Hypoglycemia is independently associated with multidimensional impairment in elderly diabetic patients.

AIM: To identify the characteristics associated with multidimensional impairment, evaluated through the Multidimensional Prognostic Index (MPI), a validated predictive tool for mortality derived from a standardized Comprehensive Geriatric Assessment (CGA), in a cohort of elderly diabetic patients treated with oral hypoglycemic drugs. METHODS AND RESULTS: The study population consisted of 1342 diabetic patients consecutively enrolled in 57 diabetes centers distributed throughout Italy, within the Metabolic Study. Inclusion criteria were diagnosis of type 2 diabetes mellitus (DM), 65 years old or over, and treatment with oral antidiabetic medications. Data concerning DM duration, medications for DM taken during the 3-month period before inclusion in the study, number of hypoglycemic events, and complications of DM were collected. Multidimensional impairment was assessed using the MPI evaluating functional, cognitive, and nutritional status; risk of pressure sores; comorbidity; number of drugs taken; and cohabitation status. The mean age of participants was 73.3 ± 5.5 years, and the mean MPI score was 0.22 ± 0.13. Multivariate analysis showed that advanced age, female gender, hypoglycemic events, and hospitalization for glycemic decompensation were independently associated with a worse MPI score. CONCLUSION: Stratification of elderly diabetic patients using the MPI might help to identify those patients at highest risk who need better-tailored treatment.

The METABOLIC Study: multidimensional assessment of health and functional status in older patients with type 2 diabetes taking oral antidiabetic treatment.

AIM: The objective of the METABOLIC Study was to evaluate overall health status, with particular focus on assessment of functional status of older patients taking oral antidiabetic drug (OAD) treatment. METHODS: The study included 1342 type 2 diabetes patients aged ≥ 65 years treated with OADs, with or without insulin, who had been referred to outpatients clinics across Italy. Information on diabetes (duration, medications taken during the last 3 months, hypoglycaemic events and diabetic complications) was collected by questionnaire, and the patients' overall health status was assessed using a multidimensional prognostic index. RESULTS: The sample recruited (mean age: 73.3 ± 5.5 years) had a mean duration of diabetes of 11.3 ± 8.2 years. Half were taking sulphonylureas alone or together with other medications, 9.7% were taking insulin in combination with other OADs, almost 30% were using biguanides and 6.2% were taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Also, 12% of patients reported hypoglycaemic events, 90% of whom were taking insulin or sulphonylureas. In addition, 81% of the participants were completely independent in their activities of daily living, while 19% were mildly, moderately or severely disabled. Age, female gender, hypoglycaemic events, neuropathy and low diastolic blood pressure were the main variables associated with disability. CONCLUSION: Disability is common in older diabetic patients and some associated factors, such as hypoglycaemia and low diastolic blood pressure, have been identified. Also identified was malnutrition as a specific factor associated with hypoglycaemic events independent of the use of insulin and sulphonylureas.

Optimized glycaemic control achieved with add-on basal insulin therapy improves indexes of endothelial damage and regeneration in type 2 diabetic patients with macroangiopathy: a randomized crossover trial comparing detemir versus glargine.

AIMS: In diabetes, endothelial damage promotes macroangiopathy and endothelial regeneration is impaired, owing to reduced endothelial progenitor cells (EPCs). Given that insulin influences endothelial biology, we compared the effects of add-on basal insulin analogues on endothelial damage and regeneration in type 2 diabetes (T2D). METHODS: This was a 6-month randomized crossover trial comparing add-on insulin detemir versus glargine in poorly controlled T2D with macroangiopathy. At baseline, crossover (3 months) and study end (6 months), we measured HbA1c, EPCs, circulating endothelial cells (CECs), VCAM-1, ICAM-1 and E-selectin. Body weight and hypoglycaemic episodes were also recorded. RESULTS: Forty-two patients completed the study, randomly assigned to the glargine-detemir (n = 21) or the detemir-glargine (n = 21) schedule. At crossover, EPC levels did not change compared with baseline, but significantly increased at study end. CECs decreased over time and were significantly reduced at study end. ICAM-1, VCAM-1 and E-selectin were significantly reduced at crossover and further decreased at study end. No differences were seen in these effects between detemir and glargine. HbA1c showed a carryover effect and its reduction was similar with detemir and glargine in the first arm. Incidence of hypoglycaemia and weight gain was lower with detemir than with glargine in both arms. CONCLUSION: Optimized glycaemic control by add-on basal insulin improved indexes of endothelial damage and regeneration. Compared to glargine, detemir achieved similar endothelial protection with lower weight gain and less hypoglycaemia. These results might have implications for therapy of aging T2D patients with cardiovascular disease.

Microangiopathy is independently associated with presence, severity and composition of carotid atherosclerosis in type 2 diabetes.

BACKGROUND AND AIMS: Common mechanisms for the development of micro- and macroangiopathic diabetic complications have been suggested. We aimed to cross-sectionally investigate strength and characteristics of the association between carotid atherosclerosis and microangiopathy in type 2 diabetic patients. METHODS AND RESULTS: Common carotid artery intima-media thickness (cIMT), carotid plaque (CP) type and degree of stenosis were evaluated by ultrasound, along with the determination of anthropometric parameters, HbA1c, lipid profile, assessment of diabetic retinopathy and nephropathy, in 662 consecutive patients with type 2 diabetes mellitus (T2DM). Patients were divided according to high/low cIMT, presence/absence of CP and of retinopathy and nephropathy. Patients with CP were older, more prevalently males, past smokers, had longer diabetes duration, significantly lower HDL cholesterol and more prevalent ischemic heart disease (all p<0.05) as compared to those with cIMT < 1 mm. Microangiopathies were more prevalent in patients with CP than in those without. At multivariate logistic regression, factors independently associated with the presence of CP were age, past smoke, HDL cholesterol, retinopathy and retinopathy plus nephropathy. A significant independent correlation of CP stenosis with stage of retinopathy and nephropathy was found. Finally, echolucent CPs were associated with a lower prevalence of proliferative retinopathy than CP containing calcium deposits. CONCLUSION: In T2DM, retinopathy, alone or in combination with nephropathy, is independently associated to CP, and severity of microangiopathy correlates with severity of carotid atherosclerosis. These observations, together with the different prevalence of proliferative retinopathy according to CP types, point to possible common pathogenic mechanisms in micro- and macrovascular complications.

A low-magnetic-field soft gamma repeater.

Soft gamma repeaters (SGRs) and anomalous x-ray pulsars form a rapidly increasing group of x-ray sources exhibiting sporadic emission of short bursts. They are believed to be magnetars, that is, neutron stars powered by extreme magnetic fields, B ~ 10(14) to 10(15) gauss. We report on a soft gamma repeater with low magnetic field, SGR 0418+5729, recently detected after it emitted bursts similar to those of magnetars. X-ray observations show that its dipolar magnetic field cannot be greater than 7.5 × 10(12) gauss, well in the range of ordinary radio pulsars, implying that a high surface dipolar magnetic field is not necessarily required for magnetar-like activity. The magnetar population may thus include objects with a wider range of B-field strengths, ages, and evolutionary stages than observed so far.

An ultramassive, fast-spinning white dwarf in a peculiar binary system.

White dwarfs typically have masses in a narrow range centered at about 0.6 solar mass (M(o)). Only a few ultramassive white dwarfs (mass > 1.2 M(o)) are known. Those in binary systems are of particular interest, because a small amount of accreted mass could drive them above the Chandrasekhar limit, beyond which they become gravitationally unstable. Using data from the x-ray multimirror mission (XMM)-Newton satellite, we show that the x-ray pulsator RX J0648.0-4418 is a white dwarf with mass > 1.2 M(o), based on dynamical measurements only. This ultramassive white dwarf in a post-common envelope binary with a hot subdwarf can reach the Chandrasekhar limit, and possibly explode as a type Ia supernova, when its helium-rich companion will transfer mass at an increased rate through Roche lobe overflow.

Characterization and ACE-inhibitory activity of amaranth proteins.

Amaranth seeds have been considered as an excellent alternative or complementary source of food protein due to their balanced amino acid composition. However, their potential as a source of bioactive peptides has not been explored. The present study is aimed at characterizing and evaluating the activity of the angiotensin converting enzyme inhibitor of the amaranth protein concentrate and of hydrolysates produced with Alcalase. The protein concentrate, after simulated gastrointestinal digestion, showed lower angiotensin converting enzyme-inhibitory activity (IC(50) of 0.439 +/- 0.018 mg protein/mL and 0.475 +/- 0.021 mg protein/mL, for untreated and heat treated protein concentrate, respectively) than the hydrolysates produced with Alcalase, before and after simulated gastrointestinal digestion (IC(50) 0.118 +/- 0.009, 0.123 +/- 0.007, 0.137 +/- 0.002, and 0.176 +/- 0.014 mg protein/mL, respectively). The simulated gastrointestinal digestion (pepsin-pancreatin) did not significantly alter the angiotensin-converting enzyme inhibiting activity of the Alcalase hydrolysates, suggesting that the peptides of the hydrolysates were resistant to gastrointestinal hydrolysis. These results highlight the angiotensin converting enzyme-inhibitory potential of amaranth proteins, which is an indication of their health-promoting potential.

Cerebrovascular disease in diabetes mellitus: the role of carotid intima-media thickness.

BACKGROUND AND PURPOSE: Cerebrovascular disease in diabetes appears to be less considered than coronary and peripheral disease, the reason being the intrinsic difficulty in finding available diagnostic tools for its early identification. Among these, carotid artery intima-media thickness (cIMT) represents the simplest measurable parameter for pre-atherosclerotic lesions in extra-cranic arteries. METHODS: The role of cIMT as a surrogate marker of cerebral atherosclerosis and predictor of stroke, its relationship to microangiopathy and chronic inflammation, along with its role as an outcome parameter in anti-hyperglycemic therapeutical intervention trials in type 2 and 1 diabetes mellitus are discussed in this paper. RESULTS AND CONCLUSIONS: Carotid IMT is increased in diabetes. It is an independent predictor of stroke, in particular of the ischemic subtype, and of stroke recurrence in diabetic, as well as in non-diabetic populations. A possible role of cIMT as a predictor of microangiopathy has also been suggested, but it needs further investigation. A weak association with chronic inflammation has been demonstrated in diabetic patients. Carotid IMT has been successfully employed as an outcome parameter for several anti-hyperglycemic therapeutic trials. However data on cIMT as a predictor of cerebrovascular disease are scarce in diabetic patients, particularly in type 1 diabetes, and more studies are needed to define the risk of cerebrovascular disease in diabetic patients.

Hepatic lipid metabolism and non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is an increasingly recognized pathology with a high prevalence and a possible evolution to its inflammatory counterpart (non-alcoholic steatohepatitis, or NASH). The pathophysiology of NAFLD and NASH has many links with the metabolic syndrome, sharing a causative factor in insulin resistance. According to a two-hit hypothesis, increased intrahepatic triglyceride accumulation (due to increased synthesis, decreased export, or both) is followed by a second step (or "hit"), which may lead to NASH. The latter likely involves oxidative stress, cytochrome P450 activation, lipid peroxidation, increased inflammatory cytokine production, activation of hepatic stellate cells and apoptosis. However, both "hits" may be caused by the same factors. The aim of this article is to overview the biochemical steps of fat regulation in the liver and the alterations occurring in the pathogenesis of NAFLD and NASH.

The metabolic syndrome, diabetes and lung dysfunction.

Sleep-disordered breathing and sleep apnoea are conditions frequently associated with comorbidity, including obesity, diabetes, hypertension, insulin resistance (metabolic syndrome) and cardiovascular disease. The diabetic state (type 1 and type 2 diabetes) may be associated to diminished lung function and, in particular, decreased vital capacity, and the association between chronic obstructive pulmonary disease (COPD) and type 2 diabetes may be due to a shared inflammatory process. Also, the alteration in circulating endothelial progenitor cells found in respiratory disease, the metabolic syndrome and cardiovascular disease reflect a common condition of endothelial dysfunction.

In Type 1 diabetic patients with good glycaemic control, blood glucose variability is lower during continuous subcutaneous insulin infusion than during multiple daily injections with insulin glargine.

AIMS: The superiority of continuous subcutaneous insulin infusion (CSII) over multiple daily injections (MDI) with glargine is uncertain. In this randomized cross-over study, we compared CSII and MDI with glargine in patients with Type 1 diabetes well controlled with CSII. The primary end-point was glucose variability. METHODS: Thirty-nine patients [38.1 +/- 9.3 years old (mean +/- sd), diabetes duration 16.6 +/- 8.2 years, glycated haemoglobin (HbA(1c)) 7.6 +/- 0.8%], already on CSII for at least 6 months, were randomly assigned to CSII with lispro or MDI with lispro and glargine. After 4 months they were switched to the alternative treatment. During the last month of each treatment blood glucose variability was analysed using glucose standard deviation, mean amplitude of glycaemic excursions (MAGE), lability index and average daily risk range (ADRR). As secondary end-points we analysed blood glucose profile, HbA(1c), number of episodes of hypo- and hyperglycaemia, lipid profile, free fatty acids (FFA), growth hormone and treatment satisfaction. RESULTS: During CSII, glucose variability was 5-12% lower than during MDI with glargine. The difference was significant only before breakfast considering glucose standard deviation (P = 0.011), significant overall using MAGE (P = 0.016) and lability index (P = 0.005) and not significant using ADRR. Although HbA(1c) was similar during both treatments, during CSII blood glucose levels were significantly lower, hyperglycaemic episodes were fewer, daily insulin dose was less, FFA were lower and treatment satisfaction was greater than during MDI with glargine. The frequency of hypoglycaemic episodes was similar during both treatments. CONCLUSIONS: During CSII, glucose variability is lower, glycaemic control better and treatment satisfaction higher than during MDI with glargine.

Glucose tolerance is negatively associated with circulating progenitor cell levels.

AIMS/HYPOTHESIS: Circulating progenitor cells participate in cardiovascular homeostasis. Depletion of the pool of endothelial progenitor cells (EPCs) is associated with increased cardiovascular risk. Furthermore, EPCs are reduced in the presence of classical risk factors for atherosclerotic disease, including diabetes mellitus. This study was designed to evaluate progenitor cell levels in volunteers with different degrees of glucose tolerance. METHODS: Cardiovascular parameters and the levels of circulating CD34(+) and CD34(+) kinase insert domain receptor (KDR)(+) cells were determined in 219 middle-aged individuals with no pre-diagnosed alterations in carbohydrate metabolism. Glucose tolerance was determined by fasting and 2 h post-challenge glucose levels, with IFG and IGT considered as pre-diabetic states. RESULTS: CD34(+) and CD34(+)KDR(+) cells were significantly reduced in individuals who were found to have diabetes mellitus, and were negatively correlated with both fasting and post-challenge glucose in the whole population. While only CD34(+) cells, but not CD34(+)KDR(+) cells, were significantly reduced in pre-diabetic individuals, post-challenge glucose was an independent determinant of the levels of both CD34(+) and CD34(+)KDR(+) cells. CONCLUSIONS/INTERPRETATION: Glucose tolerance was negatively associated with progenitor cell levels in middle-aged healthy individuals. Depletion of endothelial progenitors with increasing fasting and post-meal glucose may be one cause of the high incidence of cardiovascular damage in individuals with pre-diabetes.

A long-period, violently variable X-ray source in a young supernova remnant.

Observations with the Newton X-ray Multimirror Mission satellite show a strong periodic modulation at 6.67 +/- 0.03 hours of the x-ray source at the center of the 2000-year-old supernova remnant RCW 103. No fast pulsations are visible. If genetically tied to the supernova remnant, the source could either be an x-ray binary, composed of a compact object and a low-mass star in an eccentric orbit, or an isolated neutron star. In the latter case, the combination of its age and period would indicate that it is a peculiar magnetar, dramatically slowed down, possibly by a supernova debris disc. Both scenarios require nonstandard assumptions about the formation and evolution of compact objects in supernova explosions.

Educating diabetic patients about insulin use: changes over time in certainty and correctness of knowledge.

AIM: Diabetic patients should understand their disease correctly and be sure of what they know, but certainty is rarely considered by educators. Furthermore little is known about how certainty changes with time after an educational intervention. To clarify this, in 38 patients with type 1 diabetes (0.3-36 years duration) we analysed the effect of a course on insulin use by administering a questionnaire before the course, after the course and 1 and 3 years later. METHODS: Answers, accompanied by a subjective estimate of the degree of certainty, were assigned to mastered knowledge (certainty>or=90%, correctness>or=90%), hazardous knowledge (certainty>or=90%, correctnessor=90%) and residual knowledge (total-[mastered+hazardous+uncertain]). Answers were then counted and changes in distribution among areas were analysed by the chi2 test. We also followed the fate of wrong answers. RESULTS: The course increased mastered knowledge, while other types of knowledge decreased. With time mastered knowledge decreased, patients losing both correctness and certainty. The loss affected declarative knowledge, based purely on theory, more than procedural knowledge, which concerns the way things are done. Wrong answers, mostly given with high degree of certainty, were heterogeneous since some became correct after the course, some remained wrong, some became wrong after the course, some became mistaken after having been corrected earlier. CONCLUSIONS: The analysis of certainty helps in evaluating patient's knowledge; programmes tending to improve procedural knowledge are more likely to have long lasting effects; wrong answers need to be considered on a individual basis.

Lower within-subject variability of fasting blood glucose and reduced weight gain with insulin detemir compared to NPH insulin in patients with type 2 diabetes.

AIM: The aim of this study was to compare the efficacy and safety of a basal-bolus insulin regimen comprising either insulin detemir or neural protamine hagedorn (NPH) insulin in combination with mealtime insulin aspart in patients with type 2 diabetes. METHODS: This was a 26-week, multinational, open-label, parallel group trial with 505 patients with type 2 diabetes (mean age, 60.4 +/- 8.6 years; mean BMI, 30.4 +/- 5.3 kg/m(2); mean HbA(1c), 7.9 +/- 1.3%). Patients, randomized 2:1 to insulin detemir or NPH insulin, received basal insulin either once or twice daily according to their pretrial insulin treatment and insulin aspart at mealtimes. RESULTS: After 26 weeks of treatment, significant reductions in HbA(1c) were observed for insulin detemir (0.2%-points, p = 0.004) and NPH insulin (0.4%-points; p = 0.0001); HbA(1c) levels were comparable at study end (insulin detemir, 7.6%; NPH insulin, 7.5%). The number of basal insulin injections administered per day had no effect on HbA(1c) levels (p = 0.50). Nine-point self-measured blood glucose (SMBG) profiles were similar for the two treatment groups (p = 0.58), as were reductions in fasting plasma glucose (FPG) (insulin detemir, 0.5 mmol/l; NPH insulin, 0.6 mmol/l). At study end, FPG concentrations were similar for the two treatment groups (p = 0.66). By contrast, within-subject day-to-day variation in fasting SMBG was significantly lower with insulin detemir (p = 0.021). Moreover, patients receiving insulin detemir gained significantly less body weight than those who were administered NPH insulin (1.0 and 1.8 kg, respectively, p = 0.017). The frequency of adverse events and the risk of hypoglycaemia were comparable for the two treatment groups. CONCLUSIONS: Patients with type 2 diabetes, treated for 26 weeks with insulin detemir plus insulin aspart at mealtimes, experienced comparable glycaemic control but significantly lower within-subject variability and less weight gain compared to patients treated with NPH insulin and insulin aspart. Insulin detemir was well tolerated and had a similar safety profile to NPH insulin.

Role of anti-granulocyte Fab' fragment antibody scintigraphy (LeukoScan) in evaluating bone infection: acquisition protocol, interpretation criteria and clinical results.

Scintigraphy using anti-granulocyte Fab' fragment (LeukoScan) was performed in a series of 220 consecutive patients with suspected bone infection referred to our centre between September 1999 and June 2002. Two protocols were compared for interpreting scans: (1) evaluation of early 4 h imaging alone (protocol A), and (2) evaluation both of early and delayed 24 h imaging (protocol B). Protocol A and protocol B showed equal values of sensitivity (91.9% in patients with diabetic foot and 84.2% in patients with joint prosthesis/peripheral bone implants). Conversely, specificity was higher adopting protocol B than protocol A: 87.5% vs 75.0% in patients with diabetic foot, and 85.7% vs 76.2% in patients with joint prosthesis/peripheral bone implants, respectively. In particular, an improvement in specificity using protocol B was found in those patients with infection and with only a mild LeukoScan uptake in the early 4 h imaging: in these patients an increasing uptake intensity pattern observed in the delayed 24 h imaging was indicative of infection while a decreasing pattern suggested a negative result. Instead, the evidence of a high uptake intensity in the early LeukoScan imaging was a strong indicator of infection and delayed imaging in these cases did not further improve specificity. In conclusion, in our experience, LeukoScan showed high sensitivity in diagnosing bone infection in patients with diabetic foot and joint prosthesis or other peripheral bone implants. Moreover, in patients with an early high LeukoScan uptake intensity further delayed images appears unnecessary for the purpose of diagnosing infection. In contrast in patients with an early mild LeukoScan uptake intensity only, delayed imaging appears to be recommendable for improving specificity.

Effect of sodium intake on blood pressure and albuminuria in Type 2 diabetic patients: the role of insulin resistance.

AIMS/HYPOTHESIS: This study was done to measure the effect of Na+ intake on blood pressure and albuminuria, in relation with insulin sensitivity and kidney haemodynamics, in Type 2 diabetic patients with and without microalbuminuria. METHODS: Type 2 diabetic patients, 20 with microalbuminuria, 21 without, spent two consecutive 7-day periods, one on a high (250 mmol), the other on a low-Na+ (20 mmol) diet. Body weight, 24-h blood pressure and albuminuria were measured at the end of each period. At the end of high-Na+ diet insulin sensitivity (euglycaemic insulin clamp; 2 mU.kg(-1).min(-1)) and kidney haemodynamics were measured in nine patients from each group. RESULTS: Switching from low to high-Na+ diet resulted in an increase in blood pressure (7.4+/-4.7 mmHg; p<0.001), body weight (1.9+/-0.4 kg; p<0.05) and albuminuria [from 80 (31-183) microg/min to 101 (27-965) microg/min; p<0.01) in patients with microalbuminuria. No changes occurred in patients without microalbuminuria. Patients with microalbuminuria also had greater intraglomerular pressure (44+/-1 mmHg vs 36+/-1; p<0.001), calculated from glomerular filtration rate, renal plasma flow, plasma protein concentration and the relationship between pressure and natriuresis. In these patients insulin sensitivity was lower (5.16+/-49 vs 7.36+/-0.63 mg.kg(-1).min(-1); p=0.007). Urinary albumin excretion (r=0.40; p=0.009) and insulin sensitivity (r=-0.59; p=0.01) were correlated with intraglomerular pressure. CONCLUSION/INTERPRETATION: High salt intake increases blood pressure and albuminuria in Type 2 diabetic patients with microalbuminuria. These responses are associated with insulin resistance and increased glomerular pressure. Insulin resistance could contribute to greater salt sensitivity, increased glomerular pressure and albuminuria.

Visceral obesity is characterized by impaired nitric oxide-independent vasodilation.

BACKGROUND: Endothelial dysfunction has been described in obesity. This study examines the impact of visceral obesity on nitric oxide-independent relaxation in the human forearm. METHODS AND RESULTS: In ten viscerally obese and ten matched controls forearm blood flow (FBF) was measured by venous occlusion plethysmography during intrabrachial infusion of: (1) sodium nitroprusside; (2) bradykinin, before and after inhibition of vasoactive prostaglandins and nitric oxide; (3) potassium; (4) ouabain (Na(+)/K(+)ATPase inhibitor) alone or (5) in combination with BaCl(2)(K(IR)inhibitor). Baseline FBF and endothelium-independent vasodilatation were similar in the two groups. In obese patients, bradykinin-induced increase of FBF was significantly less than in controls (P<0.01). Irrespective of prostaglandins and nitric oxide inhibition, bradykinin response was lower in the viscerally obese. Intrabrachial potassium determined a significantly blunted response (P<0.05). Ouabain caused a similar, moderate decrease in basal FBF in the two groups; the coinfusion of BaCl(2)caused a more intense decline in FBF which was significantly relevant in obese (-24+/-5%, P<0.01). CONCLUSIONS: In obese patients there is a blunted nitric oxide-independent relaxation determined by a decreased response of inwardly rectifying potassium channels.

In situ protein Kinase C activity is increased in cultured fibroblasts from Type 1 diabetic patients with nephropathy.

AIMS/HYPOTHESIS: To verify whether individual susceptibility to diabetic nephropathy resides in an intrinsic difference in Protein Kinase C (PKC) activity. METHODS: We compared the effect of different glucose concentrations on PKC activity, PKC isoform expression and diacylglycerol (DAG) content in cultured fibroblasts from 14 Type 1 diabetic patients who developed nephropathy with those in cells from 14 patients without nephropathy. We recruited 14 normal subjects as control patients. Forearm skin fibroblasts were cultured in either normal (5 mmol/l) or high (20 mmol/l) glucose concentrations. RESULTS: In normal glucose, in situ PKC activity was higher in Type 1 patients with nephropathy (10.1+/-1.4 pmol/min/mg protein; p<0.01) than in those without (6.8+/-0.8) and the normal control subjects (6.3+/-0.5). This difference was due to increased concentrations of PKCalpha isoform in the membrane fraction of fibroblasts from patients with nephropathy. DAG content was also higher in cells from Type 1 patients with nephropathy. Incubation in high glucose concentration caused a further increase in PKC activity and DAG content in quiescent fibroblasts from patients with diabetic nephropathy, with no significant changes in cells from diabetic patients without nephropathy and normal control subjects. CONCLUSION/INTERPRETATION: Differences in PKC activation could contribute to the individual susceptibility to renal damage in Type 1 diabetic patients.