Molecular cloning of Saccharomyces cerevisiae MLF4/SSH4 gene which confers the immunosuppressant leflunomide resistance

Otsuka Long-Evans Tokushima Fatty (OLETF) rats showed that the distribution of plasma membrane content of insulin-regulated glucose transporter in skeletal muscle was reminiscent of that in human non-insulin-dependent diabetes mellitus (NIDDM). To obtain more information on the cellular mechanisms of muscle insulin resistance, hexokinase activities were measured in the skeletal muscle of OLETF rats. The results showed that the activity of the type II enzyme in the diabetic rats was significantly decreased (P < 0.05) compared with Long-Evans Tokushima Otsuka (LETO) control rats. No significant differences in the activity of the type I hexokinase were observed between these rats. Western blot analysis showed that the protein content of the type II in OLETF rats was also significantly lower than that in LETO rats (P < 0.05). After insulin stimulation, the intramuscular content of glucose 6-phosphate, which regulates glycogen synthesis in skeletal muscle, was significantly decreased in OLETF rats (P < 0.01). However, glycogen synthase activity in vitro and intramuscular lactate concentration in these rats did not show significant differences. These results suggest that the G6P content of the diabetic rats is decreased as a result of an impaired early event of glucose metabolism, indicating that the molecular defects of skeletal muscle in OLETF rats are similar to those in NIDDM patients.     

Glucose transporter levels in a male spontaneous non-insulin-dependent diabetes mellitus rat of the Otsuka Long-Evans Tokushima Fatty strain

Otsuka Long-Evans Tokushima Fatty (OLETF) rats are a new strain of spontaneous non-insulin-dependent diabetes mellitus (NIDDM) models. To evaluate the role of glucose transporters (GLUT) in the development of diabetes in this model, we examined the action of insulin on the translocation of GLUT4 and GLUT1 in isolated adipocytes, and the GLUT4 protein levels in muscles. Long-Evans Tokushima Otsuka (LETO) rats were used as a control strain. In adipocytes, the GLUT4 protein levels in OLETF rats at 30 weeks of age (diabetic stage) were considerably lower than those in LETO rats at the same age. At a pre-diabetic stage (7 weeks), there were no significant differences in GLUT4 protein levels in adipocytes between LETO and OLETF rats. However, the degree of GLUT4 translocation in OLETF rats was lower than that in LETO rats at 7 weeks of age. There were no differences in GLUT1 levels in adipocytes between the two strains. In muscles, the decrease in GLUT4 protein was observed in OLETF rats at 30 weeks of age. Whether such a difference is under the influence of hyperglycemia was also examined using rats rendered diabetic by 70% pancreatectomy. OLETF rats aged 7 weeks were subjected to partial pancreatectomy (Px) and sham pancreatectomy (sham). At 4 weeks after surgery, GLUT4 protein levels in adipose tissues and skeletal muscles were determined. GLUT4 decrease was observed for both tissues of hyperglycemic Px rats compared with euglycemic sham. Moreover, we examined the direct effect of glucose on GLUT4 protein using primary cultured adipocytes of OLETF rats at 5 weeks of age. After 7-day culture with normal (5.6 mmol/l) or high (25 mmol/l) concentrations of glucose, the GLUT4 protein levels in adipocytes decreased at 25 mmol/l glucose compared with 5.6 mmol/l glucose. These findings suggest an early defect in the insulin resistance of OLETF rats probably reflects impaired GLUT4 translocation. The GLUT4 decrease, which occurs later in the process appears to be a consequence, rather than a cause of diabetes in OLETF rats.     

Tissue factor in the pathogenesis of atherosclerosis

The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is an animal model for obese NIDDM. We performed a genome wide scan in F2 progenies obtained by crossing OLETF rats with two control strains, Long-Evans Tokushima Otsuka (LETO) and Fisher-344(F-344) rats. Since diabetes develops only in male progenies, we used only male F2 rats for the linkage studies.Highly significant linkage was observed between the phenotype, postprandial hyperglycemia and P-450ald locus on chromosome 1 and D7Mit 11 locus on chromosome 7. In addition, suggestive linkage was found between fasting glucose level and body weight and these two loci. Four other regions (D1Mit12, D2Mit11, D5Mgh14, and D17Arb1) on chromosome 1, 2, 5, and 17 were detected to influence body weight, fasting glucose level or postprandial hyperglycemia independently. We concluded that non-insulin-dependent diabetes mellitus(NIDDM) in OLETF rats is regulated by multiple genes which affect fasting, postprandial hyperglycemia, and obesity differently.     

Increased intestinal glucose absorption and postprandial hyperglycaemia at the early step of glucose intolerance in Otsuka Long-Evans Tokushima Fatty rats

Otsuka Long-Evans Tokushima Fatty (OLETF) rats are reported to be obese Type II (non-insulin-dependent) diabetic rats with insulin resistance and impaired insulin secretion. To investigate the contribution of intestinal glucose absorption to postprandial hyperglycaemia, we determined the plasma xylose concentrations after an 0.8 g/kg oral xylose load which was used as a test of small intestinal glucose absorption in 6-week-old OLETF rats and weight-matched Long-Evans Tokushima Otsuka (LETO) rats. An oral glucose tolerance test showed that OLETF rats developed hyperglycaemia at 60 and 90 min after the glucose load, though the fasting plasma glucose concentration, insulin concentration and insulin-induced in vivo glucose utilization rate were similar. Consistently, in an oral D-xylose loading test, the peak concentration of plasma xylose in OLETF rats was increased by 58.7% compared with that of LETO rats (p < 0.005). The disappearance rate of plasma xylose concentrations after intravenous xylose loading did not differ between the two strains. Co-treatment with 0.4 g/kg phlorizin, a specific inhibitor of sodium-dependent glucose transporter 1 (SGLT1), abolished both plasma glucose and xylose concentrations after the loads. Morphological studies showed that both the small intestinal wet weight and surface area were 30% larger in the OLETF rats than in the LETO rats. Furthermore, the SGLT1 mRNA content of OLETF rats also increased compared with LETO rats. These results suggest that an increased SGLT1 expression concomitant with intestinal hypertrophy in OLETF rats is partly associated with postprandial hyperglycaemia before the onset of insulin resistance and hyperinsulinaemia.     

A novel biomarker for hyperglycemia, MRX isolated from hydrolysate of glycated proteins

Long-lived proteins can undergo non-enzymatic glycation to form highly crosslinked structures with characteristic fluorescence during aging and diabetes processes. In this paper, a typical fluorophore, named Maillard reaction product X (MRX), was isolated from the hydrolysate of glycated proteins. MRX could be formed by incubation of bovine serum albumin with glucose, followed by acid hydrolysis. The structure of MRX was determined to be 8-hydroxy-5-methyldihydrothiazolo[3,2-alpha] pyridinium-3-carboxylate. MRX was also found to be formed by the incubation of cysteine and arginine with glucose, followed by hydrolysis. We found the formation of MRX in the recently developed genetically diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats and compared them with that in the control Long-Evans Tokushima Otsuka (LETO) rats. Significantly higher levels of MRX were observed from the serum (p < 0.005) and urinary protein (p < 0.001) of OLETF rats in comparison with those of LETO rats. MRX must be a potential candidate as a biomarker for hyperglycemia.     

Mother-Infant Interactions in Rats Lacking CCKA Receptors.

Mediation of mother-infant interactions by the brain-gut peptide cholecystokinin (CCK) was examined by observing behavior of Otsuka Long-Evans Tokushima Fatty (OLETF) rats, which lack functional CCKA receptors because of a genetic abnormality. OLETF (n = 10) and control (Long-Evans Tokushima Otsuka [LETO] n = 10) dams interacted with 1 pup of each line on Postpartum Days 6-9. OLETF pups received more body and anogenital licking and emitted substantially more ultrasonic vocalizations than LETO pups. OLETF dams carried pups less frequently and showed a nursing position more frequently than LETO dams. No significant Pup X Dam Line interactions or line differences in dams' activity were detected. The results provide convergent validity to previous pharmacological studies implicating CCK mediation of both infant and maternal behavior. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Role of cholecystokinin (CCK)-A receptor for pancreatic growth after weaning: a study in a new rat model without gene expression of the CCK-A receptor

This work extends a recent observation that Otsuka Long-Evans Tokushima Fatty (OLETF) rats, which have been established as an animal model of non-insulin-dependent diabetes mellitus, show no expression of the cholecystokinin (CCK)-A receptor gene in the pancreas. The CCK-A receptor is known to be involved in regulating pancreatic exocrine function and growth. We examined the growth of the pancreas in terms of wet weight, enzyme compositions, and protein and DNA contents at 5-6 and 24-25 weeks of age in OLETF rats and control (Long-Evans Tokushima; LETO) rats. The pancreatic wet weight increased significantly with age in both OLETF and LETO rats but was significantly lower in OLETF rats than in LETO rats. The total DNA contents in the whole pancreas (cell numbers) were comparable for both strains and increased significantly with age. However, the ratio of protein content to DNA content (the cell size) significantly increased with age in LETO rats, with no increase in OLETF rats. The changes in chymotrypsin, amylase, and insulin with respect to age were in the same direction in both strains: a decrease or no change in total and/or cellular contents of chymotrypsin and insulin and increases in amylase. These results suggest that the CCK-A receptor plays some role in the increase in cell size associated with normal growth of the pancreas from 5 to 25 weeks of age (after weaning).     

Ultrastructural examination of corneal epithelium of spontaneously obese, hyperglycemic rats

PURPOSE: Otsuka Long-Evans Tokushima fatty (OLETF) rats spontaneously become obese and hyperglycemic with age. We investigated whether the development of hyperglycemia would alter the ultrastructure of the corneal epithelium. METHODS: Scanning and transmission electron microscopy (SEM and TEM) were used to examine the morphology of corneal epithelial cells. Fourteen OLETF rats were evaluated, and 9 Long-Evans Tokushima Otsuka (LETO) rats were used as control. Non-hyperglycemic OLETF rats served as controls. RESULTS: SEM showed exfoliative changes in the surface of the central corneal epithelium of the hyperglycemic OLETF rats. These superficial epithelial cells were irregular in shape as compared to polygonal shapes of those of LETO and non-hyperglycemic OLETF rats. The mean anterior surface area of individual superficial epithelial cells was significantly smaller in the hyperglycemic OLETF than that of the LETO or the non-hyperglycemic OLETF rats. Central protrusion(s) could be found in some of the superficial cells of all rats examined, although this phenomenon was more common in the hyperglycemic rats than in the non-hyperglycemic rats. TEM revealed that there were numerous cytoplasmic vacuoles and wide intercellular spaces in the central corneal epithelium of the hyperglycemic OLETF rats, but not in the non-hyperglycemic rats. CONCLUSIONS: The development of spontaneous hyperglycemia in OLETF rats alters the ultrastructure of the corneal epithelium. The alterations included abnormalities of the corneal epithelial surface observed by SEM and the presence of intracellular vacuoles and enlarged intercellular spaces detected by TEM.     

High frequency of altered HLA class I phenotypes in invasive colorectal carcinomas

We examined the role of the cholecystokinin-A (CCK-A) receptor in acute inflammatory and regenerative stages of experimental pancreatitis using a rat model lacking the CCK-A receptor [Otsuka Long-Evans Tokushima Fatty (OLETF) rats]. OLETF and control [Long-Evans Tokushima Otsuka (LETO)] rats were prepared with an internal bile fistula and with obstruction of pancreatic flow and were sacrificed 1-14 days later. Histological examination was performed, and changes in pancreatic wet weight, protein concentration, CCK-A and -B receptor mRNA levels, tyrosine kinase activities, and plasma amylase and CCK levels were determined. The plasma amylase level showed a transient increase on day 1, the CCK level remained at high levels throughout, and tyrosine kinase activity was increased significantly on day 3 but declined thereafter. These parameters were comparable for both strains during the acute inflammatory stage. However, no regenerative findings were observed by histological examination and the protein concentration in the pancreas was significantly lower in OLETF rats on days 7-14, during which time regeneration was completed in LETO rats. These observations indicate that the absence of the CCK-A receptor did not modify the acute phase of pancreatitis but significantly retarded regeneration of the pancreatic tissue.     

The impact of metformin therapy on hepatic glucose production and skeletal muscle glycogen synthase activity in overweight type II diabetic patients

The effect of metformin therapy on glucose metabolism was examined in eight overweight newly presenting untreated type II diabetic patients (five males, three females). Patients were treated for 12 weeks with either metformin (850 mg x 3) or matching placebo using a double-blind crossover study design; patients were studied at presentation and at the end of each treatment period. Insulin action was assessed by measuring activation of skeletal muscle glycogen synthase (GS) before and during a 4-hour hyperinsulinemic euglycemic clamp (100 mU.kg-1 x h-1). Metformin therapy was associated with a significant decrease in fasting blood glucose (6.8 +/- 0.6 v 8.3 +/- 0.9 mmol.L-1, P < .01) and glycosylated hemoglobin ([HbA1] 7.7% +/- 0.4% v 8.5% +/- 0.5%, P < .01) levels. Fasting hepatic glucose production (HGP) was also significantly decreased following metformin therapy (1.98 +/- 0.13 v 2.41 +/- 0.20 mg.kg-1 x min-1, P < .02), whereas fasting insulin and C-peptide concentrations remained unaltered. The decrease in basal HGP correlated closely with the decrease in fasting blood glucose concentration (r = .92, P < .001). Insulin-stimulated glucose uptake was assessed using the hyperinsulinemic euglycemic clamp technique and was increased post-metformin (3.8 +/- 0.6 v 3.1 +/- 0.7 mg.kg-1 x min-1, P < .05). This was primarily the result of increased nonoxidative glucose metabolism (1.1 +/- 0.6 v 0.4 +/- 0.6 mg.kg-1 x min-1, P < .05); oxidative glucose metabolism did not change. Metformin had no measurable effect on insulin activation of skeletal muscle GS, the rate-limiting enzyme controlling muscle glucose storage.(ABSTRACT TRUNCATED AT 250 WORDS)     

Microstructural pattern of palatable food intake from weaning to adulthood in male and female OLETF rats.

Ontogenetic trajectories from weaning to adulthood and sex differences in feeding patterns were examined in the Otsuka Long-Evans Tokushima Fatty (OLETF) rat, an animal model of early onset overeating-induced obesity, and a natural cholecystokinin-1 receptor knockout. Overnight patterns of licking a palatable liquid diet (Ensure) were analyzed on Postnatal Days 22, 38, 60, and 90. Because different microstructure profiles may reflect alterations in the influence of positive and negative signals, we examined meal parameters to uncover developing mechanisms underlying eating behavior in this strain. OLETF rats displayed significantly greater caloric intake, larger meals (in number of licks), and more (within-meal) clusters of feeding (which were shorter in duration and contained fewer licks per cluster) than did Long-Evans Tokushima Ohtsuka (LETO) strain controls. OLETF rats also had significantly lower satiety ratios than LETO rats. Moreover, we identified sex differences in the age of emergence of microstructural patterns of obesity-related overeating, suggesting that systems other than cholecystokinin may be disrupted, possibly worsening the OLETF strain’s obesity phenotype. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Local and systemic tolerance to orally administered dinitrochlorobenzene is not broken by cholera toxin

OBJECTIVE: Withdrawal of testosterone prevents the development of hyperglycaemia in male Otsuka-Long-Evans-Tokushima Fatty (OLETF) rats, a model of non-insulin-dependent diabetes mellitus (NIDDM), but the exact mechanism has not been established. The present studies were undertaken to examine a possible role of testosterone in the development of obesity in young OLETF rats who have not shown marked hyperphagia. METHODS: Body weight, food intake and circulating concentrations of metabolic factors including immunoreactive leptin (IRL) were measured at five weeks of age in young male OLETF rats and their lean controls, Long-Evans-Tokushima-Otsuka (LETO) rats. At six weeks of age, both LETO and OLETF rats were bilaterally orchiectomized (Orchx) and half of each group implanted with a silastic tube containing testosterone. After a three week observation period, all animals were killed and circulating concentrations of metabolic factors and the ob gene expression in retroperitoneal white adipose tissues were measured. RESULTS: Body weight and 24h food intake were already increased in OLETF rats at five weeks of age. Serum testosterone concentrations were significantly lower in OLETF rats than in LETO rats. Expression of the ob gene was significantly decreased in the retroperitoneal white adipose tissue of OLETF rats, and their serum IRL concentrations were lower. Food intake and body weight gain for three weeks after the operation were significantly lower in the Orchx group of OLETF rats than in the sham-operated group. Hyperglycaemia, accompanied by hyperinsulinaemia, was attenuated by orchiectomy in OLETF rats. Circulating IRL concentrations were significantly higher in OLETF rats than in LETO rats and decreased by orchiectomy. Testosterone supplement reversed all of the changes caused by orchiectomy in OLETF rats. In contrast, the changes, which were observed after orchiectomy in OLETF rats, were not obvious in LETO rats. CONCLUSION: The present data indicate that testosterone plays a role in the development of obesity and NIDDM in young OLETF rats, but that changes of leptin production in white adipose tissue may not be important in the development of obesity in young OLETF rats.     

Mucinous cystadenocarcinoma of the lung

The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is an animal model for obese-type, non-insulin-dependent diabetes mellitus (NIDDM) in humans. The OLETF rat has poor capacity for pancreatic proliferation, which may be the critical pathogenetic event in NIDDM development. Our investigation was designed to identify quantitative trait loci (QTLs) responsible for poor pancreatic proliferation by examining compensatory proliferation of the pancreatic remnant after partial pancreatectomy and performing a genome-wide scan in an F2 intercross obtained by mating the OLETF and the Fischer-344 (F344) rats. We identified a highly significant QTL on rat Chromosome 14 with a maximum lod score of 16.7, which accounts for 55% of the total variance. The QTL co-localizes with the gene encoding cholecystokinin type A receptor (CCKAR) which is likely to mediate the trophic effect of cholecystokinin on pancreas and is defective in the OLETF rat.     

Tinnitus after head injury: evidence from otoacoustic emissions

The ability of portal vein insulin to control hepatic glucose production (HGP) is debated. The aim of the present study was to determine, therefore, if the liver can respond to a selective decrease in portal vein insulin. Isotopic ([3H]glucose) and arteriovenous difference methods were used to measure HGP in conscious overnight fasted dogs. A pancreatic clamp (somatostatin plus basal portal insulin and glucagon) was used to control the endocrine pancreas. A 40-min control period was followed by a 180-min test period. During the latter, the portal vein insulin level was selectively decreased while the arterial insulin level was not changed. This was accomplished by stopping the portal insulin infusion and giving insulin peripherally at half the basal portal rate (PID, n=5). In a control group (n=5), the portal insulin infusion was not changed and glucose was infused to match the hyperglycemia that occurred in the PID group. A selective decrease of 120 pmol/l in portal vein insulin was achieved (basal, 150+/-36 to last 30 min, 30+/-12 pmol/l) in the absence of a change in the arterial insulin level (basal, 30+/-3 to last 30 min, 36+/-4 pmol/l). Neither arterial nor portal insulin levels changed in the control group (30+/-6 and 126+/-30 pmol/l, respectively). In response to the selective decrease in portal vein insulin, net hepatic glucose output (NHGO) increased significantly, from 8+/-1 (basal) to 30+/-6 and 14+/-2 micromol x kg(-1) x min(-1) by 15 min and the last 30 min (P < 0.05) of the experimental period, respectively. Arterial plasma glucose increased from 5.9+/-0.2 (basal) to 10.5+/-0.4 micromol/l (last 30 min). Three-carbon gluconeogenic precursor uptake fell from 11.2+/-2.9 (basal) to 5.9+/-0.7 micromol x kg(-1) x min(-1) (last 30 min), and thus a change in gluconeogenesis could not account for any of the increase in NHGO. With matched hyperglycemia (basal, 5.5+/-0.3 to last 30 min, 10.5+/-0.8 micromol/l) but no change in insulin, NHGO decreased from 12+/-1 (basal) to 0 (-1+/-6 micromol x kg(-1) x min(-1), last 30 min, P < 0.05) and hepatic gluconeogenic precursor uptake did not change (basal, 8.0+/-1.7 to last 30 min, 8.9+/-2.2 micromol x kg[-1] x min[-1]). Thus, the liver responds rapidly to a selective decrease in portal vein insulin by markedly increasing HGP as a result of increased glycogenolysis. These studies indicate that after an overnight fast, basal HGP (glycogenolysis) is highly sensitive to the hepatic sinusoidal insulin level.     

The molecular markers of hemostatic activation on coronary artery disease

The male Otsuka Long-Evans Tokushima Fatty (OLETF) rat shows insulin resistance in skeletal muscle and visceral obesity. To obtain information on the mechanism of the insulin resistance in the diabetic rats, we examined the content of insulin-regulated glucose transporter (GLUT4) in skeletal muscles. The results indicate that the total content of the transporter is significantly decreased (P < 0.05) in muscles of the diabetic rats. Plasma membrane content of the GLUT4 protein in muscles of the diabetic rats was increased in the basal state as compared to control rats. Hyperinsulinemic clamps increased GLUT4 levels in the plasma membrane of control rats but failed to do so in the diabetic rats. The distribution of GLUT4 in OLETF rat is reminiscent of the characteristics of human non-insulin-dependent diabetes mellitus.     

Current trends and treatments in chronic obstructive pulmonary disease

Non-insulin-dependent diabetes mellitus (NIDDM) is a prototypical multifactorial disease. Genetic predisposition and obesity are major risk factors for NIDDM development and the interactions between these factors are likely to be important in the etiology of this disease. The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is one of the best animal models of NIDDM, since the OLETF rat develops NIDDM with mild obesity that is very similar to human NIDDM. Therefore, the OLETF rat is a powerful model for investigating the interaction between genetic susceptibility to NIDDM and obesity. In this study, our goal was to clarify the relationship between an individual NIDDM susceptibility locus and obesity in the OLETF using a molecular genetics approach. We identified four novel quantitative trait loci (QTLs) that contribute to the susceptibility to NIDDM, none of which shows significant linkage with body weight. However, Nidd1/of on chromosome 7 and Nidd2/of on chromosome 14 have an interaction with body weight. In contrast, one locus was mapped to chromosome 10 for body weight, but not to fasting or postprandial glucose levels. These data illustrate that NIDDM and body weight are under separate genetic control in the OLETF yet interact to yield the final disease phenotype in the two Nidd/of loci. In addition, body weight could be used in place of body mass index as an indicator of obesity in our experimental system of genetic study. This study will facilitate the understanding of the complex interaction between genetic susceptibility to NIDDM and obesity.     

Identification of a quantitative trait locus influencing plasma insulin levels after 70% pancreatectomy using the OLETF rat

The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is an animal model for obese-type non-insulin-dependent diabetes mellitus (NIDDM) in humans. The OLETF rat has poor capacity for proliferation of pancreatic beta-cells after partial pancreatectomy, which may be the critical pathogenetic event in NIDDM development. The poor pancreatic beta-cell proliferation in this model is characterized by reduction in beta-cell mass and decrease in insulin content in the remnant pancreas. Our investigation was designed to identify quantitative trait loci (QTLs) responsible for beta-cell mass and plasma insulin levels after partial pancreatectomy by performing a genome-wide scan in an F2 intercross obtained by mating the OLETF and the Fischer-344 (F344) rats. We have identified a suggestive QTL for the plasma insulin levels, near D20Mgh5 on rat chromosome 20, with a maximum lod score of 3.75 which accounts for 20% of the total variance, while no QTLs were detected for beta-cell mass. This chromosome 20 QTL, whose OLETF allele is associated with low plasma insulin levels through acting in an incompletely recessive manner, may affect insulin secretion itself rather than beta-cell proliferation.     

Assessment of ventricular diastolic function in AIDS patients from Congo: a Doppler echocardiographic study

The aim of this study was to evaluate the effect of transdermal clonidine on hemodynamic and metabolic parameters in patients who have elevated blood pressure and non-insulin-dependent diabetes mellitus (NIDDM). After a 2-week run in placebo period, 20 NIDDM patients who had diastolic blood pressure in the range of 90 to 105 mm Hg underwent a randomized, single blind, placebo controlled, cross-over study of 4 week treatment with clonidine (transdermal patch 2.5 mg/week) or placebo (inactive patch). Compared with placebo, clonidine significantly reduced systolic (153 +/- 6 v 163 +/- 8) and diastolic (88 +/- 2 v 98 +/- 3.5 mm Hg, P = .001) blood pressure, left ventricular mass (94 +/- 11 v 99 +/- 12 g/m2, P < .01) and fasting glucose levels. Total glucose disposal (glucose clamp) was 6.5 +/- 1.5 with placebo and 7.1 +/- 1.6 mg/kg/min with clonidine (P < .01). Oxidative glucose disposal (indirect calorimetry) was also greater after clonidine. Plasma glucose, insulin, and C-peptide responses following oral glucose (75 g) were significantly lower after clonidine, as well as urinary albumin excretion. Transdermal clonidine is effective in reducing blood pressure in hypertensive NIDDM patients and is well tolerated. It may be useful to reduce the cardiovascular impact of hypertension in diabetes mellitus.     

Acute effects of intraperitoneal versus subcutaneous insulin delivery on glucose homeostasis in patients with NIDDM. Veterans Affairs Implantable Insulin Pump Study Group

OBJECTIVE: The objective of this study is to compare the effect of intraperitoneal versus subcutaneous insulin injection on hepatic glucose production (HGP) and systemic glucose utilization (Rd) in patients with NIDDM. RESEARCH DESIGN AND METHODS: Eight male volunteers with NIDDM, each of whom had a programmable-rate, implantable insulin pump, were given an injection of insulin (0.15 units/kg body wt) by intraperitoneal or subcutaneous injection on separate days in randomized order. Plasma glucose was kept constant for 5 h using the glucose clamp technique, and HGP and Rd were measured using isotope dilution. RESULTS: Intraperitoneal insulin injection resulted in higher and earlier peak systemic insulin concentrations (1,469 +/- 245 vs. 454 +/- 48 pmol/l, P < 0.01). Glucose Rd doubled within 1 h after intraperitoneal injection and was greater than that attained with subcutaneous injection (3.91 +/- 0.27 vs. 2.60 +/- 0.19 mg.kg-1.min-1, P < 0.01). Intraperitoneal and subcutaneous injections suppressed HGP and plasma free fatty acid to a similar extent during the first 3 h, effects tht persisted through 5 h after subcutaneous insulin injection but waned 3-4 h after intraperitoneal injection. CONCLUSIONS: In patients with NIDDM, intraperitoneal insulin injection achieves more rapid and greater peak values for stimulation of glucose Rd than subcutaneous insulin injection. With regard to HGP and lipolysis, intraperitoneal and subcutaneous injections achieve similar initial suppression but this is maintained for a more limited duration with intraperitoneal as compared with subcutaneous injection. These differences in insulin action seem directly related to the rapidity of insulin absorption with intraperitoneal injection.