Diabetes Mellitus - Types 1 & 2

Diabetes Mellitus - Types 1 & 2 Diabetes mellitus refers to a collection of metabolic disorders in which a lack of insulin secretion and/or insulin action leads to hyperglycemia. Chronic hyperglycemia produces dysfunction and damage of multiple organs, including the heart, kidneys, eyes, and peripheral nervous system. SUBTYPES:

• Type 1
• Type 2
• Monogenic diabetes, which includes MODY ("maturity-onset diabetes of the young").
• Secondary diabetes, which includes diabetes caused by infections, drugs, and other disorders that produce hyperglycemia
• Gestational diabetes.

Review Diabetes Medications We can use a few different measurements for diagnosing diabetes mellitus:

• Random plasma glucose level of 200+ mg/dL or a fasting plasma glucose level of 126+ mg/dL.

The A1C test measures average blood glucose over the past two to three months. Diabetes is diagnosed at an A1C of greater than or equal to 6.5% Normal: less than 5.7% Prediabetes: 5.7% to 6.4% Diabetes: 6.5% or higher The FPG test checks fasting blood glucose levels. Diabetes is diagnosed at fasting blood glucose of greater than or equal to 126 mg/dl Normal: less than 100 mg/dL Prediabetes: 100 mg/dl to 125 mg/dL Diabetes: 126 mg/dL or higher The OGTT is a two-hour test that checks blood glucose levels before and two hours after drinking a sugary solution. Diabetes is diagnosed at two-hour blood glucose of greater than or equal to 200 mg/dl Normal: less than 140 mg/dL Prediabetes: 140 to 199 mg/dL Diabetes: 200 mg/dL or higher This test is a blood check at any time of the day. Diabetes: greater than or equal to 200 mg/dl PREDIABETES: Prediabetes is a condition where glucose levels are elevated, but not high enough to be classified as diabetes.

• Pre-diabetic patients are at high risk for Type 2 diabetes and the ensuing cardiovascular complications, and are thus advised to take steps to prevent these developments, such as increasing physical activity and losing weight.
• The CDC reports that 1 in 3 Americans is pre-diabetic.

Review Glucose Regulation via Insulin & Glucagon Type 1 diabetes accounts for 5-10% of all diabetes mellitus cases. Type 1 diabetes is caused by autoimmune destruction of pancreatic beta cells; insulitis is often visible in pancreatic tissue samples. T-cells with failed self-tolerance for islet antigens mediate this destruction. During this process, islet autoantibodies are produced and circulate in the blood. These autoantibodies serve as helpful markers of Type 1 diabetes, and include autoantibodies that target insulin, GAD65 (the 65-kD isoform of Glutamic acid decarboxylase), ZnT8 (zinc transporter 8), and IA2 (islet antigen 2). Note that these autoantibodies are not believed the source of beta cell damage, but just markers of it. Histopathology: inflammatory infiltrate in pancreatic islets ETIOLOGY Etiology of Type 1 diabetes includes both genetic and environmental factors. One of the best-studied genetic associations is with variations in HLA alleles. Recall that HLA molecules are cell-surface proteins that present peptide antigens to T-cells; variations in the genes coding for class II DR and DQ cell-surface proteins have the strongest risk association with Type 1 diabetes. It is thought that environmental triggers intersect with genetic factors, though the specific environmental triggers are uncertain. Viral infections are thought to play a role in the development of Type 1 diabetes, particularly enterovirus infections, but study results have been conflicting and causative links are uncertain. Likewise, diet during infancy and childhood are thought to play a role, and it's been proposed that breastfeeding has independent protective effects against Type 1 diabetes; however, recent studies seem to disprove this long-held notion. Onset of Type 1 diabetes is often during childhood, but not exclusively; it is likely that some adults who have been diagnosed with Type 2 diabetes based upon their age have been mis-classified, which can have deleterious effects on their treatment. Thus, to avoid perpetuating misdiagnosis, we no longer refer to this disorder as "juvenile diabetes." Because Type 1 diabetes is due to autoimmune destruction of insulin-secreting cells, we see a progressive reduction in insulin levels over time as more cells are destroyed. However, be aware that hyperglycemia may be transient in some cases, with variable insulin needs, particularly in adults diagnosed with Type 1 diabetes. TREATMENT Type 1 patients, who have absolute insulin deficiency, require exogenous insulin administration. Be aware that there is another form of Type 1 diabetes, called idiopathic Type 1 diabetes, in which the autoimmune response is not involved. This type is very rare. Type 2 diabetes is characterized by peripheral tissue insulin resistance and relative insulin deficiency due to mild beta cell destruction caused by amyloid deposits. These amyloid deposits, which are visible in histological samples, were originally called "hyaline." Amyloid polypeptides are co-secreted with insulin in the pancreas and can build up to form the characteristic deposits associated with Type 2 diabetes. Histopathology: amyloid deposits Etiology of Type 2 diabetes is complex, and is associated with obesity and central fat distribution, sedentarism (an inactive lifestyle), stress, and inflammation. The insulin resistance of peripheral tissues is due to the loss of Glut-4 receptors.

• Fortunately, exercise is known to increase the number of these receptors in skeletal muscle, which is why exercise is commonly recommended for patients with insulin resistance.

Type 2 diabetes also has strong genetic associations, which are polygenic with complex inheritance patterns. T2D is a historically adult-onset disease, but it is increasingly common in children due to higher rates of childhood obesity and inactivity. Thus, we no longer refer to it as adult-onset diabetes. Patients may initially have elevated insulin levels in response to insulin resistance in the peripheral tissues, but, because the pancreatic cells can't keep up and/or are undergoing destruction by amyloid deposits, insulin levels will fall. Because of the relatively slower onset of the disease, many patients are asymptomatic with diagnosis only occurring after a routine blood test. This is why we test patients who meet the risk factors outlined above for prediabetes and diabetes. TREATMENT Treatment of Type 2 diabetes is complex and needs to be tailored to the individual and achievable glycemic targets. The first step may be recommending diet and exercise, and perhaps administration of Metformin, which decreases hepatic glucose production. If hyperglycemia persists, patients may be prescribed insulin, GLP-1 receptor agonists (recall the incretins from the beginning of this tutorial), or SGLT2-inhibitors (sodium-glucose cotransporter-2), which allow the kidneys to get rid of excess glucose via the urine. The goal of Type 2 diabetes treatment is to reach glycemic targets to avoid the organ damage caused by hyperglycemia. However, these drugs can be costly and/or have contraindications that must be considered for each patient. The "3 P's:" polyuria, polydipsia, and polyphagia: Glycosuria: Hyperglycemia surpasses the renal glucose reabsorption threshold, which results in glycosuria – glucose in the urine. Polyuria:

• Glycosuria induces osmotic diuresis, which results in polyuria – frequent urination.

Polydypsia:

• Polyuria leads to depleted water and electrolyte stores, which causes polydipsia – increased liquid intake.

Polyphagia: Because insulin deficiency produces a chronic catabolic state*, patients are often hungry, leading to polyphagia – increased food intake. Recall that, despite the increased food intake, Type 1 diabetes patients typically have muscle weakness and weight loss due to the inability to store and use glucose as a building block for muscle or fat. Patients with under-treated Type 1 diabetes can experience diabetic ketoacidosis, which is characterized by nausea and vomiting, fatigue, a "fruity" odor, and Kussmal breathing (a deep, rapid breathing pattern).

• These features reflect the acidic state of the body, which can ultimately lead to coma.
• Fluids, electrolytes, and insulin are given to normalize the blood glucose.

Patients with Type 2 diabetes are more prone to Hyperosmolar Hyperglycemic Syndrome (HHS), which occurs when a patient with polyuria is also deficient in water intake – thus leading to severe dehydration which can be fatal.

• Insufficient water intake can occur in patients who are unable to drink on their own, such as after a stroke or other debilitating conditions that limit hydration.
• Be aware that HHS has a mortality rate of up to 20% - much higher than the mortality rate for diabetic ketoacidosis. - Patients require saline, insulin, and electrolytes.

Patients with either type of diabetes are at higher risk for vascular disease due to chronic hyperglycemia.

• Micro- and macro-vascular dysfunction can lead to heart failure and atherosclerosis (which can produce myocardial infarction or stroke), kidney damage, visual impairment, and peripheral nerve dysfunction.

• Children are at risk for impaired growth.
• Patients are more susceptible to infection due to immune suppression.
• Patients with diabetes are, ironically, susceptible to hypoglycemia due to missing a meal, excessive physical exertion, or excessive insulin administration. Watch for dizziness, sweating, palpitations, and tachycardia, and treat with glucose to correct the blood sugar levels.

For references, please see full tutorial.