Pancreas physiology and diabetes mellitus

In the fasting state, glucose levels are typically below 100 mg/dL and fatty acids are around 400 µM. After a meal (fed state), glucose rises to 120-140 mg/dL and fatty acids decrease to less than 400 µM.

Pancreatic islet cells, also known as the islets of Langerhans, constitute about 1-2% of the total pancreatic tissue. They are responsible for producing and releasing important hormones that regulate blood sugar levels.

Alpha cells are a type of pancreatic islet cell that make up 15-20% of the total islet cell population. They are responsible for secreting glucagon in response to low blood sugar (hypoglycemia).

Beta cells are the most abundant type of pancreatic islet cell, accounting for 60-85% of the total. Their primary function is to secrete insulin, a hormone that lowers blood sugar.

Delta cells are a smaller population of islet cells, comprising 3-10% of the total. They secrete somatostatin, a hormone that inhibits the release of both insulin and glucagon, helping to regulate blood sugar levels.

C-peptide is a fragment of the proinsulin molecule that is released along with insulin. Measuring C-peptide levels can differentiate between the source of insulin: whether it is being produced endogenously by the body or is exogenous (from an external source).

The insulin receptor is a complex molecule that belongs to the receptor tyrosine kinase (RTK) family. It is composed of two alpha subunits and two beta subunits. The alpha subunits are located on the extracellular side of the cell membrane and bind insulin.

Red blood cells (erythrocytes) have a limited number of insulin receptors (~40 per cell), while fat cells (adipocytes) and liver cells (hepatocytes) have significantly more (~300,000 per cell) This difference reflects the varying roles of these cells in response to insulin.

Normally, the alpha subunits of the insulin receptor inhibit the tyrosine phosphorylation activity of the beta subunits. When insulin binds, this inhibition is removed, and the beta subunits become active, leading to a cascade of intracellular signaling events.

Insulin receptor activation triggers various cellular processes, including cell growth, protein synthesis, glycogen synthesis, and the translocation of GLUT4-enriched vesicles to the cell membrane. GLUT4 is a glucose transporter protein that allows glucose to enter cells.

In low glucose conditions, the SERCA (sarco/endoplasmic reticulum Ca2+ ATPase) pumps in pancreatic alpha cells are less active. This leads to an increase in intracellular calcium levels through activation of SOCs (store-operated calcium channels). The rise in intracellular calcium depolarizes the cell and triggers the release of glucagon.

GLP-1 (glucagon-like peptide-1) and GIP (gastric inhibitory peptide) are two important gastrointestinal hormones. They are released after meals and stimulate the release of insulin from pancreatic beta cells. GLP-1 has additional benefits, like reducing glucagon secretion.

In type 1 diabetes (T1DM), there is destruction of pancreatic beta cells, leading to a lack of insulin production. This results in high blood sugar levels, increased HbA1c, and other symptoms like polyphagia (increased hunger), polydipsia (increased thirst), and polyuria (increased urination).

Type 2 diabetes (T2DM) often involves insulin resistance. While insulin may be present, the body's cells become less responsive to its effects, leading to high blood sugar. This can be due to various factors, such as genetic predisposition, lifestyle factors, and excess weight.

Maturity-onset diabetes of the young (MODY) is a rarer form of diabetes caused by genetic mutations affecting specific genes involved in insulin secretion or function. There are different types of MODY based on the specific gene mutation.

Hyperlipidemia (high levels of lipids in the blood) can occur in diabetes due to the unopposed action of hormone-sensitive lipase (HSL) in adipose tissue. This enzyme breaks down stored fat, leading to increased levels of free fatty acids in the blood.

A diagnosis of diabetes is made based on certain criteria, including: (1) symptoms of diabetes plus a casual plasma glucose concentration ≥ 200 mg/dL (11.1 mM), (2) fasting blood glucose ≥ 126 mg/dL (7.0 mM), (3) 2-hour post-load glucose ≥ 200 mg/dL during an oral glucose tolerance test (OGTT), or (4) HbA1c ≥ 6.5%.

Patients with type 1 diabetes typically have antibodies against pancreatic beta cells and against glutamic acid decarboxylase (GAD). These antibodies play a role in the autoimmune destruction of beta cells.

The major susceptibility gene for type 1 diabetes is located in the human leukocyte antigen (HLA) complex on chromosome 6. Polymorphisms within this complex account for 40-50% of the genetic risk of developing type 1 diabetes.

The HLA complex contains genes that encode class II major histocompatibility complex (MHC) molecules. These molecules are crucial for presenting antigens to helper T cells, a process that initiates an immune response. Therefore, variations in HLA genes can influence the likelihood of developing autoimmune disorders like type 1 diabetes.

Type 2 diabetes has a strong genetic component, with over 80 genetic loci identified as being associated with increased risk. This means that multiple genes collectively contribute to the development of type 2 diabetes.

Insulin resistance, a hallmark of type 2 diabetes, affects the liver, skeletal muscle, and adipose tissue. These tissues become less sensitive to insulin's actions, leading to difficulty in maintaining normal blood glucose levels.

Thiazolidinediones are a class of medications that act on PPAR-gamma (peroxisome proliferator-activated receptor-gamma), a nuclear receptor involved in lipid metabolism and glucose uptake. By activating PPAR-gamma, these drugs improve insulin sensitivity and reduce blood sugar.

DPP-4 (dipeptidyl peptidase-4) inhibitors are a class of medications that slow down the inactivation of incretin hormones, such as GLP-1 and GIP. Incretins enhance insulin secretion and suppress glucagon, leading to lower blood sugar levels.

SGLT-2 (sodium-glucose cotransporter-2) inhibitors are a newer class of diabetes medications that target the kidneys. These drugs block SGLT-2, a protein responsible for reabsorbing glucose in the kidneys. This action leads to increased urinary glucose excretion and reduces blood glucose levels.

Thiazolidinediones have been linked to an increased risk of cardiovascular events and heart failure. This potential side effect needs to be carefully considered when prescribing these medications.

SGLT-2 inhibitors have been associated with an increased risk of urinary tract infections (UTIs) and diabetic ketoacidosis (DKA). While UTIs are more common, DKA is a serious condition that needs immediate medical attention.

Metformin is a biguanide medication that improves insulin sensitivity, reduces hepatic glucose production, and increases insulin secretion. It is a first-line medication for type 2 diabetes and has been shown to have a favorable safety profile.

Sulfonylureas are a class of oral hypoglycemic agents that stimulate insulin release from the pancreas. They work by increasing the release of insulin from beta cells, lowering blood sugar levels.

Common side effects associated with metformin include gastrointestinal upset, such as nausea, vomiting, and diarrhea. These side effects are usually mild and tend to improve over time.

Common side effects of sulfonylureas include hypoglycemia (low blood sugar), weight gain, and hypoglycemic unawareness. Hypoglycemic unawareness can be dangerous because individuals may not experience the typical symptoms of low blood sugar, such as dizziness or sweating.

Oral hypoglycemic agents are medications taken by mouth to manage blood sugar levels in individuals with type 2 diabetes. These drugs work by different mechanisms, such as stimulating insulin release, improving insulin sensitivity, or reducing glucose absorption in the intestines.

Parenteral hypoglycemics are insulin medications that are administered by injection. These medications mimic the action of naturally produced insulin, helping to regulate blood sugar levels.

Amylin analogs are injectable medications that help improve blood sugar control in individuals with type 2 diabetes. They work by mimicking the action of amylin, a hormone that regulates blood sugar after meals.

Some forms of neonatal diabetes are caused by mutations in the inward rectifying K+ (Kir6.2) channel on beta cells, which is involved in insulin secretion. Mutations in the insulin gene can also lead to neonatal diabetes.

Most patients with MODY (maturity-onset diabetes of the young) can effectively manage their blood sugar with sulfonylureas, a class of medications that stimulate insulin release from pancreatic beta cells.

Chronic diseases of the pancreas, such as pancreatitis and cystic fibrosis, can disrupt the normal function of pancreatic beta cells, leading to diabetes. Certain endocrine disorders, like acromegaly and Cushing's disease, can also contribute to the development of diabetes by affecting hormone levels.

Gestational diabetes (GDM) affects between 2-10% of all pregnancies. It is a form of diabetes that develops during pregnancy and usually resolves after delivery. However, women who have had GDM have an increased risk of developing type 2 diabetes later in life.