A high-sucrose diet increases gluconeogenic capacity in isolated periportal and perivenous rat hepatocytes

A high-sucrose (SU) diet increases gluconeogenesis (GNG) in the liver. The present study was conducted to determine the contribution of periportal (PP) and perivenous (PV) cell populations to this SU-induced increase in GNG. Male Sprague-Dawley rats were fed an SU (68% sucrose) or starch (ST, 68% starch) diet for 1 wk, and hepatocytes were isolated from the PP or PV region of the liver acinus. Hepatocytes were incubated for 1 h in the presence of various gluconeogenic substrates, and glucose release into the medium was used to estimate GNG. When incubated in the presence of 5 mM lactate, which enters GNG at the level of pyruvate, glucose release (nmol x h(-1) x mg(-1)) was significantly increased by the SU diet in both PP (84.8 +/- 3.4 vs. 70.4 +/- 2.6) and PV (64.3 +/- 2.5 vs. 38.2 +/- 2.1) cells. Addition of palmitate (0.5 mM) increased glucose release from lactate in PP cells by 11.6 +/- 0.5 and 20.6 +/- 1.5% and in PV cells by 11.0 +/- 4.4 and 51.1 +/- 9.1% in SU and ST, respectively. When cells were incubated with 5 mM dihydroxyacetone (DHA), which enters GNG at the triosephosphate level, glucose release was significantly increased by the SU diet in both cell types. In contrast, glucose release from fructose (0.5 mM) was significantly increased by the SU diet in PV cells only. These changes in glucose release were accompanied by significant increases in the maximal specific activities of glucose-6-phosphatase (G-6-Pase) and phosphoenolpyruvate carboxykinase (PEPCK) in both PP and PV cells. These data suggest that the SU diet influences GNG in both PP and PV cell populations. It appears that SU feeding produces changes in GNG via alterations in at least two critical enzymes, G-6-Pase and PEPCK.     

Insufficient islet compensation to insulin resistance vs. reduced glucose effectiveness in glucose-intolerant mice

This study evaluated the relative contribution of insulin-dependent mechanisms vs. mechanisms independent on dynamic insulin for glucose intolerance induced by high-fat diet. C57BL/6J mice underwent a frequently sampled intravenous glucose tolerance test (1 g/kg glucose) at 1 wk and 1, 3, and 10 mo after initiation of a high-fat diet (58% fat; control diet 11% fat) to measure glucose effectiveness (S(G)) and disposition index (DI), i.e., insulin sensitivity (S(I)) times early or total insulin secretion. Glucose disappearance (K(G)) and S(I) were reduced in high-fat-fed mice at all time points. Total (50 min) insulin secretion was sufficiently increased at all time points to compensate for the reduced S(I), as judged by normal DI(50) (min). In contrast, early (10 min) insulin secretion was not sufficiently increased; DI(10) (min) was reduced after 1, 3, and 10 mo. S(G) was reduced after 1 wk; the reduction persisted throughout the study period. Thus glucose intolerance induced by high-fat diet is, in early phases, solely explained by reduced glucose effectiveness, whereas insufficient early insulin secretion is of importance after long-term feeding.     

Does high-sucrose diet alter skeletal muscle and liver mitochondrial respiration?

A diet high in sucrose or fructose progressively impairs glucose and lipid metabolism, which leads to insulin resistance. As mitochondria are the sites of the oxidation and utilization of these substrates, we hypothesized that a high sucrose diet would alter mitochondrial respiration. Male Wistar rats were fed high-sucrose (SU) or control (CTL) diet for one week; mitochondrial respiration was investigated in mitochondria isolated from liver and both glycolytic and oxidative muscles, with pyruvate and palmitate as substrates. To test for metabolic disturbances, we measured not only glycogen content in muscles and liver, but also lactate, glucose and triglyceride blood concentrations. After one week of high-sucrose intake, we found no change in blood concentration of these variables, but glycogen content was significantly increased in liver (17.28 +/- 2.98 mg/g tissue SU vs 6.47 +/- 1.67 mg/g tissue CTL), oxidative muscle (1.59 +/- 0.21 mg/g tissue SU vs 0.70 +/- 0.24 mg/g tissue CTL) though not in glycolytic muscle (1.72 +/- 0.44 mg/g tissue SU vs 1.52 +/- 0.20 mg/g tissue CTL). State 3 mitochondrial respiration was significantly decreased in SU rats compared with CTL (p < 0.05) with pyruvate, while no change was observed with palmitate. This study shows that 1-week of high-sucrose diet altered mitochondrial pyruvate oxidation in rats and suggests that, in the context of a high-sucrose diet, impaired mitochondrial respiration could contributed to the development of insulin resistance.     

Inclusion of low amounts of fructose with an intraportal glucose load increases net hepatic glucose uptake in the presence of relative insulin deficiency in dog

The effect of small amounts of fructose on net hepatic glucose uptake (NHGU) during hyperglycemia was examined in the presence of insulinopenia in conscious 42-h fasted dogs. During the study, somatostatin (0.8 microg.kg(-1).min(-1)) was given along with basal insulin (1.8 pmol.kg(-1).min(-1)) and glucagon (0.5 ng.kg(-1).min(-1)). After a control period, glucose (36.1 micromol.kg(-1).min(-1)) was continuously given intraportally for 4 h with (2.2 micromol.kg(-1).min(-1)) or without fructose. In the fructose group, the sinusoidal blood fructose level (nmol/ml) rose from <16 to 176 +/- 11. The infusion of glucose alone (the control group) elevated arterial blood glucose (micromol/ml) from 4.3 +/- 0.3 to 11.2 +/- 0.6 during the first 2 h after which it remained at 11.6 +/- 0.8. In the presence of fructose, glucose infusion elevated arterial blood glucose (micromol/ml) from 4.3 +/- 0.2 to 7.4 +/- 0.6 during the first 1 h after which it decreased to 6.1 +/- 0.4 by 180 min. With glucose infusion, net hepatic glucose balance (micromol.kg(-1).min(-1)) switched from output (8.9 +/- 1.7 and 13.3 +/- 2.8) to uptake (12.2 +/- 4.4 and 29.4 +/- 6.7) in the control and fructose groups, respectively. Average NHGU (micromol.kg(-1).min(-1)) and fractional glucose extraction (%) during last 3 h of the test period were higher in the fructose group (30.6 +/- 3.3 and 14.5 +/- 1.4) than in the control group (15.0 +/- 4.4 and 5.9 +/- 1.8). Glucose 6-phosphate and glycogen content (micromol glucose/g) in the liver and glucose incorporation into hepatic glycogen (micromol glucose/g) were higher in the fructose (218 +/- 2, 283 +/- 25, and 109 +/- 26, respectively) than in the control group (80 +/- 8, 220 +/- 31, and 41 +/- 5, respectively). In conclusion, small amounts of fructose can markedly reduce hyperglycemia during intraportal glucose infusion by increasing NHGU even when insulin secretion is compromised.     

Metabolic response to [13C]glucose and [13C]fructose ingestion during exercise

Seven healthy male volunteers exercised on a cycle ergometer at 50 +/- 5% VO2max for 180 min, on three occasions during which they ingested either water only (W), [13C]glucose (G), or [13C]fructose (F) (140 +/- 12 g, diluted at 7% in water, and evenly distributed over the exercise period). Blood glucose concentration (in mM) significantly decreased during exercise with W (5.1 +/- 0.4 to 4.2 +/- 0.1) but remained stable with G (5.0 +/- 0.4 to 5.3 +/- 0.6) or F ingestion (5.4 +/- 0.5 to 5.1 +/- 0.4). Decreases in plasma insulin concentration (microU/ml) were greater (P less than 0.05) with W (11 +/- 3 to 3 +/- 1) and F (12 +/- 4 to 5 +/- 1) than with G ingestion (11 +/- 2 to 9 +/- 5), and fat utilization was greater with F (103 +/- 11 g) than with G ingestion (82 +/- 9 g) and lower than with W ingestion (132 +/- 14 g). However F was less readily available for combustion than G; over the 3-h period 75% (106 +/- 11 g) of ingested G was oxidized, compared with 56% (79 +/- 8 g) of ingested fructose. As a consequence, carbohydrate store utilizations were similar in the two conditions (G, 174 +/- 20 g; F, 173 +/- 17 g; vs. W, 193 +/- 22 g). These observations suggest that, during prolonged moderate exercise, F ingestion maintains blood glucose as well as G ingestion, and increases fat utilization when compared to G ingestion. However, due to a slower rate of utilization of F, carbohydrate store sparing is similar with G and F ingestions.     

Influence of partial replacement of starch by sucrose in high fat-cholesterol diet on serum lipoprotein responses of cynomolgus monkeys

The influence of partial replacement of starch by sucrose on dietary cholesterol-induced serum lipoprotein responses was examined in 10 male cynomolgus monkeys (Macaca fascicularis). In a crossover design two semipurified diets provided either starch or starch and sucrose (1:1) as carbohydrate (49% by calories) with 0.4 mg cholesterol/kcal. Six weeks of starch + sucrose diet resulted in significantly reduced levels (mean +/- SE, mg/dl) of serum total cholesterol (264 +/- 9 vs 244 +/- 8) and apo B (110 +/- 6 vs 96 +/- 6) when compared with starch diet, whereas serum triglyceride levels remained similar between diets. With respect to changes in lipids and apolipoproteins (A-I or B) of very low (VLDL), low (LDL), intermediate (IDL), and high (HDL) density lipoproteins, starch + sucrose diet significantly increased VLDL-apo B (+34%), and decreased LDL-cholesterol (-18%) and LDL-apo B (-15%) as compared with starch alone; no differences were found in IDL and HDL between diets. The relative proportion of starch to sucrose in a diet appears to influence the magnitude of response of lipoproteins to dietary cholesterol.     

Glucose and fructose feeding lead to alterations in structure and function of very low density lipoproteins

Young male rats were fed regular lab chow, or a diet containing 66% of total calories as either glucose or fructose. Both experimental diets led to hypertriglyceridemia, with fasting TG concentrations after one week of 195 +/- 20 and 296 +/- 44 mg/dl for rats fed glucose and fructose, respectively, compared to 94 +/- 10 mg/dl in the control rats. Moderate changes in VLDL composition were observed with both test diets, characterized by slight increases in TG: protein ratio, and increased total cholesterol and phospholipid content. In addition, VLDL isolated from rats fed high carbohydrate diets were increased in size, with a mean VLDL particle diameter of 666 A and 720 A in glucose-fed and fructose-fed rats, as compared to 536 A in control rats. The changes in lipid composition and size of VLDL particles isolated from glucose and fructose-fed donor rats were associated with an increase in their rate of removal from the circulation following their injection into normal recipient rats (half-life time 2.4 +/- 0.2 and 3.2 +/- 0.3 min respectively) as compared to VLDL-TG derived from chow fed donors (4.1 +/- 0.2 min). These data indicate that diets high in either glucose or fructose can lead to both structural and functional changes in VLDL, and provide additional evidence that the ability of fructose to induce profound hypertriglyceridemia is not secondary to a defect in VLDL-TG catabolism.     

Sucrose-induced cardiomyocyte dysfunction is both preventable and reversible with clinically relevant treatments

We recently identified cardiomyocyte dysfunction in the early stage of type 2 diabetes (i.e., diet-induced insulin resistance). The present investigation was designed to determine whether a variety of clinically relevant interventions are sufficient to prevent and reverse cardiomyocyte dysfunction in sucrose (SU)-fed insulin-resistant rats. Subsets of animals were allowed to exercise (free access to wheel attached to cage) or were treated with bezafibrate in drinking water to determine whether these interventions would prevent the adverse effects of SU feeding on cardiomyocyte function. After 6-8 wk on diet and treatment, animals were surgically prepared to assess whole body insulin sensitivity (intravenous glucose tolerance test), and isolated ventricular myocyte mechanics were evaluated (video edge recording). SU feeding produced hyperinsulinemia and hypertriglyceridemia, with euglycemia, and induced characteristic whole body insulin resistance. Both exercise and bezafibrate treatment prevented these metabolic abnormalities. Ventricular myocyte shortening and relengthening were slower in SU-fed rats (42-63%) compared with starch (ST)-fed controls, and exercise or bezafibrate completely prevented cardiomyocyte dysfunction in SU-fed rats. In separate cohorts of animals, after 5 wk of SU feeding, animals were either switched back to an ST diet or given menhaden oil for an additional 7-9 wk to determine whether the cardiomyocyte dysfunction was reversible. Both interventions have previously been shown to have favorable metabolic effects, and both improved myocyte mechanics, but only the ST diet reversed all indications of cardiomyocyte dysfunction induced by SU feeding. Thus phenotypic changes in cardiomyocyte mechanics associated with early stages of type 2 diabetes were found to be both preventable and reversible with clinically relevant treatments, suggesting that the cellular processes contributing to this dysfunction are modifiable.     

Pancreatic B-cell function in non-insulin-dependent diabetes mellitus during successive periods of sulfonylurea and insulin treatment: serum C-peptide response to glucagon and urine C-peptide excretion

Serum C-peptide responses to glucagon and daily urine C-peptide excretion in successive periods of different treatment in two groups of patients with non-insulin-dependent diabetes mellitus (NIDDM) (mean interval between two tests less than 1 month) were compared. In group A patients (n = 8), the glycemic control was improved after transferring the treatment from sulfonylurea (SU) to insulin (fasting plasma glucose: SU: 192 +/- 47, insulin: 127 +/- 21 mg/dl, mean +/- S.D., p less than 0.01). Fasting serum C-peptide immunoreactivity (CPR) was significantly lower at the period of insulin treatment (SU: 1.93 +/- 1.01, insulin: 1.47 +/- 0.79 ng/ml, p less than 0.05), but there was no difference in the increase in serum CPR (maximal--fasting) (delta serum CPR) during glucagon stimulation in the two periods of treatment (SU: 1.70 +/- 0.72, insulin: 1.47 +/- 0.98 ng/ml). In group B patients (n = 7), there was no significant difference in glycemic control after transferring the treatment from insulin to SU (fasting plasma glucose: insulin: 127 +/- 24, SU: 103 +/- 13 mg/dl). Fasting serum CPR was significantly lower during the period of insulin treatment (insulin: 1.39 +/- 0.64, SU: 2.21 +/- 0.86 ng/ml, p less than 0.025), but delta serum CPR during glucagon stimulation still showed no significant difference between the two periods (insulin: 1.97 +/- 1.16, SU: 2.33 +/- 1.57 ng/ml).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of PPARgamma and PPARalpha agonists on serum leptin levels in diet-induced obese rats.

Leptin and peroxisome proliferator-activated receptors are two important adipose tissue factors involved in energy metabolism regulation. It has been shown that PPARgamma agonists decrease leptin levels. However, the effects of PPARalpha agonists on leptin have not been investigated much. The aim of this study was to compare the effects of a PPARgamma agonist rosiglitazone (RSG) and PPARalpha agonist gemfibrozil (G) on body weight and serum insulin and leptin levels in diet-induced obese rats. Male Wistar rats were divided into six groups according to diet and drug therapy. After four weeks, serum glucose, triglyceride, insulin and leptin levels were significantly decreased in the high-fat-fed and RSG-treated groups compared to the group fed a high-fat diet only (162 +/- 19 vs. 207 +/- 34 mg/dl, 58 +/- 20 vs. 112 +/- 23 mg/dl, 3.1 +/- 1.0 vs. 15.2 +/- 4.0 ng/ml, 1.6 +/- 0.5 vs. 3.6 +/- 1.6 ng/ml, respectively). However, these parameters were not statistically different in RSG animals treated with a standard diet compared to the standard diet group. The high fat+RSG group gained much more weight compared to high-fat and high-fat+G groups (p > 0.05). Additionally, serum glucose, insulin and leptin levels were significantly decreased in the high-fat-fed and G-treated group compared to high-fat group (149 +/- 19 vs. 207 +/- 34 mg/dl, 57 +/- 16 vs. 112 +/- 23 mg/dl, 4.3 +/- 2.1 vs. 15.2 +/- 4.0 ng/ml, 1.6 +/- 0.4 vs. 3.6 +/- 1.6 ng/ml, respectively). These results suggest that PPARalpha agonists may decrease serum glucose, insulin and leptin levels as PPARgamma agonists do in diet-induced obese rats.     

Substrate utilization during exercise with glucose and glucose plus fructose ingestion in boys ages 10--14 yr.

We measured substrate utilization during exercise performed with water (W), exogenous glucose (G), and exogenous fructose plus glucose (FG) ingestion in boys age 10-14 yr. Subjects (n = 12) cycled for 90 min at 55% maximal O(2) uptake while ingesting either W (25 ml/kg), 6% G (1.5 g/kg), or 3% F plus 3% G (1.5 g/kg). Fat oxidation increased during exercise in all trials but was higher in the W (0.28 +/- 0.023 g/min) than in the G (0.24 +/- 0.023 g/min) and FG (0.25 +/- 0.029 g/min) trials (P = 0.04). Conversely, total carbohydrate (CHO) oxidation decreased in all trials and was lower in the W (0.63 +/- 0.05 g/min) than in the G (0.78 +/- 0.051 g/min) and FG (0.74 +/- 0.056 g/min) trials (P = 0.009). Exogenous CHO oxidation, as determined by expired (13)CO(2), reached a maximum of 0.36 +/- 0.032 and 0.31 +/- 0.030 g/min at 90 min in G and FG, respectively (P = 0.04). Plasma insulin levels decrease during exercise in all trials but were twofold higher in G than in W and FG (P < 0.001). Plasma glucose levels decreased transiently after the onset of exercise in all trials and then returned to preexercise values in the W and FG (approximately 4.5 mmol/l) trials but were elevated by approximately 1.0 mmol/l in the G trial (P < 0.001). Plasma lactate concentrations decreased after the onset of exercise in all trials but were lower by approximately 0.5 mmol/l in W than in G and FG (P = 0.02). Thus, in boys exercising at a moderate intensity, the oxidation rate of G plus F is slightly less than G alone, but both spare endogenous CHO and fat to a similar extent. In addition, compared with flavored W, the ingestion of G alone and of G plus F delays exhaustion at 90% peak power by approximately 25 and 40%, respectively, after 90 min of moderate-intensity exercise.     

Induction of cholesteryl ester transfer protein in adipose tissue and plasma of the fructose-fed hamster

Cholesteryl ester transfer protein (CETP) plays a pivotal role in the reverse transport of cholesterol and in the remodeling of circulating lipoproteins. While plasma and adipose tissue levels of CETP are affected by a variety of metabolic conditions, the extent of the effects of dietary factors, other than high cholesterol feeding, are not well understood. To further explore this paradigm, male Golden Syrian hamsters were fed for 4 weeks with a 60%-enriched fructose diet (F) and were compared to a matched group of animals fed with a normal chow diet (N). After feeding for 4 weeks, plasma insulin concentrations were lower in animals fed fructose than in control animals (F: 3.3+/-0.8 vs N: 7.4+/-1.9 ng/mL; p<0.03), but there was no significant difference in plasma glucose concentrations between the two groups (F: 138+/-7 vs N: 148+/-10 mg/dL; p>0.05). Fructose-fed animals showed significant increases in plasma triglyceride (F: 269+/-22 vs N: 165+/-22 mg/dL; p<0.01) and plasma cholesterol (F: 150+/-10 vs N: 113+/-6 mg/dL; p<0.02) concentrations compared with control animals. Total CETP activity and immunoreactive mass were higher in the plasma of fructose-fed animals that in that of controls (F: 1036+/-70 vs N: 826+/-43 pmol/h/mL, p<0.04 and F: 24.5+/-3.1 vs N: 37.5+/-4.3 AU, p<0.02, respectively). Adipose tissue CETP mRNA levels, assessed by the very sensitive ribonuclease protection assay, were 53% higher in fructose-fed animals than in controls (F: 14.1+/-2.0 vs N: 9.2+/-1.0 AU over a rRNA control; p<0.04). Adipose tissue CETP activity and immunoreactive mass also showed a statistically significant increase in the fructose-fed hamsters compared with those fed a normal diet (p<0.04). In conclusion, fructose feeding in Syrian hamsters induces a mixed dyslipidemia. These metabolic changes are accompanied by a significant increase in CETP levels, both in plasma and in adipose tissue. This phenomenon suggests that the increase in the expression of adipose tissue CETP may be caused either by the ambient hypercholesterolemia resulting from fructose feeding or by an attenuation of a possible inhibitory effect of plasma insulin concentrations on the expression of adipose tissue CETP in this feeding paradigm.     

Effects of fructose and/or fat in the diet on developing the type 2 diabetic-like syndrome in CD-1 mice

The aim of the present study was to examine the interactions of fructose and fat on glucose regulation and lipid metabolism in CD-1 mice. Mice were assigned in five groups. The control group was provided with tap water and a gavage of vehicle; four experimental groups were treated with 150 g/l fructose solution (FS1), fat emulsion (FE), 150 g/l fructose solution and fat emulsion (FS1+FE), or 70 g/l fructose solution and fat emulsion (FS2+FE) for 12 weeks. At the end of the 8th week, both oral glucose tolerance test and insulin tolerance test were conducted. Lipid profiles in serum, liver, and red gastrocnemius muscle, and serum insulin and glucose concentrations were assessed. The FS1+FE group showed combined glucose intolerance (CGI) and decrease of insulin sensitivity. The low-density lipoprotein cholesterol (LDL-C) concentrations were elevated in all experimental groups (p<0.05). The combined diet groups showed statistically significant (p<0.01) increase in total cholesterol (TC) level in comparison with the control FE (p<0.05), or FS1 (p<0.05) group. Triglyceride levels in liver and red gastrocnemius muscle were significantly increased in FE and combined groups. In conclusion, combination of FE and 150 g/l fructose solution for 8 weeks led to CGI. Fructose enhanced the adverse effect of FE on glucose regulation with increasing percentage in the diet. Furthermore, there was a synergistic effect of fructose and fat on elevating the serum TC level.     

Lipoic acid attenuates hypertension and improves insulin sensitivity,kallikrein activity and nitrite levels in high fructose-fed rats

Chronic feeding of fructose to normal rats causes impaired glucose tolerance, loss of tissue sensitivity to insulin, hyperinsulinemia and hypertension. -Lipoic acid (LA), a co-enzyme known for its potent antioxidant effects, stimulates insulin-mediated glucose uptake in clinical and experimental diabetes. The purpose of this study was to examine whether LA can mitigate fructose-induced insulin resistance and associated abnormalities. Male Wistar rats of body weights 150–170 g were divided into 4 groups containing 12 rats each. Control rats received a control diet containing starch and water ad libitum. Fructose rats received a fructose-enriched diet (>60% of total calories). Fructose + LA rats received a fructose diet and LA (35 mg/kg b.w.) intraperitoneally. Control + LA rats received a normal diet and LA (35 mg/kg b.w.) intraperitoneally. After the treatment period of 20 days, blood pressure (BP) was measured. Oral glucose-tolerance test, insulin-sensitivity index, urea and creatinine clearance tests, and plasma and urinary sodium and potassium levels were analysed. Kallikrein activity and nitrite content were assayed. Additionally, the activities of RBC-membrane Na⁺/K⁺ ATPase and Ca²⁺ ATPase enzymes were assayed. Fructose rats showed increased BP, decreased glucose tolerance, decreased insulin sensitivity and altered sodium and potassium levels and renal clearance. LA supplementation mitigated these alterations. The increase in BP was attenuated and the levels of biochemical parameters were brought close to normal. The BP-lowering effect of LA in fructose rats may be related to improvement in insulin sensitivity.Communicated by L.C.-H. Wang.     

Effects of a fructose-enriched diet on plasma insulin and triglyceride concentration in SHR and WKY rats

Significant increases (P less than 0.001) in plasma insulin and triglyceride concentrations and in blood pressure were seen when SHR and WKY rats ate a fructose-enriched diet for 14 days. However, all of the changes were significantly accentuated (P less than 0.02-0.001) in SHR rats. Specifically the increment in plasma insulin concentration following the fructose-enriched diet was 42 +/- 4 microU/ml in SHR as compared to 25 +/- 4 microU/ml in WKY rats (P less than 0.001). Plasma triglyceride concentrations also increased to a greater degree in response to fructose in SHR rats (260 +/- 24 vs. 136 +/- 20 mg/dl, P less than 0.001). Finally, the fructose-induced increase in blood pressure of 29 +/- 4 mm of Hg in SHR rats was greater (P less than 0.02) than that seen in WKY rats (19 +/- 2 mm of Hg). There was no change in plasma glucose concentration in response to the fructose diet. WKY rats gained more weight than did the SHR rats. Thus, although plasma triglyceride and insulin concentration and blood pressure increased when either WKY or SHR rats consumed a fructose enriched diet, the magnitude of these changes was greater in SHR rats.     

Mechanism of action of exenatide to reduce postprandial hyperglycemia in type 2 diabetes

We examined the contributions of insulin secretion, glucagon suppression, splanchnic and peripheral glucose metabolism, and delayed gastric emptying to the attenuation of postprandial hyperglycemia during intravenous exenatide administration. Twelve subjects with type 2 diabetes (3 F/9 M, 44 +/- 2 yr, BMI 34 +/- 4 kg/m2, Hb A(1c) 7.5 +/- 1.5%) participated in three meal-tolerance tests performed with double tracer technique (iv [3-3H]glucose and oral [1-14C]glucose): 1) iv saline (CON), 2) iv exenatide (EXE), and 3) iv exenatide plus glucagon (E+G). Acetaminophen was given with the mixed meal (75 g glucose, 25 g fat, 20 g protein) to monitor gastric emptying. Plasma glucose, insulin, glucagon, acetaminophen concentrations and glucose specific activities were measured for 6 h post meal. Post-meal hyperglycemia was markedly reduced (P < 0.01) in EXE (138 +/- 16 mg/dl) and in E+G (165 +/- 12) compared with CON (206 +/- 15). Baseline plasma glucagon ( approximately 90 pg/ml) decreased by approximately 20% to 73 +/- 4 pg/ml in EXE (P < 0.01) and was not different from CON in E+G (81 +/- 2). EGP was suppressed by exenatide [231 +/- 9 to 108 +/- 8 mg/min (54%) vs. 254 +/- 29 to189 +/- 27 mg/min (26%, P < 0.001, EXE vs. CON] and partially reversed by glucagon replacement [247 +/- 15 to 173 +/- 18 mg/min (31%)]. Oral glucose appearance was 39 +/- 4 g in CON vs. 23 +/- 6 g in EXE (P < 0.001) and 15 +/- 5 g in E+G, (P < 0.01 vs. CON). The glucose retained within the splanchnic bed increased from approximately 36g in CON to approximately 52g in EXE and to approximately 60g in E+G (P < 0.001 vs. CON). Acetaminophen((AUC)) was reduced by approximately 80% in EXE vs. CON (P < 0.01). We conclude that exenatide infusion attenuates postprandial hyperglycemia by decreasing EGP (by approximately 50%) and by slowing gastric emptying.     

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.     

Fructose and glucose ingestion and muscle glycogen use during submaximal exercise

Substrate utilization after fructose, glucose, or water ingestion was examined in four male and four female subjects during three treadmill runs at approximately 75% of maximal O2 uptake. Each test was preceded by three days of a carbohydrate-rich diet. The runs were 30 min long and were spaced at least 1 wk apart. Exercise began 45 min after ingestion of 300 ml of randomly assigned 75 g fructose (F), 75 g glucose (G), or control (C). Muscle glycogen depletion determined by pre- and postexercise biopsies (gastrocnemius muscle) was significantly (P less than 0.05) less during the F trial than during C or G. Venous blood samples revealed a significant increase in serum glucose (P less than 0.05) and insulin (P less than 0.01) within 45 min after the G drink, followed by a decrease (P less than 0.05) in serum glucose during the first 15 min of exercise, changes not observed in the C or F trials. Respiratory exchange ratio was higher (P less than 0.05) during the G than C or F trials for the first 5 min of exercise and lower (P less than 0.05) during the C trial compared with G or F for the last 15 min of exercise. These data suggest that fructose ingested before 30 min of submaximal exercise maintains stable blood glucose and insulin concentrations, which may lead to the observed sparing of muscle glycogen.