Glucose homeostasis,

Hyper- and hypoglycemia

Omar Abuyaman

Faculty of Allied Health Sciences

Department of Laboratory Medical Sciences
The Hashemite University
Jordan
Blood sugar regulation

Blood sugar regulation is the process by which the levels of blood sugar, primarily
glucose, are maintained by the body within a narrow range. This tight regulation is
referred to as glucose homeostasis.

Insulin, which lowers blood sugar, and glucagon, which raises it, are the most well known
of the hormones involved, but more recent discoveries of other glucoregulatory
hormones have expanded the understanding of this process.

The pancreas secrete both hormones and they are primarily responsible to regulate
glucose levels in blood.
Blood sugar regulation
Blood sugar levels are regulated by negative feedback in order to keep the body in
balance. The levels of glucose in the blood are monitored by many tissues, but the cells in
the pancreatic islets are among the most well understood and important.
Insulin
When levels of blood sugar rise, whether as a result of glycogen conversion, or from
digestion of a meal, insulin is released from beta cells found in the islets of Langerhans in
the pancreas.
This hormone, insulin, causes the liver to convert more glucose into glycogen (this
process is called glycogenesis), and to force about 2/3 of body cells (primarily muscle and
fat tissue cells) to take up glucose from the blood through the GLUT4 transporter, thus
decreasing blood sugar. When insulin binds to the receptors on the cell surface, vesicles
containing the GLUT4 transporters come to the plasma membrane and fuse together by
the process of endocytosis, thus enabling a facilitated diffusion of glucose into the cell. It
also regulates glucose by increasing glycogenesis, lipogenesis, and glycolysis and
inhibiting glycogenolysis.
Blood sugar regulation

As soon as the glucose enters the cell, it is phosphorylated into Glucose-6-Phosphate in

order to preserve the concentration gradient so glucose will continue to enter the cell.

There are also several other causes for an increase in blood sugar levels. Among them are
the 'stress' hormones such as epinephrine (also known as adrenaline), several of the
steroids, infections, trauma, and of course, the ingestion of food.
Diabetes mellitus type 1 is caused by insufficient or non-existent production of insulin,
while type 2 is primarily due to a decreased response to insulin in the tissues of the body
(insulin resistance). Both types of diabetes, if untreated, result in too much glucose
remaining in the blood (hyperglycemia) and many of the same complications. Also, too
much insulin and/or exercise without enough corresponding food intake in diabetics can
result in low blood sugar (hypoglycemia).
Blood sugar regulation

Glucagon
If the blood glucose level falls to dangerously low levels (as during very heavy exercise or
lack of food for extended periods), the alpha cells of the pancreas release glucagon, a
hormone which travels through the blood to the liver, where it binds to glucagon
receptors on the surface of liver cells and stimulates them to break down glycogen stored
inside the cells into glucose (this process is called glycogenolysis).

The cells release the glucose into the bloodstream, increasing blood sugar levels.
Hypoglycemia, the state of having low blood sugar, is treated by restoring the blood
glucose level to normal by the ingestion or administration of glucose or carbohydrate
foods. It is often self-diagnosed and self-medicated orally by the ingestion of balanced
meals. In more severe circumstances, it is treated by injection or infusion of glucagon.
Blood sugar regulation
Blood sugar regulation
Diabetes mellitus

Diabetes mellitus (DM), commonly known as diabetes, is a group of metabolic disorders

characterized by a high blood sugar level over a prolonged period of time.

Symptoms often include frequent urination, increased thirst, and increased appetite.
If left untreated, diabetes can cause many complications. Acute complications can
include diabetic ketoacidosis, hyperosmolar hyperglycemic state, or death. Serious long-
term complications include cardiovascular disease, stroke, chronic kidney disease, foot
ulcers, damage to the nerves, damage to the eyes and cognitive impairment.

Diabetes is due to either the pancreas not producing enough insulin, or the cells of the
body not responding properly to the insulin produced. There are three main types of
diabetes mellitus:
Diabetes

Diabetes could be divided into

• Type 1 diabetes
• Type 2 diabetes
• Gestational diabetes mellitus (GDM)
• Other specific types of diabetes
Diabetes overview

Type 1 diabetes is characterized by inappropriate hyperglycemia

primarily a result of pancreatic islet b-cell destruction and a tendency to
ketoacidosis.

Type 2 diabetes, in contrast, includes hyperglycemia cases that result from

insulin resistance with an insulin secretory defect.

An intermediate stage, in which the fasting glucose is increased above-normal

limits but not to the level of diabetes, has been named impaired fasting glucose.
Use of the term impaired glucose tolerance to indicate glucose tolerance values
above normal but below diabetes levels was retained.

Also, the term GDM was retained for women who develop glucose intolerance
during pregnancy.
Pathophysiology of Diabetes Mellitus

In type 1, there is an absence of insulin with an excess of glucagon. This permits

gluconeogenesis and lipolysis to occur.

In type 2, insulin is not absent and may, in fact, present as hyperinsulinemia at times;
therefore, glucagon is attenuated. Fatty acid oxidation is inhibited in type 2.

The laboratory findings of a patient with diabetes with ketoacidosis tend to reflect
dehydration, electrolyte disturbances, and acidosis. Acetoacetate, b-hydroxybutyrate,
and acetone are produced from the oxidation of fatty acids. The two former ketone
bodies contribute to the acidosis.

Serum osmolality is high as a result of hyperglycemia; sodium concentrations tend to be

lower due in part to losses (polyuria) and in part to a shift of water from cells because of
the hyperglycemia.
Pathophysiology of Diabetes Mellitus

The laboratory findings of non-ketotic hyperosmolar coma include

plasma glucose values exceeding 1,000 mg/dL (55 mmol/L),

normal or elevated plasma sodium and potassium,
slightly decreased bicarbonate,
elevated blood urea nitrogen (BUN) and creatinine,
and an elevated osmolality (>320 mOsm/dL).

The gross elevation in glucose and osmolality, the elevation in BUN, and the
absence of ketones distinguish this condition from diabetic ketoacidosis.
Pathophysiology of Diabetes Mellitus
More typical of the untreated patient with type 2 diabetes is the nonketotic
hyperosmolar state.

The individual presenting with this syndrome has an overproduction of glucose;

however, there appears to be an imbalance between production and elimination in
urine.

Glucose concentrations exceed 300 to 500 mg/dL (17 to 28 mmol/L) and severe
dehydration is present.

Glucosuria can occur after the renal tubular transporter system for glucose becomes
saturated.

This happens when the glucose concentration of plasma exceeds roughly 180 mg/dL in
an individual with normal renal function and urine output.
Type 1 diabetes mellitus

Type 1 diabetes (T1D), previously known as juvenile diabetes, is a form of diabetes in

which very little or no insulin is produced by the pancreas. Before treatment this results in
high blood sugar levels in the body.[1] The classic symptoms are polydipsia (excessive
thirst), polyphagia (increased food intake), polyuria (excessive urine production), rapid
weight loss, hyperventilation, mental confusion, and possible loss of consciousness (due
to increased glucose to brain). Complications include microvascular problems such as
nephropathy, neuropathy, and retinopathy. Increased heart disease is also found in
patients with diabetes.

The cause of type 1 diabetes is unknown, but it is believed to involve a combination of

genetic and environmental factors. Risk factors include having a family member with the
condition. The underlying mechanism involves an autoimmune destruction of the insulin
producing beta cells in the pancreas. Diabetes is diagnosed by testing the level of sugar or
glycated hemoglobin (HbA1C) in the blood. Type 1 diabetes can be distinguished from type
2 by testing for the presence of autoantibodies.[5]
Type 1 diabetes mellitus

There is no known way to prevent type 1 diabetes.Treatment with insulin is required for
survival. Insulin therapy is usually given by injection just under the skin but can also be
delivered by an insulin pump.

Type 1 diabetes mellitus is a result of cellular-mediated autoimmune destruction of the b-

cells of the pancreas, causing an absolute deficiency of insulin secretion.

Type 1 constitutes about 10% of all cases of diabetes and commonly occurs in childhood
and adolescence.

Characteristics of type 1 diabetes include: Abrupt onset, Insulin dependence,

Ketosis tendency.
Type 1 diabetes mellitus

One or more of the following markers are found in 85% to 90% of individuals with
fasting hyperglycemia:

Islet cell autoantibodies,

insulin autoantibodies,
glutamic acid decarboxylase autoantibodies,
and tyrosine phosphatase IA-2 and IA-2B autoantibodies.
Type 2 diabetes mellitus
Type 2 diabetes mellitus is characterized by hyperglycemia as a result of an individual’s
resistance to insulin with an insulin secretory defect. This resistance results in a relative,
not an absolute, insulin deficiency. Type 2 constitutes the majority of the diabetes cases.

Most patients in this type are obese or have an increased percentage of

body fat distribution in the abdominal region.

This type of diabetes often goes undiagnosed for many years and is associated with a
strong genetic predisposition, with patients at increased risk with an increase in age,
obesity, and lack of physical exercise.

Characteristics usually include adult onset of the disease and milder symptoms than in
type 1, with ketoacidosis seldom occurring. However, these patients are more likely to go
into a hyperosmolar coma and are at an increased risk of developing macrovascular and
microvascular complications.
Gestational diabetes mellitus

GDM has been defined as any degree of glucose intolerance with onset or first
recognition during pregnancy.

However, the latest recommendations suggest that “high-risk women found to have
diabetes at their initial prenatal visit, using standard criteria (Table 14-5),
receive a diagnosis of overt, not gestational, diabetes.”

Women identified through the oral glucose tolerance, listed in Table 14-8, should
receive a diagnosis of GDM.

Causes of GDM include metabolic and hormonal changes.

Gestational diabetes mellitus

Patients with GDM frequently return to normal postpartum.

However, this disease is associated with increased perinatal complications and an

increased risk for the development of diabetes in later years.

Infants born to mothers with diabetes are at increased risk for respiratory distress
syndrome, hypocalcemia, and hyperbilirubinemia.

Fetal insulin secretion is stimulated in the neonate of a mother with diabetes.

However, when the infant is born and the umbilical cord is severed, the infant’s
oversupply of glucose is abruptly terminated, causing severe hypoglycemia.
Screening for Prediabetes and Diabetes

The testing criteria for asymptomatic adults for type 2 diabetes mellitus
all adults beginning at the age of 45 years should be tested for diabetes every 3 years
using either the hemoglobin A1c (HbA1c), fasting plasma glucose, or a 2-hour 75 g
oral glucose tolerance test (OGTT).

Testing should be carried out at an earlier age or more frequently in individuals who
display overweight tendencies, i.e., BMI ≥ 25 kg/m2 (at-risk BMI may be lower in
some ethnic groups), and have additional risk factors, as follows:
• Habitually physically inactive
• Family history of diabetes in a first-degree relative
• In a high-risk minority population (e.g., African American, Latino, Native
American, Asian American, and Pacific Islander)
• History of GDM or delivering a baby weighing more than 9 lb (4.1 kg)
• Hypertension (blood pressure ≥ 140/90 mm Hg)
Screening for Prediabetes and Diabetes

• Low high-density lipoprotein (HDL) cholesterol concentrations

(<35 mg/dL [0.90 mmol/L])
• Elevated triglyceride concentrations > 250 mg/dL (2.82 mmol/L)
• History of impaired fasting glucose/impaired glucose tolerance
• Women with polycystic ovarian syndrome (PCOS)
• Other clinical conditions associated with insulin resistance (e.g., severe obesity )
• History of cardiovascular disease

In the absence of the above criteria, testing for prediabetes and diabetes should begin at
the age of 45 years.
Screening for Prediabetes and Diabetes

If results are normal, testing should be repeated at least at 3-year intervals, with
consideration of more frequent testing depending on initial results and risk status.

As the incidence of adolescent type 2 diabetes has risen dramatically in the past few
years, criteria for the testing for type 2 diabetes in asymptomatic children have been
developed.

These criteria include initiation of testing at the age 10 years or at the onset of puberty, if
puberty occurs at a younger age, with follow-up testing every 2 years.
Screening for Prediabetes and Diabetes

Testing should be carried out on children who display the following characteristics:
Overweight (BMI >85th percentile for age and sex, weight for height >85th percentile, or
weight >120% of ideal for height) plus any two of the following risk factors:
• Family history of type 2 diabetes in first- or second degree relative
• Race/ethnicity (e.g., Native American, African American, Latino, Asian American,
and Pacific Islander)
• Signs of insulin resistance or conditions associated with insulin resistance (e.g.,
hypertension, dyslipidemia, and PCOS)

• Maternal history of diabetes or GDM

Criteria for the Diagnosis of Diabetes Mellitus

Criteria for the Diagnosis of Diabetes Mellitus

Four methods of diagnosis are suggested:

(1) HbA1c ≥ 6.5% using a National Glycohemoglobin Standardization Program (NGSP)–

certified method,

(2) a fasting plasma glucose ≥ 126 mg/dL, or

(3) an OGTT with a 2-hour post load (75 g glucose load) level ≥ 200 mg/dL, and

(4) symptoms of diabetes plus a random plasma glucose level ≥ 200 mg/dL, each of which
should be confirmed on a subsequent day by any one of the first three methods (Tables
14-5, 14-6, and 14-7).
Criteria for the Diagnosis of Diabetes Mellitus

Any of the first three methods are considered appropriate for the diagnosis of diabetes.

The decision on which method to use is the decision of the healthcare provider depending
on various patient factors.

Point-of-care assay methods for either plasma glucose or HbA1c are not recommended
for diagnosis.
Criteria for the Diagnosis of Diabetes Mellitus

An intermediate group of individuals who did not meet the criteria of diabetes
mellitus but who have glucose levels above normal be placed into three
categories for the risk of developing diabetes.

First, those individuals with fasting glucose levels ≥100 mg/dL but <126 mg/
dL are placed in the impaired fasting glucose category.

Another set of individuals who have 2-hour OGTT levels ≥140 mg/dL but <200
mg/dL are placed in the impaired glucose tolerance category.

Additionally, individuals with a HbA1c of 5.7% to 6.4% are placed in the third at-
risk category.
Individuals in these three categories are referred to as having “prediabetes”
indicating the relatively high risk for the development of diabetes in these
patients.
Criteria for the Testing and Diagnosis of GDM

The diagnostic criteria for gestational diabetes that all nondiabetic pregnant
women should be screened for GDM at 24 to 28 weeks of gestation
The approach for screening and diagnosis is the performance of a 2-hour OGTT
using a 75 g glucose load.

Glucose measurements should be taken at fasting, 1 hour, and 2 hours. A

fasting plasma glucose value ≥ 92 mg/dL (5.1 mmol/L), a 1-hour value ≥ 180
mg/dL (10 mmol/L), or a 2-hour glucose value ≥ 153 mg/dL (8.5 mmol/L) is
diagnostic of GDM if any one of the three criteria are met.

This test should be performed in the morning after an overnight fast of at least 8
hours (Table 14-8).