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Diabetes Mellitus

The Centers for Disease Control and Prevention (CDC)predicts the national incidence of diabetes will rise by37.5% by the year 2025 and by 170% in developingcountries over the next 30 years.

Of particular concern is the alarming increase in theprevalence of type 2 diabetes in both adults and children.

In 2002, an estimated 18.2 million people, or 6.3% of theUnited States population, had diabetes. Of these, 5.2million or about one-third were undiagnosed.

Clinical studies have affirmed that type 2 diabetes can bedelayed or prevented in high-risk populations and thatgood glycemic control and other interventions can slow thedevastating complications of diabetes

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Definition

Diabetes is a syndrome that is caused by arelative or an absolute lack of insulin.

Clinically, it is characterized by symptomaticglucose intolerance as well as alterations in lipidand protein metabolism.

Over the long term, these metabolic

abnormalities, particularly hyperglycemia,contribute to the development of complicationssuch as retinopathy, nephropathy, andneuropathy.

Risk Factors for Diabetes Mellitus

Obesity

Familial history of diabetes mellitus

Increasing age

Ethnicity High risk groups include African

Americans, Hispanics and native Americans

Dietary factors

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Endocrine pancreas

In the pancreas there are endocrine cells found in scattered

clusters called islets of Langerhans.

These endocrine cells can be classified into three distinct

types:

- cells that produce the hormone glucagon.

- cells that produce insulin.

-cells that produce somatostatin.

Insulin Function

Increases glucose transport into tissues.

Increases glycogen synthesis in liver and

muscle. Increases triglyceride synthesis in adipose

tissue and liver.

Increases amino acid uptake and protein

synthesis.

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Carbohydrate Metabolism

Homeostatic mechanisms maintain plasma glucoseconcentrations between 55 and 140 mg/dL (3.1 to 7.8mmol/L). A minimum concentration of 40 to 60 mg/dL (2.2to 3.3 mmol/L) is required to provide adequate fuel for thecentral nervous system (CNS), which uses glucose as itsprimary energy source and is independent of insulin forglucose utilization.

When blood glucose concentrations exceed thereabsorptive capacity of the kidneys (approximately 180mg/dL), glucose spills into the urine resulting in a loss ofcalories and water.

Muscle and fat also use glucose as a major source ofenergy, but these tissues require insulin for glucose uptake.If glucose is unavailable, these tissues are able to use othersubstrates such as amino acids and fatty acids for fuel.

Postprandial Glucose Metabolism in

the Nondiabetic Individual

After food is ingested, blood glucose concentrations rise and stimulate

insulin release.

Insulin is the key to efficient glucose utilization. It promotes the uptake of

glucose, fatty acids, and amino acids as well as their conversion to storageforms in most tissues:

In muscle, insulin promotes the uptake of glucose and its storage as

glycogen. It also stimulates the uptake of amino acids and their

conversion to protein.

In adipose tissue, glucose is converted to free fatty acids and stored as

triglycerides. Insulin also prevents a breakdown of these triglycerides

to free fatty acids, a form that may be transported to other tissues for

utilization.

The liver does not require insulin for glucose transport, but insulin

facilitates the conversion of glucose to glycogen and free fatty acids.

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Fasting Glucose Metabolism in the

Nondiabetic Individual As blood glucose concentrations drop toward normal during the

fasting state, insulin release is inhibited.

Simultaneously, a number of counter-regulatory hormones thatoppose the effect of insulin and promote an increase in blood sugarare released (e.g., glucagon, epinephrine, growth hormone,glucocorticoids).

As a result, several processes maintain a minimum blood glucoseconcentration for the CNS:

Glycogen in the liver is broken down into glucose(glycogenolysis).

Amino acids are transported from muscle to liver, where theyare converted to glucose through gluconeogenesis.

Uptake of glucose by insulin-dependent tissues is diminishedto conserve glucose for the brain.

Triglycerides are broken down into free fatty acids, which areused as alternative fuel sources.

Types of Diabetes

Type 1 Diabetes (insulin-dependent diabetes

mellitus (IDDM)).

Type 2 Diabetes (noninsulin-dependentdiabetes mellitus (NIDDM)).

Gestational diabetes mellitus (GDM).

Impaired glucose tolerance (IGT).

Impaired fasting glucose (IFG).

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Type 1 Diabetes

Pathogenesis:

The loss of insulin secretion in type 1 diabetes mellitus

results from autoimmune destruction of the insulin-

producing -cells in the pancreas(such as viruses or toxins)

or may be Idiopathic (without evidence of autoimmunity).

This form of diabetes is associated closely with

histocompatibility antigens (HLA- DR3 or HLA-DR4) and the

presence of circulating insulin and islet cell antibodies (ICAs).

-Cell destruction may occur rapidly but is more likely totake place over a period of weeks, months, or even years.

Type 1 Diabetes Contd

Pathogenesis:

Fasting hyperglycemia occurs when -cell mass is reduced

by 80% to 90%.

On presentation, approximately 65% to 85% of patients

have circulating antibodies directed against islet cells and

20% to 60% of patients have measurable antibodies

directed against insulin.

Within 8 to 10 years following clinical presentation, -cell

loss is complete and insulin deficiency is absolute.

Circulating ICAs can no longer be detected.

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Type 1 Diabetes Contd

Clinical Presentation:

Polyuria.

Polydipsia.

Polyphagia.

weight loss.

Recurrent respiratory, vaginal, and other

infections.

Honeymoon Period

Within days or weeks after the initial diagnosis, manypatients with type 1 diabetes experience an apparentremission, which is reflected by decreased blood glucoseconcentrations and markedly decreased insulin

requirements. It may last for only a few weeks to months.

Once hyperglycemia, metabolic acidosis, and ketosisresolve, endogenous insulin secretion recovers temporarily.

Honeymoon period may last for up to a year.

During this time, patients should be maintained on insulineven if the dose is very low, because interrupted treatmentis associated with a greater incidence of resistance andallergy to insulin.

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Type 2 Diabetes

Pathogenesis: Metabolic Syndrome (Insulin Resistance

Syndrome, Syndrome X):

Impaired insulin secretion and resistance to the action of

insulin characterize patients with type 2 diabetes.

In the presence of insulin resistance, glucose utilization by

tissues is impaired, hepatic glucose output or production is

increased, and excess glucose accumulates in the

circulation. This hyperglycemia stimulates the pancreas toproduce more insulin in an effort to overcome the insulin

resistance.

Type 2 Diabetes

Pathogenesis: Metabolic Syndrome (Insulin Resistance Syndrome,

Syndrome X):

The simultaneous elevation of both glucose and insulin is

strongly suggestive of insulin resistance. Type 2 diabetes is associated with a variety of disorders,

including obesity, atherosclerosis, hyperlipidemia, and

hypertension.

People with type 2 diabetes have a stronger family history

of diabetes than do those with type 1 diabetes. Circulating

ICAs are absent, and there is no association with human

lymphocyte antigen (HLA) types.

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Type 2 Diabetes

Clinical Presentation:

Symptoms are so mild and their onset sogradual.

When giving a history of their illness, peoplewith type 2 diabetes acknowledge fatigue,polyuria, and polydipsia.

Weight loss is uncommon in these individualsbecause relatively high endogenous insulinlevels promote lipogenesis.

Types of DiabetesTable 50-1 Type 1 and Type 2 Diabetes

Characteristics Type 1 Type 2

Other names Previously, type I; insulin-

dependent diabetes mellitus

(IDDM); juvenile-onset

diabetes mellitus

Previously, type II; noninsulin-dependent

diabetes mellitus (NIDDM); adult onset

diabetes mellitus

Percentage of

diabetic

population

510% 90%

Age at onset Usually 40 yr, but increasing prevalence

among obese children

Pancreatic

function

Usually none, although some

residual C-peptide can

sometimes be detected at

diagnosis, especially in adults

Insulin present in low, normal, or high

amounts
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Pathogenesis Associated with certain HLA

types; presence of islet cell

antibodies suggests autoimmune

process

Defect in insulin secretion; tissue

resistance to insulin; hepatic glucose

output

Family history Generally not strong Strong

Obesity Uncommon unless

overinsulinized with exogenous

insulin

Common (6090%)

History of

ketoacidosis

Often present Rare, except in circumstances of unusual

stress (e.g., infection)Clinical presentation Moderate to severe symptoms that

generally progress relatively

rapidly (days to weeks): polyuria,

polydipsia, fatigue, weight loss,

ketoacidosis

Mild polyuria, fatigue; often diagnosed

on routine physical or dental examination

HLA, human leukocyte antigen.



Treatment Insulin Diet

Diet Exercise

Exercise Oral antidiabetic agents (-glucosidase

inhibitors, biguanides, non-sulfonylureainsulin secretagogues, sulfonylureas,

thiazolidinediones)

Insulin
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Gestational Diabetes Mellitus

(GDM) Affects about 7% of all pregnancies.

Any carbohydrate intolerance with onset or firstrecognition during pregnancy.

Most commonly seen during the third trimester ofpregnancy.

Resolves itself in most patients after birth but a certainpercentage(50 to 60%) will go on to develop diabetesmellitus in the years following the pregnancy.

May be associated with an increased risk of fetalabnormalities.

Currently recommended that all pregnant women bescreened for the presence of gestational diabetes

Impaired glucose tolerance (IGT)

Subclinical glucose intolerance or prediabetes.

Patients with IGT do not meet the criteria for diagnosis of DM. Patients are at high risk of DM.

Patients with normal fasting plasma glucose levels (> 110 & 200 mg/dl at 0.5, 1, or

1.5 hr & 140 200 mg/dl at 2 hr.

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Impaired fasting glucose (IFG).

Subclinical glucose intolerance or prediabetes.

Patients with IFG do not meet the criteria for diagnosis of DM.

Patients are at high risk of DM.

Patients with fasting plasma glucose levels (> 110 &

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Fasting Blood Glucose

The categories of FPG values are as follows:

A normal FPG is

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Oral Glucose Tolerance Test Many factors can impair glucose tolerance or increase plasma glucose, and

these must be excluded before a firm diagnosis of diabetes is made. For

example:

An individual who has not fasted for a minimum of 8 hours may have an

elevated FPG.

One who has fasted too long (>16 hours) or has ingested insufficient

carbohydrates before testing may have an IGT.

Patients who are tested for glucose tolerance during, or soon after, an

acute illness (e.g., a myocardial infarction [MI]) may be misdiagnosed

because of the presence of high concentrations of counter-regulatory

hormones that increase glucose concentrations.

Pregnancy, many forms of stress, and lack of physical activity can affectthe glucose tolerance similarly.

Many drugs may alter glucose tolerance due to their effects on insulin

release and tissue response to insulin, as well as through direct cytotoxic

effects on the pancreas.

Complications

Acute metabolic complications:

Diabetic ketoacidosis (DKA).

Hyperglycemic, hyperosmolar, nonketotic

coma (HHNK). Hypoglycemia (< 70 mg/dl).

Chronic long term complications:

Macrovascular complications (coronary

artery disease, peripheral artery disease,

stroke).

Microvascular complications (retinopathy,

nephropathy, and neuropathy).

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