Diabetes Mellitus: Types, Complications, and Treatment
Diabetes Mellitus
Role of Glucose
Glucose is the primary source of cellular energy. Most cells can utilize free fatty acids as an alternative energy source, but the brain, retina, and a few other tissues rely solely on glucose. Homeostatic mechanisms maintain glucose levels to prevent hypoglycemia. Excess blood glucose can lead to dehydration.
Insulin and glucagon play crucial roles in glucose metabolism and regulation. Low blood sugar stimulates glucagon secretion, while high glucose levels stimulate insulin release. The liver stores glucose by converting it into glycogen. When glycogen stores are depleted, the liver can synthesize glucose from amino acids and triglycerides. Insulin and glucagon promote glucose uptake by cells, restoring blood glucose to normal levels.
Types and Mechanisms of Diabetes
Type 1 Diabetes (5-10%)
This autoimmune disorder, typically diagnosed in childhood or adolescence, results in little or no insulin production. The immune system attacks the pancreatic β-cells, impairing insulin production.
Type 2 Diabetes (90-95%)
Characterized by varying degrees of insulin resistance, insulin deficiency, and excess glucagon production. Pathophysiological factors include:
- Insulin Resistance: Decreased ability of insulin to act effectively in peripheral tissues (muscle, fatty liver).
- Pancreatic Islet Dysfunction: Impaired β-cell and α-cell function, leading to inadequate glucose response and insulin secretion.
- Excessive Hepatic Glucose Production: Increased glucose production by the liver.
Diagnosis
- Fasting plasma glucose analysis
- Oral glucose tolerance test
- HbA1c analysis: Evaluates average glucose levels over the preceding 2-3 months. The ADA recommends a target of <7%. HbA1c levels are currently the only endpoint.
Complications of Diabetes
Diabetic Ketoacidosis
In the absence of adequate insulin, cells cannot absorb glucose and utilize fat as an alternative energy source. This leads to the accumulation of acidic substances called ketones, causing a relative acidity of the blood.
Hyperosmolar Hyperglycemic State (HHS)
Insulin deficiency and excessive hepatic glucose production lead to osmotic diuresis, resulting in decreased blood volume and severe dehydration.
Vascular Complications
- Microvascular: Affects small blood vessels, including those in the eyes and kidneys.
- Macrovascular: Affects larger blood vessels, increasing the risk of cardiovascular disease.
Diabetic Retinopathy
Progressive microvascular damage to the eyes caused by diabetes, leading to vision loss.
Diabetic Nephropathy
Microvascular complication affecting the blood vessels in the nephrons of the kidney.
Diabetic Neuropathy
Microvascular damage to the nervous system. The most common form is peripheral neuropathy, characterized by loss of sensation (dysesthesia), pain, and weakness in the hands, arms, feet, and legs.
Cardiovascular Disease
Patients with type 2 diabetes have a 2-4 times higher risk of death from cardiovascular diseases, such as coronary artery disease, peripheral arterial disease, and cerebrovascular disease.
Antidiabetic Agents
Sulfonylureas
Stimulate insulin secretion (potential cause of hypoglycemia).
Biguanides (Metformin)
Primarily treat hepatic insulin resistance by reducing liver glucose production through gluconeogenesis. Secondarily improve glucose utilization by muscle tissue. Cannot be used in patients with renal insufficiency, liver disease, or congestive heart failure due to the potential for lactic acidosis. Gastrointestinal adverse reactions are common.
Alpha-glucosidase Inhibitors
Decrease the rate of carbohydrate breakdown in the small intestine. Gastrointestinal adverse reactions, including flatulence, may occur.
Glitazones
Improve muscle tissue sensitivity to insulin, increasing insulin uptake and suppressing hepatic glucose production. Associated with fluid retention, requiring caution in patients with congestive heart failure. Can cause weight gain and hepatic reactions.
Meglitinides
Stimulate insulin secretion in response to food intake. Potential for hypoglycemia and no significant drug interactions.
Injectable Incretin Mimetics
Mimic the effects of the incretin GLP-1, increasing glucose-dependent insulin release and suppressing glucagon.
DPP-4 Inhibitors
Inhibit dipeptidyl peptidase-4, which inactivates the incretins GLP-1 and GIP. These incretins are responsible for increasing insulin secretion and suppressing glucagon release after a meal. DPP-4 inhibitors improve β-cell function and glucose sensitivity of α and β cells in the pancreatic islet. They have a neutral effect on weight and a very low incidence of hypoglycemia.
Incretin Effect
Oral glucose administration leads to a greater increase in insulin secretion compared to intravenous administration of the same amount of glucose. This suggests that intestinal glucose absorption triggers insulin release, known as the “incretin effect”. Two incretins, GLP-1 and GIP, have been identified. One of the most prominent actions of incretins is the increase in insulin release in response to food (60% of insulin secretion). GLP-1 significantly increases insulin secretion and inhibits glucose-dependent glucagon secretion. Unlike GIP, GLP-1 does not inhibit glucagon secretion in the fasting state.
GLP-1 and GIP are inactivated by DPP-4, which removes two amino acids from the N-terminus of these peptides, leading to their inactivation within 1-2 minutes.