411: Diabetes

Diabetes Mellitus (DM)

Definition of Diabetes Mellitus

Diabetes Mellitus is defined as a metabolic disease that results from defects in insulin secretion, insulin action, or both. It is a chronic, systemic disorder characterized by hyperglycemia (high blood sugar levels) and a disruption in the metabolism of carbohydrates, fats, and proteins. A chronic state of hyperglycemia can lead to dysfunction and impairment in tissues and organs.

Types of Diabetes Mellitus

  1. Type I Diabetes Mellitus (Insulin Dependent/Juvenile)

    • Caused by an autoimmune response that destroys islet cells in the pancreas, leading to an absolute deficiency in insulin production and secretion.

    • Typically diagnosed before the age of 14 and requires exogenous (external) insulin for survival.

    • Peak onset is around age 11.

  2. Type II Diabetes Mellitus (Non-Insulin Dependent/Adult Onset)

    • Previously known as NIDDM (non-insulin dependent diabetes mellitus).

    • Characterized by a combination of cellular insulin resistance and inadequate insulin secretion to compensate for this desensitization of receptors.

    • Although there is an autoimmune component identified, it generally does not impact pancreatic beta cells.

    • Individuals possess endogenous insulin production, but its action is ineffective at the cellular level. Exogenous insulin may not effectively reduce systemic hyperglycemia and its associated complications.

Characteristics of Type II Diabetes

  • Obesity: Approximately 80% of individuals with type II DM are obese. The remaining 20% typically have increased fat percentages based on body composition.

  • Inactivity: Type II DM is often associated with a prolonged sedentary lifestyle.

  • Other Risk Factors: Smoking, age, genetic susceptibility all contribute to the development of Type II DM.

  • Diabesity: Refers to obesity-dependent diabetes in children, which is considered an inflammatory metabolic disease.

Prediabetes

Prediabetes is characterized by the body's inability to utilize glucose effectively. When less glucose moves into cells, plasma glucose levels rise, resulting in prediabetes. Key features include:

  • Reduced insulin sensitivity or insulin resistance, where cells stop responding appropriately to insulin.

  • Blood glucose levels that exceed normal but do not meet the diagnostic threshold for diabetes, ranging from 100 mg/dl to 125 mg/dl.

Incidence and Prevalence of Diabetes Mellitus

According to the American Diabetes Association (ADA):

  • More than 14.6 million Americans have been diagnosed with diabetes (with an additional 6.2 million undiagnosed), resulting in a total of approximately 20.8 million individuals affected.

  • There are about 41 million Americans estimated to have prediabetes.

Complications of Diabetes

Severe complications due to diabetes arise from oxidative stress and systemic inflammation, leading to conditions such as:

  • Heart disease

  • Stroke

  • Kidney disease

  • Blindness

  • Loss of limbs
    Diabetes is the most common endocrine disease and is a leading cause of death from disease in the US, primarily due to its association with coronary artery disease (CAD).

Demographics and Risk Factors

  • 90% of diagnosed diabetes cases are Type II.

  • Certain ethnic groups (African, Native, Hispanic, Mexican, and Asian Americans) are 1.5 to 2.0 times more likely to develop diabetes compared to White Americans.

  • Half of all Americans with diabetes are aged 60 years or older, and 25% of individuals over 65 years have Type II DM.

  • There has been a significant increase in diabetes incidence since 1970 due to prolonged life expectancy and rising obesity rates.

  • 30% of all diabetes cases culminate in end-stage renal failure, with about 67,000 leg amputations performed annually.

  • Diabetes Insipidus is a condition marked by a lack of antidiuretic hormone (ADH) production.

Risk Factors for Type II Diabetes Mellitus

Key lifestyle-related risk factors for developing Type II DM include:

  • Watching 2 or more hours of television daily.

  • Skipping breakfast regularly.

  • Consuming a daily carbonated beverage.

  • Eating fast food more than two days per week (contributing to obesity).

  • Having a waist circumference greater than 35 inches for women and 40 inches for men.

  • Lack of adequate sleep, which is implicated in insulin resistance.

  • Chronic stress and consumption of processed meats.

Pathophysiology of Diabetes Mellitus

Insulin, which is secreted by the beta cells of the pancreas, plays a crucial role in glucose metabolism by facilitating the transport of glucose into cells for fuel or storage (as glycogen/adipose tissue) and promoting protein synthesis and free fatty acid storage. Upon an elevation of blood glucose levels post-meal, beta cells increase insulin secretion to assist in reestablishing homeostasis by lowering blood glucose levels as glucose is taken up by cells.

Role of Insulin in Various Tissues

  • Muscle: Muscle cells and most other body tissues are largely impermeable to glucose unless insulin is present. Insulin increases the permeability of cell membranes to glucose significantly.

  • Liver: The liver has moderate permeability to glucose and can facilitate glucose exit unless glucose has been phosphorylated. Insulin promotes the activity of the gluco-kinase enzyme, essential for this phosphorylation and glycogen synthesis.

  • Protein: Insulin enhances protein storage in muscle cells and stimulates amino acid uptake across the plasma membrane while inhibiting protein catabolism.

  • Lipids: Insulin stimulates triglyceride synthesis and storage while inhibiting lipolytic enzymes like hormone-sensitive lipase.

Consequences of Insulin Resistance

An increase in plasma lipid levels (approximately 500%) can lead to complications such as:

  • Atherosclerosis and cardiovascular issues

  • Impaired protein utilization

  • Damage to small blood vessels leading to microangiopathy (e.g., retina and kidney damage) and nerve damage (neuropathies).

  • Increased susceptibility to infections due to delayed healing.

Hemoglobin A1C and Blood Glucose Levels

The Hemoglobin A1C test serves as an important indicator of average blood glucose levels over the preceding 30-60 days. Cut-off values include:

  • A1C = 6 corresponds to 135 mg/dl

  • A1C = 7 corresponds to 170 mg/dl

  • A1C = 8 corresponds to 205 mg/dl

  • A1C = 9 corresponds to 240 mg/dl

  • A1C = 12 corresponds to 345 mg/dl
    The desired A1C level is less than 5.

Insulin Characteristics

Insulin is a large polypeptide composed of 51 amino acids. It facilitates glucose entry into peripheral tissues and is produced by different pancreatic cell types:

  • Alpha cells: Produce glucagon.

  • Beta cells: Produce insulin.

  • Delta cells: Produce somatostatin, which regulates gastrointestinal absorption and motility.

  • F cells: Produce pancreatic polypeptide.

Glucose Transporters (GLUT)

GLUT proteins act as glucose transporters to aid glucose entry from intracellular storage sites to the cell membrane of skeletal muscle and other peripheral tissues. GLUT-4 is specifically the glucose transporter found in muscle and fat cells, promoting facilitated diffusion for glucose transport across the plasma membrane.

Mechanism of Insulin Action

Insulin binds to its specific receptor, which has an alpha and beta component. The alpha component serves as a receptor site while the beta component is an enzyme that activates autophosphorylation via a tyrosine kinase mechanism, initiating essential biochemical cellular reactions. Insulin Receptor Substrates (IRSs) then become phosphorylated, leading to:

  • Increased glucose uptake by cells.

  • Translocation of glucose transporters to the plasma membrane.
    As plasma glucose levels rise, beta cells increase insulin synthesis and release to return blood glucose concentrations to normal.

Factors Influencing Insulin Release

Insulin release is influenced by:

  • Elevated blood glucose levels

  • Rising levels of amino acids and fatty acids

  • Acetylcholine secretion via parasympathetic pathways, which increases insulin secretion

  • Somatostatin and stimulation of sympathetic nervous pathways, which inhibit insulin secretion, allowing for increased blood glucose levels.

Consequences of Inadequate Insulin Action

Due to hyperglycemia and lack of insulin-mediated glucose uptake, conditions including microangiopathy and macroangiopathy can result:

  • Microangiopathy leads to thickening of the basement membrane of small blood vessels, causing ischemia and damage to tissues (e.g., retina, kidneys) and poor wound healing.

  • Macroangiopathy results in thickening of large vessels, increasing risks for atherosclerosis, hypertension (HTN), myocardial infarction (MI), and cerebrovascular accidents (CVA).

Insulin Treatments for Diabetes

Exogenous insulin can be administered in Type I diabetes; however, adverse effects include hypoglycemia. Immunosuppressants are increasingly utilized for Type I DM due to its autoimmune nature.

Medications for Type II Diabetes Mellitus

  1. Sulfonylureas: Stimulate the release of endogenous insulin from pancreatic beta cells.

    • Circulate to the liver, helping reduce hepatic glucose production.

    • Examples: Glypizide, Glyburide.

  2. Biguanides: Such as Metformin (Glucophage), work directly on the liver to decrease glucose production and increase peripheral tissue sensitivity to insulin.

  3. Alpha-Glucosidase Inhibitors: Slow sugar breakdown in the intestines, thereby delaying glucose absorption.

  4. Thiazolidinediones: Have a similar mechanism as biguanides, enhancing insulin sensitivity.

Non-Pharmacologic Interventions

Dietary Management

It involves managing calorie intake and the proportion of carbohydrates consumed. Effective weight loss can reduce the amount of tissue requiring insulin, thereby lowering the need for exogenous medications. Tissue transplants and gene therapy are also considered recent advancements.

Exercise Interventions

Regular exercise plays a critical role in facilitating weight loss and enhancing insulin sensitivity. Research indicates that exercise can significantly mitigate risks for cardiovascular diseases and improve overall health. Specific findings include:

  • Four Group Research Study: Included control, placebo, exercise with placebo, and exercise with metformin.

    • Results showed that exercise combined with placebo led to the greatest increase in insulin sensitivity after 12 weeks of aerobic and resistance training, occurring three days a week for 60-75 mins.

    • Recommended to use Rate of Perceived Exertion (RPE) to gauge exercise intensity, which could be more accurate than heart rate (HR) due to varying autonomic neuropathy effects.

Monitoring and Safety Precautions

  • Monitor hydration and glucose levels during exercise.

  • Careful monitoring of foot and vision health is crucial due to the risk for neuropathy.

  • Testing should utilize an ergometer to prevent neuropathic ulceration during exercise, particularly when weight-bearing activities pose risks.