Hepatic Glucose Cycling Research Articles

Regulation of energy substrate utilization and hepatic insulin sensitivity by phosphatidylcholine transfer protein/StarD2

Phosphatidylcholine transfer protein (PC-TP, also known as StarD2) is a highly specific intracellular lipid binding protein with accentuated expression in oxidative tissues. Here we show that decreased plasma concentrations of glucose and free fatty acids in fasting PC-TP-deficient (Pctp(-/-)) mice are attributable to increased hepatic insulin sensitivity. In hyperinsulinemic-euglycemic clamp studies, Pctp(-/-) mice exhibited profound reductions in hepatic glucose production, gluconeogenesis, glycogenolysis, and glucose cycling. These changes were explained in part by the lack of PC-TP expression in liver per se and in part by marked alterations in body fat composition. Reduced respiratory quotients in Pctp(-/-) mice were indicative of preferential fatty acid utilization for energy production in oxidative tissues. In the setting of decreased hepatic fatty acid synthesis, increased clearance rates of dietary triglycerides and increased hepatic triglyceride production rates reflected higher turnover in Pctp(-/-) mice. Collectively, these data support a key biological role for PC-TP in the regulation of energy substrate utilization.

Defect in glucokinase translocation in Zucker diabetic fatty rats.

Hepatic glucose fluxes and intracellular movement of glucokinase (GK) in response to increased plasma glucose and insulin were examined in 10-wk-old, 6-h-fasted, conscious Zucker diabetic fatty (ZDF) rats and lean littermates. Under basal conditions, plasma glucose (mmol/l) and glucose turnover rate (GTR; micromol.kg(-1).min(-1)) were slightly higher in ZDF (8.4 +/- 0.3 and 53 +/- 7, respectively) than in lean rats (6.2 +/- 0.2 and 45 +/- 4, respectively), whereas plasma insulin (pmol/l) was higher in ZDF (1,800 +/- 350) than in lean rats (150 +/- 14). The ratio of hepatic uridine 5'-diphosphate-glucose 3H specific activity to plasma glucose 3H specific activity ([3H]UDP-G/[3H]G; %), total hepatic glucose output (micromol.kg(-1).min(-1)), and hepatic glucose cycling (micromol.kg(-1).min(-1)) were higher in ZDF (35 +/- 5, 87 +/- 16, and 33 +/- 10, respectively) compared with lean rats (18 +/- 3, 56 +/- 6, and 11 +/- 2, respectively). [3H]glucose incorporation into glycogen (micromol glucose/g liver) was similar in lean (1.0 +/- 0.7) and ZDF (1.6 +/- 0.8) rats. GK was predominantly located in the nucleus in both rats. With elevated plasma glucose and insulin, GTR (micromol.kg(-1).min(-1)), [3H]UDP-G/[3H]G (%), and [3H]glucose incorporation into glycogen (micromol glucose/g liver) were markedly higher in lean (191 +/- 22, 62 +/- 3, and 5.0 +/- 1.4, respectively) but similar in ZDF rats (100 +/- 6, 37 +/- 3, and 1.4 +/- 0.4, respectively) compared with basal conditions. GK translocation from the nucleus to the cytoplasm occurred in lean but not in ZDF rats. The unresponsiveness of hepatic glucose flux to the rise in plasma glucose and insulin seen in prediabetic ZDF rats was associated with impaired GK translocation.

Hepatic glucose cycling does not contribute to the development of hyperglycemia in Zucker diabetic fatty rats.

Hepatic glucose cycling, whereby glucose is taken up by the liver, partially metabolized, then recycled to glucose, makes a substantial contribution to the development of hyperglycemia in IDDM. This stimulation of glucose cycling appears to be associated with elevated rates of fatty acid oxidation. Whether hepatic glucose cycling also contributes to the development of hyperglycemia in NIDDM is unclear. Using a model of NIDDM, the Zucker diabetic fatty (ZDF) rat, we determined whether glucose cycling was enhanced. Hepatocytes from ZDF rats exhibited higher rates of glucose phosphorylation and glycolysis, but there was no increase in the rate of cycling between glucose and glucose-6-phosphate or between glycolytically derived pyruvate and glucose. Despite the increased rates of glycolysis, the production of CO2 in liver cells from ZDF rats was no different from rates measured in cells from control animals. Instead, there was a large increase in the accumulation of lactate and pyruvate in the ZDF liver cells. The addition of 2-bromopalmitate, an inhibitor of fatty acid oxidation that inhibited glucose cycling in hepatocytes from IDDM rats, had no effect on glucose cycling in cells from ZDF rats. We therefore conclude that, unlike in IDDM, hepatic glucose cycling does not contribute to the development of hyperglycemia in the NIDDM Zucker rat.

Hepatic glucose-6-phosphatase flux and glucose phosphorylation, cycling, irreversible disposal, and net balance in vivo in rats. Measurement using the secreted glucuronate technique

Measurement of hepatic glucose production (HGP) by standard isotope dilution reveals only the net release of glucose from the liver, not the flux across glucose-6-phosphatase ([G6Pase] or total hepatic glucose output), hepatic glucose cycling (HGC), irreversible glucose disposal into glycogen in the liver (hepatic Rd), or net hepatic glucose balance. We describe two independent isotopic techniques for measuring these parameters in vivo, both of which use secreted glucuronate (GlcUA), HGC can be quantified by measuring a correction factor for glucose label retained in hepatic glucose-6-phosphate (G6P), sampled as GlcUA. A complementary technique for measuring total hepatic glucose output is also described (reverse dilution), requiring administration of no labeled glucose but instead a labeled gluconeogenic precursor and unlabeled glucose. Hepatic Rd is calculated by multiplying the rate of appearance (Ra) of hepatic UDP-glucose ([UDP-glc] based on dilution of labeled galactose in GlcUA) times the direct entry of glucose into hepatic UDP-glc and the fraction of labeled UDP-glc retained in the liver. The sum of hepatic Rd plus HGC represents the total hepatic glucose phosphorylation rate. Rats received intravenous (IV) glucose infusions at a rate of 15 to 30 mg/kg/min after a 24-hour fast. Despite a suppression of net HGP more than 50%, total hepatic glucose output was not significantly decreased, because of increased HGC. Total hepatic glucose output calculated by reverse dilution yielded similar results during IV glucose infusions at 15 mg/kg/min, although values were higher than obtained by the correction-factor method at 30 mg/kg/min. The fraction of labeled UDP-glc released into blood glucose, representing a hepatic glycogen cycle, decreased from 35% (fasted) to nearly 0% (IV glucose 30 mg/kg/min). Hepatic Rd was 1.4, 4.6, and 7.5 mg/kg/min (fasted and IV glucose 15 and 30 mg/kg/min, respectively); total hepatic glucose phosphorylation increased substantially (from 4.2 to 8.5 to 12.7 mg/kg/min) and net hepatic glucose balance changed from negative to positive during IV glucose. In conclusion, hepatic G6Pase flux, glucose phosphorylation, HGC, disposal of glucose into glycogen, and net glucose balance can be measured noninvasively in vivo under various metabolic conditions by techniques involving the GlcUA probe.

Insulin action and hepatic glucose cycling in Cushing's syndrome.

Although it is well established that hypercortisolism causes insulin resistance, the mechanisms responsible for impaired insulin action in Cushing's syndrome are unclear. This study investigated the contribution of the glucose/glucose-6-phosphate substrate cycle (G/G6P). Eight patients with Cushing's syndrome and seven control subjects were studied. All had normal fasting plasma glucose. Insulin action was assessed using the euglycaemic glucose clamp at insulin infusion rates of 0.4 and 2.0 mU/kg/min combined with a simultaneous infusion of [2(3)H]- and [6(3)-H]-glucose. Glucose/ glucose-6-phosphate cycle activity was calculated as the difference in glucose turnover rates determined separately for [2(3)H]- and [6(3)H]-glucose by selective enzymatic detritiation. Exogenous glucose infusion rates required to maintain euglycaemia were significantly lower in Cushing's patients compared to controls, during the 0.4 mU/kg/min (7.8 +/- 1.2 vs 15.7 +/- 0.5 mumol/kg/min, P < 0.001) and the 2.0 mU/ kg/min insulin infusions (26.2 +/- 2.8 vs 51.5 +/- 3.5 mumol/ kg/min, P < 0.001). Endogenous glucose production was similar in both groups in the postabsorptive state (10.2 +/- 0.3 vs 10.8 +/- 0.4 mumol/kg/min, P = 0.50) and suppressed to a similar degree during hyperinsulinaemia. G/G6P cycle activity was markedly increased in the Cushing's group in the postabsorptive state (5.4 +/- 1.1 vs 2.0 +/- 0.5 mumol/kg/min, P = 0.028) and during the 0.4 mU/kg/min (3.2 +/- 0.6 vs 1.2 +/- 0.4 mumol/kg/min, P = 0.014) and 2.0 mU/kg/min insulin infusions (3.3 +/- 0.8 vs 1.1 +/- 0.5 mumol/kg/min, P = 0.049). Patients with Cushing's syndrome show marked peripheral insulin resistance and enhanced hepatic G/G6P cycle activity. In the fasting state increased glucose/glucose-6-phosphate cycle activity may be a protective mechanism limiting hyperglycaemia. During hyperinsulinaemia G/G6P cycle activity was increased but insulin resistance was predominantly due to reduced peripheral glucose uptake.

Altered fluxes responsible for reduced hepatic glucose production and gluconeogenesis by exogenous glucose in rats.

The net release of glucose from the liver, or hepatic glucose production (HGP), and apparent gluconeogenesis (GNG) are reduced by exogenous glucose. We investigated the changes in metabolic fluxes responsible. Flux through the hepatic GNG pathway was quantified by mass isotopomer distribution analysis (MIDA) from [2-13C]glycerol. Unidirectional flux across hepatic glucose-6-phosphatase (G-6-Pase), or total hepatic glucose output (THGO), and hepatic glucose cycling (HGC) were also measured by using glucuronate (GlcUA) to correct for glucose 6-phosphate (G-6-P) labeling. Infusion of glucose (15-30 mg.kg-1.min-1 iv) to 24 h-fasted rats caused two important metabolic alterations. First was a significant increase in hepatic glucose uptake and HGC: > 60% of THGO was from HGC. Second, although flux through hepatic G-6-P increased (from 15.7 to 17.7-22.7 mg.kg-1.min-1), the partitioning of G-6-P flux changed markedly [from 30-35% to 55-60% entering UDP-glucose (UDP-Glc), P < 0.01]. Total flux through the GNG pathway remained active during intravenous glucose, but increased partitioning into UDP-Glc lowered GNG flux plasma glucose by 50%. In summary, the suppression of HGP and GNG flux into glucose is not primarily due to reduced carbon flow through hepatic G-6-Pase or the hepatic GNG pathway. THGO persists, but hepatic G-6-P is derived increasingly from plasma glucose, and flow through GNG persists, but the partitioning coefficient of G-6-P into UDP-Glc doubles. These adjustments permit net HGP to fall despite increased total production of hepatic G-6-P during administration of glucose.

Quantitation of hepatic glucose fluxes and pathways of hepatic glycogen synthesis in conscious mice.

Mice were studied with the euglycemic hyperinsulinemic and the hyperglycemic clamp techniques after a 6-h fast: 1) euglycemic (6.7 +/- 0.2 mM) hyperinsulinemia (approximately 800 microU/ml); 2) hyperglycemic (15.3 +/- 0.4 mM) hyperinsulinemia (approximately 800 microU/ml). All mice received an infusion of [3-3H]glucose and [U-14C]lactate. Basal hepatic glucose production (HGP) averaged approximately 170 mumol.kg-1.min-1 in both groups. During euglycemic and hyperglycemic hyperinsulinemia, HGP decreased by 53% (to 76.7 +/- 11.1 mumol.kg-1.min-1; P < 0.01) and 74% (to 43.3 +/- 7.2 mumol.kg-1.min-1; P < 0.01), respectively. Hyperglycemia increased glucose cycling (by 2.1-fold; P < 0.01) and the contribution of gluconeogenesis to HGP (88 vs. 43%; P < 0.01) while decreasing that of glycogenolysis (12 vs. 57%; P < 0.01). The percentage of neosynthetized hepatic glycogen formed via the direct pathway was markedly increased during hyperglycemia (53 +/- 2% vs. 23 +/- 3%; P < 0.01): These data indicate that the assessment of hepatic glucose fluxes can be accomplished in conscious unrestrained mice and that, in the presence of hyperinsulinemia, hyperglycemia causes 1) a further inhibition of HGP mainly via inhibition of glycogenolysis and increase in hepatic glucose cycling; and 2) about a fivefold stimulation in the direct pathway of hepatic glycogen formation.

Failure of glucagon suppression contributes to postprandial hyperglycaemia in IDDM.

Carbohydrate ingestion results in a fall in glucagon concentration in non-diabetic but not in diabetic individuals. To determine if, and the mechanism by which, lack of postprandial suppression of glucagon contributes to hyperglycaemia, nine subjects with insulin-dependent diabetes mellitus (IDDM) ingested 50 g of glucose containing both [2-3H] glucose and [6-3H] glucose on two occasions. [6-14C] glucose, insulin and low-dose somatostatin were infused intravenously at the same rates on both occasions. A basal glucagon infusion was started either at the same time ("constant glucagon") or 2 h following ("suppressed glucagon") glucose ingestion. This resulted in lower (p < 0.001) glucagon concentrations during the first 2 h of the suppressed than during the constant glucagon study days (63 +/- 1 vs 108 +/- 2 pg/ml). Lack of suppression of glucagon led to higher (p < 0.01) postprandial glucose concentrations (10.3 +/- 0.9 vs 8.1 +/- 0.7 mmol/l) and a greater (p < 0.02) integrated glycaemic response. The excessive rise in glucose was due to higher (p < 0.02) rates of postprandial hepatic glucose release during the constant than during the suppressed glucagon study days, whether measured using either [6-3H] glucose (2.6 +/- 0.2 vs 2.0 +/- 0.2 mmol.kg-1 per 6 h) or [2-3H] glucose (3.0 +/- 0.3 vs 2.4 +/- 0.2 mmol.kg-1 per 6 h) as the meal tracer. Glucose disappearance, initial splanchnic glucose clearance and hepatic glucose cycling did not differ on the two occasions. Thus, the present studies demonstrate that lack of postprandial suppression of glucagon, by increasing hepatic glucose release, contributes to hyperglycaemia in subjects with IDDM.

Failure of glucagon suppression contributes to postprandial hyperglycaemia in IDDM

Carbohydrate ingestion results in a fall in glucagon concentration in non-diabetic but not in diabetic individuals. To determine if, and the mechanism by which, lack of postprandial suppression of glucagon contributes to hyperglycaemia, nine subjects with insulin-dependent diabetes mellitus (IDDM) ingested 50 g of glucose containing both [2-3H] glucose and [6-3H] glucose on two occasions. [6-14C] glucose, insulin and low-dose somatostatin were infused intravenously at the same rates on both occasions. A basal glucagon infusion was started either at the same time (“constant glucagon”) or 2 h following (“suppressed glucagon”) glucose ingestion. This resulted in lower (p<0.001) glucagon concentrations during the first 2 h of the suppressed than during the constant glucagon study days (63±1 vs 108±2 pg/ ml). Lack of suppression of glucagon led to higher (p<0.01) postprandial glucose concentrations (10.3±0.9 vs 8.1±0.7 mmol/l) and a greater (p<0.02) integrated glycaemic response. The excessive rise in glucose was due to higher (p<0.02) rates of postprandial hepatic glucose release during the constant than during the suppressed glucagon study days, whether measured using either [6-3H] glucose (2.6±0.2 vs 2.0±0.2 mmol·kg−1 per 6 h) or [2-3H] glucose (3.0±0.3 vs 2.4±0.2 mmol·kg−1 per 6 h) as the meal tracer. Glucose disappearance, initial splanchnic glucose clearance and hepatic glucose cycling did not differ on the two occasions. Thus, the present studies demonstrate that lack of postprandial suppression of glucagon, by increasing hepatic glucose release, contributes to hyperglycaemia in subjects with IDDM.

Rate of glucose entry into hepatic uridine diphosphoglucose by the direct pathway in fasted and fed states in normal humans

We used the glucuronate (GlcUA) probe technique to measure the rate of glucose entry into hepatic uridine diphosphoglucose (UDP-glc) by the direct pathway, to quantify the rate of appearance (Ra) of hepatic UDP-glc, and to calculate hepatic glucose cycling in vivo in normal humans. The direct pathway contribution to UDP-glc as determined by the ratio of [1-d1]-GlcUA to plasma [LD1]-glucose enrichments was minor (15% to 20%) in normal men after an overnight fast. After 9 hours of refeeding with intravenous (IV) glucose or an oral liquid formula meal each at a rate of 7 mg carbohydrate/kg/min, the direct pathway increased to 66.3% +/- 6.7% and 61.6% +/- 6.0% (mean +/- SE), respectively. Plasma glucose concentrations remained below 7.8 mmol/L and could not account for most of the variability in direct pathway contribution. The dilution of labeled [L-D1]-galactose in excreted acetaminophen-GlcUA was used to measure Ra UDP-glc, on the assumption that labeled galactose passes through the liver during its assimilation. Ra UDP-glc was 1.1 +/- 0.1 mg/kg/min after an overnight fast and increased to 2.0 +/- 0.1 with i.v. glucose and 2.6 +/- 0.2 with the oral liquid mixed meal. By combining the fractional glucose contribution with the Ra of hepatic UDP-glc, the rate of direct glucose entry into hepatic UDP-glc was 0.2 mg/kg/min (fasted) and increased to 1.3 to 1.6 (fed). This represented approximately 18% to 21% of systemic glucose disposal or 19% to 23% of the administered carbohydrate load during i.v. or oral refeeding.(ABSTRACT TRUNCATED AT 250 WORDS)

Importance of substrate changes in the decrease of hepatic glucose cycling during insulin infusion and declining glycemia in the depancreatized dog.

We wished to determine whether the elevated glucose cycling (GC) between glucose and glucose-6-phosphate (G<-->G6P) in diabetes can be reversed with acute insulin treatment. In six insulin-deprived, anesthetized, depancreatized dogs, insulin was infused for 6-9 h at a starting dose of 45-150 pmol.kg-1.min-1 to normalize plasma glucose from 23.9 +/- 1.4 to 5.0 +/- 0.4 mmol/l and gradually decreased to and maintained at a basal rate (1.7 +/- 1.0 pmol.kg-1.min-1) during the last 3 h. GC, measured with [2-3H]- and [6-3H]glucose, fell markedly from 15.3 +/- 2.7 and normalized at 1.3 +/- 0.6 mumol.kg-1.min-1 (P < 0.001). This occurred because total hepatic glucose output fell much more (from 41.2 +/- 3.1 to 11.6 +/- 1.2) than did glucose production (from 25.9 +/- 1.9 to 10.3 +/- 1.0 mumol.kg-1.min-1) (both P < 0.01). Freeze-clamped liver biopsies were taken at timed intervals for measurements of hepatic enzymes and substrates. The elevated hepatic hexose-6-phosphate levels decreased with insulin infusion (151 +/- 24 vs. 71 +/- 13 nmol/g, P < 0.01). Maximal activities of glucose-6-phosphatase (G6Pase) (from 17.6 +/- 0.8 to 19.6 +/- 2.6 U/g) and glucokinase (from 1.1 +/- 0.2 to 1.0 +/- 0.2 U/g) did not change. Insulin infusion resulted in a threefold increase (P < 0.05) in the activity of glycogen synthase (active form), but had no effect on hepatic glycogen content.(ABSTRACT TRUNCATED AT 250 WORDS)

Importance of Substrate Changes in the Decrease of Hepatic Glucose Cycling During Insulin Infusion and Declining Glycemia in the Depancreatized Dog

We wished to determine whether the elevated glucose cycling (GC) between glucose and glucose-6-phosphate (G⇆G6P) in diabetes can be reversed with acute insulin treatment. In six insulin-deprived, anesthetized, depancreatized dogs, insulin was infused for 6–9 h at a starting dose of 45–150 pmol-kg−1-min−1 to normalize plasma glucose from 23.9 ± 1.4 to 5.0 ± 0.4 mmol/1 and gradually decreased to and maintained at a basal rate (1.7 ± 1.0 pmol · kg−1 · min−1) during the last 3 h. GC, measured with [2-3H]- and [6-3H]glucose, fell markedly from 15.3 ± 2.7 and normalized at 1.3 ± 0.6 μmol · kg−1 · min−1 (P &amp;lt; 0.001). This occurred because total hepatic glucose output fell much more (from 41.2 ± 3.1 to 11.6 ± 1.2) than did glucose production (from 25.9 ± 1.9 to 10.3 ± 1.0 μmol · kg−1 · min−1) (both P &amp;lt; 0.01). Freeze-clamped liver biopsies were taken at timed intervals for measurements of hepatic enzymes and substrates. The elevated hepatic hexose-6-phosphate levels decreased with insulin infusion (151 ± 24 vs. 71 ± 13 nmol/g, P &amp;lt; 0.01). Maximal activities of glucose-6-phosphatase (G6Pase) (from 17.6 ± 0.8 to 19.6 ± 2.6 U/g) and glucokinase (from 1.1 ± 0.2 to 1.0 ± 0.2 U/g) did not change. Insulin infusion resulted in a threefold increase (P &amp;lt; 0.05) in the activity of glycogen synthase (active form), but had no effect on hepatic glycogen content. We therefore conclude that in the depancreatized dog, 1) acute insulin infusion with a concurrent correction of hyperglycemia can markedly reduce and normalize GC, and 2) the acute reduction in GC is primarily mediated by reduced substrate fluxes through glucokinase and G6Pase and does not require stable changes in maximal activities of the two enzymes. However, in vivo allosteric changes in enzyme activities (particularly G6Pase), immeasurable in vitro, cannot be excluded. In addition to enzyme measurements, the importance of tracer methods that allow for in vivo measurements of fluxes through glucokinase and G6Pase is emphasized.

Insulin dissociates hepatic glucose cycling and glucagon-induced thermogenesis in man

The quantitative contribution of hepatic glucose cycling to basal and glucagon-stimulated thermogenesis was investigated in seven normal healthy volunteers in whom energy expenditure (EE) was measured simultaneously with indirect calorimetry. Primed-constant infusions of 2-( 2H 1)-glucose and 6-6′-( 2H 2)-glucose were used to calculate hepatic glucose cycling. Gas chromatography/mass spectrometry was used to measure the plasma enrichment of isotopes. In response to hyperglucagonemia, basal EE increased an average of 7.1% ± 2.3% ( P < .05). This thermogenic effect of glucagon was completely blunted when insulin levels were increased sevenfold over the basal concentration. Hepatic glucose cycling comprised 15% ± 4% of basal glucose turnover and increased more than 100% in response to isolated hyperglucagonemia. The increase in liver glucose cycling was observed also when serum insulin concentrations were increased sevenfold above baseline. Thus, we were able to induce dissociation of the activation of hepatic glucose cycling and the thermogenic response induced by hyperglucagonemia. From the quantitative point of view, the thermogenic cost of the cycles was less than 1% in both the basal and stimulated state. Thus, we concluded that hepatic glucose cycles play a quantitatively minor role in EE in man.

Effects of fatty acid oxidation on glucose utilization by isolated hepatocytes

We have studied the inhibitory action of long- and short-chain fatty acids on hepatic glucose utilization in hepatocytes isolated from fasted rats. The rates of hepatic glucose phosphorylation and glycolysis were determined from the tritiated products of [2- 3H] and [6- 3H]glucose metabolism, respectively. The difference between these was taken as an estimate of the ‘cycling’ between glucose and glucose-6-phosphate. In the presence of 40 mM glucose this cycling was estimated at 0.68 μ;molmin g wet wt. Glucose phosphorylation was unaffected during palmitate and hexanoate oxidation to ketone bodies but glycolysis was inhibited. The rate of glucose cycling was increased during this phase to 1.25 μmol min>g . Following the complete metabolism of the fatty acids, glycolysis was reinstated and cycling rates returned to control levels. Hepatic glucose cycling appears to be an important component of the glucose/fatty acid cycle.

Insulin action and hepatic glucose cycling in essential hypertension

Peripheral insulin resistance is a feature of essential hypertension, but there is little information about hepatic insulin sensitivity. To investigate peripheral and hepatic insulin sensitivity and activity of the hepatic glucose/glucose 6-phosphate (G/G6P) substrate cycle in essential hypertension, euglycemic glucose clamps were performed in eight untreated patients and eight matched controls at insulin infusion rates of 0.2 and 1.0 mU · kg −1 · min −1. A simultaneous infusion of (2 3H)- and (6 3H)glucose, combined with a selective detritiation procedure, was used to determine glucose turnover, the difference being G/G6P cycle activity. Endogenous hepatic glucose production (EGP) determined with (6 3H)glucose was similar in hypertensive and control groups in the postabsorptive state (11.0 ± 0.3 v 10.9 ± 0.3 μmol · kg −1 · min −1) and with the 0.2 mU insulin infusion (4.9 ± 0.5 v 4.0 ± 0.8 μmol · kg −1 · min −1). With the 1.0 mU insulin infusion, glucose disappearance determined with (6 3H)glucose was lower in the hypertensive group (21.8 ± 2.4 v 29.9 ± 2.4 μmol · kg −1 · min −1, P < .001). G/G6P cycle activity was similar both in the postabsorptive state (2.2 ± 0.4 v 2.7 ± 0.4 μmol · kg −1 · min −1) and during insulin infusion (0.2 mU, 2.5 ± 0.3 v 2.9 ± 0.4; 1.0 mU, 4.7 ± 0.3 v 5.3 ± 1.1 μmol · kg −1 · min −1, for hypertensive and control groups, respectively). Following 12 weeks' therapy with cyclopenthiazide 500 μg/d in the hypertensive group, there were increases in fasting glucose (5.2 ± 0.2 to 5.6 ± 0.2 mmol · L −1, P < .05), fasting insulin (8.5 ± 1.8 to 11.1 ± 3.1 mU · L −1, P < .05), and postabsorptive endogenous glucose production (11.0 ± 0.3 to 12.3 ± 0.4 μmol · kg −1 · min −1, P < .05). EGP during the 0.2-mU infusion and glucose turnover with the 1.0-mU infusion did not change. In conclusion, peripheral but not hepatic insulin sensitivity is diminished in essential hypertension. Activity of the G/G6P substrate cycle is similar in hypertensive and control groups. Cyclopenthiazide therapy causes postabsorptive hyperglycemia, but insulin sensitivity is not affected during hyperinsulinemia.

Contribution to Postprandial Hyperglycemia and Effect on Initial Splanchnic Glucose Clearance of Hepatic Glucose Cycling in Glucose-Intolerant or NIDDM Patients

Excessive amounts of glucose enter the systemic circulation when patients with non-insulin-dependent diabetes mellitus (NIDDM) eat a carbohydrate-containing meal. To determine the contribution of hepatic glucose cycling (defined as the net effect of glucose/glucose-6-phosphate cycling and uptake and release of glucose from hepatic glycogen) to postprandial hyperglycemia, diabetic, glucose-intolerant, and nondiabetic subjects were fed mixed meals. The meal contained both [2-3H]glucose (an isotope that is extensively detritiated during hepatic glucose cycling) and [6-3H]glucose (an isotope that is not detritiated during hepatic glucose cycling). Of the 50 g of carbohydrate contained in the meal, approximately 4-8 g underwent hepatic glucose cycling. Although total cycling of ingested glucose did not differ between diabetic, glucose-intolerant, and nondiabetic subjects (361 +/- 67 vs. 494 +/- 106 vs. 322 +/- 44 mumol.kg-1.5 h-1, respectively), the data suggested that hepatic cycling was increased in the diabetic and glucose-intolerant individuals but not in the nondiabetic subjects during the first 2 h after eating. Hepatic cycling during the first 2 h after eating was correlated with the prevailing glucagon concentration (r = 0.6, P less than 0.01) and increased (P less than 0.05) as hepatic glucose release increased. Hepatic glucose cycling had a marked effect on the measurement of so-called initial splanchnic glucose uptake. Nevertheless, however measured, initial splanchnic glucose uptake was not decreased and, if anything, was increased in diabetic and glucose-intolerant patients. Integrated postprandial hepatic glucose release increased (r less than 0.01) with the severity of fasting hyperglycemia.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Glucose Turnover in Hyperthyroid Patients with Normal Glucose Tolerance*

To determine the diabetogenic effect(s) of thyroid hormones, we simultaneously measured glucose turnover in six hyperthyroid patients and six normal subjects. All had normal fasting blood glucose concentration and oral glucose tolerance test values. We determined hepatic total glucose output (HTGO) and total glucose phosphorylation with [2-3H]glucose and hepatic glucose production (HGP) and irreversible glucose uptake using [6-3H]glucose. The difference between the two turnover rates indicates the extent of hepatic glucose cycling (glucose in equilibrium glucose-6-phosphate). Measurements were made both in the postabsorptive steady state and during a 2-h glucose infusion (11.1 mumol/kg.min). The postabsorptive HTGO and total glucose phosphorylation were increased in the hyperthyroid patients [13.5 +/- 0.8 (+/- SE) vs. 11.3 +/- 0.4 mumol/kg.min; P less than 0.05]. HGP and irreversible glucose uptake also were slightly but not significantly higher. During the glucose infusion, HTGO and HGP were less suppressed in the hyperthyroid patients than in the normal subjects, while the increments in peripheral glucose uptake were normal. In hyperthyroidism, glucose cycling was increased both postabsorptively (2.35 +/- 0.27 vs. 1.17 +/- 0.25 mumol/kg.min; P less than 0.025) and during glucose infusion (2.57 +/- 0.34 vs. 1.31 +/- 0.35 mumol/kg.min; P less than 0.05). We conclude that increases in HTGO and HGP are important features of hyperthyroidism, especially during glucose infusion. The increase in GC indicates increased activities of both glucokinase and glucose-6-phosphatase. The diabetogenic effect of hyperthyroidism, as revealed most markedly by [2-3H]glucose, could be accounted for by augmented glucose production, possibly due to increased glucose-6-phosphatase activity.