Progression of peripheral occlusive arterial disease in diabetes mellitus. What factors are predictive?

The clinical, biochemical, and vascular laboratory measurements potentially associated with the development and/or progression of peripheral occlusive arterial disease (POAD) were assessed during a 4-year period in 110 normal control subjects, 112 patients with POAD without diabetes mellitus, 240 patients with diabetes mellitus without POAD, and 100 patients with diabetes mellitus and POAD. Age, history of hypertension or coronary heart disease, history of cigarette smoking, presence of POAD, systolic blood pressure, and beta-thromboglobulin level were associated with progression of POAD. A multivariate logistic regression model indicated that the presence of diabetes mellitus or POAD or both at baseline, decreased postexercise ankle-brachial index, increased arm systolic blood pressure, and current smoking were independently associated with progression of POAD. This study suggests that cessation of smoking and control of hypertension are essential treatment modifications to decrease the risk of progression of peripheral vascular disease in diabetic patients.

Course of peripheral occlusive arterial disease in diabetes. Vascular laboratory assessment.

To determine comparative rates of development and progression of peripheral occlusive arterial disease, 110 healthy nondiabetic control subjects, 112 patients with peripheral occlusive arterial disease (POAD), 240 patients with diabetes mellitus (DM), and 100 patients with diabetes mellitus and peripheral occlusive arterial disease (DM + POAD) were studied over 4 yr with noninvasive techniques. The presence of peripheral occlusive arterial disease was determined by postexercise ankle-brachial index (ABI) values; progression of peripheral occlusive arterial disease was determined by the rate of change in postexercise ABI. Patients who underwent peripheral arterial reconstructive surgery or amputation were also classified as having progression of their peripheral occlusive arterial disease. On this basis, follow-up revealed that peripheral occlusive arterial disease developed and therefore progressed in 1 (1%) of the control group and 22 (9%) of the DM. Peripheral occlusive arterial disease progressed in 31 (28%) of the POAD and 26 (26%) of the DM + POAD. The presence of peripheral occlusive arterial disease predisposes to progression of disease, and peripheral occlusive arterial disease is more likely to develop in diabetic patients who do not have peripheral occlusive arterial disease than in nondiabetic control subjects. However, the presence of diabetes mellitus in patients with peripheral occlusive arterial disease does not seem to increase the risk of progression.

The classification of diabetes by clinical and C-peptide criteria. A prospective population-based study.

OBJECTIVE: To evaluate both the concordance in the classification of diabetes by clinical and C-peptide criteria and, prospectively, the consistency of the classification by C-peptide. RESEARCH DESIGN AND METHODS: Individuals with diabetes who were enlisted in the prospective epidemiological study of diabetic neuropathy (Rochester Diabetic Neuropathy Study [RDNS]) were classified clinically by National Diabetes Data Group (NDDG) criteria to IDDM and NIDDM at entry to the study. In addition, C-peptide response to 1 mg glucagon was measured at entry for the classification to IDDM (basal C-peptide, < 0.17 pmol/ml; increment above basal, < 0.07 pmol/ml) and NIDDM (all other responses) and for concordance with the clinical classification made. The consistency of the C-peptide response was assessed every 2 years for up to 8 years. RESULTS: Among 346 individuals with diabetes, 84 were classified as IDDM and 262 as NIDDM by clinical algorithm. COncordance with the C-peptide response occurred in 89% of the patients and remained consistent during 8 years of follow-up. Among the 37 patients with discordant clinical and C-peptide classification, those considered clinically to have NIDDM had a consistent IDDM C-peptide response during follow-up, and most of those considered to have IDDM clinically eventually showed an IDDM C-peptide response during follow-up. CONCLUSIONS: Clinical criteria for the classification of diabetes are highly correlated with the assessment of insulin secretory reserve. A small number of individuals considered to have NIDDM clinically or by C-peptide have or develop an IDDM peptide response.

Impact of a diabetes electronic management system on the care of patients seen in a subspecialty diabetes clinic.

OBJECTIVE: To compare the compliance with diabetes care performance indicators by diabetes specialists using a diabetes electronic management system (DEMS) and by those using the traditional paper medical record. RESEARCH DESIGN AND METHODS: A DEMS has been gradually introduced into our subspecialty practice for diabetes care. To assess the value of this DEMS as a disease management tool, we completed a retrospective review of the medical records of 82 randomly selected patients attending a subspecialty diabetes clinic (DC) during the first quarter of 1996. Eligible patients were defined by the suggested criteria from the American Diabetes Association Provider Recognition Program. During the first quarter of 1996, approximately one half of the providers began using the DEMS for some but not all of their patient encounters. Neither abstractors nor providers were aware of the intent to examine performance in relationship to use of the DEMS. RESULTS: Several measures were positively influenced when providers used the DEMS. The number of foot examinations, the number of blood pressure readings, and a weighted criterion score were greater (P < 0.01) for providers using the DEMS. There was evidence, although not statistically significant, for lower mean diastolic blood pressures (P = 0.043) in patients and for number of glycated hemoglobins documented (P = 0.018) by users of the DEMS. CONCLUSIONS: Performance and documentation of the process of care for patients with diabetes in a subspecialty clinic are greater with the use of a DEMS than with the traditional paper record.

Sterol excretion and cholesterol absorption in diabetics and nondiabetics with and without hyperlipidemia.

Fecal neutral and acidic sterols and cholesterol absorption were measured in 12 normal control subjects, 40 diabetic subjects with and without hyperlipidemia, and 27 subjects with hyperlipidemia but without diabetes mellitus. All subjects were on a low-cholesterol diet (less than 300 mg cholesterol/day). Fecal excretion of neutral and acidic sterols was increased in patients with hypertriglyceridemia and was more marked in diabetic patients with hypertriglyceridemia. Cholesterol absorption was decreased in diabetic patients with hypertriglyceridemia. Otherwise, there were no significant differences in sterol excretion or cholesterol absorption in diabetic and nondiabetic subjects compared with control groups with similar lipid levels. The best predictors of fecal neutral- and acidic-sterol excretion and of estimated cholesterol synthesis were very low [corrected]-density lipoprotein triglycerides and high-density lipoprotein cholesterol. Correction of hyperlipidemia may be beneficial in decreasing cholesterol synthesis and, thereby, in decreasing the risk of atherogenesis.

Sulfonylureas.

Sulfonylureas have been available for the treatment of non-insulin-dependent diabetes mellitus (NIDDM) since the 1950s. With the introduction of new oral agents, there is a tendency to discount the value of sulfonylurea therapy. Sulfonylureas have the advantage of multiple formulations, low costs, minimal side effects, and demonstrated efficacy in controlling hyperglycemia. The major disadvantage of sulfonylureas is secondary failure, which may occur with all oral agents as part of the progression of NIDDM. Sulfonylureas should continue to play an important role in the treatment of NIDDM.

Postprandial hyperglycemia: implications for practice.

Despite the growing consensus that postprandial glucose levels provide a more accurate and valuable early marker of diabetes symptoms than fasting plasma glucose, the ability to forestall diabetic complications by managing postprandial hyperglycemia has not been proved. Patients who are not considered to have diabetes mellitus may have impaired glucose tolerance (and increased risk for developing cardiovascular disease), and targeting nonfasting glucose can reduce insulin requirements for patients with insulin-dependent diabetes mellitus (type 1 diabetes mellitus). The challenge now is to determine what fasting glucose levels merit intervention, when and how they should be determined, and who should measure them. After outlining the discrepancies and lack of consensus between measurement guidelines developed by different professional organizations, the author then reviews options for treating postprandial hyperglycemia, including prepackaged meals, alpha-glucosidase inhibitors, acarbose therapy, and fast-acting insulin preparations.

Influence of the degree of control of diabetes on the prevention, postponement and amelioration of late complications.

The relationship between hyperglycaemia and the chronic complications of diabetes has been disputed for many years. Some physicians believe that the evidence that hyperglycaemia is the primary determinant of the chronic complications is convincing; others believe the question remains unsettled. Several types of study provide information. In vitro and in vivo studies demonstrate biochemical alterations induced by hyperglycaemia which could lead to structural changes and diabetic complications. Animal models demonstrate that the complications develop with induction of hyperglycaemia and are ameliorated when blood glucose is returned toward normal. Many uncontrolled clinical studies demonstrate an association between diabetes control and complications but cannot prove causality. Controlled clinical trials have sometimes, but not always, shown functional changes suggestive of amelioration of complications with control of hyperglycaemia. A definitive clinical trial has not yet been completed. Pancreas transplantation has the potential of completely normalising blood glucose, but studies to date have been limited by small numbers of patients, the advanced state of complications, and the lack of adequate controls. On balance, the evidence is highly suggestive that hyperglycaemia is a major determinant of the chronic complications of diabetes. Even if the relationship is established, the risk involved in treatment programmes to achieve near normoglycaemia must be better defined so that potential risk versus benefit can be evaluated in the individual patient when making treatment decisions.

Preventing long term complications. Implications for combination therapy with acarbose.

Long term complications continue to be the major source of morbidity and mortality in patients with diabetes. Acarbose could potentially help to reduce diabetic complications if it improved glucose control, reduced lipid levels and hyperinsulinaemia. Acarbose has been shown to effectively reduce postprandial hyperglycaemia and haemoglobin A1c. This effect might be helpful in patients with insulin-dependent diabetes mellitus, as insulin injections do not provide complete control of rises in postprandial glucose levels, and in patients with non-insulin-dependent diabetes mellitus, because it simplifies the treatment programme. If improved control is shown to reduce complications, acarbose may be helpful. Although acarbose does not reduce hyperinsulinaemia, it reduces lipid levels and thus could reduce the risk of atherosclerosis.

Glycaemia control in diabetes mellitus. Towards the normal profile?

The Diabetes Control and Complications Trial and the Stockholm Study have conclusively demonstrated that improving the blood glucose control in patients with insulin-dependent diabetes mellitus (IDDM) reduces the risk of developing retinopathy, nephropathy and neuropathy. Each patient with IDDM should be carefully evaluated for the appropriateness of institution of an intensive insulin treatment programme. In particular, the risk of severe hypoglycaemia must be considered and the goals modified if necessary to reduce the risk. Successful implementation of an intensive treatment programme requires an experienced healthcare team and a knowledgeable and well motivated cooperative patient. Several variations of intensive treatment programmes can be used, with no definite superiority of one treatment method over the others. Individualization is the key to success. Each programme has the same general principles. Regular insulin is used to control the postprandial glucose excursion and a slow infusion of regular insulin by a pump or injected intermediate or long-acting insulin is used to balance fasting glucose utilisation and production. The treatment will not be successful without self-monitoring of blood glucose by the patient and frequent adjustment of the insulin doses to compensate for variations in blood glucose levels, diet and activity. The treatment should be followed with quarterly glycated haemoglobin determinations and a regular follow-up plan. During follow-up the main challenge for the healthcare team will be to maintain motivation in the patient and to assist with behaviour modification. A detailed understanding of intensive treatment programmes may be beyond the skill of the average primary care physician, but any physician caring for patients with diabetes will benefit from an understanding of the general treatment principles outlined in this article.

Practical aspects of intensive insulin therapy.

Application of the principles of intensive insulin therapy in an attempt to achieve near-normal glycemia necessitates making many practical decisions for each patient. Often these decisions must be based on experience and opinion because the questions have not been studied adequately enough to be answered definitively. One approach to selection of patients, initiation of therapy, insulin management, blood glucose monitoring, and patient follow-up is reviewed.

Prolonged follow-up in diabetic retinopathy treated by sectioning the pituitary stalk.

Because no complete long-term follow-up of visual status after pituitary ablation has been reported, records were reviewed on all 40 patients undergoing sectioning of the pituitary stalk for diabetic retinopathy at the Mayo Clinic from 1961 through 1968. One patient died and another was blind immediately postoperatively. One patient was lost to follow-up after 125 months. Twenty-seven patients have died after a follow-up interval of 7 to 120 months (mean, 63 months). The last available evaluation of these patients indicated stable or improved visual acuity in 20 patients. Eleven patients remain alive. Seven of these have stable or improved visual acuity and retinopathy. We conclude that although late post-operative mortality is high, in carefully selected patients with florid retinopathy but no fibrosis, pituitary ablation is an effective method for maintaining visual acuity.

Chronic diarrhea in diabetes mellitus: mechanisms and an approach to diagnosis and treatment.

In this study, our aim was to develop a practical strategy to facilitate the management of patients with diabetes mellitus and chronic diarrhea in a tertiary referral practice. We reviewed the pertinent English-language literature of the past 30 years that described the pathophysiologic mechanisms and treatment of patients with diabetic diarrhea and retrospectively reviewed the medical records of all patients with diabetic diarrhea examined at the Mayo Clinic during 1990. Three typical case studies are described to illustrate the diverse mechanisms that lead to chronic diarrhea in patients with diabetes. No report in the literature has systematically evaluated all the putative mechanisms of chronic diarrhea in any group of patients with diabetes. In our tertiary referral practice, diabetic diarrhea was frequently due to celiac sprue, bacterial overgrowth in the small bowel, or fecal incontinence in conjunction with anorectal dysfunction; however, in almost 50% of the patients, these causes were excluded, and abnormal intestinal motility or secretion was postulated to be one of the likely causes of the diarrhea. These data suggest a practical algorithm based on three sequential assessments: first, tests of blood and stool specimens and flexible sigmoidoscopy to detect evidence of malabsorption or disease in the distal colon; second, small bowel aspirate and biopsy if the results of initial blood or stool tests are abnormal or anorectal function tests if those test results are normal; and, finally, measurement of gastrointestinal transit or therapeutic trials with opioids, clonidine hydrochloride, and, rarely, cholestyramine resin or octreotide acetate (or both methods). The mechanisms whereby abnormal neural function due to diabetes results in altered digestive, secretory, absorptive, or motor function necessitate further elucidation. The management of chronic diarrhea in patients in a tertiary referral practice, however, can be based on a practical algorithm to determine the cause and to adopt specific treatment to correct it.

Hyperlipidemia and diabetes mellitus.

The increased risk of coronary artery disease in subjects with diabetes mellitus can be partially explained by the lipoprotein abnormalities associated with diabetes mellitus. Hypertriglyceridemia and low levels of high-density lipoprotein are the most common lipid abnormalities. In type 1 diabetes mellitus, these abnormalities can usually be reversed with glycemic control. In contrast, in type 2 diabetes mellitus, although lipid values improve, abnormalities commonly persist even after optimal glycemic control has been achieved. Screening for dyslipidemia is recommended in subjects with diabetes mellitus. A goal of low-density lipoprotein cholesterol of less than 130 mg/dL and triglycerides lower than 200 mg/dL should be sought. Several secondary prevention trials, which included subjects with diabetes, have demonstrated the effectiveness of lowering low-density lipoprotein cholesterol in preventing death from coronary artery disease. The benefit of lowering triglycerides is less clear. Initial approaches to lowering the levels of lipids in subjects with diabetes mellitus should include glycemic control, diet, weight loss, and exercise. When goals are not met, the most common drugs used are hydroxymethylglutaryl coenzyme A reductase inhibitors or fibrates.

A prospective study of peripheral occlusive arterial disease in diabetes. I. Clinical characteristics of the subjects.

This paper describes the clinical characteristics of a group of normal control subjects, patients with clinical peripheral occlusive arterial disease, patients with diabetes and no clinical peripheral arterial disease, and patients with diabetes and peripheral arterial disease at the time of the enrollment of all subjects in a 5-year study of the factors involved in the progression of peripheral occlusive arterial disease in diabetes. Obesity and hypertension were more common in subjects with diabetes or peripheral occlusive arterial disease (or both) than in the control subjects. Smoking was more common in both groups with occlusive arterial disease than in those without it. The diabetic patients with occlusive arterial disease had a longer duration of diabetes mellitus and a higher rate of other diabetic complications than those without arterial disease.

Pancreas transplantation at Mayo: I. Patient selection.

From October 1987 to December 1988, 59 patients underwent assessment for combined kidney and pancreas transplantation or pancreas transplantation after receiving a kidney allograft. We report our criteria for accepting candidates for transplantation, the results of the selection process, and the clinical and laboratory profile of those patients who underwent transplantation. Of the overall group, 22 patients (37%) were approved medically, 3 of whom were awaiting financial approval. Of the 59 patients, 15 (25%) were not approved for the transplantation program for medical reasons; in addition, 16 patients declined participation and 3 were not accepted because of lack of financial resources. Medical reasons for exclusion from pancreas transplantation were coronary artery disease in six patients, severe peripheral vascular disease in six patients, other medical problems in two patients, and noncompliance in one patient. Thus, many patients who underwent assessment for pancreas transplantation did not enter the program because of medical, financial, or personal preference reasons. In most cases, the medical reason for exclusion from pancreas transplantation was a cardiovascular disorder.

Effect of blood glucose control on peripheral nerve function in diabetic patients.

A prospective, stratified, randomized 3-year clinical trial was conducted on the effect of rigorous versus conventional glucose control on peripheral nerve function in 33 insulin-treated diabetic patients with a duration of diabetes of less than 2 years. The goals for conventional glucose control were the mean of fasting and 80-minute postprandial plasma glucose of 150 mg/dl for non-insulin-dependent diabetes and 200 mg/dl for insulin-dependent diabetes. The goal of rigorous glucose control was an approximation of nondiabetic glucose control. No significant difference in glucose control or peripheral nerve function was observed between the rigorously and the conventionally controlled groups. Eight patients in the conventional-control group spontaneously achieved glucose control in the range that was the objective for the rigorous-control group, and five patients in the rigorous-control group never achieved the desired glucose control. In the remaining 20 patients, with similar baseline glucose control and peripheral nerve function characteristics, observed over a median of 2 years, improved blood glucose control (P less than 0.01) was not associated with any significant improvement in peripheral nerve function. Nevertheless, a significant (P less than 0.05) correlation was found between the degree of abnormal nerve function at entry into the study and change in nerve function during the study. If control of hyperglycemia benefits peripheral nerve function of diabetic patients, its demonstration may require a closer approximation of normoglycemia, a larger difference in glucose control between the two study groups, a longer duration of treatment, and the use of patients with more advanced peripheral nerve function abnormalities than those in this study.

A prospective study of peripheral occlusive arterial disease in diabetes. III. Initial lipid and lipoprotein findings.

Lipid and lipoprotein findings are described in a group of 707 persons consisting of normal control subjects, patients with clinical peripheral occlusive arterial disease, patients with diabetes and no occlusive arterial disease, and diabetic patients with occlusive arterial disease. The mean serum triglycerides were elevated in all groups compared with the normal controls and varied, depending on the type and treatment of the diabetes and fasting plasma glucose concentration. Mean total serum cholesterol did not change among the groups. Unexpectedly, the mean level of low-density lipoprotein cholesterol was significantly lower in patients with diabetes who had no occlusive arterial disease than in normal subjects. The mean high-density lipoprotein cholesterol level was higher in normal-weight, insulin-treated diabetic patients than in obese diabetics regardless of their treatment. Disturbances in triglyceride metabolism and the related lipoproteins appear to characterize both diabetes and occlusive arterial disease, with the highest mean levels of serum triglycerides being found in subjects with both diabetes and occlusive arterial disease.

A prospective study of peripheral occlusive arterial disease in diabetes. II. Vascular laboratory assessment.

Noninvasive tests of the peripheral circulation were used to quantify the presence and severity of occlusive arterial disease in the lower extremities in 707 subjects on entry into a prospective study. Four groups were studies: 124 normal subjects, 157 patients with clinically evident occlusive arterial disease, 295 patients with diabetes mellitus without clinically evident occlusive arterial disease, and 131 patients with diabetes mellitus and clinically evident occlusive arterial disease. The lower extremity-to-arm systolic blood pressure ratios at rest, ankle-to-arm systolic blood pressure ratios after exercise, and segmental plethysmographic recordings accurately identified the groups with occlusive arterial disease and quantified the spectrum of severity in each of the groups. The 1-minute postexercise ankle-to-arm systolic blood pressure ratio was the single best indicator in discriminating between normal subjects and patients with occlusive arterial disease. The exercise electrocardiogram was positive in 30 of the 583 patients and in none of the group of normal subjects. The systolic blood pressure was falsely elevated as a result of sclerotic, noncompressible arteries in the segment of the limb under the pneumatic cuffs in 12 of the patients but in none of the normal subjects.

A prospective study of peripheral occlusive arterial disease in diabetes. IV. Platelet and plasma functions.

Platelet factor 4-like activity, circulating platelet-aggregate ratios, ristocetin cofactor, Willebrand antigen, ADP-induced platelet aggregation-enhancing factor, and quantitative platelet aggregation response to ADP, epinephrine, and collagen in platelet-rich plasma were measured in four groups of subjects with similar age and sex distribution. Neither platelet factor 4-like activity nor circulating platelet-aggregate ratios differentiated these four groups. Platelet aggregation studies with ADP a subthreshold concentration support the concept of hypersensitivity of diabetic platelets in males. Male and female subjects differ significantly in their quantitative response to aggregating agents when such studies are done under similar conditions. Willebrand factor activity and Willebrand antigen normally increase with age. Elevation in these activities above that accounted for by age characterizes the presence of vascular disease but not diabetes mellitus in the absence of vascular disease. A plasma factor enhancing platelet aggregation could not be demonstrated in most diabetic patients in this study.