Clinically silent corticotroph tumors of the pituitary gland.

OBJECTIVE: To determine the clinical presentation, imaging characteristics, microscopic and ultrastructural characteristics, and treatment outcomes of patients with clinically silent pituitary corticotroph adenomas. METHODS: All silent corticotroph adenomas diagnosed at the Mayo Clinic during the years 1975 through 1997 were selected from the files of the Mayo Tissue Registry. RESULTS: We studied 23 cases, occurring in 16 male and 7 female patients (age range, 11-79 yr; mean age, 48 yr), who presented with headaches (50%), visual field defects (61%), extraocular muscle paresis (13%), hypopituitarism (26%), and galactorrhea/amenorrhea (43%/29% of the female patients). No patients exhibited clinical hypercortisolism. All tumors were macroadenomas (2.4+/-0.8 cm; range, 1.5-4.0 cm) and exhibited suprasellar extension in 87% of the cases and hemorrhage, necrosis, and/or cystic changes in 61%. All tumors stained were variably periodic acid-Schiff-, adrenocorticotropic hormone-, and beta-endorphin-positive, particularly Subtype I lesions. Ultrastructural classification was performed in 19 cases. In a comparison of Subtype I and II tumors, differences were observed with respect to sex (male/female, 1.4:1 versus 6:1), preoperative hyperprolactinemia (5 of 16 versus 0 of 6 cases), preoperative hypopituitarism (9 of 16 versus 5 of 7 cases), radiographic or gross invasion (7 of 16 versus 5 of 7 cases), and partial or total postoperative pituitary failure (6 of 16 versus 6 of 6 cases). The overall median postoperative follow-up period was 4.9 years (range, 0.3-16.6 yr); 54% of the patients had persistent or recurrent tumors. CONCLUSION: Clinically silent corticotroph adenomas behave in an aggressive manner and are characterized by the following: lack of clinical signs or symptoms of Cushing's syndrome and normal cortisol levels; no or only minor elevations of serum adrenocorticotropic hormone levels; macroadenomas with hemorrhagic infarction; and presentation dominated by mass effect symptoms. The high persistence/recurrence rate underscores the need for long-term follow-up.

Diabetic nephropathy is associated with an increased familial risk of stroke.

OBJECTIVE: To test the hypothesis that genetic susceptibility to diabetic nephropathy is associated with an increased familial risk of vascular disease, we have examined the causes and rates of death of parents of individuals with type 1 diabetes complicated by diabetic nephropathy compared with the causes and rates of death of parents of control subjects with diabetes uncomplicated by nephropathy. RESEARCH DESIGN AND METHODS: Individuals with at least a 14-year duration of type 1 diabetes complicated by diabetic nephropathy were identified and matched for age, sex, and duration of diabetes to control subjects. A total of 118 patients and 118 matched control subjects were identified and approached to obtain information on parental age and cause of death. For parents who had died, the cause of death was ascertained from the death certificate. RESULTS: Kaplan-Meier curves showed that parents of subjects with nephropathy (PN) had reduced survival compared with parents of diabetic subjects without nephropathy (PC) (log rank test P < 0.05). There was an excess of all vascular deaths and, in particular, strokes in the parents of subjects with nephropathy (PN: 20 of 103 deaths, 19% vs. PC: 3 of 66 deaths, 4%; Fisher's exact test P < 0.01). CONCLUSIONS: Parents of diabetic patients with nephropathy have reduced survival. This seems to be largely explained by an increase in vascular deaths and, in particular, a four-fold increase in the number of strokes. This supports the hypothesis that a common hereditary risk factor predisposes to both vascular death and diabetic renal disease.

The atherogenic lipoprotein phenotype and vascular endothelial dysfunction.

There is accumulating evidence that elevated plasma triglycerides and related abnormalities constitute an independent cardiovascular risk factor. Although the pathogenetic basis for the apparent relationship between elevated triglyceride-rich lipoproteins and CAD is still uncertain, evidence is accumulating to suggest that endothelial dysfunction is involved. There is evidence to suggest that triglyceride-rich particles may be directly damaging to the endothelium; this may be principally via oxidative mechanisms. Triglyceride-rich particles can cross the endothelial barrier and enter the arterial wall, thus placing them in a position to promote direct endothelial damage. These particles stimulate endothelial expression of adhesion molecules and the prothrombotic factor PAI-1. By reducing LDL size and HDL cholesterol concentrations, thereby further increasing the endothelial oxidative burden, triglyceride-rich particles may indirectly promote endothelial dysfunction. In addition, free fatty acids, which are the major substrates for endogenous synthesis of triglyceride-rich particles, are also potentially damaging to the endothelium. This occurs via oxidative stress, by facilitating transfer of LDL across the endothelium, and by enhancing toxicity of triglyceride-rich particles. Finally, there is recent strong evidence to suggest that increased postprandial circulating concentrations of triglyceride-rich particles and remnant particles may be deleterious to the endothelium.

Perceived symptoms of hypoglycaemia in elderly type 2 diabetic patients treated with insulin.

Elderly insulin-treated diabetic patients have a high risk of severe hypoglycaemia, yet their hypoglycaemic symptom profile has attracted little research. In this study, the frequency and intensity of symptoms of hypoglycaemia were recorded using a validated questionnaire in 132 insulin-treated diabetic patients, aged 70 years or more. Principal components analysis (PCA) was used to discover the factorial structure of the symptoms. Lightheadedness and unsteadiness were prominent symptoms in the elderly patients. PCA suggested three separate groups of symptoms: (1) those related specifically to impairment of co-ordination and articulation; (2) more general neuroglycopenic symptoms, and (3) autonomic symptoms. The frequency and classification of hypoglycaemic symptoms in this elderly population is different from those seen in younger diabetic patients treated with insulin. Neurological symptoms of hypoglycaemia were more commonly reported and may be misinterpreted as features of cerebrovascular disease. Health professionals and carers involved in the treatment and education of diabetic patients should be aware of the age-specific differences in hypoglycaemic symptoms.

Relationship of insulin resistance to microvascular dysfunction in subjects with fasting hyperglycaemia.

Microvascular hyperaemia is decreased in subjects at risk of developing non-insulin-dependent diabetes mellitus (NIDDM) who have fasting hyperglycaemia. Such microvascular abnormalities may be involved in the pathogenesis of diabetic microangiopathy. To investigate the relationship of reduced microvascular hyperaemia to metabolic and blood pressure abnormalities associated with the prediabetic state, we studied 24 subjects with fasting hyperglycaemia and 24 age- and sex-matched control subjects. The microvascular hyperaemic response to local heating of the skin on the dorsum of the foot measured by laser Doppler fluximetry was reduced in the subjects with fasting hyperglycaemia (1.18 [0.87-1.83] volts vs 1.51 [1.30-2.14] volts normal subjects; p = 0.0002) and was negatively correlated with fasting plasma insulin concentration (Rs = 0.70; p = 0.001) and positively related to insulin sensitivity determined by continuous infusion of glucose with model assessment (CIGMA) (Rs = 0.52; p = 0.01), but showed no association with fasting plasma glucose, beta-cell function 24 h ambulatory blood pressure profiles or serum lipid concentrations. These results suggests that hyperinsulinaemia, as a result of insulin resistance, may have a detrimental effect on microvascular function in the prediabetic state.

Lipoatrophy with human insulin.

We describe a case of lipoatrophy that was secondary to human insulin. The patient had only ever been treated with human insulin, and the lipoatrophy appeared to partially resolve with continued use of the same insulin preparations. Possible underlying pathogenic mechanisms are discussed.

Hormone replacement therapy and cardiovascular risk in post-menopausal women with NIDDM.

Female patients with NIDDM have a high prevalence of, and mortality from, coronary heart disease (CHD). Hormone replacement therapy (HRT) may favourably influence several CHD risk factors in post-menopausal NIDDM patients, including dyslipidaemia, hypertension, prothrombotic changes, and endothelial dysfunction. Insulin resistance appears to have a central role in the pathogenesis of these abnormalities and can also be modified by HRT. However, the potentially beneficial effects of HRT in women with NIDDM have been extrapolated from the results of studies in non-diabetic females, as to date there have been few studies in NIDDM patients. In view of their excessive CHD mortality, further research is needed to investigate the effects of different HRT preparations on lipid and non-lipid risk factors in this high-risk population.

Skin capillary density in subjects with impaired glucose tolerance and patients with type 2 diabetes.

In view of recent interest in the role of impaired early development and the pathogenesis of cardiovascular disease and carbohydrate intolerance in adults, this study examines whether reduced skin capillary density contributes to the limited microvascular hyperaemic responses observed in patients with Type 2 diabetes and subjects with impaired glucose tolerance (IGT). Fifteen patients with Type 2 diabetes, 15 subjects with IGT and 15 matched non-diabetic control subjects were studied. Capillary videomicroscopy was used to record images of the skin capillaries on the dorsum of the middle phalanx of the left middle finger before and after 10 min venous occlusion at 35 mmHg. There were no significant differences between the three groups in either basal capillary density (112 (71-144) caps mm-2 Type 2 patients (median and range) vs 107 (76-140) caps mm-2 IGT subjects vs 112 (76-138) caps mm-2 control subjects; p = 0.9, Kruskal Wallis), or following venous occlusion (122 (87-157) caps mm-2 vs 121 (90-143) caps mm-2 vs 123 (81-147) caps mm-1; p = 0.9). In addition there were no differences in blood pressure, BMI or skin temperature. These results do not support the concept of impaired early development of the skin microcirculation in patients with Type 2 diabetes or IGT and suggest that mechanisms other than reduced capillary density are involved in limiting microvascular vasodilation.

Differences in microvascular fluid permeability between long-duration type I (insulin-dependent) diabetic patients with and without significant microangiopathy.

1. To further investigate the role of microvascular functional changes in the pathogenesis of diabetic microangiopathy in type 1 diabetes, microvascular fluid permeability was measured in nine patients with a long disease duration and no or minimal (background retinopathy alone) microangiopathy, nine age-, sex- and duration-matched patients with microalbuminuria and nine control subjects. Microvascular fluid permeability was assessed by determination of the forearm capillary filtration coefficient using a sensitive strain-gauge plethysmographic technique. 2. Microvascular fluid permeability was significantly higher in the patients with microalbuminuria [8.5 (6.8-15.2) x 10(-3)ml min-1 100g-1 of tissue mmHg-1; median (range)] than in the patients with no or minimal complications [5.2 (3.6-7.0) x 10(-3) ml min-1 100g-1 of tissue mmHg-1, P < 0.001]. There was, however, no significant difference in microvascular fluid permeability between the patients with no or minimal complications and control subjects [4.5 (3.2-5.7) x 10(-3) ml min-1 100g-1 of tissue mmHg-1, P = 0.31]. Blood pressure and glycaemic control were similar in the two groups of diabetic patients. 3. These results provide further evidence that changes in microvascular permeability are found in other vascular beds in patients with incipient nephropathy, whereas no such changes are found in patients with a long disease duration and little evidence of microangiopathy.

Microvascular function in type 2 (non-insulin-dependent) diabetes: improved vasodilation after one year of good glycaemic control.

Abnormalities of microvascular function may be important in the development of diabetic microangiopathy. The major functional abnormality identified in patients with Type 2 diabetes has been a marked limitation of microvascular vasodilation, which is present from the time of diagnosis. The effects of sustained improvements in glycaemic control on vasodilator capacity in Type 2 diabetes are unknown. Twelve Type 2 diabetic patients were studied prospectively for 1 year after diagnosis. The reduced maximum hyperaemic response to local heating of the foot skin present at the time of diagnosis remained unchanged after 3 months of improved glycaemic control (1.12 +/- 0.56 V at diagnosis vs 1.21 +/- 0.69 V at 3 months, mean +/- SD; p = 0.25), but was improved after 1 year (1.42 +/- 0.91 V; p = 0.04 vs 3 months). The percentage increase in maximum hyperaemia correlated with the percentage decrease in HbA1c (rs = 0.53, p = 0.04). These results suggest that the early microvascular abnormalities demonstrated in Type 2 diabetes are potentially reversible and provide a further reason for striving for optimal glycaemic control in this patient group.

The influence of hypertension on microvascular blood flow and resistance to flow in the skin of patients with type 2 (non-insulin-dependent) diabetes.

Maximum microvascular blood flow and resistance to flow were determined in the skin of nine hypertensive and nine normotensive Type 2 (non-insulin-dependent) diabetic patients and nine control subjects to determine the influence of hypertension on these variables. Maximum blood flow was reduced in both the hypertensive (1.05 (0.70-1.42) V) and normotensive (1.04 (0.79-1.63) V) Type 2 diabetic patients when compared with control subjects (1.40 (1.26-2.13) V, p < 0.01 for hypertensive and p < 0.05 for normotensive patients, respectively); however, maximum blood flow was similar in both groups of diabetic patients (p = 0.82). In contrast, resistance to flow was significantly greater in the diabetic patients with hypertension (127.2 (87.5-181.3) mmHg V-1 vs 84.7 (61.9-123.0) mmHg V-1 normotensive diabetic patients, p < 0.02). In addition, R was greater in the normotensive Type 2 diabetic patients than in control subjects (70.7 (44.7-79.9) mmHg V-1, p < 0.05). These results suggest that hypertension is associated with an additional rise in pre-capillary vascular resistance in Type 2 diabetes which, while protecting the microcirculation from the effects of increased arterial pressure, may further diminish protective hyperaemic responses.

Capillary pressure in patients with NIDDM.

The hemodynamic hypothesis suggests that raised capillary pressure may play a role in the pathogenesis of diabetic microangiopathy. Although patients with non-insulin-dependent diabetes mellitus (NIDDM) and insulin-dependent diabetes NIDDM) develop a similar range of microvascular complications, differences in their expression and prevalence suggest that different pathogenic mechanisms may be operational. Capillary pressure is elevated in IDDM; the aim of this study was to assess whether capillary pressure was also elevated in NIDDM. Twenty-one patients with NIDDM (15 men) and 21 healthy control subjects matched for age, sex, and skin temperature were investigated supine with the hand at heart level. Finger nailfold capillary pressure was measured after direct cannulation at the summit of the capillary loops using glass micropipettes. The groups were matched for skin temperature (30.4 [24.2-33.8] degrees C, median [95% confidence interval], NIDDM patients vs. 30.0 [23.4-33.6] degrees C control subjects), age (62.0 [39.4-72.7] years NIDDM patients vs. 62.0 [39.4-72.0] years control subjects), and both systolic (sBP) and diastolic (dBP) blood pressures (133.0 [111.0-167.3]/78.0 [57.0-89.5] mmHg NIDDM patients vs. 133.0 [114.1-158.9]/80.0 [68.2-88.9] mmHg control subjects). Capillary pressure did not differ in the two groups (17.6 [13.1-21.2] mmHg NIDDM patients vs. 19.1 [14.1-23.6] mmHg control subjects [NS]). There was no correlation of capillary pressure with either HbA1c or glucose; however, there was a negative association between capillary pressure and diabetes duration (Rs = -0.50, P = 0.020).(ABSTRACT TRUNCATED AT 250 WORDS)

Capillary filtration coefficient in type II (non-insulin-dependent) diabetes.

Changes in microvascular permeability may be important in the pathogenesis of diabetic microangiopathy. In order to assess microvascular fluid permeability, the capillary filtration coefficient was determined in the forearm of 24 normotensive type II diabetic patients with minimal evidence of microangiopathy and satisfactory glycemic control, and 24 age- and sex-matched control subjects, using a sensitive strain gauge plethysmographic system. The median capillary filtration coefficient was not significantly different in the type II diabetic patients and control subjects [5.3 (3.2 - 9.1) x 10(-3) mL.min-1.100 g tissue-1.mm Hg-1 versus 5.4 (3.5 - 8.0) x 10(-3) mL.min-1.100 g tissue-1.mm Hg-1, p = 0.98)]. There were no correlations between capillary filtration coefficient and age, blood pressure, body mass index, duration of diabetes, glycemic control, or the presence of microvascular complications. These findings contrast with type I diabetes, where capillary filtration coefficient is elevated at an early stage in the disease, and lend support to the theory that there are differences in early microvascular functional abnormalities between type I and type II diabetes.

Reduced microvascular hyperaemia in subjects at risk of developing type 2 (non-insulin-dependent) diabetes mellitus.

Abnormalities of microvascular function may be important in the pathogenesis of diabetic microangiopathy. As such changes are already present at diagnosis in patients with Type 2 (non-insulin-dependent) diabetes mellitus, subjects at risk of developing the disease, who had elevated fasting plasma glucose concentrations below the diabetic range, were studied. The maximal microvascular hyperaemic response to local heating was determined in the feet of 11 subjects with fasting hyperglycaemia and 11 age- and sex-matched control subjects. There was reduced maximal hyperaemia in the subjects with fasting hyperglycaemia (1.01 [0.71-1.57]V, median and range), when compared to control subjects (1.41 [1.32-2.13]V, p < 0.001). It is unlikely that this limited vasodilation is a result of the mild degree of hyperglycaemia observed in the subjects included in this study. Further studies are therefore required to address the possible mechanisms of limited microvascular reactivity in subjects at risk of developing Type 2 diabetes.

Increased microvascular fluid permeability in young type 1 (insulin-dependent) diabetic patients.

Microvascular fluid permeability was assessed by determination of the capillary filtration coefficient in the forearm of ten young Type 1 (insulin-dependent) diabetic patients with a short duration of diabetes, satisfactory glycaemic control and minimal evidence of microangiopathy, and ten age- and sex-matched control subjects. A strain gauge plethysmographic method with a computer based logging and analysis system was used. This enabled differentiation between the volume filling and fluid filtration components of the response to venous pressure elevation. The median capillary filtration coefficient was found to be significantly higher in the young diabetic patients in comparison with control subjects (9.2 x 10(-3) ml.min-1.100 g tissue-1.mmHg-1 vs 3.8 x 10(-3) ml.min-1.100 g tissue-1.mmHg-1, p < 0.001). There were no significant correlations between capillary filtration coefficient and either plasma glucose concentration, haemoglobin A1c or duration of diabetes. As there is no evidence from other studies to support an increase in capillary surface area in the forearms of young Type 1 diabetic patients, these results may reflect a primary change in microvascular fluid permeability.