Effects of a high-fat-sucrose diet on enzymes in homocysteine metabolism in the rat

Hyperhomocysteinemia (HH) and hyperinsulinemia are both risk factors for cardiovascular disease. To examine the effects of hyperinsulinemia on homocysteine metabolism, we fed rats a high-fat-sucrose (HFS) diet and then measured the hepatic mRNA and activity of 2 key enzymes involved in this metabolic pathway: 5,10-methylenetetrahydrofolate reductase (MTHFR) and cystathionine-beta-synthase (CbetaS). Fischer rats made insulin-resistant by a HFS diet were examined at 6 months and 2 years of age and compared with control rats fed a low-fat, complex-carbohydrate (LFCC) diet. At the end of 6 months, the HFS rats were heavier than the LFCC rats (214 +/- 3.4 v 188 +/- 1.4 g, P < .01). There were no differences in blood glucose between HFS and LFCC rats; however, plasma insulin and homocysteine concentrations were elevated in HFS rats (insulin, 56 +/- 12 v 14.5 +/- 2.9 microU/mL; homocysteine, 10.77 +/- 0.9 v 6.89 +/- 0.34 micromol/L, P < .01). Hepatic CbetaS enzyme activity was significantly lower in HFS compared with LFCC rats (0.45 v 0.64 U/mg, P = .0001), and this decrease was reflected in a decrease of the CbetaS mRNA concentration. In contrast, hepatic MTHFR enzyme activity and mRNA concentration were significantly elevated in the HFS group compared with controls (HFS and LFCC, 8.62 and 4.8 nmol/h/mg protein, respectively, P = .0001). These changes in plasma homocysteine, CbetaS, and MTHFR were significantly correlated with the degree of obesity and hyperinsulinemia. Fasting plasma insulin correlated significantly and positively with plasma homocysteine (r = .51, P < .01) and MTHFR activity (r = .48, P < .01) and negatively with CbetaS activity (r = -.54, P < .001). CbetaS and MTHFR activities were inversely correlated with each other (r = -.58, P < .001). In conclusion, rats fed a HFS diet are hyperinsulinemic, and the hyperinsulinemia is associated with an elevated homocysteine concentration and changes in 2 key enzymes in homocysteine metabolism.     

Intimal hyperplasia following carotid endarterectomy in an insulin-resistant rat model

Hyperhomocysteinemia, a known risk factor for cardiovascular disease, results in an elevation of intimal hyperplasia (IH) following a carotid endarterectomy (CEA) in a rat model. An exaggerated IH response following CEA has been observed in rats with dietary induced hyperhomocysteinemia. Type 2 diabetics often present with hyperhomocysteinemia and are at higher risk for developing vascular blockage following surgical procedures. To determine if insulin resistance increases IH risks following endarterectomy, the 3 goals of this study were: (1) to establish plasma homocysteine concentrations in dietary induced insulin-resistant rats and their controls, (2) to investigate whether a positive correlation of IH and plasma homocysteine response occurs following CEA in the insulin-resistant rat model, and (3) if so, to attempt to decrease IH by supplementation with folic acid, a known enzymatic cofactor in the homocysteine metabolic pathway. To achieve these aims, male rats (275 to 300 g) were fed 1 of 4 diets for a 4-month period: (1) high-fat sucrose (HFS), (2) low-fat complex carbohydrate (LFCC), (3) HFS + 25 mg/kg folic acid (HFS+F), or (4) LFCC + 25 mg/kg folic acid (LFCC+F). At the end of the 4-month period the rats underwent an open (non-balloon) unilateral CEA. Two weeks post-endarterectomy, blood, liver and carotid tissue were removed to measure plasma insulin, folic acid, and homocysteine, 2 key enzymes of homocysteine metabolism-methylenetetrahydrofolate reductase (MTHFR) and cystathionine beta-synthase (CBS)-and percent lumenal stenosis (IH%). Computer-assisted morphometric analysis was used to measure the percentage of IH in the carotid artery. Plasma homocysteine was significantly higher in the HFS group when compared with the LFCC group (11.3+/-1.3 micromol/L v 7.4+/-0.6 mircomol/L, P=.008) as was post-endarterectomy IH producing lumenal stenosis (30.7%+/-4.2% v 14.0%+/-4.3%, P=.008). Plasma insulin in the HFS group was higher than the LFCC (control) group and was significant (36.3+/-3.0 microU/mL v 21.1+/-0.8 microU/mL, P=.0004). Folic acid supplementation in the HFS group resulted in reductions of plasma homocysteine (HFS v HFS+F, 11.3+/-1.3 micromol/L v 7.95+/-1.0 micromol/L, P=.02) and post-endarterectomy IH (HFS v HFS+F, 30.7%+/-4.2 % v 10.4%+/-1.6%, P=.0001). The control or LFCC group was not statistically different from the HFS+F group in homocysteine or IH. Folate supplementation did not decrease insulin concentrations in the HFS+F group compared to the LFCC group. We conclude that the HFS diet produced an insulin-resistant state with an elevated plasma homocysteine and an exaggerated IH response following carotid endarterectomy in this rat model. Dietary folate supplementation reduced plasma homocysteine concentrations in the HFS diet, which implicates hyperhomocysteinemia as an etiologic factor in the development of post-CEA IH in this insulin-resistant rat model.     

A high-fat diet worsens metabolic control in streptozotocin-treated rats by increasing hepatic glucose production.

The aim of this study was to determine the mechanism by which a high-fat diet exacerbates the diabetes produced by a low dose of streptozotocin (STZ). The glucose clamp technique was used to determine hepatic glucose production (HGP) and the disappearance rate (Rd) of glucose, basally and during insulin infusions of 1.0 and 3.0 mU/kg/min in control of STZ-treated rats fed either a low-fat or high-fat diet. Fasting plasma glucose in the high fat-STZ (HFS) group was significantly higher than in any of the other groups: low fat-STZ (LFS), high-fat controls (HFC), or low-fat controls (LFC) (18.1 +/- 1.6 v 8.1 +/- 0.8 mmol/L, P less than .001; 6.0 +/- 0.2 mmol/L, P less than .001; 5.4 +/- 0.1 mmol/L, P less than .001, respectively). Basal HGP was markedly higher in the HFS group compared with each of the other three groups (98.8 +/- 5.9 v 61.4 +/- 3.7, P less than .001; 42.9 +/- 1.6, P less than .001; 39.6 +/- 1.3 mumol/kg/min, P less than .001; HFS v LFS, HFC, and LFC, respectively). Following insulin infusion, no differences were observed in HGP between the LFC and LFS groups at either insulin dose. However, HGP was not suppressed to control levels in either of the high-fat diet groups, and this defect was more marked in the HFS group. It is concluded that a high-fat diet exacerbates mild STZ diabetes primarily by increasing HGP.     

Effect of diet on adipose tissue and skeletal muscle VLDL receptor and LPL: implications for obesity and hyperlipidemia

This study was designed to examine the effect of a high-fat (primarily saturated), refined-carbohydrate (sucrose) diet (HFS), which is known to induce obesity and hyperlipidemia, on adipose tissue and skeletal muscle lipoprotein lipase (LPL) and very-low density lipoprotein receptor (VLDL-R) protein expressions. Female Fischer rats were placed on either a HFS or a low-fat, complex-carbohydrate (LFCC) diet for 22 months beginning at 2 months of age. After 20 months, a subgroup of the HFS rats were switched to the LFCC diet for 2 months (HFS/LFCC). Body weight, feed efficiency, plasma total cholesterol, VLDL-C, low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG) concentrations and LDL-C to high-density lipoprotein cholesterol ratio were all significantly raised by the HFS diet and improved by conversion to the LFCC diet. Adipose tissue heparin-releasable, extractable and total LPL activity expressed per cell were significantly increased in the HFS-fed group. However, LPL protein abundance normalized against total cellular protein was unchanged in the HFS group. This observation is consistent with the presence of adipose tissue hypertrophy. Skeletal muscle LPL protein abundance and heparin-releasable activity were reduced by the HFS diet and improved after switching to the LFCC diet. Both adipose tissue and skeletal muscle VLDL-R protein levels were significantly reduced by the HFS diet and increased after conversion to the LFCC diet. We conclude that an HFS diet induces changes in LPL and VLDL-R in a manner which favors shunting of dietary fat from skeletal muscle to adipose tissue and decreases TG-rich lipoprotein clearance contributing to increased plasma lipids and obesity. Conversion to a LFCC diet can ameliorate the dyslipidemia and tissue changes induced by long-term HFS diet consumption.     

Correction of long-term diet-induced hypertension and nitrotyrosine accumulation by diet modification

Several recent studies have demonstrated that various forms of hypertension are associated with enhanced reactive oxygen species (ROS) activity. We have recently shown that long-term consumption of a diet similar to that ingested in westernized societies, containing high saturated fat and refined carbohydrate, induces oxidative stress and hypertension in normal rats. We hypothesized that diet modification may reverse diet-induced hypertension via (among other mechanisms) decreased ROS activity and improved nitric oxide (NO) availability. To test this hypothesis, female Fischer rats were placed on either a high-fat (primarily saturated), refined carbohydrate (sucrose) diet (HFS) or low-fat, complex-carbohydrate diet (LFCC) starting at 2 months of age. After 2 years when hypertension was well established, a group of HFS rats was converted to the LFCC diet (HFS/LFCC group) for a period of 2 months. Plasma malondialdehyde, a marker of lipid peroxidation by ROS, was elevated in the HFS group. Hypertension was present in the HFS group at 2 years as was a significant accumulation, in various tissues, of nitrotyrosine, which is the footprint of NO inactivation by ROS. Conversion from the HFS to the LFCC diet for 2 months led to normalization of blood pressure and reduced nitrotyrosine accumulation in the absence of caloric restriction. These results demonstrate that oxidative stress and hypertension induced by long-term consumption of an HFS diet are reversible with implementation of a low-fat, unrefined carbohydrate diet. The effects of the HFS diet and subsequent conversion to the LFCC diet on blood pressure appear to be, in part, mediated by changes in NO availability.     

Effects of a high-fat, sucrose diet on serum insulin and related atherosclerotic risk factors in rats

Hyperinsulinemia, hypertension, hypertriglyceridemia and obesity are all risk factors for atherosclerosis. The clustering of these risk factors in the same individual greatly increases the risk for atherosclerosis and has been termed ‘Syndrome X’ or ‘The Deadly Quartet’ The purpose of the present study was to investigate the effects of diet on these risk factors in inbred, female Fischer 344 rats. Animals were raised on ad lib diets consisting of high-fat, sucrose (HFS) or low-fat, complex-carbohydrate (LFCC). After 2 years, the HFS rats were obese (38% ± 1% vs. 15% ± 1% body fat), hypertensive (140 ± 3 vs. 123 ± 3 mmmHg), hyperinsulinemic (439 ± 118 vs. 98 ± 10 pmol/l), and hypertriglyceridemic (1.1 ± 0.2 vs. 0.4 ± 0.07 mmol/l). The HFS rats also exhibited enhanced clotting and impaired fibrinolytic response to streptokinase. All these differences between the two groups were statistically significant (P < 0.05). Insulin was significantly correlated with body weight (r = 0.71), triglycerides (= 0.48), and systolic blood pressure (r = 0.70). Total cholesterol was slightly, but not significantly higher, in the HFS group (2.8 ± 0.3 vs 2.2 ± 0.1 mmol/l) while HDL-cholesterol was unchanged. These results show that many risk factors for atherosclerosis can be induced in inbred rats by feeding a HFS diet. Aggregation of risk factors was found in the HFS group but not in the LFCC group. In fact, most of the rats on the LFCC diet developed no risk factors after 2 years, indicating that the development of risk factors is not an aging phenomenon.     

Enhanced NO inactivation and hypertension induced by a high-fat, refined-carbohydrate diet

We have recently demonstrated that long-term consumption of a high-fat, refined-carbohydrate (HFS) diet induces hypertension (HTN) in normal rats compared with a low-fat, complex-carbohydrate (LFCC) diet. Limited evidence suggests that high-fat or high-sugar diets cause enhanced generation of reactive oxygen species (ROS). We therefore hypothesized that by inducing oxidative stress, the HFS diet may promote nitric oxide (NO) inactivation and HTN. To test this hypothesis, female Fischer rats were placed on either the HFS or the LFCC diet starting at 2 months of age. Blood pressure, urinary NO metabolites (NO(x)), and total renal NO synthase activity were monitored, and the tissue abundance of nitrotyrosine (NT), which is the stable "footprint" of NO oxidation by ROS, was determined. The HFS diet group exhibited a gradual rise in arterial blood pressure and were hypertensive by 18 months. This trend was accompanied by a marked accumulation of NT in all tested tissues, an initial rise and a subsequent fall in NO synthase activity, and a fall in urinary NO(x) excretion. The HFS diet-fed animals had a blunted blood pressure response to the NO synthase inhibitor N:(omega)-nitro-L-arginine methyl ester (L-NAME) compared with the LFCC diet group, which showed a marked hypertensive response to L-NAME. L-NAME-induced HTN was reversible with L-arginine in the LFCC diet group; however, HTN was not corrected by L-arginine supplementation in the HFS diet group. These findings point to enhanced ROS-mediated inactivation and sequestration of NO, which may contribute to the reduction of bioactive NO and HTN in the HFS diet-fed animals.     

Glyburide enhances the responsiveness of the beta-cell to glucose but does not correct the abnormal patterns of insulin secretion in noninsulin-dependent diabetes mellitus

Eleven patients with noninsulin-dependent diabetes mellitus were studied before and after 6-10 weeks of glyburide therapy. Patients were studied during a 24-h period on a mixed diet comprising 30 Cal/kg divided into three meals. The following day a hyperglycemic clamp study was performed, with glucose levels clamped at 300 mg/dL (16.7 mmol/L) for a 3-h period. Insulin secretion rates were calculated by deconvolution of peripheral C-peptide concentrations using individual C-peptide clearance kinetics derived after bolus injection of biosynthetic human C-peptide. After 6-10 weeks on glyburide, the identical studies were repeated. In response to glyburide, the fasting plasma glucose level decreased from 12.3 +/- 1.2 to 6.8 +/- 0.9 mmol/L. Although the mean glucose over the 24 h of the meal study decreased from 12.7 +/- 1.4 to 10.8 +/- 1.2 mmol/L, postprandial hyperglycemia persisted on therapy, and after breakfast, glucose levels exceeded 10 mmol/L and did not return to fasting levels for the remainder of the day. Fasting serum insulin, plasma C-peptide, and the insulin secretion rate were not different before (152 +/- 48 pmol/L, 0.82 +/- 0.16 pmol/mL, and 196 +/- 34 pmol/min, respectively) and after (186 +/- 28 pmol/L, 0.91 +/- 0.11 pmol/mL, and 216 +/- 23 pmol/min, respectively) glyburide treatment despite lowering of the glucose level. However, average insulin and C-peptide concentrations over the 24-h period increased from 366 +/- 97 pmol/L and 1.35 +/- 0.19 pmol/mL to 434 +/- 76 pmol/L and 1.65 +/- 0.15 pmol/mL, respectively. The total amount of insulin secreted over the 24-h period rose from 447 +/- 58 nmol before therapy to 561 +/- 55 nmol while receiving glyburide. Insulin secretion was demonstrated to be pulsatile in all subjects, with periodicity ranging from 2-2.5 h. The number of insulin secretory pulses was not altered by glyburide, whereas pulse amplitude was enhanced after lunch and dinner, suggesting that the increased insulin secretion is characterized by increased amplitude of the individual pulses. In response to a hyperglycemic clamp at 300 mg/dL (16.7 mmol/L), insulin secretion rose more than 2-fold, from 47 +/- 9 nmol over the 3-h period before treatment to 103 +/- 21 nmol after glyburide therapy. We conclude that the predominant mechanism of action of glyburide in patients receiving therapy for 6-10 weeks is to increase the responsiveness of the beta-cell to glucose.(ABSTRACT TRUNCATED AT 400 WORDS)     

Evidence that glucose transport is rate-limiting for in vivo glucose uptake.

To determine whether glucose transport or intracellular glucose metabolism is rate-limiting for in vivo glucose uptake, rates of glucose disposal were measured in a group of normal subjects at varying levels of hyperglycemia designed to attain saturating rates of glucose disposal at low and high physiological insulin concentrations. At insulin levels of approximately 200 pmol/L, glucose disposal rates were 2.9 +/- 0.4, 4.7 +/- 0.5, 6.4 +/- 0.6, and 6.5 +/- 0.8 mg/kg/min at plasma glucose concentrations of 5.55, 11.10, 13.88, and 19.43 mmol/L (or 100, 200, 250, and 350 mg/dL, respectively). At insulin levels of approximately 750 pmol/L, glucose disposal rates were 1.7 to 2.1-fold higher: 6.2 +/- 0.7, 9.2 +/- 1.1, 11.0 +/- 1.1, and 12.3 +/- 1.4 mg/kg/min at glucose levels of 5.55, 11.10, 13.88, and 19.43 mmol/L. Thus, during both the 15- and 40-mU/m2/min insulin infusions, glucose disposal increased in a linear fashion from 5.55 to 13.88 mmol/L (r = .90) and then effectively plateaued at the same plasma glucose level. If the plateau of glucose disposal during the 40-mU/m2/min insulin infusion was due to saturation of the intracellular capacity to metabolize glucose, then when plasma glucose was increased from 13.88 to 19.43 mmol/L at the lower insulin level, the glucose disposal should have continued to increase and not plateau, since the rate of glucose disposal was only approximately 50% of that attained at the higher insulin infusion rate.(ABSTRACT TRUNCATED AT 250 WORDS)     

Mechanism of metformin action in obese and lean noninsulin-dependent diabetic subjects

The effect of metformin on glucose metabolism was examined in eight obese (percent ideal body weight, 151 +/- 9%) and six lean (percent ideal body weight, 104 +/- 4%) noninsulin-dependent diabetic (NIDD) subjects before and after 3 months of metformin treatment (2.5 g/day). Fasting plasma glucose (11.5-8.8 mmol/L), hemoglobin-A1c (9.8-7.7%), oral glucose tolerance test response (20.0-17.0 mmol/L; peak glucose), total cholesterol (5.67-4.71 mmol/L), and triglycerides (2.77-1.52 mmol/L) uniformly decreased (P less than 0.05-0.001) after metformin treatment; fasting plasma lactate increased slightly from baseline (1.4 to 1.7 mmol/L; P = NS). Body weight decreased by 5 kg in obese NIDD subjects, but remained constant in lean NIDD. Basal hepatic glucose production declined in all diabetics from 83 to 61 mg/m2.min (P less than 0.01), and the decrease correlated (r = 0.80; P less than 0.01) closely with the fall in fasting glucose concentration. Fasting insulin (115 to 79 pmol/L) declined (P less than 0.05) after metformin. During a 6.9 mmol/L hyperglycemic clamp, glucose uptake increased in every NIDD subject (113 +/- 15 to 141 +/- 12 mg/m2.min; P less than 0.001) without a change in the plasma insulin response. During a euglycemic insulin clamp, total glucose uptake rose in obese NIDD subjects (121 +/- 10 to 146 +/- 9 mmol/m2.min; P less than 0.05), but decreased slightly in lean NIDD (121 +/- 10 to 146 +/- 0.5; P = NS). Hepatic glucose production was suppressed by more than 80-90% in all insulin clamp studies before and after metformin treatment. In conclusion, metformin lowers the fasting plasma glucose and insulin concentrations, improves oral glucose tolerance, and decreases plasma lipid levels independent of changes in body weight. The improvement in fasting glucose results from a reduction in basal hepatic glucose production. Metformin per se does not enhance tissue sensitivity to insulin in NIDD subjects. The improvement in glucose metabolism under hyperglycemic, but not euglycemic, conditions suggests that metformin augments glucose-mediated glucose uptake. Metformin has no stimulatory effect on insulin secretion.     

Coronary heart disease risk factor profiles in black patients with non-insulin-dependent diabetes mellitus: paradoxic patterns.

PURPOSE: Non-insulin-dependent diabetes mellitus (NIDDM) in black Americans consists of two variants: one with insulin resistance and one with normal insulin sensitivity. This study examined whether cardiovascular disease risk factors are significantly different between the two variants. PATIENTS AND METHODS: Twenty-two black patients with NIDDM in near-normoglycemic remission who were receiving no pharmacologic therapy for NIDDM were evaluated for insulin sensitivity by the euglycemic insulin clamp, plasma insulin levels, degree of obesity, glucose metabolism, serum total, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) cholesterol levels, and fasting plasma triglyceride levels. RESULTS: Fifty-nine percent of these patients had normal insulin sensitivity (glucose disposal rate in response to a 1 mU.kg-1.minute-1 insulin infusion greater than 6.0 mg.kg-1.minute-1). The insulin-sensitive patients were less obese (body mass index [BMI] 26.5 +/- 0.6 versus 30.8 +/- 0.9 kg/m2) and had lower fasting plasma insulin levels (56.9 +/- 7.8 versus 88.0 +/- 6.0 pmol/L), lower serum cholesterol (4.47 +/- 0.30 versus 6.39 +/- 0.26 mmol/L), lower serum LDL cholesterol (2.77 +/- 0.31 versus 4.51 +/- 0.27 mmol/L), and lower fasting plasma triglyceride levels (0.83 +/- 0.08 versus 1.45 +/- 0.16 mmol/L) than the insulin-resistant patients. Serum HDL cholesterol was not different between the two groups and was in the high-normal range (1.31 +/- 0.08 and 1.19 +/- 0.07 mmol/L). Univariate analysis demonstrated that serum total cholesterol, LDL cholesterol, and fasting plasma triglycerides were highly correlated with insulin-mediated glucose disposal and fasting plasma insulin. The differences in insulin sensitivity and lipid profiles were independent of obesity, as they were present in six insulin-resistant and six insulin-sensitive patients matched for BMI. CONCLUSIONS: Black patients with the insulin-sensitive variant of NIDDM have a low risk factor profile for cardiovascular disease as compared with those with the insulin-resistant variant, who have a high risk factor profile. A high prevalence of the insulin-sensitive variant of NIDDM in the black population might explain the lower prevalence of angina and myocardial infarction in black patients with NIDDM as compared with white patients with NIDDM.     

Differences in pharmacokinetics and pharmacodynamics of insulin lispro and aspart in healthy volunteers.

Pharmacokinetic and pharmacodynamic profiles of the rapid-acting insulin analogues lispro and aspart were compared in a randomized, double-blind crossover study of 20 fasting healthy men following a single subcutaneous injection. Either insulin lispro or aspart, 0.05 U/kg-body-weight, was injected subcutaneously and followed by determination of 5-h profiles of plasma glucose, serum C-peptide and insulin concentrations. Lowest glucose concentrations were observed after 50 min in the aspart group (3.2 +/- 0.1 mmol/l versus lispro 3.5 +/- 0.1 mmol/l; p = 0.026) and after 60 min in the lispro group (3.4 +/- 0.1 mmol/l). For blood glucose t min was 59.3 +/- 3.4 min in the aspart and 63.5 +/- 5.3 min in the lispro group (ns). After 40 min a lower C-peptide was determined for aspart (225 +/- 21 pmol/l versus lispro 309 +/- 33 pmol/l; p = 0.031), whereas minimal C-peptide concentrations were reached in both groups after 105 min (lispro 117 +/- 21 pmol/l versus aspart 105 +/- 18 pmol/l). The maximal concentration of insulin was detected in both groups after 40 min (lispro 20.8 +/- 1.1 mU/l versus aspart 24.6 +/- 1.3 mU/l; p = 0.032). For insulin t max was 33.0 +/- 2.6 min in the aspart versus 33.3 +/- 2.6 min in the lispro group (ns). The present results indicate a more rapid absorption of insulin aspart in comparison to insulin lispro. Higher insulin concentrations after subcutaneus injection may be advantageous in meal-related treatment of diabetes.     

Effect of short-term consumption of a high-fat, low-carbohydrate diet on metabolic control in insulin-deficient diabetic rats

This study examined the effect of changing the proportion of dietary fat on metabolic control in rats rendered mildly diabetic with streptozotocin (STZ). The high-fat (HF) diet contained 66% energy as fat and 12% as carbohydrate while the low-fat (LF) diet contained 12% energy as fat and 66% as carbohydrate. Both diets had a P/S ratio of 1:3. Young male rats weighing 100 g were treated with STZ (60 mg/kg IV) and randomly allocated to either the LF of HF diet. After 2 weeks, the fasting plasma glucose concentrations were significantly higher in the HF-STZ rats than in the LF-STZ rats (13.2 +/- 1.2 mmol/L v 7.1 +/- 0.8 mmol/L, respectively, P less than 0.001). The increase in plasma glucose above the basal level following the intravenous glucose load (0.5 g/kg body wt) was similar in both groups of STZ-treated rats and glucose clearance was similarly impaired. The fall in glucose concentrations in the 30 minutes following the IV insulin (0.5 U Actrapid insulin/kg body wt) was greater in the LF-STZ rats (delta AUC = -1.60 +/- 0.20 mmol/L 0.5h) than in the HF-STZ group (delta AUC = -0.97 +/- 0.20 mmol/L 0.5 h, P less than 0.05) and either of the control groups (delta AUC = -0.94 +/- 0.37, -0.83 +/- 0.09 mmol/L 0.5 h for LF and HF rats, respectively, P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Insulin and glucagon secretion are suppressed equally during both hyper- and euglycemia by moderate hyperinsulinemia in patients with diabetes mellitus

Hyper- and euglycemic clamp studies were performed in patients with noninsulin-dependent diabetes mellitus to examine the effects of exogenous insulin administration on insulin and glucagon secretion. Plasma glucose was kept at the fasting level [mean, 10.0 +/- 0.2 (+/- SE) mmol/L; hyperglycemic clamp], and graded doses of insulin (1, 3, and 10 mU/kg.min, each for 50 min) were infused. The plasma C-peptide level gradually decreased from 523 +/- 66 to 291 +/- 43 pmol/L (n = 13; P less than 0.005) by the end of the hyperglycemic clamp study. After 90 min of equilibration with euglycemia (5.4 +/- 0.1 mmol/L; euglycemic clamp), the same insulin infusion protocol caused a similar decrease in the plasma C-peptide level. With the same glucose clamp protocol, physiological hyperinsulinemia for 150 min (676 +/- 40 pmol/L), obtained by the infusion of 2 mU/kg.min insulin, caused suppression of the plasma C-peptide level from 536 +/- 119 to 273 +/- 65 pmol/L during hyperglycemia and from 268 +/- 41 to 151 +/- 23 pmol/L during euglycemia (n = 9; P less than 0.005 in each clamp). Plasma glucagon was suppressed to a similar degree in both glycemic states. These results demonstrate that 1) insulin secretion in non-insulin-dependent diabetes mellitus is suppressed by high physiological doses of exogenous insulin in both the hyper- and euglycemic states, the degree of inhibition being independent of the plasma glucose level; and 2) glucagon secretion is also inhibited by such doses of exogenous insulin.     

Effect of gemfibrozil treatment in sulfonylurea-treated patients with noninsulin-dependent diabetes mellitus

This study was initiated to 1) assess gemfibrozil's ability to lower plasma triglyceride (TG) concentration in patients with NIDDM, and 2) determine whether this effect was associated with any changes in glycemic control. Measurements were made of mean hourly plasma glucose, insulin, TG, and FFA concentrations from 1200-1600 h in response to a test meal; hepatic glucose production (HGP); insulin-stimulated glucose uptake during a hyperinsulinemic glucose clamp study (MCR); and fasting plasma lipoprotein TG and cholesterol concentrations in 12 patients with NIDDM before and 3 months after gemfibrozil treatment. Although ambient plasma TG and FFA concentrations fell significantly, plasma glucose, insulin, HGP, concentrations fell significantly, plasma glucose, insulin, HGP, and glucose MCR did not change. However, when patients were divided into two groups, those with fasting plasma glucose levels above 9 mmol/L (fair control) and those with levels below 9 mmol/L (good control), a different phenomenon was observed. Patients in fair control had significant decreases in mean hourly plasma concentrations of glucose (15.1 +/- 1.7 to 12.6 +/- 0.9 mmol/L; P less than 0.001), insulin (523 +/- 59 to 471 +/- 75 pmol/L; P less than 0.001), FFA (652 +/- 150 to 504 +/- 76 mumol/L), and HGP (9.5 0.4 to 8.1 +/- 0.4 mumol/kg.min; P less than 0.005), and an increase in glucose MCR (2.63 +/- 0.49 to 3.72 +/- 0.54 mL/kg.min; P less than 0.07) in association with a fall in TG from 6.9 +/- 1.3 to 3.5 +/- 0.9 mmol/L (P less than 0.001). Although fasting low density lipoprotein cholesterol increased (1.8 +/- 0.2 to 2.7 +/- 0.2 mmol/L; P less than 0.05), the ratio of total to high density lipoprotein cholesterol decreased (6.84 +/- 0.88 to 5.80 +/- 1.05; P less than 0.02). Despite a significant fall in mean hourly TG concentration (4.6 +/- 0.7 to 3.8 +/- 0.7 mmol/L; P less than 0.001), neither insulin, FFA, HGP, nor glucose MCR changed in patients in good control. Furthermore, the mean hourly plasma glucose concentration increased from 9.2 +/- 0.7 to 11.7 +/- 1.4 mmol/L (P less than 0.001). Low density lipoprotein cholesterol also increased in this group (1.9 +/- 0.2 to 2.7 +/- 0.2 mmol/L; P less than 0.02), but, as before, the ratio of total to high density lipoprotein cholesterol decreased (8.15 +/- 1.93 to 6.36 +/- 1.03; P less than 0.02).     

Reversal of diet-induced catabolism by infusion of recombinant insulin-like growth factor-I in humans.

Treatment of catabolic conditions with insulin-like growth factor I (IGF-I), the peptide that mediates some of the anabolic growth-promoting effects of GH, offers potential advantages of avoiding the hyperglycemia caused by treatment with GH. A state of moderate catabolism was produced in six normal, young adult volunteers by restricting their daily dietary intake to 20 kilocalories/kg/day. During the last 6 days of two 2-week diet-study periods, they received either IGF-I (12 micrograms/kg/h by i.v. infusion over 16 h) or GH (0.05 mg/kg/day by sc injection). IGF-I improved nitrogen balance from -236 +/- 45 mmol/day (+/- SE) during diet alone, to -65 +/- 40 mmol/day (P less than 0.001) during the last 4 days of IGF-I infusion. A similar effect was produced by GH. IGF-I infusion decreased fasting blood glucose from 4.94 +/- 0.91 mmol/L to 3.13 +/- 0.44 mmol/L (P less than 0.001), while GH raised blood glucose values (4.75 +/- 1.01 mmol/L on diet alone, to 5.48 +/- 1.00 during the period of GH treatment; P less than 0.05). Despite these differences in blood glucose, IGF-I infusions decreased serum insulin (74.9 +/- 26.8 pmol/L on diet alone, to 16.7 +/- 1.5 pmol/L during IGF-I) and serum connecting-peptide concentrations (2.14 +/- 0.89 mmol/L on diet alone, to 0.97 +/- 0.14 during IGF-I), while GH raised insulin (109.4 +/- 31.3 pmol/L, P less than 0.05 during GH) and connecting-peptide (3.12 +/- 0.59 mmol/L, P less than 0.02). At the dose of each hormone used, the attenuation of nitrogen wasting produced by infusions of IGF-I was similar in magnitude and timing to that produced by injections of GH. The reduction in serum glucose concentrations produced by IGF-I compared with the increase in glucose noted during GH treatment, could benefit hyperglycemic catabolic patients.     

Association of insulin resistance with hyperglycemia in streptozotocin-diabetic pigs: effects of metformin at isoenergetic feeding in a type 2-like diabetic pig model

Insulin-mediated glucose metabolism was investigated in streptozotocin (STZ)-treated diabetic pigs to explore if the STZ-diabetic pig can be a suitable model for insulin-resistant, type 2 diabetes mellitus. Pigs (approximately 40 kg) were meal-fed with a low-fat (5%) diet. Hyperinsulinemic (1, 2, and 8 mU kg(-1) min(-1)) clamps and/or 6,6-(2)H-glucose infusion studies were performed in 36 pigs. Diabetic (slow, 30-minute infusion of 130 mg STZ/kg) vs normal pigs were nonketotic, showed fasting hyperglycemia (21.7 +/- 1.1 vs 5.3 +/- 0.2 mmol/L), comparable plasma insulin (9 +/- 7 vs 5 +/- 1 mU/L), and elevated triglyceride concentrations (1.0 +/- 0.3 vs 0.2 +/- 0.1 mmol/L). After a standard meal, plasma triglycerides, cholesterol, and nonesterified fatty acid concentrations were significantly higher in diabetic vs normal pigs (1.2 +/- 0.3 vs 0.3 +/- 0.1, 2.3 +/- 0.2 vs 1.7 +/- 0.1, and 1.5 +/- 0.5 vs 0.2 +/- 0.1 mmol/L, respectively, P < .05). Fasting whole-body glucose uptake, hepatic glucose production, and urinary glucose excretion were increased (P < .01) in diabetic vs normal pigs (9.1 +/- 0.6 vs 4.8 +/- 0.4, 11.4 +/- 0.6 vs 4.8 +/- 0.4, and 2.3 +/- 0.2 vs 0.0 +/- 0.0 mg kg(-1) min(-1)). During hyperinsulinemic euglycemia (approximately 6 mmol/L), whole-body glucose uptake was severely reduced (P < .01) and hepatic glucose production was moderately increased (P < .05) in diabetic vs normal pigs (6.7 +/- 1.3 vs 21.1 +/- 2.2 and 1.7 +/- 0.5 vs 0.8 +/- 0.3 mg kg(-1) min(-1)) despite plasma insulin concentrations of 45 +/- 5 vs 24 +/- 5 mU/L, respectively. Metformin vs placebo treatment of diabetic pigs (twice 1.5 g/d) for 2 weeks during isoenergetic feeding (1045 kJ/kg body weight(0.75)) resulted in a reduction in both fasting and postprandial hyperglycemia (14.7 +/- 1.5 vs 19.4 +/- 0.6 and 24.9 +/- 2.2 vs 35.5 +/- 4.9 mmol/L), a reduction in daily urinary glucose excretion (approximately 250 vs approximately 350 g/kg food), and an increase in insulin-stimulated glucose disposal (9.4 +/- 2.2 vs 5.8 +/- 1.7 mg kg(-1) min(-1); P < .05), respectively. In conclusion, a slow infusion of STZ (130 mg/kg) in pigs on a low-fat diet induces the characteristic metabolic abnormalities of type 2 diabetes mellitus and its sensitivity to oral metformin therapy. It is therefore a suitable humanoid animal model for studying different aspects of metabolic changes in type 2 diabetes mellitus. Insulin resistance in STZ-diabetic pigs is most likely secondary to hyperglycemia and/or hyperlipidemia and therefore of metabolic origin.     

Combined metformin-sulfonylurea treatment of patients with noninsulin-dependent diabetes in fair to poor glycemic control.

The effect of metformin treatment was studied in 13 patients with noninsulin-dependent diabetes mellitus (NIDDM), whose fasting plasma glucose concentration was greater than 10 mmol/L with maximal sulfonylurea doses. Patients were studied before and 3 months after receiving 2.5 g/day metformin. The fasting plasma glucose concentration (12.4 +/- 0.8 vs. 8.8 +/- 0.7 mmol/L), mean hourly postprandial plasma glucose concentration from 0800-1600 h (14.0 +/- 1 vs. 9.4 +/- 0.9 mmol/L), and glycosylated hemoglobin level (12.3 +/- 0.6% vs. 9.0 +/- 0.6%) were all significantly (P less than 0.005-0.001) lower after the administration of metformin. The improvement in glycemic control was associated with a 24% increase (P less than 0.05) in insulin-stimulated glucose uptake during glucose clamp studies and a 16% decrease in basal hepatic glucose production (P less than 0.05). Mean hourly concentrations of plasma insulin (411 +/- 73 vs. 364 +/- 73 pmol/L) and FFA concentrations (440 +/- 31 vs. 390 +/- 40 mumol/L) were also lower after 3 months of metformin treatment. However, neither insulin binding nor insulin internalization by isolated monocytes changed in response to metformin. Finally, plasma triglyceride, very low density lipoprotein triglyceride, and very low density lipoprotein cholesterol were significantly decreased (P less than 0.01-0.001), and high density lipoprotein cholesterol was significantly increased (P less than 0.001) after metformin treatment. Thus, the addition of metformin to sulfonylurea-treated patients with NIDDM not in good glycemic control significantly lowered fasting and postprandial plasma glucose concentrations, presumably due to the combination of enhanced glucose uptake and decreased hepatic glucose production. Since the dyslipidemia present in these patients also improved, the results suggest that metformin may be of significant clinical utility in patients with NIDDM not well controlled with sulfonylurea compounds.     

Hypoglycemic effect of Du-zhong (Eucommia ulmoides Oliv.) leaves in streptozotocin-induced diabetic rats

The current study investigated whether Du-zhong (Eucommia ulmoides Oliv.) leaves could improve the hyperglycemia in streptozotocin (STZ)-induced diabetic rats. Male Sprague-Dawley rats were divided into a non-diabetic group (NDM), diabetic group (DM), diabetic group supplemented with powdered Du-zhong leaves (DM-PDZ) and diabetic group supplemented with a water extract of the powdered Du-zhong leaves (DM-WDZ). Diabetes was induced by injecting STZ (70 mg/kg B.W., i.p.). The powdered Du-zhong leaves or its powdered water extract was add to a standard diet based on 1% dried Du-zhong leaves (1 g PDZ/100 g diet and 0.187 g WDZ/100 g diet, respectively) for 3 weeks. Body weight was significantly higher in both types of Du-zhong leaves supplemented groups than in the DM group. The blood glucose levels were significantly lower in the DM-PDZ and DM-WDZ groups than in the DM group (20.05+/-0.88 and 18.96+/-1.23 mmol/l versus 24.42+/-1.07 mmol/l, P<0.05), whereas the plasma insulin and C-peptide levels were significantly higher in the PDZ and WDZ supplemented groups than in the DM group (7.45+/-0.27 and 7.62+/-0.69 microl U/ml versus 3.75+/-0.27 microl U/ml for the plasma insulin, and 224.52+/-14.6 and 239.76+/-15.52 pmol/l versus 166.5+/-10.4 pmol/l for the plasma C-peptide, respectively, P<0.05). The supplementation of PDZ and WDZ also resulted in lower plasma urea nitrogen levels compared to the DM group. Du-zhong leaves supplement seemed to be helpful to preserve the normal histological appearance of pancreatic islets as well as to preserve insulin-positive beta-cells but it did not reverse the effect of STZ to a great extent. Accordingly, the reduction in plasma glucose by the powdered Du-zhong leaves and its water extract is quite small but significant, nevertheless, this was occurred with simultaneous the increase in plasma insulin and C-peptide. They improved hyperglycemia and seemingly enhance the function of pancreatic beta-cells in STZ-induced diabetic rats.     

Altered insulin sensitivity, hyperinsulinemia, and dyslipidemia in individuals with a hypertensive parent.

PURPOSE: Essential hypertension is, in some patients, complicated by impairment of insulin-mediated glucose disposal and hyperinsulinemia. Whether this metabolic disturbance is a consequence of the hypertensive process or whether it may precede, and thus possibly promote, the development of hypertension has been unknown. SUBJECTS AND METHODS: Searching for hereditary or familial defects in hypertension-prone humans, we prospectively investigated insulin sensitivity, plasma insulin and glucose, and serum lipoproteins in normotensive offspring of essential hypertensive as compared with age- and body habitus-matched offspring of normotensive families. RESULTS: Compared with 78 control subjects, 70 offspring of essential hypertensive parents had similar age (mean +/- SEM: 24 +/- 1 versus 24 +/- 1 years, respectively) and body mass index (22.3 +/- 0.2 versus 22.4 +/- 0.2 kg/m2), a blood pressure of 127/77 +/- 1/1 versus 123/76 +/- 1/1 mm Hg (p less than 0.05 for systolic), and significantly elevated (p less than 0.01 to 0.001) fasting plasma insulin levels (9.9 +/- 0.3 versus 8.6 +/- 0.3 microU/mL), serum total triglycerides (1.03 +/- 0.06 versus 0.83 +/- 0.03 mmol/L), total cholesterol (4.37 +/- 0.08 versus 3.93 +/- 0.07 mmol/L), low-density lipoprotein cholesterol (2.45 +/- 0.08 versus 2.14 +/- 0.07 mmol/L), and total/high-density lipoprotein cholesterol ratio (4.3 +/- 0.1 versus 3.7 +/- 0.1). Insulin sensitivity was lower (9.4 +/- 0.7 versus 13.2 +/- 1.1 x 10(-4) x minute-1/microU/mL, p less than 0.001), while post-glucose-load plasma insulin levels were higher (p less than 0.05) in the 41 offspring of essential hypertensive parents than in the 38 offspring of normotensive parents so investigated. CONCLUSION: These findings demonstrate that young normotensive humans in apparently excellent health but with one essential hypertensive parent tend to have an impairment of insulin-mediated glucose disposal, hyperinsulinemia, and dyslipidemia. It follows that a familial trait for essential hypertension seems to coexist commonly with defects in carbohydrate and lipoprotein metabolism that can be detected before or at least at a very early stage of the development of high blood pressure as judged by resting blood pressure measurements.