Basal Glucose Production Research Articles

Increased insulin action in rats with mild insulin deficiency induced by neonatal streptozotocin

The effect of chronic moderate insulin deficiency on in vivo insulin action was studied in young rats after neonatal (day of birth) streptozotocin (n0-STZ model) at a time (4 wk) when basal hyperglycemia is not yet established. The insulin action was quantified in vivo during insulin-glucose clamps performed on anesthetized rats while in the postabsorptive state; under basal or hyperinsulinemic conditions, total glucose production and utilization were assessed with a [3- 3H]-glucose perfusion, and local glucose utilization was estimated by measuring 2-deoxy-D-[1-3H]glucose 6-phosphate accumulation in various tissues. Compared with controls, the 4-wk-old n0-STZ rats were normoglycemic and hypoinsulinemic (P less than 0.05). The basal glucose production rate in the diabetics was significantly greater (P less than 0.05). During the clamp studies, suppression of endogenous glucose production by submaximal (1 nmol/l) or maximal (30 nmol/l) hyperinsulinemia was similar in both groups. Overall glucose utilization in the diabetics was significantly higher in the basal state and, after submaximal or maximal hyperinsulinemia, it remained significantly greater (P less than 0.001) than the corresponding utilization in the controls. This was correlated with an increased stimulation of glucose utilization in soleus muscle, diaphragm, white adipose tissue, and brown adipose tissue. In vitro studies using inguinal adipocytes showed that the glucose oxidative pathway retained normal sensitivity to insulin in the n0-STZ rats while the glucose conversion into lipids was significantly higher at sub-maximal insulin concentration compared with the control group.(ABSTRACT TRUNCATED AT 250 WORDS)

On the determination of basal glucose production rate in patients with Type 2 (non-insulin-dependent) diabetes mellitus using primed-continuous 3-3H-glucose infusion

Using primed-continuous 3-3H-glucose infusion, basal glucose production rate has been reported to be 140% higher than normal or almost normal in hyperglycaemic patients with Type 2 (non-insulin-dependent) diabetes mellitus. To determine whether these markedly different results could be due to the mode of priming: fixed or adjusted, or the mode of calculation: steady state or non-steady state equations, we studied 11 patients with Type 2 diabetes (fasting plasma glucose 8-20 mmol/l). For 6 h 3-3H-glucose (0.40 microCi/min) was infused preceded by a priming dose of 40 microCi (fixed priming), or 40 microCi.plasma glucose (mmol/l).5(-1) (adjusted priming). In diabetic patients the plasma glucose concentration was not constant but declined 0.52 +/- 0.07 mmol.l-1.h-1. Furthermore, the rate of fall was correlated to the fasting plasma glucose concentration (r = 0.90, p less than 0.01). Thus, the fasting state was not a steady state condition. Using adjusted priming a constant tracer steady state level was obtained within 60 min. In contrast, using fixed priming tracer steady state was not reached within 6 h. The initial tracer level was far below, and increased in time towards the steady state level observed after adjusted priming. Consequently, using Steele's equations after fixed priming, glucose production rates calculated after 90-120 min were overestimated in proportion to fasting hyperglycaemia. The fasting state in patients with Type 2 diabetes is not a steady state condition. Adjusted priming seems most appropriate in Type 2 diabetes.(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin resistance in rats with non-insulin-dependent diabetes induced by neonatal (5 days) streptozotocin: Evidence for reversal following phlorizin treatment

We have examined the effect of chronic (4 weeks) phlorizin treatment (osmotic minipumps) on tissue sensitivity to insulin in adult female rats with non-insulin-dependent diabetes (NIDD) induced by streptozotocin (STZ) (80 mg/kg) administered 5 days after birth. Insulin sensitivity was assessed with the euglycemic-hyperinsulinemic clamp technique in anesthetized animals. In the untreated diabetic rats, the basal glucose production (GP) and glucose utilization (GU) were increased ( P < .001), and both the liver and peripheral tissues showed insulin resistance. In the phlorizin-treated diabetic rats, postabsorptive plasma glucose levels were decreased and remained stable during the last 3 weeks of the treatment (142 ± 3 mg/dL as compared with 308 ± 19 in the untreated diabetic rats and 119 ± 3 in the phlorizin-control rats); their percent glycosylated hemoglobin values returned to normal (3.2 ± 0.2 as compared with 5.8 ± 0.4 in the untreated diabetic rats); their basal plasma insulin levels (55 ± 5 μU/mL as compared with 52 ± 3 in the untreated diabetic rats and 130 ± 10 in the phlorizin-control rats), their in vivo glucose-induced insulin secretion, and their pancreatic insulin content were kept unchanged. In the phlorizin-treated diabetic rats, the basal GP and GU were normalized. Following a submaximal or maximal hyperinsulinemia, GP was normally suppressed and GU normally enhanced. Phlorizin treatment in the control rats did not affect any of the above parameters. These data demonstrate that correction of hyperglycemia with phlorizin normalizes insulin action on glucose metabolism by the liver and peripheral tissues in this diabetic model. This is in line with the proposal that hyperglycemia per se can lead to the development of insulin resistance.

Increased Basal Glucose Production and Utilization in Nondiabetic First-Degree Relatives of Patients With NIDDM

To characterize the abnormalities in basal glucose homeostasis in people who are at increased risk for non-insulin-dependent diabetes mellitus (NIDDM), we measured the rates of basal hepatic glucose output (HGO), glucose disappearance, and metabolic clearance of glucose (MCR) in 27 nondiabetic first-degree relatives of NIDDM patients and 16 age-, sex-, and weight-matched healthy control subjects with no family history of NIDDM. Mean fasting plasma glucose was significantly lower (P less than 0.05) in control subjects (mean +/- SE 77 +/- 2 mg/dl) than in relatives (84 +/- 2 mg/dl). Mean basal insulin levels were not significantly different between relatives and control subjects (10.0 +/- 1.5 vs. 7.7 +/- 1.0 microU/ml). Mean basal HGO was significantly lower in control subjects compared with relatives (1.83 +/- 0.07 vs. 2.20 +/- 0.10 mg.kg-1.min-1, P less than 0.05). Mean MCR was similar in relatives (2.58 +/- 0.12 mg.kg-1.min-1) and control subjects (2.35 +/- 0.09 mg.kg-1.min-1). In summary, this study demonstrates that basal hepatic glucose production and glucose utilization are increased in glucose-tolerant first-degree relatives compared with healthy control subjects. We conclude that impaired basal hepatic glucose regulation rather than glucose disposal is present as an early defect in glucose-tolerant first-degree relatives of NIDDM patients.

Increased basal glucose production and utilization in nondiabetic first-degree relatives of patients with NIDDM

Increased basal glucose production and utilization in nondiabetic first-degree relatives of patients with NIDDM

Ca 2+-fatty acid interaction in the control of hepatic gluconeogenesis

Calcium depletion induced by perfusing livers with calcium-free buffer did not alter the rates of basal glucose production from pyruvate or from increasing concentrations of lactate. However, calcium deficiency selectively prevented the fatty acid-induced stimulation of gluconeogenesis from lactate. This effect is not related to the higher NAD redox potential consistently observed in Ca 2+-deficient livers. On the other hand, octanoate was capable of inducing dose-dependent changes in the [pyruvate] 0.5 in calcium-depleted livers perfused with lactate, ruling out that low cellular calcium content could perturb the mitochondrial transport of pyruvate. The observation that the effect of calcium deficiency can be overcome by supraphysiological concentrations of pyruvate supports the proposal that stimulation of the maximal capacity of the gluconeogenic pathway by fatty acid relies largely on the tricarboxylic acid cycle activity, restricted in calcium deficiency conditions.

Role of the Splanchnic Tissues in the Pathogenesis of Altered Carbohydrate Metabolism in Patients with Chronic Renal Failure

To evaluate the contribution of the splanchnic area to the carbohydrate abnormalities associated with chronic uremia, the splanchnic exchange of glucose and gluconeogenic substrates was quantitated basally and after an iv glucose load in nine uremic patients with impaired glucose tolerance and seven control subjects. In the basal state, blood glucose and splanchnic glucose production were similar in the two groups. During glucose infusion (33 mumol/kg.min for 90 min), blood glucose reached significantly higher levels in the uremic patients than in controls (P less than 0.02). Plasma insulin increased slightly more in uremic patients than in controls (P less than 0.05 at 15 min). Both basal and postglucose glucagon levels were 2- to 3-fold higher in uremic patients than in normal subjects (P less than 0.05-0.02). In both groups, splanchnic glucose balance switched from net output in the basal state (-9.4 +/- 0.5 and -8.0 +/- 1.1 mumol/kg.min in normals and uremics, respectively) to net uptake with glucose infusion. However, this response was less marked in the uremic patients than in normal subjects (P less than 0.05-0.02 at 30 and 90 min). The cumulative net splanchnic glucose balance over the 90-min study period was 538 +/- 55 mumol/kg in normal subjects and 279 +/- 89 in uremic subjects (P less than 0.05). A net splanchnic lactate uptake was present in the basal state in normal (4.2 +/- 0.5 mumol/kg.min) and uremic subjects (3.4 +/- 0.5). During glucose infusion, in normal subjects splanchnic lactate exchange switched to a net output (-4.0 +/- 1.6 mumol/kg.min), whereas in the uremic group it remained as a net uptake (1.1 +/- 0.7) throughout the study period. Splanchnic gluconeogenic amino acid uptake was similar in the two groups in the basal state (1.8 +/- 0.1 mumol/kg.min and 2.2 +/- 0.2 in normal and uremic subjects, respectively). Glucose infusion caused a marked fall in amino acid uptake by liver in normal subjects, whereas no change was observed in the uremic group (0.9 +/- 0.3 and 1.9 +/- 0.2 mumol/kg.min, respectively). Splanchnic glycerol uptake was not different in the two groups in the basal state (0.75 +/- 0.2 and 1.1 +/- 0.2 mumol/kg.min) and decreased to a similar extent during glucose infusion. We conclude the following. 1) In uremic patients with glucose intolerance but normal fasting glycemia, the splanchnic metabolism of glucose and gluconeogenic substrates is normal in the postabsorptive state.(ABSTRACT TRUNCATED AT 400 WORDS)

Insulin inhibition of overnight glucose production and gluconeogenesis from lactate in NIDDM.

Increased gluconeogenesis contributes to fasting hyperglycemia in non-insulin-dependent diabetes mellitus (NIDDM). We examined whether insulin inhibits gluconeogenesis from lactate by altering the fate of lactate and/or by reducing lactate flux. Seven patients with NIDDM (age 51 +/- 4 yr, body mass index 28 +/- 2 kg/m2) were studied before and 3 wk after achieving normoglycemia with evening insulin therapy. Basal glucose production (Ra) and utilization were measured overnight [( 3-3H]glucose infusion from 9 P.M. to 8 A.M.) and lactate turnover and conversion to glucose between 4 and 8 A.M. [( U-14C]lactate infusion) before and after insulin therapy. During insulin therapy, fasting plasma glucose decreased from 188 +/- 13 to 99 +/- 7 mg/dl (P less than 0.001) due to inhibition of glucose Ra from 3.0 +/- 0.1 to 2.2 +/- 0.1 mumol.kg-1.min-1 (P less than 0.005). Plasma free insulin increased from 6 +/- 1 to 11 +/- 1 microU/ml (P less than 0.005). Plasma lactate concentrations (1.1 +/- 0.2 vs. 1.0 +/- 0.1 mmol/l before vs. after insulin therapy) and the lactate turnover rate (15.6 +/- 0.9 vs. 14.2 +/- 0.8 mumol.kg.min) remained unchanged, whereas the amount of glucose formed from lactate decreased from 2.0 +/- 0.1 to 1.4 +/- 0.2 mumol.kg-1.min-1 (P less than 0.02) and the percent of lactate turnover converted to glucose decreased from 26 +/- 1 to 20 +/- 2% (P less than 0.05). We conclude that insulin inhibits overnight glucose Ra from lactate by decreasing the proportion of lactate diverted towards gluconeogenesis rather than by altering lactate availability or total flux.

Increased basal glucose production and utilization in children with recent obesity versus adults with long-term obesity

Increased basal glucose production and utilization in children with recent obesity versus adults with long-term obesity

Increased Basal Glucose Production and Utilization in Children With Recent Obesity Versus Adults With Long-Term Obesity

To characterize the abnormalities of glucose homeostasis and insulin action early in the course of human obesity, we studied in vivo glucose kinetics in seven children who were recently massively overweight. At time of study they were gaining weight at a rate of 13.5 +/- 1.4 kg/yr. They were compared with six age-matched control subjects. Six adults with long-term obesity and five normal adults were studied in parallel. The obese children and adults were normoglycemic and hyperinsulinemic. We found that glucose production and utilization were remarkably higher in obese children (295 +/- 18 mg/min; 7.6 mg.kg-1 lean body mass.min-1) than in control children (129 +/- 13 mg/min; 4.4 mg.kg-1 lean body mass.min-1, P less than .01) and obese adults (151 +/- 8 mg/min; 3.1 +/- 0.3 mg.kg-1 lean body mass.min-1, P less than .01). Obese adults had normal rates of glucose production and utilization. Insulin- and non-insulin-mediated glucose uptake, estimated with somatostatin-induced suppression of endogenous insulin secretion, contributed almost equally to the excess glucose utilization observed in the obese children. When studied with the euglycemic-hyperinsulinemic clamp, obese children could not increase glucose disposal to the same extent as normal children and were not able to adequately suppress their endogenous glucose production. Recently obese children are therefore characterized by an increased basal glucose turnover rate and an already established insulin resistance of the liver and probably the skeletal muscles.

In vivo insulin resistance in streptozotocin-diabetic rats--evidence for reversal following oral vanadate treatment.

Hepatic glucose production and peripheral glucose utilisation were measured in vivo with the euglycaemic-hyper-insulinaemic clamp technique in rats rendered severely diabetic with streptozotocin (45 mg/kg) and in control rats. The rats were studied in the post-absorptive state while anaesthetised. The basal glucose production and glucose utilisation were significantly higher (p less than 0.001) in diabetic rats 9 days after streptozotocin administration. During the clamp studies, suppression of glucose production by the liver induced by submaximal or maximal insulin levels was significantly less (p less than 0.01 and p less than 0.001 respectively) effective in diabetic rats as compared to control rats. Glucose utilisation was significantly lower following both submaximal (p less than 0.01) or maximal (p less than 0.001) hyperinsulinaemia as compared to control rats. Oral administration of vanadate (0.2 mg/ml in drinking water) for a 20-day period in diabetic rats lowered their plasma glucose levels to normal near values within 4 days, normalised plasma insulin levels, and increased pancreatic insulin stores. The rate of glucose disappearance (K value) and in vivo glucose-induced insulin secretion as estimated during an i.v. glucose tolerance test were not significantly improved. In control rats, vanadate treatment did not significantly affect any of the above parameters. In vanadate treated diabetic rats, basal glucose production was normalised. Following submaximal or maximal hyperinsulinaemia, glucose production was suppressed normally. Basal glucose utilisation was restored and returned to normal values during submaximal hyperinsulinaemia. However, during maximal hyperinsulinaemia, glucose utilisation still remained significantly lower (p less than 0.05) as compared to vanadate-treated control rats. (ABSTRACT TRUNCATED AT 250 WORDS)

Regulation of the hepatic response to glucagon: role of insulin, growth hormone and cortisol.

The hepatic response to glucagon was investigated in five groups of animals: (1) controls; (2) excess growth hormone (GH; tumor-bearing); (3) streptozotocin-induced diabetic; (4) cortisol-treated, and (5) insulin-treated animals. Blood samples were collected from the animal models and hepatocytes were prepared and used for glucagon-binding studies and studies of total glucose production, gluconeogenesis and glycogen determinations. Glucagon binding was elevated in GH-tumor-bearing and cortisol-treated hepatocytes but lower in hepatocytes from diabetic animals. Basal total glucose production wash higher in hepatocytes from diabetic rats but not changed in hepatocytes from GH-tumor-bearing, insulin-treated or cortisol-treated animals. Glucagon significantly stimulated total glucose production in hepatocytes from control, insulin-treated and cortisol-treated but not diabetic and GH tumor models. Gluconeogenesis as evaluated by alanine conversion to glucose was significantly increased in hepatocytes from diabetic and cortisol-treated animals and was significantly lower in hepatocytes from GH-tumor-bearing animals. Glucagon failed to significantly stimulate gluconeogenesis in hepatocytes from diabetic and tumor-bearing animals. Hepatic glycogen content was significantly decreased in diabetic and GH-tumor-bearing animals but not changed in insulin-treated and cortisol-treated animals. We conclude that increased glucagon binding was not always correlated with an increase in glucagon-stimulated glycogenolysis, gluconeogenesis or increased sensitivity to glucagon. Persistent hyperinsulinism may effectively suppress glucagon- or cortisol-stimulated pathways.

Glucose turnover rate and peripheral insulin sensitivity in alcoholic patients without liver damage.

Glucose intolerance is frequently found in alcoholic patients and an impaired insulin response has been documented in them. To look for alternative mechanisms that could explain this intolerance, a glucose turnover using tritiated glucose and an euglycemic glucose clamp were performed to measure the glucose production rate and peripheral insulin sensitivity, respectively. Two groups of recently abstinent chronic male alcoholic patients without evidence of liver damage were studied. The glucose turnover technique showed a higher basal glucose production rate in alcoholics, compared with normal volunteers (2.83 +/- 0.29 vs. 1.84 +/- 0.22 mg/kg/min); an intravenous ethanol load significantly increased this rate. The euglycemic glucose clamp did not show peripheral insulin resistance in alcoholics, compared with controls.

Kinetics of Metabolism of Glucose, Propionate and CO2 in Steers as Affected by Injecting Phlorizin and Feeding Propionate

Effects of injecting phlorizin subcutaneously and/or feeding propionate on metabolism of glucose, propionate and CO2 were determined for four steers used in a 4 x 4 Latin square design. Isotope dilution techniques were used to determine a four-pool kinetic solution for the flux of carbon among plasma glucose, rumen propionate, blood CO2 and rumen CO2. Injecting 1 g of phlorizin twice daily for 19 d resulted in 7.1 mol glucose C/d being excreted in urine. The basal glucose production of 13.4 mol C/d was increased to 17.9 mol C/d with phlorizin. There was no change in glucose oxidation or propionate production. The percentage of plasma glucose derived from propionate was unaffected by phlorizin, but 54 +/- 0.4% of total propionate was converted to plasma glucose during phlorizin treatment versus 40 +/- 0.6% during the basal treatment. When propionate was fed (18.3 mol C/d) glucose production increased to 21.2 mol C/d from the basal value of 13.4 mol C/d, and propionate oxidation to CO2 increased to 14.9 mol C/d from the basal value of 4.1 mol C/d. Glucose derived from propionate was 43 +/- 5% for the basal treatment and 67 +/- 3% during propionate feeding. The percentage of propionate converted to plasma glucose and blood and rumen CO2 was not affected by feeding propionate. An increased need for glucose, because of glucose excretion during phlorizin treatment, caused an increased utilization of propionate for gluconeogenesis, but an increased availability of propionate caused an increase in glucose production without affecting the relative distribution of carbon from propionate.

Acute effects of ethanol and acetate on glucose kinetics in normal subjects.

We compared the effects of two ethanol doses on glucose kinetics and assessed the role of acetate as a mediator of ethanol-induced insulin resistance. Ten normal males were studied on four occasions, during which either a low (blood ethanol 4 +/- 1 mmol/l) or moderate (14 +/- 1 mmol/l) ethanol, acetate, or saline dose was administered. Both ethanol doses similarly inhibited (0.4-0.5 mg.kg-1.min-1, P less than 0.01) basal glucose production. The decrease in Ra was matched by a comparable decrease in glucose utilization (Rd), resulting in maintenance of normoglycemia. During hyperinsulinemia (approximately 70 microU/ml), glucose disposal was lower (1.2-1.7 mg.kg-1.min-1, P less than 0.01) in the moderate than the low-dose ethanol or saline studies. During acetate infusion, the blood acetate level was comparable with those in the ethanol studies. Acetate had no effect on glucose kinetics. In conclusion, 1) in overnight fasted subjects, ethanol does not cause hypoglycemia because its inhibitory effect on Ra is counterbalanced by equal inhibition of Rd;2) basal Ra and Rd are maximally inhibited already by small ethanol doses, whereas inhibition of insulin-stimulated glucose disposal requires a moderate ethanol dose; and 3) acetate is not the mediator of ethanol-induced insulin resistance.

Clinical benefits and mechanisms of a sustained response to intermittent insulin therapy in type 2 diabetic patients with secondary drug failure

To test the hypothesis that short-term insulin therapy may induce long-lasting metabolic improvements in patients with type 2 diabetes resistant to oral therapy, 19 patients were studied before and four weeks after insulin therapy, and again four weeks after resumption of oral medication. The mechanisms associated with changes of glycemic control after discontinuation of insulin therapy were also evaluated. During insulin therapy, blood glucose levels (228 ± 13 versus 123 ±18 mg/dl, p <0.001) and the basal glucose production rate (p <0.001) decreased, and the insulin secretory response to glucagon at a standardized glucose level, insulin action in vivo, and insulin binding and action in vitro in fat cells improved significantly. During the postinsulin oral therapy, blood glucose levels increased (194 ± 11 mg/dl, p <0.001) but remained below pre-insulin treatment values (p <0.01). The mean daily glucose concentration after post-insulin oral therapy correlated with the initial pre-insulin therapy glucose concentration ( r = 0.83, p <0.001). The improved rate of in vivo glucose disposal and the enhanced insulin secretory response persisted during oral therapy whereas the basal glucose production rate returned to its pre-insulin therapy value. It is concluded that patients with type 2 diabetes in whom oral therapy fails show favorable responses to insulin therapy. After discontinuation of insulin therapy, blood glucose concentrations tend to return to their individual initial values. Therefore, most of these patients require long-term insulin therapy. The mechanism behind the change of glycemic control after cessation of insulin therapy seems to be an increase in the basal glucose production rate rather than deterioration of extrahepatic insulin action or the insulin secretory response.

In vivo glucose metabolism in the awake rat: Tracer and insulin clamp studies

The goals of this study were twofold: (1) to determine the in vivo dose-response relationship in the conscious, unstressed rat between the plasma insulin concentration and total body glucose uptake, and between plasma insulin and suppression of endogenous glucose production; and (2) to develop a physiologic compartmental model to describe the kinetics of plasma glucose in the rat in the basal state. In order to perform repeat insulin clamp studies in the same rat, chronic catheters were implanted in the aortic arch (via the carotid artery) and in the cardiac atrium (via the jugular vein), exteriorized, and fixed to the back of the skull with a dental cement cap. Insulin was infused at rates of 1.2, 2.4, 4.8, 12, and 24 mU/min · kg, and the plasma glucose was held constant at the basal level by a variable glucose infusion (euglycemic insulin clamp). The resulting steady-state plasma insulin concentrations ranged from 40 to 1,300 μU/mL. The dose-response curve for glucose uptake was sigmoidal in shape: in the basal state, total glucose utilization averaged 6.8 mg/min · kg at an insulin concentration of 9 μU/mL, half-maximal glucose uptake (18.3 mg/kg · min) occurred at a plasma insulin concentration between 70 and 80 μU/mL, and maximal uptake (36.6 mg/kg · min) was seen at an insulin level in excess of 100 μU/mL. Residual endogenous glucose production was evaluated by a prime-continuous infusion of (3- 3H)-glucose. The dose-response curve for suppression of endogenous glucose output also was sigmoidal: basal glucose production in the fasting state (6.8 mg/kg · min) suppressed by 71% at the lowest (1.2 mU/kg · min) insulin infusion, and by greater than 90% in animals receiving 2.4, 4.8, or 12 mU/min · kg infusions. Half-maximal inhibition of glucose production occurred at an insulin concentration between 30 and 40 μU/mL. In additional studies bolus injections of tritiated glucose were rapidly administered through the venous catheter, and the time-course of plasma radioactivity was monitored closely for 120 minutes. The plasma clearance rate of glucose determined by this method was 5.2 ± 0.7 mL/min · kg. The initial distribution volume was 159 ± 12 mL/kg. Two exponential components were identified in the tracer disappearance curve of each animal. Based on stringent statistical criteria, the data were fitted to a two-compartmental model. The total volume of the glucose space in this model was calculated to be 273 ± 16 mL/kg and contained a total amount of glucose equal to 307 ± 16 mg/kg. Of this, 179 ± 8 mg/kg resided in the rapidly exchanging compartment (assumed to be the insulin-independent pool), v only 128 ± 8 mg/kg in the insulin-dependent pool. In conclusion, in the rat as in man the curve relating glucose uptake to plasma insulin concentration is sigmoidal in shape, linear and steep at insulin concentrations between 40 and 100 μU/mL; maximal insulin effect resulted in a sixfold stimulation of glucose metabolism above baseline. Hepatic glucose production is completely suppressed at insulin concentrations greater than 70 μU/mL, with half-maximal suppression occurring at insulin concentrations of 30 to 40 μU/mL.

Potential intercellular futile cycling of carbohydrates in diabetes.

Diabetes was induced by treating rats with alloxan, and was confirmed by blood glucose values greater than 250 mg/dl. In perfused livers from both normal and diabetic rats, basal rates of O2 uptake were similar (120-130 mumol/h per g). In livers from diabetic rats, basal rates of glucose output of 60 mumol/h per g declined to around 20 mumol/h per g during 1 h of perfusion. Basal glucose production was abolished by pretreatment with an inhibitor of glycogen synthesis, galactosamine (1.5 g/kg), injected 3 h before perfusion. The subsequent infusion of lactate (2 mM) increased O2 uptake and glucose production about 40-50 mumol/h per g in both groups; however, the average maximal increase in glucose output was nearly twice as high in livers from normal (33 mumol/h per g) as from diabetic (18 mumol/h per g) rats. Rates of lactate uptake were also about 50% lower in livers from diabetic than from normal rats, yet rates of ketone-body formation were similar. Miniature O2 electrodes placed on periportal and pericentral regions of the liver lobule were employed to measure local rates of O2 uptake before, during and after infusion of lactate by stopping the flow of perfusate through the liver and measuring the decrease in local [O2]. Local rates of glucose production were calculated from the extra O2 consumed and the known stoichiometry between O2 uptake and glucose production from lactate. In livers from normal rats, glucose was synthesized predominantly in periportal regions of the liver lobule; however, glucose was produced exclusively in periportal regions in livers from diabetic rats. In pericentral regions, O2 uptake increased slightly in livers from normal rats, but declined significantly by 10 mumol/h per g in livers from diabetic rats. These data are consistent with the hypothesis that gluconeogenesis from lactate occurs exclusively in periportal regions of the liver lobule in livers from diabetic rats. A portion of this glucose is metabolized back to lactate in pericentral areas, leading to increased rates of glycolytic ATP production, thereby decreasing the demands for O2. This production of glucose from lactate in periportal regions, followed by conversion of glucose back into lactate in pericentral areas, raises the possibility of intercellular futile cycling, stimulated by diabetes.

Effect of high sucrose diet on insulin secretion and insulin action. A study in rats with non-insulin-dependent diabetes induced by streptozotocin.

The effects of chronic high sucrose feeding for 1 month on in vivo and in vitro insulin secretion and on in vivo insulin action were studied in rats with non-insulin-dependent diabetes. As compared to the standard diet, the high sucrose diet induced an increase of the in vivo insulin response to an intravenous load and deteriorated the glucose tolerance as attested by significantly lower rates of glucose disappearance (K values, p less than 0.001). The increased insulin secretion in response to glucose in vivo seems to be related to a slight increase of the pancreatic B-cell reactivity to glucose, since it was still observed in vitro with the isolated perfused pancreas preparation. By contrast, B cells of sucrose-fed rats exhibited in vitro a significantly lowered (p less than 0.01) response to acetylcholine and arginine. The insulin action in the sucrose-fed diabetic rats was quantified in vivo with the insulin-glucose clamp technique. The effects of different concentrations of insulin on glucose production and glucose utilisation were studied in anaesthetized rats while in the postabsorptive state. The basal glucose utilisation was found significantly higher (p less than 0.001) in sucrose-fed rats. During the clamp studies the glucose utilisation induced by submaximal (450 mU/l) insulin level was significantly less important (p less than 0.01) in the sucrose-fed rats than in the chow-fed rats. Following a maximal hyperinsulinaemia (5000 mU/l) the glucose utilisation was similar in both groups. This suggests that insulin-mediated glucose uptake is decreased over the range of submaximal plasma insulin levels in the sucrose-fed diabetic rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Lack of effect of β-endorphin on basal or glucagon-stimulated hepatic glucose production in vitro

β-Endorphin appears to have effects on hepatic glucose production in vivo. In order to determine whether β-endorphin modulates glucose production directly, the effects of β-endorphin on isolated rat hepatocytes were investigated. This permitted isolation of the effects of β-endorphin from hormonal and/or neuronal influences. A significant dose-related stimulatory effect of glucagon (10 −10 to 10 −6 mol/L) on both hepatic glucose production and glycogen phosphorylase a activity was demonstrated. No effect of either physiologic (10 −11 to 10 −9 mol/L) or supraphysiologic (10 −6 mol/L) concentrations of β-endorphin on these parameters, under basal or glucagon-stimulated conditions, could be detected. These results suggest that reported in vivo effects of β-endorphin to inhibit hepatic glucose production were either indirect or centrally mediated.