Phosphodiesterase activity in human subcutaneous adipose tissue in hyper- and hypothyroidism

Phosphodiesterase (PDE) activity was determined in sc adipose tissue from 12 patients with untreated hyperthyroidism, 8 patients with untreated hypothyroidism, and 10 healthy nonobese subjects. Eight of the hyperthyroid group were reexamined after treatment when they were euthyroid. The apparent Vmax of the low Km form of PDE was 25% lower in untreated hyperthyroidism (P less than 0.05) and 100% higher in untreated hypothyroidism (P less than 0.01) than in the controls; treatment of the hyperthyroidism resulted in normalization of the value. There was a positive correlation between the mean fat cell volume and the Vmax of the low Km PDE in all conditions (r = 0.64-0.85). As regards the high Km form of PDE, the Vmax values for both hyper- and hypothyroid patients did not differ from those for the control group. The results of this study suggest that in man, the apparent Vmax for the PDE with low Km is determined by the thyroid hormones.     

Effect of insulin and lipolytic hormones on cyclic AMP phosphodieterase activity in normal and diabetic rat adipose tissue.

Insulin has been shown to lower cyclic AMP (cAMP) levels in hormonally sensitive tissue. The mechanism by which this lowering occurs has not yet been fully defined. We studied the effects of insulin on rat adipose tissue cyclic nucleotide phosphodiestrase (PDE) in an incubation system. The adipose tissue used was from both normal animals and animals rendered diabetic by intravenous injections of streptozotocin. Rat epididymal fat pads were incubated in a Krebs-Ringer bicarbonate-4% albumin system with O, 100, 1,000 or 10,000 PU/ml insulin (INS); epinephrine (EPI) or glucagon (GLU) at several different concentrations. After 15 min of incubation, each tissue was homogenized, centrifugated, and the supernatant assayed for cAMP PDE activity using the breakdown of (3-H)cAMP. The data was used to characterize cAMP PDE into apparent high and low K-m PDE components. In the normal animals, INS increased Vmax of the low Km PDE components; 100 pU/ml INS, 30%, 1000 p1/ML INS, 40; and 10,000 pU/ml INS, 20%. In contrast, streptoxotocin diabetes lowered this Vmax by 30%. In the diabetic animals, INS also increased Vmax by 30%. In the diabetic animals, INS also increased Vmax of the low Km PDE component; 100 pU/ml INS, 30%; 1000 pU/ml INS, 50% and 10,000 pU/ml INS, 100%. Epinephrine at 1, 10, and 100 pg/ml stimulated low Km cAMP PDE activity by 67%, 73% and 44% respectively. The stimulatory effect of EPI on both the low and high Km cAMP PDE activity was neutralized by propranolol or adenosine. In comparison to EPI, GLU at very low concentrations, 10-9M, stimulated low Km cAMP PDE. These studies suggest that some of the biologic actions of insulin, an antilipolytic substance, are mediated through activation of low Km PDE. Furthermore, this enzymatic activity is lower in experimental diabetes. The stimulation of low Km PDE by lipolytic hormones may reflect a long-range protective action of these agents.     

Changes in phosphodiesterase activity of human subcutaneous adipose tissue during starvation

The phosphodiesterase (PDE) activity, the basal rate of lipolysis and the basal cyclic AMP level in adipose tissue were determined in hypogastric and gluteal specimens obtained from 14 obese healthy subjects before and after one week of starvation. During starvation there was a significant increase in both the tissue level of cyclic AMP and the rate of lipolysis, whereas the apparent values of Vmax of the low and high Km forms of PDE decreased significantly-i.e. by about 50 and 30 percent. respectively. The substrate concentration of cyclic AMP at Vmax of the low Km PDE corresponded to the tissue level of the nucleotide. During, but not before, starvation there was a positive correlation between Vmax of the low Km PDE and the cyclic AMP level (r = 0.7-0.8). The metabolism in the tissues from the two fat depots exhibited similar variations during starvation. The findings suggest that the low Km form of PDE is inhibited during starvation. This may be one factor responsible for the starvation-mediated increase in the cyclic AMP levels and the rate of lipolysis in adipose tissue.     

Insulin binding to circulating monocytes in children with insulin-dependent and non-insulin-dependent diabetes mellitus

This study describes insulin binding to circulating monocytes in 24 children with insulin-dependent diabetes mellitus (IDDM), five children with non-insulin-dependent diabetes mellitus (NIDDM), and 10 healthy and 12 obese control children. Insulin binding to monocytes was greatly increased in untreated IDDM children with obvious ketoacidosis (5.51 +/- 3.49 vs. 1.91 +/- 0.47 pg/10(6) cells, P less than 0.01), whereas it was decreased in those without obvious ketoacidosis (1.39 +/- 0.30 vs. 1.91 +/- 0.47 pg/10(6) cells, P less than 0.01). Insulin treatment restored insulin binding almost to the level of control children in both ketoacidotic and non-ketoacidotic patients. Insulin binding to monocytes was markedly decreased in untreated NIDDM children with hyperinsulinemia compared with healthy control children (0.73 +/- 0.27 vs. 1.91 +/- 0.47 pg/10(6) cells, P less than 0.01) or obese control children (0.73 +/- 0.27 vs. 1.33 +/- 0.35 pg/10(6) cells, P less than 0.01). These data indicate that changes in insulin secretion and metabolic conditions might be involved in the fluctuation of the number of insulin receptors in IDDM children as well as in NIDDM children.     

Abnormal lipoprotein-lipase-mediated plasma triglyceride removal in untreated diabetes mellitus associated with hypertriglyceridemia.

Hypertriglyceridemia is common in untreated diabetes mellitus. An abnormality in the interaction of lipoprotein lipase with endogenous circulating plasma lipoprotein triglyceride has been demonstrated in untreated diabetes. These diabetics have a decreased maximal removal capacity for plasma triglyceride (27.0 mg TG/kh/hr) and increased Km (390 mg/dl) for endogenous plasma triglyceride-lipoprotein lipase interaction compared to that found in nondiabetic hypertriglyceridemic subjects (Vmax, 32.0; km, 157). Diabetics treated for at least two months have a maximal removal capacity and Km similar to that of nondiabetic subjects (Vmax, 32.7; Km, 192). No evidence for an increase in triglyceride production due to diabetes per se was found. When diabetic subjects with triglyceride levels over 400 mg/dl were selected for study, most were found to have an independent familial form of hypertriglyceridemia.     

Epidemiological and immunogenetic analysis of tuberculosis and diabetes mellitus association

The prevalence of insulin-dependent diabetes mellitus (IDDM) and noninsulin-dependent diabetes mellitus (NIDDM) among adults in two Moscow okrugs was studied. It was 0.218 and 1.678%, respectively, the latter form being encountered 7.7 times more frequently. Patients with pulmonary tuberculosis followed at tuberculosis control dispensaries (n = 69,012) were found to have diabetes mellitus in 236 cases (120 with IDDM and 116 with NIDDM). The prevalence of IDDM among the tuberculosis control dispensary patients was 1.7%, which was 8 times greater than that in the general population. That of NIDDM was 1.68%, which did not significantly differ from that in the population. Epidemiological analysis showed that there was a highly significant association of tuberculosis with diabetes mellitus in the population. The risk for IDDM was 3.6% in patients and exceeded that in the population while the risk for NIDDM in the population was the same as that in the population. Analyzing the distribution of immunogenetic HLA-1 and HLA-2 markers showed that patients with tuberculosis concurrent with IDDM were intermediate between a group of patients with isolated tuberculosis and isolated IDDM.     

Modulation by thyroid status of hepatic low Km phosphodiesterase

The effects of thyroid status on the activity of hepatic cAMP phosphodiesterase (PDE) were studied in the rat. Male rats were rendered hyperthyroid by treatment with T3 or hypothyroid by treatment with propylthiouracil. The hepatic particulate low Km PDE was solubilized, and its activity was measured at concentrations of 0.12-1.3 microM cAMP. The Km decreased in hypothyroidism and tended to increase in hyperthyroidism with respect to individual controls. The maximal velocity (Vmax) was unaffected by changes in thyroid status. The increases in Km correlated with increasing plasma T3, whereas the Vmax did not. Concentrations of cAMP increased in the livers from hyperthyroid rats and decreased in those from hypothyroid, in comparison with euthyroid rat livers. The effects of thyroid status on various aspects of hepatic lipid metabolism reported from this laboratory may, in part, have resulted from alterations in hepatic cAMP concentrations. These alterations, may have resulted secondarily from changes in the activity of hepatic PDE by changes in the Km for cAMP with little change in the Vmax.     

Nutritional profile of fibrocalculous pancreatic diabetes and primary forms of diabetes seen in southern India

Plasma levels of retinol binding protein (RBP), prealbumin, total protein, albumin, transferrin and ferritin were estimated in three groups of diabetic patients seen at a diabetes centre in S. India. The groups consisted of patients with fibrocalculous pancreatic diabetes (FCPD), non-insulin-dependent diabetes mellitus (NIDDM) and insulin-dependent diabetes mellitus (IDDM). Mean RBP levels were lower in FCPD and IDDM patients compared to controls but this did not reach statistical significance. Prealbumin levels were normal in FCPD patients, but low in IDDM compared to controls (P less than 0.005) and NIDDM (P less than 0.05). FCPD patients had lower transferrin levels compared to controls (P less than 0.05). There were no differences in the levels of total protein, albumin and ferritin in any of the study groups. The study shows that biochemical evidence of undernutrition is seen in FCPD and IDDM patients while NIDDM patients are not significantly different from non-diabetic control subjects.     

Diurnal variation of blood ketone bodies in insulin-dependent diabetes mellitus and noninsulin-dependent diabetes mellitus patients: the relationship to serum C-peptide immunoreactivity and free insulin

We examined whether the rise in ketone body concentration around midnight and in the early morning was due to the lack of free insulin (IRI) or excess of insulin counterregulatory hormones such as human growth hormone (hGH), cortisol and glucagon in noninsulin-dependent diabetes mellitus (NIDDM) and insulin-dependent diabetes mellitus (IDDM) patients and whether the monitoring of blood ketone body concentration was clinically useful as an index of metabolic control for deciding to increase or decrease the insulin dose in the treatment of diabetes mellitus. Serum levels of 3-hydroxybutyrate (3-OHBA), acetoacetate (AcAc) and 3-OHBA/AcAc ratio before breakfast were significantly increased in insulin-treated NIDDM patients with well-controlled fasting plasma glucose levels and IDDM patients compared to those in normal subjects. Mirror image diurnal changes were found between serum concentrations of 3-OHBA and serum C-peptide or free IRI in normal subjects and NIDDM patients treated with diet alone or sulfonylurea during the 24-hour daily profiles. However, there were no correlations between 3-OHBA and free IRI in the NIDDM patients treated with insulin and IDDM patients who had a much larger increase in the mean concentration of serum 3-OHBA at 6 a.m. caused by a low concentration of free IRI. Counterregulatory hormones were not increased in IDDM patients compared to normal subjects in the early morning. Cortisol/free IRI and hGH/free IRI molar ratios were significantly increased in NIDDM and IDDM patients compared to normal subjects in the early morning, but glucagon/free IRI molar ratio was not changed between IDDM and normal subjects. In conclusion, the early morning rising of ketone body concentration in insulin-treated diabetic patients, particularly IDDM patients, is due to the absolute lack of free IRI and/or the relative lack of free IRI to the levels of hGH or cortisol, and the monitoring of 3-OHBA is clinically useful as a more sensitive index of metabolic control.     

Anthropometric studies in diabetes in the Tropics

Summary Anthropometric studies were carried out in three groups of diabetics seen in southern India, namely fibrocalculous pancreatic diabetes (FCPD) (n=49) (a subtype of malnutrition related diabetes), insulin dependent diabetes mellitus (IDDM) (n=55) and non-insulin dependent diabetes mellitus (NIDDM) (n=104). Both FCPD and IDDM had significantly lower body mass index, skinfold thickness (triceps, biceps, subscapular and suprailiac), mid-arm circumference and fat mass compared to controls and NIDDM patients, (p<0.001 for all parameters). FCPD and IDDM males did not show any significant differences in any of the anthropometric parameters studied. Among the females, FCPD had lower triceps skinfold measurements (p=0.007) and mid-arm circumferences (p<0.05) compared to IDDM patients. Patients with NIDDM did not show any significant difference compared to the control group. This study shows that both FCPD and IDDM patients have lower body mass and fat mass compared to NIDDM patients and control subjects.     

Glucose tolerance and insulin response in parents of patients with insulin-dependent and juvenile-onset non-insulin-dependent diabetes mellitus.

Glucose tolerance and insulin response were examined using a 100 g oral glucose tolerance test (OGTT) in 108 parents of 23 patients with insulin-dependent (IDDM) and 31 patients with non-insulin-dependent diabetes mellitus (NIDDM), whose age of onset of diabetes was less than 35 years. Thirty-two age-matched healthy volunteers without a family history of diabetes were also examined as a control group. Diabetes and impaired glucose tolerance (IGT) were significantly more frequent in parents of NIDDM (diabetes 34%, IGT 27%) than in parents of IDDM (diabetes 7%, IGT 13%) (P less than 0.001). At least one parent had diabetes or IGT in 30% of IDDM and 84% of NIDDM patients (P less than 0.001), and both parents had diabetes or IGT in 9% of IDDM and 39% of NIDDM patients (P less than 0.02). Even in cases with 'normal' glucose tolerance, the mean plasma glucose was higher in parents of NIDDM than in control subjects, suggesting a high prevalence of abnormal glucose tolerance including the marginal degree of abnormality in the families of NIDDM. The early phase insulin response was decreased more among parents of NIDDM with the greater impairment of glucose tolerance. However, among those with 'normal' glucose tolerance, early phase insulin response did not differ between parents of IDDM and NIDDM, and control subjects. The results confirmed a stronger familial background in NIDDM patients of younger onset than in IDDM. The different patterns of glucose tolerance among two parents of young-onset NIDDM patients suggest heterogeneity of the mode of inheritance of NIDDM among families.     

Elevated levels of soluble E-selectin in patients with IDDM and NIDDM: relation to metabolic control

Summary The adhesion of leucocytes to the endothelium, an early step in atherogenesis, is mediated by cell adhesion molecules. In this study we evaluated the concentration of soluble adhesion molecules in patients with insulin-dependent (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM) and studied its relation to glycaemic control. Soluble adhesion molecules E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1) were measured in 31 diabetic patients (18 with IDDM and 13 with NIDDM), 20 hyperlipoproteinaemic patients (10 with type IIa and 10 with type IIb) and 20 healthy subjects. Increased E-selectin concentrations were found in the patients with IDDM and NIDDM and in the hyperlipoproteinaemic patients when compared to the control subjects (p<0.01 for all the groups). ICAM-1 was found to be elevated only in the patients with NIDDM (p<0.01). No significant differences in VCAM-1 concentration were found in the different groups of subjects. The concentration of plasma E-selectin was positively correlated with the glycated haemoglobin (r=0.54, p<0.01) in patients with IDDM and NIDDM. In the same patients E-selectin was not related to the concentrations of plasma lipids in spite of the fact that it was found to be elevated in hyperlipoproteinaemic subjects. The results though preliminary suggest that in diabetic patients the concentration of soluble adhesion molecules and especially of E-selectin may be related to metabolic control.Abbreviations IDDM insulin-dependent diabetes mellitus - NIDDM non-insulin-dependent diabetes mellitus - ICAM-1 intercellular adhesion molecule-1 - VCAM-1 vascular adhesion molecule-1 - AGE advanced glycation end products     

Analysis of diabetic family connection in subjects with insulin-dependent diabetes mellitus (IDDM)

The family connection of diabetes was examined from the clinical records of 3,372 subjects who were seen, as an out patient population, within the frame of a Regional Health Program in Taranto, South Italy. The family connection of diabetes resulted from a questionnaire in which the subjects had to give informations about their disease, if present, and degrees of relationship that were directly verified by us with the examination (clinic and laboratory) of relatives said to have diabetes. From the analysis of records, it emerged that 112 patients were affected by insulin-dependent-diabetes mellitus (IDDM): 54 of them were related with at least one subject suffering from noninsulin-dependent diabetes mellitus (NIDDM), 13 with at least one subject affected by IDDM and the remaining 45 did not show any family connection. The corresponding figures found in a group of healthy control subjects, matched to IDDM patients for age, sex and BMI, were 19, 2 and 84, respectively (p less than 0.001). 34 IDDM patients were related with a first degree of relationship (parents, sons, sibs) to diabetic subjects (IDDM or NIDDM), but only 4 controls showed such a degree (p less than 0.001). These results seem to indicate that patients with IDDM have an increased family history of NIDDM.     

Spontaneous diabetic BB rat: studies of cyclic adenosine 3',5'-monophosphate phosphodiesterase and calmodulin

Uncontrolled diabetes in man is associated with increased plasma and tissue levels of cAMP and decreased cAMP phosphodiesterase (PDE) activity. Spontaneously diabetic BB rats (SDR) were used in these experiments. Specific tissues (i.e. liver and epididymal fat) were studied without therapeutic insulin. Another group of normal animals were rendered diabetic by streptozotocin (STZ) and killed without benefit of insulin therapy. Calmodulin (CM), a small molecular weight protein essential for activation of specific cAMP PDE was assayed. STZ diabetes is associated with a decrease (58%) in CM biological activity and in immunoreactive CM in fat (69%) and liver (13%) tissues. Similarly, SDR rats and the nondiabetic genetic controls (NDR) demonstrate decreased CM bioactivity in fat (76% and 56%, respectively) and decreased CM immunoreactivity in liver (68% and 74%, respectively) compared to normal control rats. In addition, maximum velocity (Vmax) of the low Michaelis-Menten constant (Km) cAMP PDE is decreased in SDR animals, as compared to controls in both fat (42%) and liver (39%) tissues. Similar data are presented for NDR animals. STZ diabetes is also associated with a reduction in Vmax of the low Km cAMP PDE in both liver (70%) and fat (70%) tissues. These changes found in the NDR animals suggests that the diabetic defect may be under dual regulation: genetic and environmental.     

HDL metabolism in diabetes

Based on the data reviewed, it is necessary to conclude that diabetes is associated with profound changes in HDL metabolism. However, once we go beyond this simple generalization, it is apparent that the relationship between diabetes and HDL metabolism is not a simple one. A good deal of the complication evolves from the fact that IDDM and NIDDM seem to affect HDL metabolism quite differently, with the only apparent similarity the fact that plasma HDL-cholesterol concentration can be low in untreated patients with either IDDM or NIDDM. Thus, in patients with IDDM the primary event seems to be related to the insulin-deficient state, which results in a decrease in HDL turnover rate and resultant decline in plasma HDL-cholesterol concentration. In contrast, HDL turnover appears to be accelerated, not reduced in patients with NIDDM, and the low plasma HDL-cholesterol concentration is a consequence of the increased turnover rate. In addition, patients with NIDDM are not absolutely insulin deficient, and available evidence suggests that the higher the plasma insulin level, the lower the plasma HDL-cholesterol concentration in these patients. The differences noted above in the effect of IDDM and NIDDM on HDL metabolism are of great interest, and, unfortunately, not very well understood. There is, however, one additional difference, which may be of paramount clinical importance. For reasons not totally clear, plasma HDL-cholesterol concentrations in patients with IDDM treated with insulin are not lower than normal, and even tend to be higher than these values in a nondiabetic population. Possibly as a result of this phenomenon, there is no evidence that changes in plasma HDL-cholesterol concentration play a role in the development of macrovascular complications in IDDM. Although it is apparent from the considerations discussed in this review that a great deal more needs to be learned about the effect of insulin deficiency on HDL metabolism, changes in HDL metabolism do not appear to be clinically important in patients with IDDM. Unfortunately, this does not appear to be the situation in patients with NIDDM. Plasma HDL-cholesterol concentrations are lower than normal in patients with NIDDM, and this finding seems to be related to increased morbidity and mortality from CAD. Furthermore, there is no form of anti-diabetic treatment, irrespective of how effective it has been in achieving glycemic control, that has been shown to substantially increase plasma HDL-cholesterol level. Indeed, it has been difficult to demonstrate a consistent effect of any therapeutic approach on plasma HDL-cholesterol concentration.(ABSTRACT TRUNCATED AT 400 WORDS)     

Studies of insulin resistance in the streptozotocin diabetic and BB rat: activation of low Km cAMP phosphodiesterase by insulin

The streptozotocin diabetic rat (STZ-DM) has been the best animal model for the study of insulin-deficient diabetes. A spontaneous diabetic BB Wistar Rat (SDR) has now been evaluated as a model for insulin-dependent diabetes that more closely reflects this disease in humans. The authors assessed the ability of insulin to stimulate the Vmax of a low Km cAMP phosphodiesterase (PDE) in adipose tissue of control, streptozotocin diabetic (STZ-DM) rats, and spontaneous diabetic BB rats (SDR). In addition, the authors examined the effect of streptozotocin on the nondiabetic littermates of the SDR animal, the NDR rat. Insulin stimulated Vmax of low Km cAMP PDE in control rat adipose tissue by 20% at 5 minutes. Insulin also stimulated Vmax of both SDR and NDR by 50% at 5 minutes. In contrast to control and both subgroups of the BB rat (SDR and NDR), insulin stimulated adipose tissue from STZ-DM less than 10% at 5 minutes. NDR animals rendered diabetic with streptozotocin were more responsive to insulin. The data demonstrate some similarities and differences between streptozotocin-induced diabetes and spontaneous diabetes in the BB rat. Reduced responsiveness to insulin appears to be more a part characteristic of streptozotocin diabetes than diabetes in the BB rat. The absence of significant insulin resistance in the spontaneous diabetic BB rat also is more consistent with the pathophysiological mechanisms usually seen both in other insulin-dependent diabetic rat models and insulin-dependent diabetes in man. However, both animal models of diabetes, ie, STZ-DM and BB, like man, respond to insulin therapy.     

Analysis of plasma lipids and apolipoproteins in insulin-dependent and noninsulin-dependent diabetics

Plasma triglycerides, cholesterol, high-density lipoprotein (HDL) cholesterol, and apolipoproteins (apo) A-I, A-II, C-II, and C-III were determined and analyzed in 170 diabetic patients and 46 age-matched healthy normal subjects. The diabetics were separated into two groups: insulin-dependent diabetes mellitus (IDDM, n = 78) and noninsulin-dependent diabetes mellitus (NIDDM, n = 92). Significantly increased triglycerides, low HDL cholesterol, and normal cholesterol levels were found in the diabetics. The lipid profiles were similar in the IDDM and NIDDM groups. Plasma apo A-I, but not apo A-II, was low in both groups of diabetics. However, only in the IDDM subjects was there a statistically significant decrease in apo A-I when compared to normal subjects. The decreased apo A-I level negatively correlated with plasma triglycerides. Apo C-II and apo C-III were slightly increased in the diabetics compared to normal subjects. Apo C-II and apo C-III levels significantly correlated with plasma triglycerides (apo C-II, r = 0.70, P less than 0.0001; apo C-III, r = 0.71, P less than 0.0001). Only apo C-II correlated with total cholesterol. Thirty-eight to forty-two percent of the IDDM and NIDDM subjects had a clinical diagnosis of coronary artery disease (CAD) and/or peripheral arteriovascular disease (PAD). In the IDDM subjects, but not in the NIDDM subjects the incidence of CAD and/or PAD was associated with the decreased apo A-I levels as evaluated by a univariate analysis.(ABSTRACT TRUNCATED AT 250 WORDS)     

High activity of low-Michaelis-Menten constant 3', 5'-cyclic adenosine monophosphate-phosphodiesterase isozymes in renal inner medulla of mice with hereditary nephrogenic diabetes insipidus.

Our previous studies on microdissected kidney tubule segments indicate that the failure of vasopressin (VP) to increase cAMP content in collecting ducts of mice with hereditary nephrogenic diabetes insipidus (NDI mice) is due to abnormally rapid cAMP catabolism via cyclic-3',5'-nucleotide phosphodiesterases (PDE). Furthermore, the VP-stimulated cAMP accumulation can be restored by addition of PDE isozyme-specific inhibitors. To elucidate the biochemical basis of the NDI syndrome, we analyzed PDE activities in extracts from inner medullary tissues of NDI mice and from control mice separated with the use of ionex fast protein liquid chromatography on a Mono-Q column. In extracts of inner medullary tissues from either control or NDI mice, the low Michaelis-Menten constant (Km) cAMP-PDE activity specific for cAMP as a substrate (cAMP-PDE) was eluted from a Mono-Q column with linear sodium acetate gradient as peak 3 at Na-acetate concentration (0.75-0.93 M) and was well separated from fractions containing the Ca(2+)-calmodulin sensitive PDE. The cAMP-PDE activity in peak 3 was significantly higher in NDI mice (greater than delta + 100%) than in controls. The sensitivity to effect of cAMP-PDE isozyme-specific inhibitors, rolipram and cilostamide, indicates that peak 3 consists predominantly (approximately 75%) of the rolipram-sensitive PDE-IV isozyme and a minor portion (approximately 25%) of cilostamide-sensitive PDE-III isozyme in both control and NDI mice. Higher activity of PDE-IV in NDI mice was due to 2.4 times higher apparent maximum velocity compared to controls, whereas the apparent Km for cAMP was not different. Our results show that low Km cAMP-PDE activities, predominantly PDE-IV, are higher in inner medulla of NDI mice. We suggest that the higher activity of PDE-IV, and to a lesser degree perhaps also PDE-III, accounts for rapid cAMP hydrolysis, which prevents the increase of cAMP generated in the response to VP in collecting ducts of NDI mice.     

Comparison of renal hemodynamics in early non-insulin-dependent and insulin-dependent diabetes mellitus

The differences in deranged renal hemodynamics in non-insulin-dependent diabetes mellitus (NIDDM) and insulin-dependent diabetes mellitus (IDDM) have never been fully investigated. Whether or not autoregulatory mechanism of renal hemodynamics in NIDDM and IDDM is preserved remains to be clarified.In the present study we directly compared renal hemodynamics and its autoregulatory function in the early stage of NIDDM and IDDM before and after short-term glycemic control. Before glycemic control, mildly exaggerated glomerular filtration rate (GFR), subnormal renal plasma flow (RPF), and elevated filtration fraction (FF) were found in NIDDM as well as in IDDM; but there were no differences in these parameters of renal hemodynamics between the two types of diabetics. Glycemic control decreased GFR, whereas it did not alter RPF, resulting in normalization of FF in NIDDM and in IDDM. Before glycemic control, mean blood pressure was significantly correlated with GFR, but was not correlated after glycemic control in either type of diabetes. In conclusion, hyperglycemia induced glomerular hyperfiltration evenly and disturbed autoregulation of renal hemodynamics in NIDDM and in IDDM.     

Insulin regulates the 35 kDa IGF binding protein in patients with diabetes mellitus

The serum levels of the low molecular form of insulin-like growth factor binding protein (IGFBP) was determined in 56 outpatients with diabetes mellitus by a radioimmunoassay developed for amniotic 35 kDa IGFBP. The mean level of 35 kDa IGFBP was found to be threefold higher in insulin dependent diabetes mellitus (IDDM), 112 +/- 13 ng/ml, than in age matched controls, 37 +/- 2 ng/ml, while the mean level in non-insulin dependent diabetes mellitus (NIDDM), 16 +/- 2 ng/ml, was decreased. In hospitalized IDDM patients there was a significant correlation (r = 0.91, p less than 0.01) between fasting blood-glucose and 35 kDa IGFBP levels, not found in NIDDM patients. During insulin infusion the 35 kDa IGFBP levels declined with a half-life of 60-120 min. The decline in IGFBP continued even after the establishment of steady state B-glucose at 4.7 mmol/l. In conclusion, the elevated 35 kDa IGFBP levels in IDDM can be attributed to insulin deficiency and may reflect a reduced bioavailability of the IGFs at the target cells.