Secretin-stimulated amylase release into blood is impaired in type 1 diabetes mellitus.

BACKGROUND: Prior studies have provided data indicating the existence of close interaction between pancreatic endocrine and exocrine function, but few clinical studies have explored this relationship in depth. We compared pancreatic exocrine function non-endoscopically in individuals with type 1 diabetes mellitus, type 2 diabetes mellitus, and normal glucose tolerant controls, to assess the importance of local insulin production to pancreatic exocrine function. METHODS: The plasma amylase response to intravenous secretin challenge was measured in men with type 1 diabetes mellitus (n = 5), type 2 diabetes mellitus (n = 5), and normal controls (n = 3). Patients were characterized by their urinary excretion of c-peptide and albumin over 24 hours. Autonomic neuropathy was non-invasively assessed by measuring RR variation (with deep respiration on EKG). RESULTS: Post-secretin amylase responses were generally absent with low baseline levels in the patients with type 1 diabetes mellitus. Patients with type 2 diabetes mellitus and controls showed similar twofold increases over baseline after secretin administration. When normal glucose tolerant and type 2 diabetic patients were pooled and compared against type 1 diabetes mellitus, the differences were statistically significant (p < 0.03). Total amylase response correlated positively, but weakly, with 24 h urinary C-peptide excretion (r = 0.507; p < 0.112), but not with glycemic control, duration of diabetes, or indices of autonomic neuropathy. CONCLUSIONS: Patients with type 1 diabetes mellitus, but not type 2 diabetes mellitus, have reduced pancreatic exocrine function, supporting the concept of a local paracrine effect of insulin on pancreatic acinar cells. Further studies are needed to determine the clinical impact of this deficiency, and whether such patients with type 1 diabetes mellitus would benefit from therapy with pancreatic enzyme supplementation.

Smokeless nicotine administration does not result in hypertension or a deterioration in glucose tolerance or insulin sensitivity in juvenile rats.

We have previously reported that smokeless nicotine resulted in hypertension, but not a deterioration in glucose tolerance or insulin action in young adult male rats. To evaluate the effect of nicotine in juvenile animals, we studied 6-week-old male and female Sprague-Dawley rats and implanted 25-mg nicotine (N) or placebo (P) pellets. Weight gain was controlled by chow restriction in all 4 groups of rats. Males were generally heavier than females, both before and after N or P placement; there was no difference in weight between N and P groups for each sex. Systolic blood pressure, measured noninvasively, increased modestly, but not significantly, after N placement in both male and female rats. Glucose tolerance and insulin action were assessed by an oral glucose tolerance test (OGTT). Areas under the curve (AUC) were calculated for glucose (AUC(GLU)), insulin (AUC(INS)), and free fatty acids (FFA) (AUC(FFA)). Insulin action was calculated by several indices, which have correlated with more invasive studies. None of these metabolic parameters were significantly impacted by nicotine treatment, consistent with our observations in adult male rats. In summary, smokeless nicotine at this dose has no significant effect on observed cardiovascular or metabolic parameters in sexually immature male and female rats.

Effects of ovariectomy on indices of insulin resistance, hypertension, and cardiac energy metabolism in middle-aged spontaneously hypertensive rats (SHR).

Insulin resistance is a risk factor for coronary heart disease. The protection of young women from coronary events is sharply reduced with menopause. To assess the impact of menopause on glucose tolerance, insulin resistance, body weight gain, heart size, and cardiac energy metabolism, we studied 28-week-old female SHR and Wistar-Kyoto (WKY) rats, who were either ovariectomized (SHR(OVX) and WKY(OVX)) or sham-operated (SHR(SHAM) and WKY(SHAM)). Animals underwent blood-pressure measurement and an oral glucose tolerance test (OGTT). Hearts were weighed and assayed for metabolic enzyme activities. Female SHR were 33 % lighter and hypertensive (+ 36 mmHg), with 33 % larger hearts (when corrected for body weight differences) compared to WKY. Although ovariectomized animals of both strains were heavier overall than their sham-operated counterparts, when heart weights were corrected for body weight, both OVX strains had lighter hearts than both SHAM strains. Glucose and insulin responses during OGTT were similar between the four groups; however, free fatty acid (FFA) responses were approximately 50 % greater in SHR than WKY, although less in SHR(OVX) than SHR(SHAM). WKY(OVX) demonstrated 8 % lower ventricular hexokinase activity than WKY(SHAM), which may reflect reduced cardiac glucose utilization. We also noted 16 % higher citrate synthase activity in WKY hearts. In conclusion, the insulin resistance characteristic of younger SHR is blunted in middle-aged female rats, although FFA responses remain elevated. Ovariectomy did not alter in vivo glucose tolerance in this group; however, sex hormones may be important in maintaining normal heart size and the potential for cardiac glucose metabolism.

Voluntary running improves glucose tolerance and insulin resistance in female spontaneously hypertensive rats.

We evaluated the effects of voluntary exercise training on glucose metabolism and measures of insulin sensitivity in female spontaneously hypertensive rats (SHR). Age-matched Wistar-Kyoto rats (WKY) were used as normotensive controls. Exercising SHR were housed in running wheels for 8 weeks (SHRx8) or 16 weeks (SHRx16). At 22 weeks of age, we measured systolic blood pressure, performed oral glucose tolerance tests, and determined hexokinase activity and glucose transporter (GLUT) 4 content in skeletal muscle to assess intracellular glucose metabolism. Blood pressure was lower in WKY (139+/-12 mm Hg) than untrained SHR (216+/-13 mm Hg). Exercise training caused a reduction in blood pressure (-18 mm Hg) for SHRx8. After a brief (5-h) fast, serum glucose was lower in SHR that exercised compared with sedentary SHR, whereas insulin concentrations were identical between all SHR and WKY. Corresponding free fatty acids (FFA) were twofold higher in SHR than in WKY. In response to glucose, SHR demonstrated higher glucose and FFA responses, with exercise decreasing the glucose values in a dose-dependent manner. Although the insulin response was comparable in all groups, the glucose-to-insulin ratio was higher in SHR, indicating a relative insulin resistance for both glucose disposal and suppression of free fatty acids. Hexokinase activity and GLUT4 content were elevated 1.4- and 2.8-fold, respectively, in plantaris muscle of SHRx16, suggesting an improvement in the capacity for glucose transport and phosphorylation with exercise. These results provide evidence that voluntary running in female SHR lowers blood pressure and selectively increases glucose uptake and insulin action, but not suppression of FFA.

Renal effects of angiotensin-converting enzyme inhibitors that result in cost savings and improved patient outcomes.

BACKGROUND: In some patients with renal disease, use of angiotensin-converting enzyme (ACE) inhibitors is thought to improve renal function, whereas in others their use leads to worsening. Many questions remain about the categories of patients that benefit from ACE inhibitor use. OBJECTIVE: To clarify the use of ACE inhibitors in patients with renal disease. STUDY DESIGN: A literature review focusing on various renal diseases, ACE inhibitors, and criteria of cost effectiveness was performed. RESULTS: Almost 100 clinical studies were reviewed. Treatment with ACE inhibitors seems to have beneficial effects in type 1 and type 2 diabetes mellitus with nephropathy, AIDS nephropathy, and other nondiabetic renal diseases. Use of these agents in these diseases decreases the progression of renal disease and the need for dialysis, resulting in potential cost savings and improved quality of life. Data supporting goal blood pressures indicate the need to aggressively decrease this risk factor. Use of ACE inhibitors is hazardous in bilateral renal artery stenosis, particularly with volume depletion, but may be valuable in patients with unilateral stenosis. In African Americans, ACE inhibitor treatment is likely to be of benefit, although required doses may be higher than for whites, and caution must be exercised in certain situations. The potential efficacy of angiotensin receptor blockers and other new drugs that affect the renin-angiotensin system is assessed. CONCLUSIONS: Use of ACE inhibitors has benefit in renal disease states characterized by increased glomerular perfusion pressure, their use in other renal disease states, particularly those characterized by reduced glomerular perfusion pressure, may be risky. The benefits conferred by ACE inhibitor therapy are so dramatic in terms of cost savings and improved quality of life that their use in certain clinical situations should be strongly encouraged in managed care and other practice settings.

Pioglitazone attenuates basal and postprandial insulin concentrations and blood pressure in the spontaneously hypertensive rat.

Subjects with hypertension are hyperinsulinemic and resistant to insulin-stimulated glucose uptake. A similar paradigm is found in the spontaneously hypertensive rat (SHR). These findings suggest the possibility that insulin resistance and hyperinsulinemia may play an important role in blood pressure regulation. Pioglitazone, a thiazolidinedione derivative, sensitizes target tissues to insulin and decreases hyperglycemia and hyperinsulinemia in various insulin-resistant animals. The purpose of this study was to assess the influence of pioglitazone administration on pre- and postprandial glucose and insulin concentrations and determine whether changes in beta-cell secretion resulted in any change in blood pressure measurements. Twelve SHR were fed custom diets ad libitum, six with and six without pioglitazone (20 mg/kg chow). Fasting and postprandial glucose levels were unaltered by pioglitazone treatment. Fasting insulin concentrations were similar at week 1, but were significantly lower (P < .01) in the pioglitazone group at weeks 3 (1.89 +/- 0.3 v7.94 +/- 1.5 ng/mL) and 4 (4.5 +/- 1.4 v9.1 +/- 0.7 ng/mL), compared with the control group. Pioglitazone also significantly (P < .01) lowered postprandial insulin concentrations after an oral glucose challenge. Systolic, mean, and diastolic blood pressures were significantly lower (P < .01), 177 +/- 3 v190 +/- 4.7 mm Hg, 162 +/- 2.1 v175 +/- 5.9 mm Hg, and 156 +/-2.1 v168 +/- 6.2 mm Hg, respectively, in the animals receiving pioglitazone versus the control group. Heart rate, body weight, serum cholesterol, and triglyceride levels were comparable between the two groups. In conclusion, pioglitazone significantly decreased fasting and postprandial insulin concentrations and effectively lowered blood pressure in the SHR.

Metabolic, hemodynamic, and cardiac effects of captopril in young, spontaneously hypertensive rats.

Spontaneously hypertensive rats (SHR) demonstrate elevated blood pressure, cardiac hypertrophy, glucose intolerance, and insulin resistance compared with age-matched Wistar-Kyoto rats (WKY). We investigated concurrent effects of captopril on blood pressure, cardiac mass, myocardial enzyme activities, glucose tolerance, and insulin action in young male SHR. At 10 weeks of age, SHR were randomized into two groups, one receiving distilled water, the other a captopril solution (50 mg/kg body weight/day). We also examined age-matched WKY receiving distilled water. Blood pressure was measured by tail-cuff during the 4-week treatment period and oral glucose tolerance was tested at the end of treatment. Hearts were weighed and ventricular tissue was assayed for activities of 3-hydroxyacyl-CoA dehydrogenase, citrate synthase, and hexokinase. Growth rates were similar between captopril-treated and control SHR, but less than those of WKY. Captopril reduced blood pressure (134 +/- 8 v 177 +/- 8 mm Hg, P < .05) and left ventricular mass (-18%, P < .05) in SHR. Cardiac enzyme activities also changed with captopril treatment, reflecting an increased capacity for beta-oxidation of fatty acids and reduced potential for glucose phosphorylation in the left ventricle of SHR. Serum concentrations of glucose, insulin, and free fatty acids after a brief fast and in response to oral glucose were not different after captopril treatment, suggesting no improvement in insulin action or glucose tolerance. In summary, treatment of young male SHR with captopril reduces blood pressure and cardiac mass, and promotes a small but significant increase in cardiac capacity for oxidation of fatty acids and reduction of glucose phosphorylation. In contrast, metabolic effects of captopril on oral glucose tolerance and insulin action were not evident.

Safety and efficacy of metformin in a restricted formulary.

OBJECTIVE: To assess the efficacy and safety of metformin (MET) in the Veterans' Administration Northern California Health Care System during the period from June 1995 through April 1996 when its use required approval by Endocrinology. STUDY DESIGN: A retrospective review of patient charts and computerized pharmacy and laboratory records. Patients served as their own historical controls. PATIENTS AND METHODS: Patients receiving MET (n = 251) were identified from the pharmacy database. On-line laboratory data, including the intermediate outcome variable HbA1c, were retrieved by computer for the interval 4 months prior to the initial prescription to May 1996. Clinical data including weight and blood pressure were obtained from chart review. RESULTS: Of 228 patients whose charts were available for review, 29 reported side effects, and 12 discontinued use due to these side effects. No patients were identified with lactic acidosis. Both baseline and treatment data on HbA1c were available on 164 patients. Mean HbA1c (%) data (unpaired), expressed as mean +/- SE, were as follows: between 4 months pretreatment and 1 month pretreatment, 9.41 +/- 0.19 (n = 103 tests); between 1 month pretreatment and baseline, 9.41 +/- 0.19 (n = 110 tests); 3 months of treatment, 8.79 +/- 0.16 (n = 157 tests, P < 0.05); 6 months of treatment, 8.30 +/- 0.17 (n = 79 tests, P < 0.0001); 9 months of treatment, 8.72 +/- 0.24 (n = 70 tests, P < 0.05), compared to pretreatment values. Similar analysis of unpaired weight and blood pressure data in 152 patients did not reveal any reduction in these clinical parameters over this treatment period. Serum lipids were unchanged on treatment (by paired analysis), but the number of tests was limited. CONCLUSION: In this setting, MET provided sustained beneficial effects on glycemic control and was well tolerated. Any effects on weight, blood pressure, and serum lipids were not demonstrable in this analysis. We conclude that MET can substantially improve outcome of diabetes care.

Insulin resistance and hypertension: in vivo and in vitro insulin action in skeletal muscle in spontaneously hypertensive and Wistar-Kyoto rats.

The spontaneously hypertensive rat (SHR) has been reported to be insulin-resistant compared to the Wistar-Kyoto (WKY) parent strain. Because insulin resistance usually reflects a defect in insulin action at the muscle, we compared the ability of muscle (gastrocnemius) to store glycogen in response to a standard oral glucose challenge in SHR to that in WKY. As a control, we examined the glycogen response in liver in these two rat strains. However, in vivo insulin action reflects both tissue responsiveness as well as substrate and hormone availability at the tissue level. To evaluate tissue responsiveness in vitro, we examined two parameters of insulin action: 1) muscle glycogen synthesis using 3H-glucose and 2) muscle glucose transport using 3H-2-deoxy-glucose (3H-2-DG). Thirteen-week-old male rats were studied after overnight fasting. Liver glycogen increased similarly (mean +/- SD shown) in response to glucose gavage feeding in both groups [WKY: 15.2 +/- 6.9 to 50.6 +/- 17.9 micromol/g wet wt (P < .05); SHR: 30 +/- 18 to 63.5 +/- 33.3 micromol/g wet wt (P < .01)]. On the other hand, muscle glycogen increased in WKY [13.7 +/- 2 to 17.8 +/- 1.1 micromol/g wet wt (P < .05)], whereas in SHR there was no significant change [14.6 +/- 2.1 to 15.3 +/- 2.99 micromol/g wet wt P = NS)]. Results of in vitro studies demonstrated that glycogen synthesis increased from 377 +/- 120 to 439 +/- 175 disintegrations per minute (dpm) 3H-glucose/mg extensor digitorum longus (EDL) in WKY when insulin increased from 0 to 1000 microU/mL (P < .05), whereas SHR the increase was from 289 +/- 89 to 565 +/- 187 (P < .05). Glucose transport increased from 483 +/- 74 to 785 +/- 369 dpm 3H-2-DG/mg EDL in WKY when insulin was increased from 0 to 500 microU/mL (P < .03), whereas in SHR the increase was 516 +/- 61 to 997 +/- 347 (P < .001). In summary, liver glycogen increased in response to feeding in a similar manner in both WKY and SHR, whereas muscle glycogen increased only in WKY. We conclude that in vivo muscle glycogen accumulation may represent an index of insulin resistance in SHR. In contrast, in vitro data suggest that both muscle glucose transport and glycogen synthesis were stimulated to a comparable degree by insulin in EDL strips from WKY and SHR; there were no significant differences between WKY and SHR. Further studies are needed to clarify these differences.

Smokeless nicotine administration is associated with hypertension but not with a deterioration in glucose tolerance in rats.

Cigarette smoking is a major risk factor for coronary heart disease. To further investigate the relationship of nicotine with other cardiac risk factors, we studied the impact of nicotine on blood pressure and glucose tolerance. Adult male Sprague-Dawley rats were randomly assigned to receive nicotine or placebo pellets implanted subcutaneously. Weight gain was controlled by pair-feeding, and was not significantly different between nicotine- and placebo-treated animals. Blood pressure (in mm Hg) increased throughout a 3-week treatment period in nicotine-treated animals and was significantly higher [P < .05 by two-way ANOVA] than in placebo-treated rats. Blood pressure returned to normal within 1 week following exhaustion of the pellets. Oral glucose tolerance tests performed 2.5 weeks after pellet placement showed similar glucose, insulin, and free fatty acid (FFA) profiles by two-way ANOVA. In summary, smokeless nicotine exposure leads to sustained but reversible hypertension without deterioration in glucose tolerance or insulin action when weight gain is controlled. We conclude that in rats smokeless nicotine adversely affects the coronary risk profile by increasing blood pressure.

Postmarketing analysis of lovastatin use in the VA Northern California System of Clinics: a retrospective, computer-based study.

Prevention of coronary heart disease is a major public health goal. The efficacy of lovastatin in lowering serum cholesterol has been proven in research studies, but its efficacy in practice is unclear. To evaluate our practice patterns and outcome in the Veterans Administration Northern California System of Clinics, we reviewed computer-based records of 203 unselected patients issued lovastatin; 193 (95%) were men, and the average patient age was 66 +/- 9 years. The average daily dose of lovastatin was 24 +/- 10 mg, and average duration of therapy was 22 +/- 11 months. Only 72 patients (35%) were instructed on the prescription to take their medication with the evening meal, and only 59 patients (29%) had seen a dietitian during the observed (1 to 3 years) treatment period. Nevertheless, among the 124 patients with pretreatment lipid data, total serum cholesterol decreased by 18% from 271 +/- 45 to 221 +/- 41 mg/dL (P < 0.001), and low density lipoprotein (LDL)-cholesterol decreased by 23% from 185 +/- 43 to 143 +/- 37 (P < 0.001) mg/dL. High density lipoprotein-cholesterol and triglycerides were unchanged. Of the 168 patients with LDL-cholesterol data during the treatment period, only 74 (44%) achieved an LDL-cholesterol level of less than 130 mg/dL, the minimum goal for a population of older males with a high incidence of other cardiac risk factors. Safety surveillance with liver function testing was performed at least once in 192 patients (95%), but with creatine phosphokinase (CPK) testing in only 123 patients (61%) during the survey period. Enzyme elevations were minor, but occurred at least intermittently in approximately one quarter of patients. Only 5.7% of patients on lovastatin manifested an increase in transaminases on therapy. Due to incomplete baseline data, it is unclear how many patients had elevated CPK as a result of lovastatin. We conclude that: (1) lovastatin is effective in lowering total and LDL-cholesterol in practice, but is often used in dosage insufficient to lower LDL-cholesterol to goal levels; (2) patients are not being adequately educated on dosing schedules; (3) toxicity may be underestimated by infrequent and inconsistent surveillance; and (4) nonpharmacologic therapy is underutilized.

Oral administration of the nitric oxide biosynthesis inhibitor, N-nitro-L-arginine methyl ester (L-NAME), causes hypertension, but not glucose intolerance or insulin resistance, in rats.

While essential hypertension may be characterized by insulin resistance, it is unclear which defect is primary. We therefore compared normotensive Sprague-Dawley male rats who drank N-nitro-L-arginine methyl ester (L-NAME, 1 mg/mL in distilled water), with control rats who drank distilled water. Blood pressure was measured noninvasively, weight was controlled by dietary restriction, and glucose tolerance was assessed via oral glucose tolerance tests (OGTT). Blood pressure rose by the second day of L-NAME treatment, and remained elevated throughout the study, in contrast to the rats drinking water (P < .001). Weight rose similarly in both groups. OGTT were performed after 2 weeks of L-NAME. Serum glucose and insulin responses, assessed by two-way ANOVA, were similar in the two groups (P = NS). In summary, L-NAME administration resulted in hypertension, but not a deterioration in glucose tolerance in diet-controlled Sprague-Dawley rats. We conclude that the insulin resistance of some hypertensive states is not the result of hypertension per se, or increased vasoconstriction, such as might result from inhibition of endogenous nitric oxide synthesis, but rather indicates a fundamental metabolic disorder.

Glucose tolerance and blood pressure are improved in the spontaneously hypertensive rat by ethyl-2-(6-(4-chlorophenoxy)-hexyl)oxirane-2-carboxylate (etomoxir), an inhibitor of fatty acid oxidation.

We have demonstrated that glucose tolerance and insulin action are impaired in the spontaneously hypertensive rat (SHR), and that free fatty acids are elevated. Etomoxir, an inhibitor of fatty acid oxidation, has been shown to improve hyperglycemia in diabetic rats. We therefore performed oral glucose tolerance tests in SHR to assess glucose tolerance and insulin action in response to etomoxir. Because of the proposed relation between insulin action and hypertension, we examined the effect of etomoxir on blood pressure. Thirteen-week-old male SHR were randomized into two groups. Food was withdrawn at 8 AM and at 11 AM, animals received etomoxir (50 mg/kg) or control vehicle by gavage. Oral glucose tolerance tests were started at 1 PM. In other studies, 21-week-old male SHR were randomized into two groups. Animals were treated by gavage with etomoxir (50 mg/kg) or control vehicle, and blood pressure was measured noninvasively before and after treatment. Two weeks later, these experiments were repeated, but the treatments were reversed. In etomoxir-treated rats, the glucose response was significantly lower, whereas the insulin response was not significantly different. The combination of lowered glucose response, in the face of an unchanged insulin response, suggests an improvement in insulin action. However, fasting free fatty acids were higher, as was the free fatty acid response following etomoxir treatment. There was a dramatic decrease in blood pressure following etomoxir, with significant differences at 1.25, 3, 4.5, and 21 h after dosing. In summary, etomoxir treatment improved glucose tolerance and insulin action in SHR, whereas free fatty acid values were higher.(ABSTRACT TRUNCATED AT 250 WORDS)

Impaired insulin clearance in essential hypertension.

The purpose of this study was to examine whether impaired insulin clearance contributes to the hyperinsulinemia observed in humans with essential hypertension. Previous studies from our group and others have demonstrated that individuals with essential hypertension are resistant to the glucoregulatory effect of insulin. Animal models have confirmed this finding and have suggested that hypertensive animals have impaired insulin clearance that might contribute to the observed hyperinsulinemia. The metabolic clearance rate of insulin (MCRins) was calculated during a constant infusion of glucose (320 mg/m2/min) and insulin (25 mU/m2/min), under conditions where endogenous insulin secretion was suppressed by somatostatin infusion (250 micrograms/h) for four groups of age sex and weight-matched patients: normotensive volunteers, untreated hypertensives, hypertensives treated with diuretics and hypertensives treated with diuretics and beta-blockers. MCRins was impaired in all three groups of hypertensive subjects compared with normal BP volunteers, particularly in untreated hypertensives and those treated with combination diuretic and beta-blocker therapy: normal = 0.6 +/- 0.1; untreated = 0.47 +/- 0.2; diuretic = 0.51 +/- 0.1; combination = 0.39 +/- 0.2 (in ml/min, expressed as mean +/- SD). The effectiveness of somatostatin for islet suppression was confirmed by demonstrating markedly diminished C-peptide concentrations in untreated hypertensives and normal volunteers. Thus, our previous finding of elevated steady-state plasma insulin during insulin suppression testing in hypertensives seems not to be the result of impaired pancreatic response to somatostatin but, rather, there seems to be a defect in insulin clearance in these individuals not unlike that demonstrated in animal models of hypertension and insulin resistance. The nature of this defect remains to be elucidated.

Insulin resistance and hypertension: glucose intolerance, hyperinsulinemia, and elevated free fatty acids in the lean spontaneously hypertensive rat.

Recent evidence suggests that insulin resistance may be a feature of essential hypertension in humans. However, there is some dispute over suitable animal models. To clarify these issues, we performed oral glucose tolerance tests in lean spontaneously hypertensive rats (SHR) as well as in age-matched normotensive rats from the parent Wistar-Kyoto (WKY) strain. In response to feeding, SHR were significantly hyperglycemic and hyperinsulinemic compared to WKY. In addition, free fatty acids were significantly higher throughout the oral glucose tolerance tests in SHR compared to WKY. Furthermore, this apparent insulin resistance occurred despite the fact that SHR were significantly leaner than age-matched WKY. When growth curves were compared for the two strains fed ad libitum, both SHR and WKY gained weight appropriately during the period of observation, although SHR were significantly lighter throughout. It is concluded that SHR express insulin resistance in terms of glucose and fatty acid metabolism, and therefore are a suitable model for insulin resistance and essential hypertension in non-obese humans. Further studies are needed to clarify the pathophysiologic defects leading to insulin resistance in these animals.

Microalbuminuria in a normotensive insulin-treated diabetic population.

Thirty-five insulin-treated diabetics without overt proteinuria or hypertension, and taking no antihypertensive medications were screened at three clinical centers for the presence of microalbuminuria. In addition to the presence of albuminuria, patients were evaluated for duration and type of diabetes, retinopathy, blood pressure, and degree of diabetic control. In these patients, it was possible to examine the degree of microalbuminuria as a function of systolic and diastolic blood pressures, age and sex of the patient, site of recruitment, duration of diabetes, and glycemic control. On multivariate statistical analysis, systolic blood pressure was the only factor that contributed to microalbuminuria. An additional 37 patients had urinary albumin excretion measured, although biochemical and clinical characteristics were incompletely determined. Blood pressures were documented to be normal in 23 of these individuals, while the other fourteen were normal by history. The range of urinary albumin excretion was comparable in the patients with complete data bases and those without. Overall, 22.2% of the normotensive insulin-treated patients screened had microalbuminuria, 5.5% had gross albuminuria, while 72.2% had normal urinary albumin excretion. We agree with previous reports that microalbuminuria is relatively uncommon in the normotensive diabetic population, but further conclude that even in the context of "normal" blood pressure, systolic blood pressure should be carefully observed in diabetic patients. It is possible that these individuals should be considered for more aggressive monitoring programs, e.g., ambulatory blood pressure recording.