Uncomplicated Diabetes Mellitus Research Articles

Abnormal changes in transmitral flow after acute exposure to nitroglycerin and nifedipine in uncomplicated insulin-dependent diabetes mellitus: A Doppler echocardiographic study

To study the left ventricular (LV) diastolic function in uncomplicated insulin-dependent diabetic patients without hypertension ( n = 25) and comparable controls ( n = 15), the effect of acute administration of nitroglycerin and nifedipine on cavity dimensions and transmitral flow pattern was investigated by Doppler echocardiography. At baseline no significant differences in any of the LV Doppler echocardiographic parameters were seen in the two groups. Only in diabetics did nitroglycerin diminish LV diastolic and systolic diameter significantly ( p < 0.0002 and 0.004, respectively), reducing the stroke volume from 70 ± 16 to 64 ± 20 ml, p < 0.01. The decrease in stroke volume correlated significantly to hemoglobin (Hb) A1c level ( r = 0.42, p = 0.036). An excessive preload reducing effect on venous capacitance vessels is assumed in diabetes, and this preload reducing effect was also reflected in transmitral flow pattern where E-wave/A-wave ratio decreased significantly only in the diabetic subjects ( p < 0.0005). Nifedipine induced the same degree of sympathetic activation in the two groups, but an increase in LV early peak filling rate (E wave) was seen in diabetes only (63.3 ± 13.5 to 66.8 ± 13.5 mm, p < 0.01). The atrial filling of LV (A wave) was increased significantly in both groups. Thus an abnormal LV diastolic function can be disclosed by these pharmacologic challenges. Regulation of preload and its influence on transmitral flow pattern in diabetes deserves further investigation, as does the influence of calcium antagonists on early relaxation in the diabetic myocardium.

Exposure to elevated D-glucose concentrations modulates vascular endothelial cell vasodilatory response.

The possible role of endothelial dysfunction in early stages of uncomplicated diabetes mellitus was investigated in porcine aortic endothelial cells. Prolonged exposure to various D-glucose concentrations resulted in concentration-dependent amplification of agonist-induced Ca2+ mobilization, whereas L-glucose and D-mannitol failed to mimic the effect of D-glucose. This stimulatory effect of high D-glucose on endothelial Ca2+ mobilization could be antagonized by coincubation with cytochalasin B, which prevented D-glucose uptake into the cells. In agreement with its effect on agonist-induced Ca2+ response, prolonged preincubation with pathological D-glucose concentrations amplified formation of endothelium-derived relaxing factor, which is well established to be strictly attributable to increases in endothelial free Ca2+. In contrast to endothelium-derived relaxing factor formation stimulated by receptor-interacting autacoids, preincubation with high D-glucose failed to modulate A 23,187-induced endothelium-derived relaxing factor formation, which is attributable to unphysiological increases in endothelial free Ca2+ by this ionophore. Similar to its effect on D-glucose-mediated amplification of agonist-stimulated Ca2+ mobilization, cytochalasin B abolished the stimulatory effect of high D-glucose on endothelium-derived relaxing factor formation. We therefore suggest that prolonged exposure to pathological high D-glucose concentrations results in an enhanced endothelium-derived relaxing factor formation caused by amplification of agonist-stimulated Ca2+ mobilization in endothelial cells. This mechanism may be of particular importance representing a possible basis of pathological vasodilation and reduced peripheral resistance in early stages of diabetes mellitus.

Endothelium-dependent vascular relaxation in patients with type I diabetes.

The endothelium plays an important role in the regulation of vascular tone. Although animal data show evidence for an impaired endothelium-dependent vasodilation in diabetes, human in vivo data are scarce. We investigated 11 type I diabetic patients and 11 matched healthy control subjects. The diabetic patients were selected on their relatively poor metabolic regulation (HbA1c > 8.5%), but none showed signs of microvascular complications. In all subjects, we recorded the forearm vasodilator responses to three different stimuli: 1) 5 min of forearm ischemia to obtain a maximal vasodilator response; 2) infusion of MCh into the brachial artery (dosages: 0.03-0.3-1.0 micrograms.min-1.100 ml-1 forearm volume) to evaluate endothelium-dependent vasodilation; and 3) intra-arterial infusion of SNP (dosages: 0.06-0.2-0.6 micrograms.min-1.100 ml-1) to evaluate endothelium-independent vasodilation. The diabetic patients had their usual subcutaneous insulin dose and breakfast 90 min before the start of the test. Baseline levels of BP and FBF were similar in both groups. The PORH response was similar in both groups, with a percentage fall in FVR of 92 +/- 1% in diabetic patients and 94 +/- 1% in control subjects. In the control subjects, MCh infusions exerted a dose-dependent vasodilator response with a maximal fall in the FVR of 90 +/- 2%. The highest dose of SNP induced a fall in FVR of 81 +/- 6% in this group. In diabetic patients, the percentage decrements in FVR during the several dosages of MCh and SNP were similar when compared with the control group. We conclude that chronic hyperglycemia, as occurred in our patients with uncomplicated diabetes mellitus, does not impair endothelium-dependent vasodilation in vivo.

Vascular responsiveness and cation exchange in insulin-dependent diabetes.

1. We measured forearm blood flow during brachial artery infusions of vasoconstrictors (angiotensin II and noradrenaline) and vasodilators (sodium nitroprusside and carbachol) in 16 healthy control subjects and in 18 patients with uncomplicated insulin-dependent diabetes mellitus. Erythrocyte Na+/Li+ countertransport and platelet Na+/H+ antiport activities were also measured. 2. The mean basal forearm vascular resistance was 22% lower in diabetic patients than in control subjects. The effects of each infusion on forearm vascular resistance were similar in diabetic patients and control subjects. 3. Erythrocyte Na+/Li+ countertransport activities were similar in diabetic patients and control subjects. Platelet Na+/H+ exchange (Vmax) was approximately 40% greater in diabetic patients than in control subjects, whereas the Km for Na+ was similar. 4. In diabetic patients, but not in control subjects, the responses to sodium nitroprusside and carbachol correlated inversely with Na+/Li+ countertransport in erythrocytes (rs = -0.76, P less than 0.001, and rs = -0.66, P less than 0.005, respectively), but not with Na+/H+ exchange in platelets.

Reduction of Glomerular Hyperfiltration in Normoalbuminuric IDDM Patients by 6 mo of Aldose Reductase Inhibition

Hyperglycemia causes enhanced glucose metabolism by the polyol pathway in tissues not requiring insulin for glucose uptake. It has been suggested that the high level of aldose reductase activity may cause functional and structural abnormalities in diabetes and may be involved in the development of late complications. To elucidate the effect of an aldose reductase inhibitor (ponalrestat) on kidney function in uncomplicated insulin-dependent diabetes mellitus (IDDM), 20 normoalbuminuric IDDM patients were randomized to follow either 6 mo of treatment with ponalrestat (n = 11, mean +/- SD age 30 +/- 8 yr, diabetes duration 10 +/- 6 yr) or 6 mo of placebo (age 33 +/- 7 yr, diabetes duration 12 +/- 6 yr). The glomerular filtration rate (clearance of [125I]iothalamate) was significantly reduced from 140 +/- 18 to 129 +/- 10 ml.min-1.1.73 m-2, 2P = 0.02) in the ponalrestat-treated patients, whereas no change was seen after placebo (142 +/- 12 vs. 141 +/- 12 ml.min-1.1.73 m-2). The renal plasma flow (clearance of 131I-labeled hippuran), urinary albumin excretion rate (radioimmunoassay), fractional albumin clearance, and renal vascular resistance were unchanged in both groups. HbA1c showed a modest increase during ponalrestat (7.9 +/- 1.8 vs. 8.7 +/- 1.5%, 2P = 0.01) but was unchanged during placebo. No side effects of ponalrestat were observed. Thus, inhibition of aldose reductase may reduce the characteristic hyperfiltration in uncomplicated IDDM.

Extrapancreatic insulin effect of glibenclamide

In eight patients with uncomplicated non insulin dependent diabetes mellitus, serum insulin levels, serum C-peptide levels and blood glucose levels were measured before and after oral administration of glibenclamide 0.1 mg/kg body weight and a test meal, or after a test meal alone. The rise in serum insulin levels persisted longer after glibenclamide. The initial rise in serum insulin was of the same magnitude in both situations, as was the rise in serum C-peptide levels during the entire 5 h study. It is concluded that glibenclamide is able to maintain a more prolonged increase in serum insulin levels by inhibiting the degradation of insulin in the vascular endothelial cells of the liver. The inhibition contributes to the blood glucose lowering effect of glibenclamide.

High heparin released platelet factor 4 in uncomplicated type 1 diabetes mellitus

The role of platelet activation in diabetic microangio-pathy is still controversial. We evaluated the degree of platelet activation in relation to vessel wall damage in three selected, well matched groups of subjects (10 healthy controls; 20 insulin dependent diabetic patients, 10 without microangiopathy and 10 with microangiopathy). We measured βTG and PF4 plasma levels before and 5, 15 and 90 min after a heparin bolus i.v. (5000 U). βTG basal levels were increased only in diabetic patients with microangiopathy. Diabetic patients without microangiopathy showed significantly higher levels of heparin released-PF4 (HR-PF4) in comparison with healthy controls. High levels of HR-PF4 seen to be an early marker of in vivo increased platelet activation in uncomplicated diabetes mellitus.

Platelet aggregation and vasopressin receptors in patients with diabetes mellitus.

Plasma vasopressin, vasopressin-induced platelet aggregation, and platelet vasopressin receptors were investigated in 10 normal subjects and 14 diabetic patients free of microangiopathy. Basal plasma vasopressin concentration was identical in two groups. Platelet aggregation induced by vasopressin as well as by epinephrine was not significantly altered in the diabetic patients. However, exploration of platelet V1-vasopressin receptors revealed in the diabetic group a dramatic reduction in the number of binding sites without alteration of the receptor affinity for tritiated vasopressin. Thus vasopressin-induced platelet aggregation in uncomplicated diabetes mellitus remains normal despite a decrease in the number of vasopressin receptors presumably due to alterations of the platelet membrane structure.

Assessment of impact of Medicare Prospective Payment System on care of persons with diabetes mellitus.

Professional review organizations (PROs) have been reviewing hospital admissions on diagnosis-related groups (DRGs) 294 and 295 (uncomplicated diabetes mellitus) at the direction of the Health Care Financing Administration (HCFA) to control inappropriate hospital admissions. Because of the possibility of an adverse effect from this policy on the quality of medical care for people with diabetes, letters were sent and/or telephone calls were made to each PRO to request information on denials of admissions or of reimbursement for the hospitalization of patients with diabetes. The answers revealed variations in PRO review procedures, little attention to quality of care, and an apparently inadequate data retrieval system. These inadequacies of the Medicare Prospective Payment System (PPS), which currently obscure its impact on the quality of the hospital care of diabetic patients, can be remedied.

Cognitive processes in insulin-dependent diabetes.

Cognitive processes in a group of neurologically asymptomatic patients with relatively severe but uncomplicated insulin-dependent diabetes mellitus (IDDM) were studied. In comparison with a homogeneous group of normoglycemic controls, the diabetic group performed significantly worse in global memory, abstract reasoning, and eye-hand coordination tests. The two groups scored similarly in intelligence, concentration and attention, spatial, visual, and psychomotor tests. The neuropsychological deficits did not correlate with the duration or the severity of the disease. Whether these mild neuropsychological deficits are transient or stable or whether they are caused by central nervous system vascular or metabolic dysfunctions or by the emotional influence of the chronic illness on the intellectual and educational development of patients remains unclear. Our findings need to be cautiously interpreted and perhaps could not be extended to diabetic patients with better metabolic control.

Status of platelets in complicated and uncomplicated diabetes mellitus.

Thirty patients with diabetes mellitus of more than 5 years' duration, divided into 2 groups of 15 each depending on the presence or absence of vascular complications, constituted the case material for the study. Fifteen healthy subjects of the same age group and sex served as controls. The platelet count and morphology were normal in controls as well as in patients with diabetes mellitus. The platelet adhesiveness increased signifi cantly with the increase in age and duration of diabetes and in the presence of vascular complications, irrespective of their type. The platelet aggregation time decreased with the increase in age as well as in diabetic patients with vascular complications, but the duration did not have any effect on it. The subject's sex, severity, and adequate control of diabetes mellitus with any type of therapy did not have any influence on the platelet functions studied.

Hypoglycemic therapy and hemostasis in maturity-onset diabetes mellitus: Existence of an early prethrombotic state

We studied 115 patients with uncomplicated maturity-onset diabetes mellitus, 55 males and 60 females; patients were divided into 7 groups according to the hypoglycemic therapy (diet alone, tolbutamide, glibenclamide, phenformin, combination of the last two drugs, insulin, combination of insulin and phenformin). All patients were tested for a prethrombotic state by the simultaneous determination of the following parameters: ADP-induced platelet aggregation, Factor VIII as antigen and procoagulant activity and the plasma levels of fibrinogen and antithrobin III. Our results show that these parameters were markedly altered in diabetic patients when compared to apparently normal subjects of the same age; on the contrary, differences between groups of diabetic patients were very slight and hardly ever statistically significant. These results suggest that the prethrombotic alterations of hemostatic system are very similar in all groups of diabetic patients; this is true also for patients submitted to diet alone, i.e. with slight and usually recent-onset diabetes mellitus. In conclusion, our study suggests the opportunity, at least from the theoretical point of view, of systematic antiaggregant and/or anticoagulant treatment(s) in maturity-onset diabetes mellitus, whose severe and precocious prethrombotic alterations seem to be independent of the hypoglycemic treatment applied.

Does pregnancy influence the prognosis of uncomplicated insulin-dependent diabetes mellitus?

To evaluate the effect of one or two pregnancies on the prevalence and severity of late diabetic complications, 22 pairs (44 patients) of female insulin-dependent diabetic (IDDM) patients were examined. Each pair consisted of one patient who had completed one or two pregnancies and one who had not. The two groups were carefully matched with respect to age, duration of disease, endogenous insulin secretory capacity, quality of blood glucose control, insulin requirement, hospitalization, and social status. No differences in prevalence or severity of retinopathy, nephropathy, and neuropathy were found.

Plasma cryoactivated renin and active renin in diabetes mellitus.

PRA and the inactive renin which is activated by cold (IR-C) were studied in a group of normal subjects and in patients with diabetes mellitus with and without the presence of nephropathy. The amount of renin activity, as measured after incubation of plasma at -5 C for 4 days, was called cold renin activity (CR. PRA was measured by a standard method. The difference between CR and PRA was used as a measure of IR-C. CR and PRA measurements were made on a normal salt diet, on a low salt diet, and after the administration of furosemide. In all three groups, CR and PRA were higher after salt depletion and following the administration of furosemide. A moderate but significant increase in IR-C was observed with these maneuvers in both groups of diabetes but not in normals. PRA and IR-C varied under different experimental conditions independent of each other. Although both PRA and IR-C were correlated with CR, no correlation was observed between PRA and IR-C. These findings suggest, although they do not prove, that the inactive renin is not a precursor of active renin. CR and IR-C were not significantly different between groups. PRA in patients with uncomplicated diabetes mellitus was normal or slightly high, whereas it was suppressed in patients with diabetes mellitus and nephropathy. The mechanism of suppressed PRA in patients with diabetes mellitus is not clear and may be related to the onset of renal disease itself.

The hypothalamic-pituitary axis in diabetes mellitus.

The hormonal response to LHRH and TRH was evaluated in three groups of male diaetics. Five patients were receiving therapy with the hypoglycemic agent glibenclamide, five were on NPH insulin and five were on dietary therapy alone. When compared to controls, the latter two groups had intact gonadotropin responses to LHRH. Despite normal basal gonadotropin levels, however, the group receiving glibenclamide therapy showed significantly exaggerated LH and FSH responses to LHRH. Both basal PRL and TSH levels, as well as the responses to TRH were normal in all three groups. These results indicate that LH, FSH, TSH and PRL secretion is intact in uncomplicated diabetes mellitus. The exaggerated LH and FSH responses to LHRH in the glibenclamide treated subjects are probably related to primary gonadal involvement; alternatively, there may be augmented pituitary gonadotropin secretion in this group.

Renin-aldosterone responsiveness in uncomplicated juvenile-type diabetes mellitus.

The changes in plasma renin activity (PRA) and plasma aldosterone concentration (PA) in response to dietary sodium restriction and upright posture were evaluated in 7 patients with juvenile-type, insulin-dependent, uncomplicated diabetes mellitus and in 5 healthy volunteers. All patients had normal blood pressure, 24-hour urine protein excretion and endogenous creatinine clearance. Renal sodium conservation and concentrating ability were grossly normal and 5 patients so tested, had normal renal acidification. PRA and PA were normal in every subject suggesting that abnormalities of the renin-aldosterone axis are late complications of diabetes mellitus usually associated with hypertension and nephropathy or neuropathy.

Plasma renin activity in juvenile diabetes mellitus and effect of diazoxide.

Low plasma renin activity (PRA) has been reported in patients with long-term diabetes mellitus complicated by hypertension and nephropathy. We have assayed PRA in twelve normal subjects and in eight age- and sex-matched juvenile diabetics of greater than twelve years' duration without hypertension and nephropathy under control conditions and following stimulation with diazoxide. During control conditions PRA did not decrease with time in the diabetics as it did in the normals. Following diazoxide infusion, PRA increased in both groups, and although the levels were often higher in diabetics than in normals, the mean differences were not statistically significant. The findings are consistent with the suggestion that PRA is normal or possibly elevated in clinically uncomplicated insulin-dependent diabetes mellitus and decreases with establishment of hypertension and nephropathy.

Impaired leukotactic responsiveness in patients with juvenile diabetes mellitus

The neutrophil leukocytes of 30 patients with juvenile onset diabetes mellitus were tested for leukotactic activity and compared with 30 age-matched controls to determine whether patients with uncomplicated juvenile diabetes mellitus have abnormal leukotactic responsiveness. The mean leukotactic index of patients with juvenile onset diabetes mellitus was significantly lower than that of controls ( p < 0.001). The leukotactic defect was not related to the duration of diabetes, or to the degree of control. Following incubation of the neutrophils of juvenile diabetics with insulin, the mean leukotactic index increased to normal levels. The leukotactic activity of control leukocytes after incubation with insulin remained unchanged. Random mobility and nitroblue tetrazolium dye reduction by the neutrophils of juvenile diabetic patients did not differ from that of controls. Leukotactic responsiveness in patients with uncomplicated juvenile onset diabetes is similar to that described in patients with adult onset diabetes and may explain, at least in part, the severity and chronicity of infections suffered by diabetic patients.

The Management of Uncomplicated Diabetes Mellitus

To investigate the potential role of fresh Carica papaya (C. papaya) leaf extract on haematological and biochemical parameters and toxicological changes in a murine model.In total 36 mice were used for the trial. Fresh C. papaya leaf extract [0.2 mL (2 g)/mouse] was given only to the test group (18 mice). General behavior, clinical signs and feeding patterns were recorded. Blood and tissue samples were collected at intervals. Haematological parameters including platelet, red blood cell (RBC), white blood cell (WBC), packed cell volume (PCV), serum biochemistry including serum creatinine, serum glutamic-oxaloacetic transaminase (SGOT) and serum glutamic-pyruvic transaminase (SGPT) were determined. Organs for possible histopathological changes were examined.Neither group exhibited alteration of behavior or reduction in food and water intake. Similarly, no significant changes in SGOT, SGPT and serum creatinine levels were detected in the test group. Histopathological organ changes were not observed in either group of mice except in three liver samples of the test group which had a mild focal necrosis. The platelet count (11.33±0.35)×105/μL (P=0.000 04) and the RBC count (7.97±0.61)×106/μL (P=0.000 03) were significantly increased in the test group compared to that of the controls. However, WBC count and PCV (%) values were not changed significantly in the test group. The platelet count in the test group started to increase significantly from Day 3 (3.4±0.18×105/μL), reaching almost a fourfold higher at Day 21 (11.3×105/μL), while it was 3.8×105/μL and 5.5×105/μL at Day 3 and Day 21 respectively in the control. Likewise, the RBC count in the test group increased from 6×106/μL to 9×106/μL at Day 21 while it remained near constant in the control group (6×106/μL).Fresh C. papaya leaf extract significantly increased the platelet and RBC counts in the test group as compared to controls. Therefore, it is very important to identify those chemicals of C. papaya leaves as it can be recommended to be used as a medication to boost thrombopoiesis and erythropoiesis in humans and in animals in which these cell lineages have been compromised.

Metabolic effects of ACTH upon preexisting diabetes mellitus.

THE production of a diabetic state in normal people by administration of ACTH has been demonstrated (1). In patients with diabetes mellitus administration of ACTH has been shown to result in a marked rise of blood sugar (2), and administration of cortisone has produced intensification of glycosuria and increased requirements for insulin (3, 4). An increase in excretion of ketone bodies occurs in patients with combined Addison's disease and diabetes mellitus when cortisone is given (5). A study of the metabolic effects of ACTH given over a prolonged period of time to a patient with diabetes mellitus has not been reported. Although important, such an experiment is not justifiable in a patient with uncomplicated diabetes mellitus because of the danger of permanent intensification of the diabetic state. Recently the opportunity arose to study a patient with diabetes mellitus of long standing, who received a twenty-two-daycourse of ACTH in the hope of arresting a progressive subacute myelogenous leukemia. The ...