Molecular screening of the glucokinase gene in familial type 2 (non-insulin-dependent) diabetes mellitus

The question whether penicillin V (pcV) given intermittently upon signs of upper respiratory tract infections (URTI) in otitis-prone children might prevent recurrent bouts of acute purulent otitis media (AOM) is addressed. As compared with continuous long-term antibiotic treatment as prophylaxis in otitis-prone children, intermittent administration would reduce the overall consumption of antibiotics. Seventy-six otitis-prone children less than 18 months of age were included in this double-blind, randomized, placebo-controlled multicentre study. Follow-up was from January till June. One hundred and twenty-three episodes of AOM occurred. The number of AOM episodes was reduced by 50% in the children on pcV during URTI episodes as compared with those on placebo. No obvious ecological drawbacks were noted. Thus, the described mode of pcV administration seems to be a rational and safe way to reduce the number of AOM episodes in otitis-prone children.     

Hepatocyte nuclear factor-1alpha gene and non-insulin-dependent diabetes mellitus in the Japanese population

Since natural proteins are the products of a long evolutionary process, the structural properties of present-day proteins should depend not only on physico-chemical constraints, but also on evolutionary constraints. Here we propose a model for protein evolution, in which membranes play a key role as a scaffold for supporting the gradual evolution from flexible polypeptides to well-folded proteins. We suggest that the folding process of present-day globular proteins is a relic of this putative evolutionary process. To test the hypothesis that membranes once acted as a cradle for the folding of globular proteins, extensive research on membrane proteins and the interactions of globular proteins with membranes will be required.     

Pharmacokinetics of oral glyburide in subjects with non-insulin-dependent diabetes mellitus and renal failure

There is considerable controversy about the distal clearance margin that needs to be maintained beyond the extent of a rectal tumor in order to reduce the risk of local recurrence. We investigated the rate of local recurrence, distant metastases and survival in 87 patients who had undergone radical restorative resection of the rectum for cancer and had been followed up for a median period of over 6 years, and we analyzed the statistical relation (log-rank test for trend) with the length of the distal margin. The distal margin length was divided into three categories: 1 cm, 2 cm, and > or = 3 cm. No significant correlation was found between the length of the distal clearance margin and the oncologic outcome. Taken together, our data suggest that if the resection line distally falls on healthy tissue, there is no need to resect additional rectum in order to achieve a better outcome.     

Regulation of hepatic glucose production in healthy subjects and patients with non-insulin-dependent diabetes mellitus

The regulation of endogenous glucose production is central to the control of blood glucose concentrations. In non-insulin-dependent diabetes mellitus (NIDDM), increased endogenous glucose production contributes to fasting hyperglycaemia. Gluconeogenesis appears to be exaggerated in NIDDM, and it may be hypothesized that an enhanced release of gluconeogenic precursors is responsible for increased total glucose output. However, it would appear that substrate-induced stimulation of gluconeogenesis fails to increase total glucose production in healthy humans and NIDDM patients. This autoregulation of endogenous glucose production may be attained by inhibition of glycogenolysis and/or gluconeogenesis from endogenous substrate. It has also been observed that stimulation of intrahepatic disposal of neoformed glucose (mainly as glycogen synthesis) contributes to autoregulation. These observations support the concept that intrahepatic disposal of glucose-6-phosphate plays a major role in the control of endogenous glucose production.     

Lack of association of the insulin gene region with type 1 (insulin-dependent) diabetes mellitus in Japanese subjects

Although the insulin gene region is implicated in susceptibility to Type 1 (insulin-dependent) diabetes mellitus in Caucasians, significance of this region to Type 1 diabetes in Japanese remains unclear because the class 1 alleles (shorter insertion) of the variable number of tandem repeat in the 5' region of the insulin gene are predominant in both diabetic and non-diabetic subjects. The 5' insulin gene polymorphism was analysed in 75 Japanese patients and 69 control subjects with a precise method using PvuII and a polymorphism specific probe, which enabled us to divide class 1 alleles into four subclasses. Allelic frequencies were not significantly different between Type 1 diabetic patients and control subjects. The polymorphism in the 3' untranslated region of the insulin gene (1127/PstI) was also analysed and found to be tightly linked to the 5' insulin gene polymorphism, and thus was not associated with diabetes. Interaction between HLA-DR and the insulin gene region, which was reported in the French study, was not observed in Japanese. These results suggest that the insulin gene region is not a valuable genetic risk factor for Type 1 diabetes in Japanese.     

Effects of diet composition and ketosis on glycemia during very-low-energy-diet therapy in obese patients with non-insulin-dependent diabetes mellitus

To determine whether high-ketogenic very-low-energy diets (VLEDs) can reduce hepatic glucose output (HGO) and hyperglycemia more effectively than can low-ketogenic VLEDs in obese patients with non-insulin-dependent diabetes mellitus (NIDDM), seven patients were treated with a high-ketogenic VLED for 3 wk and were compared with six patients treated with a low-ketogenic VLED. All patients were then crossed over and treated with the alternate diet for another 3 wk. Basal HGO, fasting ketone bodies, and glycemia, insulin, and C-peptide after fasting and an oral-glucose-tolerance test (OGTT) were measured. Before treatment, prediet weight and fasting, OGTT, and HGO measurements were not different between groups. After dieting, weight loss was not different between the groups. However, fasting and OGTT glycemia were lower during treatment with the high-ketogenic VLED than with the low-ketogenic VLED (treatment effect: P < 0.05, by analysis of variance). Moreover, there was a strong correlation between basal HGO and fasting plasma ketone bodies (r = -0.71 at 3 wk, r = -0.67 at 6 wk; both P < 0.05). In contrast, fasting and OGTT plasma insulin and C-peptide concentrations were not different between treatment groups. These data indicate that in obese patients with NIDDM, high-ketogenic VLEDs have a more clinically favorable effect on glycemia than do low-ketogenic VLEDs.     

Frequency of diabetes in family members of probands with non-insulin-dependent diabetes mellitus

OBJECTIVES: To describe the prevalence of known diabetes in a multi-ethnic community in South Auckland, New Zealand, in relation to family history of diabetes and past history of diabetes in pregnancy. DESIGN: A cross-sectional, household survey comparing ascertainment with local general practice diabetes registers where they existed. SETTING: An inner-city community with a high proportion of Maori, Pacific Islands people and Europeans. SUBJECTS: A total of 55,518 residents (91% response). Comparison with diabetes registers showed 91% ascertainment of known diabetic residents. More detailed interviews with 176/214 (82%) Europeans, 286/336 (85%) Maori and 495/585 (85%) Pacific Islands people with known diabetes. Fifty subjects had insulin-dependent diabetes mellitus on clinical criteria and were excluded from analyses. MAIN OUTCOME MEASURES: Prevalence of diabetes. RESULTS: Those with non-insulin-dependent diabetes mellitus were more likely to have a diabetic mother than father (Europeans, 21.7% vs. 9.9%; Maori, 17.6 vs. 11.4%; Pacific Islands, 15.7 vs. 5.3%). Diabetic women had a similar likelihood of having a diabetic father as diabetic men but were 1.84 times as likely to have a diabetic mother (95% CI, 1.27-2.69). Diabetic women with past diabetes in pregnancy had 2.05 (95% CI, 1.01-4.15) times the chance of a diabetic offspring as women who had not had past diabetes in pregnancy, who in turn had 2.69 (95% CI, 1.17-6.18) times the likelihood of having a diabetic offspring as diabetic men. CONCLUSIONS: The mother is a more important conduit for inheritance of diabetes than the father in these three ethnic groups. A history of diabetes in pregnancy confers an extra risk to the offspring above this usual maternal excess.     

Influence of 16-week monotherapy with acarbose on cardiovascular risk factors in obese subjects with non-insulin-dependent diabetes mellitus: a controlled, double-blind comparison study with placebo

A 49-year-old patient suffered from a binocular perforating trauma with metal foreign bodies in 1974. During an MRI examination in 1992 for a lumbar spine herniation a metal foreign body was mobilised from the deeper vitreal and retinal area, now causing optical disturbances freely floating in the anterior vitreous. Refusing an operation, the patient, an electrical engineer, tried himself to remove the foreign body out of the optical axis by exposing his head to the electro-magnetic field of an induction coil (pulsed magnetic induction B at t0 of 0.26 Tesla). The foreign body was split into multiple small parts no longer disturbing the patient. To early detect a siderosis regular ophthalmological controls including ERG are necessary. This example stresses that even small intraocular metal foreign bodies are a contraindication for the usually applied field strength of MRI examinations.     

The antidyslipoproteinemic activity of ufibrate in patients with non-insulin-dependent diabetes mellitus

Ufibrate (150 mg daily) was found to have a beneficial effect on main parameters characterizing lipid metabolism, with no effect being exerted on carbohydrate metabolism, as evidenced by three months' follow-up of 24 patients aged 42 to 65 presenting with insulin-nondependent type II diabetes mellitus and hyperlipidemia. Ufibrate appeared to be a most efficacious long-term drug treatment option, particularly so in those patients presenting with initially high blood levels of a great many of lipid fractions.     

Prevalence and aspects of arteriopathies in non-insulin-dependent diabetes mellitus with severe hypertension

Severe hypertension may lead to macroangiopathy complications especially when a major vascular risk factor as diabetes exists. We have studied the prevalence of macroangiopathy in a group of 40 consecutive NIDDM patients with severe hypertension (> or = 3 hypotensive drugs) (grS) that we have compared to 80 consecutive NIDDM patients with controlled hypertension (1 or 2 hypotensive drugs) (grC). All patients have had metabolic, blood pressure (ABPM) and vascular (color duplex) investigations. The two groups were similar for age (years): 61.9 > or = 9 versus 65.2 +/- 9.5, diabetes duration (years): 10.7 +/- 7 versus 12.1 +/- 8 and hypertension duration: (years) 8.9 +/- 8 versus 11.7 +/- 7.3. The mean level of blood pressure was the same in all patients (mmHg): SBP = 138 +/- 14 versus 144 +/- 20; DBP = 80 +/- 9 versus 83 +/- 13; MBP = 100 +/- 10 versus 105 +/- 15. The frequency (%) of escape SBP (> 140): 50 versus 80, p < 0.01), and DBP (> 90): 29 versus 35, p < 0.05 was significantly higher in grS. Twenty (25%) patients in grC and 20 (50%) in grS had one or more macroangiopathy which was dispatched as follow: coronary heart disease n = 8 (7%) versus 13 (32.5%), p < 0.01; lower limb arteritis n = 12 (15%) versus n = 9 (22%), NS; carotid atheroma n = 5 (25) versus n = 6 (15%), NS. All significant renal artery stenosis (RAS) n = 8 (20%) were found in grS (p < 0.001). Only plasma triglyceride level (mmol/L) was statistically higher in grS 2.5 +/- 1.2 versus +/- 1 while BMI, plasma cholesterol, HbA1C, and creatininemia were NS. The sex-ratio (F/M) 1.28 versus 3, insulin requirement (%): 11 versus 42.5, retinopathy (%) 14 versus 45 and micromacroalbuminuria were statistically significant p < 0.01. Conclusion: macroangiopathy is frequent in severe hypertension (50%) versus controlled hypertension (25%) in NIDDM patients especially coronary heart disease (32.5%); the prevalence of RAS is high in grS (20%). The following criteria are frequently noticed in high risk patients: insulin requirement, micro or macroalbuminuria and high plasma triglyceride.     

Beta-cell dysfunction in first-degree relatives of patients with non-insulin-dependent diabetes mellitus

To analyse the relationship between age, glucose tolerance, beta-cell function, and insulin sensitivity in preclinical states of non-insulin-dependent (Type 2) diabetes mellitus (NIDDM), we have done a cross-sectional, age-stratified analysis of 86 non-diabetic first-degree relatives of NIDDM patients and 49 controls with similar age, sex, and BMI. A 5 mg kg ideal body weight-1 min-1 for 60 min of continuous infusion of glucose with model assessment (CIGMA) of serum glucose and C-peptide values at the end of the infusion was used to determine glucose tolerance and beta-cell function. Insulin sensitivity was estimated by modelling basal serum glucose and insulin values. Relatives and controls were divided into tertiles on the basis of age. Relatives had higher basal (5.3 vs 5 mmol l-1, p = 0.02) and achieved serum glucose (9.1 vs 8.4 mmol l-1, p = 0.01), lower beta-cell function (128 vs 145%, p = 0.007), and lower insulin sensitivity (37 vs 43%, p = 0.002). Beta-cell function declined with age in relatives (from 139% in young subjects to 134% in intermediate subjects and to 111% in older subjects, p = 0.002) and this decline was associated with an increase in basal serum glucose (from 5.1 to 5.3 and to 5.7 mmol l-1, p = 0.000) and achieved glucose (from 8.3 to 9.1 and to 9.3 mmol l-1, p = 0.038), without significant changes in insulin sensitivity. These trends were observed even after the exclusion of subjects with mild glucose intolerance. We conclude that both beta-cell dysfunction and insulin resistance are present in first-degree relatives of NIDDM. The progression of beta-cell dysfunction and glucose intolerance with age suggests that beta-cell dysfunction is the key factor in the apparition and progression of the disease.     

Effects of glycemic control on saliva flow rates and protein composition in non-insulin-dependent diabetes mellitus

Records from patients admitted to the surgical or medical department or examined in the respective outpatient departments in a Kuwaiti district hospital were reviewed retrospectively to discern the demographic characteristics of patients with complicated urinary tract infections (UTI), underlying conditions, pathogens and their antimicrobial susceptibility patterns. Kuwaiti nationals constituted the largest group, followed by Egyptians, which in the population of 225 patients studied comprised 41% and 27%, respectively; 65 of these 225 patients (29%) had urinary stones; 33 of the 92 Kuwaiti patients (36%) had diabetes mellitus; 38 of the 60 Egyptian patients (63%) had urinary stones and 18 had bilharziasis (30%). Pathogens were isolated 353 times from 225 patients. Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and several other organisms in those patients with bilharziasis, urinary stones, and especially diabetes mellitus, displayed lower susceptibility frequencies to antimicrobials in comparison with other surgical and medical UTI isolates. Surgical and medical UTI organisms showed an overall higher antimicrobial resistance frequency than did UTI organisms from the maternity department or regional clinics. More than half of the population of Kuwaiti consists of expatriates from different countries. Such a population structure can exhibit peculiarities when health is considered. All this should be taken into consideration while dealing with disease management.     

Impaired activity and gene expression of hexokinase II in muscle from non-insulin-dependent diabetes mellitus patients

After entering the muscle cell, glucose is immediately and irreversibly phosphorylated to glucose-6-phosphate by hexokinases (HK) I and II. Previous studies in rodents have shown that HKII may be the dominant HK in skeletal muscle. Reduced insulin-stimulated glucose uptake and reduced glucose-6-phosphate concentrations in muscle have been found in non-insulin-dependent diabetes mellitus (NIDDM) patients when examined during a hyperglycemic hyperinsulinemic clamp. These findings [correction of finding] are consistent with a defect in glucose transport and/or phosphorylation. In the present study comprising 29 NIDDM patients and 25 matched controls, we tested the hypothesis that HKII activity and gene expression are impaired in vastus lateralis muscle of NIDDM patients when examined in the fasting state. HKII activity in a supernatant of muscle extract accounted for 28 +/- 5% in NIDDM patients and 40 +/- 5% in controls (P = 0.08) of total muscle HK activity when measured at a glucose media of 0.11 mmol/liter and 31 +/- 4 and 47 +/- 7% (P = 0.02) when measured at 0.11 mmol/liter of glucose. HKII mRNA, HKII immunoreactive protein level, and HKII activity were significantly decreased in NIDDM patients (P < 0.0001, P = 0.03, and P = 0.02, respectively) together with significantly decreased glycogen synthase mRNA level and total glycogen synthase activity (P = 0.02 and P = 0.02, respectively). In the entire study population HKII activity estimated at 0.11 and 11.0 mM glucose was inversely correlated with fasting plasma glucose concentrations (r = -0.45, P = 0.004; r = -0.54, P < 0.0001, respectively) and fasting plasma nonesterified fatty acid concentrations (r = -0.46, P = 0.003; r = -0.37, P = 0.02, respectively). In conclusion, NIDDM patients are characterized by a reduced activity and a reduced gene expression of HKII in muscle which may be secondary to the metabolic peturbations. HKII contributes with about one-third of total HK activity in a supernatant of human vastus lateralis muscle.     

Total cholesterol and high-density lipoprotein cholesterol in patients with non-insulin-dependent diabetes mellitus

Non-insulin-dependent diabetics often have quantitative changes in plasma lipid profiles characterised by higher triglycerides and lower HDL-cholesterol than the average population. This paper summarises the cross-sectional data (reported by the general practitioners participating in Medicos-Sentinela) concerning total and HDL-cholesterol in a cohort of non-insulin-dependent diabetics treated at primary care settings in Portugal. Total cholesterol and High Density Lipoprotein (HDL) associated cholesterol were significantly higher in women. Total cholesterol increased significantly with age (in women), regular alcohol intake, body mass index, systolic blood pressure and diastolic blood pressure (in males). HDL-cholesterol showed significant increase with age (both sexes and males only), gender, and alcohol intake in males. The increase in total cholesterol found in patients with regular alcohol intake is an infrequently reported finding.     

Increased intracellular calcium and altered phorbol dibutyrate binding to intact platelets in young subjects with insulin-dependent and non-insulin-dependent diabetes mellitus

Intracellular calcium ([Ca2+]i) and phorbol ester binding were studied in intact platelets of young patients with insulin-dependent (IDDM) and non-insulin-dependent (NIDDM) diabetes mellitus. Our objective was to evaluate disturbances in calcium regulation and signal transduction in platelets of diabetics. [Ca2+]i in platelets of the IDDM group (135 +/- 20 nmol/L) under basal conditions was significantly higher than that of the control group (81 +/- 8 nmol/L, P = .019), whereas at 60 seconds after stimulation with 0.1 National Institutes of Health (NIH) U/mL thrombin, [Ca2+]i in the NIDDM group (484 +/- 36 nmol/L) was significantly higher than that of the controls (347 +/- 22 nmol/L, P = .003) and IDDM group (360 +/- 45 nmol/L, P = .04), respectively. Phorbol 12,13-dibutyrate (PdBu) maximal binding capacity (Bmax) in the IDDM group was significantly lower than that in the control group either under basal conditions or after stimulation with thrombin (P = .0034 and P = .015, respectively). Bmax in the NIDDM group was significantly lower than that in the controls only after stimulation with thrombin (P = .047). The Kd for PdBu of the IDDM group was lower than that of the control group under basal conditions (P = .017). When analyzing the pooled data of all subjects, a significant correlation was observed between Bmax and Kd (under basal conditions, r = .544, P < .0001; after stimulation, r = .601, P < .0001). Our results support the idea that the increased affinity for PdBu may compensate for the decreased binding capacity. We interpret the data as indicating that the change in the binding of phorbol ester to protein kinase C (PKC) units may result in an altered PKC/calcium interaction in the pathogenesis of diabetes mellitus. Our study indicates that such metabolic derangements of [Ca2+]i have already been developing in young diabetic patients.     

Breastfeeding and incidence of non-insulin-dependent diabetes mellitus in Pima Indians

BACKGROUND: Early exposure to cow's milk has been implicated in the occurrence of insulin-dependent diabetes mellitus but there is little information about infant-feeding practices and subsequent non-insulin-dependent diabetes mellitus (NIDDM). We examined the association between breastfeeding and NIDDM in a population with a high prevalence of this disorder, the Pima Indians. METHODS: Glucose-tolerance status was obtained from a 75 g oral glucose-tolerance test. A standard questionnaire given to mothers was used to classify infant-feeding practices for the first 2 months of life into three groups; exclusively breastfed, some breastfeeding, or exclusively bottlefed. The association between the three infant-feeding groups and NIDDM was analysed by multiple logistic regression. FINDINGS: Data were available for 720 Pima Indians aged between 10 and 39 years. 325 people who were exclusively bottlefed had significantly higher age-adjusted and sex-adjusted mean relative weights (146%) than 144 people who were exclusively breastfed (140%) or 251 people who had some breastfeeding (139%) (p = 0.019). People who were exclusively breastfed had significantly lower rates of NIDDM than those who were exclusively bottlefed in all age-groups (age 10-19, 0 of 56 vs 6 [3.6%] of 165; age 20-29, 5 [8.6%] of 58 vs 17 [14.7%] of 116]; age 30-39, 6 [20.0%] of 30 vs 13 [29.6%] of 44). The odds ratio for NIDDM in exclusively breastfed people, compared with those exclusively bottlefed, was 0.41 (95% CI 0.18-0.93) adjusted for age, sex, birthdate, parental diabetes, and birthweight. INTERPRETATION: Exclusive breastfeeding for the first 2 months of life is associated with a significantly lower rate of NIDDM in Pima indians. The increase in prevalence of diabetes in some populations may be due to the concomitant decrease in breastfeeding.     

Insertion/deletion polymorphism in the angiotensin-converting enzyme gene associated with macroangiopathy and blood pressure in patients with non-insulin-dependent diabetes mellitus

In the search for new risk factors for diabetic macroangiopathy the insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme gene was studied in 237 consecutive patients (125 men and 112 women) with non-insulin-dependent diabetes. The female population showed an excess of ischemic electrocardiographic changes or definite myocardial infarctions in the patients homozygous for the deletion [D/D; odds ratio (OR) 2.8; 95% confidence interval (CI) 1.4-5.3] and in the insertion/deletion heterozygotes (I/D; OR 1.8; CI 1.1-3.1) compared with the patients homozygous for the insertion (I/I). In the total series coronary heart disease, cerebrovascular disease, and claudication were more often observed in the patients with I/D (OR 1.5; CI 1.0-2.2) or the D/D genotype patients (OR 1.7; CI 1.1-2.6) than in those with the genotype I/I. The systolic blood pressure was lower in patients with genotype I/I (138 +/- 19 mmHg) than in those with the genotype I/D (149 +/- 22 mmHg) or D/D (150 +/- 21 mmHg; P < 0.02). The prevalence of hypertension and the median urinary albumin excretion rate also tended to be lowest in the I/I genotype patients. Multiple logistic analysis revealed that in women the angiotensin-converting enzyme D/D genotype is independently associated with coronary heart disease. Our findings suggest that variation at the angiotensin-converting enzyme gene locus is one of the factors involved in the predisposition of diabetic patients to the development of arterial disease and hypertension.     

Early lifestyle intervention in patients with non-insulin-dependent diabetes mellitus and impaired glucose tolerance

Some adult cleft palate patients show severe maxillary transverse contraction and posterior crossbite. This case report demonstrates successful surgical-orthodontic treatment of such a patient. Surgically assisted rapid maxillary expansion (SA-RME) was completed prior to comprehensive orthodontic treatment. The osteotomy was performed on both the buccal and lingual aspects of the posterior maxillary alveolus. A Hyrax-type maxillary-expansion appliance was used, and the screw (0.2 mm, one quarter turn) was turned two or three times per day. Comprehensive orthodontic treatment was initiated after extraction of the mandibular first premolars and four third molars. The maxillary lateral incisors were also extracted after active orthodontic treatment. The amount of expansion achieved using SA-RME was greater at the posterior than at the anterior maxilla. Midpalatal suture opening occurred. After orthodontic treatment, occlusal stability was satisfactory. This case demonstrates the effectiveness of SA-RME in adult cleft palate patients with severe posterior crossbite.     

Endothelium-dependent relaxation in peripheral vasculature and kidney of non-insulin-dependent diabetes mellitus

Desmopressin (DDAVP), an AVP.V2-receptor agonist, evokes endothelium-dependent relaxation (EDR) due to nitric oxide (NO), EDR factor (EDRF) in the systemic vasculature, and glomerular afferent arterioles via AVP receptor(s). Glyceryl trinitrate (GTN) causes endothelium-independent (nonreceptor-mediated) vasodilation. We elucidated the possible involvement of EDRF in early non-insulin-dependent diabetes mellitus (NIDDM) and glomerular hyperfiltration (GHF) by DDAVP and GTN infusions. Patients with advanced DM nephropathy (DM.Np) (n = 7) were also examined. DDAVP and GTN decreased the mean blood pressure in DM with GHF (DM + GHF) and without GHF (DM-GHF) greater than that in normal subjects (N), without any difference in the heart rate changes in any group. Plasma levels of cGMP, a cellular messenger of NO, were significantly increased by DDAVP and GTN with a similar increment in each group. DDAVP caused a significant increase in urinary cGMP excretion in each group with a similar increment in each group. However, it caused a transient increase in creatinine clearance only in DM + GHF although GTN did not, and an exaggerated excretion of urinary albumin in early NIDDM, especially in DM+GHF, without a change in beta 2-microglobulin excretion. In contrast, in DM.Np GTN caused a decrease in blood pressure and an increase in plasma cGMP levels, but DDAVP did not. In conclusion, in peripheral vasculature and kidney, an enhanced sensitivity of vascular smooth muscle to NO is present in early NIDDM. The exaggerated dilation of glomerular afferent arterioles by preferentially produced NO in in situ, which causes a rise in PGC, might be partly responsible for the glomerular hyperfiltration and subsequently the increase in the glomerular protein permeation of DM+GHF. However, in peripheral blood vessels of DM.Np EDR is impaired. Thus, EDR seems to change with the development of NIDDM.