Carlos Arauz-Pacheco

Lipoprotein (a) Levels in Diabetes Mellitus: Relationship to Metabolic Control

OBJECTIVE To determine the influence of diabetes control on serum lipoprotein (a) concentrations. SETTING Diabetes clinic of a large metropolitan public hospital, with primary- and secondary-care patients. DESIGN A cross-sectional study. Comparisons of lipoprotein (a) concentrations were made between a normal control group, a group of diabetic patients with glycated hemoglobin (HbA1c) less than 8.0%, and a group of diabetic patients with HbA1c of 8.0% or higher. PATIENTS Ninety-five normal controls and 93 diabetic subjects (49 with insulin-dependent diabetes mellitus and 44 with noninsulin-dependent diabetes mellitus). RESULTS Sixty diabetic subjects with HbA1c levels of 8.0% or higher had higher (25 mg/dL) median levels of lipoprotein (a) when compared with either 93 normal controls (8.8 mg/dL) or 33 diabetic patients with HbA1c less than 8.0% (7.5 mg/dL) (P = 0.008 and P = 0.012, respectively). A similar pattern of distribution of lipoprotein (a) levels according to degree of metabolic control was seen in patients with insulin-dependent diabetes mellitus and noninsulin-dependent diabetes mellitus. No difference in the lipoprotein (a) distribution was noted between diabetic men and women. No correlation was observed between lipoprotein (a) levels and total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels. CONCLUSION Lipoprotein (a) levels are elevated in poorly controlled diabetic patients. Increased levels of lipoprotein (a) may be a contributing factor to the high risk for atherosclerosis observed in diabetic patients.

A double blind comparison of the effects of amlodipine and enalapril on insulin sensitivity in hypertensive patients.

This study compares the effects of a calcium channel blocker (amlodipine) and an angiotensin converting enzyme inhibitor (enalapril) on in vivo insulin sensitivity in patients with essential hypertension. Forty-six patients with mild and moderate hypertension were studied. After a 2-week single-blind placebo phase, they were randomly assigned to double-blind therapy with either amlodipine (2.5 to 10 mg/day) or enalapril (5 to 40 mg/day) for 16 weeks. Both groups were comparable in terms of demographic characteristics, degree of obesity, metabolic parameters, and arterial blood pressure. Insulin sensitivity was measured at baseline and at week 16 during the active phase using euglycemic hyperinsulinemic clamps. Arterial blood pressure decreased similarly in both groups. Whole body glucose uptake (M-value) increased with amlodipine from 3.63 +/- 0.32 (mean +/- SEM) to 3.97 +/- 0.31 mg/kg/min (P = .02). A similar tendency was observed with enalapril: from 3.59 +/- 0.32 to 3.94 +/- 0.30 mg/kg/min (P = .09). A trend to lower steady-state insulin level during the second clamp (compared to baseline) was observed in both groups. The clamp-derived insulin sensitivity index (that corrects for steady-state insulin levels and glucose levels during the clamp) increased similarly in both groups: from 1.15 +/- 0.11 to 1.39 +/- 0.13 with amlodipine (P = .03) and from 1.25 +/- 0.13 to 1.49 +/- 0.16 with enalapril (P = .01). LDL cholesterol decreased with amlodipine (mean change, -11.3 mg/dL, P = .004). Amlodipine and enalapril were associated with increments in insulin sensitivity. Amlodipine provided an additional benefit with decreased low density lipoprotein cholesterol levels.

Essential Hypertension Is Associated With Decreased Insulin Clearance and Insulin Resistance

Essential hypertension is associated with multiple metabolic abnormalities, among them, hyperinsulinemia. This hyperinsulinemia is attributed to the presence of decreased insulin sensitivity (insulin resistance) with consequent compensatory insulin secretion. We tested the hypothesis that decreased insulin clearance is present in hypertensive subjects and contributes to hyperinsulinemia independently of the degree of insulin resistance. Seventy-five subjects were studied (48 hypertensive and 27 normotensive). Both groups were comparable in terms of age, body fat content, waist-to-hip ratio, and sex distribution. A primed continuous insulin infusion at 40 mU/m2 per minute was performed. Glucose was maintained at baseline levels with the euglycemic clamp technique. Hypertensive subjects were characterized by decreased insulin sensitivity (insulin-mediated glucose uptake: 5.14 +/- 0.28 versus 7.26 +/- 0.61 mg glucose/kg fat-free mass per minute, hypertensive versus normotensive, P = .002), increased insulin levels during the insulin infusions (804 +/- 36 versus 510 +/- 38 pmol/L, hypertensive versus normotensive, P < .001), and decreased insulin metabolic clearance rate (328 +/- 15 versus 521 +/- 30 mL/min per meter squared, hypertensive versus normotensive, P < .001). In an ANCOVA (including sex, degree of obesity, waist-to-hip ratio, and insulin sensitivity as covariates) the differences in insulin metabolic clearance rate between normotensive and hypertensive subjects remained highly significant (P < .001). Insulin metabolic clearance rate was significantly associated with fasting insulin levels. We conclude that essential hypertension is independently associated with decreased insulin metabolic clearance rate in addition to insulin resistance. A low insulin metabolic clearance rate may be a contributory factor to the hyperinsulinemia observed in essential hypertension.

Hypoglycemia induced by angiotensin-converting enzyme inhibitors in patients with non-insulin-dependent diabetes receiving sulfonylurea therapy

C aptopril and enalapril have become popular medications for use in the treatment of essential hypertension and hypertension associated with diabetes mellitus. They are effective antihypertensive medications either when used alone or in combination with other agents [1]. Their use has been proven to be safe with few side effects [2] and they have been suggested as excellent choices of medication for use in the hypertensive diabetic patient [3,4]. In addition, they have been shown to reduce albumin excretion [5-7] and improve insulin sensitivity [8]. This latter effect, although potentially beneficial by reducing hyperinsulinemia, thought to be a risk factor for the development of atherosclerosis, could also predispose to the development of hypoglycemia in patients receiving hypoglycemic therapy. We report two patients with stable noninsulin-dependent diabetes in whom hypoglycemic episodes occurred almost immediately after the initiation of angiotensin-converting enzyme (ACE) inhibitor therapy for hypertension.

The effect of the aldose reductase inhibitor, ponalrestat, on the progression of diabetic retinopathy

The objective of this study was to evaluate the effects of ponalrestat, an aldose reductase inhibitor, on the progression of diabetic retinopathy. In this study, 62 patients with diabetes mellitus underwent a double-masked placebo-controlled clinical trial comparing the effect of ponalrestat 600 mg per day with a placebo on the progression of diabetic retinopathy. Both groups were comparable in terms of age, gender distribution, diabetes duration, metabolic control, and presence and severity of diabetic retinopathy. Seven-field stereo fundus photographs were performed at 0 (baseline), 12, and 18 months; 49 patients completed the study (26 in the ponalrestat group and 23 in the placebo group). In both treatment groups, a significant progression of diabetic retinopathy as evaluated by the Early Treatment Diabetic Retinopathy Study classification was observed (Wilcoxon Rank-Sum Test, p less than 0.05). No difference was observed in the progression of retinopathy between the two treatment groups (p = 0.96). The number of microaneurysms increased in the two study groups (from 5.6 +/- 1.2 to 10.5 +/- 1.3 in the placebo group and from 10.3 +/- 1.4 to 12.7 +/- 1.4 in the ponalrestat group); however, the increase was statistically significant only in the placebo group (p less than 0.05). When the increase in the number of microaneurysms was evaluated by change of category of microaneurysm count, no significant difference was observed. We conclude that ponalrestat at a dose of 600 mg per day has no clinically significant effect on the progression of diabetic retinopathy.

Relationship between insulin sensitivity, hyperinsulinemia, and insulin-mediated sympathetic activation in normotensive and hypertensive subjects

The adrenergic response to high physiological hyperinsulinemia was studied in 39 hypertensive subjects (28 men and 11 women) and 25 normal volunteers (15 men and 10 women), using the euglycemic clamp technique. Control studies using 0.45% saline infusions (sham studies) were also performed. Before and during the clamp procedure, plasma norepinephrine (NE) and epinephrine (E) were measured using a high performance liquid chromatographic method (HPLC). The association between the increment in NE and E levels and insulin sensitivity, steady-state insulin level during the clamps, waist to hip ratio (WHR), baseline NE levels and gender was studied. NE levels increased during the hyperinsulinemic period (mean increase 46 +/- 6 pmol P < .001 upsilon baseline and P < .01 upsilon sham studies). E levels did not differ between the insulin clamps and the sham studies. Insulin sensitivity was not significantly associated with the increment in NE. Hypertensive subjects had a higher NE increase than the normotensive individuals (55 +/- 7 upsilon 30 +/- 10 pmol, P = .03), but also had higher insulin levels during the clamps (839 +/- 43 upsilon 522 +/- 38 pmol, P < .001). Insulin levels accounted for most of the differences in NE increase between the normotensive and hypertensive groups. Gender, adiposity and WHR were also associated with NE increment. We conclude that the insulin mediated sympathetic activation is not affected in the presence of decreased insulin sensitivity for glucose utilization. The greater degree of sympathetic activation observed in hypertensive subjects is a function of the level of insulinemia obtained during the clamps.

Treatment of Diabetic Impotence with a Vacuum Device: Efficacy and Effects on Psychological Status

Twelve patients with erectile impotence related to diabetic neuropathy were treated with a vacuum device, Pos-T-Vac. Efficacy of the device and psychological evaluation (Dyadic Adjustment Scale for marital satisfaction and Hamilton Rating Scale for depression) were performed before and 3 months after treatment. Vacuum therapy was successful in 75% of the patients. Patients with successful impotence treatment and normal baseline marital satisfaction scores showed a modest increase in the scores of marital satisfaction (from 114 +/- 3 points, baseline, to 121 +/- 3 points, posttreatment; p less than 0.05). Vacuum therapy for the treatment of erectile dysfunction due to diabetic autonomic neuropathy appears to be safe and effective.

HYPERTENSION IN DIABETES MELLITUS

Hypertension should be detected and treated early in diabetic patients. It has a marked contribution to the morbidity and mortality of diabetic individuals due to both atherosclerosis and microvascular disease. Antihypertensive treatment is an effective tool in slowing the progression of early and advanced diabetic nephropathy. Prospective studies addressing the effects of antihypertensive regimens on the incidence of CHF, stroke, and coronary artery disease in the diabetic population are not available. We assume that the beneficial effects of therapy apply to both diabetic and nondiabetic subjects. Glycemic control and the lipid profile are major concerns when selecting an antihypertensive drug. Because hyperinsulinemia and insulin resistance have been advocated as hypertensive and atherosclerotic risk factors, the effects of antihypertensive drugs on insulin action and plasma insulin levels may also become an important element in the selection of an antihypertensive agent. ACE inhibitors, calcium channel blockers, and alpha-adrenergic blockers probably offer the most favorable metabolic profile when compared with diuretics and beta-blockers and should be used as the initial drugs in most clinical settings.

Relationship Between Insulin Sensitivity and Degree of Obesity in Mild Hypertension

Eighteen patients with mild hypertension (diastolic blood pressure > or = 90 and < 104 mm Hg) and 15 normotensive control subjects were studied. Insulin tolerance tests (ITT) and fasting plasma insulin (FPI) level measurements were performed to evaluate insulin sensitivity. Insulin sensitivity, as measured with the ITT, showed a strong correlation with body mass index (BMI) in the hypertensive and control groups (r = -0.68, p < 0.01 and r = -0.61, p < 0.01, respectively). The fasting insulin levels also correlated significantly with BMI in both groups (r = 0.55, p < 0.05 in the hypertensive and r = 0.76, p < 0.01 in the control group). Insulin sensitivity in the hypertensive subjects whose BMI was < or = 27.0 kg/m2 (nonobese), as measured with the ITT and FPI, was not different from the nonobese normal controls (K(itt), 5.36 +/- 1.74% min-1 versus 5.61 +/- 1.66% min-1, respectively, p > 0.2; FPI, 5.8 +/- 3.4 microU/ml versus 7.1 +/- 2.5 microU/ml, respectively, p > 0.2). Also, insulin sensitivity, as measured with the ITT, was not statistically significantly different between hypertensive and normotensive obese subjects (K(itt), 2.82 +/- 1.55% versus 3.90 +/- 0.67% min-1, respectively, p > 0.1). When fasting plasma insulin levels were compared, a higher level was observed in the obese normotensive subjects than in the obese hypertensive group (FPI, 19.8 +/- 10.0 microU/ml and 11.5 +/- 4.9 microU/ml, p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of a Large Supper on Glucose Levels the Following Morning in Patients with Type 2 Diabetes

Seventeen patients were studied to test the hypothesis that a large evening meal influences the fasting glucose level and glucose tolerance the following morning in patients with type 2 diabetes. Oral hypoglycemic agents were discontinued for 2 weeks. The baseline fasting plasma glucose levels were 12.3 +/- 0.9 mmol/L. Fasting and postprandial (post-Sustacal) glucose, insulin, and C-peptide measurements were performed the morning after the patients received three separate meal protocols spaced 1 week apart. The caloric distribution of the meal protocols was (1) 7 kcal/kg of ideal body weight breakfast and lunch and 14 kcal/kg supper (small supper); (2) 7 kcal/kg breakfast and lunch and 28 kcal/kg for supper (large supper); and (3) 14 kcal/kg breakfast and lunch (no supper). Fasting glucose level were higher the morning after the large supper compared to no supper (13.6 +/- 0.7 versus 12.3 +/- 0.5 mmol/L, p < 0.05) and also to the small supper (13.6 +/- 0.7 versus 12.5 +/- 0.6 mmol/L, p = 0.05). No difference was observed in the fasting glucose levels between the small supper and no supper (p > 0.2). The fasting insulin and C-peptide levels, and the post-Sustacal areas under the curve of glucose, insulin, and C-peptide did not differ among the meals. In patients with type 2 diabetes, a large evening meal is associated with a modest elevation in fasting glucose the following morning.