Starvation entails a progressive selection of fat as body fuel. Soon after a meal glucose utilisation by muscle ceases and fatty acids are used instead. Ketoacid levels in blood become elevated over the first week, and the brain preferentially uses these instead of glucose. The net effect is to spare protein even further, as glucose utilisation by brain is diminished. Nevertheless, there is still net negative nitrogen balance, but this can be nullified by amino acid or protein supplementation. Insulin appears to be the principal regulatory hormone. Recent data suggest that decreased levels of active T3 may play a role by sparing otherwise obligated calories by decreasing metabolic needs.

Starvation in man.

The liver and beta cells function in a negative feedback loop, which appears to have a predominant role in regulating both the basal plasma glucose and insulin concentrations. The degree of basal hyperglycemia in diabetes probably provides a bioassay of both the effect of a reduction in insulin secretory capacity and the degree of insulin resistance. A mathematic model of the interaction of insulin deficiency and insulin resistance has been constructed, based on the known response characteristics of the beta cells to glucose, and of plasma glucose and insulin control of hepatic and peripheral glucose flux. The degree to which beta cell deficiency increases basal plasma glucose reflects the hyperbolic shape of the normal insulin secretory response to different glucose concentrations. The height of basal plasma insulin is a function of the degree of insulin resistance. From the basal plasma insulin and glucose concentrations, the model provides an estimate of the degree to which both beta cell deficiency and insulin resistance contribute to diabetes. The predictions arising from the model are in accord with experimental data in man and in animals. In normal-weight diabetics who do not have increased insulin resistance, the model predicts that more than 85% of beta cell function has to be lost for the basal plasma glucose to rise to 6 mmol/liter, but a further 5%–10% loss increases the basal plasma glucose to over 10 mmol/liter. In a third of a consecutive series of 65 newly presenting, uncomplicated diabetics, both normal weight and obese, the analysis from the model suggested that insulin resistance, rather than beta cell deficit, was the predominant feature.

Insulin deficiency and insulin resistance interaction in diabetes: Estimation of their relative contribution by feedback analysis from basal plasma insulin and glucose concentrations

Employing a precise and sensitive double-isotope derivative technic, plasma norepinephrine and epinephrine were measured in twenty-three normal subjects and fourteen diabetics during various metabolic conditions. Patients with poorly controlled diabetes showed a rise in norepinephrine, which correlated with the degree of metabolic derangement, during resting conditions. High epinephrine values were seen only in patients with moderate to severe ketoacidosis. During exercise, diabetic patients with ketosis demonstrated large increments in plasma catecholamines as compared to normals. During insulin treatment, when good control had been achieved, plasma catecholaniine levels were similar to those in normal subjects.

During prolonged fasting, plasma norepinephrine rose from 0.18 to 0.40 ng. per milliliter in four normal nonobese subjects. No change was observed in plasma epinephrine.

During insulin hypoglycemia, high plasma epinephrine levels were seen only in subjects in whom the blood glucose concentration declined to values below 20 mg. per 100 ml. Plasma norepinephrine rose as blood glucose concentrations decreased even in diabetics in whom values had not reached hypoglycemic levels. No correlation was observed between plasma epinephrine and increase in pulse rate during hypoglycemia.

Plasma Norepinephrine and Epinephrine in Untreated Diabetics, During Fasting and After Insulin Administration

To determine if both phases of glucagon secretion are excessive in diabetes, arginine was admimistered intravenously as pulses and as infusions to normal subjects, insulin-dependent diabetics, and noninsulin-requiring diabetics. The acute phase of glucagon secretion, in response to arginine pulses at four different doses (submaximal to maximal alpha-cell stimulating), was indistinguishable in terms of timing, peak levels attained, and total increments comparing controls and diabetics. During the first half of the arginine infusion (500 mg/kg over 30 min) the glucagon rise in controls and diabetics was similar (P greater than 0.1), whereas during the last half of the infusion excessive glucagon levels were seen in the diabetics. No difference in the glucagon responses to arginine administered as either a pulse or an infusion was observed between the two types of diabetics. The acute phase responses of insulin to intravenous, maximal stimulating doses of glucose (20 g) and arginine (2.5 g) were measured in five insulin-independent diabetics. Although the acute insulin response to arginine was normal, there was marked attentuation of the early beta-cell response upon stimulation by glucose. From these results we conclude that although in diabetes excessive glucagon levels are observed with chronic arginine stimulation, the acute phase of glucagon secretion in response to arginine is normal. In addition, the beta-cell in noninsulin-requiring diabetics, although acutely hyporesponsive to glucose, remains normally responsive to another stimulus, arginine.

/pdf/arginine-stimulated-acute-phase-of-insulin-and-glucagon-33m6t1ege4.pdf

Arginine-stimulated acute phase of insulin and glucagon secretion in diabetic subjects.

Experimental reduction of B-cell mass: implications for the pathogenesis of diabetes.

In obese adult diabetics, the concentration of insulin in venous plasma was unrelated to the degree of hyperglycemia after an overnight fast. However, in these subjects, insulin rose and fell in proportion to the magnitude of change in plasma glucose induced by small intravenous infusions of glucose. The minimal dose of glucose to cause a significant rise in insulin above the fasting level was similar in normal subjects, obese nondiabetic subjects, and in obese, hyperglycemic adult diabetics. This dose lay between infusion of 60 and 100 mg of glucose per min for 30 min. These results suggested that the secretion of insulin was under regulation by changes in blood glucose but was not stimulated in proportion to the stable raised blood glucose concentration of the hyperglycemic diabetic. Artificial hyperglycemia was induced in fasting normal subjects by constant intravenous infusion of glucose at rates of 100-250 mg of glucose per min for periods up to 8 hr. Plasma glucose rose during the 1st hr of infusion and then remained constantly elevated for up to 8 hr. The concentration of plasma insulin paralleled that of plasma glucose. During the period of constant hyperglycemia and elevated insulin, superimposition of a brief additional glucose load resulted in a prompt rise in glucose and insulin, both returning to the previous elevated levels.

Thus in normals as well as obese diabetics, stable hyperglycemia does not produce a pancreatic response sufficient to return the blood glucose to an arbitrary normal fasting concentration, yet the beta cells remain readily responsive to a change in plasma glucose. These data suggest that the beta cells do not operate as a control system with an absolute reference point when presented with systemic hyperglycemia. The behavior of the beta cells during hyperglycemia in the fasting obese adult diabetic suggests that the regulation of the basal insulin secretion may not be determined by factors directly related to the prevailing concentration of glucose. It is postulated that the beta cells adapt to hyperglycemia perhaps through the operation of controls directed toward a normal delivery of free fatty acids or some other cellular metabolic substrate during fasting.

/pdf/control-of-insulin-secretion-during-fasting-hyperglycemia-in-4683twk2va.pdf

Control of insulin secretion during fasting hyperglycemia in adult diabetics and in nondiabetic subjects during infusion of glucose.

The effects of autonomic blocking agents on serum GH, immunoreactive insulin (IRI), plasma FFA and plasma glucose were studied in fasted conscious baboons adapted to living in primate chairs. Alpha adrenergic blockade with phentolamine significantly depressed GH secretion and resulted in an increase in IRI and a fall in glucose. Beta adrenergic blockade with propranolol or butoxamine and ganglionic blockade with trimethaphan (Arfonad) were associated with a significant prompt rise in GH, and decreases in IRI, FFA and plasma glucose. When beta adrenergic or ganglionic blockade was superimposed upon alpha adrenergic blockade, the GH-elevating effects of beta and ganglionic blockade were prevented, suggesting direct effects of these agents upon GH secretion independent of hemodynamic changes and hypoglycemia. These data show that blockade of adrenergic mechanisms causes synchronous reciprocal changes in GH and IRI and suggest that alpha adrenergic activity stimulates, and beta adrenergic activity inhibits, t...

Effects of autonomic blocking agents on growth hormone, insulin, free fatty acids and glucose in baboons.

The effect of glucose infusion on rates of lipolysis were studied in a group of chair-trained papio baboons that had been prepared for chronic intravenous and intracarotid infusion. All studies were carried out after a 24 hr period of fasting and when the animals were fully awake. After a control interval of 1 hr, a glucose infusion was begun either intravenously or intra-arterially. The infusion was continued at a constant rate for 2 hr and then changed directly to the alternate route and continued an additional 2 hr. Blood samples were collected at 30-min intervals for glucose, free fatty acid (FFA), glycerol, insulin, and in some studies, growth hormone (GH) determination. When glucose doses less than 0.5 mg/kg per min were used, no change in the products of lipolysis was noted during either venous or carotid administration, and glucose and insulin levels remained stable or fell gradually. With doses of glucose between 0.5 and 0.6 mg/kg per min, a greater fall in both FFA and glycerol was noted during carotid administration. No definite changes in plasma glucose or insulin levels were noted during either infusion period. These changes in lipolysis were noted regardless of the sequence of infusion, and a similar differential suppression of FFA was noted during a 24 hr period of carotid glucose administration. When doses of glucose larger than 0.6 mg/kg per min were used, inhibition of lipolysis was noted during both phases of infusion. No definite change in GH levels was noted during the periods of fasting, and the levels of the hormone did not appear to be related to changes in glucose, insulin, or FFA levels.

These data provide additional evidence for the presence in the central nervous system of a glucose-sensitive center which alters lipolytic rates independently of insulin and GH, probably by altering sympathetic tone to adipose tissue.

/pdf/studies-of-substrate-regulation-in-fasting-ii-effect-of-4te4av8a6q.pdf

Studies of substrate regulation in fasting: II. Effect of infusion of glucose into the carotid artery upon fasting lipolysis in the baboon

A B S T R A C T The effect of glucose infusions on rates of lipolysis were studied in a group of chair-trained papio baboons that had been prepared for chronic intravenous and intracarotid infusion. All studies were carried out after a 24 hr period of fasting and when the animals were fully awake. After a control interval of 1 hr., a glucose infusion was begun either intravenously or intra-arterially. The infusion was continued at a constant rate for 2 hr and then changed directly to the alternate route and continued an additional 2 hr. Blood samples were collected at 30-min intervals for glucose, free fatty acid (FFA), glycerol, insulin, and in some studies, growth hormone (GH) determination. When glucose doses less than 0.5 mg/kg per min were used, no change in the products of lipolysis was noted during either venous or carotid administration, and glucose and insulin levels remained stable or fell gradually. With doses of glucose between 0.5 and 0.6 mg/kg per min, a greater fall in both FFA and glycerol was noted during carotid administration. No definite changes in plasma glucose or insulin levels were noted during either infu

/pdf/ii-effect-of-infusion-of-glucose-into-the-carotid-artery-2sdltbycyc.pdf

Ii. effect of infusion of glucose into the carotid artery upon fasting lipolysis in the baboon

The effect of chlorpropamide therapy upon glucose-insulin relationships in adult diabetics.

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