Mladen Vranic

Estimation of Endogenous Glucose Production During Hyperinsulinemic-Euglycemic Glucose Clamps: Comparison of Unlabeled and Labeled Exogenous Glucose Infusates

Tracer methodology has been applied extensively to the estimation of endogenous glucose production (Ra) during euglycemic glucose clamps. The accuracy of this approach has been questioned due to the observation of significantly negative estimates for Ra when insulin levels are high. We performed hyperinsulinemic (300 μU/ml)-euglycemic glucose clamps for 180 min in normal dogs and compared the standard approach, an unlabeled exogenous glucose infusate (cold GINF protocol, n = 12), to a new approach in which a tracer (D-[3-3H]glucose) was added to the exogenous glucose used for clamping (hot GINF protocol, n = 10). Plasma glucose, insulin and glucagon concentrations, and glucose infusion rates were similar for the two protocols. Plasma glucose specific activity was 20 ± 1% of basal (at 120–180 min) in the cold GINF studies, and 44 ± 3 to 187 ± 5% of basal in the hot GINF studies. With the one-compartment, fixed pool volume model of Steele, Ra, for the cold GINF studies was –2.4 ± 0.7 mg · min−1 · kg−1 at 25 min and remained significantly negative until 110 min (P < .05). For the hot GINF studies, Ra was never significantly less than zero (P > .05) and was greater than in the cold GINF studies at 20–90 min (P < .05). There was substantially less between-(78%) and within- (40%) experiment variation for the hot GINF studies compared with the cold GINF studies. An alternate approach (regression method) to the application of the one-compartment model, which allows for a variable and estimable effective distribution volume, yielded Ra estimates that were suppressed 60–100% from basal. In conclusion, the one-compartment, fixed pool volume model of glucose kinetics is inadequate for the estimation of Ra during euglycemic glucose clamps. Two new strategies for estimating Ra from the one-compartment model, the hot GINF protocol and the regression method calculation, yielded more accurate and physiologically plausible estimates of Ra than currently used methodology.

Exercise and Diabetes Mellitus

(All are verbatim summaries) Wood, P. D.; Haskell, W. L; Stern, M. P.; Lewis, S.; and Perry, C. (Stanford Univ. Sch. of Med., CA): Plasma lipoprotein distributions in male and female runners. Ann. N.Y. Acad. Sci. 307:748-63, 1977. Recent studies have shown a consistent association between relatively low plasma concentrations of high-density lipoprotein (HDL) cholesterol and increased risk of coronary heart disease. A cross-sectional comparison was made of the distribution of plasma lipids and lipoproteins in groups of 41 male and 43 female long distance runners versus larger control groups matched for age and sex, randomly selected from northern California towns. The runners showed modestly lower total cholesterol concentrations, while their triglyceride levels were only 50% of control. HDL-cholesterol was higher in runners than controls (75 ± 14 vs 56 ± 14 mg/100 ml for women; 64 ± 13 vs 43 ± 10 for men), while low-density lipoprotein cholesterol was lower (113 ±133 vs 124 ±34 for women; 125 ±21 vs 139 ±32 for men). All differences were statistically significant (p < 0.05), and only partially attributable to known factors other than high physical activity level. Since the runners were predominantly normotensive, relatively lean, and exclusively nonsmokers, they appear to constitute a remarkably favored group with respect to risk of cardiovascular disease. Issekutz, B. (Dept. of Physiol., Sch. of Med., Dalhousie Univ., Halifax, N.S.): Energy mobilization in exercising dogs. Diabetes 28 (Suppl. 1):39-44, 1979. The relative importance of the three major energy stores— adipose tissue, liver and muscle glycogen—was studied in dogs during prolonged exercise (slope 15%, speed 100 m/min). Using palmitate-C and 3-H-glucose, the rates of release of FFA (Ra-FFA) and that of hepatic glucose (Ra-G) were measured simultaneously. Glucose-C (U) was used to estimate the rate of glycogenolysis in the working muscle (M-GLY) by measuring both glucose and lactate specific DIABETES, VOL. 28, FEBRUARY 1979 163 EXERCISE AND DIABETES MELLITUS activity in the plasma. The ratio Ra-FFA/Ra-G decreases from about 1 to 0.6 during exercise and, at the end of a 3-h run, some 90% of the energy expenditure could have been covered by Ra-FFA and an additional 40% from CHO sources. Blocking the /3-receptors (propranolol) during exercise caused a sharp decrease of both Ra-FFA and M-GLY with a significant increase of the metabolic clearance rate (MCR) of glucose. Since Ra-G could not match the rise of MCR, blood glucose declined prematurely. When the infusion of the ^-antagonist preceded the run, it suppressed the exercise-induced rise of plasma cAMP and increased the rate of decline of plasma glucose. Blockade of the a adrenergic system did not yield consistent and interpretable results. It is concluded that the continuous stimulation of the /3 adrenergic system and not the elevated energy demand is directly responsible for the mobilization of both FFA and muscle glycogen. The former is stimulated by norepinephrine and the latter by epinephrine. The excessive flow of energy sources is an attempt to reduce the glucose uptake of the muscle and to prevent hypoglycemia for as long as possible. Pirnay, F.; Lacroix, M.; Mosora, F.; Luyckx, A.; and Lefebvre, P. (Inst. Provincial E. Malvoz, Dept. of Atomic and Molecular Physics and Div. of Diabetes, Inst. of Med., Univ. of Liege, Belgium): Glucose oxidation during prolonged exercise evaluated with naturally labeled C-glucose. J. Appl. Physiol. 43:258-61, 1977. Using naturally enriched C-glucose as metabolic tracer, the utilization of exogenous glucose ingested during muscular exercise was investigated. Four subjects walked on an uphill treadmill for two hours, and three others for four hours. The energy expenditure, close to fifty percent of the individual maximum VO2, varied from 1.9 to 2.1 I of 02/min, while the heart rate ranged between 142 and 165 beats/min. The subjects, who were on a mixed diet and who had fasted overnight, were given 100g of naturally labeled C-glucose. Following this intake, the expired CO2 became rapidly enriched in carbon 13. The increase was observed as early as 15 minutes after the oral intake, and reached a maximum within 1 to 2 hours, when utilization of exogenous glucose varied between 500 and 650 mg/min, and represented as much as 55% of the carbohydrate metabolism and 24% of the total energy expenditure. Wahren, J.; Felig, P.; Ahlborg, G.; and Jorfeldt, L. (Dept. of Clin. Physiol., Karolinska Inst. of the Serafimer Hosp., Stockholm, Sweden, and Dept. of Intern. Med., Yale Univ. Sch. of Med., New Haven, CN): Glucose metabolism during leg exercise in man. J. Clin. Invest. 50:271525, 1971. Arterial concentrations and net substrate exchange across the leg and splanchnic vascular bed were determined for glucose, lactate, pyruvate, and glycerol in healthy postabsorptive subjects at rest and during 40 min of exercise on a bicycle ergometer at work intensities of 400, 800 and 1200 kg m/min. Rising arterial glucose levels and small decreases in plasma insulin concentrations were found during heavy exercise. Significant arterial-femoral venous differences for glucose were demonstrated both at rest and during exercise, their magnitude increasing with work intensity as well as duration of the exercise performed. Estimated glucose uptake by the leg increased 7-fold after 40 min of light exercise and 10to 20-fold at moderate to heavy exercise. Blood glucose uptake could at this time account for 28-37% of total substrate oxidation by leg muscle and 75-89% of the estimated carbohydrate oxidation. Splanchnic glucose production increased progressively during exercise reaching levels 3 to 5-fold above resting values at the heavy work loads. Close agreement was observed between estimates of total glucose turnover during exercise based on leg glucose uptake and splanchnic glucose production. Hepatic gluconeogenesis—estimated from splanchnic removal of lactate, pyruvate, glycerol and glycogenic amino acids—could supply a maximum of 25% of the resting hepatic glucose production but could account for only 6-11% of splanchnic glucose production after 40 min of moderate to heavy exercise. It is concluded that: (a) blood glucose becomes an increasingly important substrate for muscle oxidation during prolonged exercise of this type; (b) peripheral glucose utilization increases in exercise despite a reduction in circulating insulin levels; (c) increased hepatic output of glucose, primarily by means of augmented glycogenolysis, contributes to blood glucose homeostasis in exercise and provides an important source of substrate for exercising

Modeling Error and Apparent Isotope Discrimination Confound Estimation of Endogenous Glucose Production During Euglycemic Glucose Clamps

We previously demonstrated that conventional tracer methods applied to euglycemic-hyperinsulinemic glucose clamps result in substantially negative estimates for the rate of endogenous glucose production, particularly during the first half of 180-min clamps. We also showed that addition of tracer to the exogenous glucose infusate resulted in nonnegative endogenous glucose production (Ra) estimates. In this study, we investigated the underlying cause of negative estimates of Ra from conventional clamp/tracer methods and the reason for the difference in estimates when tracer is added to the exogenous glucose infusate. We performed euglycemic-hyperinsulinemic (300-μU/ml) clamps in normal dogs without (cold GINF protocol, n = 6) or with (hot GINF protocol, n = 6) tracer (D-[3-3H]glucose) added to the exogenous glucose infusate. In the hot GINF protocol, sufficient tracer was added to the exogenous glucose infusate such that arterial plasma specific activity (SAa) did not change from basal through the clamp period (P > .05). In the cold GINF studies, plasma SAa fell 81 ± 2% from the basal level by the 3rd h of clamping. We observed a significant, transient, positive venous-arterial difference in specific activity (SAv-SAa difference) during the cold GINF studies. The SAv-SAa difference reached a peak of 27 ± 6% at 30 min and diminished to a plateau of 7 ± 1% between 70 and 180 min. We also observed a positive but constant SAv-SAa difference (4.6 ± 0.2% between 10 and 180 min) during the hot GINF studies. The observations of a difference between hot and cold GINF endogenous Ra estimates and a positive but transient SAv-SAa difference during the cold GINF studies are consistent with the interpretation that a portion of the underestimation of Ra is due to insufficient mixing of endogenous and exogenous glucose for the one-compartment, fixed-pool volume model to be applicable. Alternatively, our results suggest that the one-compartment, fixed-pool volume model of glucose kinetics is insufficient to account for the complex dynamics of labeled and unlabeled glucose during euglycemic-hyperinsulinemic clamps. Improved mixing through addition of tracer to the exogenous glucose infusate or improved modeling by allowing for a variable-pool volume appears to improve the accuracy of the tracer methods; however, these approaches remain to be validated. The constant positive SAv-SAa difference observed during the hot GINF studies is consistent with the interpretation that an additional contributor to underestimation of endogenous Ra is apparent isotope discrimination. Whether this apparent discrimination is due to a true isotope effect or contamination of the tracer infusate remains to be determined.

Insulin induces the translocation of GLUT4 from a unique intracellular organelle to transverse tubules in rat skeletal muscle.

Skeletal muscle surface membrane is constituted by the PM domain and its specialized deep invaginations known as TTs. We have shown previously that insulin induces a rapid translocation of GLUT4s from an IM pool to the PM in rat skeletal muscle (6). In this study, we have investigated the possibility that insulin also stimulates the translocation of GLUT4 proteins to TTs, which constitute the largest area of the cell surface envelope. PM, TTs, and IM components of control and insulinized skeletal muscle were isolated by subcellular fractionation. The TTs then were purified further by removing vesicles of SR origin by using a Ca-loading procedure. Ca-loading resulted in a five- to sevenfold increase in the purification of TTs in the unloaded fraction relative to the loaded fraction, assessed by immunoblotting with an anti-OHP-receptor monoclonal antibody. In contrast, estimation of the content of Ca2+-ATPase protein (a marker of SR) with a specific polyclonal antibody revealed that most, if not all, SR vesicles were recovered in the Ca-loaded fraction. Western blotting with an anti-COOH-terminal GLUT4 protein polyclonal antibody revealed that acute insulin injection in vivo (30 min) increased the content of GLUT4 (by 90%) in isolated PMs and markedly enhanced (by 180%) GLUT4 content in purified TTs. Importantly, these insulin-dependent changes in GLUT4 content of PM and purified TTs were seen in the absence of changes in the α1-subunit of the Na+-K+-ATPase, a surface membrane marker. Isolated IM components such as LSR, HSR, and triads (terminal cisternae plus junctional TT) contained low or barely detectable amounts of GLUT4; furthermore, insulin treatment did not change the distribution of the transporter protein within these fractions. In contrast, a unique IM fraction that was not associated with either SR or triad markers, contained significant amounts of GLUT4 and showed an insulin-dependent decrease (40%) in GLUT4 protein content. These results show that acute insulin treatment induces the translocation of GLUT4s to both the PM and TTs from a unique intracellular organelle not associated with the SR.

The essentiality of insulin and the role of glucagon in regulating glucose utilization and production during strenuous exercise in dogs.

UNLABELLED In order to elucidate the role of insulin and glucagon during strenuous exercise (100 m/min, slope 10-12 degrees), we have determined the rates of production (Ra), utilization (Rd), and metabolic clearance (M) of glucose in normal dogs before pancreatectomy and 2 wk after total pancreatectomy (a) when they were being maintained on constant intraportal basal insulin infusion, (245 muU/kg-min) and (b) when insulin supply had been withheld before and during exercise. Such an intense exercise induced in normal dogs a prompt decrease in mean immunoreactive serum insulin (IRI) from 20 +/- 3 to 11 +/- 2 muU/ml. In depancreatized insulin-infused dogs serum IRI during rest and exercise was between 14 +/- 1 and 12 +/- 2 muU/ml. In the third group, after cessation of insulin infusion, IRI decreased by 76% (from 17 +/- 5 to 4 +/- 1) and did not decrease futher during exercise. During exercise, serum immunoreactive glucagon (IRG) increased threefold in normal dogs. In depancreatized dogs serum IRG was the same as in normal resting dogs (indicating a nonpancreatic source of the hormone) but it did not increase during exercise. In normal dogs exercise induced proportional increases in Ra, Rd, and M (threefold) and normoglycemia was maintained. Changes in glucose turnover in depancreatized insulin-infused dogs were similar to those seen in normal dogs suggesting that a decrease in insulin secretion and a rise in IRG are not essential to prevent hypoglycemia in diabetic dogs. With the cessation of insulin infusion in resting depancreatized dogs, Ra increased, M decreased, and hyperglycemia ensued. During exercise, Ra continued to rise, but M did not increase significantly. CONCLUSIONS (a) Regulation of glucose production by liver during exercise is multifactorial. A decrease in IRI and an increase in IRG are not the only factors which can promote delivery of glucose to the peripheral tissues. The insulin glucagon molar ratio was found not to be an essential metabolic functional unit in regulating glucose metabolism during exercise. (b) It is hypothesized that increases in blood flow and capillary surface area can lead to an increase in the amount of insulin delivered to the muscle even when serum levels of IRI are reduced during exercies. It is suggested that small, but adequate amounts of insulin (as found in normal and depancreatized insulin-infused dogs) are essential in regulating glucose uptake in the working muscle. (c) Since totally depancreatized dogs had normal serum levels of IRG (originating presumably from the gastrointestinal tract), the question of essentiality of basal glucagon activity in glucose homeostasis during exercise could not be resolved by these experiments. It appears, however, that regulation of secretion of nonpancreatic glucagon differs from that of pancreatic glucagon.

Increased “Glucagon Immunoreactivity” in Plasma of Totally Depancreatized Dogs

Elevated plasma glucagon immunoreactivity (IRG) observed in overt diabetes and during prolonged fasting is assumed to be the result of increased secretion of pancreatic glucagon. In seven healthy mongrel dogs diabetes was induced by total pancreateetomy During the first two weeks following surgery, porcine NPH (6 to 12 U, once daily) and Regular insulin (6 to 12 U twice daily) were administered. Thereafter, insulin treatment was discontinued and the dogs were fasted for periods up to seven days. Plasma IRG was measured using antiglucagon serum G9-I which is 95 per cent specific for pancreatic glucagon. Fifteen hours after the last insulin injection an intraportal infusion of Regular insulin was given in amounts sufficient to achieve normoglycemia: mean IRG (pg./ml.) was 118 ± 34, a value similar to that observed in the fasting intact animals (134 ± 33). After insulin withdrawal, as fasting continued, plasma IRG increased progressively in all dogs. On Days 5 and 6-7, after insulin withdrawal, when peripheral plasma insulin was undetectable and marked hyperglycemia, hyperlipacidemia and ketonuria prevailed, mean IRG was 624 ± 136 and 986 ±184, respectively. The highest level of IRG observed was 1450 in one dog on Day 7. These results are confirmed by using three other antiglucagon sera considered to be specific for pancreatic glucagon. We conclude that: 1) Progressively increasing amounts of material crossreacting with “specific” antiglucagon sera appear in plasma of totally depancreatized dogs fasting for up to seven days. 2) This event appears to be the consequence of metabolic derangements induced by insulin lack. 3) Hyperglucagonemia can result onoly from a defect of the pancreatic α cell, but can also be the consequence of excessive production of IRG from a nonpancreatic source. It could be that glucagon deficiency cannot be easily demmonstrated, because the release of nonpancreatic IRG can compensate for lack of pancreatic glucagon.

Fatty Acids Mediate the Acute Extrahepatic Effects of Insulin on Hepatic Glucose Production in Humans

We have shown previously in humans that insulin partly suppresses hepatic glucose production (HGP) by an extrahepatic (indirect) mechanism. In the present study, we investigated the role of free fatty acids (FFAs) in mediating the extrahepatic effects of insulin in humans and determined the extent to which insulin can regulate HGP by a non–FFA-mediated effect. Sixteen healthy men received an intravenous tolbutamide infusion for 3 h, and pancreatic insulin secretion was calculated by deconvolution of peripheral C-peptide levels. On a subsequent occasion, equimolar exogenous insulin was infused by peripheral vein. In both studies, glucose was clamped at euglycemia. We have previously validated this method and shown no independent insulin-like activity of tolbutamide. During the clamp, 9 of the 16 subjects received a low dose of heparin and Intralipid to prevent the insulin-induced suppression of FFAs, while 7 subjects received a high dose of heparin and Intralipid to raise FFAs ∼2.5-fold. In both the highand low-dose groups, peripheral insulin was higher and calculated portal insulin lower with peripheral versus portal insulin delivery. In the low-dose group, HGP decreased by 68.3 ±2.1% with portal insulin delivery and 64.7 ± 3.7% with peripheral insulin delivery (NS). In the high-dose group, HGP decreased by 58.0 ± 4.5% with portal insulin and 48.3 ± 5.0% with peripheral insulin (P < 0.05). Four individuals who participated in the high-dose group underwent an additional peripheral insulin study in which the same dose of exogenous insulin was infused as in the high-dose group but in the absence of heparin and Intralipid. During this latter study, FFA levels declined by ∼90% during hyperinsulinemia, and HGP was suppressed by 71.8 ± 5.6%, which was a much greater suppression (P < 0.01) than when FFA levels were raised in these subjects during the equivalent rate insulin infusion. In summary, the previously observed greater suppression of HGP with equimolar peripheral versus portal insulin is eliminated or reversed, depending on plasma FFA levels, if FFAs are prevented from decreasing, suggesting an important role of FFAs in mediating the extrahepatic effects of insulin on HGP. However, the effect of FFA clamping is relatively small with a significant degree of suppression of HGP (by ∼50%), which remains evenwhen FFAs are elevated above basal levels, suggesting that in the physiological range FFAs only partially influence the suppression of HGP in humans. This suggests that other mechanisms, most likely hepatic, dominate the acute insulin-induced suppression of glucose production.

Hepatic Glucose Production Is Regulated Both by Direct Hepatic and Extrahepatic Effects of Insulin in Humans

The present study examines the effect of the route of insulin delivery on glucose turnover in humans. By using a new noninvasive in vivo method, the acute effect of insulin secreted by the pancreas can be compared with that of insulin delivered by a peripheral vein. Three euglycemic-hyperinsulinemic studies were performed in lean healthy men. In the first study (n = 10), constant portal hyperinsulinemia was produced using a programmed intravenous tolbutamide infusion algorithm, and the insulin secretion rate was mathematically derived by deconvolution from peripheral plasma C-peptide levels. In the second study (n = 10), exogenous insulin was infused by peripheral vein at the same rate as that determined in the first study. In the third study (n = 7), the peripheral insulin levels in the first study were matched by infusing exogenous insulin into a peripheral vein at half that rate. Peripheral insulin levels were higher (P < 0.001) with the full-rate peripheral insulin infusion (266.3 ± 28.1 pmol/l) than with the portal delivery of insulin (171.1 ± 30.4 pmol/l) or the half-rate peripheral insulin infusion (158.6 ± 7.4 pmol/l) (portal versus half-rate peripheral insulin infusion, NS). Calculated hepatic insulin levels were higher (P < 0.001) in the portal insulin study (443.1 ± 52.6 pmol/l) than in the full-rate peripheral insulin study (303.6 ± 30.9 pmol/l) or in the half-rate peripheral insulin study (204.5 ± 9.8 pmol/l). Hepatic glucose production (HGP) was suppressed to a greater extent with the full-rate peripheral insulin infusion (69.3 ± 7.8%, P < 0.001 vs. portal or half-rate peripheral insulin) than portal (50.3 ± 9.8%) or half-rate peripheral insulin infusion (36.8 ± 3.8%). In the portal insulin study, however, suppression was > in the half-rate peripheral insulin study (P < 0.01), in spite of equal peripheral insulin levels. The assumption that tolbutamide, when used in this fashion, has no independent effect on glucose turnover, glucagon, or gluconeogenic precursor and energy substrates for gluconeogenesis was validated in five C-peptide-negative patients with IDDM. We conclude that in nondiabetic humans, 1) peripheral effects of insulin are important in suppressing HGP, as evidenced by the greater suppression of HGP with equivalent rate peripheral versus portal insulin delivery, and 2) because HGP was suppressed to a greater extent with portal verus peripheral insulin delivery at half the rate when peripheral insulin levels were matched, insulin-induced suppression of HGP is also partly mediated by a direct hepatic effect.

Interactions between glucagon and other counterregulatory hormones during normoglycemic and hypoglycemic exercise in dogs.

Somatostatin (ST)-induced glucagon suppression results in hypoglycemia during rest and exercise. To further delineate the role of glucagon and interactions between glucagon and the catecholamines during exercise, we compensated for the counterregulatory responses to hypoglycemia with glucose replacement. Five dogs were run (100 m/min, 12 degrees) during exercise alone, exercise plus ST infusion (0.5 micrograms/kg-min), or exercise plus. ST plus glucose replacement (3.5 mg/kg-min) to maintain euglycemia. During exercise alone there was a maximum increase in immunoreactive glucagon (IRG), epinephrine (E), norepinephrine (NE), FFA, and lactate (L) of 306 +/- 147 pg/ml, 360 +/- 80 pg/ml, 443 +/- 140 pg/ml, 541 +/- 173 mu eq/liter, and 6.3 +/- 0.7 mg/dl, respectively. Immunoreactive insulin (IRI) decreased by 10.2 +/- 4 micro/ml and cortisol (C) increased only slightly (2.1 +/- 0.3 micrograms/dl). The rates of glucose production (Ra) and glucose uptake (Rd) rose markedly by 6.6 +/- 2.2 mg/kg-min and 6.2 +/- 1.5 mg/kg-min. In contrast, when ST was given during exercise, IRG fell transiently by 130 +/- 20 pg/ml, Ra rose by only 3.6 +/- 0.5 mg/kg-min, and plasma glucose decreased by 29 +/- 6 mg/dl. The decrease in IRI was no different than with exercise alone (10.2 +/- 2.0 microU/ml). As plasma glucose fell, C, FFA, and L rose excessively to peaks of 5.4 +/- 1.3 micrograms/dl, 1,166 +/- 182 mu eq/liter and 15.5 +/- 7.0 mg/dl. The peak increment in E (765 +/- 287 pg/ml) coincided with the nadir in plasma glucose and was four times greater than during normoglycemic exercise. Hypoglycemia did not affect the rise in NE. The increase in Rd was attenuated and reached a peak of only 3.7 +/- 0.8 mg/kg-min. During glucose replacement, IRG decreased by 109 +/- 30 pg/ml and the IRI response did not differ from the response to normal exercise. Ra rose minimally by 1.5 +/- 0.3 mg/kg-min. The changes in E, C, Rd, and L were restored to normal, whereas the FFA response remained excessive. In all protocols increments in Ra were directly correlated to the IRG/IRI molar ratio while no correlation could be demonstrated between epinephrine or norepinephrine and Ra. In conclusion, (a) glucagon controlled approximately 70% of the increase of Ra during exercise. This became evident when counterregulatory responses to hypoglycemia (E and C) were obviated by glucose replacement; (b) increments in Ra were strongly correlated to the IRG/IRI molar ratio but not the plasma catecholamine concentration; (c) the main role of E in hypoglycemia was to limit glucose uptake by the muscle; (d) with glucagon suppression, glucose production was deficient but a further decline of glucose was prevented through the peripheral effects of E, (e) the hypoglycemic stimulus for E secretion was facilitated by exercise; and (f) we hypothesize that an important role of glucagons during exercise could be to spare muscle glycogen by stimulating glucose production by the liver.

Mild type II diabetes markedly increases glucose cycling in the postabsorptive state and during glucose infusion irrespective of obesity.

Glucose cycling (GC; G in equilibrium G6P) equals 14% of glucose production in postabsorptive man. Our aim was to determine glucose cycling in six lean and six overweight mild type II diabetics (fasting glycemia: 139 +/- 10 and 152 +/- 7 mg/dl), in postabsorptive state (PA) and during glucose infusion (2 mg/kg per min). 14 control subjects were weight and age matched. GC is a function of the enzyme that catalyzes the reaction opposite the net flux and is the difference between hepatic total glucose output (HTGO) (2-[3H]glucose) and hepatic glucose production (HGP) (6-[3H]-glucose). Postabsorptively, GC is a function of glucokinase. With glucose infusion the flux is reversed (net glucose uptake), and GC is a function of glucose 6-phosphatase. In PA, GC was increased by 100% in lean (from 0.25 +/- 0.07 to 0.43 +/- .08 mg/kg per min) and obese (from 0.22 +/- 0.05 to 0.50 +/- 0.07) diabetics. HGP and HTGO increased in lean and obese diabetics by 41 and 33%. Glucose infusion suppressed apparent phosphatase activity and gluconeogenesis much less in diabetics than controls, resulting in marked enhancement (400%) in HTGO and HGP, GC remained increased by 100%. Although the absolute responses of C-peptide and insulin were comparable to those of control subjects, they were inappropriate for hyperglycemia. Peripheral insulin resistance relates to decreased metabolic glucose clearance (MCR) and inadequate increase of uptake during glucose infusion. We conclude that increases in HGP and HTGO and a decrease of MCR are characteristic features of mild type II diabetes and are more pronounced during glucose infusion. There is also an increase in hepatic GC, a stopgap that controls changes from glucose production to uptake. Postabsorptively, this limits the increase of HGP and glycemia. In contrast, during glucose infusion, increased GC decreases hepatic glucose uptake and thus contributes to hyperglycemia. Obesity per se did not affect GC. An increase in glucose cycling and turnover indicate hepatic insulin resistance that is observed in addition to peripheral resistance. It is hypothesized that in pathogenesis of type II diabetes, augmented activity of glucose-6-phosphatase and kinase may be of importance.