We studied whether microalbuminuria (30 to 140 micrograms of albumin per milliliter) would predict the later development of increased proteinuria and early mortality in Type II diabetics. During 1973, morning urine specimens of diabetic clinic patients 50 to 75 years of age whose disease had been diagnosed the age of 45 were examined for albumin level by radioimmunoassay. Seventy-six patients with albumin concentrations of 30 to 140 micrograms per milliliter were identified for long-term follow-up. They were compared with normal controls, diabetic patients with lower albumin concentrations (75 patients with concentrations less than 15 micrograms per milliliter and 53 with concentrations of 16 to 29 micrograms per milliliter), and 28 diabetic patients with higher concentrations (greater than 140). Age, duration of diabetes, treatment method, fasting blood glucose level, blood pressure, height, and weight were determined for the four diabetic groups. After nine years the group with albumin concentrations of 30 to 140 micrograms per milliliter was more likely to have clinically detectable proteinuria (greater than 400 micrograms per milliliter) than were the groups with lower concentrations. Mortality was 148 per cent higher in this group than in normal controls--comparable to the increase (116 per cent) in the group with heavy proteinuria (albumin levels greater than 140 micrograms per milliliter). In addition, mortality was increased 76 per cent in the group with albumin levels of 16 to 29 micrograms per milliliter and 37 per cent in the group with levels below 15. We conclude that microalbuminuria in patients with Type II diabetes is predictive of clinical proteinuria and increased mortality.

There are limited data regarding whether albuminuria and reduced estimated GFR (eGFR) are separate and independent risk factors for cardiovascular and renal events among individuals with type 2 diabetes. The Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation (ADVANCE) study examined the effects of routine BP lowering on adverse outcomes in type 2 diabetes. We investigated the effects of urinary albumin-to-creatinine ratio (UACR) and eGFR on the risk for cardiovascular and renal events in 10,640 patients with available data. During an average 4.3-yr follow-up, 938 (8.8%) patients experienced a cardiovascular event and 107 (1.0%) experienced a renal event. The multivariable-adjusted hazard ratio for cardiovascular events was 2.48 (95% confidence interval 1.74 to 3.52) for every 10-fold increase in baseline UACR and 2.20 (95% confidence interval 1.09 to 4.43) for every halving of baseline eGFR, after adjustment for regression dilution. There was no evidence of interaction between the effects of higher UACR and lower eGFR. Patients with both UACR Ͼ300 mg/g and eGFR Ͻ60 ml/min per 1.73 m 2 at baseline had a 3.2-fold higher risk for cardiovascular events and a 22.2-fold higher risk for renal events, compared with patients with neither of these risk factors. In conclusion, high albuminuria and low eGFR are independent risk factors for cardiovascular and renal events among patients with type 2 diabetes.

Alterations in renal function and structure are found even at the onset of diabetes mellitus. Studies performed over the last decade now allow definition of a series of stages in the development of renal changes in diabetes. Such a classification may be useful both in clinical work and in research activities. Stage 1 is characterized by early hyperfunction and hypertrophy. These changes are found at diagnosis, before insulin treatment. Increased urinary albumin excretion, aggravated during physical exercise, is also a characteristic finding. Changes are at least partly reversible by insulin treatment. Stage 2 develops silently over many years and is characterized by morphologic lesions without signs of clinical disease. However, kidney function tests and morphometry on biopsy specimens reveal changes. The function is characterized by increased GFR. During good diabetes control, albumin excretion is normal; however, physical exercise unmasks changes in albuminuria not demonstrable in the resting situation. During poor diabetes control albumin excretion goes up both at rest and during exercise. A number of patients continue in stage 2 throughout their lives. Stage 3, incipient diabetic nephropathy, is the forerunner of overt diabetic nephropathy. Its main manifestation is abnormally elevated urinary albumin excretion, as measured by radioimmunoassay. A level higher than the values found in normal subjects but lower than in clinical disease is the main characteristic of this stage, which appeared to be between 15 and 300 micrograms/min in the baseline situation. A slow, gradual increase over the years is a prominent feature in this very decisive phase of renal disease in diabetes when blood pressure is rising. The increased rate in albumin excretion is higher in patients with increased blood pressure. GFR is still supranormal and antihypertensive treatment in this phase is under investigation, using the physical exercise test. Stage 4 is overt diabetic nephropathy, the classic entity characterized by persistent proteinuria (greater than 0.5 g/24 h). When the associated high blood pressure is left untreated, renal function (GFR) declines, the mean fall rate being around 1 ml/min/mo. Long-term antihypertensive treatment reduces the fall rate by about 60% and thus postpones uremia considerably. Stage 5 is end-stage renal failure with uremia due to diabetic nephropathy. As many as 25% of the population presently entering the end-stage renal failure programs in the United States are diabetic. Diabetic nephropathy and diabetic vasculopathy constitute a major medical problem in society today.

Motor function in type 2 diabetes is largely unknown. In 36 type 2 diabetic patients and in 36 control subjects matched for sex, age, weight, height, and physical activity, strength of flexors and extensors at elbow, wrist, knee, and ankle was assessed at isokinetic dynamometry. The degree of neuropathy was determined by clinical scores, nerve conduction studies, and quantitative sensory testing. Eventually, all results were summed to obtain a neuropathy rank-sum score (NRSS). The degree of nephropathy and retinal condition were also evaluated. Diabetic patients had a 17 and 14% reduction of strength of ankle flexors (P < 0.02) and ankle extensors (P < 0.03), respectively. At the knee, strength of extensors and flexors was reduced by 7% (NS) and 14% (P < 0.05), respectively. At the elbow and wrist, muscle strength was preserved. The NRSS was related to the strength at the ankle (r ‫؍‬ ؊0.45, P < 0.01) and knee (r ‫؍‬ ؊0.42, P < 0.02). Following multiple regression analysis, the NRSS but not the degree of nephropathy or retinopathy was related to strength at the ankle and knee. In conclusion, type 2 diabetic patients may have muscle weakness at the ankle and knee related to presence and severity of peripheral neuropathy. Diabetes 53:1543-1548, 2004 S ensory symptoms and deficits are frequent in distal diabetic polyneuropathy. Motor symptoms are less dramatic, and motor deficits are more difficult to recognize. Not surprisingly, the literature on this manifestation of diabetic polyneuropathy is sparse. In patients with long-term type 1 diabetes, we have found impaired muscle strength at the ankle and knee closely related to the severity of neuropathy (2). Motor dysfunction is known to occur in type 2 diabetic patients; however, the severity and distribution of the weakness has not been reported (3).In a population-based study from the U.K., a similar frequency of neuropathy was found in type 1 and 2 diabetic patients after age correction (4). Nevertheless, a considerably lower frequency of severe neuropathy, defined as an inability to walk on heels, was observed in type 2 diabetes in a population-based study from Minnesota (3). This observation may indicate less motor dysfunction in type 2 diabetes. However, the relation between inability to walk on heels and muscle strength has not been established, so there is a clear need for quantitative studies of motor function in type 2 diabetes.In the present study, we evaluated muscular performance of lower and upper extremities quantitatively in type 2 diabetic patients, applying isokinetic dynamometry, which has high reliability in the determination of maximal strength in both neuropathic and healthy subjects (5). To study the relationship of muscle strength with the prevalence and severity of diabetic neuropathy, other diabetes complications, and metabolic control, patients were characterized clinically, biochemically, and with electrophysiological and sensory function tests. RESEARCH DESIGN AND METHODSAll patients and control subjects gave informed consent for partici...

Six men aged 26-35 years with proteinuria due to insulindependent juvenile-onset diabetes were treated for moderate hypertension (mean blood pressure 162/103 mm Hg) and studied for a mean of 73 months for the effect on the progression of nephropathy. All patients were of normal weight. During a mean control period of 28 months before treatment the mean glomerular filtration rate (three or four measurements) was 86-1 ml/ min and mean 24-hour urinary albumin excretion (also three or four measurements) 3 9 g (range 0-5-8-8 g).During antihypertensive treatment the mean systolic blood pressure fell to 144 mm Hg and mean diastolic pressure to 95 mm Hg. In the control period five patients had shown a mean monthly decline in glomerular filtration rate of 1-23 ml/min; with antihypertensive treatment, however, this decline fell to 0 49 ml/min (2p=0 042). In the remaining patient the glomerular filtration rate was 137 ml/min before treatment and 135 ml/min at the end of the treatment period. In all patients the mean yearly increase in albumin clearance (expressed as a percentage of the glomerular filtration rate) fell from 107% before treatment to 5% during treatment (2p =0-0099).This small study indicates that antihypertensive treatment slows the decline in renal function in diabetic nephropathy. Clinical trials beginning treatment in the incipient phase of diabetic nephropathy will define the optimal modality of treatment in this large patient population.Introduction Diabetic nephropathy is a major medical problem, yet we still do not know why some patients develop proteinuria and renal failure and others not despite a long history of diabetes.1 2 Characteristically diabetics without perceptible renal disease have normal blood pressure,3 whereas patients with nephropathy are hypertensive.4 Only in the past few years,5 however, has the possible role of high blood pressure in the progression of diabetic nephropathy and other vascular lesions attracted interest. In a previous study I identified high blood pressure as a possible factor in the rapid deterioration of kidney function seen in some patients.5I now report a study in which the rate of progression of nephropathy was measured by serial determination of glomerular filtration rate, renal plasma flow, and urinary albumin excretion before and during long-term antihypertensive treatment in six juvenile-onset diabetics with established nephropathy. The results show that the rate of progression can be impeded, thus postponing renal insufficiency in these patients.