Diabetes 2025

Insulin Glulisine has a rapid onset of 5-15 minutes and a short duration of action.

Insulin Glulisine should be injected immediately before meals.

During fasting:

• Fasting state: Insulin levels are low, glucagon levels are high.
• Glucose: <100 mg/dL (5.6 mM)
• Fatty Acids: 400 μM

During feeding:

• Prandial state: Insulin levels increase, glucagon levels decrease.
• Glucose: 120-140 mg/dL (6.7-7.8 mM)
• Fatty Acids: <400 μM
• Amino acids and incretins are also present in the prandial state.

Diabetes can be caused by a variety of factors including genetic predisposition, obesity, sedentary lifestyle, and autoimmune destruction of pancreatic beta cells. Manifestations include increased thirst, frequent urination, fatigue, blurred vision, and slow healing of wounds.

The main types of diabetes are:

In Insulin Aspart, Proline 28 in the B chain is switched to Aspartate.

Insulin Aspart has a rapid onset of 5-15 minutes and a short duration of action.

Insulin Aspart should be injected immediately before meals.

Insulin Glulisine is modified by switching Asn 3 and Lys 29 in the B chain to Lys and Glu, respectively.

Nephropathy in diabetes is characterized by renal vascular changes and alterations in the glomerular basement membrane, which can impair kidney function.

Diabetes can lead to ocular complications such as cataracts, retinal microaneurysms, and hemorrhage, affecting vision.

Insulin lowers blood glucose levels by facilitating cellular uptake of glucose, promoting glycogen synthesis, and inhibiting gluconeogenesis. Glucagon raises blood glucose levels by stimulating glycogenolysis and gluconeogenesis in the liver. Somatostatin regulates the secretion of both insulin and glucagon, thus playing a role in maintaining glucose homeostasis.

Insulin release from pancreatic beta cells occurs through the following mechanism:

1. Glucose uptake: Glucose enters the beta cells via GLUT2 transporters.
2. ATP production: Glucose is metabolized, increasing ATP levels.
3. Closure of K_ATP channels: Increased ATP causes closure of ATP-sensitive potassium channels, leading to depolarization of the cell membrane.
4. Calcium influx: Depolarization opens voltage-gated calcium channels, allowing calcium to enter the cell.
5. Insulin secretion: The rise in intracellular calcium triggers the exocytosis of insulin-containing granules.

The insulin receptor consists of two α and two β subunits:

• α subunits: Located outside the cell, they bind insulin and are responsible for the receptor's specificity.
• β subunits: Span the cell membrane and contain a tyrosine kinase domain that becomes activated upon insulin binding, initiating a signaling cascade that promotes glucose uptake and metabolism.

Insulin preparations can be classified based on their onset and duration:

HbA1c levels reflect average blood glucose levels over the past 2-3 months. Clinically, it is significant because:

• It helps assess long-term glycemic control.
• Higher HbA1c levels are associated with an increased risk of diabetes-related complications such as neuropathy, nephropathy, and retinopathy.
• It guides treatment decisions and adjustments in diabetes management plans.

Thiazolidinediones (TZDs) improve insulin sensitivity and reduce insulin resistance. Adverse effects include weight gain and increased risk of heart failure. Sulfonylureas stimulate insulin secretion from pancreatic beta cells, with adverse effects like hypoglycemia. Glinides also stimulate insulin secretion but have a shorter duration of action. Drug interactions can occur with other medications affecting glucose metabolism.

Metformin primarily works by decreasing hepatic glucose production and improving insulin sensitivity. Its advantages over sulfonylureas include a lower risk of hypoglycemia and weight gain, making it a preferred first-line treatment for type 2 diabetes. Contraindications include renal impairment and conditions that may lead to lactic acidosis.

α-Glucosidase inhibitors delay carbohydrate absorption in the intestines, reducing postprandial blood glucose levels. SGLT2 inhibitors work by preventing glucose reabsorption in the kidneys, leading to increased glucose excretion. The main difference is that α-glucosidase inhibitors primarily affect the gastrointestinal tract, while SGLT2 inhibitors act on the renal system.

Adipokines, which are cytokines secreted by adipose tissue, play a significant role in insulin sensitivity and inflammation. Dysregulation of adipokine secretion can lead to insulin resistance, contributing to the development of type 2 diabetes.

GLP-1 analogs enhance glucose-dependent insulin secretion, slow gastric emptying, and promote satiety, leading to weight loss. Amylin therapy complements insulin by regulating postprandial glucose levels and reducing appetite. Both therapies target different aspects of glucose metabolism and can improve glycemic control in diabetes.

Various drugs can influence blood glucose levels, including corticosteroids (which can increase glucose levels), beta-blockers (which may mask hypoglycemia symptoms), and certain antipsychotics (which can induce insulin resistance). Understanding these effects is crucial for managing diabetes effectively.

In obesity, insulin resistance is often due to increased free fatty acids, inflammatory cytokines, and altered adipokine secretion. During pregnancy, hormonal changes, including increased levels of placental lactogen and cortisol, can lead to insulin resistance to ensure adequate glucose supply for the fetus.

The classic symptoms observed are:

• Polydipsia: Excessive thirst, as indicated by frequent drinking of half a gallon of fruit juice.
• Polyuria: Frequent urination.
• Polyphagia: Increased appetite despite lack of weight gain.

The criteria for the diagnosis of diabetes include:

1. A1C ≥ 6.5%
2. Fasting plasma glucose (FPG) ≥ 126 mg/dL (7.0 mmol/L)
3. 2-h plasma glucose ≥ 200 mg/dL (11.1 mmol/L) during an OGTT
4. Random plasma glucose ≥ 200 mg/dL (11.1 mmol/L) with symptoms of diabetes

Type 1 Diabetes, also known as Insulin-Dependent Diabetes Mellitus (IDDM), accounts for 10% of the diabetic population. Key characteristics include:

• Glucose intolerance
• No functional insulin secretion due to near complete loss of pancreatic beta cells
• Dependency on exogenous insulin and a tendency toward ketoacidosis
• Early age of onset, with a mean age of 12
• Autoimmune response targeting pancreatic beta cells, potentially triggered by viruses or chemicals in genetically predisposed individuals
• Family history often negative
• Also referred to as juvenile onset diabetes mellitus (JODM).

As age increases, the beta-cell mass (BCM) gradually declines, while the fasting blood glucose (FBG) remains normal until approximately 70% of BCM is lost. After this point, FBG begins to rise above normal levels, indicating the onset of diabetes.

The graph indicates three stages:

1. Stage 1: Normal glucose-stimulated insulin release with normal FBG.
2. Stage 2: Progressive loss of glucose-stimulated insulin release as BCM declines.
3. Stage 3: Overt diabetes with abnormal oral glucose tolerance test (OGTT) results and elevated FBG levels.

C-peptide is a marker for insulin secretion, indicating the presence of endogenous insulin production. In the context of Type 1 Diabetes, it is particularly relevant when assessing insulin secretion in the presence of exogenous insulin (injected insulin), as it helps differentiate between endogenous and exogenous sources of insulin.

Examples of autoantigens include:

• Insulin
• Islet antigen 2 (IA-2)
• Phogrin (IA-2β)
• Zinc Transporter (ZnT-8)
• Glutamic acid decarboxylase (GAD65)
• Voltage-gated Ca2+ (Caᵥ1.3)
• Vesicle-associated membrane protein-2 (VAMP-2)

IA-2 has:

• 57% sensitivity: 57% of non-diabetics who have it will develop Type 1 diabetes.
• 99% selectivity: 99% of Type 1 diabetics have antibodies against IA-2.

This indicates that antibodies against one or more β-cell proteins signal an increased risk for developing Type 1 Diabetes.

The incidence of Type 2 Diabetes in the non-obese population is 10%, while in the obese population it is 80%.

For non-obese individuals, the age of onset is often under 25 (Maturity Onset Diabetes of the Young - MODY). For obese individuals, it is usually over 35 (Adult Onset Diabetes Mellitus).

In both non-obese and obese individuals, insulin secretion in response to a glucose challenge is low. However, in obese individuals, it is low relative to body mass.

Both non-obese and obese individuals with Type 2 Diabetes typically have a family history of the condition.

In non-obese individuals, Type 2 Diabetes may be associated with mutations in specific proteins. In obese individuals, it is often related to insulin resistance and decreased body cell mass (BCM).

1. Hyperglycemia:

   • Decreased glucose uptake in insulin-dependent cells.
   • Decreased glycogen synthesis.
   • Increased conversion of amino acids to glucose.

2. Glucosuria: Caused by high blood glucose levels.

3. Hyperlipidemia:

   • Increased fatty acid mobilization from fat cells.
   • Increased fatty acid oxidation leading to ketoacidosis.

4. Uninhibited glucagon: Increased glucagon levels despite high blood glucose levels.

Diabetes complications can lead to both microangiopathies (small blood vessel damage) and macroangiopathies (large blood vessel damage), affecting cardiovascular health.

Increased blood glucose levels lead to enhanced utilization of the polyol pathway via Aldose Reductase, resulting in water accumulation in neurons and reduced protection from oxidative damage, contributing to neuropathy.

Diabetes increases susceptibility to infections due to factors such as impaired immune response and changes in blood flow, which can hinder the body's ability to fight off pathogens.

The historical goals of insulin therapy include reducing acute symptoms such as polyuria, dehydration, and ketoacidosis.

The current goals of insulin therapy are to keep average blood glucose levels below 150 mg/dl, prevent or delay the onset of complications, and manage the increased risk of hypoglycemia.

There is a positive correlation between HbA1c levels and the prevalence of retinopathy. As HbA1c increases, the prevalence of retinopathy also increases, indicating that higher glycemic levels are associated with a greater risk of developing this complication.

Type 1 DM results from autoimmune destruction of pancreatic beta-cells.

Acute symptoms of Type 1 DM include polydipsia, polyuria, polyphagia, and potentially ketoacidosis.

Diabetic ketoacidosis results from uncontrolled oxidation of fatty acids and accumulation of by-products known as ketone bodies.

Long-term complications include damage to:

1. Blood vessels (angiopathies)
2. Kidneys (nephropathies)
3. Nerves (neuropathies)
4. Eyes (retinopathies)

The presence of antibodies to beta-cell proteins is a risk factor for Type 1 DM.

Type 2 DM results from insulin resistance and/or inadequate insulin secretion.

Diagnosis of DM requires multiple elevated blood glucose or A1c readings.

Hyperglycemia causes the oxidation of D-glucose to Glyoxal and Methylglyoxal, which then react irreversibly with proteins. This process involves the formation of Schiff bases and Amadori products, ultimately leading to AGEs. AGEs are theorized to contribute to the loss of normal protein function and accelerate the aging process, accounting for many long-term complications of diabetes.

AGEs are associated with the loss of normal protein function and are theorized to accelerate the aging process. They are believed to account for many long-term complications of diabetes, impacting overall health and disease progression.

The Receptor for AGE (RAGE) interacts with Advanced Glycation End-products (AGEs), which may contribute to the pathophysiology of diabetes and its complications by promoting inflammatory responses and cellular dysfunction.

RAGE is part of the MHC complex and belongs to the immunoglobulin superfamily of cell surface proteins. It binds to peptides containing CML and CEL, which promotes inflammation, a key factor in the pathophysiology of diabetes.

CML (Nε-carboxymethyllysine) and CEL (Nε-carboxyethyllysine) are advanced glycation end products that bind to RAGE, leading to the activation of inflammatory pathways. This contributes to the chronic inflammation observed in diabetes.

The main metabolic pathways involved are:

1. Polyol Pathway:

   • Glucose is converted to sorbitol by aldose reductase, then to fructose.

2. Hexosamine Pathway:

   • Glucose is converted to glucose-6-P, then to fructose-6-P, and subsequently to glucosamine-6-P and UDP-GlcNAc.
   • This pathway is associated with protein modification.

3. AGE Pathway:

   • Glyceraldehyde-3-P is converted to methylglyoxal, leading to the formation of advanced glycation end-products (AGEs).

The alpha subunits serve as the regulatory unit of the receptor, which represses the catalytic activity of the beta subunit. This repression is relieved by insulin binding.

The beta subunits contain the tyrosine kinase catalytic domains and are responsible for autophosphorylation upon activation.

Upon insulin binding, the insulin receptors come together to form an activated receptor, transitioning from a basal state to a high-affinity state.

Insulin receptor signaling leads to the following effects on glucose transporters:

1. Increased Glucose Uptake: Insulin promotes the translocation of glucose transporters (GLUT4) to the cell membrane, enhancing glucose uptake in muscle and fat cells.

2. Regulation of Glycolysis: Insulin signaling stimulates glycolysis, facilitating the conversion of glucose to pyruvate for energy production.

3. Glycogen Synthesis: Insulin promotes glycogen synthesis in liver and muscle cells by activating glycogen synthase.

4. Inhibition of Gluconeogenesis: Insulin signaling inhibits gluconeogenesis in the liver, reducing glucose production from non-carbohydrate sources.

Inhibits:

• Glycogenolysis
• Ketogenesis
• Gluconeogenesis

Stimulates:

• Glycogen Synthesis
• Triglyceride Synthesis

Stimulates:

• Glucose transport
• Amino acid transport

Stimulates:

• Triglyceride storage
• Glucose transport

During fasting, 75% of glucose disposal is non-insulin-dependent, primarily involving the liver, gastrointestinal tract, and brain.

Glucagon is secreted during fasting to prevent hypoglycemia.

In the fed state, 80-85% of glucose disposal is insulin-dependent in skeletal muscle.

Insulin inhibits the release of free fatty acids (FFA) from adipose tissue.

Decreased serum FFA enhances insulin action on skeletal muscle and reduces hepatic glucose production.

GLUT 1 is a constitutive glucose transporter that is widely expressed throughout the body. It has a Km of 1-6 mM and is particularly important in β-cells of the pancreas.

GLUT 2 is also a constitutive glucose transporter but is specifically found in β-cells and the liver. It has a higher Km value of 15-20 mM, indicating a lower affinity for glucose compared to GLUT 1.

GLUT 3 is a constitutive glucose transporter primarily found in neurons. It has a very low Km of <1 mM, allowing it to effectively transport glucose even at low concentrations.

GLUT 4 is an insulin-induced glucose transporter that is primarily located in skeletal muscle and adipocytes. It has a Km of 5 mM, and its expression is increased in response to insulin, facilitating glucose uptake in these tissues.

The Islets of Langerhans contain three main cell types:

1. A-cells: Produce Glucagon
2. B-cells: Produce Insulin and Amylin
3. D-cells: Produce Somatostatin

• Stimulates glycogen breakdown
• Increases blood glucose levels

Somatostatin acts as a general inhibitor of secretion, regulating the release of various hormones.

Insulin stimulates the uptake and utilization of glucose by cells, facilitating energy production and lowering blood glucose levels.

Amylin is co-secreted with insulin and has the following effects:

• Slows gastric emptying
• Decreases food intake
• Inhibits glucagon secretion

Insulin is initially synthesized as a single peptide known as proinsulin.

In the secretory granules, proinsulin is cleaved into A and B chains and the C (Connecting) peptide by proconvertases.

C-peptide and insulin are released in a 1:1 ratio from the granule.

Insulin granules are specialized storage vesicles in pancreatic beta cells that contain insulin. They play a crucial role in glucose metabolism by releasing insulin in response to elevated blood glucose levels. The proper functioning and release of insulin from these granules are essential for maintaining normal blood sugar levels, and dysfunction can lead to diabetes.

Recombinant human insulin is produced using human insulin cDNA in plasmids expressed in:

1. E. Coli: Produces Humulin (Lilly)
2. Transformed Yeast: Produces Novolin (Novo Nordisk)

Additionally, Humulin R is available in a concentration of 500 Units/ml.

• Onset: 0.25 hours
• Peak: 0.5-1.5 hours
• Duration: 6-8 hours

• Glargine (Lantus): Duration >24 hours
• Regular (R): Duration 8-12 hours

Comparison: Glargine has a significantly longer duration of action than Regular insulin.

NPH (N) insulin has a cloudy appearance.

• Aspart (Novolog): Peak 1-3 hours
• Glulisine (Apidra): Peak 0.5-1.5 hours

Ultra Rapid Onset/Very Short Action insulins like Lispro (Humalog), Aspart (Novolog), and Glulisine (Apidra) all have an onset of 0.25 hours, making them the fastest.

Modified insulins are designed to alter the availability and absorption from subcutaneous injection sites, providing flexibility and convenience in dosing. They can delay absorption to prolong onset and duration or increase absorption to decrease time to onset and duration.

The graph illustrates two phases of insulin release:

1. 1st Phase: An initial peak of insulin levels followed by a slight decline.
2. 2nd Phase: A second, lower peak of insulin levels after the initial phase.

Semilente insulin consists of small amorphous particles that are non-crystalline and is characterized by slow absorption and long-acting effects.

Larger insulin complexes result in more prolonged absorption from the Sub Q injection site, leading to a longer duration of action.

Ultralente insulin is characterized by only large crystalline complexes, which results in very slow absorption and a very long duration of action.

Insulin Hexamar Nucleated by Zinc is described as a trimer of dimers, indicating that it consists of three dimers that come together to form a hexameric structure. The presence of zinc ions plays a crucial role in stabilizing this complex structure.

NPH insulin, also known as Neutral Protamine Hagedorn or isophane, is injected subcutaneously.

NPH insulin has slow absorption and a long duration of action.

Lispro insulin is created by reversing the positions of P28 and K29 on the insulin B chain, which results in decreased self-association.

Lispro insulin has an onset of 5-15 minutes, while regular insulin has an onset of 30-60 minutes.

Lispro insulin is injected immediately before meals as part of insulin therapy.

The two polypeptide chains of human insulin are the B-Chain and the A-Chain.

B-Chain Sequence: F, V, N, Q, H, L, C, G, S, H, L, V, E, A, L, Y, L, V, C, G, G, R, E, HOOC, T, K, P, T, Y, F, F, G.

A-Chain Sequence: G, I, V, E, Q, C, C, T, S, I, C, S, L, Y, Q, L, E, N, Y, C, N.

The disulfide bonds in human insulin are crucial for maintaining the three-dimensional structure of the protein, which is essential for its biological activity. These bonds link the two chains (B-Chain and A-Chain) and also form within the A-Chain, stabilizing the overall structure of insulin.

The zinc ion (Zn2+) is important in the structure of human insulin as it helps to stabilize the insulin hexamer formation, which is essential for the storage and secretion of insulin in the pancreas. This stabilization is crucial for the proper functioning of insulin in regulating blood glucose levels.

Insulin Glargine has the following key modifications:

1. Asn 21 of the A-chain is changed to Gly.
2. Two Arg residues are added to the end of the B-chain (positions 30 & 31).

Insulin Glargine is a clear solution at a pH of approximately 4.0. Upon neutralization (post-injection), it precipitates, which contributes to its slow and steady release from the injection site.

Insulin Glargine shows a large peak in glucose utilization rate around 6 hours after subcutaneous injection, while NPH insulin shows a much smaller peak. This indicates that Insulin Glargine provides a more sustained effect without pronounced peaks.

Insulin Glargine is administered as a once daily injection and is characterized by a slow and steady release from the injection site over a period of 24 hours without a pronounced peak.

Insulin Detemir has a deletion of Thr 30 in the B-chain and Lys 29 is myristylated, which allows it to bind extensively to serum albumin.

Insulin Detemir is administered as a clear solution, injected once or twice daily.

The myristylation of Lys 29 enhances the binding of Insulin Detemir to serum albumin, which affects its pharmacokinetics and duration of action.

The Thr 30 of the B-chain is replaced by γ-Glu/C16 fatty acid, which allows it to bind extensively to serum albumin.

Insulin Degludec is injected once daily.

Insulin Degludec is a clear solution when prepared for injection.

The peak times for different insulin preparations are as follows:

1. Insulin Lispro, Aspart, Glulisine: Peaks around 1 hour.
2. Regular Insulin: Peaks around 3 hours.
3. NPH Insulin: Peaks around 6 hours.
4. Insulin Detemir and Insulin Glargine: Have a flatter profile and last longer without a distinct peak.

Insulin Icodec is the first acylated insulin analogue designed for once-weekly administration. Its significance lies in its ultra-long acting properties, allowing for less frequent dosing compared to traditional insulins, which can improve patient adherence and convenience.

Insulin Icodec exhibits the following pharmacokinetic properties:

1. Rat half-life (t½): ~26 hours
2. Dog half-life (t½): ~60 hours
3. Human half-life (t½): ~196 hours

These properties indicate its potential for ultra-long acting effects in humans.

The low affinity of Insulin Icodec for the insulin receptor results in decreased clearance of insulin due to reduced receptor internalization. This contributes to its ultra-long acting profile, allowing for once-weekly administration.

The molecular engineering of Insulin Icodec includes modifications such as:

• yGlu
• C20 diacid
• 2xOEG

These modifications are designed to enhance its suitability for once-weekly administration.

Insulin analogs exhibit three distinct peaks in insulin effect during the morning, afternoon, and evening, while glargine maintains a steady level of insulin effect throughout the day and night.

Regular insulin shows three distinct peaks during the morning, afternoon, and evening, whereas NPH has a lower, broader peak that spans from the morning into the evening.

Bolus insulin has three distinct peaks during the morning, afternoon, and evening, while basal infusion maintains a steady, lower level of insulin effect throughout the day and night.

The glucose infusion rates for different insulin mixtures show that:

• Humalog has a higher initial peak and a faster decline.
• Humalog Mix50/50 and Humalog Mix75/25 have lower peaks and slower declines compared to Humalog.
• The NPL component exhibits the slowest decline in glucose infusion rate.

These mixtures provide a transient preprandial bolus and a prolonged basal level in a single injection.

Afrezza is an inhaled insulin approved by the FDA in June 2014. It is a regular human insulin in a dry powder form that is administered using an inhaler device.

Afrezza has a rapid onset and a shorter duration of action compared to subcutaneous (SC) injection, making it suitable for use as pre-prandial insulin.

Afrezza is contraindicated in patients with asthma and COPD because it may reduce lung function, leading to decreased FEV (forced expiratory volume).

FDKP is a complex ring structure that includes carbon, hydrogen, nitrogen, and oxygen atoms, featuring double bonds and various functional groups.

Inhaled insulin shows a sharp peak in concentration followed by a rapid decline, while subcutaneous insulin peaks later and declines more gradually, indicating different pharmacokinetic profiles.

Technosphere® Particle, composed of FDKP and polysorbate 80, is designed to enhance the delivery and absorption of inhaled insulin, as observed through electron microscopy.