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glucose and other fuel metabolites occurring as a consequence of changes in anabolism and catabolism in the various tissues.

B. Regulation of Blood Glucose

The blood concentration of glucose normally lies within the range of 80-110 mg/100 ml (4.4-6.1 mM). Reduction in blood glucose levels below 45-55 mg / 100 ml for a continued interval of time will lead to an impairment of brain function, tremors, and convulsions due to activation of the sympathetic nervous system and, ultimately, death. Conversely, prolonged hyperglycemia (a relative lack of insulin) leads to a devastating wasting of metabolic energy, osmotic diuresis, and metabolic acidosis. Because glucose is a "small molecule," all blood glucose is completely filtered by the glomerulus of the kidney (see Figure 153). Under normal physiological circumstances, virtually all of this filtered glucose is reabsorbed; however, since this reabsorptive process is saturable and can only accommodate a finite throughput of glucose, in instances of excessive hyperglycemia, a significant fraction of the filtered blood glucose will be lost in the urine. If there is not a balanced increase in the dietary intake of glucose, there will be, of necessity, a compensatory breakdown or catabolism of the storage forms of glucose, namely, glycogen; over an extended interval of time this can result in a significant loss of "stored" metabolic energy.

Related to prolonged hyperglycemia and its concomitant glucosuria is an associated increase in the loss of body water from the general circulatory system; this is due to the passive loss of water across the kidney tubule, which occurs as a consequence of the high osmotic pressure of the sugar-rich urine. In extreme cases of chronic glucosuria there will be cellular dehydration, leading to a loss of potassium and a reduction in blood volume, which can ultimately lead to a marked lowering of systemic blood pressure (see Chapter 15). In a normal (70 kg) man, the 24-hr urine volume ranges from 600 to 2500 ml, with a glucose concentration of 10-20 mg/100 ml of urine. In a typical untreated diabetic (without renal complications), the 24-hr urine volume may exceed 3000-3500 ml, with a glucose concentration of 500-5000 mg/100 ml of urine.

However, the adverse consequences of a relative lack of insulin (hyperglycemia) are not restricted to a derangement of carbohydrate metabolism. In the absence of insulin, triglycerides and fatty acids will be mobilized from adipose tissue and amino acids from muscle tissue (discussed in detail later). These substances then proceed to the liver, where the fatty acids and branched chain amino acids are converted into ketone bodies. The ketone bodies include ¡3-hydroxybutyrate, acetoacetate, and acetone. Eventually, this results in progressive ketonemia, and when the renal threshold for acetoacetate and /3-hydroxybu-tyrate is exceeded, both substances will appear in the urine. Because they are excreted as the sodium salts, this has the consequence, when extended over a period of time, of depleting the body of base. This in turn elevates the [H2COs] / [NaHC03] ratio and leads to the condition of metabolic acidosis (see footnote 1). Ultimately this will trigger a rapid and deep respiratory rate, which is diagnostic of diabetic acidosis. Tabulated in Table 7-1 is a resume of the changes in several blood and urine components that may result as a consequence of altered blood glucose levels.1

In addition to the dominant partnership of insulin and glucagon in maintaining glucose homeostasis, there is an extensive contribution of other physiological factors and hormones to the regulation of blood glucose. These are summarized in Table 7-2.

C. Nutritional and Metabolic Interrelationships

1. Introduction

Any detailed understanding of the integrated actions of glucagon and insulin to effect blood glucose homeostasis cannot be achieved by limiting the assessment of their actions to those on carbohydrate metabolism alone. Due to the ready metabolic interchanges that occur between carbohydrate, protein, and fat constituents, it is essential to have a clear understanding of the intermediary metabolism of all of these substances. In addition, some appreciation of the principles of dietary nutrition is required because many key enzymes of intermediary metabolism of higher animals are adaptively regulated to reflect the current dietary intake of carbohydrate, protein, and lipid. The general design is such that the ingested components are diverted to storage sites during periods of feeding and are later reutilized by the metabolic processes of glycogenosis, gluconeogenesis, and ketogenesis during intervals of food deprivation.

1 It should be recalled that both acetoacetic acid and /3-hydroxy-butyric acid have a primary carboxyl group with a pK = 4.2; thus, at the physiological pH of 7.2-7.4, both acids are ionized so as to generate acetoacetate, /3-hydroxybutyrate, and protons (H+). These protons will be neutralized by the physiological base bicarbonate (HC03). Over time, if large quantities of acetoacetate and /3-hydroxybutyrate are produced (as in diabetes) and are excreted, there is a significant reduction in the available HCO~3/ thus elevating the ratio of [H2C03] / [HCO"3], which ultimately leads to the condition of metabolic acidosis.

TABLE 7-1 Effects of Altered Blood Glucose Levels on Several Constituents of the

Blood and Urine

TABLE 7-1 Effects of Altered Blood Glucose Levels on Several Constituents of the

Blood and Urine

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