Regulation Of Endogenous Glucose Production Research Articles

Magnitude of gluconeogenesis and endogenous glucose production: are they predictable in clinical settings?

Rationale: Regulation of endogenous glucose production (EGP) is essential for glucose homeostasis. It includes gluconeogenesis (GNG) from non-carbohydrate substrates and hepatic glycogenolysis. Both these pathways are dysregulated in acute stress, but the magnitude of this deregulation cannot be assessed in clinical practice. The study aims at identifying clinically available variables predictive of EGP and GNG magnitude by modeling routinely available data.

Magnitude of gluconeogenesis and endogenous glucose production: are they predictable in clinical settings?

Regulation of endogenous glucose production (EGP) is essential for glucose homeostasis. It includes gluconeogenesis (GNG) from non-carbohydrate substrates and hepatic glycogenolysis. Both these pathways are dysregulated in acute stress, but the magnitude of this deregulation cannot be assessed in clinical practice. The study aims at identifying clinically available variables predictive of EGP and GNG magnitude by modeling routinely available data. This exploratory study is based on the data from the Supplemental Parenteral Nutrition study 2 (SPN2), which measured EGP and GNG at days 4 and 10 in 23 critically ill patients. The correlation between EGP and GNG and 83 potential clinical indicators were explored, using single-stage and multivariate analysis. On single-stage analysis, the strongest correlations were noradrenaline dose at day 4 with GNG (R=0.71; P=0.0004) and Nutrition risk screening score (NRS) with EGP (R=0.42; P=0.05). At day 10, VO2 (R=0.59, P=0.04) was correlated with GNG and VCO2 with EGP (R=0.85, P=0.00003). Cumulated insulin dose between days 5 and 9 was correlated to EGP at day 10 (R=0.55, P=0.03). Our multivariate model could predict EGP at day 4 (VCO2, glucose and energy intake) with an error coefficient (e.c.) between 7.8% and 23.4% (minimal and maximal error), and GNG at day 10 (age, mean and basal blood glucose), with an e.c. of 18.5% and 29.9%. GNG at day 4 and EGP at day 10 could not be predicted with an e.c. < 40%. This preliminary exploratory study shows that GNG and EGP have different predictors on days 4 and 10; EGP is more correlated with the metabolic level, while GNG is dependent on external factors. Nevertheless, a bundle of variables could be identified to empirically assess the magnitude of both values. Our results suggest that a robust model might be built, but requires a prospective study including a larger number of patients.

Endogenous Glucose Production in Critical Illness.

Regulation of endogenous glucose production (EGP) by hormonal, neuronal, and metabolic signaling pathways contributes to the maintenance of euglycemia under normal physiologic conditions. EGP is defined by the generation of glucose from substrates through glycogenolysis and gluconeogenesis, usually in fasted states, for local and systemic use. Abnormal increases in EGP are noted in patients with diabetes mellitus type 2, and elevated EGP may also impact the pathogenesis of nonalcoholic fatty liver disease and congestive heart failure. In this narrative review, we performed a literature search in PubMed to identify recently published English language articles characterizing EGP in critical illness. Evidence from preclinical and clinical studies demonstrates that critical illness can disrupt EGP through multiple mechanisms including increased systemic inflammation, counterregulatory hormone and catecholamine release, alterations in the hypothalamic-pituitary axis, insulin resistance, lactic acidosis, and iatrogenic insults such as vasopressors and glucocorticoids administered as part of clinical care. EGP contributes to hyperglycemia in critical illness when abnormally elevated and to hypoglycemia when abnormally depressed, each of which has been independently associated with increased mortality. Increased EGP may also promote protein catabolism that could worsen critical illness myopathy and impede recovery. Better understanding of the mechanisms and factors contributing to dysregulated EGP in critical illness may help in the development of therapeutic strategies that promote euglycemia, reduce intensive care unit-associated catabolism, and improve patient outcomes.

Central KATP Channels Modulate Glucose Effectiveness in Humans and Rodents.

Hyperglycemia is a potent regulator of endogenous glucose production (EGP). Loss of this “glucose effectiveness” is a major contributor to elevated plasma glucose concentrations in type 2 diabetes (T2D). KATP channels in the central nervous system have been shown to regulate EGP in humans and rodents. We examined the contribution of central KATP channels to glucose effectiveness. Under fixed hormonal conditions (studies using a pancreatic clamp), hyperglycemia suppressed EGP by ∼50% in both humans without diabetes and normal Sprague-Dawley rats. By contrast, antagonism of KATP channels with glyburide significantly reduced the EGP-lowering effect of hyperglycemia in both humans and rats. Furthermore, the effects of glyburide on EGP and gluconeogenic enzymes were abolished in rats by intracerebroventricular administration of the KATP channel agonist diazoxide. These findings indicate that about half of the suppression of EGP by hyperglycemia is mediated by central KATP channels. These central mechanisms may offer a novel therapeutic target for improving glycemic control in subjects with T2D.

227-OR: Novel Method of Assessing Hypothalamic KATP Channel Activation in Humans Using Magnetic Resonance Imaging (MRI)

Hypothalamic KATP channels play an important role in regulating metabolism: activation of these channels with diazoxide (DZX) reduces endogenous glucose production (EGP) in rodents. When insulin is maintained at basal levels, oral DZX similarly suppresses EGP in humans (JCI 121:4916, 2011). Given the need to directly examine central regulation of EGP in humans, we developed a novel non-invasive measure of hypothalamic KATP channel activation. Since cerebral blood flow (CBF) and neuronal activity are coupled, we mapped hypothalamic neuronal activity using pseudo-continuous arterial spin labeling (pCASL) to measure CBF using 3 Tesla MRI with high resolution 3-dimensional (3D) acquisition and published analyses approaches (MRM 73: 102, 2015). The hypothalamus was extracted from each 3D map (3x3x3mm) using a hypothalamus region-of-interest (ROI) mask delineated upon the Johns Hopkins Template. To directly assess hypothalamic KATP channel activity using pCASL, we examined the time dependent effects of DZX (6mg/kg) vs. placebo in a randomized, double blinded fashion. Eight healthy nondiabetic individuals (42±4 yr, BMI 24±1 kg/m2, 7M) underwent a baseline scan, with repeat scans at 2.5 and 5 hours following DZX or placebo. This time course was determined based on previous observations that DZX appearance in rat CSF precedes EGP suppression, which is maximal at ∼6 hours in rats and humans. DZX induced an ∼11% drop in hypothalamic CBF, from 59.5±2.5 to 53.0±3.1 ml/100g/min at 2.5 hours (p=0.06), returning to baseline at 5 hours (57.7±2.7 ml/100g/min, p=0.3). Following placebo there was no change in CBF (p=0.8 by repeated measures ANOVA). No change in CBF was observed in other brain regions (e.g., cerebral cortex, thalamus, or hippocampus). In conclusion, pCASL provides a novel image-based measure of hypothalamic response to KATP channel activation in vivo, and can thus be used to examine the metabolic significance of hypothalamic KATP channel activation in humans. Disclosure S. Sharma: None. S. Aleksic: None. R. Maginley: None. E. Lontchi Yimagou: None. L. Upadhyay: None. S. Bhansali: None. O. Sandu: None. C.A. Branch: None. M. Hawkins: Other Relationship; Self; Novo Nordisk Inc. Funding National Institutes of Health (R01DK069861); Albert Einstein College of Medicine

Effects of intranasal insulin on endogenous glucose production in insulin-resistant men.

The effects of intranasal insulin on the regulation of endogenous glucose production (EGP) in individuals with insulin resistance were assessed in a single-blind, crossover study. Overweight or obese insulin-resistant men (n = 7; body mass index 35.4 ± 4.4 kg/m2 , homeostatic model assessment of insulin resistance 5.6 ± 1.6) received intranasal spray of either 40 IU insulin lispro or placebo in 2 randomized visits. Acute systemic spillover of intranasal insulin into the circulation was matched with a 30-minute intravenous infusion of insulin lispro in the nasal placebo arm. EGP was assessed under conditions of a pancreatic clamp with a primed, constant infusion of glucose tracer. Under these experimental conditions, compared with placebo, intranasal administration of insulin did not significantly affect plasma glucose concentrations, EGP or glucose disposal in overweight/obese, insulin-resistant men, in contrast to our previous study, in which an equivalent dose of intranasal insulin significantly suppressed EGP in lean, insulin-sensitive men. Insulin resistance is probably associated with impairment in centrally mediated insulin suppression of EGP.

Indirect Regulation of Endogenous Glucose Production by Insulin: The Single Gateway Hypothesis Revisited.

On the basis of studies that investigated the intraportal versus systemic insulin infusion and transendothelial transport of insulin, we proposed the "single gateway hypothesis," which supposes an indirect regulation of hepatic glucose production by insulin; the rate-limiting transport of insulin across the adipose tissue capillaries is responsible for the slow suppression of free fatty acids (FFAs), which in turn is responsible for delayed suppression of hepatic endogenous glucose production (EGP) during insulin infusion. Preventing the fall in plasma FFAs during insulin infusion either by administering intralipids or by inhibiting adipose tissue lipolysis led to failure in EGP suppression, thus supporting our hypothesis. More recently, mice lacking hepatic Foxo1 in addition to Akt1 and Akt2 (L-AktFoxo1TKO), all required for insulin signaling, surprisingly showed normal glycemia. Inhibiting the fall of plasma FFAs in these mice prevented the suppression of EGP during a clamp, reaffirming that the site of insulin action to control EGP is extrahepatic. Measuring whole-body turnover rates of glucose and FFAs in L-AktFoxo1TKO mice also confirmed that hepatic EGP was regulated by insulin-mediated control of FFAs. The knockout mouse model in combination with sophisticated molecular techniques confirmed our physiological findings and the single gateway hypothesis.

Intranasal insulin suppresses endogenous glucose production in humans compared with placebo in the presence of similar venous insulin concentrations.

Intranasal insulin (INI) has been shown to modulate food intake and food-related activity in the central nervous system in humans. Because INI increases insulin concentration in the cerebrospinal fluid, these effects have been postulated to be mediated via insulin action in the brain, although peripheral effects of insulin cannot be excluded. INI has been shown to lower plasma glucose in some studies, but whether it regulates endogenous glucose production (EGP) is not known. To assess the role of INI in the regulation of EGP, eight healthy men were studied in a single-blind, crossover study with two randomized visits (one with 40 IU INI and the other with intranasal placebo [INP] administration) 4 weeks apart. EGP was assessed under conditions of an arterial pancreatic clamp, with a primed, constant infusion of deuterated glucose and infusion of 20% dextrose as required to maintain euglycemia. Between 180 and 360 min after administration, INI significantly suppressed EGP by 35.6% compared with INP, despite similar venous insulin concentrations. In conclusion, INI lowers EGP in humans compared with INP, despite similar venous insulin concentrations. INI may therefore be of value in treating excess liver glucose production in diabetes.

Reducing Liver Fat by Low Carbohydrate Caloric Restriction Targets Hepatic Glucose Production in Non-Diabetic Obese Adults with Non-Alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) impairs liver functions, the organ responsible for the regulation of endogenous glucose production and thus plays a key role in glycemic homeostasis. Therefore, interventions designed to normalize liver fat content are needed to improve glucose metabolism in patients affected by NAFLD such as obesity. Objective: this investigation is designed to determine the effects of caloric restriction on hepatic and peripheral glucose metabolism in obese humans with NAFLD. Methods: eight non-diabetic obese adults were restricted for daily energy intake (800 kcal) and low carbohydrate (<10%) for 8 weeks. Body compositions, liver fat and hepatic glucose production (HGP) and peripheral glucose disposal before and after the intervention were determined. Results: the caloric restriction reduced liver fat content by 2/3 (p = 0.004). Abdominal subcutaneous and visceral fat, body weight, BMI, waist circumference and fasting plasma triglyceride and free fatty acid concentrations all significantly decreased (p < 0.05). The suppression of post-load HGP was improved by 22% (p = 0.002) whereas glucose disposal was not affected (p = 0.3). Fasting glucose remained unchanged and the changes in the 2-hour plasma glucose and insulin concentration were modest and statistically insignificant (p > 0.05). Liver fat is the only independent variable highly correlated to HGP after the removal of confounders. Conclusion: NAFLD impairs HGP but not peripheral glucose disposal; low carbohydrate caloric restriction effectively lowers liver fat which appears to directly correct the HGP impairment.

The Involvement of the T1R3 Receptor Protein in the Control of Glucose Metabolism in Mice at Different Levels of Glycemia.

The heterodimeric protein T1R2/T1R3 is a chemoreceptor mediating taste perception of sugars, several amino acids, and non-caloric sweeteners in humans and many other vertebrate species. The T1R2 and T1R3 proteins are expressed not only in the oral cavity, but also in the intestine, pancreas, liver, adipose tissue, and in structures of the central nervous system, which suggests their involvement in functions other than gustatory perception. In this study, we analyzed the role of the T1R3 protein in regulation of glucose metabolism in experiments with the gene-knockout mouse strain C57BL/6J-Tas1r3tm1Rfm (Tas1r3-/-), with a deletion of the Tas1r3 gene encoding T1R3, and the control strain C57BL/6ByJ with the intact gene. Glucose tolerance was measured in euglycemic or food-deprived mice after intraperitoneal or intragastric glucose administration. We have shown that in the Tas1r3-/- strain, in addition to the disappearance of taste preference for sucrose, glucose tolerance is also substantially reduced, and insulin resistance is observed. The effect of the Tas1r3 gene knockout on glucose utilization was more pronounced in the euglycemic state than after food deprivation. The baseline glucose level after food deprivation was lower in the Tas1r3-/- strain than in the control strain, which suggests that T1R3 is involved in regulation of endogenous glucose production. These data suggest that the T1R3-mediated glucoreception interacts with the KATP-dependent mechanisms of regulation of the glucose metabolism, and that the main role is likely played by T1R3 expressed in the pancreas and possibly in the central nervous system, but not in the intestinal mucosa, as it was suggested earlier.

The impact of obesity, sex, and diet on hepatic glucose production in cats

Obesity is a risk factor for type 2 diabetes in cats. The risk of developing diabetes is severalfold greater for male cats than for females, even after having been neutered early in life. The purpose of this study was to investigate the role of different metabolic pathways in the regulation of endogenous glucose production (EGP) during the fasted state considering these risk factors. A triple tracer protocol using (2)H(2)O, [U-(13)C(3)]propionate, and [3,4-(13)C(2)]glucose was applied in overnight-fasted cats (12 lean and 12 obese; equal sex distribution) fed three different diets. Compared with lean cats, obese cats had higher insulin (P < 0.001) but similar blood glucose concentrations. EGP was lower in obese cats (P < 0.001) due to lower glycogenolysis and gluconeogenesis (GNG; P < 0.03). Insulin, body mass index, and girth correlated negatively with EGP (P < 0.003). Female obese cats had approximately 1.5 times higher fluxes through phosphoenolpyruvate carboxykinase (P < 0.02) and citrate synthase (P < 0.05) than male obese cats. However, GNG was not higher because pyruvate cycling was increased 1.5-fold (P < 0.03). These results support the notion that fasted obese cats have lower hepatic EGP compared with lean cats and are still capable of maintaining fasting euglycemia, despite the well-documented existence of peripheral insulin resistance in obese cats. Our data further suggest that sex-related differences exist in the regulation of hepatic glucose metabolism in obese cats, suggesting that pyruvate cycling acts as a controlling mechanism to modulate EGP. Increased pyruvate cycling could therefore be an important factor in modulating the diabetes risk in female cats.

Specific Reduction of Hepatic Glucose 6-Phosphate Transporter-1 Ameliorates Diabetes while Avoiding Complications of Glycogen Storage Disease

D-Glucose-6-phosphatase is a key regulator of endogenous glucose production, and its inhibition may improve glucose control in type 2 diabetes. Herein, 2'-O-(2-methoxy)ethyl-modified phosphorothioate antisense oligonucleotides (ASOs) specific to the glucose 6-phosphate transporter-1 (G6PT1) enabled reduction of hepatic D-Glu-6-phosphatase activity in diabetic ob/ob mice. Treatment with G6PT1 ASOs decreased G6PT1 expression, reduced G6PT1 activity, blunted glucagon-stimulated glucose production, and lowered plasma glucose concentration in a dose-dependent manner. In contrast to G6PT1 knock-out mice and patients with glycogen storage disease, excess hepatic and renal glycogen accumulation, hyperlipidemia, neutropenia, and elevations in plasma lactate and uric acid did not occur. In addition, hypoglycemia was not observed in animals during extended periods of fasting, and the ability of G6PT1 ASO-treated mice to recover from an exogenous insulin challenge was not impaired. Together, these results demonstrate that effective glucose lowering by G6PT1 inhibitors can be achieved without adversely affecting carbohydrate and lipid metabolism.

How the hypothalamus controls glucose production: an update

Recent evidence highlights a crucial role of the brain in the control of glucose homeostasis. The hypothalamus senses and integrates signals of fuel abundance, such as circulating macronutrients (glucose and fatty acids) and nutrient-induced hormones (insulin and leptin). This, in turn, results in the activation of neural pathways that return circulating nutrients to baseline by reducing hepatic glucose production and food intake. In Type 2 diabetes and obesity, the ability of the brain to sense and respond to circulating signals is impaired. In this review, the neuroendocrine circuits that have recently been involved in the regulation of endogenous glucose production in rodents will be described. The study of these neural pathways promises to unveil new targets for the therapy of Type 2 diabetes and obesity.

Glucose Toxicity Is Responsible for the Development of Impaired Regulation of Endogenous Glucose Production and Hepatic Glucokinase in Zucker Diabetic Fatty Rats

The effect of restoration of normoglycemia by a novel sodium-dependent glucose transporter inhibitor (T-1095) on impaired hepatic glucose uptake was examined in 14-week-old Zucker diabetic fatty (ZDF) rats. The nontreated group exhibited persistent endogenous glucose production (EGP) despite marked hyperglycemia. Gluconeogenesis and glucose cycling (GC) were responsible for 46 and 51% of glucose-6-phosphatase (G6Pase) flux, respectively. Net incorporation of plasma glucose into hepatic glycogen was negligible. Glucokinase (GK) and its inhibitory protein, GK regulatory protein (GKRP), were colocalized in the cytoplasm of hepatocytes. At day 7 of drug administration, EGP was slightly reduced, but G6Pase flux and GC were markedly lower compared with the nontreated group. In this case, GK and GKRP were colocalized in the nuclei of hepatocytes. When plasma glucose and insulin levels were raised during a clamp, EGP was completely suppressed and GC, glycogen synthesis from plasma glucose, and the fractional contribution of plasma glucose to uridine diphosphoglucose flux were markedly increased. GK, but not GKRP, was translocated from the nucleus to the cytoplasm. Glucotoxicity may result in the blunted response of hepatic glucose flux to elevated plasma glucose and/or insulin associated with impaired regulation of GK by GKRP in ZDF rats.

Diabetogenic impact of long-chain omega-3 fatty acids on pancreatic beta-cell function and the regulation of endogenous glucose production.

In healthy individuals, peripheral insulin resistance evoked by dietary saturated lipid can be accompanied by increased insulin secretion such that glucose tolerance is maintained. Substitution of long-chain omega-3 fatty acids for a small percentage of dietary saturated fat prevents insulin resistance in response to high-saturated fat feeding. We substituted a small amount (7%) of dietary lipid with long-chain omega-3 fatty acids during 4 wk of high-saturated fat feeding to investigate the relationship between amelioration of insulin resistance and glucose-stimulated insulin secretion (GSIS). We demonstrate that, despite dietary delivery of saturated fat throughout, this manipulation prevents high-saturated fat feeding-induced insulin resistance with respect to peripheral glucose disposal and reverses insulin hypersecretion in response to glucose in vivo. Effects of long-chain omega-3 fatty acid enrichment to lower GSIS were also observed in perifused islets suggesting a direct effect on islet function. However, long-chain omega-3 fatty acid enrichment led to hepatic insulin resistance with respect to suppression of glucose output and impaired glucose tolerance in vivo. Our data demonstrate that the insulin response to glucose is suppressed to a greater extent than whole-body insulin sensitivity is enhanced by enrichment of a high-saturated fat diet with long-chain omega-3 fatty acids. Additionally, reduced GSIS despite glucose intolerance suggests that either long-chain omega-3 fatty acids directly impair the beta-cell response to saturated fat such that insulin secretion cannot be augmented to normalize glucose tolerance or beta-cell compensatory hypersecretion represents a response to insulin resistance at the level of peripheral glucose disposal but not endogenous glucose production.

Regulation of endogenous glucose production after a mixed meal in type 2 diabetes.

The extent and time course of suppression of endogenous glucose production (EGP) in type 2 diabetes after a mixed meal have been determined using a new tracer methodology. Groups of age-, sex-, and weight-matched normal controls (n = 8) and diet-controlled type 2 diabetic subjects (n = 8) were studied after ingesting a standard mixed meal (550 kcal; 67% carbohydrate, 19% fat, 14% protein). There was an early insulin increment in both groups such that, by 20 min, plasma insulin levels were 266 +/- 54 and 190 +/- 53 pmol/l, respectively. EGP was similar basally [2.55 +/- 0.12 mg x kg(-1) x min(-1) in control subjects vs. 2.92 +/- 0.16 mg x kg(-1) x min(-1) in the patients (P = 0.09)]. After glucose ingestion, EGP declined rapidly in both groups to approximately 50% of basal within 30 min of the meal. Despite the initial rapid decrease, the EGP was significantly greater in the diabetic group at 60 min (1.75 +/- 0.12 vs. 1.05 +/- 0.14 mg x kg(-1) x min(-1); P < 0.01) and did not reach nadir until 210 min (0.96 +/- 0.17 mg x kg(-1) x min(-1)). Between 60 and 240 min, EGP was 47% higher in the diabetic group (0.89 +/- 0.09 vs. 1.31 +/- 0.13 mg x kg(-1) x min(-1), P < 0.02). These data quantitate the initial rapid suppression of EGP after a mixed meal in type 2 diabetes and the contribution of continuing excess glucose production to subsequent hyperglycemia.

Regulation of endogenous glucose production by glucose per se is impaired in type 2 diabetes mellitus.

We examined the ability of an equivalent increase in circulating glucose concentrations to inhibit endogenous glucose production (EGP) and to stimulate glucose metabolism in patients with Type 2 diabetes mellitus (DM2). Somatostatin was infused in the presence of basal replacements of glucoregulatory hormones and plasma glucose was maintained either at 90 or 180 mg/dl. Overnight low-dose insulin was used to normalize the plasma glucose levels in DM2 before initiation of the study protocol. In the presence of identical and constant plasma insulin, glucagon, and growth hormone concentrations, a doubling of the plasma glucose levels inhibited EGP by 42% and stimulated peripheral glucose uptake by 69% in nondiabetic subjects. However, the same increment in the plasma glucose concentrations failed to lower EGP, and stimulated glucose uptake by only 49% in patients with DM2. The rate of glucose infusion required to maintain the same hyperglycemic plateau was 58% lower in DM2 than in nondiabetic individuals. Despite diminished rates of total glucose uptake during hyperglycemia, the ability of glucose per se (at basal insulin) to stimulate whole body glycogen synthesis (glucose uptake minus glycolysis) was comparable in DM2 and in nondiabetic subjects. To examine the mechanisms responsible for the lack of inhibition of EGP by hyperglycemia in DM2 we also assessed the rates of total glucose output (TGO), i.e., flux through glucose-6-phosphatase, and the rate of glucose cycling in a subgroup of the study subjects. In the nondiabetic group, hyperglycemia inhibited TGO by 35%, while glucose cycling did not change significantly. In DM2, neither TGO or glucose cycling was affected by hyperglycemia. The lack of increase in glucose cycling in the face of a doubling in circulating glucose concentrations suggested that hyperglycemia at basal insulin inhibits glucose-6-phosphatase activity in vivo. Conversely, the lack of increase in glucose cycling in the presence of hyperglycemia and unchanged TGO suggest that the increase in the plasma glucose concentration failed to enhance the flux through glucokinase in DM2. In summary, both lack of inhibition of EGP and diminished stimulation of glucose uptake contribute to impaired glucose effectiveness in DM2. The abilities of glucose at basal insulin to both increase the flux through glucokinase and to inhibit the flux through glucose-6-phosphatase are impaired in DM2. Conversely, glycogen synthesis is exquisitely sensitive to changes in plasma glucose in patients with DM2.

Role of glucokinase and glucose-6 phosphatase in the nutritional regulation of endogenous glucose production

Two specific enzymes, glucokinase (GK) and glucose-6 phosphatase (Glc6Pase) enable the liver to play a crucial role in glucose homeostasis. The activity of Glc6Pase, which enables the liver to produce glucose, is increased during short-term fasting, in agreement with the enhancement of liver gluconeogenesis. During long-term fasting, Glc6Pase activity is increased in the kidney, which contributes significantly to the glucose supply at that time. On the other hand, GK activity, which allows the liver to utilize glucose, is decreased during fasting. In the fed state, the mechanisms of short-term regulation of the activity of both enzymes takes place during the postprandial period. Liver GlcPase activity is inhibited after refeeding in rats. The inhibition mechanism could involve intracellular metabolites of glutamine and glutamic acid, such as alpha-ketoglutarate, and/or of triglycerides, such as unsaturated fatty acids and acyl-CoA esters. Liver GK activity is activated during the postprandial period. The activation mechanism involves a regulatory protein and the intrahepatic metabolites of fructose, ie fructose-1 phosphate and fructose-6 phosphate.

Role of glucose in the regulation of endogenous glucose production in the human newborn.

The role of plasma glucose concentration in the regulation of endogenous glucose production in the human newborn was examined by infusing glucose at 2.6-4.6 mg/kg . min as a continuous infusion to eight normal term appropriate for gestational age infants, five preterm, and six small for gestational age infants. All infants were healthy, had no overt clinical problems and were studied 6 h after their last feed. Glucose production rates were measured during the basal state and during glucose infusion by tracer dilution using [6,6(2)H2]glucose. The rate of glucose production during the basal state was similar in preterm and term appropriate for gestational age infants (appropriate for gestational age 3.53 +/- 0.32, preterm 3.49 +/- 0.38 mg/kg . min, mean +/- SD), while it was higher in the small for gestational age infants (4.25 +/- 0.98, p less than 0.03) as compared with appropriate for gestational age. During glucose infusion, the peak glucose concentration was related to the rate of glucose infusion. The endogenous glucose production rates during glucose infusion were variable in the three groups. However, a negative correlation between peak glucose concentration and endogenous glucose production rate was observed (r = 0.59, p = 0.006). The insulin response to glucose infusion was comparable in all infants. In addition, three small gestational age and one preterm infants, who had become hypoglycemic in the immediate newborn period, were studied while they were receiving parenteral glucose and their plasma glucose had stabilized at 55.5 +/- 10.25 mg/dl. Tracer kinetic studies showed persistence of endogenous glucose production in these infants even though they were receiving high rates of exogenous glucose infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

1216 ROLE OF PLASMA GLUCOSE IN THE REGULATION OF ENDOGENOUS GLUCOSE PRODUCTION IN THE HUMAN NEWBORN

Although the endogenous glucose production rate (Ra) in the newborn human and animals is high compared with adults, their plasma glucose concentrations are low. The newborn frequently develop hyperglycemia in response to glucose infusions. Previous data have shown that glucose release by isolated liver from human fetus is regulated by glucose concentration. In the present study, the role of glucose in the regulation of endogenous glucose production was examined by infusing glucose at 2.6 - 4.6 mg/kg·min to 8 normal term, 5 preterm and 8 small-for-gestational age (SGA) infants. All infants were healthy and had no overt clinical problems. Ra was measured during basal state and during glucose infusion by tracer dilution using [6, 6, 2H2]glucose. (mean ± SD) There was a negative correlation between peak glucose (PG) and Ra during glucose infusion (r = -0.59 P = .006). PG was also related to the rate of glucose infusion. These data show that as in human adults, Ra is regulated by plasma glucose in the newborn infant.