
As with most autoimmune diseases, the pathogenesis of type 1 diabetes
involves the interplay of genetic susceptibility and environmental factors. It
has been found that patients with type1 diabetes have certain genes in
common, more specifically HLA-DR3, or DR4. Several non-HLA genes also
confer susceptibility to type 1 diabetes, including polymorphisms within the
gene encoding insulin itself, as well as CTLA4 and PTPN22.
Environmental factors especially infections, may be involved in type 1
diabetes. It has been proposed that certain viruses (mumps, rubella, and
coxsackie B viruses, in particular) may be an initiating trigger, perhaps because
some viral antigens are antigenically similar to beta cell antigens (molecular
mimicry), leading to bystander damage to the islets, but this idea is not
conclusively established.
Diabetic ketoacidosis may develop in T1DM because insulin-glucagon balance
tip in favour of ketone bodies synthesis ( insulin is virtually absent and thus
lipolysis and ketone synthesis is unchecked).

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Type 2 diabetes (T2D)
It is caused by a combination of peripheral resistance to insulin action and an
inadequate compensatory response of insulin secretion by the pancreatic beta
cells (relative insulin deficiency). Approximately 80% to 90% of diabetic
patients have type 2.
Mechanism
Type 2 diabetes is a complex multifactorial disease. Environmental factors,
such as a sedentary life style and unhealthy diet habit as well as genetic
factors are involved in its pathogenesis. The study of monozygotic twins
showed that having an identical twin with T2DM alone increases the risk in
folds of developing the disease. Studies have also identified diabetogenic
genes.
Unlike type 1 diabetes, however, the disease is not linked to genes involved
in immune tolerance and regulation (e.g., HLA, CTLA4), and evidence of an
autoimmune basis is lacking.
Insulin resistance and beta cell dysfunction that is manifested as inadequate
insulin secretion in the face of insulin resistance and hyperglycaemia are
characteristic of T2DM.

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Insulin resistance predates the development of hyperglycaemia and usually is
accompanied by compensatory beta cell hyperfunction and hyperinsulinemia
in the early stages of the evolution of diabetes.
Insulin Resistance
With Insulin resistance , target cells in tissues are unable respond normally
to insulin. Therefore the cell functions that require insulin such as glucose
uptake and inhibition of glucose synthesis is reduced or absent causing build
up of glucose in the blood.
The mechanism by which insulin resistance develops is not very clear but it is
thought that several factor play important roles. Some of which are;
 Obesity
 excess free fatty acids (FFA
 Inflammation
 Adipokines
 Peroxisome proliferator-activated receptor-γ (PPARγ)

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Gestational diabetes develop by similar mechanisms to that of type 2
diabetes. It is believed that pregnancy hormones mediate insulin resistance by
mechanisms that are still not very clear.
A variety of monogenic and secondary causes make up the remaining cases of
diabetes. Although the major types of diabetes have different pathogenesis,
the long-term complications in kidneys, eyes, nerves, and blood vessels are the
same and are the principal causes of morbidity and death.
Type 1 Type2
Age Younger (<30yrs) Older (>30 yrs)
Weight Lean Overweight
Symptoms duration Weeks Months, years
High risk ethnicity Northern european Asian african
polynesian ,Indian-
American
Seasonal onset Yes No
Heredity HLA-DR3 or DR4
in >90%
No HLA links
Pathogenesis Autoimmune disease No immune disturbance
Ketonuria Yes No
Clinical Insulin deficiency
ketoacidosis
Always need
insulin
Partial insulin
deficiency
initially
hyperosmolar
hyperglycaemic
State
Need insulin when
beta cells fail
over time
Biochemical c-peptide disapppears c-peptide persists

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E. Diagnosis
Glycaemia is normally maintained in a very narrow range, usually 70 to
120mg/dL. The diagnosis of diabetes is established by elevation of blood
glucose by any one of three criteria:
1. A fasting glucose concentration of 126 mg/dL or higher on more than one
occasion.
2. A random blood glucose concentration of 200 mg/dL or higher, with
classical signs and symptoms (glycosuria, polydipsia,polyphagia and polyuria).
3. An abnormal oral glucose tolerance test (OGTT), in which the glucose
concentration is 200 mg/dL or higher 2 hours after a standard carbohydrate
load (75 g ofglucose).
A fourth test is the measure of glycated haemoglobin.
Fasting
glucose
Random or
non fasting
glycaemia
Oral glucose
tolerance
HbA1c
Prediabetes 100-125mg/dl ------- 140-199mg/dl 5.7-6 .4%
Diabetes
≥126mg/dl
≥200mg/dl ≥200mg/dl ≥6.5%
F. Complications
Virtually all the body systems are affected by abnormalities of metabolism.
The most significant complications of diabetes are
 vascular abnormalities,
 renal damage, and
 lesions affecting the peripheral nerves and eyes.
The time of onset and severity of these complications are very variable in
patients. In persons with tight control of their diabetes, the onset may be

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delayed. The pathogenesis of the long-term complications of diabetes is
multifactorial, although persistent hyperglycaemia (glucotoxicity)
seems to be a key mediator. At least three distinct metabolic pathways seem
to be involved in the pathogenesis of longterm complications; it is likely that
all of them play a role in a tissue-specific manner.
1. Formation of advanced glycation end products (AGEs).
AGEs bind to a specific receptor (RAGE), which is expressed
Macrophages, T cells, endothelial cells and vascular smooth muscle. The
detrimental effects of the AGE-RAGE signaling axis within the vascular
compartment include
• Release of pro-inflammatory cytokines and growth factors from intimal
macrophages
• Generation of reactive oxygen species in endothelial cells
• Enhanced proliferation of vascular smooth muscle cells and synthesis of
extracellular matrix.
AGEs can directly bind to extracellular matrix proteins, and enhance protein
deposition.
2. Activation of protein kinase C.
PKC can be activated by ca2+ and DAG. Intracellular hyperglycemia can
stimulate the de novo synthesis of DAG from glycolytic intermediates and
hence cause activation of PKC. The downstream effects of PKC activation are
include production of proangiogenic molecules such as vascular endothelial
growth factor (VEGF), which is implicated in the neovascularization seen
in diabetic retinopathy, and profibrogenic molecules
such as transforming growth factor-β, leading to increased deposition of
extracellular matrix and basement.
3.Disturbances in polyol pathways
Diabetes and Its Late Complications
Pancreas. Lesions in the pancreas are inconstant and rarely of diagnostic
value. One or more of the following alterations may be present:
• hypotrophy and hypoplasia of beta cells of the islets.

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• Leukocytic infiltration of the islets.
• Amyloid replacement of islets in long-standing type 2 diabetes,
• An increase in the number and size of islets (this change is seen in the
beginning to compensate for insulin resistance and is also characteristic of
nondiabetic newborns of diabetic mothers)
Diabetic Macrovascular Disease.
Diabetes is a precipitating factor for artherosclerosis Myocardial infarction,
caused by atherosclerosis of the coronary arteries, is the most common cause
of death in diabetics. Gangrene of the lower extremities, as a result of
advanced vascular disease, is about 100 times more prevalent in persons with
diabetes than in the non-diabetic population.
Hyaline arteriolosclerosis.
It takes the form of an amorphous, hyaline thickening
of the wall of the arterioles, which causes narrowing of the
lumen . Its severity is related not only to the duration but also to the presence
or absence of hypertension.
Diabetic Microangiopathy.
Diffuse thickening of basement membranes is one of the most consistent
morphologic features of diabetes.
The capillaries of the skin, skeletal muscle, retina, renal glomeruli,
and renal medulla are most often affected. Thickening may be seen also in
such nonvascular structures as renal tubules, the Bowman capsule, peripheral
nerves, and placenta. concentric layers of hyaline material composed
predominantly of type IV collagen are seen in the affected part note, as
counter intuitive as it may seem, the thickened basement membranes makes
diabetic capillaries more leaky than normal to plasma proteins
Diabetic Nephropathy. The kidneys are prime targets of diabetes. Renal
failure is second only to myocardial infarction as a cause of death from this
disease.
Three lesions are encountered:
 glomerular lesions (including basement membrane thickening, diffuse
mesangial sclerosis, and nodular glomerulosclerosis);
 renal vascular lesions, principally arteriolosclerosis; and
 pyelonephritis, including necrotizing papillitis

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The most important glomerular lesions are capillary. The glomerular capillary
basement membranes are thickened along their entire length. This change can
be detected by electron microscopy within a few years of the onset of
diabetes, sometimes without any associated change in renal function.
Diabetic retinopathy
Uncrontrolled diabetes in the long term can cause damage to the retina and
iris, which can lead to blindness. This can be associated with cataract, external
ocular palsies or glaucoma.
Diabetic neuropathies
Microangiopathy underlies the development of impotence and diabetic
mononeuropathy, which may manifest as sudden footdrop or wristdrop or
isolated cranial nerve palsies. The neurologic changes may also be a result of
increased permeability of the capillaries that supply the nerves, as well as
direct axonal damage.
G.Treatment and management

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The methods of treatment of diabetes are: dietary/lifestyle modification, oral
anti-diabetic drugs and injected therapies.
In patients with suspected type 1 diabetes, urgent treatment with insulin is
required and prompt referral to a
specialist is usually needed. In patients with suspected type 2 diabetes, the
first line of therapy involves advice about dietary and lifestyle modification.
Oral anti-diabetic drugs are added in those who do not achieve glycaemic
targets as a result, or who have severe symptomatic hyperglycaemia at
diagnosis and a high HbA1.
In parallel with treatment of hyperglycaemia, other risk factors for
complications of diabetes need to be addressed, including treatment of
hypertension and dyslipidaemia and advice on smoking cessation
Educating patients
It is essential that people with diabetes understand their disorder and learn to
handle all aspects of their management as comprehensively and quickly as
possible. Ideally, this can be achieved by a multidisciplinary team (doctor,
dietitian, specialist nurse and podiatrist) in the outpatient setting. However,
patients commencing insulin need daily advice at first and admission to
hospital
Type 1 diabetes

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