Pathophysiology:
1. Normal glucose regulation:
Involves both insulin and counter regulatory hormones.
a. Insulin is responsible for a variety of effects throughout body tissues:
(1) Stimulates glucose transport across cell membranes and promotes the storage of
glucose as glycogen in muscle and liver cells .
(2) Enhances fat storage ( lipogenesis) and prevents the mobilization of fat for energy
(Lipolysis and ketogenesis).
(3) Inhibits production of glucose from liver or muscle glycogen (glycogenolysis).
(4) Promotes incorporation of amino acids into proteins(protein synthesis).
(5) Inhibits the formation of glucose from amino acids (gluconeogenesis) .
(6) Decreased the breakdown of fatty acids to ketone bodies.
b. Counter regulatory hormones: antagonize the glycemic effects of insulin :
(1) Glucagon : produced in the alpha cells of the pancreas.
(2) Epinephrine.
(3) Norepinephrine.
(4) Growth hormone.
(5) Cortisol.
2. Abnormal glucose regulation:
Associated with diabetes.
In untreated type I and type II DM, the disease follows a predictable progression from
initial abnormalities of glucose metabolism to life-threatening diabetic ketoacidosis or
hyperglycemic hyperosmolar nonketonic syndrome, as described below.
a. Diabetic ketoacidosis (DKA)(Type I DM):
(1) Insulin deficiency results in hyperglycemia.
(a) Impaired glucose uptake in the peripheral tissues (primarily muscle) .
(b) Reduction in the conversion of glucose to glycogen (impaired glycogenesis),
primarily in the liver.
(c) Impaired insulin-induced suppression of hepatic glucose production
(neoglucogenesis and glycogenolysis).
(2) As blood glucose concentrations increase, the glucose reabsorptive capacity of
the kidneys will be exceeded.
This occurs at about 180 mg/dl, referred to as the renal threshold for glucose.
Glucose is then excreted into the urine resulting in an osmotic diuresis with subsequent
dehydration and electrolyte abnormalities.
(3) Insufficient glucose uptake in the peripheral tissues (due to insulin deficiency)
causes the cells to use protein and fat as energy sources rather than glucose.
(4) Breakdown of triglycerides (the stored form of fat) yields free fatty acids and
glycerol through the process of lipolysis.
Without the administration of insulin, type I DM will progress to
ketonemia and ketoacidosis, described below:
(a) Increasing amounts of glycerol leads to enhanced hepatic glucose production,
further worsening hyperglycemia.
(b) Free fatty acids are broken down (in the liver) into ketone bodies, which are
excreted by the kidneys (ketonuria).
Acetoacetate ( a ketone body) is converted (in the liver) to acetone, which is excreted
through the lungs.
This is associated with a fruity odor and can sometimes be detected on the breath of the
patient.
(c) As the utilization (breakdown) of adipose tissue continues, ketone production
exceeds the capacity for excretion, leading to accumulation in the bloodstream
(ketonemia).
(d) Increasing levels of free fatty acids contribute to the development and worsening
of acidosis.
(e) Initially, there is compensation for acidosis by changes in breathing patterns
(kussmaul breathing) and by buffering system of the blood (proteins; bicarbonate; and
others).
(f) As acidosis continues, breathing compensation and bicarbonate stores are
insufficient or depleted.
A state of ketosis with acidosis (ketoacidosis) then exists.
(g) If ketoacidosis is not promptly treated by insulin,coma and death will ensue in type
I diabetes.
(h) The total lack of insulin in type I DM is a predisposing factor for DKA.
Patients with type I DM are described as ketosis-prone.
b. Hyperglycemic hyperosmolar nonketotic syndrome (HHNK)
(Type II DM):
(1) Insulin deficiency, often with concomitant insulin resistance, results in
hyperglycemia.
(a) Impaired glucose uptake in the peripheral tissues (primarily muscle).
(b) Reduction in the conversion of glucose to glycogen (impaired glycogenesis),
primarily in the liver.
(c) Impaired insulin-induced suppression of hepatic glucose production
(neoglucogenesis and glycogenolysis).
(2) Increasing blood glucose concentrations exceed the glucose reabsorptive capacity
of the kidneys ( occurs at about 180 mg/dl, referred to as the renal threshold for glucose).
Glucose is then excreted into the urine resulting in an osmotic diuresis with subsequent
dehydration and electrolyte abnormalities.
(3) Insufficient glucose uptake in the peripheral tissues (due to insulin deficiency
and/or insulin resistance) causes the cells to use protein as energy sources rather than
glucose.
(4) Breakdown of protein yields carbohydrate/glucose moieties, but within sufficient
insulin, the additional glucose worsen hyperglycemia rather than serving as an energy
source.
(5) In type II DM the presence of even minimal blood levels of endogenous insulin
usually prevents the breakdown of fats and subsequent ketonemia and ketoacidosis. Thus,
patients with type II DM are described as ketosis- resistant.
(6) Although sufficient to suppress ketosis, endogenous insulin secretion in type II
DM is insufficient for glycemic control. If insulin is not administered, profound dehydration
with very high blood glucose levels may occur; this state is described as HHNK. Coma and
death may result.
1. Normal glucose regulation:
Involves both insulin and counter regulatory hormones.
a. Insulin is responsible for a variety of effects throughout body tissues:
(1) Stimulates glucose transport across cell membranes and promotes the storage of
glucose as glycogen in muscle and liver cells .
(2) Enhances fat storage ( lipogenesis) and prevents the mobilization of fat for energy
(Lipolysis and ketogenesis).
(3) Inhibits production of glucose from liver or muscle glycogen (glycogenolysis).
(4) Promotes incorporation of amino acids into proteins(protein synthesis).
(5) Inhibits the formation of glucose from amino acids (gluconeogenesis) .
(6) Decreased the breakdown of fatty acids to ketone bodies.
b. Counter regulatory hormones: antagonize the glycemic effects of insulin :
(1) Glucagon : produced in the alpha cells of the pancreas.
(2) Epinephrine.
(3) Norepinephrine.
(4) Growth hormone.
(5) Cortisol.
2. Abnormal glucose regulation:
Associated with diabetes.
In untreated type I and type II DM, the disease follows a predictable progression from
initial abnormalities of glucose metabolism to life-threatening diabetic ketoacidosis or
hyperglycemic hyperosmolar nonketonic syndrome, as described below.
a. Diabetic ketoacidosis (DKA)(Type I DM):
(1) Insulin deficiency results in hyperglycemia.
(a) Impaired glucose uptake in the peripheral tissues (primarily muscle) .
(b) Reduction in the conversion of glucose to glycogen (impaired glycogenesis),
primarily in the liver.
(c) Impaired insulin-induced suppression of hepatic glucose production
(neoglucogenesis and glycogenolysis).
(2) As blood glucose concentrations increase, the glucose reabsorptive capacity of
the kidneys will be exceeded.
This occurs at about 180 mg/dl, referred to as the renal threshold for glucose.
Glucose is then excreted into the urine resulting in an osmotic diuresis with subsequent
dehydration and electrolyte abnormalities.
(3) Insufficient glucose uptake in the peripheral tissues (due to insulin deficiency)
causes the cells to use protein and fat as energy sources rather than glucose.
(4) Breakdown of triglycerides (the stored form of fat) yields free fatty acids and
glycerol through the process of lipolysis.
Without the administration of insulin, type I DM will progress to
ketonemia and ketoacidosis, described below:
(a) Increasing amounts of glycerol leads to enhanced hepatic glucose production,
further worsening hyperglycemia.
(b) Free fatty acids are broken down (in the liver) into ketone bodies, which are
excreted by the kidneys (ketonuria).
Acetoacetate ( a ketone body) is converted (in the liver) to acetone, which is excreted
through the lungs.
This is associated with a fruity odor and can sometimes be detected on the breath of the
patient.
(c) As the utilization (breakdown) of adipose tissue continues, ketone production
exceeds the capacity for excretion, leading to accumulation in the bloodstream
(ketonemia).
(d) Increasing levels of free fatty acids contribute to the development and worsening
of acidosis.
(e) Initially, there is compensation for acidosis by changes in breathing patterns
(kussmaul breathing) and by buffering system of the blood (proteins; bicarbonate; and
others).
(f) As acidosis continues, breathing compensation and bicarbonate stores are
insufficient or depleted.
A state of ketosis with acidosis (ketoacidosis) then exists.
(g) If ketoacidosis is not promptly treated by insulin,coma and death will ensue in type
I diabetes.
(h) The total lack of insulin in type I DM is a predisposing factor for DKA.
Patients with type I DM are described as ketosis-prone.
b. Hyperglycemic hyperosmolar nonketotic syndrome (HHNK)
(Type II DM):
(1) Insulin deficiency, often with concomitant insulin resistance, results in
hyperglycemia.
(a) Impaired glucose uptake in the peripheral tissues (primarily muscle).
(b) Reduction in the conversion of glucose to glycogen (impaired glycogenesis),
primarily in the liver.
(c) Impaired insulin-induced suppression of hepatic glucose production
(neoglucogenesis and glycogenolysis).
(2) Increasing blood glucose concentrations exceed the glucose reabsorptive capacity
of the kidneys ( occurs at about 180 mg/dl, referred to as the renal threshold for glucose).
Glucose is then excreted into the urine resulting in an osmotic diuresis with subsequent
dehydration and electrolyte abnormalities.
(3) Insufficient glucose uptake in the peripheral tissues (due to insulin deficiency
and/or insulin resistance) causes the cells to use protein as energy sources rather than
glucose.
(4) Breakdown of protein yields carbohydrate/glucose moieties, but within sufficient
insulin, the additional glucose worsen hyperglycemia rather than serving as an energy
source.
(5) In type II DM the presence of even minimal blood levels of endogenous insulin
usually prevents the breakdown of fats and subsequent ketonemia and ketoacidosis. Thus,
patients with type II DM are described as ketosis- resistant.
(6) Although sufficient to suppress ketosis, endogenous insulin secretion in type II
DM is insufficient for glycemic control. If insulin is not administered, profound dehydration
with very high blood glucose levels may occur; this state is described as HHNK. Coma and
death may result.
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Diabetes Mellitus
