Systemic Glucose Production Research Articles

Sodium-glucose co-transporter 2 inhibitors: mechanisms of renal action. Implications for diabetes and heart failure

The liver is not the exclusive site of glucose production in humans in the post-absorption state. Experimental data showed that the kidney is able of carrying out gluconeogenesis. Renal glucose production accounts for 20% of systemic glucose production. Evidence indicates that the kidney is able to reabsorb glucose from the glomerular filtrate through the sodium-glucose co-transporters (SGLT) 1 and 2 placed under the Bowman's capsule, in the thick portion of the proximal convoluted tubule, preserving this essential energy substrate for the organism. The maximal renal glucose reabsorption capacity (TmG), as well as the threshold for the spillover of glucose in the urine, are higher in diabetics than normal subjects and contribute to the hyperglycemic state in the absence of glycosuria. The administration of SGLT2 inhibitors in diabetics improves the excretion of sodium and glucose, reducing the threshold of glycosuria and TmG. This also restores the sodium concentration in the filtrate that reaches the macula densa (juxtaglomerular apparatus), which signals the appropriate perfusion of the kidney, defusing the secretion of renin and the activation of the neurohormonal axis that leads to the production of angiotensin II.Large clinical trials conducted with SGLT2 inhibitors in subjects with type 2 diabetes mellitus have demonstrated the great ability of this new class of drugs to achieve cardiac and renal benefits. All studies have shown SGLT2 inhibitors reduce the risk of hospitalizations for heart failure and the progression of kidney damage. A part of the favorable mechanisms is mediated by the natriuretic effect that is associated with the glycosuric effect, which reduces the activation of the renin-angiotensin-aldosterone system together with glomerular hyperfiltration.The aim of this review is to expand the knowledge among general cardiologists on the role of SGLT2 and SGLT1 in renal glucose homeostasis in healthy and diabetic subjects in the light of a potent class of drugs counteracting heart failure.

Glucose Metabolism in the Kidney: Neurohormonal Activation and Heart Failure Development.

The liver is not the exclusive site of glucose production in humans in the postabsorptive state. Robust data support that the kidney is capable of gluconeogenesis and studies have demonstrated that renal glucose production can increase systemic glucose production. The kidney has a role in maintaining glucose body balance, not only as an organ for gluconeogenesis but by using glucose as a metabolic substrate. The kidneys reabsorb filtered glucose through the sodium‐glucose cotransporters sodium‐glucose cotransporter (SGLT) 1 and SGLT2, which are localized on the brush border membrane of the early proximal tubule with immune detection of their expression in the tubularized Bowman capsule. In patients with diabetes mellitus, the renal maximum glucose reabsorptive capacity, and the threshold for glucose passage into the urine, are higher and contribute to the hyperglycemic state. The administration of SGLT2 inhibitors to patients with diabetes mellitus enhances sodium and glucose excretion, leading to a reduction of the glycosuria threshold and tubular maximal transport of glucose. The net effects of SGLT2 inhibition are to drive a reduction in plasma glucose levels, improving insulin secretion and sensitivity. The benefit of SGLT2 inhibitors goes beyond glycemic control, since inhibition of renal glucose reabsorption affects blood pressure and improves the hemodynamic profile and the tubule glomerular feedback. This action acts to rebalance the dense macula response by restoring adenosine production and restraining renin‐angiotensin‐aldosterone activation. By improving renal and cardiovascular function, we explain the impressive reduction in adverse outcomes associated with heart failure supporting the current clinical perspective.

Altered proximal tubular cell glucose metabolism during acute kidney injury is associated with mortality.

Acute kidney injury (AKI) is strongly associated with mortality, independently of its cause. The kidney contributes to up to 40% of systemic glucose production by gluconeogenesis during fasting and under stress conditions. Whether kidney gluconeogenesis is impaired during AKI and how this might influence systemic metabolism remain unknown. Here we show that glucose production and lactate clearance are impaired during human and experimental AKI by using renal arteriovenous catheterization in patients, lactate tolerance testing in mice and glucose isotope labelling in rats. Single-cell transcriptomics reveal that gluconeogenesis is impaired in proximal tubule cells during AKI. In a retrospective cohort of critically ill patients, we demonstrate that altered glucose metabolism during AKI is a major determinant of systemic glucose and lactate levels and is strongly associated with mortality. Thiamine supplementation increases lactate clearance without modifying renal function in mice with AKI, enhances glucose production by renal tubular cells ex vivo and is associated with reduced mortality and improvement of the metabolic pattern in a retrospective cohort of critically ill patients with AKI. This study highlights an unappreciated systemic role of renal glucose and lactate metabolism under stress conditions, delineates general mechanisms of AKI-associated mortality and introduces a potential intervention targeting metabolism for a highly prevalent clinical condition with limited therapeutic options.

OR-014 Chronic exercise potentiates anorectic effects of leptin in hypothalamic Pomc neurons

OR-014 Chronic exercise potentiates anorectic effects of leptin in hypothalamic Pomc neurons

Comparison of glycaemic control over 1 year with pioglitazone or gliclazide in patients with Type 2 diabetes

To compare long-term (1 year) efficacy and safety of pioglitazone and gliclazide in patients with Type 2 diabetes. This was a double-blind, multicentre, comparative, parallel group trial in 283 patients with Type 2 diabetes, who were randomized to receive 1-year treatment with pioglitazone 30-45 mg/day or gliclazide 80-320 mg/day. Drug dose was titrated on the basis of self-monitored blood glucose (SMBG) measurements and HbA1c values. The 1-year changes in HbA1c, fasting blood glucose (FBG), insulin, HOMA-S (HOmeostatic Model Assessment) and SMBG were compared. In a subgroup of patients (n = 10), systemic glucose production and utilization were determined by a combination of isotopic (deuterated glucose) and clamp techniques. In both groups, there were similar decreases in HbA1c (pioglitazone: -0.79%; gliclazide: -0.79%) and FBG (pioglitazone: -1.0 mmol/l; gliclazide: -0.7 mmol/l), whereas the slope of the reduction of fasting blood glucose was different between groups (P = 0.004). Insulin levels as well as insulin resistance assessed using HOMA-S decreased significantly only after pioglitazone treatment (-11.94 pmol/l and -1.03, respectively, both P = 0.002 vs. baseline). A significantly greater reduction in systemic glucose production was observed in the pioglitazone group (-2.48 micromol/kg/min, P = 0.042) than in the gliclazide group (-1.02 micromol/kg/min). A few, mild adverse events occurred in both groups. A comparable decrease in HbA1c and FBG was observed with pioglitazone and gliclazide. However, with pioglitazone there was a continuous decrease in FBG over 1 year, whereas gliclazide failed to maintain a similar trend. This favourable effect of pioglitazone was due to its insulin-sensitizing effect and ability to decrease systemic glucose production.

Mechanism of Increased Plasma Glucose Levels after Oral Glucose Ingestion in Normal-Weight Middle-Aged Subjects

Background/Aims: To determine the decline in glucose tolerance in normal-weight middle-aged subjects, we performed a cross-sectional study using double-labelled oral glucose tolerance tests in 8 middle-aged (46.3 ± 0.9 years) and in 8 young (23.6 ± 0.5) subjects with similar normal body weight. Methods: Plasma glucose was labelled by an infusion of dideuterated glucose started 120 min before ingestion of 1 g/kg of naturally ¹³C-enriched corn starch glucose. Glucose levels, substrate oxidation (indirect calorimetry) and exogenous glucose oxidation (¹³C enrichment of expired CO₂) were monitored for 330 min. Results: In the middle-aged subjects, the appearance of exogenous glucose was reduced (723 ± 52 mg/kg/330 min) compared to young subjects (864 ± 38; p < 0.05), and systemic glucose production was normal. Plasma glucose levels were increased due to a reduced glucose disappearance rate (middle aged: 1,046 ± 61 mg/kg/330 min vs. young 1,242 ± 67; p < 0.05), concerning both oxidative and non-oxidative disposal. This reduction was no longer apparent when the results were normalized for fat-free mass. Insulin levels were similar in young and middle-aged subjects. Conclusion: In normal-weight middle-aged individuals, glucose intolerance is mainly due to the reduction in the mass of fat-free glucose-utilizing tissues. The higher plasma glucose levels enable normal glucose supply to peripheral tissues, and increase splanchnic glucose uptake.

The glucose-6 phosphatase gene is expressed in human and rat small intestine: Regulation of expression in fasted and diabetic rats

Background & Aims: Glucose-6 phosphatase (Glc6Pase) is the last enzyme of gluconeogenesis and glycogenolysis, previously assumed to be expressed in the liver and kidney only, conferring on both tissues the capacity to produce endogenous glucose in blood. Methods: Using Northern blotting and reverse-transcription polymerase chain reaction and a highly specific Glc6Pase assay, we studied expression of the Glc6Pase gene in human and in rat tissues (fasted and diabetic). Results: The Glc6Pase gene is expressed in the duodenum and jejunum in normal fed rats and in the duodenum, jejunum, and ileum in humans. The Glc6Pase messenger RNA (mRNA) abundance was increased eightfold and sixfold in the duodenum and jejunum of streptozotocin diabetic rats. It was normalized in both tissues after 10 hours of insulin treatment. Glc6Pase activity was increased by 300% in the duodenum and jejunum in diabetic rats compared with normal rats. The Glc6Pase mRNA abundances and enzymatic activities were increased in a similar manner in both tissues in 48-hour-fasted rats. Normalization of mRNA abundance was achieved after refeeding for 7 hours. In addition, Glc6Pase mRNA and activity were also expressed in the ileum during fasting in rats. Conclusions: These data show that the small intestine has the ability to release endogenous glucose and strongly suggest that its contribution to systemic glucose production might be increased in situations of insulinopenia (type 1 diabetes) and insulin resistance (type 2 diabetes and others). GASTROENTEROLOGY 1999;117:132-139

Mechanisms of glucose intolerance during triglyceride infusion.

Lipid infusions may affect glucose tolerance by effects on glucose production or utilization. We performed double-labeled oral glucose tolerance tests with and without a lipid infusion in eight normal subjects. During the lipid infusion, plasma glucose and insulin levels were higher, showing some insulin resistance. The increased glucose level was due to a higher total glucose appearance rate, partly reproducible by a control infusion of glycerol [saline 1,181 +/- 71 mg . kg-1 . 330 min-1 vs. lipid 1,388 +/- 100 (P < 0.05) vs. glycerol 1,276 +/- 126 (NS)]. The tracer-determined appearance rate of exogenous glucose was higher with lipid infusion but was probably overestimated because of higher 13C recycling into glucose. Residual systemic glucose production was increased but was reproducible by the glycerol infusion. Total glucose disposal was increased. This was observed despite a lower stimulation of total glucose oxidation as measured by indirect calorimetry, whereas oxidation of exogenous glucose was normal after correction for the lipid-induced modification of excretion rate of 13CO2. Accordingly, glucose nonoxidative disposal was increased. These moderate modifications of glucose metabolism (increased appearance, increased nonoxidative disposal, and lower total oxidation) have been reported in starvation-induced or spontaneously impaired glucose tolerance. Further impairment, especially decreased nonoxidative glucose disposal, seems to be required to produce non-insulin-dependent diabetes mellitus.

Renal glucose production and utilization: new aspects in humans.

According to current textbook wisdom the liver is the exclusive site of glucose production in humans in the postabsorptive state. Although many animal and in vitro data have documented that the kidney is capable of gluconeogenesis, production of glucose by the human kidney in the postabsorptive state has generally been regarded as negligible. This traditional view is based on net balance measurements which, other than after a prolonged fast or during metabolic acidosis, showed no significant net renal glucose release. However, recent studies have refuted this view by combining isotopic and balance techniques, which have demonstrated that renal glucose production accounts for 25% of systemic glucose production. Moreover, these studies indicate that glucose production by the human kidney is stimulated by epinephrine, inhibited by insulin and is excessive in diabetes mellitus. Since renal glucose release is largely, if not exclusively, due to gluconeogenesis, it is likely that the kidney is as important a gluconeogenic organ as the liver. The most important renal gluconeogenic precursors appear to be lactate, glutamine and glycerol. The implications of these recent findings on the understanding of the physiology and pathophysiology of human glucose metabolism are discussed.

Evidence of increased systemic glucose production and gluconeogenesis in an early stage of NIDDM

Evidence of increased systemic glucose production and gluconeogenesis in an early stage of NIDDM

Alterations of fasting glucose and fat metabolism in intrauterine growth-retarded newborn dogs.

Maternal nutritional deprivation resulted in reduced fetal weight at term gestation (251 +/- 7 vs. 277 +/- 7 g, P less than 0.01) in newborn dogs. Growth-retarded pups developed lower blood glucose levels after 3, 6, and 9 h of neonatal fasting, reduced plasma levels of free fatty acids (FFA) at 9 and 24 h, and lower ketone bodies at 24 h compared with age-matched newborn control pups. Systemic rates of palmitate and alanine turnover were not affected, but systemic glucose turnover was reduced for 3-9 h after birth. The rate of alanine incorporation into glucose from 3 to 9 h was also reduced in growth-retarded pups compared with timed controls. Paradoxically, the rate of incorporation of palmitate into triglycerides was augmented in the smaller growth-retarded pups. Hepatic glycogen content was reduced at every time in the study among growth-retarded pups, whereas the rates of glycogenolysis between birth and 24 h were equivalent in the two pup groups. In contrast, hepatic triglyceride levels were augmented throughout the study in pups with growth retardation. Maternal starvation and lower glucose levels resulted in a lower hepatic energy charge, and augmented cytoplasmic and mitochondrial NAD-to-NADH ratios in intrauterine growth-retarded pups. These data suggest that intrauterine growth retardation in dogs results in fasting neonatal hypoglycemia that is due in part to reduced systemic glucose production. We speculate that reduced rates of gluconeogenesis from alanine and reduced oxidation of alternate fuels such as FFA contribute to hypoglycemia. FFA recycling to triglyceride synthesis rather than oxidative pathways may contribute to the observed reduction of circulating glucose levels.

Partitioning and Extraction of Glucose Regulates Cerebral Glucose Utilization in Newborn Dogs

We investigated the amount of fasting steady-state systemic glucose production utilized by the neonatal canine cerebral cortex. The relationship of systemic glucose production and cerebral glucose utilization were analyzed as functions of cerebral blood flow, cerebral oxygen uptake, and indirect measures of alternate fuel utilization. Fasting arterial blood glucose was 3.36 mM and glucose production was 49.6 mumol/kg/min. Average cerebral blood flow was 0.83 ml/g/min, and cerebral glucose uptake was 0.60 +/- 0.15 mumol/g/min. 36.6% of systemic glucose production was utilized by the cerebral cortex. There were no correlations between systemic glucose production, cerebral blood flow, or cerebral glucose uptake with blood glucose concentration. Furthermore, total cerebral glucose uptake was static across a wide range of glucose levels. Nonetheless, the percent of glucose production used by the brain was an inverse function of systemic glucose production (r = -0.71, p less than 0.001). The cerebral extraction of glucose (27.6 +/- 4.1%) decreased as a function of increasing blood glucose levels (r = -0.51, p less than 0.05), while brain uptake index correlated with increasing systemic glucose production (r = 0.61, p less than 0.02). We can conclude that the canine neonatal cerebral cortex may utilize only 37% of systemic glucose production. At low rates of glucose turnover, a larger proportion of systemic glucose production is allotted to the brain. Mechanisms that may regulate total cerebral glucose influx may be glucose permeability, or the increased extraction of glucose at lower blood glucose levels.

Allocation of systemic glucose output to cerebral utilization as a function of fetal canine growth.

To determine whether the neonatal canine brain consumes a major proportion of the systemic glucose production, we investigated the cerebral glucose requirement and hepatic glucose production in beagle pups. Sixteen pups received D-[6-3H]-glucose to determine systemic glucose production. Cerebral blood flow was measured by [N-methyl-14C]antipyrine, and the brain uptake index (BUI) of glucose was determined using 2-[14C]deoxy-D-glucose. Glucose production was 49.6 +/- 11.0 mumol.kg-1.min-1. Cerebral blood flow was 0.83 ml.g-1.min-1; cerebral uptake of glucose was 0.60 +/- 0.15 mumol.g-1.min-1. Of the total glucose production 36.6 +/- 7.9% was accounted for by the cerebral uptake of glucose. Brain-to-body weight and brain-to-liver weight ratios were the greatest in the smallest pups, suggesting brain sparing. The effect of growth status on cerebral substrate availability could not be correlated with cerebral uptake of glucose or oxygen or with systemic glucose production. However, the percentage of systemic glucose production allotted to the cerebral cortex increased with increasing body weight (r = 0.50, P less than 0.05). Cerebral glucose entry measured by BUI was demonstrated to be 0.108 +/- 0.014; BUI inversely correlated with canine birth weight (r = -0.832, P less than 0.001). We conclude that the percentage of glucose production utilized by the neonatal canine brain is not proportionately larger in the smaller pups despite a proportionately larger brain. Because the absolute cerebral glucose utilization may be static, we speculate that BUI (glucose entry) may be less of a rate-limiting factor for cerebral glucose entry in the smallest pups.

The metabolic response of the canine neonate to twenty-four hours of fasting

The metabolic effects of 24 hours of neonatal fasting in unanesthetized dogs were compared to fasting for three hours during the first day of life. Blood glucose, lactate, and ketones were unaltered while FFA (0.94 ± 0.07 v 0.70 ± 0.04 mmol/L, P < .001), glycerol (0.21 ± 0.01 v 0.12 ± 0.01 mmol/L, P < .01), and triglycerides (0.41 ± 0.03 v 0.23 ± 0.03 mmol/L, P < .01) were lower at 24 hours. Glucose production and lactate and alanine turnover were unaffected while palmitate turnover declined (8.8 ± 0.7 v 5.1 ± 0.5 μmol/kg/min, P < .01). Oxygen consumption decreased (6.9 ± 0.4 v 6.0 ± 0.3 mL/kg/min, P < .02) while RQ increased (0.79 ± 0.02 v 0.86 ± 0.03, P < 0.05) at 24 hours. Hepatic glycogen content declined (575 ± 37 to 266 ± 32 μmol/g, P < .001) and could account for a GP of 12 μmol/kg/min between 3 and 24 hours of age. Both gluconeogenesis from lactate and alanine increased, together accounting for 7% and 21% of glucose production at 3 and 24 hours. The increment in gluconeogenesis may be facilitated by augmented hepatic cytosolic phosphoenolpyruvate carboxykinase at 24 hours (1.8 ± 0.2 v 14.1 ± 0.8 nmol/min mg protein, P < .01). Despite the decline in VO 2, hepatic ATP and energy charge were unaltered by 24 hours of fasting. These data suggest that FFA availability diminishes during a prolonged neonatal canine fast resulting in lower VO 2. Furthermore, as FFA availability declines, glucose utilization becomes the predominant precursor for energy production. As hepatic glycogen becomes depleted, gluconeogenesis must now constitute a greater proportion of systemic glucose production. Nevertheless, VO 2 is not maintained. The paradoxical stability of hepatic ATP with lower VO 2 suggests that hepatic ATP utilization may have also declined.

Fetal and neonatal responses to extended maternal canine starvation. II. Fetal and neonatal liver metabolism.

Summary: The effects of maternal canine starvation (MCS) for 5 days on hepatic intermediates in fetus and fasted neonates were studied at 0, 3, 6, 9, and 24 h of age. Maternal starvation reduced the birth weights of the pups by 23% (232 ± 6 versus 300 ± 10 g). In the MCS fetuses, hepatic glycogen concentration was significantly decreased (416 versus 526 μmole/g) whereas uridine diphosphate glucose concentration was significantly increased (0.196 versus 0.135 μmole/g), suggesting diminished glycogen synthetase activity. After birth, hepatic glucose levels were significantly decreased at 3 (2.90 versus 5.95 μmole/g) and 24 (3.09 versus 5.29) h in the MCS pups. Glucose-6-phosphate (G6P) and fructose-6-phosphate (F6P) levels were low in MCS pups throughout the study, G6P being significantly decreased at 9 and 24 h, and F6P at 0, 6, 9, and 24 h in the MCS group. Fructose 1,6-diphosphate did not show any changes among groups. Of greater importance, hepatic ATP concentrations were significantly reduced in the MCS pups throughout the first day of life. Maternal fasting results in attenuated fetal hepatic glycogen synthesis and an altered transition from fetal to neonatal life. Diminished G6P and F6P levels suggest that hepatic glycolytic activity may be enhanced at the level of phosphofructokinase. In the presence of lactate carbon incorporation into glucose that approaches control rates of gluconeogenesis, the diminished G6P and F6P levels also suggest significant recycling of lactate carbon between glucose and lactate. Furthermore, despite the apparent predominance of glycolysis, diminished hepatic ATP levels suggest that MCS plus neonatal fasting produced a hepatic energy deficiency state. Hepatic substrate deficiency and altered energy production may result from the diversion of glycogen derived glucose to support systemic glucose production.

Glucose Production in Pregnant Women at Term Gestation

The effects of pregnancy and diabetes on systemic glucose production rates and the sources of glucose for the human fetus in utero were evaluated in five normal, four gestationally diabetic, and one insulin-dependent diabetic subject undergoing elective caesarean section at term gestation. Five normal nonpregnant women were studied for comparison. Systemic glucose production rates were measured with stable tracer [1-(13)C]glucose according to the prime-constant rate infusion technique. Even though the plasma glucose concentration during normal pregnancy had declined as compared with the nonpregnant subjects (P < 0.0005), the systemic glucose production rate was 16% greater, a rate sufficient to provide the glucose requirement of the fetus at term gestation. The decline in glucose concentration could be the result of an increase in apparent volume of distribution of glucose. Systemic glucose production rates in well-controlled, gestationally diabetic subjects were similar to those in normal pregnant subjects (2.07+/-0.53 vs. 2.42+/-0.51 mg/kg.min). The sources of glucose for the human fetus at term gestation were evaluated by comparing (a) natural variation in (13)C:(12)C ratio of plasma glucose and (b) enriched (13)C:(12)C ratio of plasma glucose during [1-(13)C]glucose infusion in maternal and fetal blood at delivery in both normal and diabetic subjects. These data showed that the fetal glucose pool was in equilibrium with the maternal glucose pool in both normal and diabetic subjects, indicating that a brief maternal fast did not initiate systemic glucose production in human fetus. A materno-fetal gradient was observed for betahydroxybutyrate.

867 ESTIMATION OF GLUCOSE PRODUCTION IN THE HUMAN NEWBORN USING SIMULTANEOUS 13C-AND D-LABELLED GLUCOSE

In order to compare two methods of quantifying systemic glucose production (SGP), 5 newborn infants age 2 h-3 days were infused simultaneously with glucose-1-13C (G113C) and glucose-6-6-D2 (G6D2) tracers. The older infants were studied 6 h after a meal. G113C was infused at 6μg/Kg min according to the prime constant rate infusion technique and 13C enrichment of C-1 of glucose measured by enzymatic decarboxylation and mass spectrometry. G6D2 was infused at 60μg/Kg min and deuterium enrichment of glucose measured by gas chromatography-mass spectrometry. SGP was calculated from the tracer dilution assuming steady state kinetics, from 30 min for 13C and from 120 min for D. Although 13C was expected to randomize away from C-1, recycling occurred and was estimated from the difference in rate of SGP quantified by dilution of the two tracers (mean ± S.D.) SGP ranged from 3.5 to 5.1 mg/Kg min. Recycling of glucose C-1 was 11-15% of SGP and it did not change with the age of infant. Conclusion: 1) SGP is established in the human newborn by 2 hours of age. 2) The two stable tracers used give similar estimates of SGP.

Measurement of glucose turnover in the human newborn with glucose-1-13C.

Systemic glucose production rates were measured in 6 normal newborn infants by dilution of glucose-1-13C tracer according to the prime constant-rate infusion technique. Glucose production rates were 4.4 +/- 0.39 mg/kg. min. (Mean +/- S.D.) in 4 infants at 2 hours of age, and were 3.83 and 3.86 mg/kg. min. in 2 infants at 1 day of age. Systemic glucose production accounts for 50% of the substrate utilized for oxidative metabolism in newborn infants.

Glucose Production in the Newborn Dog. I. Effects of Glucagon in Vivo

Extract: Systemic glucose production rates were evaluated 4 hr after feeding in 14 newborn beagle dogs at ages between 1 and 5 days. After a prime injection of radioisotopic tracers, glucose production was determined during infusion of intermixed tracer [2-3H]glucose and [1-14C]glucose at a constant rate. Seven of the newborn dogs served as controls throughout the 3-hr period of infusion, while seven of their littermates, infused simultaneously, received glucagon at a constant rate of 3.3 μg/min between 90 and 180 min of study. In control dogs, mean glucose production, determined by dilution of [2-3H]glucose, was 55 ± 3 μmol/min · kg body weight. During the control period, their littermates produced glucose at a similar rate; however, glucagon infusion raised glucose production to 81 ± 4 μmol/min · kg.The average glucose production rate estimated with [1-14C]glucose was 88% of that with the 3H tracer during the initial control period and 77% during the glucagon infusion. In order to confirm that this discrepancy reflected the recycling of 14C and the early development of gluconeogenesis, an additional 14 newborn dogs were infused with potential substrates for [14C]glucose. In separate studies, [U-14C]lactate, [3-14C]lactate, [U-14C]alanine, and [6-14C]-glucose were incorporated into glucose and [1-14C]glucose. Quantification of gluconeogenesis by simultaneous infusion of [6-3H]glucose and [3-14C]lactate in a 5-day-old dog demonstrated that 25% of the glucose produced originated from lactate, whereas 10% was incorporated into carbon 1. Thus, systemic glucose production was established rapidly in newborn dogs and responded to stimulation with glucagon. A significant proportion of the glucose originated from recycling via the gluconeogenic pathway.Speculation: Even in well nourished newborn mammals, recycling of glucose is important in maintaining homeostasis during the postabsorptive period. Based on comparisons between dogs infused with [3-14C]lactate or [6-14C]glucose, 25% or more of hepatic glucose production may originate from glucose recycled through lactate and pyruvate. Presumably most of the rest is derived from hepatic glycogen stored in utero..

Glucose production in the newborn dog. I. Effects of glucagon in vivo.

Systemic glucose production rates were evaluated 4 hr after feeding in 14 newborn beagle dogs at ages between 1 and 5 days. After a prime injection of radioisotopic tracers, glucose production was determined during infusion of intermixed tracer [2-3H] glucose and [1-14C] glucose at a constant rate. Seven of the new born dogs served as controls throughout the 3-hr period of infusion, while seven of their littermates, infused simultaneously, received glucagon at a constant rate of 3.3 mug/min between 90 and 180 min of study. In control dogs, mean glucose production, determined by dilution of [2-3H] glucose, was 55 +/- 3 mumol/min-kg body weight. During the control period, their littermates produced glucose at a similar rate; however, glucagon infusion raised glucose production to 81 +/- 4 mumol/min-kg. The average glucose production rate estimated with [1-14C]glucose was 88% of that with 3H tracer during the initial control period and 77% during the glucagon injusion. In order to confirm that this discrepancy reflected the recycling of 14C and the early development of gluconeogenesis, and additional 14 new born dogs were infused with potential substrates for [14C] glucose. In separate studies, [U-14C] lactate, [3-14C] lactate, [U-14C] alanine, and [6-14C]- glucose were incorporated into glucose and [1-14C] glucose. Quantification of gluconeogenesis by simultaneous infusion of [6-3H] glucose and [3-14C] lactate in a 5-day-old dog demonstrated that 25% of the glucose produced originated from lactate, whereas 10% was incorporated into carbon 1. Thus, systemic glucose production was established rapidly in newborn dogs and responded to stimulation with glucagon. A significant proportion of the glucose originated from recycling via the gluconeogenic pathway.