Hyperglycemia - Clinical Tree

Introduction

Because hyperglycemia due to poorly controlled diabetes mellitus is a common disorder associated with a number of disturbances in fluid and electrolyte balances, we thought it would be useful to have a separate chapter on hyperglycemia to address these different issues.

Abbreviations

P _Glucose , concentration of glucose in plasma
GFR, glomerular filtration rate
ECF, extracellular fluid
ICF, intracellular fluid
DKA, diabetic ketoacidosis
P _Creatinine , concentration of creatinine in plasma
P _Na , concentration of sodium (Na ⁺ ) ions in plasma
P _K , concentration of potassium (K ⁺ ) ions in plasma
P _Cl , concentration of chloride (Cl ^– ) ions in plasma
$P_{{HCO}_{3}}$ $P_{{HCO}_{3}}$ , concentration of bicarbonate (HCO ₃ ^– ) ions in plasma
P _{Anion gap} , anion gap in plasma
BBS, bicarbonate buffer system
Hct, hematocrit
EABV, effective arterial blood volume
PCT, proximal convoluted tubule
MCD, medullary collecting duct
PDH, pyruvate dehydrogenase
NAD ⁺ , nicotinamide adenine dinucleotide
NADH,H ⁺ , reduced form of nicotinamide adenine dinucleotide
ATP, adenosine triphosphate
ADP, adenosine diphosphate
P _{Effective osm} , effective osmolality of plasma
U _Osm , urine osmolality
SLGT, sodium linked glucose transporter
GLUT, glucose transporter

We begin this chapter with a brief description of the quantitative aspects of glucose metabolism, which illustrates that, although a relative lack of insulin is required to develop hyperglycemia, a marked reduction in glomerular filtration rate (GFR) and/or a very large intake of glucose causes the degree of hyperglycemia to become severe. This is followed by a section that examines the renal handling of glucose and the impact of hyperglycemia on volume and composition of body fluid compartments. In the clinical section, we discuss the clinical approach to the patient with a severe degree of hyperglycemia to determine its cause and design the appropriate treatment to restore the volume and composition of the extracellular fluid (ECF) and intracellular fluid (ICF). We also emphasize how to minimize the risk of developing cerebral edema, a complication that may arise during therapy, particularly in children with diabetic ketoacidosis (DKA).

Objectives

▪
To illustrate that to develop a severe degree of hyperglycemia, a marked reduction in GFR and/or a very large intake of glucose is/are required.
▪
To examine the implications of hyperglycemia for salt and water balance, and discuss the clinical approach to the management of hyperglycemia with an emphasis on strategies to minimize the risk of development of cerebral edema, especially in children with DKA.

Part A

Background

Case 16-1: And I Thought Water Was Good for Me!

A 50-kg, 14-year-old female has a long history of poorly controlled type 1 diabetes mellitus because she does not take her insulin regularly. In the past 48 hours, she felt thirsty and drank large volumes of fruit juice. She noted that her urine volume was very high. While in the Emergency Department, because she did not have access to fruit juice and continued to feel very thirsty, she drank large volumes of tap water. On physical examination, her blood pressure was 105/66 mm Hg, her heart rate was 80 beats/min, there were no significant postural changes in her blood pressure or in her heart rate, and her jugular venous pressure was not low. Her urine flow rate was 10 mL/min over the first 100-minute period of observation in the Emergency Department, and remained in the same level during the following 100-minute period. The following table shows measurements of the concentration of glucose in her plasma (P _Glucose ), the concentration of sodium (Na ⁺ ) ions in her plasma (P _Na ), the osmolality in her plasma, and the hematocrit from venous blood samples obtained at admission, 100 minutes later, and 200 minutes later. The concentrations of glucose and Na ⁺ ions and osmolality in her urine at these time periods are shown in the table. The arterial blood pH on admission was 7.33. Other laboratory data from measurements in a venous blood sample include the concentration of bicarbonate (HCO ₃ ^– ) ions in plasma (P _HCO3 ), 28 mmol/L; the anion gap in plasma (P _{Anion gap} ), 16 mEq/L; the concentration of potassium (K ⁺ ) ions in plasma (P _K ), 4.8 mmol/L; the concentration of creatinine in plasma (P _Creatinine ), 1.0 mg/dL (88 μmol/L) (her usual P _Creatinine was 0.7 mg/dL [60 μmol/L]); blood urea nitrogen (BUN), 22 mg/dL (concentration of urea in plasma (P _Urea ) 8 mmol/L).

		Admission		At 100 Min		At 200 Min
		Plasma	Urine	Plasma	Urine	Plasma	Urine
Glucose	mg/dL	1260	6300	1260	6300	630	6300
Glucose	mmol/L	70	350	70	350	35	350
Na ⁺	mmol/L	125	500	125	500	123	500
Osmolality	mosmol/kg H ₂ O	320	500	320	500	281	500
Hematocrit		0.45	–	0.45	–	0.45	–

Questions

What is the basis of the polyuria in this patient?
In what way might a severe degree of hyperglycemia have “helped” this patient?
How can the effective arterial blood volume (EABV) and plasma effective osmolality (P _{Effective osm} ) be defended during therapy as the P _Glucose falls?
Why did her P _Glucose fail to fall in the first 100 minutes despite the large loss of glucose in the urine?
Why did the P _Glucose and the P _{Effective osm} fall in the second 100 minutes?

Review of Glucose Metabolism

A more comprehensive discussion of principles of metabolic control was provided in Chapter 5 . The following points summarize the normal metabolism of glucose.

1.
Brain fuels: Glucose is the principal fuel oxidized by the brain in the fed state ( Figure 16-1 ). In a state of a lack of insulin or a resistance to its actions (see margin note), fatty acids become almost the only fuel available for oxidation in the brain. Notwithstanding, fatty acids cannot cross the blood–brain barrier at a rapid enough rate—hence, they are not an important fuel for the brain. To provide a fat-derived fuel for the brain, fatty acids must be converted in the liver into water-soluble compounds—ketoacids.

The brain oxidizes ketoacids in preference to glucose if both are present, even if the P _Glucose is high. The basis for this hierarchy of fuel oxidation is explained in the following paragraphs.

Relative Lack of Insulin

This term describes the combination of low levels of insulin and high levels of hormones with actions that oppose the actions of insulin (i.e., glucagon, cortisol, adrenaline, and the pituitary hormones—adrenocorticotropic hormone (ACTH) and growth hormone).

2.
Hierarchy of fuel oxidation: To conserve glucose for the brain, fatty acids and/or ketoacids must be oxidized first when available.

To state it broadly, absolute control of the rate of glucose oxidation is mediated by the availability of nicotinamide adenine dinucleotide (NAD ⁺ ). Oxidation of fuels converts NAD ⁺ to its reduced form, NADH,H ⁺ . Because NAD ⁺ is present in only tiny concentrations in both the cytosol and the mitochondria, NADH,H ⁺ must be converted back to NAD ⁺ . This occurs during coupled oxidative phosphorylation, in which adenosine triphosphate (ATP) is regenerated from adenosine diphosphate (ADP) plus inorganic phosphate (Pi). In turn, ADP is formed from hydrolysis of ATP when biological work is performed. Hence, the rate of performing biologic work sets a limit on the rate of coupled oxidative phosphorylation (see Chapter 6 ). Oxidation of glucose is diminished when ketoacids in the brain or fatty acids in skeletal muscle are oxidized because their oxidation “steals NAD ⁺ and/or ADP,” making them unavailable for the oxidation of glucose.

This hierarchy of fuel oxidation is the result of controls exerted at the level of two key enzymes in glucose metabolism: pyruvate dehydrogenase (PDH) and phosphofructokinase-1 (PFK-1). PDH is tightly regulated by its own specific kinase and phosphatase, inhibiting and activating it, respectively. PDH is inhibited when one or more of the following ratios are increased as a result of oxidation of fatty acids or ketoacids: ATP/ADP, NADH,H ⁺ /NAD ⁺ , and acetyl CoA/CoA (see Figure 16-1 ).

PFK-1 is a key regulatory enzyme in glycolysis in skeletal muscle and in brain cells. PFK-1 catalyzes an important “committed” step in glycolysis, the conversion of fructose 6-phosphate and ATP to fructose 1,6-bisphosphate and ADP. An increase in the concentration of ATP (or more precisely a decrease in the concentration of adenosine monophosphate [AMP]), as a result of oxidation of fat-derived fuels, diminishes the activity of PFK-1 and hence the flux in glycolysis (see Chapter 6 ).

Quantitative Analysis of Glucose Metabolism

To understand why the concentration of a metabolite is abnormal requires an analysis of its rate of input and its rate of output. The daily input of glucose typically exceeds the pool size of glucose by close to 20-fold ( Figure 16-2 ). Therefore, extremely sensitive control mechanisms are needed to maintain such a tiny pool of glucose in the body. If these control mechanisms do not operate properly, hyperglycemia will develop, and this may occur rapidly.

Figure 16-2, Glucose Content in the Body Versus Turnover of Glucose on a Typical Western Diet.

Pool of Glucose in the Body

Most of the glucose in the body is in the extracellular fluid (ECF) compartment. Glucose is also present in cells of organs that do not require the effect of insulin to transport glucose across their cell membranes. These include most organs other than skeletal muscle. The ICF volume of these organs is ∼5 L. Hence, in a 70-kg adult, the volume of distribution of glucose under conditions of a relative lack of insulin actions is ∼19 L (14 L ECF + 5 L ICF), P _Glucose is 5 mmol/L (90 mg/dL), and the pool of glucose in the body is 95 mmol (17 g).

Input of Glucose

From the diet

The daily intake of carbohydrates in an adult subject consuming a typical Western diet is about 270 g (∼1500 mmol) (see Figure 16-2 ). Some glucose may also be synthesized during the metabolism of ingested proteins (60% of the daily protein intake of 100 g can be made into glucose [60 g (333 mmol)]) and some glucose is also synthesized from the metabolism of the glycerol portion of dietary triglycerides (about 18 g [100 mmol]). To put it in quantitative perspective, the quantity of the daily input of glucose (270 g + 60 g + 18 g = 348 g/day) is 20-fold larger than the entire pool of glucose in the body.

From glycogen stores

Glycogen is stored primarily in the liver and in skeletal muscle.

Glycogen in the liver

The size of the pool of glycogen in the liver is only about 100 g (560 mmol). The major function of glycogen in the liver is to supply the brain with glucose when the P _Glucose declines (e.g., between meals). The breakdown of glycogen in the liver is stimulated by low insulin/high glucagon levels.

Glycogen in skeletal muscle

Large amounts of glucose are stored as glycogen in skeletal muscles (about 450 g [∼2500 mmol]). The major function of glycogen in skeletal muscle is to enable the regeneration of ATP at the fastest possible rate during vigorous exercise. This storage fuel is “reserved” because it permitted our starved ancestors to sprint and obtain food for survival. The major stimulus for the breakdown of glycogen in exercising muscle is a high adrenergic release. The first step in glycogen breakdown is catalyzed by the enzyme glycogen phosphorylase, and the product is glucose-1-phosphate. Because muscles lack the enzyme glucose-6-phosphatase, breakdown of this storage of glycogen does not result in the release of glucose into the circulation. L-Lactic acid is released when glycogenolysis is rapid—i.e., during a sprint—and lactate anions can be converted to glucose primarily in the liver and to a lesser extent in the kidneys.

Conversion of protein to glucose

The liver is the only organ where this pathway occurs, because it contains all the enzymes required for the metabolism of all 20 different amino acids in proteins. In the fed state, dietary proteins are metabolized initially in the liver. Oxidation of 100 g of protein in the liver would yield 400 kcal (4 kcal/g), whereas the liver needs only ∼300 kcal/day for the performance of its biological work. Hence, conversion of protein to glucose is an obligatory pathway in the fed state; but usually glycogen rather than glucose is the final carbon product in the fed state.

It is important to recognize when protein is being converted to glucose at an accelerated rate because this will signify a catabolic event or the loss of blood in the gastrointestinal tract. Approximately only 60% of the weight of proteins can be converted to glucose because some of the amino acids cannot be metabolized in this pathway (i.e., ketogenic amino acids such as leucine and lysine) and other amino acids must be partially oxidized in the citric acid cycle to be made into the gluconeogenic precursor pyruvate (e.g., the five-carbon skeleton in glutamine, the most abundant amino acids in proteins, is first converted to pyruvate, a three carbon compound). This process of conversion of the carbon skeleton in amino acids to pyruvate is obligatorily linked to the conversion of their nitrogen to urea ( Figure 16-3 ). Therefore, the rate of appearance of urea provides a clue to the rate of endogenous production of glucose from protein. The stoichiometry of the process of the conversion of 100 g of protein to glucose and urea results in the production of 60 g (333 mmol) of glucose and 16 g of nitrogen (close to 600 mmol) of urea (see Chapter 12 ).

Figure 16-3, Linkage Between the Synthesis of Glucose and Urea During Amino Acid Oxidation.

Removal of Glucose

Metabolic removal of glucose occurs via its oxidation or its conversion to storage compounds. During insulin deficiency, metabolic pathways for the removal of glucose are inhibited. Accordingly, renal excretion becomes the only major pathway for the removal of glucose.

Removal of glucose via metabolism

There are two major metabolic pathways for the removal of glucose: oxidation to regenerate ATP in the brain and conversion to storage forms of energy. Glucose is converted into glycogen to replenish its stores in the liver and muscle. Although some glucose may be oxidized in muscle, fatty acids are the major fuel consumed by muscle. Excess glucose is then converted in the liver into fat (triglycerides), which is stored in adipose tissues.

Oxidation of glucose

Glucose is the principal fuel oxidized by the brain in the fed state. The brain oxidizes close to 120 g (666 mmol) of glucose per day. Oxidation of glucose in the brain is markedly curtailed if ketoacids are present (see margin note).

Conversion to storage fuels

The pathway for conversion of glucose to glycogen requires the hormonal setting of sustained high net insulin actions, which leads to induction/synthesis of the enzymes required for conversion of glucose to glycogen in the liver. In addition, there must be a high P _Glucose to drive the conversion of glucose by glucokinase to glucose-6-phosphate (G6P), the substrate for hepatic glycogen synthesis. Conversely, there is virtually no conversion of glucose to glycogen when net insulin actions are low; said another way, a high P _Glucose is not a sufficient stimulus on its own to drive glycogen synthesis. Similarly, the conversion of glucose to fatty acids is much slower in this hormonal milieu because the key enzyme, acetyl-CoA carboxylase (ACC), which catalyzes the conversion of acetyl-CoA to malonyl-CoA (the first committed step in fatty acids synthesis), is inhibited by a low concentration of insulin in blood delivered to the liver and/or a high level of β ₂ -adrenergics (see Figure 5-4 , Chapter 5 ).

Thus, removal of glucose via metabolic means is slow initially when insulin is given to a patient with hyperglycemia. The fall in the P _Glucose during therapy is largely caused by expansion of the ECF volume with the administration of intravenous saline. This lowers the P _Glucose by dilution, and, importantly, by the excretion of glucose as the GFR increases.

Hyperosmolar Hyperglycemic State

This is usually described as a nonketotic state because these patients do not have an appreciable degree of ketoacidosis. They usually, however, have sufficient circulating ketoacids for regeneration of ATP in the brain, which may markedly decrease the need for glucose and hence lead to the development of a more severe degree of hyperglycemia.

Excretion of glucose in the urine

Because only a small quantity of glucose is stored in the body, the excretion of glucose in the urine must be avoided to prevent the loss of a precious fuel for the brain. In addition, if the body has to rely on high rates of production of glucose from endogenous proteins to provide the brain with its need for glucose, the cost in terms of loss of lean body mass will be high (see margin note). Further, if excreted in the urine, glucose will “drag” valuable ions (e.g., Na ⁺ and K ⁺ ) and water during an osmotic diuresis. Therefore, glucose is not excreted in the urine unless its filtered load exceeds the tubular maximum capacity for its reabsorption.

Reabsorption of glucose in the proximal convoluted tubule (PCT) reflects a critical property of this nephron segment—a high capacity relative to the normal filtered load of glucose ( Figure 16-4 ). Quantitatively, the maximal reabsorption of glucose is usually 10 mmol (1.8 g) of glucose per liter of GFR (i.e., 1800 mmol [325 g]/day with a usual GFR in a 70-kg adult of 180 L/day).

Figure 16-4, Reabsorption of Glucose by the Proximal Convoluted Tubule.

The sodium-linked glucose cotransporter gene family includes six members, namely SLGT1 to SLGT6. SLGT1 is a low-capacity, high affinity sodium and glucose cotransporter and is expressed mainly in the small intestine. In contrast, SLGT2 is a high-capacity, low affinity sodium and glucose cotransporter, localized almost exclusively in the apical membranes of PCT cells. Unlike SLGT1, which mediates the sodium and glucose cotransport in a 2:1 ratio, SLGT2 mediates the sodium and glucose cotransport in a 1:1 ratio. SLGT2 inhibitors have been recently used to inhibit glucose reabsorption by the PCT and therefore to lower the P _Glucose in patients with type 2 diabetes.

The exit of glucose from PCT cells is via a glucose transporter (GLUT2) on the basolateral membrane, which is independent of Na ⁺ ion transport.

Production of Glucose From Protein Catabolism

In an adult, catabolism of 1 kg of lean body mass can supply the brain with its need for glucose for less than 24 hours:
- The brain oxidizes ~120 g of glucose per day.
- Since only 60% of the weight of protein can be converted to glucose, catabolism of 200 g of protein is required to provide this amount of glucose. Because 80% of the weight of muscle is water, the amount of protein contained in 1 kg of muscle is close to 180 g.

Under conditions of relative lack of insulin, metabolic pathways for the removal of glucose are inhibited. Accordingly, renal excretion becomes the only major pathway for the removal of glucose. If the filtered load of glucose exceeds the capacity for glucose reabsorption by the PCT, glucosuria ensues. The excretion of glucose in the urine diminishes when the GFR falls. The GFR falls as a result of a significantly decreased EABV because of the glucose-induced osmotic natriuresis and diuresis. Expansion of the ECF volume with the administration of intravenous saline lowers the P _Glucose by dilution, and, importantly, as the EABV is restored, the GFR rises, and excretion of glucose in the urine increases.

To maintain a severe degree of hyperglycemia in the absence of a marked reduction of GFR requires the intake of a large amount of glucose (e.g., ingestion of large volumes of fruit juice or sweetened soft drinks). Stomach emptying is usually very slow in a patient with hyperglycemia, and hence a large amount of glucose may be retained in the stomach. A sudden increase in stomach emptying and the absorption of glucose in the small intestine may result in a sudden large rise in the P _Glucose because the volume of distribution of glucose is relatively small under conditions of relative lack of insulin.

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