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The global increase in chronic kidney disease (CKD) parallels the obesity epidemic. Obesity conveys a gradual but independent risk of progression of CKD that seems irrespective of the underlying nephropathy. Obesity has been associated with a secondary focal segmental glomerulosclerosis coined obesity-related glomerulopathy (ORG). Pathways through which obesity might cause renal disease are not well understood, and early clinical biomarkers for incipient ORG or renal relevant obesity are currently lacking. Recent human and experimental studies have associated ectopic lipid accumulation in the kidney (fatty kidney) with obesity-related renal disease. There is enough growing insight that ectopic lipid--the accumulation of lipid in non-adipose tissue--is associated with structural and functional changes of mesangial cells, podocytes, and proximal tubular cells to propose the development of ORG as a maladaptive response to hyperfiltration and albuminuria. Recent advances in metabolic imaging might validate ectopic lipid as a biomarker and research aid, to help translate novel therapeutics from experimental models to patients.

Diabetic nephropathy (DN) affects an estimated 20%–40% of patients with type 2 diabetes mellitus (T2DM). Key modifiable risk factors for DN are albuminuria, anaemia, dyslipidaemia, hyperglycaemia and hypertension, together with lifestyle factors, such as smoking and obesity. Early detection and treatment of these risk factors can prevent DN or slow its progression, and may even induce remission in some patients. DN is generally preceded by albuminuria, which frequently remains elevated despite treatment in patients with T2DM. Optimal treatment and prevention of DN may require an early, intensive, multifactorial approach, tailored to simultaneously target all modifiable risk factors. Regular monitoring of renal function, including urinary albumin excretion, creatinine clearance and glomerular filtration rate, is critical for following any disease progression and making treatment adjustments. Dipeptidyl peptidase (DPP)-4 inhibitors and sodium-glucose cotransporter 2 (SGLT2) inhibitors lower blood glucose levels without additional risk of hypoglycaemia, and may also reduce albuminuria. Further investigation of the potential renal benefits of DPP-4 and SGLT2 inhibitors is underway.

BACKGROUND: Tools are needed to predict which individuals with diabetes will develop kidney disease and its complications. STUDY DESIGN: An observational analysis of a randomized controlled trial. SETTING & PARTICIPANTS: The ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation) Study followed up 11,140 participants with type 2 diabetes for 5 years. PREDICTOR: Readily available baseline demographic and clinical variables. OUTCOMES: (1) Major kidney-related events (doubling of serum creatinine to ≥2.26 mg/dL [≥200 μmol/L], renal replacement therapy, or renal death) in all participants, and (2) new-onset albuminuria in participants with baseline normoalbuminuria. MEASUREMENTS: Cox proportional hazard regression models predicting the outcomes were used to generate risk scores. Discrimination of the risk prediction models was compared with that of models based on estimated glomerular filtration rate (eGFR) alone, urinary albumin-creatinine ratio (ACR) alone, and their combination. RESULTS: Risk scores for major kidney-related events and new-onset albuminuria were derived from 7- and 8-variable models, respectively. Baseline eGFR and ACR were dominant although models based on the 2 factors, alone or combined, had less discrimination (P

OBJECTIVE: The efficacy and safety of blood pressure lowering in elderly patients have not been sufficiently investigated in patients with diabetes. Using data from the Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation study, we assessed the efficacy and safety of routine blood pressure lowering to prevent major clinical outcomes in elderly patients with type 2 diabetes. METHODS: Eleven thousand one hundred and forty patients aged at least 55 years with type 2 diabetes (mean 66+/-6 years) were randomly assigned to perindopril-indapamide or placebo. The primary endpoint was a composite of major macrovascular and microvascular disease. The effects of active treatment on outcomes were estimated in subgroups according to age: below 65, 65-74 and at least 75 years. RESULTS: During a mean 4.3-year follow-up, 1799 (16.1%) patients experienced a major event. Active treatment produced similar relative risk reductions for the primary outcome, major macrovascular disease, death and renal events across age groups (all P heterogeneity >0.3). Over 5 years, active treatment was estimated to prevent one primary outcome in every 21, 71 and 118 patients of at least 75, 65-74 and below 65 years, respectively. Similar patterns of benefits were observed for secondary outcomes. There were no differences in the tolerability between randomized allocations across age groups (all P heterogeneity >0.6) CONCLUSION: Routine administration of perindopril-indapamide lowers blood pressure safely and reduces the risk of major clinical outcomes in patients of at least 75 years with type 2 diabetes. The greater absolute benefits in older patients in this age group were not offset by an increased risk of side effects.

A number of controversies in diabetes have had too little attention. I discuss the following issues: (i) drug therapy; (ii) genetics; (iii) antihypertensive treatment in patients with normoalbuminuria and with abnormal albuminuria; (iv) insulin analogs; (v) cancer in diabetes; (vi) hypophysectomy; (vii) renal biopsy; (viii) low protein diet; and (ix) glycated hemoglobin. A closer look at these items is required in order to have a more realistic picture of diabetes research. A scheme of other controversies is also provided. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00012.x, 2010).

Left ventricular wall mass, thickness and movement were investigated by echocardiography in 80 insulin-dependent diabetic patients with no signs of ischaemic heart disease and in 40 healthy controls. In diabetics with a disease duration of greater than 30 yr, urinary albumin excretion rate greater than 200 micrograms/min (clinical nephropathy), proliferative retinopathy or autonomic neuropathy, both the posterior wall thickness and the septal thickness were increased compared to controls. The posterior wall thickness and the septal thickness were positively correlated to blood pressure (p less than 0.001), disease duration (p less than 0.001), urinary albumin excretion rate (p less than 0.001), and negatively correlated to the heart variation during deep respiration (p less than 0.01). The left ventricular wall mass was correlated to both blood pressure (p less than 0.01) and urinary albumin excretion rate (p less than 0.01). By multiple regression analysis urinary albumin excretion rate, disease duration and heart rate variation during deep respiration did not add significantly to the correlation between left ventricular wall mass/wall thickness and blood pressure. The septal movement was reduced in diabetics with proliferative retinopathy or clinical nephropathy. In conclusion, left ventricular wall thickness and wall mass were closely related to blood pressure in insulin-dependent diabetics. Signs of impaired cardiac function, such as reduced septal movement, were seen only in patients with severe microvascular disease.

Creatinine clearance and daily urinary albumin and beta2-microglobulin excretion rates (radio-immunoassays) were measured several times in 14 patients with acromegaly. Eleven patients were treated with bromocriptine, 5 to 55 mg/day. The activity of the disease was assessed by measuring urinary growth hormone excretion (radio-immunoassay). In agreement with previous investigations we found the creatinine clearance elevated. However, no correlation was found between this variable and urinary growth hormone excretion. Urinary albumin and beta 2-microglobulin excretion rates were not significantly different from our previous results in 27 adults control subjects. There was no correlation between urinary growth hormone excretion and urinary albumin or beta 2-microglobulin excretion rates. Bromocriptine treatment reduced urinary growth hormone excretion from 220 to 91 ng/24 hours, p less than 0.01, but no significant alterations were induced in the above mentioned kidney function variables.

Aims: This study sought to assess the risk of developing coronary artery disease (CAD) associated with initial treatment of type 2 diabetes with different sulphonylureas. Methods: In type 2 diabetic patients, cases who developed CAD were compared retrospectively with controls that did not. The 20-year risk of CAD at diagnosis of diabetes, using the UKPDS risk engine, was used to match cases with controls. Results: The 76 cases of CAD were compared with 152 controls. The hazard of developing CAD (95% CI) associated with initial treatment increased by 2.4-fold (1.3‐4.3, P = 0.004) with glibenclamide; 2-fold(0.9‐4.6,P = 0.099)with glipizide;2.9-fold(1.6‐5.1,P = 0.000)witheither, and was unchanged with metformin. The hazard decreased 0.3-fold (0.7‐1.7, P = 0.385) with glimepiride, 0.4-fold (0.7‐1.3, P = 0.192) with gliclazide, and 0.4-fold (0.7‐1.1, P = 0.09) with either. Conclusions: Initiating treatment of type 2 diabetes with glibenclamide or glipizide is associated with increased risk of CAD in comparison to gliclazide or glimepiride. If confirmed, this may be important because most Indian patients receive the cheaper older sulphonylureas, and present guidelines do not distinguish between individual agents. # 2008 Published by Elsevier Ireland Ltd.

Reduced diurnal blood pressure (BP) variation ("non-dipping") is associated with both micro- and macrovascular complications in patients with type 2 diabetes. The relation between endothelial perturbation and diurnal BP variation in diabetic subjects has not previously been studied. Seventy-six subjects, stratified to 4 gender-, age-, and duration-matched groups of 19 subjects each, were studied (group A: non-diabetic subjects; group B to D, type 2 diabetic subjects; group B: no retinopathy; group C: minimal background retinopathy; group D: diabetic maculopathy). All subjects underwent a 24-hour ambulatory BP monitoring. von Willebrand factor (vWF), fibrinogen, E-selectin, and intercellular adhesion molecule-1 were measured in plasma. Systolic night/day BP ratio increased gradually in groups A to D: 85.2 +/- 5%, 85.7 +/- 7%, 88.5 +/- 6%, and 90.5 +/- 7%, respectively, P < .05. Among diabetic patients, non-dippers had significantly higher plasma levels of vWF and fibrinogen than dippers (median/interquartile range 1.7/1.4 to 2.1 vs. 1.2/0.9 to 1.5 U/mL, P < .01 and 3.6/3.6 to 3.7 vs. 2.9/2.5 to 3.6 g/L, P = .01). Non-dipping is associated with elevated plasma levels of proteins related to endothelial cell activation as well as with retinopathy in subjects with type 2 diabetes. This finding suggests a possible mechanism linking non-dipping with microvascular complications in these subjects.

This article will discuss classification of early diabetic renal involvement or disease in diabetic patients, with the perspective of effective intervention, considering glycemic as well as nonglycemic treatment modalities

Purpose: To study retinal response in terms of arteriole diameter and retinal thickness secondary to an increase in arterial blood pressure during acute hyperglycaemia. Methods: In a randomized, double-blinded, cross-over study, nine healthy persons were subjected to clamping of blood glucose to either 5 mmol/l or 15 mmol/l using somatostatin to control endogenous insulin secretion. The response of retinal arterioles in terms of diameter as determined with the retinal vessel analyser (RVA) and retinal thickness as assessed by optical coherence tomography (OCT) were measured after an increase in arterial blood pressure induced by isometric exercise. Arterial feeding pressure in the eye was assessed from the ophthalmic artery pressure and pulse amplitude measured by ophthalmodynamometry. Results: Isometric exercise induced a significant increase in mean arterial blood pressure and a significant contraction of the retinal arterioles. An acute increase in blood glucose from 5 mmol/l to 15 mmol/l did not affect either the diameter of retinal vessels or retinal thickness. Conclusions: Acute hyperglycaemia per se does not change isometric exercise-induced retinal arteriolar contraction. Metabolic factors other than blood glucose are suspected to be involved in the impairment of retinal autoregulation as seen in hyperglycaemia induced by oral glucose intake.

The ratio between urinary albumin concentration (UAC) and urinary creatinine concentration (UCC) is widely used to estimate renal involvement. We examined how UAC and UCC associate with each other, with other risk factors, and with diabetic complications in a population-based sample of Type 2 diabetic patients.A freshly voided morning urine specimen was provided by 1,284 consecutive, newly diagnosed diabetic patients aged 40 years or over in general practice. Albumin was measured by a polyethyleneglycol radioimmunoassay and creatinine by a modified Jaffe method.In a multivariate model including UAC, UCC, age, sex, HbA1c, and urinary glucose concentration, UAC increased with both age (P=.042) and HbA1c (P=.014), while UCC decreased (P.001 and P.001, respectively). In two regression models, the prevalence of diabetic retinopathy (P.001) and relatively high resting heart rate (P.001) increased with increasing UAC but decreased with increasing UCC (P=.002 and P=.005, respectively).The use of albumin/creatinine ratio (ACR) may introduce bias of unpredictable size and direction in comparisons of ACR with variables that are associated with UCC in their own right. In daily clinical practice, renal involvement in the individual patient can be estimated reliably with UAC or ACR measured in a freshly voided morning urine specimen, especially when considered together. However, the associations of the combined measure ACR should be interpreted with great caution in clinical and epidemiological research.

A key issue in the analysis of outcome trials is the adjustment for baseline covariates that influence the primary outcome. Imbalance of an important covariate between treatment groups at baseline is of considerable concern if one treatment group is favored over another with respect to the hypothesis testing outcome. With the use of the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study database as an example, the influence of baseline proteinuria on the primary composite endpoint, ESRD, and ESRD or death after adjusting for baseline proteinuria as a continuous covariate was examined. Increasing baseline proteinuria was associated with increased risk for renal events, confirming that proteinuria is an important covariate for renal outcomes. When the randomization was stratified according proteinuria = 2000 mg/g, within the higher proteinuria stratum (>= 2000 mg/g), patients in the losartan group had a higher baseline mean proteinuria value. When the imbalance was adjusted, an increase in the magnitude and the significance of the risk reduction with losartan for each outcome was observed. No apparent interaction between treatment effect and baseline proteinuria was found, and there was no heterogeneity in the treatment response in patients with different baseline proteinuria levels. After proteinuria was adjusted as a continuous variable, greater treatment effects were observed in the RENAAL study. This effect was due solely to the imbalance in baseline proteinuria. Considering the importance of proteinuria as a risk factor, adjustment for baseline proteinuria as a continuous covariate should be prespecified in the design and analysis of clinical trials involving renal outcomes, even when patients are stratified on the basis of level of proteinuria.

OBJECTIVE—To assess and compare the long-term effects of the combination of candesartan and lisinopril with high-dose lisinopril on systolic blood pressure in patients with hypertension and diabetes. RESEARCH DESIGN AND METHODS—This was a prospective, randomized, parallel-group, double-blind, double-dummy study with a 12-month follow-up. Drug therapy was either lisinopril 40 mg once daily or dual-blockade treatment with candesartan 16 mg once daily and lisinopril 20 mg once daily. The study comprised 75 type 1 and type 2 diabetic patients aged 35–74 years. The main outcome measures were seated and 24-h ambulatory systolic blood pressure. RESULTS—Reduction in systolic blood pressure (24-h systolic blood pressure) reduction was obtained in both treatment arms (mean reduction at final follow-up: dual blockade 6 mmHg vs. lisinopril 2 mmHg), but no significant difference was found between dual-blockade and lisinopril 40 mg once daily (P = 0.10). Both treatments were generally well tolerated, and similar low rates of side effects were found in the two groups. CONCLUSIONS—There was no statistically significant difference between lisinopril 40 mg once daily and lisinopril 20 mg in combination with candesartan 16 mg once daily in reducing systolic blood pressure in hypertensive patients with diabetes.

ResumeL’hypertension arterielle contribue a alterer la fonction renale en accelerant les remaniements structurels au niveau des reins, ce qui entraine une diminution progressive de la filtration glomerulaire. L’hypertension arterielle et les anomalies microcirculatoires peuvent creer un cercle vicieux, dans lequel les lesions renales contribuent a majorer le niveau de pression arterielle. La prevention de l’alteration de la fonction renale est une priorite, en particulier dans la population de plus en plus nombreuse des patients hypertendus diabetiques. Il est etabli que les inhibiteurs de l’enzyme de conversion (IEC) et les antagonistes des recepteurs a l’angiotensine II (AAII) exercent des effets nephroprotecteurs; de plus, les IEC diminuent le risque de survenue d’une microalbuminurie, laquelle constitue le stade inaugural de l’insuffisance renale chez le diabetique. Des resultats trEs interessants ont ete obtenus avec une pluritherapie fixe faiblement dosee associant un IEC, le perindopril, et un diur...

Dual blockade of the renin angiotensin system is based on a principle of obtaining the broadest and most efficient blockade of the effects of angiotensin II, by using the combination of an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin II-receptor blocker (ARB). By combining two, different pharmacologic principles and inhibiting both the ACE and the angiotensin II type 1 receptor, it seems possible to block both the production and the action of angiotensin II, which would serve as efficient antihypertensive therapy. Exploring the beneficial effects of dual-blockade therapy is a work in rapid progress, in both diabetic and non-diabetic nephropathy. But evidence is also emerging in cardiovascular medicine, an overview of which is provided in this article.

The hepatic protein mannan-binding lectin (MBL) activates the complement system on binding to carbohydrate patterns and is involved in first-line defense against invading microorganisms. Emerging evidence indicates that in some situations MBL may cause inexpedient complement activation and tissue injury through binding to endothelial glycosylations. MBL levels are suppressed by insulin treatment in critically ill patients, and, hypothetically, hepatic portal hypoinsulinemia could lead to increased levels of MBL in patients with type 1 diabetes. We measured MBL and C-reactive protein (CRP) levels in 132 normoalbuminuric type 1 diabetic patients and 66 healthy age- and sex-matched controls. The median MBL concentration was higher in diabetic patients than in healthy controls [1290 micro g/liter (interquartile range, IQR 354-2961 micro g/liter) vs. 970 micro g/liter (IQR 277-1607 micro g/liter), P = 0.025], whereas CRP concentrations were similar among patients and controls [1.42 mg/liter (IQR 0.95-2.21) vs. 1.21 mg/l (IQR 0.74-2.13), NS]. In diabetic subjects, CRP levels correlated with poor glycemic control as indicated by hemoglobin A(1c) and daily insulin dose, which was not the case with MBL. MBL concentrations were positively correlated with urinary albumin excretion (r = 0.22; P = 0.013) and increased with increasing urinary albumin excretion tertile (P = 0.036). In conclusion, our data demonstrate that circulating MBL concentrations are significantly elevated in patients with type 1 diabetes and suggest a possible role of MBL in the pathogenesis of renovascular complications in diabetes.

Several treatment guidelines have made strong recommendations to physicians that treatment of nephropathy and hypertension should be based on the use of a long-acting angiotensin converting enzyme (ACE) inhibitor if tolerated. The recently published clinical trials, based on angiotensin II receptor blockers' effects on diabetic nephropathy and essential hypertension, have also shown significant endpoint reduction. Perhaps the time has come to broaden the recommendations to include the use of a renin-angiotensin-aldosterone system altering drug. But what if the treatment goal cannot be reached, and incessant proteinuria and high blood pressure levels persist despite high dosage treatment of either drug? How should this be handled? The dual blockade principle can possibly provide the solution by obtaining the broadest and most efficient blockade of circulating angiotensin II by using the combination of an ACE inhibitor and an angiotensin II receptor blocker. But large clinical trials are yet to come, and at present large endpoint trials have not been published. This article provides an overview of how far we have come with dual blockade treatment in hypertension and nephropathy.

Left ventricular hypertrophy and albuminuria have both been shown to predict increased cardiovascular morbidity and mortality. However, the relationship between these markers of cardiac and renal glomerular damage has not been evaluated in a large hypertensive population with target organ damage. The present study was undertaken to determine whether albuminuria is associated with persistent electrocardiographic (ECG) left ventricular hypertrophy, independent of established risk factors for cardiac hypertrophy, in a large hypertensive population with left ventricular hypertrophy who were free of overt renal failure.Patients with stage II-III hypertension were enrolled in the study if they had left ventricular hypertrophy on a screening ECG by Cornell voltage-duration product and/or Sokolow-Lyon voltage criteria, and clinic blood pressures between 160 and 200/95-115 mmHg and plasma creatinine160 mmol/l. A second ECG and morning spot urine were obtained after 14 days of placebo treatment. Renal glomerular permeability was evaluated by urine albumin/creatinine (UACR, mg/mmol). Microalbuminuria was present if UACR3.5 mg/mmol and macroalbuminuria if UACR35 mg/mmol.The mean age of the 8029 patients was 66 years, 54% were women. Microalbuminuria was found in 23% and macroalbuminuria in 4% of patients. Microalbuminuria was more prevalent in patients of African American (35%), Hispanic (37%) and Asian (36%) ethnicity, heavy smokers (32%), diabetics (36%) and in patients with ECG left ventricular hypertrophy by both ECG-criteria (29%). Urine albumin/creatinine was positively related to Sokolow-Lyon voltage criteria and Cornell voltage-duration product criteria. In multiple regression analysis, higher UACR was independently associated with older age, diabetes, higher blood pressure, serum creatinine, smoking and left ventricular hypertrophy. Patients smoking20 cigarettes/day had a 1.6-fold higher prevalence of microalbuminuria and a 3.7-fold higher prevalence of macroalbuminuria than never-smokers. ECG left ventricular hypertrophy by Cornell voltage-duration product or Sokolow-Lyon criteria was associated with a 1.6-fold increased prevalence of microalbuminuria and a 2.6-fold increase risk of macroalbuminuria compared to no left ventricular hypertrophy on the second ECG.In patients with moderately severe hypertension, left ventricular hypertrophy on two consecutive ECGs is associated with increased prevalences of micro- and macroalbuminuria compared to patients without persistent ECG left ventricular hypertrophy. High albumin excretion was related to left ventricular hypertrophy independent of age, blood pressure, diabetes, race, serum creatinine or smoking, suggesting parallel cardiac damage and albuminuria.

Over the last 35 years an increasing number of patients with type 2 diabetes mellitus have developed advanced renal disease and the need for dialysis. At present in the US, about 50% of the patients in dialysis units have type 2 diabetes mellitus. The explanation for the increase in the number of patients with type 2 diabetes mellitus in end-stage renal disease programs is not completely clear, but the overall number of patients with this type of diabetes is rapidly increasing - and is expected to continue to increase over the next years. The diagnosis of renal disease in type 2 diabetes mellitus is usually straightforward, and is mainly dependent upon measurements of urinary albumin or urinary protein excretion as well as serum creatinine measurements. Renal biopsies or exact glomerular filtration rate measurements are rarely necessary. Microalbuminuria is the first sign of renal disease in diabetes mellitus. It predicts overt nephropathy and cardiovascular disease. Several studies document that albuminuria and microalbuminuria can be reduced by treatment with antihypertensives, especially agents that block the renin angiotensin system. New studies show that end-stage renal disease can be postponed by the use of angiotensin II receptor antagonists. ACE inhibitors are also useful, and dual blockade of the renin angiotensin system has been utilized as well. However, generally speaking, patients with proteinuria have a poor prognosis. Screening for microalbuminuria is therefore proposed, and glycemic control and blood pressure should be optimized.

Summary Largely on the basis of data from patients with type 1 diabetes, the natural history of diabetic renal disease has been classified as a sequence of three stages: normoalbuminuria, microalbuminuria, and macroalbuminuria. Progressive decline of glomerular filtration rate (GFR) was thought to parallel the onset of macroalbuminuria (overt nephropathy), whereas glomerular hyperfiltration was deemed a hallmark of early disease. However, researchers have since shown that albuminuria is a continuum and that GFR can start to decline before progression to overt nephropathy. In addition to proteinuria, other risk factors might contribute to GFR deterioration including female sex, obesity, dyslipidaemia (in particular hypertriglyceridaemia), hypertension, and glomerular hyperfiltration, at least in a subgroup of patients. This phenomenon could explain why patients with type 2 diabetes can have renal insufficiency even before the onset of overt nephropathy, and might also suggest why the heterogeneous phenotype of type 2 diabetic renal disease does not necessarily associate with typical histological lesions of diabetic renal disease, unlike in type 1 diabetic renal disease. Patients with renal insufficiency but without albuminuria are usually excluded from randomised clinical trials in overt nephropathy, thus optimum treatment for this group of patients is unknown. The wide inter-patient variability of the disease probably needs individually tailored intervention.

The incidence and prevalence of diabetes mellitus (DM) continue to grow markedly throughout the world, due primarily to the increase in type 2 DM (T2DM). Although improvements in DM and hypertension management have reduced the proportion of diabetic individuals who develop chronic kidney disease (CKD) and progress to end-stage renal disease (ESRD), the sheer increase in people developing DM will have a major impact on dialysis and transplant needs. This KDIGO conference addressed a number of controversial areas in the management of DM patients with CKD, including aspects of screening for CKD with measurements of albuminuria and estimated glomerular filtration rate (eGFR); defining treatment outcomes; glycemic management in both those developing CKD and those with ESRD; hypertension goals and management, including blockers of the renin-angiotensin-aldosterone system; and lipid management.Kidney International advance online publication, 30 April 2014; doi:10.1038/ki.2014.128.

Poulsen PL, Ebbehoj E, Mogensen CE (Medical Department M (Diabetes & Endocrinology) Aarhus Kommunehospital, Aarhus, Denmark). Lisinopril reduces albuminuria during exercise in low grade microalbuminuric Type 1 diabetic patients: a double blind randomized study. J Intern Med 2001; 249: 433–440. Background. Antihypertensive treatment is presently recommended in most type 1 diabetic patients with microalbuminuria. The long-term effect of angiotensin converting enzymes (ACE) inhibitor (ACE-i) treatment on exercise urinary albumin excretion (E-UAE) and exercise blood pressure (E-BP) in type 1 diabetic patients with low grade microalbuminuria is not well documented. In addition, the possible predictive effect of baseline E-UAE on the progression of overnight UAE remains to be clarified. Design and Methods. In a randomized placebo controlled double blind study the effects of 2 years treatment with either lisinopril (20 mg o.d.) or placebo was evaluated in 21 normotensive type 1 diabetic patients with overnight UAE between 20 and 70 μg min–1. Determinations of E-UAE and E-BP were performed after exercise on an ergometercycle with a load of 70% of estimated maximal VO2 for 20 min. Patients in the placebo and lisinopril groups were similar with regard to age (35.8 ± 11.3 vs. 29.3 ± 8.6 years), duration of diabetes (19.4 ± 8.2 vs. 16.8 ± 5.3 years), and HbA1c (9.0 ± 1.0 vs. 9.4 ± 1.7%). Results. At baseline, E-UAE was similar in the two groups (placebo: 150.1 ×/÷ 3.7, lisinopril: 96.8 ×/÷ 1.8 μg min–1 (geometric mean ×/÷ tolerance factor)). After 2 years treatment E-UAE had increased in the placebo group, whereas E-UAE was reduced in the lisinopril treated patients (placebo: 213.6 ×/÷ 6.9, lisinopril: 48.3 ×/÷ 3.1 μg min–1, P=0.04). The relative increase in E-UAE (E-UAE/Pre-exercise UAE) was similar at baseline in both groups (3.7 ×/÷ 2.3 vs. 2.8 ×/÷ 2.0) but significantly higher in the placebo group after 2 years (4.4 ×/÷ 2.4 compared with 1.6 ×/÷ 1.7 in the lisinopril group, P

The clear-cut and detailed pathogenesis of diabetic renal disease is not yet elucidated, but it is clear that both initiation and progression of renal disease in diabetes is related to glycemic control and blood pressure (BP) regulation, also seen in intervention studies. Consequently, optimal control of glycemia and antihypertensive treatment have become the cornerstones in the management of patients with diabetes. Naturally, modulating factors need to be discussed in further detail. The genetics of diabetes and its renal complications are still very complex issues that need to be explored further. Few and inconclusive data are available with respect to clinical management, for which genotyping is not required. Dietary protein content has long been an interesting avenue for possible treatment, but to date, data from patients with nondiabetic renal disease and with diabetes are not totally convincing, although further results may be published very soon. The issue is also complex because a low-protein diet may increase BP according to new studies, rendering the issue of low-protein content in the diet still more complex and controversial. Metabolic issues remain a key question, specifically with regard to glycemic control, in which data have accumulated over the past decade from epidemiological and interventional studies. There is no doubt that optimal glycemic control is crucial, but issues regarding specific glucose-related mechanisms and protein and lipid metabolism are still under investigation. The renin-angiotensin system has emerged as a key issue in diabetes, especially with regard to its inhibition by angiotensin-converting enzyme (ACE) inhibition and angiotensin-receptor blockade. New studies suggest that more complete inhibition of this system by dual blockade may be an avenue for further study according to positive results in patients with microalbuminuric type 2 diabetes, who are at great risk. Antihypertensive treatment still remains a fundamental component, although the metabolic effects of some antihypertensive agents may be important, especially with respect to diuretics, β-blockers, and possibly α-blockers. The situation becomes complex with the frequent combination of various agents in the treatment of hypertension in patients with diabetes. Conversely, ACE inhibitors may have some diabetes-protective effect, but further studies are needed.

Diabetes mellitus and hypertension is often associated, but with a different type of development in type 1 and type 2 diabetes. Type 1 diabetes, renal disease, starting with microalbuminuria, is associated with increasing blood pressure or hypertension, whereas the patient without renal disease is most often normotensive. Poor metabolic control is a predictor of microalbuminuria or incipient nephropathy, but with microalbuminuria hypertension is an important risk factor for progression along with poor glycemic control. The same is the case for overt renal disease, and metabolic control is important in all stages of renal disease in type 1 diabetes. It has also been shown that good metabolic control as well as antihypertensive treatment, especially with ACE-inhibitors, often combined with other agents is quite effective in preventing progression in renal disease in all its stages. In type 2 diabetes, blood pressure elevation is often found as early as at the actual diagnosis, and blood pressure significantly increases according to the degree of albuminuria, normo-microalbuminuria and clinical proteinuria (macroalbuminuria). Elevated blood pressure is an important risk for renal disease but more importantly so also for cardiovascular disease. Several studies document that antihypertensive treatment in particular with ACE-inhibitors is important in preventing microalbuminuria, in treating microalbuminuria and thus preventing progression, also in overt renal disease. Near-normalization of blood pressure is vital. Regarding cardiovascular disease, a series of studies now document that antihypertensive treatment with various antihypertensive agents is able to significantly reduce a number of major cardiovascular complications in diabetes, such as cardiac disease, stroke, and also microvacular disease, including retinopathy. Several studies show that antihypertensive treatment should be started at a level higher than 140-150/90. The blood pressure to be achieved during treatment is probably around 140/85 mmHg or even 130/80 mmHg as a pragmatic goal. However, there is no sign of a J-shaped curve in any of the studies, and therefore even lower blood pressure could be advantageous. Even mortality, at least from diabetes-related causes can be effected by antihypertensive treatment. With more advanced renal disease, normalization of blood pressure is increasingly difficult, especially systolic blood pressure, and therefore it is recommendable to screen patients much earlier on with focus on blood pressure recordings and measurements of albuminuria, including microalbuminuria, and to treat early.

Alterations in cardiovascular function may be an aetiological factor for the development of microalbuminuria in patients with insulin-dependent diabetes mellitus. We studied cardiac function with echocardiography in relation to the degree of albuminuria in 27 insulin-dependent diabetes mellitus patients and 13 healthy subjects. Patients were grouped according to urinary albumin excretion

Objective To examine the effect of the combination of enalapril with a very low dose of hydrochlorothiazide versus atenolol on urinary albumin excretion in normoalbuminuric patients with mild to moderate essential hypertension. A secondary objective was to compare the effects of the two regimens in patients with different levels of albuminuria. Design A 12 weeks, randomized, double-blind, double-dummy, multicenter, comparative study with two parallel groups. Setting General practices in Denmark and Finland. Patients The subjects comprised 174 patients with mild to moderate essential hypertension, normal serum creatinine and no proteinuria. Interventions Enalapril/hydrochlorothiazide (20/6 mg) daily or atenolol (50 mg) daily. Main outcome measures Urinary albumin: creatinine ratio and blood pressure. Results At baseline, normoalbuminuria was found in 74 and 85 patients in the enalapril/hydrochlorothiazide and atenolol groups, respectively. Blood pressure was reduced similarly by both treatments. The ratio of urinary albumin to creatinine in normoalbuminuric patients was significantly reduced during treatment with enalapril/hydrochlorothiazide at 20/6 mg (from geometic mean x/divided by antilog SD of 0.53 x/divided by 1.77 to 0.47 x/divided by 1.58 mg/mmol, P=0.02) but was unchanged during atenolol treatment (0.55 x/divided by 1.74 and 0.58 x/divided by 1.87 mg/mmol). The difference between the two treatments was statistically significant (P=0.03) and was predominantly achieved through a reduction of albuminuria in the upper-normal range during enalapril/hydrochlorothiazide treatment. Conclusions Therapy with enalapril/hydrochlorothiazide at 20/6 mg and atenolol at 50 mg once daily reduced blood pressure similarly in patients with essential hypertension. Suppression of urinary albumin excretion within the normoalbuminuric range was observed during treatment with enalapril/hydrochlorothiazide at 20/6 mg.

Smoking is an important risk factor for the development and progression of diabetic nephropathy. The mechanisms by which smoking increases albuminuria and promotes nephropathy are unknown. Considering the acute pressor effect of smoking and the close association between blood pressure elevation and development of diabetic nephropathy, blood pressure increase might be implicated in the association between smoking and diabetic nephropathy. However, among nondiabetics, smokers have repeatedly been found to have lower blood pressure than nonsmokers. This is possibly mediated by an autonomic adjustment to sustained sympathetic stimulation by nicotine. Impaired modulation of the sympathovagal activity has been described in diabetes. In diabetic patients, the effect of smoking on blood pressure and autonomic function remains unclarified. We examined 24-h ambulatory blood pressure (oscillometric technique) and autonomic function (short-term power spectral analysis as well as conventional tests) in 24 smokers and 24 nonsmokers matched for sex, age, and diabetes duration. All patients were normoalbuminuric insulin-dependent diabetes mellitus patients. Smoking status was assessed by questionnaire with confirmatory determinations of urinary cotinine. Diabetic smokers had significantly higher 24-h mean arterial blood pressure (94 ± 6.7 mm Hg compared to diabetic nonsmokers 90 ± 5.8 mm Hg, P = .04) including higher diastolic nighttime blood pressure (68 ± 7.3 mm Hg v 64 ± 5.2 mm Hg, P = .03). Smokers also had significantly higher 24-h heart rate (80 ± 7.2 compared to 72 ± 9.2 beats/min, P 2 in smokers compared to 6.31 ± 1.11 ln ms 2 in nonsmokers, P v 42.1 ± 16.0 in nonsmokers, P

The role of blood pressure elevation in the incidence and progression of diabetic retinopathy is not clearly established and results have been conflicting. Blood pressure and urinary albumin excretion (UAE) are closely related. In order to evaluate the independent relationship between retinopathy and blood pressure elevation, precise information on UAE is essential, as confounding by renal disease (incipient or overt), cannot otherwise be excluded. The aim of the present study was to evaluate the association between diabetic retinopathy and 24-h ambulatory blood pressure (AMBP) in a group of well-characterized normoalbuminuric IDDM patients. In 65 normoalbuminuric (UAE < 20 microg/min) IDDM patients we performed 24-h AMBP (Spacelabs 90207) with readings at 20-min intervals. Fundus photographs were graded independently by two experienced ophthalmologists. UAE was measured by RIA and expressed as geometric mean of three overnight collections made within 1 week. HbA1c was determined by HPLC. Tobacco use and level of physical activity were assessed by questionnaire. Fifteen patients had no detectable retinal changes [grade 1], 35 had grade 2 retinopathy; and 15 had more advanced retinopathy [grade 3-6]. Diastolic night blood pressure was significantly higher in patients with diabetic retinopathy compared to patients without retinopathy (68 +/- 8 mmHg [grade 3-6] and 65 +/- 6 mmHg [grade 2], compared to 61 +/- 4 mmHg [grade 1], p = 0.02). Diurnal blood pressure variation was significantly blunted in the patients with retinopathy as indicated by a higher night/day ratio of diastolic blood pressure (84.6% +/- 4 [grade 3-6], and 81.2% +/- 6 [grade 2] compared to 79.1% +/- 4 [grade 1], p = 0.01). Heart rate tended to be higher in patients in group 2 and 3-6 compared to patients without retinopathy with p values of 0.07 and 0.11 for day-time and 24 h values, respectively. Mean HbA1c increased significantly with increasing levels of retinopathy (p < 0.01). Patients were similar regarding sex, age, tobacco use, and level of physical activity. Notably, UAE was almost identical in the three groups (5.0 x /divided by 1.7 [grade 1], 3.9 x /divided by 1.8 [grade 2], and 5.1 x /divided by 1.6 microg/min [grade 3-6]). In conclusion, night blood pressure is higher and circadian blood pressure variation blunted in patients with retinopathy compared to patients without retinopathy despite strict normoalbuminuria and similar UAE levels in the groups compared. Our data suggest that the association between blood pressure and diabetic retinopathy is present also when coexisting renal disease is excluded. Disturbed diurnal variation of blood pressure is a pathophysiological feature related to the development of both retinopathy and nephropathy in IDDM patients.

The blood pressure lowering effect and tolerability of the angiotensin-converting enzyme inhibitor enalapril combined with a very low dose of hydrochlorothiazide (HCTZ) were compared with the selective betareceptor blocker atenolol in patients with mild-to-moderate hypertension. Three hundred seventy-four patients were randomized into a triple-blind, parallel, active-controlled 12-week study period comparing enalapril/HCTZ (20/6 mg) with atenolol (50 mg) after a 4-week placebo baseline period. Blood pressure (BP), clinical and laboratory safety, and metabolic laboratory variables were assessed. Enalapril/HCTZ as well as atenolol reduced both sitting and standing diastolic and systolic BP (P < .001), but enalapril/HCTZ had a more pronounced effect than atenolol on sitting systolic BP (P = .019); there was a trend toward more patients achieving target diastolic BP (

The isokinetic muscle strength in 56 IDDM patients with > 20 years of diabetes duration and in their individually sex-, age-, weight-, and height-matched control subjects was assessed. Peak torque of foot dorsal and plantar flexion and knee and wrist extension and flexion was measured. The neuropathic condition was assessed by a neurological disability score, a neuropathy symptom score, nerve conduction studies, and quantitative sensory examination. All results were summed to obtain a neuropathy rank-sum score for each patient. According to their renal albumin excretion, the patients were classified to have normo-, micro-, or macroalbuminuria. In addition, according to their retinal status, patients were classified as having no, simple, or proliferative retinopathy. The IDDM patients had a 21% reduction of muscle strength of both ankle dorsal (P < 1 × 10™4) and plantar flexors (P < 0.01), compared with control subjects. A 16% reduction of knee extensors (P < 0.005) and a 17% reduction of knee flexors (P < 0.01) was found. In contrast, muscle strength in wrist flexors and extensors was not significantly reduced (10 and 11%, respectively [NS]). In patients with the most severe weakness, muscle strength of the calf muscles was only 50% of the expected performance. Correlations were found between the neuropathy rank-sum score and the muscle strength of ankle dorsal (r = −0.66, P < 1 × 10™7) and plantar flexors (r = −0.51, P < 0.0005), knee extensors (r = −0.51, P < 0.0005) and flexors (r = −0.44, P < 0.005), and wrist flexors (r = −0.41, P < 0.005). No correlation was found for wrist extensors (r = 0). Neither were there any relationships between muscle strength at the ankle and knee and the degree of albuminuria or retinopathy. In conclusion, motor performance is substantially impaired in long-term IDDM patients, and the weakness is related to the presence of neuropathy but not to albuminuria or retinopathy per se.

Albuminuria and cardiovascular risk in hypertensive patients with left ventricular hypertrophy: The LIFE Study. Studies have shown that albuminuria is associated with increased risk for cardiovascular events. We tested the relationship between albuminuria (UACR) and cardiovascular risk in 8206 hypertensive patients with left ventricular hypertrophy included in the LIFE Study. Follow-up was 39,122 patient years. The risk for the primary composite cardiovascular end point increases continuously from the lowest to the highest decile of baseline UACR. No specific threshold could be identified. In conclusion, albuminuria predicts the outcome in the LIFE Study. The risk for cardiovascular morbidity and mortality among hypertensive patients with left ventricular hypertrophy increases at much lower UACR than has been reported in diabetic patients.

OBJECTIVE To assess the long-term relationships between 24-h ambulatory blood pressure (AMBP), urinary albumin excretion (UAE) rate, and metabolic control in non-insulin-dependent diabetes mellitus (NIDDM) patients with normo- and microalbuminuria. RESEARCH DESIGN AND METHODS We conducted a prospective study of 23 NIDDM patients (11 with normoalbuminuria and 12 with microalbuminuria) receiving standard clinical care, including antihypertensive treatment, attending the outpatient clinic and 8 healthy control subjects. Twenty-four-hour AMBP and UAE were measured synchronously in addition to fasting plasma glucose, HbA1c, and serum creatinine at baseline and after 4.6 (4.2−5.1) years [mean (range)]. RESULTS Baseline systolic, but not diastolic, 24-h AMBP was significantly higher in diabetic patients compared with control subjects (146/80 [16/11] vs. 133/78 [9/9] mmHg, P < 0.05), but was similar in normoalbuminuric (143/81 [11/11] mmHg) and microalbuminuric (148/80 [20/10] mmHg) patients during strict blood pressure control. The annual increase in 24-h AMBP was equivalent in diabetic patients (0.6/−0.2 [2.6/1.5] mmHg/year) and control subjects (0.7/0.2 [1.2/1.4] mmHg/year, NS) and not significantly different from zero. Overall UAE did not change in control subjects (5.6 [1.6] vs. 4.4 [1.9]) (geometric mean [antilog SD]) or in the normoalbuminuric (8.7 [1.7] vs. 11.3 [3.0] ¼g/min) and microalbuminuric (35.7 [2.1] vs. 34.5 [3.2] μg/min) patients. In diabetic patients, the annual change in UAE correlated significantly with the annual change in the systolic (r = 0.61, P < 0.002) and diastolic (r = 0.54, P < 0.008) 24-h AMBP. In microalbuminuric patients, only the annual increase in systolic 24-h AMBP correlated significantly with the annual change in UAE (r = 0.71, P = 0.010), whereas in the normoalbuminuric patients, only the annual increase in diastolic 24-h AMBP and the annual change in UAE were significantly correlated (r = 0.66, P = 0.026). In a stepwise multiple linear regression analysis, the annual progression in albuminuria in NIDDM patients was significantly determined by increases in systolic (parameter estimate 0.018, SE 0.006, P < 0.008) as well as in diastolic 24-h AMBP (parameter estimate 0.026, SE 0.011, P < 0.033). CONCLUSIONS In an outpatient clinical setting, 24-h AMBP is similar in NIDDM patients with normo- and microalbuminuria. Alterations in both 24-h AMBP and UAE are on average moderate and equivalent compared with those in healthy control subjects. Although the average change in albuminuria is small, a progression in albuminuria relates to increments in both systolic and diastolic 24-h AMBP.

Ambulatory blood pressure (AMBP) is of particular interest in diabetes because of the close association between elevated BP and diabetic nephropathy and the attenuated night drop in some diabetic subgroups: (1) Normoalbuminuric patients: If standardized for type of day (work or day off), coefficient of variation (CV) for 24 h AMBP is 2%–3% and 5%–6% for night/day ratio. The male-female difference in AMBP seen in healthy subjects is reduced in diabetes. Smoking did not significantly affect AMBP. AMBP is increased in patents with high normal urinary albumin excretion (UAE). Night/day ratio of AMBP and night heart rate is higher in long than short term diabetic patients. This difference in night/day ratio is not significant if the slightly higher UAE in long-term patients is accounted for. (2) Microalbuminuric patients: Diastolic night/day ratio is increased compared with healthy controls, with the value for normoalbuminuric patients in between. A large overlap between groups is evident. Thus the prognostic value of a single abnormal night/day ratio is doubtful. If divided into dippers and nondippers, no difference in extracellular- or plasma volume is found, but nondippers have a lower plasma aldosterone and arginine vasopressin level, possibly to counteract volume expansion. (3) Patients with overt nephropathy: A marked increased in AMBP and a clear reduction of the nocturnal blood pressure fall is seen. In conclusion, AMBP (but not night/day ratio) is highly reproducible. The association between elevated AMBP, elevated night/day ratio, and pathological UAE is detectable even in normoalbuminuric patients. The prognostic importance of abnormal circadian variation of BP is unsettled.

In the past year six sets of recommendations on the prevention of diabetic nephropathy, with special reference to microalbuminuria, have been published [1–6]. The background to this activity was the large and increasing number of diabetic patients in whom end-stage renal failure (ESRD) develops and who therefore require dialysis or renal transplantation. Throughout the world about half a million patients are registered as being on renal replacement therapy, and diabetic nephropathy is the cause in nearly one-fifth of them [7]. These data are extrapolated from countries which have registries but in many areas, especially in the densely populated countries of the Far East, accurate information on numbers of patients with ESRD is not yet available. Moreover, the half-million figure probably underestimates the number of diabetic patients with ESRD because selection criteria for renal replacement therapies vary from country to country. Both insulin dependent (IDDM) and non-insulin-diependent (NIDDM) diabetic patients contribute to the increase in ESRD. Prevention of diabetic renal disease, or at least the postponement or slowing down of the disease process, has emerged as a key issue. Our strategy is to develop programmes for all patients with diabetes, focused on early detection of renal disease followed by intervention.

Over the past two decades there has been an increasing interest in hypertension as a risk factor for diabetic renal disease and in particular for the possibility of early antihypertensive intervention. Therefore, it would seem timely to review the history of hypertension in diabetes, with special reference to renal disease and the need for normotension, in a manner resembling glycaemic control. Elevated blood pressure (BP) associated with diabetes mellitus has been recognized since the beginning of the century and was initially particularly documented in association with the demonstration of the striking histological lesion in glomeruli, starting with the observation of Kimmelstiel and Wilson in 1936. These patients in many cases also showed hypertension, as confirmed in several subsequent reports, very similar to the studies of Kimmelstiel and Wilson. However, the development was hampered by the lack of effective antihypertensive agents and also by some who believed that elevated BP could be of importance to preserve renal function in these individuals. Indeed, it was suggested that reduction of BP could mean permanent deterioration in renal function. BP remained very high in the standard care of diabetic patients up to the middle 1970s. At this time it was documented that elevated BP was very closely related to development of diabetic renal disease in Type 1 (insulin-dependent) diabetic (IDDM) patients, and studies also showed a correlation between blood pressure and rate of progression. This correlation stimulated research in intervention, and indeed in the 1980s and 1990s several long-term studies reported that antihypertensive treatment can reduce the rate of decline in glomerular filtration rate (GFR) from about 12ml min-1yr-1 down to about 2ml min-1 yr-1 in the most optimistic reports; usually a mean level of 2–5 ml min-1yr-1 is achievable by antihypertensive treatment, in clinical situations where glycaemic control often is far from perfect. Many studies have also documented that BP starts to rise in the early phase of incipient diabetic nephropathy characterized by microalbuminuria. This is a stage with well-preserved GFR and therefore probably an ideal stage for intervention in these at risk patients. Many studies, in particular those employing angiotensin converting enzyme (ACE) inhibitors based on important pathophysiological concepts proposed by Brenner, have shown that microalbuminuria can be reduced or stabilized by early antihypertensive treatment, just as we see with optimized glycaemic control. ACE inhibitors have also been widely used in patients with overt nephropathy and the rate of decline in GFR has been reduced considerably. However, it seems likely that an equal rate of decline in GFR may be achieved also by other BP-reducing agents, but there is some disagreement in the literature. With respect to strong end-points such as mortality and development of uraemia, retrospective studies suggest a beneficial effect of antihypertensive treatment with beta-blockers and diuretics. Importantly, there is, however, only one formal randomized study showing effects on these end-points, namely by ACE inhibitors, as compared to other antihypertensive agents, but still BP was more extensively reduced with the former treatment. Thus, the history of hypertension in diabetes in IDDM patients documents that BP is now being intensively treated in comparison to 15–20 years ago. Also the indication for prescription of treatment has been modified downwards and it has even been proposed that microalbuminuria should be an indication for treatment irrespective of BP. Parental hypertension or pre-diabetic or pre-nephropathy BP has been suggested to play a role for progression in renal disease, but there is still some controversy in this area, although this concept has gained strong support in the Pima-Indian studies. A new development is the use of ambulatory 24-h BP recordings (comparable to HbA1c measurements) which must be used when a correlation between BP (and glycaemia) and progression of renal disease and intervention is in focus. Documentation of white-coat hypertension is important to avoid unnecessary treatment in the normoalbuminuric IDDM patients. Generally speaking, the quest for normotension is just as strong or stronger (and better achievable) as a quest for near-normoglycaemia, at least in IDDM patients and in particular in patients with incipient or overt renal disease.

OBJECTIVE To investigate whether insulin resistance and microalbuminuria are associated in non-insulin-dependent diabetes mellitus (NIDDM). RESEARCH DESIGN AND METHODS Insulin sensitivity was assessed using a hyperinsulinemic euglycemic clamp in 11 normoalbuminuric and 9 microalbuminuric NIDDM patients matched for sex, age, body composition, glycemic control, diabetes duration, and therapy. RESULTS Isotopically determined glucose disposal was similar in normo- and microalbuminuric patients in the basal state (mean ± SD; 3.30 ± 1.01 vs. 3.46 ± 0.82 mg·kg lean body mass [LBM]−1 · min−1; NS) and during hyperinsulinemia (7.16 ± 2.65 vs. 6.63 ± 2.88 mg·kg LBM−1 · min−1;NS). No difference was observed in nonoxidative glucose disposal or lipid oxidation. Endogenous glucose production was equally suppressed by insulin (−0.08 ± 0.99 vs. 0.30 ± 1.12 mg·kg−1 LBM·min−1; NS). Glucose oxidation tended to be lower in the normoalbuminuric patients in the basal state (1.16 ± 0.37 vs. 1.41 ± 0.36 mg·kg LBM· min−1) and during hyperinsulinemia (2.35 ± 0.72 vs. 2.90 ± 0.77 mg·kg LBM· min−1; both P < 0.15). Urinary albumin excretion rate correlated with the insulin-stimulated glucose oxidation rate (r = 0.59, P = 0.0064), and a similar trend was seen in the basal state (r = 0.42, P = 0.063). Protein oxidation was higher in normoalbuminuric patients (1.6 ± 0.5 vs. 1.0 ± 0.4 mg·kg LBM · min−1; P = 0.017) and correlated inversely with albuminuria (r = −0.70, P = 0.0007). Serum growth hormone increased during insulin infusion; however, the increase was significantly greater in microalbuminuric patients. Plasma lipoproteins, maximal aerobic capacity, and 24-h ambulatory blood pressure were similar in the two groups. CONCLUSIONS Basal and insulin-stimulated glucose uptakes are comparable in carefully matched normo- and microalbuminuric NIDDM patients, and glucose oxidation may be positively related to albuminuria. The inverse relation between protein oxidation and albuminuria may be due to higher growth hormone levels during daily life perturbations in glucose in microalbuminuric patients.

▪ Abstract Diabetic patients go through several stages of renal disease, moving from normo- to micro- to macroalbuminuria. Good metabolic control can prevent or postpone the development of microalbuminuria, the earliest sign of diabetic renal disease. Thus, efforts should focus on obtaining the best possible control before the onset of microalbuninuria. In patients with microalbuminuria, blood pressure starts to increase, and early antihypertensive treatment becomes important. Good glycemic control may be difficult to achieve. With overt nephropathy, defined as clinical proteinuria, a relentless decline in glomerular filtration rate (GFR) occurs unless patients are carefully treated with antihypertensive agents. Protein restriction may also be necessary, but a clear beneficial effect of optimized diabetes care is difficult to document. Early screening is recommended, with an emphasis on testing for albuminuria, including microalbuminuria, along with careful control of blood pressure.