Chemistry 1 Solo 2 Lecture 2 Hyperglycemia and Hypoglycemia

High blood glucose

The most frequently encountered disorder of carbohydrate metabolism is high blood glucose concentration due to diabetes mellitus (DM)

DM is a group of metabolic disorders of carbohydrate metabolism in which glucose is underused, producing hyperglycemia

Low blood glucose

Hypoglycemia is an abnormally diminished concentration of glucose in the blood

Diabetes mellitus causes microvascular complications

Diabetic retinopathy (causing blindness)

Diabetic nephropathy (causing renal failure)

Neuropathy (nerve damage)

Diabetes mellitus causes macrovascular complications

Atherosclerosis: hardening of the arteries

• cardiac (myocardial infarction)

• cerebral (stroke)

• peripheral large vessels (limb amputation)

Diabetes mellitus symptoms

Urinating often

Feeling very thirsty

Feeling very hungry even when eating

Extreme fatigue

Blurry vision

Cuts/bruises slow to heal

Weight loss even when eating more (type 1)

Tingling, pain, or numbness in the hands/feet (type 2)

Diabetes mellitus - ketone bodies

When the body doesn’t have enough carbohydrates for cells to burn for energy, it burns fat instead

As part of this process, it makes three acidic, intermediate products known as ketones

• Acetone

• Beta-hydroxybutyrate

• Acetoacetic acid

The primary substrates for the formation of ketone bodies are free fatty acids from fat tissue

Normally, long chain fatty acids are

• Taken up by the liver

• Re-esterified to triglycerides

• Stored in the liver or incorporated in very low density lipoproteins (VLDL), and then

• Returned to plasma

In uncontrolled diabetes, low insulin concentrations result in increased lipolysis and decreased re-esterification of these fatty acids to triglycerides

Increased counter-regulatory hormones also increase lipolysis and ketogenesis in adipose tissue and liver; free fatty acids are the precursors for ketone bodies

Excessive formation of ketone bodies results in

• Increased blood concentrations of ketones

• Increased excretion of ketones in the urine

Diabetes mellitus and alcohol consumption are the common causes of ketoacidosis

May form due to low availability of carbohydrates

• Starvation

• Frequent vomiting

May form due to low use of carbohydrates

• Diabetes mellitus

• Glycogen storage disease

• Alkalosis

Diabetic ketoacidosis

Complication of type 1 diabetes mellitus

Without enough insulin, the body can’t use sugar properly for energy

This prompts the release of hormones that break down fat as fuel, which produces acidic ketones

Excess ketones build up in the blood and eventually “spill over” into the urine to be measured

Hyperosmolar nonketotic coma

Characterized by severe hyperglycemia, extreme dehydration, hyperosmolar plasma, and altered consciousness; complications include coma, seizures, and death

Metabolic complication of diabetes mellitus, most often type 2 in the setting of physiologic stress (acute illness, infection, myocardial infarction, or stroke)

Response to stress increases hormones that favor elevated glucose levels

Hyperglycemia → fluid shift from cells to blood → increased urine output (osmotic diuresis) → dehydration

Serum ketones are not present because the amount of insulin present in most patients with type 2 diabetes mellitus is adequate to suppress ketogenesis

Diagnosed by severe hyperglycemia and plasma hyperosmolality and absence of significant ketosis

Symptoms of Diabetes mellitus include all of the following except

Polychromasia

The development of ketosis in uncontrolled diabetes is a result of

Increased lipolysis of fatty acids from adipose stores and decreased re

Table 9.3 Classification of Diabetes Mellitus

The terms juvenile-onset and adult-onset diabetes were abolished in 1979 by the National Diabetes Data Group (NDDG)

The terms insulin-dependent diabetes mellitus (IDDM) and non-insulin dependent diabetes mellitus (NIDDM) were eliminated in 1997 by the American Diabetes Association (ADA)

Type 1 Diabetes Mellitus Overview

5-10% of DM cases

Peak incidence in childhood and adolescence

Acute onset: Symptoms occur abruptly

• Polyuria: Increased urine output

• Polydipsia: Increased thirst

• Rapid weight loss

Patients have deficiency of insulin caused by loss/destruction of pancreatic islet beta cells

Patients are dependent on insulin to sustain life and prevent ketosis

Most patients have antibodies that identify an autoimmune process

Type 1 diabetes mellitus etiology

Type 1A

• Caused by cell mediated autoimmune destruction of Beta cells of the pancreas

• Autoantibodies may be detected in circulation, including islet cell cytoplasmic antibodies and insulin autoantibodies

Type 1B

• Called idiopathic T1DM

• Patients experience Beta cell destruction, but it is due to a chromosomal abnormality or an unknown cause rather than an autoimmune process

Genetic predisposition

• Complex, undefined mode of inheritance

• Associated with HLA-DR3 or HLA-DR4; screening by determining HLA type is not currently warranted except in research studies

• Routine measurement of genetic markers is not of value at this time

Environmental factors contribute to onset of disease

• Viruses such as rubella, mumps, or coxsackie virus B have been implicated

• Autoimmunity to beta cells may be initiated by a viral protein that shares an amino acid sequence with a beta cell protein

Table 9.15 Autoantibody Markers

Type 2 Diabetes mellitus overview

90% of all cases of diabetes mellitus

Most acquire disease after age 40

Minimal symptoms, not prone to ketosis, not dependent on insulin to prevent ketonuria

Insulin concentrations may vary among patients, but most have impaired insulin action

Obesity is commonly associated; weight loss typically improves condition

To control hyperglycemia, these patients may require change in diet, hypoglycemia oral medications, or insulin

Glycemic Index

A relative ranking of carbohydrate in foods according to how they affect blood glucose levels

Carbohydrates with a low value (55 or less) are more slowly digested, absorbed, and metabolized

Type 2 diabetes mellitus - Two pathological Defects are present

Insulin resistance: Decreased ability of insulin to act on tissues

Loss of beta cell function: There is an inability of the pancreas to produce sufficient insulin to compensate for the insulin resistance

Type 2 diabetes mellitus etiology

Environment

• Lack of diet and exercise; 60-80% of T2DM patients are obese; distribution of fat and duration of obesity play a role

Diabetogenes

• Genes that contributes to the development of diabetes

• >30 genetic loci have been identified that contribute to the T2DM

• Genetics account for only 5% of patients with T2DM

• Multiple genetic factors interact with environmental influences to produce the phenotype

Diabetes mellitus Treatment

Type 1

• Control carbohydrate intake

• Insulin with or without and immunosuppressive drug

Type 2

• Control carbohydrate intake

• May require insulin or oral hypoglycemic agent

• Weight reduction

Hyperglycemia and Underlying Disorders

Formerly called secondary diabetes, hyperglycemia may be due to specific underlying disorders

• Genetic defects of beta cell function

• Genetic defects of insulin action

• Disease of exocrine pancreas

• Endocrinopathies such as Cushing disease (excess cortisol), acromegaly (excess growth hormone), glucagonoma (excess glucagon)

• Hormones or drugs known to induce beta cell dysfunction or to impair insulin action

• Infections

• Uncommon immune mediated diabetes

• Other genetic syndromes: Down syndrome, Klinefelter syndrome, porphyria

Gestational diabetes mellitus Overview

Occurs in 6-8% of all pregnancies in the US

Carbohydrate intolerance of variable severity with onset or first recognition during pregnancy

Carbohydrate intolerance often reverts to normal after delivery

Potential Risks for mother

Usually asymptomatic and not life-threatening to mother

• High rate of C-sections

• Hypertension

• Women with GDM are more likely to develop DM later in life

Potential risks for baby

Associated with increased morbidity and mortality in neonate that can be reduced if recognized early

• Macrosomia: maternal hyperglycemia causes the fetus to secrete more insulin, resulting in fetal growth and hypoglycemia

Gestational Diabetes Mellitus

Normal pregnancy is associated with increased insulin resistance, especially in the late second and third trimesters

Euglycemia is maintained by increased insulin secretion; Gestational diabetes mellitus develops in women who fail to increase insulin sufficiently

Risk factors

• family history of diabetes in first degree realtive

• Obesity

• Advanced maternal age

• Glycosuria

• Selected adverse outcomes in a previous pregnancy (miscarriages, stillbirths, macrosomia)

Treatment for GDM

Treatment strategies include daily blood sugar monitoring, a healthy diet, exercise, and monitoring the baby

If blood sugar is too high, medication is needed. Anti-diabetic medications control the amount of sugar (glucose) in the blood. Common drugs include metformin

Impaired fasting glucose

Diagnosed in people with intermediate fasting glucose levels

Fasting glucose values are 100-125 mg/dL

Increased prevalence of cardiovascular disease

Metabolic syndrome

Also known as insulin resistance syndrome, Syndrome X, Reaven’s syndrome, obesity dyslipidemia syndrome

Metabolic syndrome is a cluster of conditions that occur together, increasing risk of heart disease, stroke and diabetes

Type 2 diabetes

Is associated with resistance to the action of insulin

Gestational diabetes mellitus refers to

Women that develop DM during pregnancy

Hypoglycemia

Low blood glucose concentration

• The most widely used cutoff is 70 mg/dL

• May occur without symptoms or evidence of underlying disease

• Symptoms of hypoglycemia are common, but actual hypoglycemic disorders are very rare

• Epinephrine produces the classic signs and symptoms of hypoglycemia

Table 9.9 Classification of Hypoglycemia

Hypoglycemia brain effects

The brain needs glucose for energy production

One third of glucose use in resting adults occurs in the central nervous system (CNS)

Impairment of cerebral function begins when glucose <50 mg/dL

Very low blood glucose (<20-30mg/dL) may cause severe damage to the CNS, leading to symptoms referred to as neuroglycopenia

Hypoglycemia in neonates and infants

Neonates have lower glucose concentrations than adults

Glucose levels decline after birth due to depletion of liver glycogen stores

Causes of hypoglycemia in neonates

• Prematurity

• Maternal diabetes

• Preeclampsia (maternal toxemia)

• Inborn error of metabolism

Hypoglycemia in adults

More than 100 specific causes

Results form a low rate of glucose production in the liver OR an increased rate of glucose use

Postprandial hypoglycemia

Postprandial: 1 hour period immediately after a meal

Symptoms occur 1 to 3 hours after ingestion of food and last for 30 to 35 minutes

Whipple’s Triad

Hypoglycemia may be the cause of otherwise unexplained symptoms

A diagnosis of hypoglycemia should not be made unless a patient meets the criteria of Whipple’s triad

1. Symptoms are known or likely to be caused by hypoglycemia

2. Low glucose is measured when symptoms occur

3. Relief of symptoms occurs when glucose is increased to normal

Hypoglycemia with diabetes mellitus

Occurs frequently in both type 1 and type 2 diabetes

Causes include

• Defective glucose counter-regulation, which involves the ability to increase glucose, counter to the effect of insulin

• - Early type 1 diabetes: the secretion of glucagon in response to hypoglycemia is impaired

• - Later in type 1 diabetes: The secretory response of epinephrine to hypoglycemia becomes deficient

  • Unawareness of hypoglycemia, due to lack of symptoms, in long-standing type 1 diabetes

Glycogen storage disease

Inherited disorders of defective glycogen storage

Glycogen is not being converted to glucose due to enzyme deficiency involved in glycogen metabolism

Liver and skeletal muscles are most affected

Hepatomegaly may be present due to increased liver glycogen stores

Hypoglycemia may be present due to inability to convert glycogen to glucose

The most widley used cutoff for hypoglycemia is a glucose value in mg/dL of less than

75

Which statement is incorrect concerning carbohydrates?

The brain functions normally with a low concentration of plasma glucose (<20 to 30 mg/dL)

Deficiency of a specific enzyme involved in glycogen metabolism will produce some type of

Glycogen storage disease

The typical cause of an inborn error of carbohydrate metabolism is

The absence of an enzyme involved in carbohydrate metabolism