Rise In Hepatic Glucose Production Research Articles

Chronic exposure to glucagon impairs net liver glucose uptake by activating the gluconeogenic pathway

Elevated glucagon levels and impaired liver glucose uptake are commonly observed in stressed and diabetic patients. We observed that if dogs are placed on continuous (5 days) nutritional support the liver adapts to become a major consumer of glucose. The majority of the glucose is not stored as glycogen, but is released as lactate (i.e reverse Cori Cycle). We have recently reported (AJP 292: E928, 2007) that if glucagon (2.4 ng/kg/min) is chronically infused during nutritional support, it impairs net glucose uptake by the liver (5.1±0.4 vs. −1.0±0.4 mg/kg/min). This decrease was due to a rise in hepatic glucose production rather than to suppression of glucose uptake. In the present study we assessed mRNA expression in liver tissue (Affymetrix Canine genome 2.0 array). PEPCK and fructose‐1,6‐bisphosphatase‐1 expression were increased 11 fold and 3 fold, while the expression of glucokinase (GK) and acetyl‐CoA carboxylase (ACC) were decreased by 4.8 and 2.4 fold. CREB‐3 mRNA was increased 3 fold (positive regulator of PEPCK) and AtF‐3 decreased 5.4 fold (negative regulator of PEPCK). We are performing both rt‐PCR and westerns to confirm these observations. We also observed that the ratio of AMP/ATP (a negative regulator of ACC) increased 1.8 fold, while the total nucleotide pool did not change. In summary, the long term inhibition of liver glucose uptake by glucagon is mediated by the upregulation of gluconeogenesis. While many of the glucagon‐mediated effects can be explained by activation of the cyclic‐AMP pathway, changes in AMP may also contribute to these effects. (Support DK43748 and ADA)

Glucose infusion attenuates endogenous glucose production and enhances glucose use of horses during exercise.

We examined the effects of increased glucose availability on glucose kinetics and substrate utilization in horses during exercise. Six conditioned horses ran on a treadmill for 90 min at 34 +/- 1% of maximum oxygen uptake. In one trial [glucose (Glu)], glucose was infused at a mean rate of 34.9 +/- 1.1 micromol. kg(-1). min(-1), whereas in the other trial [control (Con)] an equivalent volume of isotonic saline was infused. Plasma glucose increased during exercise in Glu (90 min: 8.3 +/- 1.7 mM) but was largely unchanged in Con (90 min: 5.1 +/- 0.4 mM). In Con, hepatic glucose production (HGP) increased during exercise, reaching a peak of 38.6 +/- 2.7 micromol. kg(-1). min(-1) after 90 min. Glucose infusion partially suppressed (P < 0.05) the rise in HGP (peak value 25.8 +/- 3.3 micromol. kg(-1). min(-1)). In Con, glucose rate of disappearance (R(d)) rose to a peak of 40.4 +/- 2.9 micromol. kg(-1). min(-1) after 90 min; in Glu, augmented glucose utilization was reflected by values for glucose R(d) that were twofold higher (P < 0.001) than in Con between 30 and 90 min. Total carbohydrate oxidation was higher (P < 0.05) in Glu (187.5 +/- 8.5 micromol. kg(-1). min(-1)) than in Con (159.2 +/- 7.3 micromol. kg(-1).min(-1)), but muscle glycogen utilization was similar between trials. We conclude that an increase in glucose availability in horses during low-intensity exercise 1) only partially suppresses HGP, 2) attenuates the decrease in carbohydrate oxidation during such exercise, but 3) does not affect muscle glycogen utilization.

Effect of adrenaline on glucose kinetics during exercise in adrenalectomised humans.

1. The role of adrenaline in regulating hepatic glucose production and muscle glucose uptake during exercise was examined in six adrenaline-deficient, bilaterally adrenalectomised humans. Six sex- and age-matched healthy individuals served as controls (CON). 2. Adrenalectomised subjects cycled for 45 min at 68 +/- 1 % maximum pulmonary O2 uptake (VO2,max), followed by 15 min at 84 +/- 2 % VO2, max without (-ADR) or with (+ADR) adrenaline infusion, which elevated plasma adrenaline levels (45 min, 4.49 +/- 0.69 nmol l-1; 60 min, 12.41 +/- 1.80 nmol l-1; means +/- s.e.m.). Glucose kinetics were measured using [3-3H]glucose. 3. Euglycaemia was maintained during exercise in CON and -ADR, whilst in +ADR plasma glucose was elevated. The exercise-induced increase in hepatic glucose production was similar in +ADR and -ADR; however, adrenaline infusion augmented the rise in hepatic glucose production early in exercise. Glucose uptake increased during exercise in +ADR and -ADR, but was lower and metabolic clearance rate was reduced in +ADR. 4. During exercise noradrenaline and glucagon concentrations increased, and insulin and cortisol concentrations decreased, but plasma levels were similar between trials. Adrenaline infusion suppressed growth hormone and elevated plasma free fatty acids, glycerol and lactate. Alanine and beta-hydroxybutyrate levels were similar between trials. 5. The results demonstrate that glucose homeostasis was maintained during exercise in adrenalectomised subjects. Adrenaline does not appear to play a major role in matching hepatic glucose production to the increase in glucose clearance. In contrast, adrenaline infusion results in a mismatch by simultaneously enhancing hepatic glucose production and inhibiting glucose clearance.

Glucose production during strenuous exercise in humans: role of epinephrine.

The increase in hepatic glucose production (HGP) that occurs during intense exercise is accompanied by a simultaneous increase in epinephrine, which suggests that epinephrine may be important in regulating HGP. To further investigate this, six trained men were studied twice. The first trial [control (Con)] consisted of 20 min of cycling at 40 +/- 1% peak oxygen uptake (VO2 peak) followed by 20 min at 80 +/- 2% VO2 peak. During the second trial [epinephrine (Epi)], subjects exercised for 40 min at 41 +/- 2% VO2 peak. Epinephrine was infused during the latter 20 min of exercise and resulted in plasma levels similar to those measured during intense exercise in Con. Glucose kinetics were measured using a primed, continuous infusion of [3-3H]glucose. HGP was similar at rest (Con, 11.0 +/- 0.5 and Epi, 11.1 +/- 0.5 micromol. kg-1. min-1). In Con, HGP increased (P < 0.05) during exercise to 41.0 +/- 5.2 micromol. kg-1. min-1 at 40 min. In Epi, HGP was similar to Con during the first 20 min of exercise. Epinephrine infusion increased (P < 0.05) HGP to 24.0 +/- 2.5 micromol. kg-1. min-1 at 40 min, although this was less (P < 0.05) than the value in Con. The results suggest that epinephrine can increase HGP during exercise in trained men; however, epinephrine during intense exercise cannot fully account for the rise in HGP. Other glucoregulatory factors must contribute to the increase in HGP during intense exercise.

Effect of increased blood glucose availability on glucose kinetics during exercise

This study examined the effect of increased blood glucose availability on glucose kinetics during exercise. Five trained men cycled for 40 min at 77 +/- 1% peak oxygen uptake on two occasions. During the second trial (Glu), glucose was infused at a rate equal to the average hepatic glucose production (HGP) measured during exercise in the control trial (Con). Glucose kinetics were measured by a primed continuous infusion of D-[3-3H]glucose. Plasma glucose increased during exercise in both trials and was significantly higher in Glu. HGP was similar at rest (Con, 11.4 +/- 1.2; Glu, 10.6 +/- 0.6 micromol . kg-1 . min-1). After 40 min of exercise, HGP reached a peak of 40.2 +/- 5.5 micromol . kg-1 . min-1 in Con; however, in Glu, there was complete inhibition of the increase in HGP during exercise that never rose above the preexercise level. The rate of glucose disappearance was greater (P < 0.05) during the last 15 min of exercise in Glu. These results indicate that an increase in glucose availability inhibits the rise in HGP during exercise, suggesting that metabolic feedback signals can override feed-forward activation of HGP during strenuous exercise.

Gestational diabetes mellitus screening and obstetrical complications: a review

Gestational diabetes mellitus (GDM) is a common medical complication that can have a profound impact on the mother and infant. It is defined as Carbohydrate intolerance of variable severity with onset or first recognition during the present pregnancy. The definition applies irrespective of whether or not insulin is used for treatment or the condition persists after pregnancy. It does not exclude the possibility that unrecognized glucose intolerance may have antedated the pregnancy. The fasting plasma glucose levels are lower in normal pregnancy than in the nonpregnant state, and this decline occurs before any rise in fasting plasma insulin levels can be detected. The fasting levels of glucose fall despite a rise in hepatic glucose production, which serves to provide the needs of the developing fetus. The rise in plasma glucose following an oral glucose load or a normal meal is exaggerated. This occurs despite an increase in insulin secretion in response to both oral and intravenous glucose and to normal meals. This indicates that insulin sensitivity declines as pregnancy progresses. The postprandial glucose and insulin levels are increased further in the pregnant woman who is obese. Although glucose tolerance deteriorates in human pregnancy, about 97 to 98% of all pregnant women retain a normal glucose tolerance and only 2 to 3% develop gestational diabetes. However, the prevalence of GDM depends upon the genetic characteristics and environment of the population under study.

SPLANCHNIC GLUCOSE PRODUCTION AND BLOOD FLOW DURING EXERCISE: THE RENIN-ANGIOTENSIN SYSTEM 247

The importance of the renin-angiotensin system for liver glucose output and flow was tested in 8 male subjects (age:25 +/- 1 yrs (mean and SE), Vo2max:4.0+/- 0.2 l/min). They performed semisupine cycling for 40 min at 50% Vo2max and 30 min at 70%Vo2max without (C) or with i.v. administration of an angiotensin-converting-enzyme inhibitor (10mg enalapril) (ACE) prior to exercise. Whole body glucose turnover was measured by primed constant infusion of 3H-glucose, and splanchnic substrate exchange and flow was measured by constant ICG-infusion and blood sampling from arterial and hepatic venous catheters. During exercise heart rate, mean arterial blood pressure, arterial lactate and RER increased similarly in drug and control studies (p>0.05). Hepatic glucose production increased during exercise similar in both experimental situations measured with 3H-glucose isotope dilution as well as with arterial and hepatic vein measurements (2.11 +/- 0.23 mg/min/kg to 7.29+/- 1.03 (ACE) and 2.21 +/- 0.18 to 7.82 +/- 0.70 (C)). Glucose production matched peripheral glucose uptake, and in both ACE and C arterial glucose did not change significantly during exercise (5.27 +/- 0.10 mM to 4.71 +/- 0.28(ACE) and 5.22 +/- 0.11 to 4.69 +/- 0.23 (C)). Splanchnic blood flow fell by 10% during moderate and 45% during intense exercise in both ACE (1.64 +/- 0.22 l/min to 1.52 +/- 0.20 (35 min) and 0.92 +/- 0.12 (65min)) and C (1.55 +/- 0.20 to 1.36 +/- 0.18 and 0.81 +/- 0.13) experiments. In conclusion Inhibition of the renin-angiotensin system does not influence neither the rise in hepatic glucose production nor the reduction in splanchnic flow during moderate or intense dynamic exercise in humans.

Abnormal transient rise in hepatic glucose production after oral glucose in non-insulin-dependent diabetic subjects

A transient rise in hepatic glucose production (HGP) after an oral glucose load has been reported in some insulin-resistant states such as in obese fa/fa Zucker rats. The aim of this study was to determine whether this rise in HGP also occurs in subjects with established non-insulin-dependent diabetes mellitus (NIDDM). Glucose kinetics were measured basally and during a double-label oral glucose tolerance test (OGTT) in 12 NIDDM subjects and 12 non-diabetic ‘control’ subjects. Twenty minutes after the glucose load, HGP had increased 73% above basal in the NIDDM subjects (7.29 ± 0.52 to 12.58 ± 1.86 μmol/kg/min, P < 0.02). A transient rise in glucagon (12 pg/ml above basal, P < 0.004) occurred at a similar time. In contrast, the control subjects showed no rise in HGP or plasma glucagon. HGP began to suppress 40–50 min after the OGTT in both the NIDDM and control subjects. A 27% increase in the rate of gut-derived glucose absorption was also observed in the NIDDM group, which could be the result of increased gut glucose absorption or decreased first pass extraction of glucose by the liver. Therefore, in agreement with data in animal models of NIDDM, a transient rise in HGP partly contributes to the hyperglycemia observed after an oral glucose load in NIDDM subjects.

Thiamin deficiency impairs endotoxin-induced increases in hepatic glucose output

We addressed the role of thiamin, a cofactor for several enzymes involved in glucose metabolism, in the glucose metabolic response to endotoxin. Characterized by hyperglycemia, increased hepatic glucose production exceeding elevated rates of whole-body glucose utilization, this response is mediated by hormones and cytokines and is dependent on the immune and nutritional status of the host. We hypothesized that a thiamin-deficient state would impair the metabolic response to endotoxin. Rats were fed a thiamin-deficient or control diet for 6 wk before in vivo assessment of glucose kinetics. In control rats, Escherichia coli endotoxin increased the rate of glucose appearance (+76%), disappearance (+70%), and metabolic clearance (+50%). Thiamin deficiency resulted in increased plasma glucose (18%) and lactate (3- to 4-fold) as well as in a 30% decrease in insulin and an increase in glucagon (2.6-fold) and corticosterone (3.6-fold). Thiamin deficiency inhibited the endotoxin-induced hyperglycemia and the rise in hepatic glucose production, glucose utilization, and metabolic clearance rate.

Central NMDA enhances hepatic glucose output and non-insulin-mediated glucose uptake by a nonadrenergic mechanism

One of the hallmarks of the stress response is an increased rate of hepatic glucose production (HGP) which, in conjunction with the presence of insulin resistance, leads to hyperglycemia. Excitatory amino acids (EAA) within the brain mediate some of the cardiovascular responses to stress, but their role in the hormonal and metabolic alterations is poorly defined. The aim of the present study was to determine whether the intracerebroventricular (i.c.v.) injection of either N-methyl- d-aspartate (NMDA) or kainate would produce metabolic alterations comparable to those observed under stress conditions. An i.c.v. cannula and vascular catheters were placed in rats prior to the experiment. After an overnight fast, HGP and peripheral glucose utilization (GU) were assessed in conscious unrestrained rats using [3- 3H]glucose. Arterial glucose levels were increased 34% by 15 min after the i.c.v. injection of NMDA (1 μg) and remained elevated throughout the 3-h protocol. The hyperglycemia resulted from an early increase in HGP (84%) that exceeded a smaller elevation (66%) in GU. The increased glucose flux was associated with sustained insulinopenia (−30%), and elevated levels of corticosterone (40–100%) and epinephrine (75–216%). The hormonal and glucose metabolic responses were quantitatively similar, although of shorter duration, in rats injected with kainate (10 ng). Intravenous adrenergic blockade completely prevented the NMDA-induced hyperglycemia. Adrenergic blockade blunted the early rise in HGP, so that in this group the NMDA-induced increase in HGP was offset by a comparable elevation in GU. These data indicate that NMDA and kainate, two EAA that bind to different receptor subtypes, act centrally to increase circulating levels of stress hormones and enhance glucose flux. EAA increase HGP and noninsulin-mediated GU by peripheral tissues, with the later response being influenced by both the mass action effect of hyperglycemia as well as an increased avidity of tissues for glucose. These data support the involvement of EAA in the central control of glucoregulation following brain injury.

Hepatic fuel metabolism during muscular work: role and regulation

The increased fuel demands of the working muscle necessitate that metabolic processes within the liver be accelerated accordingly. The sum of changes in hepatic glycogenolysis and gluconeogenesis are closely coupled to the increase in glucose uptake by the working muscle, due to the actions of the pancreatic hormones. The exercise-induced rise in glucagon and fall in insulin interact to stimulate hepatic glycogenolysis, whereas the increase in gluconeogenesis is determined primarily by glucagon action. The increment in gluconeogenesis is caused by increases in hepatic gluconeogenic precursor delivery and fractional extraction as well as in the efficiency of intrahepatic conversion to glucose. Glucagon stimulates the latter two processes. Epinephrine may become important in the regulation of hepatic glucose production during prolonged or heavy exercise when its levels are particularly high. On the other hand, there is no evidence that hepatic innervation is essential for the rise in hepatic glucose production during exercise. Nonesterified fatty acid (NEFA) delivery to, uptake of, and oxidation by the liver are accelerated during prolonged exercise, resulting in an increase in ketogenesis. The rate of the first two of these processes is largely determined by factors that stimulate fat mobilization. The third step is regulated by both NEFA delivery to and glucagon-stimulated fat oxidation within the liver. The increase in hepatic fat oxidation produces energy that fuels gluconeogenesis. The shuttling of amino acids to the liver provides carbon-based compounds that are used for gluconeogenesis, transfers nitrogen to the liver, and supplies substrate for protein synthesis. During exercise, metabolic events within the liver, which are regulated by hormone levels and substrate supply, integrate pathways of carbohydrate, fat, and amino acid metabolism. These processes function to provide substrates for muscular energy metabolism and conserve carbon in glucose and nitrogen in protein.

Glucagon and hepatic glucose production: Modulation by low-dose bradykinin infusion

The effect of a low-dose bradykinin (BK) infusion (30 ng/kg min) on glucagon-induced hepatic glucose production and glucose cycling was studied in five normal volunteers. Studies were performed during constant insulin concentration as achieved by simultaneous somatostatin infusion and insulin replacement. In the basal period glucagon was infused at a rate of 0.5 ng/kg min. Then, glucagon infusion rate was increased to 3 ng/kg min to test the response to hyperglucagonemia. In a second set of experiments BK was infused concomitantly with the high dose glucagon. Each subject served as his own control. BK infusion did not prevent the glucagon-induced rise in hepatic glucose production and glucose cycling. However, at a later stage BK accelerated the negative feedback mechanisms activated by glucagon (decrease in hepatic glucose production) significantly. These findings suggest that intravenous BK may interact with mechanisms involved in the down-regulation of hepatic glucagon effects.

Superior efficacy of pulsatile versus continuous hormone exposure on hepatic glucose production in vitro.

To elucidate the potency of continuous vs. intermittent exposure to hormonal stimuli, hepatic glucose production of isolated perfused rat livers was monitored in response to glucagon and insulin infusion. Using a nonrecirculating perfusion system, continuous exposure to glucagon (35 pM) induced a rise in hepatic glucose production from basal 0.33 +/- 0.03 mmol/(96 min X 100 g BW) to 0.65 +/- 0.02 mmol/(96 min X 100 g BW), while intermittent exposure (3 min on/off intervals; total dose 50%) to the same glucagon concentration elicited an almost identical rise in hepatic glucose production to 0.59 +/- 0.12 mmol/(96 in X 100 g BW). Insulin (100 mU/liter) given continuously and intermittently (3 min on/off intervals) inhibited glucagon-stimulated (70 pM) hepatic glucose production to the same extent, i.e. by 37.4% and 41.1%, respectively. Doubling the off period to 6 min and thereby reducing the total hormone dose to 33% did not diminish insulin's suppressive effect on glucagon-stimulated hepatic glucose release (34.6%). When the latter infusion protocol was applied with insulin at 300 mU/liter, hepatic glucose production during the first 40 min of glucagon infusion was more restrained (P less than 0.01) than during continuous delivery of 100 mU/liter, although the same amount of insulin was infused per period of time. In parallel, glucagon-stimulated cAMP release was similarly suppressed by insulin in all experiments. From this we conclude that the effect on hepatic glucose production of pulsatile administration of glucagon as well as of insulin, depending on the applied time interval of hormone exposure, is equipotent or even superior to the respective hormones' continuous infusion even if the hormone load is significantly reduced.

Contribution by the glycogen pool and adenosine 3',5'-monophosphate release to the evanescent effect of glucagon on hepatic glucose production in vitro.

To elucidate in vitro the transience of glucagon-induced hepatic glucose release, the effects of glucagon on hepatic glucose production and cAMP release were evaluated in the isolated rat liver preparation perfused by a nonrecirculating system. Glucagon was added to the infusate in stepwise increasing concentrations at 0, 60, and 100 min to give final concentrations of 2.5 X 10(-11), 10(-9), and 5 X 10(-8) M, respectively. Glucagon at 2.5 X 10(-11) M caused cAMP release [basal (mean +/- SD), 11.2 +/- 3.0 pmol/(min X 100 g BW)] to rise rapidly and plateau at 23.3 +/- 7.0 pmol/(min X 100 g BW), whereas hepatic glucose production [basal, 3.7 +/- 1.6 mumol/(min X 100 g BW)] increased only transiently to a maximum of 15.3 +/- 3.1 mumol/(min X 100 g BW) and fell thereafter. The enhanced cAMP release during the consecutive glucagon infusion was accompanied by a transient rise in hepatic glucose production during the second, but not during a third, glucagon infusion. When 3-isobutyl-1-methylxanthine, a potent phosphodiesterase inhibitor, was added to the perfusion medium (0.5 mM), the cAMP response to 2.5 X 10(-11) M glucagon was enhanced [247 +/- 124 pmol/(min X 100 g BW)] as was hepatic glucose production (+ 21%; P less than 0.05). Further augmentation of the glucagon concentration was followed by an increase in hepatic cAMP, but not glucose, release. When glucagon infusion (2.5 X 10(-11) M) was repeated with a glucagon-free period of 30 min in between, no stimulation of cAMP and consecutive glucose release was found during the second period. However, when the second glucagon dose was increased to 10(-9) M, glucose and cAMP release were again stimulated to the same extent as in experiments with no glucagon-free period in between. We conclude that the size of the glycogen pool and the cAMP concentration directly modulate hepatic glucose production and are responsible for evanescent glucagon action. This mechanism can be described by computer simulation.

Indomethacin and salicylate decrease epinephrine-induced glycogenolysis

Epinephrine (E) produces an immediate (0–30 minutes) rise in hepatic glucose production (Ra), largely due to activation of glycogenolysis; thereafter, E-stimulated gluconeogenesis becomes the major factor maintaining glucose production. To investigate the possible role of arachidonic acid metabolites on Ra during E stimulation, we infused E in trained conscious dogs before and during administration of two inhibitors of arachidonic acid metabolism, indomethacin (INDO) and salicylate (S). On separate days, experimental animals were treated with both oral and IV INDO and oral acetylsalicylic acid and IV sodium salicylate. Ra and glucose utilization (Rd), both in mg · kg −1min −1, were calculated by isotope dilution using 3- 3H-glucose. After achieving steady state specific activity, control (C) and experimental animals (n = 6 per group) received E (0.1 ug · kg −1min −1) for 150 minutes, raising plasma levels to approximately 1500 pg/mL in each group. In C, plasma glucose (G; mg/dL) rose by 17 ± 5 at 10 minutes and 19 ± 3 at 20 minutes due to an initial spike in Ra (2.7 ± 0.2 to 4.9 ± 0.5; P < 0.01) at 10 minutes. INDO and S treatment attenuated this initial (10–20 minutes) rise in G ( P < 0.05) due to a lower stimulated Ra at 10 minutes (3.3 ± 0.1 with INDO; 3.0 ± 0.5 with S; P < 0.05). After 20 minutes Ra was not different in the 3 groups; no overall differences in Rd, glucose clearance, or plasma insulin levels occurred with INDO or S treatment. In conclusion, INDO and S blunt the early (0–20 minutes) E-induced rise in G and Ra without changing Rd, glucose clearance, or insulin secretion. These results suggest that arachidonic acid metabolites may modulate E-induced glycogenolysis.

Adrenergic blockade alters glucose kinetics during exercise in insulin-dependent diabetics.

We investigated the effects of alpha and/or beta adrenergic blockade (with phentolamine and/or propranolol) on glucose homeostasis during exercise in six normal subjects and in seven Type I diabetic subjects. The diabetics received a low dose insulin infusion (0.07 mU/kg X min) designed to maintain plasma glucose at approximately 150 mg/dl. In normals, neither alpha, beta, nor combined alpha and beta adrenergic blockade altered glucose production, glucose uptake, or plasma glucose concentration during exercise. In diabetics, exercise alone produced a decline in glucose concentration from 144 to 116 mg/dl. This was due to a slightly diminished rise in hepatic glucose production in association with a normal increase in glucose uptake. When exercise was performed during beta adrenergic blockade, the decline in plasma glucose was accentuated. An exogenous glucose infusion (2.58 mg/kg X min) was required to prevent glucose levels from falling below 90 mg/dl. The effect of beta blockade was accounted for by a blunted rise in hepatic glucose production and an augmented rise in glucose utilization. These alterations were unrelated to changes in plasma insulin and glucagon levels, which were similar in the presence and absence of propranolol. In contrast, when the diabetics exercised during alpha adrenergic blockade, plasma glucose concentration rose from 150 to 164 mg/dl. This was due to a significant increase in hepatic glucose production and a small decline in exercise-induced glucose utilization. These alterations also could not be explained by differences in insulin and glucagon levels. We conclude that the glucose homeostatic response to exercise in insulin-dependent diabetics, in contrast to healthy controls, is critically dependent on the adrenergic nervous system.

Physical exercise and fuel homeostasis in diabetes mellitus.

During the initial phase of physical exercise muscle glycogen is the primary source of fuel for contracting muscle in normal man. When exercise continues beyond the first 5–10 min blood glucose and free fatty acids (FFA) become increasingly important substrates. Glucose utilization may account for 25–35% of the total substrate supply during mild to moderately heavy exercise. The augmented glucose utilization by working muscle is balanced by a rise in hepatic glucose production. The latter is achieved primarily by hepatic glycogenolysis during brief work, but during prolonged exercise gluconeogenesis may account for as much as 40–50% of the hepatic glucose output. Muscle uptake of FFA is determined primarily by its availability to the working muscle, and it may account for 30–60% of the total fuel supply. Ketone bodies are not utilized by working muscle in normal man. In patients with diabetes mellitus the metabolic effects of physical exercise are to a large extent determined by the time interval between insulin administration and the onset of exercise. Thus, in insulin treated patients with mild hyperglycaemia and no or minimal ketonaemia the utilization of glycogen, blood glucose and FFA by working muscle is similar to that of healthy subjects, and exercise is accompanied by a fall in blood glucose levels. In contrast, patients with more marked hyperglycaemia and hyperketonaemia may respond to exercise with a further rise in both blood glucose and ketone body levels, reflecting augmented rates of hepatic gluconeogenesis as well as ketogenesis. The repletion of muscle and liver glycogen, which takes place for 24–48 h after exercise, requires — besides carbohydrate feeding — a minimum concentration of insulin. Glycogen resynthesis probably accounts for a major part of the empirically well established beneficial effect of physical exercise in diabetic patients. The above considerations underscore the importance of adequate insulin administration in connection with exercise in diabetic patients.

An important role for glucagon in the regulation of glucose production in vivo.

I N the overnight fasted dog, basal hepatic glucose production increases when basal glucagon levels are maintained during acute insulin deficiency and decreases when glucagon is made deficient along with insulin. In postabsorptive insulin-dependent diabetic man, a glucagon infusion at 5 ng/kg/min is associated with a prompt rise in hepatic glucose production followed by a return to basal production despite continued glucagon infusion. From these observations, it is concluded that in the postabsorptive state, glucagon is important in maintaining basal glucose production, but physiologic elevations of glucagon cannot maintain increased production.