Luis C. Ramirez

Glycemic control and cardiopulmonary function in patients with insulin- dependent diabetes mellitus

BACKGROUND We studied cardiopulmonary function during exercise in young subjects with long-standing insulin-dependent diabetes mellitus (IDDM) who have no clinical cardiopulmonary disease to determine the relationships of aerobic capacity, gas exchange, ventilatory power requirement, and cardiac output to chronic glycemic control. METHODS Eighteen subjects with IDDM and 14 normal control subjects were studied. Nine diabetic subjects received twice daily insulin injections and had chronically elevated levels of glycosylated hemoglobin (hyperglycemic group); 9 other diabetic subjects received insulin via continuous infusion pumps and maintained chronic near-normal levels of glycosylated hemoglobin (normoglycemic group). At the end of at least 7 years of regular follow-up, aerobic capacity was determined by cycle ergometry. Lung volume, diffusing capacity, and cardiac output during exercise were measured by a rebreathing technique. Ventilatory power was measured by the esophageal balloon technique. RESULTS Maximal work load and oxygen uptake were markedly impaired in chronically hyperglycemic diabetic patients associated with significant restrictions of lung volume, lung diffusing capacity, and stroke index during exercise. Membrane diffusing capacity was significantly reduced at a given cardiac index. The normoglycemic patients consistently showed less impairment than the hyperglycemic patients. CONCLUSION Physiologically significant cardiopulmonary dysfunction develops in asymptomatic patients with long-standing IDDM. Chronic maintenance of near-normoglycemia is associated with improved cardiopulmonary function.

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.

Relationship between diabetes control and pulmonary function in insulin-dependent diabetes mellitus

PURPOSE To evaluate the effect of different levels of glycemic control on the pulmonary function of subjects with type I insulin-dependent diabetes mellitus. PATIENTS AND METHODS Eighteen subjects with type I insulin-dependent diabetes mellitus with no history or physical findings of respiratory disease. Patients were given insulin therapy with a standard twice-daily insulin injection regimen (standard treatment group) or a subcutaneous insulin infusion device (insulin pump) (intensive treatment group). Glycosylated hemoglobin (HbA1c) levels were determined at quarterly intervals in both groups of patients (standard treatment group, n = 10; intensive treatment group, n = 8). Pulmonary function and diffusing capacity for carbon monoxide (DLCO) were measured after 6 years of continuous follow-up. RESULTS The average HbA1c in the standard treatment group was significantly higher than that of the intensive treatment group throughout the 6 years of follow-up (p less than 0.001). The forced vital capacity of the standard treatment group was 85 +/- 3% of predicted as compared with 106 +/- 4% of predicted in the intensive treatment group (p less than 0.001). The DLCO was also significantly diminished in the standard treatment group as compared with that in the intensive treatment group (65 +/- 2% versus 87 +/- 4% of predicted) (p less than 0.001). CONCLUSION These data confirm previous reports of abnormal respiratory function in subjects with insulin-dependent diabetes mellitus and suggest that long-term near-normoglycemia may be beneficial in preventing the deterioration of pulmonary function associated with diabetes mellitus.

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.

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)

Is Pancreas Transplantation in Nonuremic Patients a Viable Option

The experience with pancreas transplantation must be acknowledged as an important step in the search for a cure for type I (insulin-dependent) diabetes mellitus. Nevertheless, we are concerned that a recent article from the University of Michigan (1) and the supporting editorial (2) might be easily misconstrued. The message for the health-care provider and eventually our patients is that pancreas transplantation is a viable therapeutic option for individuals with type I diabetes. In these articles the authors suggest that in an early stage of established diabetic nephropathy, it would be beneficial for patients to undergo pancreas transplantation to become normoglycemic and insulin independent and to increase the chances of stopping the progression of renal damage. The article from the University of Michigan describes proposed candidate criteria for pancreatic transplantation before end-stage diabetic nephropathy (1). The group suggests that patients who would undergo pancreas transplantation would have established diabetic nephropathy defined as proteinuria >150 mg but <3 g/24 h with a creatinine clearance of at least 60 ml/min. They might also have autonomic neuropathy that could be objectively measured. Theoretically, we agree with the fundamental issue that pancreas transplantation should move one step forward from combined kidney and pancreas transplantation. We also concur that near normoglycemia may not be enough and complete euglycemia might be required to impact on complications. This may explain why near normoglycemia has proven to be of little value in preventing the decline in glomerular filtration or reducing the elevated albumin excretion rates even when nephropathy was discovered at the stage of intermittent proteinuria (3). It is also conceivable that an early intervention is required, and even euglycemia may not be sufficient when microvascular complications are advanced. Therefore, theoretically it makes sense to attempt pancreas transplantation at earlier stages. However, it is exactly at this point that we question pancreas transplantation as a therapeutic option. We chose not to discuss the neuropathy criteria outlined, because we find them totally arbitrary with no sound rationale, and we have no clear understanding of their clinical significance (4,5). However, the criteria of diabetic nephropathy are important. Unfortunately proteinuria from 150 to 3000 mg/24 h with creatinine clearance >60 ml/min is extremely vague and covers too broad a spectrum of disease. It is likely, then, that microalbuminuric patients may be offered this cure for their disease. We want to remind the authors that the natural history of microalbuminuria remains unknown. Furthermore, if the issue is intervention, perhaps other less invasive measures may prove beneficial (6). The Michigan group mentions the abstract of Bilous et al. (7) to support the suggestion that pancreas transplantation may be beneficial for the progression of established diabetic nephropathy. We interpret the data of Bilous et al. as demonstrating the renal toxicity of cyclosporin A rather than showing beneficial effects of pancreas transplantation on renal function. In this study of seven patients, the creatinine clearance fell from 90.2 ± 21.3 to 60.0 ± 14.1 ml/min after pancreas transplantation and administration of cyclosporin A. Although end-stage diabetic nephropathy in proteinuric subjects can be anticipated to develop within 2-5 yr, the range of individual survival after overt proteinuria develops is extremely wide (1-24 yr) (8,9). Therefore,