Mechanism by which hypokalemia reduces insulin secretion

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Is there any known mechanism by which hypokalemia reduces insulin secretion?

This video explains a mechanism, but its inherently wrong because ATP dependent K+ channels will allow movement of K+ from inside of cell to outside.

Tl;dr

Hypokalemia hyperpolarizes membranes by increasing the $$K^+$$ gradient, making $$mathcal{E}_K$$ and consequently $$mathcal{E}_m$$ more negative. This makes any signaling event controlled by depolarization less responsive.

It's complicated, but we can understand the effect by looking at \$K^+\$ alone

Good catch. Yes, the video (and diagram) are incorrect. The electrophysiology of pancreatic $$eta$$-cells is still an area of active research. Your textbooks (e.g., Costanzo Chapter 9, under Regulation of Insulin Secretion) will tell you that an increase in the $$frac{[ATP]}{[ADP]}$$ ratio closes ATP-sensitive $$K^+$$ channels, which depolarizes the membrane. This is, in large part, correct, but not thoroughly understood, and not only by decreasing the $$K^+$$ conductance of the membrane. Further work in the years since that linked article supports the importance of a $$Cl^-$$ gradient and anion current, but $$K^+$$ conductance is still involved, and probably still underlies the mechanism through which hypokalemia reduces insulin secretion.

Membrane potential is determined by the concentration gradients and permeabilities of ions

The membrane potential of the pancreatic $$eta$$-cell, as with the neuron, is determined by both concentration gradients and permeabilities of the membrane to ions. I'm sure the OP understands this, but for the general reader, you can read about this basic principle in any neuroscience or physiology textbook. You can calculate the membrane potential using the Goldman equation or chord conductance equation. Both are representations of the same principle, but I think the chord conductance equation is more intuitive. We'll simplify for our purposes to.

$$mathcal{E}_m = frac{g_{i}}{g_T} mathcal{E}_i + frac{g_{j}}{g_T} mathcal{E}_j + frac{g_{k}}{g_T} mathcal{E}_k +…$$

Here, for ions i, j, k,… , the membrane potential is equal to the sum of a series of terms for each ion, with each ion term being a product of the equilibrium potential of that ion ($$mathcal{E}_i$$) and the portion of the total conductance across the membrane that the conductance of that ion represents. Conductance can roughly be understood as permeability. More open ion channels means a greater permeability/conductance to that ion.

Short term changes in membrane potential used in signaling are accomplished by changing the conductance of the membrane to specific ions. If the $$frac{g_i}{g_T}$$ increases for ion i, the membrane potential moves closer to the equilibrium potential for ion i.

The concentration gradient determines the equilbrium potential

Each ion has an equilibrium potential, a membrane potential at which the net current of an ion across the membrane is 0. From the Nernst equation, we can say:

$$mathcal{E}_i propto log_{10}frac{[I]_{out}}{[I]_{in}}$$.

Here $$[I]_{out}$$ is the concentration of the ion outside the cell, and $$[I]_{in}$$ is the concentration inside the cell. We've eliminated the proportionality constant because, in physiological conditions, it's constant, it's different for pancreatic $$eta$$-cells (vs. neurons), and it's not relevant to our discussion (since we're not going to make any calculations with real numbers. If you are very careful, you'll notice the log term has outside concentration on the top, inside concentration on the bottom. You may find the Nernst equation written with a negative proportionality constant and with the inside concentration on top. These are equivalent because of how logs work.

Changing conductance, or permeability, changes the membrane potential

When you increase the conductance of a membrane to a particular ion, the membrane potential moves closer to the equilibrium potential for that ion. This is why in the neuron, for example, increasing the conductance of the axon membrane to $$Na^+$$ causes depolarization. The equilibrium potential $$mathcal{E}_{Na}$$, is positive. The resting membrane potential is negative. Higher permeability to $$Na^+$$ moves the membrane potential closer to $$mathcal{E}_Na$$. Similarly, increasing the conductance of the axon membrane to $$K^+$$ (after the membrane has depolarized) repolarizes and then hyperpolarizes the membrane. $$mathcal{E}_K$$ is negative (more negative than resting membrane potential). Higher permeability to $$K^+$$ moves the membrane potential closer to that large negative $$mathcal{E}_K$$.

Increasing the permeability of pancreatic \$eta\$-cells to \$K^+\$ hyperpolarizes the membrane

I'm using examples of the neuron because this is typically where these concepts are most thoroughly taught, but lets try to apply our understanding to the pancreatic $$eta$$-cell. Concentrations, permeabilities, and membrane potentials are a little different, but not that much. Resting membrane potential for a $$eta$$-cell is about -60mV. Threshold potential for $$Ca^{++}$$ release (which leads to insulin secretion) is between -50 and -40 mV. (Refer to my earlier linked articles). I don't have an exact number for $$mathcal{E}_K$$, the equilibrium potential of $$K^+$$ in $$eta$$-cells, but it is more negative than the resting membrane potential of that cell. We know this because (as is demonstrated in the linked studies), the OP is correct, increasing the conductance of the membrane to $$K^+$$ causes a net $$K^+$$ current out of the cell, rather than in, moving the membrane potential to a more negative state (hyperpolarizing the membrane), similar to what we see in neurons.

Decreasing the permeability of pancreatic \$eta\$-cells to \$K^+\$ DEPOLARIZES the membrane

As discussed in Constanzo Chapter 9, ATP-sensitive $$K^+$$ channels close (not open) in response to an increase in the $$frac{[ATP]}{[ADP]}$$ ratio. This decreases the $$K^+$$ conductance of the membrane, allowing the membrane potential to move closer to other equilbrium potentials (e.g., $$mathcal{E}_{Na}$$, which is positive). With $$mathcal{E}_K$$, which is more negative than the prior membrane potential, contributing less, the membrane potential becomes less negative, or depolarizes.

You can use a less mathematical reasoning to work out what happens when the $$K^+$$ conductance decreases as well. Close a $$K^+$$ channel and positive ions that would have moved out of the cell stay inside the cell, making membrane potential less negative, depolarizing the membrane. This is effectively the same as bringing positive ions inside the cell.

When the membrane depolarizes, $$Ca^{++}$$ is released, which causes secretion of insulin.

Hypokalemia

In hypokalemia, outside concentrations of $$K^+$$ decrease. This has an effect on the equilibrium potential, $$mathcal{E}_K$$. From the Nernst equation above, we can look at the log term to see how $$mathcal{E}_K$$ changes when $$[K^+]_{out}$$ decreases. The fraction $$frac{[K^+]_{out}}{[K^+]_{in}}$$ is less than 1 in all human cells (there is more $$K^+$$ inside the cell than out), so the log term is going to be log(some number between 0 and 1). You can work this out using a calculator, but in this domain (0-1), the log is negative. It is larger and negative the closer you get to 0, smaller (but still negative), the closer you get to 1. If this behavior is unfamiliar to you, I encourage you to explore it with a calculator.

If you decrease the numerator in the log term ($$log_{10} frac{out}{in}$$), as we do in hypokalemia, you get a larger negative number. This doesn't change the net direction of flow, or current for $$K^+$$ at levels that occur in the cell. It's still net out. $$mathcal{E}_K$$ is more negative than it would otherwise be, so why doesn't decreasing conductance/permeability by closing the ATP sensitive $$K^+$$ channels do the same thing and depolarize the membrane?

Closing ATP sensitive $$K^+$$ channels in the setting of hypokalemia does cause depolarization, but not enough. You have to go back to the chord conductance or Goldman equation and consider the effect of $$mathcal{E}_K$$ on the membrane potential before the ATP sensitive $$K^+$$ channels are closed. With a more negative $$mathcal{E}_K$$, the chord conductance term $$frac{g_{K}}{g_T} mathcal{E}_K$$ is more negative, and the overall $$mathcal{E}_m$$ is more negative. Global hypokalemia effectively hyperpolarizes the membrane, not just in the pancreatic $$eta$$-cell, but everywhere. This is an important principle for understanding the consequences of hypokalemia, not just in insulin secretion, but in all settings. As a rule, excitable membranes are sluggish in hypokalemia (except Purkinje fibers). This is why, for example, it causes muscle weakness.

Potassium as a link between insulin and the renin-angiotensin-aldosterone system

Purpose: To focus on the interactions between insulin secretion, glucose tolerance and insulin sensitivity on the one hand and the renin-angiotensin-aldosterone system on the other.

Effects on insulin: Insulin is a potent stimulus for hypokalaemia, sparing body potassium from urinary excretion by transporting it into cells. Potassium also appears to play a key role in the antinatriuretic effect of insulin. Insulin-induced hypokalaemia increases plasma renin and angiotensin II levels while decreasing the serum aldosterone concentration. In turn, the renin-angiotensin-aldosterone system affects glucose tolerance by modulating plasma potassium levels, which act as a stimulus for glucose-induced insulin release.

Effects of angiotensin converting enzyme (ace) inhibition: Interference with the renin-angiotensin-aldosterone system by ACE inhibition blunts the hypokalaemic response to insulin, thereby improving glucose-induced insulin release and oral glucose tolerance. ACE inhibition, however, does not cause major changes in insulin sensitivity.

Potassium and blood pressure: Plasma potassium levels are inversely related to blood pressure, both in population surveys and in intervention studies. In addition, in patients with essential hypertension, the level of plasma potassium appears to predict the blood pressure response to ACE inhibition.

Summary: Potassium metabolism is an important link between carbohydrate metabolism and the renin-angiotensin-aldosterone system by way of a double-feedback mechanism. Through the potential effects on blood pressure control, plasma levels of potassium represent a link between insulin and blood pressure in humans.

Gastric Secretion: Mechanism and Hormones | Digestive System | Biology

In this article we will discuss about:- 1. Mechanism of Gastric Secretion 2. Hormones of Gastric Secretion 3. Effects of Various Chemicals and Drugs 4. Investigation.

Mechanism of Gastric Secretion:

The mechanism of gastric secretion has been chiefly studied on animals. Some direct evidence has been obtained in man, from cases of accidental gastric fistula through which gastric juice could be collected. In man another method is often applied known as fractional test meal. This method is commonly adopted for investigating gastric functions in man at bedside.

In animals two very important experiments have been done for investigating the mechanism of gastric secretion:

(1) The experiment of sham feeding, and

(2) The preparation of Pavlov’s pouch.

(Fig. 9.31). The oesophagus of a dog is exposed and divided in the middle of the neck and the two cut ends are brought to the surface. When the dog swallows food, the latter comes out through the upper cut end and does not enter the stomach. This experiment is very important to prove whether the food can stimulate gastric secretion even before entering stomach.

2. Pavlov’s Pouch (Fig. 9.32):

It is a small diverticulum prepared from the body of the stomach and representing about one-eighth of the whole stomach. The pouch is prepared in such a way that its inner end is shut off from the main cavity of the stomach by two layers of mucous membrane while the outer end opens outside through an wound in the abdominal wall. During the surgical procedure least injury is done to the vessels and nerves, so that the pouch secretes a juice identical with that secreted by the body of the stomach.

This preparation has got the following advantages:

i. Pure gastric juice can be collected from this pouch unmixed with food. This is a great help in studying the variations of gastric secretion—both in quality and quantity—as may be produced by different stimuli.

ii. It is found in dogs, that the juice secreted by the pouch is always a constant fraction of the total amount of juice secreted by the main stomach. From this the total secretion can be found out.

Hormones on Gastric Secretion:

Hormones secreted by different endocrine glands influence gastric secretion.

i. Glucocorticoids secreted by adrenal cortex stimulated by ACTH increases acid and pepsin secretion by the stomach but decrease the mucous secretion, and thus make it more susceptable to ulceration.

ii. Epinephrine and norepinephrine, on the other hand, decrease gastric secretion.

iii. Hypophysectomy causes characteristic changes in the chief cells of the gastric glands, consisting of a decrease in the size of nucleus and loss of most of the pepsinogen granules. Secretion of hydrochloric acid is also reduced.

iv. Serotonin, possibly a hormone secreted by certain enterochromaffin cells in the intestinal mucosa, inhibits gastric secretion particularly that activated reflexly or by cholinergic drugs.

v. Reserpine, which is used as a tranquiliser and in the treatment of high blood pressure, produces increased acid production in the stomach when given in a high dose for a long time. The mode of action is not clear.

vi. Insulin acts through its effect on glucose metabolism and has an effect on the gastric glands similar to that of stimulation of the vagi. Release of gastrin is reduced by insulin.

Effects of Various Chemicals and Drugs on Gastric Secretion:

Numerous chemical agents and various drugs affect gastric secretion.

i. Histamine is a powerful stimulant of gastric secretion. It is thought that it acts directly on the parietal cells. Histalog, an anlog of histamine, is also a powerful gastric stimulant.

ii. Caffeine and alcohol are strong secretory stimulants, producing a juice of high acidity and rich in mucin.

iii. Parasympathetic agents, such as acetylcholine, mecholyl, etc., are secretory stimulants.

iv. Secretory depressants are also known. Alkali and acids depress gastric secretion. Belladona, atropine, hyoscine, etc., are secretory depressants.

Investigation of Gastric Secretion in Man:

The method which is commonly adopted for investigating gastric secretion in man is called fractional test meal or gastric analysis.

The procedure is as follows:

The subject is given diet on the previous evening. In the next morning the patient is made to swallow a thin flexible rubber tube known as the stomach tube (Ryle’s tube, Lyon’s tube or some other modification, (Fig. 9.34). The tube has got three markings on it. When swallowed up to the first mark coinciding with incisor teeth (about 30 cm or 12 inches from the end) the end is near the cardiac end of the oesophagus if up to the second mark the end is within the stomach when up to the third mark the end has entered the duodenum.

During gastric analysis, the subject swallows the tube up to the second mark. The resting content of the stomach are aspirated out and is preserved. Then the patient takes about a pint of oat meal gruel, the stomach tube remaining swallowed as it was. Every fifteen minutes a sample of about 20 ml is drawn out and the procedure is continued for three hours. Altogether thirteen samples are obtained, the resting contents being the first sample.

Each sample is then tested for the following:

Normally the free HCI of the rest­ing contents lies between 1.5 and 2.0 mEq or 54 – 60 mgm (34.46 mgm = lmEq) of HCI. Af­ter the gruel is taken the acidity is reduced by dilution. The free HCI then steadily rises and becomes maximum 40 – 50 mEq of HCI in the second hour. Then it gradually declines. When bile enters due to regurgitation, gastric acidity is reduced (Fig. 9.35). In gastric ulcer the value increases up to 3 times.

This includes HCI com­bined with protein, mucus, etc., as well as or­ganic acids such as lactic acid, produced by fermentation. Normally it varies from 10-55 mEq of HCI. In hypochlorhydria or achlorhydria the rate of fermentation is more, so that, this Figure becomes high.

This is the sum total of free HCI organic acids, combined acid and acid salts.

This includes free HCI, com­bined HCI and inorganic chlorides. Its impor­tance lies in the fact that the free acid level is always disturbed by the entry of bile, but the total chlorides remain unaffected. Hence, esti­mation of total chlorides, along with estimation of free acidity, will give more correct information about the secreting capacity of stomach.

Sugar is produced by salivary digestion of starch. Presence of sugar and starch indicates that stomach has not yet completely emptied. Their absence, therefore, indicates the emptying time.

Presence of bile as indicated by yellow or green colour of the stomach contents shows duodenal regurgitation. It also indicates that pyloric sphincter has opened and gastric emptying has begun. Generally bile first appears in the second hour.

It is not a normal constituent. Its presence shows ulcer, cancer or other haemorrhagic conditions of stomach. In case of ulcer the blood might be bright red or brown in colour and in case of cancer it is brownish-black.

Derived mainly from fermentation of carbohydrate when there is a fall in the gastric hydrochloric acid. Hence, if free HCI is low, lactic acid will be high.

Excess of mucus indicates an irritated condition of the stomach. [Gastritis, etc.]

xi. Presence of Pepsin:

It indicates the functional condition of the peptic cells.

In addition to this, microscopic examination of each sample is carried out for blood cells, epithelial cells, tumour cells, bacteria, etc. Taking these facts into account a normal gastric analysis curve will be as shown in Fig. 9.36.

It will be seen from there that, this test not only gives an idea of the secreting capacity of stomach but the degree of motility (to be obtained from the emptying time), opening time of pylorus, duodenal regurgitation, etc., can be also known from it. In certain pathological condi­tions, characteristic variation of the curve is seen, viz., in gastric cancer and pernicious anaemia there will be achlorhydria, in duodenal ulcer the curve will be high ‘climbing’ type and so on.

To make a complete inves­tigation of gastric functions only fractional test meal is not enough radiological exam­ination after barium meal has also to be performed. This will show the size, shape, motility, emptying time, presence of ul­cer, etc., in the stomach.

Other Functional Tests:

Other functional tests of stom­ach are as follows:

i. Histamine Test of Gastric Secretion:

Histamine is a strong stimulant for the oxyntic cells. Only 0.5 mgm histamine chloride, injected subcutaneously, will stim­ulate gastric secretion at the rate of 200 ml per hour. In those patients who show achlorhydria with ordinary gastric analysis, this histamine test is performed in order to see the condition of the oxyntic cells. If per­formed in a normal subject, it shows the maximum secretory capacity of the oxyntic cells. Negative response indicates atrophy of oxyntic cells.

ii. Insulin Test of Gastric Secretion:

Insulin reduces blood sugar which in its turn, stimulates vagus and thereby excites gastric secretion. A positive insulin test is proof of the presence of intact vagal fibres but a negative result is less conclusive since some subjects with intact vagi fail to secrete in response to insulin.

However, the test is effective in most cases. Seven units of insulin given subcutaneously produce marked secretion of gastric juice (which is rich in HCI and pepsin content) although reduction of blood glucose by insulin to moderate degree causes inhibition of secretion. The secretion takes place after a latent period of 40 minutes.

This test also shows the secretory capacity of stomach. Since the response does not occur in absence of vagus so the absense of gastric secretion following insulin induced hypoglycaemia is a test for the vagal denervation. A combined insulin-histamine test (7 units of insulin, followed 20 minutes later by 0.5 mgm of histamine) is also advocated by some, to test the maximum secretory power of the gastric mucosa.

In about 2 – 5% of normal healthy people neither any HCI nor any pepsin is found in the gastric juice. This condition is called achylia gastrica. This is a congenital error due to non-development of oxyntic and peptic cells. This condition does not affect health. Because pancreatic enzymes can digest all the ingested foodstuffs. In certain pathological conditions (pernicious anaemia, cancer of the stomach, etc.), the acidity is very low (hypochlorhydria) or it may be altogether absent (achlorhydria).

On the other hand, some people may have higher acidity in the gastric juice (hyperchlorhydria). In females the acidity is proportionally lower than in males. In the infants and children it is much lower than in adults. In men after thirty and women after fifty both free and total acidity gradually decline. A high gastric acidity is generally associated with hypermotile stomach. In people with poor muscular built and sedentary habits the acidity is low.

Role of Hormones on Carbohydrate Metabolism | Organisms | Biology

The principal effect of insulin on carbohydrate metabolism is to increase the utilisation of glucose by most tissues. The most important effect of insulin is to increase the rate of glycogen formation. It has been described earlier that insulin is secreted from the β-cells of the islets of Langerhans. It should be borne in mind that the degree of insulin activity and probably the actual production of insulin by the β-cells of the pancreatic islets are effected by the level of blood sugar.

Hyperglycaemia stimulates the pancreas to produce the increased quantity of insulin and if the hyperglycaemia is maintained for a longer period then the permanent damage to the β-cells may ensue and thus permanent diabetes prevails. But it is difficult to say that the hypoglycaemia leads to decrease in insulin secretion in same level. Because during such state adrenaline is secreted and this hormone thus masks the effect of insulin on liver glycogen.

There are other factors which either suppress the production of insulin or may render its action less effective. Growth hormone, glucocorticoids (cortisone and hydrocortisone) and also thyroxine act in such process. There is evidence that growth hormone and glucocorticoids inhibit phosphorylation of glucose by affecting hexokinase activity. These two hormones have got no action on the entry of glucose into the cells.

Glucagon, the α-cell hormone of pancreatic islets and also of gastro-intestinal tract seems to counteract the insulin by exhaustion atrophy of β-cells. Alloxan also counteracts the insulin by damaging the β-cells.

The insulin is mostly concerned with the utilisation of glucose by the tissues and this involves the phosphorylation in which the chain of conversions of glucose and its combination is controlled by a series of enzymes of which hexokinase is an important one. Insulin stimulates the catalytic action of hexokinase.

Insulin has been found to increase the glycogen synthetase activity in muscle. It is claimed that considerably more blood sugar is converted to fatty acids and eventually deposited in the fat depots than that which is turned into tissue glycogen. Insulin increases the conversion of sugar to fatty acids.

Furthermore, formation of liver glycogen is quantitatively higher than the formation of tissue glycogen. The influence of insulin on carbohydrate metabolism has been presented schematically in Fig. 10.18.

2. Role of Glucagon:

Glucagon is known as hyperglycaemic—glycogenolytic factor (HGF). Main effect of glucagon on carbo­hydrate metabolism is to increase the breakdown of liver glycogen to glucose and hence hyperglycaemia. It does not cause the breakdown of muscle glycogen. Glucagon is secreted from the a-cells of the islets of Langerhans, walls of duodenum and stomach. If glucose is placed in the gastro-intestinal tract then gluca­gon is secreted from the gastro-intestinal tract directly in the circulation.

Glucagon raises the blood glucose level by stimulating the adenyl cyclase in the liver leading to the formation of cyclic AMP that activates the phosphorylase. Glucagon has got no effect on muscle phosphorylase. Due to action of glucagon on adenyl cyclase, cyclic AMP is formed from ATP. The cyclic AMP thus activates the phosphorylation process of liver glycogen and thus glucose is formed.

Besides this, glucagon also stimulates the process of neoglucogenesis from available amino acids in the liver. Thus increased activity of glucagon increases the blood glucose level which may indirectly stimulate the β-cells activity for the production of excess insulin. Thus prolonged treatment with glucagon causes exhaus­tion of β-cells and diabetes is produced. Role of glucagon on carbohydrate metabolism has been presented schematically in Fig. 10.19.

3. Growth Hormone:

It is established that growth hormone opposes the hexokinase mechanism, so that the phosphorylation of glu­cose is depressed causing hyperglycaemia. This hyperglycaemia causes secretion of insulin from the β-cells. Prolonged effect of growth hormone may eventually exhaust the β-cells. Histologically it is proved that α-cells remains unaffected when the β-cells are damaged due to prolonged glucagon therapy. Role of growth hor­mone on carbohydrate metabolism has been presented schematically in Fig. 10.20.

Like growth hormone adrenal glucocorticoids also elevate the blood sugar level. It is claimed that these hor­mones produce the hyperglycaemic effect by increased neoglucogenesis in the liver. It also produces hyper­glycaemia by decreasing the glucose utilisation in the liver and peripheral tissue possible through the inhibi­tion of phosphorylation. In patients with adrenal insufficiency, the blood glucose-lowering effect of insulin is greatly enhanced. In experimental diabetes, adrenalectomy may markedly ameliorate the diabetic state.

In cats and rats after bilateral adrenalectomy, the carbohydrate reserves of the liver and muscles are deplet­ed and hypoglycaemia is produced. But this hypoglycaemic condition is corrected only when corticoids and glucose together, but not glucose only is provided.

Epinephrine increases the blood sugar level and this is one of the most important factors in the normal or­ganism for counteracting the hypoglycaemic action of insulin. Epinephrine causes rapid breakdown of liver glycogen to glucose with the production of hyperglycaemia. In muscle, the epinephrine causes the breakdown of glycogen to lactic acid.

Epinephrine is released as an emergency in response to emotional excitement, in­jury, fright, stress, exercise, etc., and consequently augments blood sugar. Hypoglycaemia from any cause leads to secretion of epinephrine from adrenal medulla and brings the blood glucose level back to normal. Epinephrine exerts its hyperglycaemic effects by increasing the rate of glycogenolysis in the liver and muscles.

Muscle glycogen is not directly available for the replenish of glucose. By the action of epinephrine, both liver and muscle glycogen are converted into hexose phosphate. In the liver, glucose is formed by the action of phosphatase on the hexose phosphate. But the enzyme, phosphatase, is lacking in muscle and for this reason it has to complete the whole glycolytic process with the formation of lactic acid.

Some amount of lactic acid may be transformed into liver glycogen which under the action of epinephrine or glucagon, may be convert­ed into glucose. So the ultimate action of epinephrine on the muscle glycogen is the increased deposition of liver glycogen. The breakdown of the liver and muscle glycogen under the action of epinephrine takes place through the activation of adenyl cyclase that catalyses the formation of cyclic AMP.

Epinephrine also influences the carbohydrate metabolism indirectly by stimulating the adenophysis in releasing the ACTH. ACTH on the other hand augments the release of glucocorticoids from the adrenal cor­tex. This is observed in emergency, stress, fright, exercise, hypoglycaemia, etc. Insulin and epinephrine play important part in the homeostatic regulation of blood sugar. Because hypoglycaemia stimulates the secretion of epinephrine whereas hyperglycaemia stimulates the secretion of insulin.

Summarily, epinephrine elevates the blood sugar in three ways:

(i) By mobilising the carbohydrate stores of the liver

(ii) By indirect formation of glucose from muscle glycogen and

(iii) By excessive formation of glucocorticoids indirectly through liberation of ACTH.

6. Role of Posterior Pituitary Hormones (Vasopressin and Oxytocin):

A large dose of vasopressin and oxytocin raise the blood sugar level temporarily. In rabbits vasopressin is more effective in raising the blood sugar level, whereas in dogs oxytocin has greater hyperglycaemic effect.

7. Role of Thyroid Hormones:

Thyroid hormones increase the glucose absorption from the intestine. The rate of glucose absorption from the intestine is decreased in hypothyroidism. The principal diabetogenic effect of thyroid hormones is possibly due to this increased absorption of glucose from the gut. The hormone also depletes some liver glycogen. Administrations of thyroid hormones to normal animals do not cause immediate effect on blood sugar but liver glycogen is depleted within six to eight hours.

In hyperthyroidism the diabetic condition is aggravated but thyroidectomy markedly decreases the inten­sity of the diabetes. Rate of protein catabolism is increased by excessive thyroid hormone and for this reason increased hyperglycaemia is observed due to neoglucogenesis from amino acids. Besides this, the thyroid hor­mones sensitise the adrenaline and the hepatic depletion of glycogen may be the indirect effect of adrenaline by thyroid hormones. Thyroid hormones also raise the renal threshold for glucose.

8. Role of Anterior Pituitary Hormones:

Like growth hormone, the anterior pituitary hormones ACTH and TSH may have some indirect role on the glucose metabolism through acting on the respective target organs. Direct role on the metabolism is possible lacking.

9. Role of Prolactin:

Has got some anti-insulin effect. It reduces the sensitivity of the animals to insulin. The diabetogenic action of prolactin is probably due to this desensitisation of animals to insulin. After hypophysectomy, the blood sugar level is reduced but administration of prolactin raises the level towards normal.

10. Role of Sex Hormones:

Female sex hormones, oestrone and oestradiol, decrease the diabetic condition possible by stimulating the se­cretion of insulin.

Male sex hormones, testosterone also markedly increases the severity of the diabetic condition of the castrated animals.

The endocrine control of carbohydrate metabolism has been presented schematically in Fig. 10.21.

Dissection of the cellular and molecular mechanisms of insulin secretion

The objective of β-cell electrical activity is to generate the signal that initiates insulin secretion, i.e., the increase in intracellular Ca 2+ concentration ([Ca 2+ ]i). The recent development of techniques that allow the detection of secretion in single cells [capacitance measurements and carbon fiber amperometry (1, 3)], combined with the tools of molecular biology, have resulted in a dramatic increase in the knowledge of the processes involved. Many of the proteins that are involved in the regulation of neurotransmitter release have recently been identified also in the pancreatic β-cells. These include the SNARE proteins synaptobrevin/VAMP, SNAP-25, syntaxin, α-SNAP, and the putative Ca 2+ -sensing proteins synaptotagmin I and II (for review, see Ref. 15).

In this review, we focus on the characterization of the functional properties of exocytosis in the β-cells. The experiments we describe were conducted by a combination of the whole cell configuration of the patch-clamp technique with capacitance measurements as a single-cell indicator of insulin secretion (1, 2). This experimental approach enables us to study the properties of secretion in single voltage-clamped β-cells. Exocytosis can thereby be determined independently of any spontaneous changes of the membrane potential, which would (via modulation of voltage-dependent Ca 2+ influx) influence the rate of Ca 2+ -induced secretion. Additional advantages of capacitance measurements over more traditional approaches to detecting insulin secretion include 1) that the measurements can be conducted on individual cells and 2) the high (1–10 ms) temporal resolution.

Hyperkalemia

Pseudohyperkalemia.

Pseudohyperkalemia should be excluded before concluding that hyperkalemia is due to cell shift or abnormal renal K + excretion. Pseudohyperkalemia is the result of release of K + from cells during the phlebotomy procedure, or specimen processing, and is defined by a serum K + concentration 0.5 mEq/l greater than the plasma K + concentration. In addition to fist clenching, application of tourniquets, and use of small-bore needles, high cell counts such as thrombocytosis (>500,000/cm 3 ) and pronounced leukocytosis (70,000/cm 3 ) are risk factors for this disorder (37).

Increased dietary intake.

It is difficult to ingest enough K + to become hyperkalemic in the presence of normal renal and adrenal function. Dietary intake as a contributor to hyperkalemia is usually in the setting of impaired kidney function. Melons, citrus juice, potatoes, avocado, and salt substitutes are just a few of the common dietary sources enriched in K + content that should be avoided in patients with hyperkalemia.

Cell shift.

Cellular redistribution is a more important cause of hyperkalemia than hypokalemia. It is important to note that as little as a 2% shift of intracellular K + to the extracellular fluid will result in a serum K + of 8 mEq/l (Table 1). Disturbances in serum K + concentration due to cell shifts are generally transient in nature, whereas sustained hyperkalemia is due to impaired renal excretion. Metabolic acidosis promotes K + exit from cells dependent upon the type of acid present. Mineral acidosis (NH4Cl or HCl) causes the greatest efflux of K + from cells, whereas organic acidosis (i.e., lactic, β-hydroxybutyric, or methylmalonic acid) results in no significant efflux of K + (Fig. 6). Hyperkalemia associated with lactic acidosis is the result of cell ischemia.

Fig. 6.Mineral acidosis (normal gap hyperchloremic acidosis) tends to cause a greater decrease in intracellular Na + compared with organic acidosis, and therefore, they are more likely to be accompanied by hyperkalemia. Decreased intracellular Na + leads to greater K + exit from the cell due to decreased activity of the Na + -K + -ATPase. Sodium-hydrogen antiporter 1(NHE1) and electrogenic sodium bicarbonate cotransporter 1 and 2 (NBCe1 and −2) are membrane transporters that serve to defend cell pH particularly in skeletal muscle. Mineral acidosis reduces the activity of NHE1 and NBCe1 and −2 due to increased extracellular H + concentration and reduced extracellular HCO3 − concentration, respectively. In addition, the decrease in HCO3 − concentration accompanied by an increase in Cl − will favor movement of Cl − into the cell by way of Cl − -HCO3 − exchange, secondarily enhancing K + efflux by K + -Cl − cotransport. During organic acidosis, there is inward movement of H + and the accompanying organic anion on the monocarboxylate transporter 1 and 4 (MCT1 and −4), which results in a larger fall in cell pH in comparison to mineral acidosis. This more acidic intracellular pH allosterically increases activity of the Na + -H + exchanger and provides a more favorable gradient for inward Na-HCO3 cotransport. An adequate amount of intracellular Na + is available to better maintain activity of the Na + -K + ATPase, thus minimizing any change in extracellular K + concentration.

Cell shift is a potential complication of hypertonic states (38). Hyperglycemia leads to water movement from the intracellular to extracellular compartment. This water movement favors K + efflux through K + channels driven by solvent drag. In addition, cell shrinkage causes intracellular K + concentration to increase, creating a more favorable concentration gradient for K + efflux. This same phenomenon has been described in neurosurgical patients given large amounts of hypertonic mannitol. Table 1 lists various causes of hyperkalemia due to cell shift.

Impaired renal excretion.

Although redistribution of K + can result in hyperkalemia, the rise in K + is generally mild and not sustained. Prolonged and severe hyperkalemia implies the presence of concomitant decreases in renal K + excretion. In most instances, the clinical setting will allow the clinician to determine whether there is a disturbance in renal K + excretion or not. Decreased renal excretion of K + can be due to one or more of three abnormalities: decreased distal delivery of Na + , mineralocorticoid deficiency, and/or abnormal cortical collecting tubule function (34), which will be discussed in further detail below.

Decreased distal delivery of Na + .

Acute decreases in glomerular filtration rate (GFR), as occurs in acute kidney injury, would not be expected to have a marked effect on K + excretion. However, acute decreases in GFR may lead to marked decreases in distal delivery of salt and water, which may secondarily decrease distal K + secretion. Thus, when acute kidney injury is oliguric, hyperkalemia is a frequent problem when nonoliguric, distal delivery is usually sufficient, and hyperkalemia is unusual.

Chronic kidney disease is more complicated. In addition to the decreased GFR and secondary decreases in distal delivery, there is nephron dropout and less collecting tubule mass to secrete K + . However, this is counterbalanced by a K + adaptation, in which the remaining nephrons develop an increased ability to excrete K + (52). Although patients with chronic kidney disease do not excrete a K + load as rapidly as individuals without chronic kidney disease, hyperkalemia is unusual until the GFR has fallen to <10 ml/min. The occurrence of hyperkalemia with a GFR of >10 ml/min should raise the clinician’s question if there might be decreased mineralocorticoid activity or a specific lesion of the cortical collecting tubule.

Decreased mineralocorticoid activity.

Decreased mineralocorticoid activity can result from disturbances that originate at any point along the renin-angiotensin-aldosterone system. Such disturbances can be the result of a disease state or be due to effects of various drugs (Fig. 7). The syndrome of hyporeninemic hypoaldosteronism accounts for the majority of unexplained hyperkalemia in patients where the GFR and K + intake would not be expected to result in hyperkalemia (22). Diabetic nephropathy and interstitial renal disease are the most common clinical entities associated with this syndrome.

Fig. 7.Disease states or drugs that interfere in the renin-angiotensin-aldosterone axis interfere in the mechanisms of renal K + secretion. In many clinical settings, the system is disrupted at multiple sites, magnifying the risk of hyperkalemia. NSAIDs, nonsteroidal anti-inflammatory drugs.

Distal tubular defect.

Certain interstitial renal diseases can affect the distal nephron specifically and lead to hyperkalemia in the presence of mild decreases in GFR and normal aldosterone levels. Many of these diseases are the same ones associated with hyporeninemic hypoaldosteronism, and frequently, the impaired renin release and defect in tubular secretion coexist. Examples include renal transplant patients, lupus erythematosus, amyloidosis, urinary obstruction, and sickle cell disease.

The K + sparing diuretics impair the ability of the cortical collecting tubule to secrete K + . The non-testosterone-derived progestin drospirenone contained in certain oral contraceptives possesses mineralocorticoid-blocking effects similar to what is seen with spironolactone. The serum K + should be monitored when these drugs are prescribed in patients receiving K + supplements, renin-angiotensin blockers, or nonsteroidal anti-inflammatory drugs (41).

Pseudohypoaldosteronism type II (Gordon syndrome) is an autosomal dominant form of hypertension in which hyperkalemia and metabolic acidosis are key features. Plasma concentrations of aldosterone are low despite the presence of hyperkalemia, which normally exerts a stimulatory effect on aldosterone released from the adrenal gland. The hypertension and hyperkalemia are particularly responsive to the administration of thiazide diuretics. Mutations in the WNK4 and WNK1 protein kinases and their regulatory proteins SPAK and OxSR1 are responsible for this disease (40).

Pseudohypoaldosteronism type I is a disorder characterized by mineralocorticoid resistance that typically presents in newborns. Clinical findings include hyperkalemia, metabolic acidosis, and a tendency toward volume depletion due to renal salt wasting (44). In the autosomal-recessive form of the disease, the defect has been localized to homozygous mutations in the three subunits of the epithelial sodium channel. The autosomal-dominant form of the disease results from mutations in the mineralocorticoid receptor that in turn result in mineralocorticoid resistance.

Clinical features of hyperkalemia.

All of the clinically important manifestations of hyperkalemia occur in excitable tissues. Neuromuscular manifestations include paresthesias and fasciculations in the arms and legs. As the serum K + continues to rise, an ascending paralysis with eventual flaccid quadriplegia supervenes. Classically, trunk, head, and respiratory muscles are spared however, respiratory failure also can occur, albeit rarely.

The depolarizing effect of hyperkalemia on the heart is manifested by changes observable in the electrocardiogram (ECG). The progressive changes of hyperkalemia are classically listed as peaking of T waves, ST segment depression, widening of the PR interval, widening of the QRS interval, loss of the P wave, and development of a sine-wave pattern. The appearance of a sine-wave pattern is ominous and is a harbinger of impending ventricular fibrillation and asystole.

Less common patterns on the ECG include a right-bundle branch block and right precordial ST segment elevations reminiscent of the Brugada syndrome. The tall, narrow, and symmetrical peaked T waves typical of hyperkalemia can occasionally be confused with the hyperacute T-wave change associated with a ST segment elevation myocardial infarction. A pseudoinfarct pattern has also been described, resembling both an anteroseptal and inferior wall myocardial infarction.

The correlation of ECG changes and serum K + concentration depend on the rapidity of the hyperkalemia onset. Generally, with acute onset of hyperkalemia, ECG changes appear at a serum K + of 6–7 mEq/l. However, with chronic hyperkalemia, the ECG may remain normal up to a concentration of 8–9 mEq/l. Despite these generalities, clinical studies show a poor correlation between serum K + concentration and cardiac manifestations (29).

Treatment of chronic hyperkalemia.

The initial approach is to review the patient’s medication profile and whenever possible discontinue drugs that can impair renal K + excretion (32). Patients should be questioned specifically as to the use of over-the-counter, nonsteroidal, anti-inflammatory drugs as well as herbal remedies since herbs may be a hidden source of dietary potassium. Patients should be placed on a low K + diet, with specific counseling against the use of K + containing salt substitutes. Diuretics are particularly effective in minimizing hyperkalemia. In patients with an estimated glomerular filtration rate >30 ml/min, thiazide diuretics can be used, but with more severe renal insufficiency, loop diuretics are required.

In patients with chronic kidney disease and metabolic acidosis, administration of sodium bicarbonate is an effective strategy to minimize increases in the serum K + concentration. Ensuring that the patient is first on effective diuretic therapy will lessen the likelihood of developing volume overload as a complication of sodium bicarbonate administration.

The development of hyperkalemia after the administration of renin-angiotensin blockers is of particular concern because patients at highest risk for this complication are often times the same ones who derive the greatest cardiovascular benefit. In addition to the steps mentioned previously, the risk of hyperkalemia with these drugs can be minimized by initiating therapy at low doses. The serum K + should be checked within 1 wk of starting the drug. If the K + is normal, then the dose of the drug can be titrated upward. With each increase in dose, the serum K + should be remeasured 1 wk later. For increases in the serum K + concentration of ≤5.5 mEq/l one can lower the dose, and in some cases the K + concentration will improve, allowing the patient to remain on the renin-angiotensin blocker, albeit at a lower dose. Angiotensin receptor blockers and direct renin inhibitors should be used with the same caution as ACE inhibitors in patients at risk for hyperkalemia.

Sodium polystyrene sulfonate is commonly used to treat hyperkalemia in the acute setting. However, chronic use is poorly tolerated because the resin is usually given in a suspension with hypertonic sorbitol to promote an osmotic diarrhea. In addition, chronic use has been associated with mucosal injury in the lower and upper gastrointestinal tract (1). There are new oral K + binding drugs that have been shown to be effective in preventing development of hyperkalemia. Patiromer is approved for clinical use, and ZS-9 is pending approval. Both agents exhibit good tolerability and are not associated with serious adverse effects. Clinical trials demonstrate that these compounds lower the risk of incident hyperkalemia associated with renin-angiotensin-aldosterone system blockade in people with diabetes and heart failure and/or who have chronic kidney disease (4, 23, 59).

Hypokalemia can be caused by decreased intake of potassium or shift of extracellular potassium into cells, but it is usually caused by excessive losses of potassium in the urine or from the gastrointestinal tract.

Clinical signs include muscle weakness, cramping, fasciculations, paralytic ileus, and when hypokalemia is severe, hypoventilation, and hypotension.

ECG changes typically occur when serum potassium is < 3 mEq/L (< 3 mmol/L), and include ST segment sagging, T wave depression, and U wave elevation. With marked hypokalemia, the T wave becomes progressively smaller and the U wave becomes increasingly larger.

Hypokalemia may cause premature ventricular and atrial contractions, ventricular and atrial tachyarrhythmias, and 2nd- or 3rd-degree atrioventricular block eventually, ventricular fibrillation may occur.

Replace potassium orally, giving 20 to 80 mEq (20 to 80 mmol)/day unless patients have ECG changes or severe symptoms.

For hypokalemic arrhythmia, give IV potassium chloride through a central vein at a maximum of 40 mEq (40 mmol)/hour and only with continuous cardiac monitoring routine IV infusion should be no more than 10 mEq (10 mmol)/hour.

Diagnosis

The initial diagnostic approach begins with the clinical history, review of medications, and physical examination. Symptoms and signs include muscular weakness or flaccid paralysis, ileus, and characteristic electrocardiograph (ECG) changes ( Figure 1 21) . Laboratory tests should be directed towards causes suggested by the history and physical examination, with attention to serum electrolytes, creatinine, and blood urea nitrogen. A spot urine test for potassium, creatinine, and osmoles should be obtained to calculate the fractional excretion of potassium and the transtubular potassium gradient (Table 422 , 23) . The transtubular potassium gradient is an assessment of renal potassium handling, with a normal value of eight to nine, rising at times to 11 after an increase in potassium intake. Values lower than five in the face of hyperkalemia suggest an inappropriate renal response to high potassium22 a very low value suggests hypoaldosteronism.

Typical electrocardiograph changes seen in patients with hyperkalemia

Reprinted with permission from Slovis C, Jenkins R. ABC of clinical electrocardiography: conditions not primarily affecting the heart. BMJ 2002324:1320 .

Typical electrocardiograph changes seen in patients with hyperkalemia

Reprinted with permission from Slovis C, Jenkins R. ABC of clinical electrocardiography: conditions not primarily affecting the heart. BMJ 2002324:1320 .

Diagnostic Equations for Hyperkalemia

Fractional excretion of potassium (FEK)

FEK less than 10 percent indicates renal etiology FEK greater than 10 percent indicates extrarenal cause

Values can be increased in chronic renal failure.

Gradient less than 6 to 8 indicates renal cause Gradient greater than 6 to 8 indicates extrarenal cause.

Values can be increased in chronic renal failure.

UK = urine potassium SK = serum potassium UCr = urine creatinine SCr = serum creatinine Uosm = urine osmolality Sosm = serum osmolality.

*— For the most accurate representation of the kidney’s response to hyperkalemia, these measurements should be drawn before the serum potassium is corrected .

†— Plasma values for potassium and osmolality are recommended for this equation, but serum values are listed because these are more commonly available .

Information from references 22 and 23 .

Diagnostic Equations for Hyperkalemia

Fractional excretion of potassium (FEK)

FEK less than 10 percent indicates renal etiology FEK greater than 10 percent indicates extrarenal cause

Values can be increased in chronic renal failure.

Gradient less than 6 to 8 indicates renal cause Gradient greater than 6 to 8 indicates extrarenal cause.

Values can be increased in chronic renal failure.

UK = urine potassium SK = serum potassium UCr = urine creatinine SCr = serum creatinine Uosm = urine osmolality Sosm = serum osmolality.

*— For the most accurate representation of the kidney’s response to hyperkalemia, these measurements should be drawn before the serum potassium is corrected .

†— Plasma values for potassium and osmolality are recommended for this equation, but serum values are listed because these are more commonly available .

Information from references 22 and 23 .

Hyporeninemic hypoaldosteronism should be considered in patients with diabetes and hyperkalemia, who generally have a low serum aldosterone. A trial of oral fludrocortisone (Florinef) is generally the most practical way to empirically establish this diagnosis if the patient has hyporeninemic hypoaldosteronism, potassium levels will return to normal in a day or two after initiation of fludrocortisone.24

Cerebral regulation of hepatic metabolism

High energy requirements and limited energy storage capacity in the brain may explain why cerebral energy supply by glucose and ketones is completely dependent on the liver and, to some extent, kidney, during starvation and nearly independent of direct endocrine regulation. Conversely, cerebral insulin action may affect appetite control, mood, cognitive function and possibly peripheral glucose metabolism 128 . In mice, insulin and leptin act directly on the hypothalamic arcuate nucleus to activate proopiomelanocortin and inhibit Agouti-related protein neurons, whereas adipostatic signals stimulate melanocortin 4-expressing paraventricular neurons to induce satiety and energy expenditure 129 . Hypothalamic inflammation, reflected by higher mediobasal hypothalamic gliosis in obese rodents and humans 130 , has been suggested to lead to chronic central insulin and leptin resistance, which would promote excessive food intake and bodyweight gain. In rodents, central insulin action lowered EGP, hepatic gluconeogenesis, WAT lipolysis and glucagon secretion, but increased muscle glucose uptake 131,132,133,134,135 (Fig. 3). However, carefully controlled studies failed to confirm similar brain insulin action to regulate hepatic glucose fluxes in awake dogs 136,137 . In humans, intranasal insulin application did not affect fasting EGP, slightly decreased hepatic fat and increased ATP content in glucose-tolerant individuals, but not in people with T2D 138 . Similarly, KATP-channel activation decreased EGP only in glucose-tolerant humans 139,140 . Some studies suggested that cerebral insulin action results in parasympathomimetic IL-6 secretion by Kupffer cells to inhibit hepatic gluconeogenesis 133,141 . All of these studies are limited by experimental conditions such as application and dosing of insulin, spillover of intranasally delivered insulin into systemic circulation and suitable metabolic control. Nevertheless, the brain can be involved in other aspects of interorgan crosstalk, orchestrated by metabolites 11 , adipokines (leptin) or enteroendocrine circuits (such as glucagon-like peptide 1, gastric inhibitor peptide, ghrelin, cholecystokinin or fibroblast growth factor (FGF)-19). The hypoleptinaemia-mediated stimulation of the HPA axis with subsequent stimulation of WAT lipolysis 10 might be an example of how the human brain could indirectly regulate hepatic gluconeogenesis and EGP during starvation 12 .

Treatment of Hyperkalemia

GENERAL PRINCIPLES

The goals of acute treatment are to prevent potentially life-threatening cardiac conduction and neuromuscular disturbances, shift potassium into cells, eliminate excess potassium, and resolve the underlying disturbance. Patients with chronic hyperkalemia should be counseled to reduce dietary potassium. Although redistributive hyperkalemia is uncommon, a cautious approach is warranted because treatment may not involve attempts to eliminate potassium, and correction of the underlying problem can provoke rebound hypokalemia. Indications for prompt intervention are symptoms of hyperkalemia, changes on ECG, severe hyperkalemia (greater than 6.5 mEq per L), rapid-onset hyperkalemia, or underlying heart disease, cirrhosis, or kidney disease.24 , 30 , 33 – 35 Potassium should be monitored often because patients are at risk of redeveloping hyperkalemia until the underlying disorder is corrected and excess potassium is eliminated. Figure 3 is an algorithm for the management of hyperkalemia, and Table 3 22 , 30 , 36 summarizes medications used in the treatment of the condition.

Management of Hyperkalemia

Suggested algorithm for the management of hyperkalemia. (ECG = electrocardiography.)

Management of Hyperkalemia

Suggested algorithm for the management of hyperkalemia. (ECG = electrocardiography.)

Medications for the Treatment of Hyperkalemia

Calcium chloride, 10 mL of 10% solution IV over 5 to 10 minutes, or calcium gluconate, 30 mL of 10% solution IV over 5 to 10 minutes

Stabilizes cardiac muscle cell membrane no effect on serum potassium or total body potassium

May potentiate digoxin toxicity calcium chloride can cause phlebitis and tissue necrosis

Regular insulin, 10 units IV followed immediately by 50 mL of 50% glucose (25 g) IV

0.7 to 1 mEq per L (0.7 to 1 mmol per L)

Shifts potassium into cells no effect on total body potassium

May cause hypoglycemia glucose is unnecessary if serum glucose level is > 250 mg per dL (13.9 mmol per L) additive effect when combined with albuterol

0.5 to 1 mEq per L (0.5 to 1 mmol per L)

Shifts potassium into cells no effect on total body potassium

Can cause tachycardia and thus should be used with caution in patients with underlying heart disease potassium-lowering effect not reliable in all patients additive effect when combined with insulin

Sodium polystyrene sulfonate (Kayexalate)

Oral: 15 g, 1 to 4 times daily

Rectal: 30 to 50 g every 6 hours in a retention enema

Binds potassium in exchange for sodium lowers total body potassium

Association with gastrointestinal complications, particularly when combined with sorbitol should be avoided in patients at risk of abnormal bowel function

Information from references 22 , 30, and 36 .

Medications for the Treatment of Hyperkalemia

Calcium chloride, 10 mL of 10% solution IV over 5 to 10 minutes, or calcium gluconate, 30 mL of 10% solution IV over 5 to 10 minutes

Stabilizes cardiac muscle cell membrane no effect on serum potassium or total body potassium

May potentiate digoxin toxicity calcium chloride can cause phlebitis and tissue necrosis

Regular insulin, 10 units IV followed immediately by 50 mL of 50% glucose (25 g) IV

0.7 to 1 mEq per L (0.7 to 1 mmol per L)

Shifts potassium into cells no effect on total body potassium

May cause hypoglycemia glucose is unnecessary if serum glucose level is > 250 mg per dL (13.9 mmol per L) additive effect when combined with albuterol

0.5 to 1 mEq per L (0.5 to 1 mmol per L)

Shifts potassium into cells no effect on total body potassium

Can cause tachycardia and thus should be used with caution in patients with underlying heart disease potassium-lowering effect not reliable in all patients additive effect when combined with insulin

Sodium polystyrene sulfonate (Kayexalate)

Oral: 15 g, 1 to 4 times daily

Rectal: 30 to 50 g every 6 hours in a retention enema

Binds potassium in exchange for sodium lowers total body potassium

Association with gastrointestinal complications, particularly when combined with sorbitol should be avoided in patients at risk of abnormal bowel function

Information from references 22 , 30, and 36 .

URGENT TREATMENT

Intravenous Calcium . Intravenous calcium, which helps prevent life-threatening conduction disturbances by stabilizing the cardiac muscle cell membrane, should be administered if ECG changes are present.24 , 25 , 35 Intravenous calcium has no effect on plasma potassium concentration. If after five minutes, follow-up ECG continues to show signs of hyperkalemia, the dose should be repeated.37 Clinicians should be aware that intravenous calcium has a short duration, ranging from 30 to 60 minutes.

Insulin and Glucose . The most reliable method for shifting potassium intracellularly is administration of glucose and insulin. Typically, 10 units of insulin are administered, followed by 25 g of glucose to prevent hypoglycemia.37 Because hypoglycemia is a common adverse effect even with the provision of glucose, serum glucose levels should be monitored regularly. Patients with a serum glucose level of more than 250 mg per dL (13.9 mmol per L) typically do not require coadministration of glucose.

Inhaled Beta Agonists . Albuterol, a beta2 agonist, is an underutilized adjuvant for shifting potassium intracellularly.24 , 37 All forms of administration (i.e., inhaled, nebulized, and intravenous where available) are effective. It should be noted that the recommended dose of nebulized albuterol (10 to 20 mg) is four to eight times greater than the typical respiratory dose. There is an additive effect when albuterol is combined with insulin.38 Albuterol's potassium-lowering effect is mitigated in some patients, particularly those with end-stage kidney disease therefore, albuterol should not be used as monotherapy.30

Sodium Bicarbonate . Although sodium bicarbonate is often used to treat hyperkalemia, the evidence to support this use is equivocal, showing minimal to no benefit.39 Therefore, sodium bicarbonate should not be used as monotherapy. It may have a role as adjuvant therapy, particularly among patients with concurrent metabolic acidosis.24 , 39 , 40

LOWERING TOTAL BODY POTASSIUM

Potassium can be removed via the GI tract or the kidneys, or directly from the blood with dialysis. Dialysis should be considered in patients with kidney failure or life-threatening hyperkalemia, or when other treatment strategies fail.23 , 37 Other modalities are not rapid enough for urgent treatment of hyperkalemia.39

Currently available cation exchange resins, typically sodium polystyrene sulfonate (Kayexalate) in the United States, are not beneficial for the acute treatment of hyperkalemia but may be effective in lowering total body potassium in the subacute setting.25 , 39 Because sodium polystyrene sulfonate can be constipating, many formulations include sorbitol for its laxative effects. However, case reports linking the concomitant use of sodium polystyrene sulfonate and sorbitol to GI injury prompted a U.S. Food and Drug Administration boxed warning.41 , 42 More recent reports implicate sodium polystyrene sulfonate alone.43 Therefore, use of the drug with or without sorbitol should be avoided in patients with or at risk of abnormal bowel function, such as postoperative patients and those with constipation or inflammatory bowel disease.42

There is no evidence supporting the use of diuretics for the acute treatment of hyperkalemia. However, diuretics, particularly loop diuretics, may play a role in the treatment of some forms of chronic hyperkalemia, such as that caused by hyporeninemic hypoaldosteronism.39 , 44 Fludrocortisone is an option for hyperkalemia associated with mineralocorticoid deficiency, including hyporeninemic hypoaldosteronism.29

Strategies to prevent chronic hyperkalemia include instructing patients to eat a low-potassium diet, discontinuing or adjusting medications, avoiding nonsteroidal anti-inflammatory drugs, and adding a diuretic if the patient has sufficient renal function.

Data Sources : An Essential Evidence search was conducted. Searches of PubMed, the Cochrane Database of Systematic Reviews, and the National Guideline Clearinghouse were completed using the key terms hypokalemia and hyperkalemia. The search included meta-analyses, randomized controlled trials, clinical trials, and reviews. Search dates: February, September, and December 2014.