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Pathophysiology of Diabetes Mellitus

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 Pathophysiology of Diabetes Mellitus
Introduction
There is a glycemic homeostasis in the human body that works 24 hours a day to maintain the
balance of glucose level in blood stream and in every single cell. Glucose is crucial for human
cells to perform its functions as the glucose is considered the main source of energy, as it turned
into pyruvate by the Krebs cycle to produce the final energy product of ATP (adenosine tri
phosphate). Glucose is allowed to enter the cell via a glucose channel opens only by the insulin
hormone; is a hormone produced by the beta cells in the pancreas and its role is to allow the entry
of glucose from the bloodstream into the cells. Once the glucose is utilized by the cells, the excess
glucose is stored as reservoirs in adipose tissues as triglycerides and in the liver as glycogen. When
the body needs energy it will use these reservoirs to convert glycogen into glucose in a process
called glycogenolysis. This process is done by the hormone glucagon which is also produced by
the pancreas (figure 1). Hyperglycemia occurs when glucose level is high in the blood vessels, it
is dangerous as it may cause coma and death because the brain can’t withstand energy supply
deprivation for long time. Both hypoglycemia and hyperglycemia manifestations resembles each
other in many symptoms; dizziness, blurred vision, general weakness and fatigue. But there is
some major difference which is; in case of hypoglycemia the patient’s skin becomes wet and cold
with heavy sweat, unlike the hyperglycemic patient who has a dry warm skin with no sweating as
the patient is suffering from dehydration resulted from the excessive diuresis triggered by the high
glucose levels in his blood circulation. In some cases when there is an insulin deficiency or high
insulin resistance the glucose accumulate outside the cells in the bloodstream, the cells become
starved and it will search for an alternative source of energy. ( Wile & Wilding, 2014)

Definition
Diabetes mellitus is metabolic disorder due to absolute or relative insulin deficiency, known by
presence of hyperglycemia associated with impairment in carbohydrates, lipids, and proteins
metabolism.

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 Figure 1 Regulation of glucose level using glucagon and insulin

Classification of diabetes mellitus

It is critical to mention that term diabetes mellitus is used for a group of diseases that leads to
prolonged hyperglycemia.

Type 1 diabetes mellitus

It was known previously as insulin dependent diabetes (Juvenile onset diabetes), which can be
characterized as autoimmune disorder which involves severe destruction of the beta cell, absolute
insulin deficiency. In most cases affect non-obese people. (Joseph, et al., 2010)

Type 2 diabetes mellitus

Type two diabetes is known by its insufficient synthesis of insulin and its secretion, in addition,
the body become acquires insulin resistance. It happens due to relative insulin deficiency, it occurs
usually to obese patients, as obesity causes down regulation if insulin receptors. Over eating lead
to excess insulin release and excess internalization of receptors which lead to decrease the available
receptors results to down regulation. The number of available receptors are inversely proportional
to serum insulin. (Joseph, et al., 2010)

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Gestational diabetes mellitus

Gestational diabetes mellitus is classified as an operational one; identifies the woman who develop
diabetes mellitus during the gestation. Gestational diabetes mellitus develops in women who have
type 1 diabetes mellitus during pregnancy and in those who have undiagnosed asymptomatic type
2 diabetes mellitus. In most cases, it happens in the third trimester of pregnancy. (Joseph, et al.,
2010)

Other specific type (Monogenic diabetes)

“Other specific types”, a group of diabetes mellitus with known etiologies. It concerns people with
genetic defects in beta-cell function, in some cases this type of diabetes called MODY “maturity-
onset diabetes in youth”. In addition, it concerns people with defects in insulin action, diseases in
the exocrine pancreas, for instance, pancreatitis or cystic fibrosis, and people with dysfunction
linked with other endocrinopathies. Furthermore, it affects people with pancreatic dysfunction
induced by drugs, chemical or infections. They represent less than 10% of diabetes mellitus cases.
(Joseph, et al., 2010)

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Pathophysiology
There is direct association between hyperglycemia and the physiological responses. The brain
recognizes the hyperglycemia and send a message via nerve impulses to pancreas to decrease its
effect. Figure (2)

Figure 2 the physiological response to hyperglycemia

Type 1 diabetes mellitus

Type 1 diabetes mellitus is known by autoimmune reduction of insulin producing cells in the
pancreas by CD4+ and CD8+ T cells and macrophages which infiltrates the islets. Various features
classify type 1 diabetes mellitus as an autoimmune disease:

 Immune-competent and accessory cells present and infiltrates in pancreatic islets.

 The associated susceptibility for the disease with class II genes of major histocompatibility
complex and human leucocyte antigen.

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  Islet specific autoantibodies are present.
 The remarked alteration if T cell mediated immune-regulation, especially in CD4+ T cell
compartment.
 The participation of monokines and TH1 cells which aid in production of interleukins in
the disease process.
 The response of the disease to immunotherapy.
 Usual occurrence of other organ specific auto-immune disease in the affected person.

The majority of islet antibodies are move against glutamic acid decarboxylase (GAD) inside the
pancreatic B cells. As a result of the autoimmune destruction of the pancreatic beta cells; a
deficiency in insulin secretion, which leads to metabolic derangement linked with type 1 diabetes
mellitus. Beside the loss of insulin secretion, the main function of pancreatic alpha cells seems
abnormal which leads to excessive secretion of glucagon. In the normal cases, hyperglycemia
results in reduction of glucagon secretion, although, type 1 diabetes mellitus patients, the glucagon
secretion is not suppressed by hyperglycemia. Therefore, the result is inappropriate elevation of
glucagon which exacerbate metabolic defects because of the insulin deficiency. However insulin
deficiency consider as the primary defect in type 1 diabetes mellitus, also it was found that there
is a defect in administration of insulin. From the consequences of insulin deficiency uncontrollable
lipolysis and elevation in free fatty acids in the plasma, which lead to suppression in glucose
metabolism especially in peripheral tissues, for instance, skeletal muscle. Thus, this mainly impairs
the proper utilization of glucose and insulin deficiency, also reduce their function to express
number of genes that significant to respond normally to insulin, such as Glucokinase which present
in the liver only and has its main function in storage of glucose as glycogen, which aids in
phosphorylation of glucose to enter glycolysis and gain more ATP. In addition, it results in poor
expression of GLUT 4 class of glucose transporters which present in the adipose tissue. (Figure
3). (Baynest, 2015)

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 Figure 3 In Figure 3A it shows the normal physiological effect of
reduction in insulin linked with a low glucose concentration which
leads to stimulation of alpha cell glucagon secretion. In Figure 3B
presents the pathophysiological failure of beta cell, which leads to no
decrease in insulin and no increase in alpha-cell glucagon secretion, in
spite of the low glucose concentration.

Type 2 diabetes mellitus

These mechanisms are break down in type 2 diabetes, the main consequences in the
pathology of type 2 diabetes are impaired insulin secretion via a dysfunction of the
pancreatic beta cells, in addition, impairment of insulin action through insulin resistance.
In cases where the insulin resistance dominates, the mass of beta cells been transformed
and has the capability to increase the insulin supply, compensation for the excessive and

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anomalous demand. In other words, the plasma insulin concentration been elevated in both
fasting and feeding state. (Figure 4) (Baynest, 2015)

Figure 4 Pathophysiology of hyperglycemia and increased

fatty acids in type 2 diabetes

Insulin resistance
It is believed through the primary events, that there is initial deficit in insulin secretion and
mainly this relative insulin deficiency associated with peripheral insulin resistance. The
significant resistance to the insulin leads to impaired insulin mediated glucose uptake in
the peripheral, in addition, incomplete suppressed hepatic glucose output and impaired
triglyceride uptake by fat. In order to overcome the insulin resistance, a significant increase
in islet cells leads to increase in amount of insulin secreted. Patients with type 2 diabetes
has elevated and accelerated endogenous glucose production or impairment in fasting
glucose. As this increase happens in hyperinsulinemia. (Baynest, 2015)

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Clinical symptoms and signs
The majority of symptoms are typical in both types of diabetes, but they may vary in the degree
and development, as they more severe in type 1 than type 2. (Figure 5) (Baynest, 2015)

Figure 5 Clinical symptoms and signs of diabetes mellitus

Clinical picture of type 1 diabetes

 Weight loss
 Polyuria
 Polydipsia
 Constipation fatigue
 Blurred vision
 Candidiasis
 Lethargy
 Stupor
 Hyperventilation
 Smell of acetone

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Clinical picture of type 2 diabetes
 Atherosclerosis
 Hyperlipidemia
 Hypertension
 Obesity
 Cardiovascular complications

Complications of diabetes mellitus

Complications of diabetes may be acute or chronic. Acute complications include hypoglycemia,
diabetic ketoacidosis, and diabetic hypersmolar non-ketoacidotic coma. Chronic complications
may be microvascluar complications or macrovascular complications. Microvascular
complications includes neuropathy, retinopathy, nephropathy, and diabetic food. Macrovascular
complications include hypertension, cardiovascular disease, cerebrovascular disease, peripheral
vascular disease, and erectile dysfunction. (Figure 6) (Sampson & Waller , 2008)

Figure 6 Complications of diabetes mellitus

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Diagnosis and follow up
Glucose tolerance testing is of value for the early detection of diabetes in a high-risk patient with
a glucose level close to the diagnostic cut-off value. The oral glucose tolerance test (OGTT) also
has a role in women with impaired fasting glucose (fasting glucose 5.6–6.9 mmol/L), who often
have postprandial glucose excursions in the diabetic range. The OGTT uses the 2-hour glucose
response following a 75 g oral glucose load to determine the presence of diabetes. The glucose
load is given as a drink. The cut-off values are shown in the below table (1). The current criteria
from the ADA require confirmation by repeat testing on a subsequent day. This should be tempered
by the clinical situation. For example, it would not be necessary to confirm in a young
hyperglycemic patient with symptoms and ketoacidosis. Similarly, confirmation would be
unnecessary for the unwell patient found to be hyperglycemic with sepsis, acute infection or acute
myocardial infarction, or following a transplant procedure, where treatment of both the acute
underlying illness and associated hyperglycemia is indicated. (Joseph, et al., 2010)

Table 1 Diagnostic cut-offs for disorders of glucose metabolism

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Management of diabetes mellitus

Type 1 diabetes mellitus (Insulin dependent diabetes mellitus): use insulin, diet, and exercise

Type 2 diabetes mellitus (Non-insulin dependent diabetes mellitus)

1- Start with diet regulation and exercise.

2- If failed (Diet regulation and exercise), so:
a- Monotherapy: Metformin or Acarbose.
b- If the above failed, add a sulfonylurea.
c- If the above failed, add a glitazone.
d- If the above failed, stop the sulfonylurea (Continue with Metformin and glitazone), and
start insulin therapy.
3- If stress (infection, operation, pregnancy); stop temporarily oral hypoglycemic and use
soluble insulin subcutaneous 30 minutes before the three main meals toll recovery then go
back to the previous treatment.
4- If renal impairment; stop permanently oral hypoglycemic, and use intermediate acting
insulin such as lente or isophane. (Baynest, 2015)

Table 2 Oral Anti-diabetic drugs

1- Insulin secretagogues = oral hypoglycemic drugs

First generation
Short acting Tobutamide
Intermediate acting Acetohexamide
Long acting Chloropropamide
Second generation
Glibenclamide
Glipizide
Glimepiride
Other Insulin secretagogues
Meglitinides Repaglinide
D-phenylalanines Nateglinide
2- Insulin sensitizers = euglycemics
Biguanides Metformin
Phenformin
Thiazolidinediones (Glitazones) Rosiglitazone
Pioglitazone
3- Other oral anti-diabetic drugs
Alpha-Glucosidase Inhibitors Acarbose, Miglitol.

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 References
1. Wile, D. B. & Wilding, J. B., 2014. Clinical Biochemistry: Metabolic and Clinical Aspects.
In: CHAPTER 15 - Glucose metabolism and the pathophysiology of diabetes mellitus. 3rd
ed. s.l.:Churchill Livingstone, pp. 273-304.

2. Baynest, H. W., 2015. Classification, Pathophysiology, Diagnosis and Management of

Diabetes Mellitus. Journal of Diabetes and Metabolism, 6(5), pp. 1-19.

3. Greydanus, D. E. & Merick, J., 2016. Diabetes Mellitus : A Medical History Journey.. New
York: Nova Science Publishers, Inc (Public Health: Practices, Methods and Policies)..

4. Joseph, H., Sanoyata, M. & Berg, J., 2010. Diagnosis and classification of diabetes
mellitus.. In: Diabetes Mellitus. California : s.n., pp. 23-50.

5. Sampson, A. P. & Waller , D. G., 2008. 40 - Diabetes mellitus. In: D. G. Waller & A. G.
Sampson, eds. Medical Pharmacology and Therapeutics. 5th ed. s.l.:s.n., pp. 459-473.

6. Scobie, I., Campbell, I. W. & Samaras, K., 2009. Diabetes Mellitus. Abingdon: Oxford,
UK: Health Press Limited.

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