Diabetes is labeled as the most common endocrine disorder seen by healthcare providers. There are millions of people that suffer from diabetes and must live with insulin dependence. It is important to understand the normal cellular physiology of how glucose is introduced to the body and the blood. After eating a meal, glucose is absorbed into the blood through a series of gradients and proteins, and then is distributed through the body via a network of vasculature, where it is delivered to target tissues to undergo glycolysis and the citric acid cycle, in addition series of anabolic reactions for energy storage.
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Before it can enter the cycle, it must enter the cells via glucose transporters. In addition to the normal physiology, hyperglycemic crises such as DKA and HHS must be understood, in addition to their pathophysiological features, treatments, and ideas for new treatments, based on the important features of cellular physiology to optimize patient care.
What is Diabetes?
The National Institute of Health (NIH) describes diabetes as the most common endocrine disorder.1 Many individuals, health professionals more so than others, are aware of diabetes and its components. It can be classified as an endocrine disorder resulting in varying levels of blood glucose. The common forms of diabetes mellitus are Type 1 and Type 2. Type 1, which can also be referred to as insulin-dependent diabetes, occurs when the body’s immune system mistakes beta cells, the insulin producing cells of the pancreas, for foreign cells. The immune system then attacks and destroys the beta cells, leaving them with the ability to produce little to no insulin.
Type 2 diabetes is more common than Type 1, and is commonly associated with genetics, sedentary lifestyle and obesity. The Type 2 diabetic can produce insulin. However, the manipulation is that the cells do not respond to the insulin the same way, resulting in glucose not being able to cross the membrane into the cell.2 Glucose is a key player in the aerobic metabolism and the synthesis of ATP. When glucose is not able to enter the cells due to either lack of insulin or insulin resistance, the homeostatic function is disrupted, causing an altered, and possibly life-threatening physiological response, leading to the following questions. What is happening at the cellular level? How is this currently treated in hospital and in the prehospital setting, without the presence of insulin? Can we modify the current prehospital treatment by changing solute concentrations or by administering medications that act on existing transporters?
Normal Cell Physiology and Solute Transport
Before the concepts of cellular disruption can be evaluated, it is vital to understand the normal homeostatic state of cells, in addition to normal solute transport. Each of the millions of cells in the human body contain a plasma membrane. This organelle is vital to the process of solute transport, organelle protection and separation of intercellular components from extracellular components. This small but fascinating biological feature is comprised of a fatty-acid, phospholipid bilayer. It is polarized such that the inside and outside are hydrophilic heads, and the middle are hydrophobic tails. Given its unique structure, it allows smaller molecules such as gasses, water and small polar molecules like glycerol and urea to pass.
Water also moves across the plasma membrane by the passive process of osmosis, which will be described in further detail later in this paper. Larger and charged molecules such as proteins, glucose and ions do not have the luxury of passive diffusion. If they want to get into the cell, they need to enter via channels or protein transporters in an active process. An example of this can be seen in the transporter known as Sodium/Potassium Adenosine Triphosphatase, also known as the Sodium/Potassium Pump. “Since in the normal state of a cell, large concentration differences in K+, Na+ and Ca2+ are maintained, it is evident that active transport mechanisms are at work.”3 Adenosine Triphosphate (ATP) is used to power this pump, and bring two molecules of potassium into the cell, while sending three molecules of sodium out of the cell, against the concentration gradient.
The constant movement of ions is also a major contributor of electrochemical membrane potential and osmosis of water, since water follows non-permeable solutes. In the normal cell, ions, molecules, and water move to maintain equilibrium. Two physiological factors to determine equilibrium are osmolarity and tonicity. In a normal physiological state, Isotonicity can be defined as having the same concentration of non-permeable solutes inside, and outside the cell, and tonicity itself refers to the effect that the solution will have on the intracellular fluid (ICF) and water movement.
One clinical application for this is with use of 0.9% NaCl in sterile water, or normal saline solution. This is given in IVs to maintain hydration and fluid balance because it is an isotonic solution. Thus, since it has the same composition of non-permeable solute, sodium, in the ICF and the ECF, water will move equally across the membrane. A hypertonic solution has a higher solute and lower water concentration outside of the cell and will pull water from the cell to equilibrate. A hypotonic solution has a lower solute concentration and higher water concentration outside of the cell and will push water into the cell to equilibrate.
Osmolarity is like tonicity, but is the concentration of all solutes, permeable and impermeable, in a solution. The normal bodily cell has a serum osmolarity of 300 mOsm/L, which relates to 300 mmol of solute per 1 L of plasma. This number can change, based on the buildup or lack thereof in serum solutes. A hyperosmotic solution has a higher concentration of total solutes, pulling water from the cell. A hypoosmotic solution has a lower concentration of total solutes, pushing water into the cell. In patient lab values osmolarity is the measurement of choice.
Since osmolarity and tonicity rely on different parameters, it is also possible to have a normal tonicity and an altered osmolarity, and vice-versa. For example, if a solution has equal amounts of impermeable solute in the ICF and the ECF, it is isotonic; if there are 400 millimoles of a gas such as CO2 in the serum, that gives you a serum osmolarity of 400 mOsm/L, and the result would be an isotonic, hyperosmotic solution.
With the previous baseline information for normal solute transport, the main solute of discussion, glucose, can be added. For glucose to get into the blood, it must first be introduced to the body. This is done by eating food. Much of the food consumed by animals contains carbohydrates, one of the main groups of functional macromolecules. The carbohydrates consumed in food are considered complex. As the food is passed through the digestive tract, the nutrients are absorbed through the lumen of the small intestine, which is lined with epithelial cells. However, to get across the cell membranes, the complex carbohydrates must be hydrolyzed into the smaller, easier to pass monosaccharide, glucose. After the glucose is hydrolyzed by different chemicals in the digestive tract, it is ready to be absorbed by the intestinal epithelium.
The epithelial cells have microvilli, which provide extra surface area for maximal transfer across the apical side of the plasma membrane. “This is predominantly mediated by SGLT1, a membrane protein that couples two molecules of Na+ together with one molecule of glucose.4 This article also states that the SGLT receptor does not use ATP, but the sodium concentration gradient that has been created by the Na+/K+ ATP-ase. Once absorbed into the intestinal epithelium, “… A facilitated-diffusion glucose transporter (GLUT2) allows glucose to move from the ICF into the extracellular medium near the blood capillaries,” thus the molecule can enter the bloodstream.
Once glucose enters the blood, the vascular system works to deliver the molecules to cells throughout the body, to the tissues and cells to synthesize ATP in cellular respiration. As noted in how glucose can enter the bloodstream, not every tissue in the human body requires insulin to uptake glucose. The need for the hormone is cell and receptor specific. Though there are other SGLT proteins on varying tissues throughout the body, the focus for glucose movement and insulin dependence will be on the Glucose Transporters (GLUTs).
Unlike the SGLTs, GLUTs are not sodium ion coupled, thus they do not rely on the sodium gradient to move glucose across the membrane, they rely on facilitated diffusion of the glucose concentration gradient. When sugars are present both inside and outside of the cell, these transporters catalyze unidirectional sugar uptake and unidirectional sugar exit, to work towards transmembrane equilibrium.5 The GLUTs are divided into different categories based on their diffusive properties, glucose affinity, and need for insulin.
To get glucose into cells, let’s first discuss the insulin-independent pathways. GLUT1 is a highly important glucose transporter that does not require insulin. It is a high-affinity transporter and helps regulate basal glucose uptake throughout the entire body. “GLUT1 is critical for glucose transport across the blood-brain barrier…GLUT1 in the brain are critical for cerebral glucose homeostasis.”5 Not only is it important in the brain, but GLUT1 can be found in almost every tissue in the body, whereas other GLUT proteins are very tissue specific. Having insulin-independent facilitated transporters is an important physiological feature to help aid in glucose equilibrium, especially in those who have fluctuations in blood glucose, and deficiencies with insulin. Additionally, this allows tissues with high glucose demand, such as the brain, to obtain the sugar without the complex insulin process.
Not every tissue can uptake glucose independently, thus GLUT4 comes into play. GLUT4 is known as the insulin-sensitive glucose transporter. This type of transporter is most highly expressed in skeletal muscle, cardiac muscle and fatty tissue. Inside of the cells, the GLUT4 protein is stored in vesicles where it awaits insulin stimulation, where it then is moved to, and inserted into the plasma membrane. “Exposure to insulin causes a rapid, 3- to 12-fold increase in plasma membrane GLUT4 levels in muscle and fat, thereby increasing glucose uptake from the blood and lowering blood glucose.”5 Since GLUT4 is such a powerful glucose transporter, it plays a big role in blood-glucose regulation.
To activate the transporter, the cells must first have insulin delivered. This hormone is synthesized in the pancreas by beta (β) cells and released into the bloodstream in response to rising blood glucose levels. Insulin receptors on the plasma membrane are Tyrosine Kinase Receptors. As the insulin is delivered by the bloodstream, it finds the extracellular α subunit and binds to it. This causes a conformation change and allows ATP to bind to the intracellular β subunit, which triggers phosphorylation of the subunit, and results in tyrosine phosphorylation of intracellular protein substrates known as the Insulin Responsive Substrates (IRS).6
As the cascade continues, “Phosphorylated IRS proteins bind specific src-homology-2 domain proteins (SH2), which include important enzymes such as phosphatidylinositol 3-kinase (PI 3-kinase) and phosphotyrosine phosphatase SHPTP2 (or Syp)….”6 Lastly, the PI 3-kinase activates serine and threonine kinases such as protein kinase C, to cause translocation of the GLUT4 protein to the plasma membrane, and the successful uptake of glucose to form fatty acids, glycogen and ATP.
Since Diabetes mellitus is a major endocrine disorder, dealing with such a physiologically vital substrate, there is no surprise when it comes to encountering complications with the disease. Without the presence of insulin, blood glucose is very poorly regulated. Although there are proteins such as the GLUT1 that can control serum-cellular glucose levels without the hormone, that is not enough to maintain homeostasis. Blood glucose can fluctuate in two directions, up and down. Low blood sugar (hypoglycemia <70 mg/dL) is an emergency, however, this paper will be focusing on high blood sugar (hyperglycemia >150 mg/dL), and even more refined, the metabolic complications of hyperglycemia.
This first hyperglycemic crisis of discussion is Diabetic Ketoacidosis, more commonly referred to as DKA. This syndrome is a result of hyperglycemia in the Type I diabetic [refer to introduction for the specification of Type I and Type II]. DKA is a combination of hyperglycemia, ketonic-metabolic acidosis, and dehydration, and is also typically rapid onset. In the prehospital setting, DKA can present with: Kussmaul respirations (deep and rapid), fruity/acetone smell on the breath, somnolent or stupor mentation, respiratory alkalosis (ETCO2 <35 mmHg), and a blood glucose of >250 mg/dL. With more advanced lab techniques acquired in the hospital, additional information can be added such as an arterial pH <7.35, a serum bicarbonate <18 mEq/L, anion gap acidosis, positive urine ketones, and a variable serum osmolarity (Rohrlich, Williams, Benitez, & Velez, 2017). These signs are variable depending on the severity of the DKA.
Since the Type I diabetic has a deficit of insulin, the blood glucose levels are free to rise, since there is nothing to activate insulin receptors and GLUT4 proteins. Without the presence of insulin, adipose tissues release fatty acids into the blood. The liver converts these fatty acids into acetyl-CoA, however, in instances of low insulin and reciprocal high glucagon, which is also produced by the pancreas for opposite effects of insulin, the liver cannot oxidize acetyl-CoA. The acid is eventually converted to acetone, a ketone. The ketones are excreted in the urine as anions. This ketonic state also converts the metabolic pathway from carbohydrate energy to burning fat for energy.7
Additionally, the glucose concentrations exceed kidney filtration and glucose gets into the urine. The elevated urine osmolarity causes osmotic diuresis to rid the body of the excess glucose, however, it takes a large volume of water and electrolytes with it. In addition to the internal mechanisms, the patient is often in a state of Kussmaul respirations in a physiological attempt to blow off acetone and use respiratory alkalosis to compensate for the metabolic acidosis.
Hyperglycemic crisis in the Type II diabetic, is like the Type I in symptomology, but different in pathogenesis and laboratory values. For Type II diabetics, the term used for hyperglycemic crisis is Hyperglycemic Hyperosmolar State, referred to as HHS, the most serious hyperglycemic complication in Type II Diabetes, and is typically slower in onset. In the prehospital setting, this condition portrays DKA in a similar fashion. The patient will present with polydipsia, polyuria, polyphagia, a mentation of somnolent, stupor, or comatose, an ETCO2 of >35 mmHg and a blood glucose reading of >600 mg/dL, if the EMS glucometer will read that high, likely the meter will read “high.” Additional hospital lab readings will present with an arterial pH of >7.3, a bicarbonate level >15 mEq/L, minimal to no urine ketones, anion gap <12, and a serum osmolarity >320 mOsm/L.7
It can be noted that there is a noticeable difference between DKA and HHS. For example, the bicarbonate, pH, ETCO2, and anion gap are all within fairly normal limits. Since the Type II diabetic can still produce insulin, there is a high enough concentration to prevent lipolysis and ketogenesis, thus there is not an acidic metabolic response.8 To add, the absence of ketones is the most common in diagnosis, however some cases report minimal ketones in HHS. The noticeably higher level of blood glucose in HHS results in a heavy osmotic diuresis. Since the normal level of serum osmolarity is 300 mOsm/L, the higher solute concentration outside of the cells is cause for the hyperosmotic state, drawing water from the cells. This water is then excreted, along with electrolytes, causing moderate to severe dehydration.
Assessment & Treatments
Treating hyperglycemic crises can be difficult, however, understanding the physiological features of the crises can aid in better treatment and better patient outcomes. Starting with the prehospital setting, EMTs and paramedics must approach the scene with an appropriate EMS mindset. The prehospital signs, symptoms, and tests as mentioned before (in addition to a superb medical assessment) must be achieved to correctly identify the cause of the symptoms.
Upon entering the scene of a hyperglycemic emergency, the EMS provider needs to look for distinct signs and symptoms. With both types of hyperglycemic emergencies, patients will present with weakness, polydipsia, polyphagia and polyuria, as this condition results in osmotic changes. There may also be signs of volume depletion which can be assessed by observing skin turgor, sunken eyes, hypotension, and tachycardia, all which can be assessed by BLS and ALS crews. “Neurological status in patients with DKA may vary from full alertness to a profound lethargy and coma, However, mental status changes in DKA are less frequent than HHS.” Respirations are also important to assess. DKA patients are in a state of metabolic acidosis, and compensate for this with Kussmaul, fast and deep, respirations to compensate via respiratory alkalosis. Since the HHS patient has little to no production of ketoacids, this compensatory mechanism will be absent. The final assessment that can be completed by both ALS and BLS crews is blood glucose analysis. In DKA, ketoacids can be produced at glucose values as low as 250 mg/dL. With HHS, serum glucose will likely be >600 mg/dL (Rohrlich, Williams, Benitez, & Velez, 2017), and the glucometer will likely indicate “high” rather than an actual value.8.
As an ALS provider, one can take the next step in identifying a hyperglycemic crisis and determining whether it is DKA or HHS. Paramedics have access to waveform capnography. When assessing a patient’s end-tidal CO2, the DKA patient will have an EtCO2 of <35 mmHg, as the Kussmaul respirations induce compensatory respiratory alkalosis as mentioned above.10 The HHS patient will have an EtCO2 within normal limits, >35 mmHg, as they are not experiencing an acid-base dysfunction.
Once a hyperglycemic emergency is established, the EMS crew must then work at a fast, but manageable pace to get the patient the appropriate treatment. At the BLS level, there is little to do aside from transport to the nearest facility, as the treatment involves procedures outside the EMT scope of practice. For ALS providers, the number one prehospital treatment is fluid replacement, this is the same for DKA and HHS in the prehospital setting. This is important to initiate, especially in rural areas where there is a larger transport time to the hospital. A 2017 Australian study showed only 21.5% of the hyperglycemic patients receiving fluid replacement in the prehospital setting, which delays care and leaves the patient in a critical state.11 Ideally, the patient should be given isotonic, 0.9% saline solution at a rate of 500-1000 mL/h depending on the patient’s size.12 Fluid replacement will aid in the redelivery of fluids lost to osmotic diuresis, in addition to helping dilute excess glucose in the blood.
Once arrived at the hospital, further treatment can be administered, preferably after the drawing of a metabolic panel. In addition to the fluid management that will continue in the hospital, an insulin regimen is also started. “Most treatment protocols recommend the administration of 0.1 unit/kg body weight bolus followed by continuous insulin infusion at 0.1 u/kg/hr until blood glucose is ~ 200 mg/dL. At this point, the dose is reduced by half (0.05 u/kg/hr) and rate is adjusted between 0.02–0.05 u/kg/hr.”12 In addition to the insulin, IV dextrose 5% needs to be added to maintain a blood glucose of 140-200 mg/dL until the ketoacidosis is corrected. Similarly, for HHS, patients are treated with insulin and fluid to achieve normal metabolic readings. In addition to the treatment for dehydration, potassium also needs to be replaced in addition to fluid, to maintain a normal electrolyte balance and serum potassium of 4-5 mEq/L.13
The treatments listed above are current, and the among the most taught among health professionals. However, we need to consider comorbidities. For example, patients with congestive heart failure, CHF, are subject to pulmonary edema. If the patient is suffering a hyperglycemic crisis, and gets fluid overload, the likelihood of flash pulmonary edema is increased, resulting in two medical emergencies. In the prehospital setting, the only treatment is fluid resuscitation. In a rural EMS setting, under contraindicative circumstances, the decision to withhold a life-saving treatment to avoid a secondary life-threating reaction is not a decision that a paramedic wants to make. However, with basic cell physiology, could this be avoided by changing fluid concentrations, or administering a secondary medication?
In patients with DKA, fluid replacement is essentially the only prehospital treatment, under the circumstance that insulin is not available in the body, or to be administered. However, administration of a smaller amount of hypotonic saline such as 0.45% should dilute the serum solute concentration and cause the osmotic movement of water back into the cells. This would not be favorable for volumetric replacement but could help slow or stop the outward movement of water by osmotic diuresis in DKA and HHS especially.
Evaluating a patient with a comorbidity such as CHF, the lower salt concentration facilitating water movement might be enough to reduce the total amount of fluid given, reducing the likelihood of a secondary complication. Hypertonic saline such as 3% may also need to be incorporated to maintain sodium levels and prevent cerebral edema, but according to a study on hypertonic saline and hyperglycemia in children, “3% saline solution did not preclude the development of cerebral edema and has the potential to cause hypernatremia, hyperchloremia and hyperchloremic metabolic acidosisd.”14
Additionally, for HHS in the Type II diabetic, there is already a concentration of insulin in the body, just a lack of acceptance to the receptors. In addition to the fluid to correct the diuretic dehydration, a drug that will agonize the insulin tyrosine kinase receptors could be an alternative solution to insulin administration and could be given in the prehospital setting like other agonistic medications. A receptor agonist as an IV medication could allow the residual insulin to bind to the receptor and stimulate the GLUT proteins prior to hospital intervention. Furthermore, with respect to renal physiology, there is also the possibility of an SGLT inhibitor. Using a Sodium-Glucose Cotransporter 2 (SGLT-2) inhibitor such as canagliflozin in the proximal convoluted tubule would prevent glucose reabsorption and excrete the excess glucose with diuresis.8 However, administering a drug like this would require the patient to be carefully monitored for hyponatremia, and the patient would still require fluid replacement to counter-balance the diuresis.
Diabetes mellitus is a complex disease with a variety of factors, syndromes and physiological effects. Though research has come a long way, the understanding and treatments of the disease are far from perfected. The cascade of proteins and receptors is advanced, but not impossible to discern. Their research on new treatments for hyperglycemic crises, especially without the presence of insulin, is advancing and a basic understanding of cellular physiological concepts can help construct new evidence and treatment ideas for such common, yet complicated cellular emergencies. Solute transport is far from simple but understanding what happens at the cellular level is a vital piece in the physiological puzzle.
This review is dedicated to those individuals working in the EMS system. We are forever changing and updating our practice and techniques, while continuing our education to provide the best possible care for patients in the prehospital setting. With evidence-based medicine, we have been able to advance our skills, and earn the title of “clinicians,” rather than simply “ambulance drivers.” I would like to thank my EMS family at Cheboygan Life Support Systems for mentoring me and for supporting me as I further my education.
I would also like to thank Gina Leinninger, Ph.D., of Michigan State University’s Department of Physiology, for overseeing this endeavor, in addition to reviewing the information within it. The exquisite education I have received from the university will surely continue to aid me on a path to my successful future.
- Endocrine diseases. (2019, July 15). Retrieved 2019, from Medline Plus: US National Library of Medicine: https://medlineplus.gov/endocrinediseases.html#targetText=In%20the%20United%20States%2C%20the,much%20hormone%20your%20body%20makes.
- Differences between Type 1 and Type 2 Diabetes. (2016, July 11). Retrieved 2019, from Diabetes Research Connection: https://diabetesresearchconnection.org/differences-type-1-type-2-diabetes/?gclid=Cj0KCQjw8svsBRDqARIsAHKVyqGV1Ll4I2BmeFK83r7f2oIRQ8lKThKR4JKesQYJc5DLTZxcQVMmj7MaAgWWEALw_wcB.
- Nave, R. (n.d.). Active transport across cell membranes. Active Transport Across Cell Membranes. Georgia State University. Retrieved 2019, from http://hyperphysics.phy-astr.gsu.edu/hbase/Biology/actran.html.
- Chen, L., Tuo, B., & Dong, H. (2016). Regulation of intestinal glucose. Nutrients , 8(1), 43. doi:10.3390/nu8010043
- Cura, A., & Carruthers, A. (2012). The role of Monosaccharide Transport Proteins in carbohydrate assimilation, distribution, metabolism and homeostasis. Comprehensive Physiology, 2(2), 863-914. doi:10.1002/cphy.c110024
- Wilcox, G. (2005). Insulin and insulin resistance. The Clinical Biochemist Reviews, 26(2), 19-39. Retrieved 2019, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1204764/.
- Rohrlich, J., Williams, R., Benitez, F., & Velez, L. (2017). Diabetic emergencies. Emergency Medicine Reports, 38(3), 49-55. Retrieved 2019, from https://search-proquest-com.ezproxy.ncmich.edu/docview/1985652648/145B029DD3924099PQ/3?accountid=35861
- Gosmanov, A., Gosmanova, E., & Kitabchi, A. (2018). Hyperglycemic crises: diabetic ketoacidosis (DKA), and hyperglycemic hyperosmolar state (HHS). Endotext. Retrieved 2020, from https://www.ncbi.nlm.nih.gov/books/NBK279052/#:~:text=The%20common%20clinical%20presentation%20of,and%20shock%20in%20severe%20cases.
- Umpierrez, G. E., Murphy, M. B., & Kitabchi, A. E. (2002). Diabetic ketoacidosis and hyperglycemic hyperosmolar syndrome. Diabetes Spectrum, 15(1). Retrieved 2019, from https://search-proquest-com.ezproxy.ncmich.edu/docview/228711569/120B714C801046EAPQ/1?accountid=35861.
- Chebl, R. B., Madden, B., Belsky, J., Harmouche, E., & Yessayan, L. (2016). Diagnostic value of end tidal capnography in patients with hyperglycemia in the emergency department. BMC Emergency Medicine, 16(7). doi: 10.1186/s12873-016-0072-7
- Villani, M, et al. (2017). Utilisation of prehospital emergency medical services for hyperglycaemia: A community-based observational study. PloS One, 12(8). doi:10.1371/journal.pone.0182413
- Fayfman, M., Pasquel, F. J., & Umpierrez, G. E. (2017). Management of Hyperglycemic Crises: Diabetic ketoacidosis and hyperglycemic hyperosmolar state. Med Clin North Am., 101(3), 587-606. doi:10.1016/j.mcna.2016.12.011
- Dhatariya, K., & Vellanki, P. (2017). Treatment of Diabetic Ketoacidosis (DKA)/Hyperglycemic Hyperosmolar State (HHS): Novel Advances in the Management of Hyperglycemic Crises (UK Versus USA). Current Diabetes Reports, 17(5), 33. doi:10.1007/s11892-017-0857-4
- Shafi, O., & Kumar, V. (2018). Initial Fluid Therapy in Pediatric Diabetic Ketoacidosis: A comparison of Hypertonic Saline Solution and Normal Saline Solution. Pediatric Endocrinology, Diabetes, and Metabolism, 24(2), 56-64. doi:10.18544/PEDM-24.02.0103