Lesson 14

Question 1

How is glycemia controlled? what is diabets mellitus? what are its complications?

Answer 1

Glucose concentration in blood is important also because it is the only source of nutriment for our brain, so its concentration needs to be very well controlled by our body, if there is hypoglycaemia the first organ to suffer will be the brain leading to consequences like fainting. To control its concentration, our body has evolved systemsto absorb and store all the sugars and using them during the starvation period. In this regulation there are many molecules and hormones involved. Insulin promotes the uptake and storage of glucose in different tissues mainly skeletal muscle, liver, and adipose tissue; on the other hand there are counterregulatory hormones which promote the release of glucose from the storage. These hormones are glucagon, norepinephrine , epinephrine and growth hormone. The liver, adipose tissue and skeletal muscles are the primary targets of insulin.

Leptin is a signal to stop eating, it is released when the storage in the adipose tissue has enough fat so we have enough energy storage. Leptin suppresses appetite, it is also a message to start using energy instead of accumulating.

When blood glucose concentrations diminish, pancreatic alpha cells enhance the secretion of glucagon, while pancreatic beta cells diminish their secretion of insulin. Glucagon promotes the mobilization of glucose from the liver by stimulating both gluconeogenesis and glycogenolysis. Concurrently, levels of catecholamines and glucocorticoids increase, which further promotes the release of fatty acids and glycerol. When we are missing glycogen form the muscles during prolonged fasting, we also have the conversion of muscle proteins.

In low-energy states, indicated by low ATP levels, cells can sense the energy deficit and respond by releasing adenosine 5-monophosphate-activated protein kinase (AMPK). AMPK activation signals a metabolic shift from anabolic to catabolic processes. This is evident during exercise, during which the activation of AMPK increases muscle glucose uptake and simultaneously decreases hepatic glucose production and the synthesis of lipids and proteins in the liver.

Diabetes mellitus encompasses a heterogeneous group of metabolic disorders characterized by chronic hyperglycemia. These disorders can broadly be divided into two categories with distinct etiologies:

• Type 1 diabetes mellitus results from an autoimmune-mediated destruction of pancreatic beta cells, leading to an absolute deficiency of insulin. The exact cause of this autoimmune reaction is unclear, but it may sometimes be prompted by a viral infection. This condition typically manifests in children or adolescents and is characterized by symptoms such as excessive thirst, frequent urination, weight loss, blurred vision, and fatigue due to the inability to utilize glucose effectively for energy. Type 1 diabetes is strongly associated with the presence of autoantibodies to beta-cell proteins, and while there is a genetic predisposition, environmental and nutritional factors also play a role in disease development. Among identical twins, if one twin has type 1 diabetes, the likelihood of the other twin developing the condition is approximately 50%. Insulin therapy is the cornerstone of treatment for type 1 diabetes.
• Type 2 diabetes mellitus is characterized by a combination of peripheral insulin resistance (Insulin resistance is a condition in which cells in the body become less responsive to the effects of insulin) ****and an inadequate compensatory insulin secretory response. While some patients may have a relative decrease in insulin production, others may exhibit normal or even increased levels of insulin due to a compensatory mechanism. Obesity is a significant risk factor for the development of type 2 diabetes, which can also occur in younger individuals. The disease frequently shows a gradual onset, often without noticeable symptoms initially, and may be detected through routine screening tests. The pathogenesis of insulin resistance may involve the ectopic deposition of lipids in the liver and muscle and inflammation, which can be exacerbated by obesity or aging. Although increased insulin production by pancreatic beta cells initially compensates for insulin resistance, over time, this compensation may become inadequate, leading to beta cell dysfunction or increased apoptosis. Type 2 diabetes has been traditionally referred to as adult-onset diabetes; however, it is increasingly diagnosed in younger individuals, paralleling the rise in obesity rates. Insulin resistance in type 2 diabetes is associated with the accumulation of lipids in non-adipose tissues and inflammation, which can be mitigated by anti-inflammatory medications.

Diabetes is a complex, polygenic disorder, with polymorphisms in various genes contributing to susceptibility.

Both type 1 and type 2 diabetes can lead to severe long-term complications affecting both the microvascular and macrovascular systems. Complications can range from accelerated atherosclerotic cardiovascular disease to retinopathy, nephropathy, and neuropathy. In type 2 diabetes, complications can also affect the extremities, particularly the legs, leading to diabetic foot issues. Diminished sensation and numbness in the feet due to peripheral nerve damage can result in undetected injuries and poor wound healing, potentially leading to gangrene and, in severe cases, amputation.

Diabetes mellitus management involves a range of therapies tailored to the specific needs of the individual, with the primary objectives being to normalize blood glucose levels and other metabolic parameters. Achieving these goals is crucial for reducing the risk of long-term complications associated with diabetes. Lifestyle modifications are fundamental in managing both type 1 and type 2 diabetes.

A central challenge in diabetes therapy is to achieve glycemic control without inducing hypoglycemia, which can result from overtreatment and is often considered more hazardous than hyperglycemia.

The management of type 1 diabetes is primarily through the administration of exogenous insulin preparations. It is also applicable in late-stage type 2 diabetes, although in the early stages, alternative pharmacologic agents are preferred.

For type 2 diabetes, several classes of medications act on different physiological targets, such as adipose cells, hepatocytes, pancreatic beta cells, and the gastrointestinal tract.

Question 2

Speak about exogenous insuln therapy for people who suffer from type 1 diabetes, how is it administred? why is self monitoring important?

Answer 2

TYPE 1 DRUGS: EXOGENOUS INSULIN

Insulin therapy is essential for individuals with type 1 diabetes and is also used in type 2 diabetes when other treatments are inadequate. Early insulin preparations were derived from animal sources, with bovine insulin differing by three amino acids and porcine insulin by one, compared to human insulin. This difference could trigger immunogenic responses with prolonged use. Recombinant DNA technology has enabled the production of recombinant human insulin, which was among the first drugs produced using genetic engineering.

In the body, insulin production involves several steps:

1. It begins with preproinsulin, which includes a signal peptide required for endoplasmic reticulum processing, a portion retained in mature insulin, a connecting peptide, and terminal sequences.
2. The signal peptide is removed, converting preproinsulin to proinsulin.
3. Finally, the connecting peptide is cleaved, leaving the A and B chains of insulin connected by disulfide bonds. we have obtained insulin

Early strategies for producing human insulin involved separately synthesizing the A and B chains and then allowing them to form disulfide bonds.

Physiologically, insulin is released into the portal system, primarily affecting the liver. Ideally, insulin should be administered orally to mimic this process; however, due to degradation by gastrointestinal enzymes, subcutaneous injection is the preferred route. This does not replicate the high physiological concentration of insulin delivered to the liver, but it does ensure similar exposure to the liver and peripheral tissues.

Insulin delivery aims to mimic physiological levels through two types of administration:

• Basal insulin provides a consistent background level of insulin. Basal long-acting insulins provide a steady release of insulin throughout the day. NPH insulin, which is a suspension of insulin combined with protamine and zinc, which helps to prolong its action in the body. It is derived from recombinant DNA technology or extracted from animal sources, such as pigs or cows. with its protamine and zinc formulation, NPH insulin was commonly used, but new engineered long-acting insulin analogues with modified pharmacokinetics are now available.
  
  • Long-Acting Analogues: such as Insulin Detemir, also known as basal insulins, are designed to provide a steady and prolonged release of insulin over an extended period. They are formulated to have a more consistent and predictable action, providing a basal level of insulin throughout the day and night, even between meals. Their onset of action is usually within 1 to 2 hours, and they have a relatively flat and sustained effect that can last for up to 24 to 36 hours. These insulins are typically taken once or twice a day, providing a basal insulin coverage to help maintain stable blood sugar levels between meals and overnight.
• Prandial bolus insulin is administered around meals to simulate the postprandial insulin spike. Prandial bolus insulins act rapidly and for short durations, peaking around mealtime. There are two main kinds of prandial bolus insulin: Lispro, also known as insulin lispro, is a rapid-acting insulin analogue. It is designed to have a faster onset of action compared to regular insulin, meaning it starts working more quickly after injection. Lispro insulin typically starts working within 15 minutes after injection, which allows for more flexibility in mealtime dosing. It reaches its peak effect within 1 to 2 hours after injection, meaning it has a relatively short duration of action. The total duration of lispro insulin is usually around 3 to 5 hours, allowing for better coverage of postprandial (after-meal) glucose spikes. And Regular insulin, also known as short-acting insulin, is a soluble insulin with a more delayed onset and longer duration of action compared to lispro. It typically takes effect within 30 minutes to 1 hour after injection, which is slower than lispro. It reaches its peak effect within 2 to 3 hours after injection, indicating a longer duration of action compared to lispro. The total duration of regular insulin can last up to 6 to 8 hours, providing more prolonged coverage of blood glucose levels.
  
  • Fast-Acting Analogues, such as **insulin aspart, **are designed to mimic the rapid onset and short duration of action of natural insulin. These insulins are absorbed quickly after injection and are designed to be taken just before or right after meals to control the rise in blood sugar that occurs after eating. These insulins are commonly used to cover mealtime spikes in blood sugar and to manage postprandial (after-meal) glucose levels in individuals with diabetes.

The development of these analogues has improved the pharmacokinetic profiles of insulin, providing more predictable effects and reducing the risk of hypoglycemia.

Insulin, being a peptide hormone, is unable to be orally ingested as it would be degraded by digestive enzymes. Therefore, daily subcutaneous injections are the primary method of administration:

• Patients typically use a short needle that is part of an injection system resembling a pen, known as an insulin pen. This device allows for the injection of small, measured doses of insulin. Each pen contains a reservoir of insulin that can last for a week or more, depending on the patient’s dosage requirements.
• Despite the relative ease and minimal pain of injections, repeated administration can still cause discomfort. To address this, alternative delivery systems such as jet injectors are available. Jet injectors do not use needles; instead, they deliver insulin subcutaneously by exerting high pressure on the skin. This needle-free method is particularly appealing for individuals with type 1 diabetes, who often require lifelong insulin therapy and may prefer less invasive options.
• The latest advancements include insulin pumps, which are wearable devices that continuously deliver insulin through a small catheter placed under the skin. These pumps can be programmed to release insulin at predetermined intervals and are increasingly integrated with continuous glucose monitoring (CGM) systems. These systems allow for real-time blood glucose tracking and can be remotely controlled. However, they require the patient to actively manage their insulin dosing, which may not be ideal for all individuals, particularly the elderly. Younger patients with an active lifestyle may find insulin pumps advantageous.
• For those with needle phobia, an inhalable insulin known as Afrezza has been developed. This form of insulin is rapidly absorbed through the lungs into the bloodstream, typically within a minute, and begins to take effect within 12 minutes. However, Afrezza is not suitable for smokers and may induce cough or irritate the bronchi as a side effect.

Appropriate insulin therapy must be synchronized with proper carbohydrate intake to prevent hypoglycemia, which can have serious consequences if not managed correctly.

Effective diabetes management requires regular monitoring of blood glucose levels to adjust therapy as needed. This typically involves:

• Self-Monitoring of Blood Glucose (SMBG): Using glucometers, patients can track their glucose levels throughout the day. It involves using a blood glucose meter to measure blood sugar levels at a specific point in time. It requires the individual to prick their finger to obtain a small blood sample, which is then applied to a test strip inserted into the glucose meter. It is used to make immediate decisions regarding insulin dosing, dietary choices, or other diabetes management actions. It is typically performed several times a day, including before and after meals, before bedtime, or as recommended by healthcare professionals.
• Continuous Glucose Monitoring (CGM): Provides real-time glucose readings, trends, and alerts. It continuously measures and tracks blood glucose levels throughout the day and night. It involves wearing a small sensor that is inserted under the skin, usually on the abdomen or arm, which measures glucose levels in the interstitial fluid. The sensor is connected to a transmitter that wirelessly sends the glucose readings to a receiver or a smartphone app, providing real-time glucose data.

Also the therpy might need adjustments considering factors such as: Diet and exercise, Stress, Illness, Menstrual cycle, Other medications. Also, It is important that patients are educated for what concerns diabetes. Education is a cornerstone of diabetes management, encompassing: Carbohydrate counting, Hypoglycemia recognition and management, insulin administration techniques, Regular foot and eye exams

Question 3

Speak about metformin

Answer 3

Upon diagnosis of type 2 diabetes, treatment typically begins with oral medications rather than insulin. Metformin is the first-line pharmacological choice and is derived from a natural compound found in the French lilac (Galega officinalis). It acts on multiple pathways that contribute to hyperglycemia with three primary actions: on the liver, on the peripheral muscles and in the intestine.

• Starting from the liver: It reduces hepatic glucose production, as well as fatty acid and cholesterol synthesis in the liver.
• In the peripheral muslces: It enhances glucose uptake in peripheral muscles, which often become insulin resistant.
• It decreases the intestinal absorption of carbohydrates.

Recent studies suggest metformin may also have beneficial effects on certain aspects of aging. and its multifaceted actions collectively contribute to lowering blood glucose levels.

The precise mechanism of metformin is not fully understood. It seems to be associated with the activation of AMP-activated protein kinase (AMPK), which is stimulated in low-energy conditions by AMP. Some effects of metformin are AMPK-dependent, while others are independent of AMPK. Crucially, metformin does not stimulate insulin production but enhances the efficiency of existing insulin by reducing insulin resistance. Consequently, it is not typically associated with hypoglycemia. AMPK activation in the muscles promotes increased glucose uptake, improving muscle function. In the liver, AMPK activation leads to reduced gluconeogenesis and a decrease in the expression of lipogenic enzymes. These changes can reduce fatty liver and enhance hepatic insulin sensitivity, addressing one hypothesis that links hepatic fat accumulation to insulin resistance. Metformin is favored as a first-choice diabetes treatment partly because it does not provoke hypoglycemia, as it does not increase insulin secretion.

Question 4

Speak about insulin secretagogues

Answer 4

Insulin secretagogues are pharmacological agents used to treat type 2 diabetes by enhancing the release of insulin. Sulfonylureas stimulate the secretion of insulin from pancreatic beta-cells, thereby increasing its circulation levels to overcome insulin resistance. The release of insulin is regulated metabolically, with its secretion promoted in the presence of high glucose levels. The key players in the control of insulin secretion are the glucose transporters known as GLUT2 and ATP-sensitive K channels KATP.

• During fasting when glucose levels are low, glucose transporters deliver minimal glucose to the cells, among these transporters we find the GLUT2 able to carry glucose to pancreas, liver, kidneys etc.. resulting in slow cell metabolism and ATP production. ATP controls specific potassium channels, the KATP which remain open when ATP levels are low, causing hyperpolarization of the cell membrane. KATP channels are supramolecular structures which can also be found in the beta cells. when these cells are hyperpolarized, they cannot produce insulin.
• However, when food is ingested, glucose levels increase, leading to higher glucose transport into beta cells, increased ATP production, and subsequent closure of the KATP. This partial depolarization is sufficient to trigger insulin release from the granules present in the cells.

Sulfonylureas work by stimulating the release of insulin from the beta cells in the pancreas. Sulfonylureas bind to specific receptors called sulfonylurea receptors (SUR) on the surface of pancreatic beta cells. These receptors are part of the KATP channels present in beta cells. When blood glucose levels are low, the KATP channels in pancreatic beta cells are open, but Sulfonylureas bind to the SUR on the KATP channels, causing the channels to close. The closure of the KATP channels leads to a reduction in the outward potassium flow, causing the beta cell membrane to depolarize and triggering the release of stored insulin vesicles from within the cells. On the other hand when we have increased Insulin levels, by stimulating the release of insulin, sulfonylureas increase the availability of insulin in the bloodstream. This increase in insulin helps to lower blood glucose levels by promoting glucose uptake by cells, particularly in muscle and fat tissues.

It’s important to note that sulfonylureas require functioning beta cells in the pancreas to be effective. They are generally used in individuals with sufficient beta cell function who are unable to achieve adequate blood glucose control through lifestyle modifications alone. Sulfonylureas are typically taken orally, usually before meals, and their effects can last for several hours, depending on the specific medication.

There are two generations of sulfonylureas (also known as sulphonamide derivatives):

• 1st generation: These drugs have low potency but a long half-life, which increases the risk of hypoglycemia.
• 2nd generation: These drugs are safer than those in the first generation. They have a shorter half-life but higher potency, resulting in a better profile for reducing the risk of hypoglycemia. We also have glinides, which bind to SUR1 but at a different site. They belong to the second generation of sulfonylureas and are used specifically after a meal. These pharmacological features make them an attractive option for patients with irregular meal schedules or those prone to late postprandial hypoglycemia.

Question 5

Speak about GPL-1 based “incretin” therpies

Answer 5

Newer drugs for diabetes management are more easily accessible to diabetic patients. GLP-1-Based “Incretin” therapies encompass GLP-1 receptor agonists and DPP-4 inhibitors.

Incretins are hormones derived from the gut that are secreted in response to nutrient ingestion. These molecules act even before insulin because food first reaches the gut before being absorbed. These therapies are designed to enhance the release of insulin from islet β-cells in a glucose-dependent manner. Unlike glucose itself, these drugs work on islet α-cells, reducing their glucagon secretion. By increasing glucose-dependent insulin secretion, they are not associated with hypoglycemia. In type 2 diabetes, there is also a deficiency in incretin production, even after a meal. Patients with diabetes have impaired incretinfunction, resulting in inadequate insulin secretion.

GLP-1 receptor agonists are synthetic analogs of the hormone GLP-1 (glucagon-like peptide-1). GLP-1 is an incretin hormone that is released from the gut in response to food intake. GLP-1 receptor agonists bind to and activate the GLP-1 receptors on pancreatic beta cells, leading to increased insulin secretion. They also slow down gastric emptying, reduce appetite, and promote weight loss. GLP-1 receptor agonists are administered by injection (subcutaneous or intramuscular) and are available in different formulations with varying dosing frequencies.

The first agonists were discovered while studying the salivary glands of a lizard called the Gila monster. This lizard produces a substance called exenatide, which shares 53% homology with human GLP-1 and was originally used by the animal to induce hypoglycemia in its prey through bites. From that molecule drug called lixisenatide was later developed, which is similar to exenatide but has a lysine residue at the end. These two drugs required daily administration, but to overcome this inconvenience, new molecules were developed.

• Albiglutide: This drug is more similar to human GLP-1, with 95% homology. It has been modified by adding albumin, which increases its half-life.
• Dulaglutide: This drug consists of two molecules of GLP-1 bound together. It has 90% homology to human GLP-1.

These drugs require weekly administration and need to be injected since they are peptides. Albiglutide and dulaglutide are safe for patients because they only work when glucose is present in the blood. If glucose is not present, they remain inactive. These compounds are produced through DNA engineering and are relatively expensive, which is why they are typically prescribed by specialists.

DPP-4 inhibitors work by inhibiting the enzyme dipeptidyl peptidase-4 (DPP-4), which breaks down GLP-1 and other incretin hormones. DPP-4 is a specific protease that cleaves the N-terminal dipeptide and inactivates more than 50% of GLP-1 within approximately 1 minute. By inhibiting DPP-4, these drugs increase the levels of GLP-1 and enhance its effects on insulin secretion. DPP-4 inhibitors are available in oral form and are taken once daily. The mechanism of action of these inhibitors is based on increasing the half-life of incretins, resulting in higher circulating concentrations. As a result, there is an increased insulin concentration and a decreased glucagon concentration, which produces effects similar to those of incretins. When taken alone, they are generally safe, but when combined with sulfonylureas, they can cause hypoglycemia.

Both GLP-1 receptor agonists and DPP-4 inhibitors are well-tolerated and have a low risk of hypoglycemia. They are often used as add-on therapy to metformin or other oral antidiabetic drugs when blood glucose levels are not adequately controlled.

Question 6

Speak about SGLT-2 inhibitors and Thiazolidinediones

Answer 6

Another method to control the amount of glucose in the blood is by targeting the kidneys. After glomerular filtration, glucose passes through the nephron where it would normally be completely reabsorbed by two transporters:

• SGLT2: These transporters are present at the beginning of the nephron (proximal tubule) and are responsible for reabsorbing 90% of the filtered glucose.
• SGLT1: These transporters are present in the distal segment of the proximal tubule and are responsible for only 10% of glucose reabsorption.

The reabsorption of glucose is coupled with the reabsorption of sodium and water. However, these transporters can become saturated when the amount of glucose is excessively high. The maximum transport capacity of SGLT-2 for glucose is reached at blood glucose levels of 180-200 mg/dL. Above these levels, glucose is excreted in the urine. Glucose excretion in the urine represents the net difference between the amount of glucose filtered at the glomerulus and the amount reabsorbed by low-affinity, high-capacity SGLT-2 transporters in the proximal convoluted tubule.

To control glucose levels, inhibitors of glucose reabsorption have been developed, mainly known as SGLT-2 inhibitors. By blocking the SGLT-2 transporter, less glucose is reabsorbed, resulting in a greater amount of glucose being excreted in the urine, especially in patients with high plasma glucose concentrations.

SGLT-2 inhibitors have limited or no effect in patients with chronic kidney disease. They have a low risk of hypoglycemia since they do not increase insulin release. However, the increased presence of glucose in the urine can potentially trigger the proliferation of microorganisms and increase the risk of urinary tract infections, particularly in females.

DRUGS TO TREAT TYPE 2 DIABETES: THIAZOLIDINEDIONES

Thiazolidinediones (TZDs) are agonists of the peroxisome proliferator-activated receptors (PPARs), specifically PPARgamma. These receptors, which act as transcription factors, form dimers RXRs and translocate to the nucleus, where they promote the expression of genes involved in adipose cell differentiation and lipid metabolism. TZDs are also known as “insulin sensitizers” because they increase the sensitivity of target tissues to insulin. By reducing the accumulation of lipids in the liver and skeletal muscles, TZDs improve insulin resistance and can be effective in the treatment of type 2 diabetes. Obesity is often associated with insulin resistance due to excessive lipid accumulation. Weight loss can alleviate insulin resistance in obese individuals, leading to improved glycemic control.

While TZDs have shown potential benefits in glucose control and reducing inflammation, they are associated with adverse effects such as weight gain, edema, and an increased risk of heart failure and bone fractures. These side effects have limited their use in clinical practice.

Question 7

Speak about pramlintide and inhibitors of intestinal glucose absorption

Answer 7

Amylin is a peptide hormone co-secreted with insulin by beta cells in the pancreas. It plays a role in regulating postprandial glucose levels. People with type 1 diabetes lack endogenous amylin due to the loss of beta cells, while those with type 2 diabetes have relative amylin deficiency. Amylin acts on the brain to reduce appetite, slow gastric emptying, and suppress postprandial glucagon production.

Pramlintide is a synthetic analog of amylin used as a medication. It is administered subcutaneously before meals. Unlike insulin, pramlintide does not promote insulin release and is not associated with hypoglycemia when used alone. However, when combined with insulin, hypoglycemia can occur.

Pramlintide has been genetically engineered to improve its pharmacokinetics and dynamics. It has enhanced stability and a reduced tendency to form aggregates, leading to more reliable and predictable effects. Pramlintide’s pharmacokinetic and dynamic properties closely resemble those of endogenous human amylin.

DRUGS TO TREAT TYPE 2 DIABETES: INHIBITORS OF INTESTINAL GLUCOSE ABSORPTION

Alpha-glucosidase is an enzyme present in the enterocytes of the intestine, involved in the absorption of dietary carbohydrates. Alpha-glucosidase inhibitors are carbohydrate analogs that inhibit the alpha-glucosidase enzymes, thereby delaying the absorption of dietary carbohydrates. By reducing the cleavage of complex carbohydrates into glucose, these inhibitors lower the postprandial peak in blood glucose levels. They are most effective when taken with meals and have limited efficacy at other times.

Acarbose is an example of an alpha-glucosidase inhibitor.

These inhibitors can cause side effects such as flatulence, diarrhea, and abdominal pain.