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Glucose, Starvation and Critical Illness

February 10, 2013

by Adi Mehta
(International Journal for Diabetes in Developing Countries, Vol. 18, 1998)

The pathophysiology of glucose metabolism in critical illness is a complex spectrum ranging from protein calorie malnutrition and starvation of the one hand, to a hypermetabolic response engendered by injury, inflammation and infection on the other.

In their pure state, the two can exhibit almost diametrically opposite pathophysiological changes. An understanding of the hormonal, cytokine and growth factor changes occurring in these two states is crucial for the appropriate assessment and management of the patient with a critical illness.

The continuum from one to the other is a dynamic flux so that a patient may present acutely, usually with a hypermetabolic stress response and evolve into starvation and malnutrition if and when the acute stress is overcome. Similarly a malnourished patient may, by virtue of a catastrophic event, be thrown into a hypermetabolic state and have few or no reserves to deal with the acute decompensation.

Simple starvation results in physiological changes that are all geared to protect and preserve the body and especially its protein integrity and stores. Thus, hormonal change occurs to mobilize alternative sources of fuel. Insulin levels fall, and contra-insulin hormones like cortisol and growth hormone increase, so that adipose tissue stores are primarily mobilized to act as the fuel.

In simple starvation, there is a relatively clear cascade of events. In the face of a lack of nutrient supply, to meet nutrient demands, the body activates specific adaptive responses to preserve lean body mass. There is a relative immediate decrease in energy expenditure and thus a lowering of the basal metabolic rate. This is accomplished by changes in thyroid hormone metabolism mainly by an increased conversion of T4 to reverse T3, rather than T3, as well as a changed activity of the sympathetic nervous system.

Alternative fuel sources are mobilized and utilized and there is a reduction in protein wasting. Initially, stored glycogen is utilized as the fuel source and is able to, on an average, yield about 1200 kcal (in a 70-kg subject). Since glycogen stores are obviously limited, the next important fuel source is glucose synthesis from amino acids by gluconeogenesis. At the same time, the body begins to mobilize and oxidize fat stores, which have the capability of roviding 1,60,000 Kcal in a 70kg subject.

By 72 hours of onset of starvation, the adaptive response is fully functional and all except obligate glucose dependent tissues (like brain and red blood cells) utilize fatty acids, glycerol and ketones as the primary fuel source. This is reflected in a decrease in the respiratory quotient to 0.6-0.7 in the starved patient. It is important to note that while there is reduced protein synthesis there is a significant decrease in protein catabolism because of reduced utilization of gluconeogenetic protein substrate so that there is net preservation of protein stores and decreased ureagenesis.

Obviously, if this state is further prolonged, adipose tissue reserves can be depleted to the point where skeletal muscle can no longer be protected. The average time total starvation can be sustained by humans, at standard body weight, seems to be 60-70 days, with an average loss of about 33% of standard body weight prior to demise, as shown in individuals who opt for hunger strikes.

As a corollary, death usually ensues because of pneumonia occurring secondary to weak respiratory effort, heart failure, liver failure and Wernicke’s encephalopathy with an oculogyric crisis.

Stress hypermetabolism represents the other end of the spectrum from starvation. Physiologically, there is a generalized response of the body to mobilize energy and substrate to support the inflammatory response, immune function and tissue repair. There is no attempt to preserve lean body mass; as well resources are mobilized to deal with the acute stress.

Carbohydrate metabolism continues apace and characteristically there is increased glucose oxidation as indicated by a respiratory quotient of 0.8-0.9, thus reflecting a very mixed fuel source. Gluconeogenesis is accelerated in the face of stress hypermetabolism and it cannot be adequately suppressed by exogenous glucose or insulin infusions. Furthermore, there is increased activity of the Cori cycle, which synthesizes glucose from glucose and maintain it as the primary fuel source. Thus, the hyperglycemia seen in the stressed individual is secondary to more than simple insulin resistance engendered by an excess of contra-insulin hormones.

While insulin resistance usually occurs because of decreased cellular glucose uptake, the hyperglycemia of the non-diabetic septic patient occurs in the face of maximal glucose oxidation, indicating a relatively healthy influx of glucose into cells. Thus, the hyperglycemia of the hypermetabolic patient is secondary to increased glucose synthesis by gluconeogenesis and Cori cycle activity.

In the patient with diabetes, especially Type 2 diabetes, where insulin resistance is already present in the premorbid condition, the excess mobilization of glucose synthesis caused by the hypermetabolic state continues apace, since there does not seem to be any feedback by glucose on any of the glucogensis pathways stimulated by the hypermetabolic state. If anything, at least theoretically, any defect in insulin action would further augment the gluconeogenesis pathways.

Glucose oxidation remains at or close to maximal in such patients and exogenous insulin is therefore unlikely to adequately control the hyperglycemia, just as it has been shown in the individual without diabetes.


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