This is the final episode of the diabetes series. In this episode we will talk more in depth about the different pharmaceuticals used in the therapy of diabetes. We will talk about the different types of insulins and the common therapy schemas. In addition to that different types of oral antidiabetic drugs will be presented and for all the nerds we will also take a closer look at the biochemical basis of insulin, it’s synthesis and effects. Let us dive into it!
Insulin
Insulin & Blood Sugar
Insulin is a peptide hormone being synthesized in the β-cells of the pancreas and stored with zink ions in so-called vesicles (intracellular storage compartments). The secretion process can be divided in the following steps:
Absorption of glucose in to the β-cells trough the GLUT-1-transporter
Breakdown of glucose leads to a rise of the intracellular ATP-concentration
ATP binds to the ATP-dependant potassium-channels & inhibits them
The decrease in potassium conductivity leads to depolarization
Calcium influx through voltage-dependent Calcium channels
Exocytosis (Secretion) of the insulin vesicle into the blood
The insulin secretion is regulated mainly by the blood sugar level – other stimulating factors are:
- amino acids (e.g. arginine)
- fatty acids
- enteric hormones (e.g. GLP-1 & GIP)
- parasympathetic nervous system (“rest & digest”)
According to that inhibiting factors are: - Sympathetic nervous system (“fight or flight”)
- Somatostatin (enteric hormone)
It is also interesting to know that insulin is created by modifying preproinsulin via proinsulin to insulin + it's C-peptide as a cleavage product. The C-peptide can be used as a diagnostic marker for insulin production, which correlates with the number of β-cells in the pancreas and is therefore a marker for their decline in e.g. DMT1. On the other hand, it can be found out whether hypoglycaemia is caused by an excess of insulin. This would be expected in a B-cell tumour of the pancreas (insulinoma).
Concerning the blood sugar levels the normal reference range is between 50 – 100 mg/dl. Levels over or under that range are considered as hypoglycaemia or hyperglycaemia. Hhowever, there are differences depending on the source.
The effects of insulin
Insulin mediates its effect via the membrane-bound insulin receptor (receptor tyrosine kinase – tetramer of 2x α subunits & 2x β subunits). When insulin binds to the receptor, the following biochemical cascade takes place:
Insulin binds to the insulin receptor and activates the tyrosine kinase domain (β subunit)
Autophosphorylation of the receptor
Phosphorylation of tyrosine of different signal transduction proteins, especially the insulin receptor substrate (IRS)
Activation of different intracellular signal transduction pathways including MAPK-pathway (mitogen-activated protein kinase pathway) & the decrease of the intracellular cAMP (cyclic adenosine monophosphate) trough the activation of Pl3-Kinase & protein kinase B.
In general insulin has an anabolic effect inducing metabolic pathways filling the energy storages of the body and inhibiting metabolic pathways that reduce/mobilize the energy storage. In general there are fast effects concerning the metabolism and the slow effects due to altered gene expression. The following effects take place:
- Reducing the blood sugar level: through an increase of glucose intake of skeletal & fat cells by installation of GLUT4-transporters in their cell membranes
- Adjustment of the glucose, fat & protein metabolism: anabolic metabolism ⬆️ & katabolic metabolism ⬇️
- Stimulation of growth & differentiation: especially trough IGF-1-receptors (insulin like growth factor 1)
- Stimulation of the Sodium[Na]/Potassium[K]-ATPase (transporter using ATP as fuel)
Nice to know: Insulin also effects Na/K-ATPase leading to an increased import of potassium into the cells. This is used therapeutically to treat hyperkalemia (elevated level of potassium in the blood). Hyperkalemia can lead to life-threating heart rhythm disorders. The administration of insulin ensures that the increased potassium is redistributed intracellularly - at best, this normalizes the potassium levels in the blood.
Another important hormone that regulates blood sugar levels in our body is glucagon. Don’t worry, we can keep this short: glucagon is simply the opponent/antagonist of insulin. It is being produced by the α-cells of the pancreas and is stimulated by a low blood sugar level. The effects of glucagon are exactly the opposite of insulin. That’s it!
Insulin as a Drug
Sources, application & insulin types
Especially people with DMT1 or without a pancreas are dependent on an external source of insulin. Luckily, insulin can be easily produced out of pig insulin or in bacteria – the resulting insulin is 100% identical with human insulin.
In general insulin is applied subcutaneous with a syringe according to the individual medication regimes. You can image that in this case it is not possible to mimic the natural supply of insulin by the pancreas concerning the course of insulin levels after application. The effect of subcutaneous application depends on the absorption in the tissue or the blood flow. Delay in absorption is caused by cold, obesity and peripheral injection. The absorption is accelerated by injecting close to the navel and manipulating the tissue (e.g. massages).
In addition to that the insulin secretion is linked to the blood sugar levels – in order to prevent any hypo- or hyperglycaemia it is important to apply the right amount of insulin at the right time.
In general, the insulin drugs are divided into short-acting insulins, long-acting insulins & mixed insulins. These differences in availability and effective period are achieved through minimal modifications - short and long-acting insulins therefore have a slightly different structure than human insulin. In the case of short-acting analogues, one or more amino acids are usually exchanged, while in long-acting analogues the β-chain of the insulin is lengthened. Concerning long-acting insulin the hexamer (6 units) formation is strengthened by zinc or protamine additive (NPH) – therefore insulin remains in an inactive formation for longer and is released piece by piece.
Human insulin acts for about 4 – 6 hours and the effect unfolds approx. 30 minutes after application
Short-acting insulin acts for 2 – 3 hours and the effect unfolds approx. 15 minutes after application
Long-acting insulin acts for 8 – 12 hours and the effect unfolds approx. 1 hour after application
Mixed insulin has a biphasic effect and consists of an defined mixing ratio – e.g. 30 % human insulin & 70 % long-acting insulin
Types of insulin therapy
Conventional Insulin Therapy
It is a simple, not time-consuming implementation of set applications throughout the day, but due to the non-physiological insulin levels it is only used in patients who are not suitable for intensive insulin therapy and who have a fixed, regular daily nutrition plan.
In this case mixed insulin is used: e.g. 1x in the morning (2/3 of daily dose) and 1x in the evening (1/3 of daily dose) pre-prandial (before food intake)
Intensified Conventional Insulin Therapy (ICT)
In this case 1-2x per day a long-action basal insulin is applied and in addition to that short-acting insulin is applied pre-prandial. This requires an intensive training of the patient, because you need to adjust the amount of pre-prandial applied insulin to your blood sugar level, meal and individual daytime factor (e.g. 2:1:1.5 for morning, lunch & evening). Depending on the amount of carbs you are about to ingest you are applying a set amount of insulin – e.g. 1 IU of insulin per 10 g carbohydrates/ 1 carbohydrate unit (CU). You need to multiply that with the daytime factor. On top of that you may need to include a correction factor (30/60-rule again depending on the daytime), if you blood sugar is higher than your individually set goal.
So, e.g. your target blood sugar level is 120 mg/dl. You are checking your blood sugar level in the morning showing 150 mg/dl and you are about to digest approx. 40g of carbs. So as a correction factor you need to apply 1 IU of insulin due to the fact that you are 30 mg/dl above your target (30-rule in the morning). In addition to that you need to apply 8 IU (2 x 4 CU) resulting into 9 IU in total.
Insulin Pump Therapy (IPT)
This is an more expensive option for more life quality and irregular daily routines. Similar to the ICT, frequent blood sugar checks are necessary and patient compliance must be high. The pump is injecting fast acting insulin continuously and can be programmed individually – there are even new models with an integrated blood sugar measuring device. The patient can then apply a bolus pre-prandial via a button.
Supplementary Insulin Therapy (SIT)
In this case oral antidiabetic drugs a combined with fast acting insulins for pre-prandial application. This is often used for very advanced DMT1. In addition to that it is also possible to add an slow acting insulin before bedtime to counteract high blood sugar levels in the morning.
Pharmaceuticals for Treating Diabetes
Antidiabetic Drugs
While insulin is the preferred therapy for DMT1, it is the last level of escalation concerning the therapy of DMT2. One of the main reasons is that DMT2 comes along with an insulin resistance, while DMT1 is the result of the lack of insulin and errors in its synthesis in the β-cells of the pancreas. Therefore, other drugs are preferrable concerning the treatment of DMT2.
In general we distinguish between an
- Insulinotropic antidiabetic drugs
- Non-insulinotropic antidiabetic drugs
Insulinotropic effects are archived by the increase of the liberation of Insulin, while non-insulinotropic effects are independent of endogenous insulin synthesis. Logically the antidiabetic drugs based on insulinotropic effects are dependent on the (residual) function of the pancreas – if the insulin synthesis of the pancreas is totally shutdown, there will be no benefit. In contrast to that non-insulinotropic effects are occur even under those circumstances.
Common examples for insulinotropic antidiabetic drugs are sulfonylurea, GLP-1-Agonists and DPP-4 inhibitors/gliptins.
On the other hand examples for non-insulinotropic antidiabetic drugs are biguanides & SGLT2-inhibitors.
Biguanide [e.g. Metformin]
Effects
These are the means of first choice for all DMT2 patients. Appetite, insulin requirement & hyperinsulinemia decrease, and it leads to better glucose metabolism – hepatic (= referring to the liver) gluconeogenesis ⬇️, glucose release ⬇️ & intestinal glucose absorption ⬇️. Overall, the insulin resistance is decreased.
Side effects
Possible are weight loss (often desired) and gastrointestinal discomfort including diarrhoea & stomach cramps.
A possible dramatic complication is a life threatening lactic acidosis – by blocking the mitochondrial respiratory chain, the anaerobic metabolism is increased, whereby more lactate is formed.
Contraindications
Mainly situations with metformin accumulation (e.g. renal failure), with anaerobic metabolism (e.g. hypoxemia) or with an acidotic metabolism
- Alcoholism
- Chronic respiratory failure
- NYHA III or IV (classifying a severe heart failure)
- Renal failure
SGLT2-inhibitors/Gliflozins [e.g. Canagliflozin & Dapagliflozin]
Effects
The sodium-glucose-linked-transporter-2 is i.a. located in the intestine and the kidney. The inhibition of SGLT-2 in the proximal tubule of the kidneys leads to increased renal elimination of glucose with polyuria (higher urine volume) and glucosuria (excretion of glucose in the urine).
Side effects
- Hypoglycaemia (especially in combination with insulin or sulfonylurea)
- increased urinary tract infections
- diabetic ketoacidosis
- Exsiccosis/Dehydration
Contraindications
- DMT1
- Renal failure
Sulfonylurea/Glinides [e.g. Nateglinid & Repaglinid]
Effects
Basically, sulfonylurea increases the secretion of insulin the tβ-cells of the pancreas regardless of the blood sugar level. Sulfonylurea binds to the SUR1 of the β-cells, whereby the ATP-dependent potassium channels close and the membrane is depolarized. The resulting influx of calcium mediates exocytosis/secretion of the insulin vesicles.
Side effects
Even with normo- or hypoglycaemia, insulin secretion occurs, which massively increases the risk of hypoglycaemia
- Hypoglycaemia
- Weight gain
Contraindications
- DMT1
- Renal failure
GLP-1-Agonists [e.g. Exenatide, Liraglutid]
Effects
Direct stimulation at the GLP-1 receptor and thus an increase in the glucose-dependent insulin release and inhibition of glucagon secretion.
It also leads to weight loss due to slower gastric emptying, greater satiety and less hunger.
Side effects
Since the insulinotropic effect is glucose dependent there is almost no risk for hypoglycaemia.
- Gastric emptying disorders
- Pancreatitis (Inflammation of the pancreas)
Contraindications
Nothing particular - contraindicated in case of hypersensitivity.
DPP-4-Inhibitors/Gliptins [e.g. Saxaglitpin & Sitagliptin]
Effects
Inhibition of the degrading enzyme of GLP-1, whereby the effect of GLP-1 is increased and accordingly the glucose-dependent release of insulin increases.
Side effects
- Gastrointestinal complaints
- Pancreatitis
Contraindications
- DMT1
- Renal failure
- Chronic pancreatitis
Hall of Fame of Obsolte Drugs
α-glucosidase inhibitors
Effects
Due to the inhibition of glucosidase in the small intestine, polysaccharides are not correctly split and thus enteral glucose absorption is reduced - the blood sugar peaks postprandially (after eating) are thus reduced.
Side effects
- Gastrointestinal complaints
- Flatulency
- Meteorism (due to trapped air in gastrointestinal tract)
- Bloating
Contraindications
- pre-existing indigestion
- renal failure
PPAR-γ-Agonists/Thiazolidinediones/Glitazones [e.g. Pioglitazon]
Effects
TZDs bind to nuclear receptors and ultimately act as insulin sensitizers by reducing insulin resistance. This is mainly done on adipocytes, where more triglycerides are stored and fewer hyperglycaemia-promoting products are released
Side effects
- Weight gain
- Edema (water retention)
- Cardiac decompensation
- Increased risk of fractures due to osteoporosis
- Increased risk of cancer - especially bladder cancer
Checklist
By now ...
✅ you know the effects of insulin and glucagon in the human body
✅ you know about the different types of insulin drugs used
✅ you can distinguish different insulin therapy regimens
✅ you know the different effects of antidiabetic drugs
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See you soon!
Noogie 👨⚕
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