Microalbuminuria is strongly associated with NIDDM and hypertension, but not with the insulin resistance syndrome: the Hoorn Study

Microalbuminuria is a strong predictor of cardiovascular disease. The aim of this study was to investigate whether microalbuminuria is part of a cluster of risk factors, the insulin resistance syndrome (IRS), or whether it is only associated with, and presumably a complication of, hypertension and non-insulin-dependent diabetes mellitus (NIDDM). An age-, sex- and glucose tolerance-stratified random sample from a 50-75 year old general population (n = 622) was investigated. The urinary albumin-to-creatinine ratio was measured in an early morning spot urine sample. Microalbuminuria was defined as an albumin-to-creatinine ratio greater than 2.0 mg/ mmol. We considered, as IRS-related variables, fasting hyperinsulinaemia, insulin resistance (IR; calculated from the formula of the homeostasis model assessment), dyslipidaemia, glucose intolerance, hypertension and waist-to-hip ratio (WHR). Dyslipidaemia was defined as levels of HDL-cholesterol in the lowest and/or levels of triglyceride in the highest tertile. Fasting insulin levels, IR and WHR were divided into tertiles; the highest tertiles were compared to the lowest tertiles. Age-, sex- and glucose tolerance-adjusted analyses showed microalbuminuria to be significantly associated with hypertension, NIDDM and WHR. In multiple logistic regression analyses, microalbuminuria showed independent associations with hypertension, NIDDM and WHR, with odds ratios (ORs [95% confidence interval]) of 3.33 (1.86-5.96), 2.26 (1.14-4.48) and 2.49 (1.09-5.70), respectively. No associations were found with impaired glucose tolerance, hyperinsulinaemia, IR or dyslipidaemia. Multiple logistic regression analyses in diabetic and non-diabetic subjects separately showed that microalbuminuria was independently associated only with hypertension (ORs 4.31 and 2.69). In this Caucasian population, microalbuminuria was associated with hypertension, NIDDM and WHR and not with other variables of the IRS. It is therefore likely that microalbuminuria is a complication of hypertension and NIDDM, and not an integral part of the IRS.     

Albuminuria and glycemic control. The significance for mortality in non-insulin-dependent diabetes mellitus]

The impact of microalbuminuria and macroalbuminuria on mortality was evaluated prospectively in 328 Caucasian patients with non-insulin-dependent diabetes mellitus (NIDDM) followed for five years. One hundred and ninety-one patients with normoalbuminuria (albumin excretion rate (AER) < 30 mg/24 h), 86 patients with microalbuminuria (AER 30-299 mg/24 h), and 51 patients with macroalbuminuria (AER > or = 300 mg/24 h) all less than 66 years old at start of the study were followed from 1987 until death or until 1 January 1993. Eight percent of patients with normoalbuminuria, 20% of patients with microalbuminuria, and 35% of patients with macroalbuminuria had died, predominantly from cardiovascular disease. Significant predictors of all-cause mortality included preexisting coronary heart disease, AER, HbA1c level and age. Significant predictors of cardiovascular mortality included preexisting coronary heart disease, macroalbuminuria, HbA1c level and systolic blood pressure. Abnormally elevated urinary albumin excretion and poor glycaemic control indicate a substantially increased all-cause, mainly cardiovascular, mortality risk in NIDDM patients.     

Microalbuminuria: a marker to increased renal and cardiovascular risk in diabetes mellitus

The presence of persistent microalbuminuria in IDDM is strongly predictive of the future development of end stage renal failure and of cardiovascular disease to a lesser extent. Screening for microalbuminuria is an essential component of modern diabetes practice, as effective antihypertensive therapy, and particularly, the use of angiotensin converting enzyme inhibitors is of proven benefit in retarding progression of renal disease. Cost benefit analysis justifies the expense of microalbuminuria screening programmes and early intervention. It has been estimated that the use of angiotensin converting enzyme inhibitors in microalbuminuric IDDM will save 5200 Pounds-11,000 Pounds per year of life saved. Angiotensin converting enzyme inhibitors are not free of side-effects, and it is therefore essential, given the intrinsic variability of the albumin excretion rate, and the regression to normoalbuminuria of a significant proportion of patients, to confirm the diagnosis of microalbuminuria by repeated measurements prior to the commencement of treatment. The value of intensive glycaemic control is unproven, and further prospective studies are required. There are no proven therapies for the prevention of macrovascular disease in IDDM, although the value of cessation of smoking and aggressive blood pressure control are undoubted in the non-diabetic population. Controversy persists about the value of lipid lowering therapy, especially in young patients, although even in this group there is an increased risk of cardiovascular disease. Microalbuminuria is the strongest known predictor of cardiovascular disease in NIDDM; in contrast to the situation in the non-diabetic population, active lipid lowering therapy is not of proven cardiac benefit, but intervention seems justifiable when taken in the context of the very high prevalence of cardiovascular disease. Microalbuminuria is also predictive of end stage renal disease in NIDDM. Although intervention with angiotensin converting enzyme inhibitors has not been proven to prevent end stage renal disease, stabilisation of albumin excretion rate and creatinine clearance have been demonstrated in normotensive NIDDM, and it seems likely that longer term follow-up studies will confirm the benefit of angiotensin converting enzyme inhibitors in the prevention of end-stage renal disease. The observed predictive power of microalbuminuria as regards both cardiac and renal risk in NIDDM when considered in conjunction with the preliminary results of the benefits of angiotensin converting enzyme inhibition lend further support to the employment of microalbuminuria screening in NIDDM.     

The diabetes mellitus regimen

Some patients with essential hypertension manifest increased urinary albumin excretion (UAE). Hypertensive patients with microalbuminuria manifest abnormal circadian variation of blood pressure, increased serum levels of LDL-cholesterol and lipoprotein(a), a greater rise of serum insulin in response to an oral glucose tolerance test, and greater thickness of the carotid artery than patients without microalbuminuria. A 7 year follow-up of 141 hypertensive patients, 54 with microalbuminuria and 87 without microalbuminuria, we observed 12 cardiovascular events in patients with microalbuminuria and only 2 events in the patients with normal urine albumin excretion (P < 0.0002). Creatinine clearance decreased more in patients with microalbuminuria than in those with normal UAE. In conclusion, hypertensive individuals with microalbuminuria manifest a greater incidence of cardiovascular events and more decline in renal function than patients with normal UAE. We propose that measurements of UAE may be a useful marker for cardiovascular risk in patients with essential hypertension.     

Insulin resistance precedes microalbuminuria in patients with insulin-dependent diabetes mellitus

BACKGROUND: Insulin resistance has been associated with hypertension and with renal complications in patients with type 1 diabetes mellitus. Causal relationships have not been fully explained. METHODS: We investigated whether insulin resistance precedes microalbuminuria by measuring insulin resistance with a euglycaemic clamp in combination with indirect calorimetry in 16 uncomplicated type 1 diabetic patients and in six healthy control subjects. The patients had over 10 year duration of diabetes, and were expected to experience either a complication-free or complicated disease course within the next few years. They have thereafter been followed for the development of microalbuminuria for 3 years. RESULTS: In a euglycaemic insulin clamp glucose disposal was lower in diabetic patients compared with control subjects (7.5 +/- 2.9 and 12.6 +/- 2.0 mg/kg LBM/min; P<0.002), mainly due to impaired glucose storage (4.3 +/- 2.3 vs 8.6 +/- 1.6 mg/kg LBM/min; P<0.001). Three years later seven IDDM patients had albumin excretion rate over 30 mg/24 h; glucose disposal (5.5 +/- 2.1 vs 9.0 +/- 2.2 mg/kg LBM/min; P<0.01) had been lower in patients who developed microalbuminuria compared with those who remained normoalbuminuric. CONCLUSIONS: Insulin resistance predicts the increment in urinary albumin excretion. Insulin resistance depends mainly on impaired glucose storage in uncomplicated IDDM.     

Hypertension and insulin resistance

Non insulin dependent diabetes mellitus (NIDDM) and obesity are defined as classical insulin resistant states. Essential hypertension is now also considered to be an insulin resistant state, even in absence of NIDDM or obesity, as shown in epidemiological, clinical and experimental studies. Neither the underlying mechanism nor a direct causality between the two phenomena has been detected as yet, but different hypotheses have been postulated where, on the one hand, insulin resistance and hypertension are considered to be causally related and, on the other hand, they are considered to be parallel phenomena due to genetic and acquired factors. The clarification of the connection between hypertension and insulin resistance seems to be of great clinical importance, since they are both independent risk factors for cardiovascular disease and mortality from cardiovascular complications. This paper gives an overview of the results of recent research on the possible underlying pathogenetic mechanisms linking hypertension and insulin resistance.     

Epidemiologic studies on the pathogenesis of non-insulin-dependent diabetes mellitus (NIDDM)

The diagnostic criteria of the US National Diabetes Data Group and the World Health Organization have stimulated a major increase throughout the world in epidemiologic studies on the pathogenesis of non-insulin-dependent diabetes mellitus (NIDDM). They have established that much of NIDDM is undiagnosed, that onset of NIDDM occurs at least 7 y before its diagnosis, and that significant morbidity and premature mortality occur in subjects with undiagnosed diabetes. New studies have shown that rural or traditional-living populations are experiencing a major increase in the burden of NIDDM as they move to urban or nontraditional situations, often with 5- to 10-fold increases in NIDDM prevalence. Epidemiologic studies have documented that major risk factors for NIDDM include increasing age, greater obesity, longer duration of obesity, unfavourable body fat distribution, physical inactivity, and hyperinsulinemia. All these factors interact with unknown genetic factors to produce NIDDM. Studies have shown that genes for diabetes, as yet undetermined, are a necessary cause of NIDDM. Hyperinsulinemia exists in childhood in populations at high risk for NIDDM. Stimulated by obesity, upper body obesity, and physical inactivity, insulin resistance develops, accompanied by impaired glucose tolerance. The pressure of the NIDDM risk factors continues this process of insulin resistance/hyperinsulinemia/hyperglycemia, until glucose toxicity to the beta cell results in inability to secrete sufficient insulin, resulting in decompensated fasting hyperglycemia.     

Plasma homocysteine is related to albumin excretion rate in patients with diabetes mellitus: a new link between diabetic nephropathy and cardiovascular disease?

The high risk of cardiovascular disease in patients with diabetes mellitus, particularly in those with nephropathy, is not completely explained by classical risk factors. A high plasma homocysteine concentration is an independent risk factor for cardiovascular disease but information on its association with diabetes is limited. Fasting homocysteine concentrations were measured in the plasma of 165 diabetic patients (75 with insulin-dependent [IDDM]; 90 with non-insulin-dependent diabetes [NIDDM]) and 56 non-diabetic control subjects. Other measurements included the prevalence of diabetic complications, glycaemic control, lipid and lipoprotein levels, vitamin status and renal function tests. Patients with NIDDM had higher homocysteine levels than control subjects, whereas IDDM patients did not (9.2 +/- 4.5 vs 7.7 +/- 2 micromol/l, p < 0.01; and 7.0 +/- 3 vs 7.4 +/- 2 micromol/l, NS). Univariate correlations and multiple regression analysis showed albumin excretion rate to be the parameter with the strongest independent association with homocysteine. Patients with both types of diabetes and nephropathy had higher plasma homocysteine concentrations than those without nephropathy. Increases of homocysteine in plasma were related to increases in the severity of the nephropathy. Fasting hyperhomocysteinaemia was considered as the mean of the plasma homocysteine for all control subjects (7.5 +/- 2.1 micromol/l) + 2 SD (cut-off = 11.7 micromol/l). Nephropathy was present in 80 % of diabetic patients with fasting hyperhomocysteinaemia. In conclusion, increases in fasting homocysteine in diabetic patients are associated with increased albumin excretion rate, especially in those with NIDDM, thus providing a potential new link between microalbuminuria, diabetic nephropathy and cardiovascular disease.     

Assessment of ventricular diastolic function in AIDS patients from Congo: a Doppler echocardiographic study

The aim of this study was to evaluate the effect of transdermal clonidine on hemodynamic and metabolic parameters in patients who have elevated blood pressure and non-insulin-dependent diabetes mellitus (NIDDM). After a 2-week run in placebo period, 20 NIDDM patients who had diastolic blood pressure in the range of 90 to 105 mm Hg underwent a randomized, single blind, placebo controlled, cross-over study of 4 week treatment with clonidine (transdermal patch 2.5 mg/week) or placebo (inactive patch). Compared with placebo, clonidine significantly reduced systolic (153 +/- 6 v 163 +/- 8) and diastolic (88 +/- 2 v 98 +/- 3.5 mm Hg, P = .001) blood pressure, left ventricular mass (94 +/- 11 v 99 +/- 12 g/m2, P < .01) and fasting glucose levels. Total glucose disposal (glucose clamp) was 6.5 +/- 1.5 with placebo and 7.1 +/- 1.6 mg/kg/min with clonidine (P < .01). Oxidative glucose disposal (indirect calorimetry) was also greater after clonidine. Plasma glucose, insulin, and C-peptide responses following oral glucose (75 g) were significantly lower after clonidine, as well as urinary albumin excretion. Transdermal clonidine is effective in reducing blood pressure in hypertensive NIDDM patients and is well tolerated. It may be useful to reduce the cardiovascular impact of hypertension in diabetes mellitus.     

Role of the beta 3-adrenergic receptor locus in obesity and noninsulin-dependent diabetes among members of Caucasian families with a diabetic sibling pair

Obesity and insulin resistance are important risk factors for the development of noninsulin-dependent diabetes (NIDDM) and are prevalent among predisposed first degree relatives of diabetic individuals. Recent molecular screening and analysis of a common missense mutation of the beta 3-adrenergic receptor gene suggested this locus as a strong candidate for increased obesity, earlier age of diabetes onset, and insulin resistance. To test the hypothesis that the beta 3-adrenergic receptor locus affects diabetes susceptibility, obesity as measured by body mass index, and components of the insulin resistance syndrome, we examined the role of this region in families ascertained for two or more NIDDM siblings. Linkage analysis was conducted using both parametric and nonparametric analyses, including multipoint sibling pair analysis. We found no evidence for linkage to NIDDM as a dichotomous trait and no evidence for linkage to body mass index, waist/hip ratio, insulin levels, or glucose levels as quantitative traits or to reported age of onset among NIDDM individuals. The Trp64 Arg missense mutation was present in 11% of the population. The mutation was not associated with NIDDM, and Arg64 carriers did not have earlier NIDDM onset, higher body mass index, or higher waist/hip ratio than Trp64 homozygotes. Among relatives, Arg64 carriers had significantly lower fasting glucose levels and lower waist/hip ratios than Trp64 homozygotes, but no characteristics of the insulin resistance syndrome. We conclude that the beta 3-adrenergic receptor locus does not play an important role in NIDDM susceptibility or in the insulin resistance syndrome among members of families with a strong predisposition to NIDDM.     

Effects of locus coeruleus stimulation on the responses of SI neurons of the rat to controlled natural and electrical stimulation of the skin

Recent epidemiologic data demonstrate a dramatic increase in the incidence of end-stage renal disease (ESRD) in patients with non-insulin-dependent diabetes mellitus (NIDDM), thus dispelling the mistaken belief that renal prognosis is benign in NIDDM. Currently, the leading cause of ESRD in the United States, Japan, and in most industrialized Europe is NIDDM, accounting for nearly 90% of all cases of diabetes. In addition to profound economic costs, patients with NIDDM and diabetic nephropathy have a dramatically increased morbidity and premature mortality. NIDDM-related nephropathy varies widely among racial and ethnic groups, genders and lifestyles; and gender may interact with race to affect the disease progression. While the course of insulin-dependent diabetes mellitus (IDDM) progresses through well-defined stages, the natural history of NIDDM is less well characterized. NIDDM patients with coronary heart disease have a higher urinary albumin excretion rate at the time of diagnosis and follow-up. This greater risk may also be associated with hypertension and hyperlipidemia, and genes involved in blood pressure are obvious candidate genes for diabetic nephropathy. Hyperglycemia appears to be an important factor in the development of proteinuria in NIDDM, but its role and the influence of diet are not yet clear. Tobacco smoking can also be deleterious to the diabetic patient, and is also associated with disease progression. Maintaining euglycemia, stopping smoking and controlling blood pressure may prevent or slow the progression of NIDDM-related nephropathy and reduce extrarenal injury. Treatment recommendations include early screening for hyperlipidemia, appropriate exercise and a healthy diet. Cornerstones of management should also include: (1) educating the medical community and more widely disseminating data supporting the value of early treatment of microalbuminuria; (2) developing a comprehensive, multidisciplinary team approach that involves physicians, nurses, diabetes educators and behavioral therapists; and (3) intensifying research in this field.     

How I evaluate...diabetic nephropathy. First part: micro- and macroalbuminuria

Diabetic nephropathy (DN) appears in about 30% of patients with type 1 diabetes (D1) and 15 to 60% of patients with type 2 diabetes (D2). It is preceded by microalbuminuria. Microalbuminuria is defined as an albumin excretion rate between 30 and 300 mg/24 h (on a 24-hour urine collection) or between 20 and 200 micrograms/min (on an overnight collection) in at least two out of three consecutive collections made within a 6-month period. Alternative screening techniques use either dipstick (Micral-Test II) or the albumin to creatinine ratio on an early morning urine sample (30-300 mg/g creatinine). Once persistent microalbuminuria is confirmed, 80% of type 1 diabetic patients and 20 to 50% of type 2 diabetic patients will progress to DN. In D2, microalbuminuria also represents a powerful predictor of early mortality from cardiovascular disease. Macroalbuminuria (AER > 300 mg/24 h, corresponding to a total protein excretion > 500 mg/24 h) will eventually lead to a end-stage renal insufficiency within 10 to 20 years. In D2, numerous patients will die from cardiovascular disease before reaching end-stage renal failure. Angiotensin-converting enzyme inhibitors can slow down the evolution toward DN when prescribed when microalbuminuria appears. Screening for microalbuminuria should therefore be a part of the annual clinical assessment in every diabetic patient.     

Troglitazone

Troglitazone decreases insulin resistance (improves insulin sensitivity), which results in reduced plasma glucose and insulin levels in patients with non-insulin-dependent diabetes mellitus (NIDDM). Risk factors for cardiovascular disease such as elevated proinsulin and triglyceride levels are also reduced by troglitazone. In clinical trials, troglitazone 200 to 800 mg daily (alone or in combination with other oral antidiabetic agents or insulin) reduced plasma or serum glucose levels and glycosylated haemoglobin compared with both baseline and placebo in patients with NIDDM refractory to other oral antidiabetic agents (usually sulphonylureas). Troglitazone was generally well tolerated in clinical trials. In patients in the US, the incidence of adverse events in troglitazone recipients was similar to that in placebo recipients.     

Cardiovascular risk factors prior to the development of non-insulin-dependent diabetes mellitus in persons with impaired glucose tolerance: the Hoorn Study

The aim of the study was to analyze cardiovascular risk factors as predictors for developing non-insulin-dependent diabetes mellitus (NIDDM) in people with impaired glucose tolerance. A cross-sectional survey of glucose tolerance was conducted in people, aged 50-74, who were randomly selected from the registry of the middle-sized town Hoorn (The Netherlands). Based on the mean values of two oral glucose tolerance tests, people were classified in glucose tolerance categories according to the WHO criteria. The mean follow-up time was 36 months (range 13-55 months). The cumulative incidence of NIDDM was 34% (95% CI 16.9-45.1). In multiple logistic regression analysis, cardiovascular risk factors at baseline did not predict the conversion from impaired glucose tolerance to NIDDM, in contrast with the two-hour plasma glucose level (odds ratio 3.56, p < 0.001) and the fasting proinsulin level, as one of the determinants of beta-cell dysfunction (Odds ratio 2.1, p < 0.05). The baseline HDL-cholesterol level, one of the components of the insulin resistance syndrome, was associated with the conversion from impaired glucose tolerance to normal glucose tolerance (Odds ratio 1.58, p < 0.05). The results of our study seem to support the hypothesis that conversion from impaired glucose tolerance to normal glucose tolerance depends on insulin resistance and the development of NIDDM from impaired glucose tolerance depends on beta-cell dysfunction.     

Microalbuminuria and its relation to cardiovascular disease and risk factors. A population-based study of 1254 hypertensive individuals

Microalbuminuria has been proposed as a potential atherosclerotic risk factor in hypertensive individuals. The aim of this cross-sectional population study was to analyse whether microalbuminuria is related to a higher prevalence of cardiovascular disease, and a more atherogenic risk profile, and reversely related to the use of antihypertensive drugs. In a major health screening at the State University Hospital in Copenhagen, including urinary albumin excretion, glomerular filtration rate, blood pressure (BP), electrocardiogram, body mass index, plasma lipoproteins, fibrinogen, and albumin, and information regarding a history of acute myocardial infarction, smoking, and antihypertensive drugs, 1254 participants without diabetes mellitus or renal/urinary tract disease had arterial hypertension. Age range was 30-70 years. Microalbuminuria (nocturnal urinary albumin excretion >15 microg/min) occurred in 5%, and cardiovascular disease (previous acute myocardial infarction or electrocardiographic Q-waves) also in 5% of the study population. Microalbuminuric hypertensive subjects were characterized by higher age and systolic BP, and a male predominance, as compared to normoalbuminuric hypertensive subjects. The frequency of cardiovascular disease was similar in the two groups. In contrast, when analysed as a continuous variable, a one unit increase in the logarithmically transformed urinary albumin excretion significantly increased the likelihood of cardiovascular disease (odds ratio [95% confidence interval] 1.32 (1.02-1.70); P < 0.05), and this relation was independent of age, sex, and conventional atherosclerotic risk factors. Participants who were effectively treated with antihypertensive drugs did not have a lower urinary albumin excretion than insufficiently treated or untreated participants. It is concluded that slightly elevated albumin excretion in the urine is not only a pressure-dependent functional phenomenon in the glomerular vessel walls, but associated with permanent atherosclerotic abnormalities in the entire vascular system.     

Modern antihypertensive treatment and the progression of renal disease

BACKGROUND: In animal models of hypertension, the resistance state of the preglomerular (afferent) and postglomerular (efferent) capillary arterioles may determine whether a particular form of antihypertensive therapy will spare the kidney from hemodynamic-mediated glomerular injury. In experimental models of renal disease with impaired autoregulation, control of systemic blood pressure is a prerequisite for normalizing glomerular capillary hydraulic pressure. CLINICAL STUDIES: In humans, effective blood pressure control reverses renal hemodynamic abnormalities in hypertensive patients, reduces microalbuminuria in essential hypertensive, nondiabetic, and diabetic renal diseases, and attenuates but does not prevent the progression of nondiabetic and diabetic renal disease. Although some researchers have concluded that angiotensin converting enzyme inhibitors are the renal protective drugs of choice, these pronouncements are not based on clinical trials correlating specific drug-mediated changes in albumin or protein excretion with the longitudinal assessment of glomerular filtration rate (GFR), permitting derivation of a slope-defining change in GFR, and/or the longitudinal assessment of renal structure (i.e. renal biopsy). Definitive clinical trials have not been reported. It is important to recognize that an elevated serum creatinine is a powerful predictor of mortality and that, in most patients, death is caused by a cardiovascular or cerebrovascular event, rather than by renal failure. CONCLUSION: Because morbidity and mortality of essential hypertension and nondiabetic or diabetic renal disease is related primarily to cardiovascular or cerebrovascular events, the antihypertensive 'drugs of choice' should be those that reduce these risks, prevent or regress target-organ damage, and optimize treatment of concomitant diseases.     

Effects of the herbicide atrazine on Ambystoma tigrinum metamorphosis: duration, larval growth, and hormonal response

Microalbuminuria is not only a predictor of diabetic nephropathy in type 1 diabetes, but also a potent marker of cardiovascular risk, especially in type 2 diabetes. Microalbuminuria also predicts cardiovascular morbidity in the general population. We describe semi-quantitative and quantitative methods for determination of low urinary excretion of albumin. Pathogenetic hypotheses common to both renal and endothelial dysfunction are discussed, suggesting that microalbuminuria may be a link between micro- and macroangiopathy. Improved glycemic control and antihypertensive treatment postpone and potentially prevent development of nephropathy in diabetic patients with microalbuminuria. These interventions must be instituted early in the development of diabetic nephropathy. In type 2 diabetes, prospective studies are needed to evaluate the precise impact of such a therapy on the cardiovascular risk.     

Insulin resistance versus insulin deficiency in non-insulin-dependent diabetes mellitus: problems and prospects

A definitive assessment of the relative roles of insulin resistance and insulin deficiency in the etiology of NIDDM is hampered by several problems. 1) Due to better methodology, data on insulin resistance are generally more accurate and consistent than data on insulin deficiency. 2) In source data, case-control studies are prone to selection bias, while epidemiological associations, whether cross-sectional or longitudinal, are liable to misinterpretation. 3) Insulin secretion and action are physiologically interconnected at multiple levels, so that an initial defect in either is likely to lead with time to a deficit in the companion function. The fact that both insulin resistance and impaired insulin release have been found to precede and predict NIDDM in prospective studies may be in part a reflection of just such relatedness. 4) Direct genetic analysis is effective in rarer forms of glucose intolerance (MODY, mitochondrial mutations, etc.) but encounters serious difficulties with typical late-onset NIDDM. Despite these uncertainties, the weight of current evidence supports the view that insulin resistance is very important in the etiology of typical NIDDM for the following reasons: 1) it is found in the majority of patients with the manifest disease; 2) it is only partially reversible by any form of treatment (117); 3) it can be traced back through earlier stages of IGT and high-risk conditions; and 4) it predicts subsequent development of the disease with remarkable consistency in both prediabetic and normoglycemic states. Of conceptual importance is also the fact that the key cellular mechanisms of skeletal muscle insulin resistance (defective stimulation of glucose transport, phosphorylation, and storage into glycogen) have been confirmed in NIDDM subjects by a variety of in vivo techniques [ranging from catheter balance (118) to multiple tracer kinetics (119) to 13C nuclear magnetic resonance spectroscopy (120)], and have been detected also in normoglycemic NIDDM offspring (121). If insulin resistance is a characteristic finding in many cases of NIDDM, insulin-sensitive NIDDM does exist. On the other hand, given the tight homeostatic control of plasma glucose levels in humans, beta-cell dysfunction, relative or absolute, is a sine qua non for the development of diabetes. If insulin deficiency must be present whereas insulin resistance may be present, is this proof that the former is etiologically primary to the latter? If so, do we have convincing evidence that the primacy of insulin deficiency is genetic in nature? The answer to both questions is negative on several accounts. The defect in insulin secretion in overt NIDDM is functionally severe but anatomically modest: beta-cell mass is reduced by 20-40% in patients with long-standing NIDDM (122). Moreover, the insulin secretory deficit is progressively worse with more severe hyperglycemia (123) and recovers considerably upon improving glycemic control (124). These observations indicate that part of the insulin deficiency is acquired (through glucose toxicity, lipotoxicity, or both). In addition, although insulin deficiency is necessary for diabetes, it may not always be sufficient to cause NIDDM. In fact, subtle defects in the beta-cell response to glucose may be widespread in the population (108, 125) and only cause frank hyperglycemia when obesity/insulin resistance stress the secretory machinery. Conceivably, there could be beta-cell dysfunction without NIDDM just as there is insulin resistance without diabetes. Incidentally, any defect in insulin secretion, whether in normoglycemic or hyperglycemic persons, could be due to other factors than primary beta-cell dysfunction: amyloid deposits in the pancreas (126), changes in insulin secretagogues (amylin, GLP-1, GIP, galanin) (127-130), early intrauterine malnutrition (131). Finally, the predictive power of early changes in insulin secretion for the development of typical NIDDM is generally lower than that of insulin     

Experimental benefit of moxonidine on glucose metabolism and insulin secretion in the fructose-fed rat

OBJECTIVE: Non-insulin-dependent diabetes mellitus (NIDDM) is often associated with hypertension leading to a specifically high cardiovascular risk in these patients. However, there is evidence that insulin resistance and hyperinsulinaemia are not only characteristic for diabetic patients but also for some non-diabetic populations in which a cluster of cardiovascular risk factors is observed (hypertension, hypertriglyceridaemia, obesity). Therefore, hyperinsulinaemia and insulin resistance have been suggested to be of major pathophysiological importance for the development of this syndrome (syndrome X). Since imidazoline receptors are currently considered to be a specific pharmacological target for blood pressure reduction, it is important to know whether and in which way these compounds affect the glucose homoeostasis and insulin release. DESIGN: The influence of moxonidine on glucose tolerance in vivo was determined in healthy control rats, in rats receiving a high fructose diet for 6 weeks to induce insulin resistance, hyperinsulinaemia and hypertension, and in rats receiving in addition to a high fructose diet moxonidine (1.5 mg/kg body weight daily). In vitro, using isolated pancreatic islets of mice, long-lasting effects (chronic) and immediate (acute) effects of moxonidine on beta-cell function were determined by basal and glucose stimulated insulin release in two different experimental systems: (1) islets were exposed for 24 h (37 degrees C) to various concentrations of moxonidine ranging from 1 nmol/l to 1 mmol/l, followed by a washing procedure to remove excess of moxonidine and then used for the beta-cell function test; (2) islet cultures were incubated again with moxonidine for 24 h (37 degrees C) with either 1 nmol/l or 1 micromol/l. In contrast to the first experiments, however, after the washing procedure moxonidine was added at the same concentration as used for preincubation to test its direct effect on beta-cell function. RESULTS: In healthy control rats acute administration of moxonidine in vivo impaired the glucose tolerance in high dosages, which effectively reduced the blood pressure (>1 mg/kg body weight). This effect was, however, smaller that that observed by clonidine. In fructose-fed rats, moxonidine completely prevented the development of insulin resistance, hyperinsulinaemia and hypertension. In vitro, pancreatic islets preincubated with moxonidine exhibited dose-dependently both stimulatory and inhibitory chronic effects on beta-cell function compared with that in controls. Preincubation of islet cultures with moxonidine at concentrations between 1 nmol/l and 1 mmol/l resulted in a reduction of basal insulin release which was very pronounced at concentrations higher than 100 nmol/l. The results obtained for glucose-stimulated insulin release opposed in part those for basal insulin release, since the preincubation with moxonidine up to 10 micromol/l gave rise to an increased insulin release. An additional direct effect of moxonidine with a marked reduction of glucose-stimulated insulin release was observed, however, when moxonidine was present during the preincubation (24 h) and the functional test at a concentration of 1 nmol/l or 1 micromol/l. CONCLUSIONS: Our data suggest that a causal linkage exist between the development of hypertension and insulin resistance/hyperinsulinaemia in the high fructose diet rat model. Since central activation of imidazoline receptors by moxonidine can prevent this syndrome, it follows that an overactivity of the sympathetic nervous system is of major importance. Suppression of this sympathetic overactivity might be an effective approach to reduce hypertension and the concomitant metabolic defect. Therefore, such an interventional strategy could contribute to reduce the cardiovascular risk of NIDDM patients and patients with other forms of insulin resistance/hyperinsulinaemia such as metabolic cardiovascular syndrome.     

Role of exercise training in the prevention and treatment of insulin resistance and non-insulin-dependent diabetes mellitus

Recent epidemiological studies indicate that individuals who maintain a physically active lifestyle are much less likely to develop impaired glucose tolerance and non-insulin-dependent diabetes mellitus (NIDDM). Moreover, it was found that the protective effect of physical activity was strongest for individuals at highest risk of developing NIDDM. Reducing the risk of insulin resistance and NIDDM by regularly performed exercise is also supported by several aging studies. It has been found that older individuals who vigorously train on a regular basis exhibit a greater glucose tolerance and a lower insulin response to a glucose challenge than sedentary individuals of similar age and weight. While the evidence is substantial that aerobic exercise training can reduce the risk of impaired glucose tolerance and NIDDM, the evidence that exercise training is beneficial in the treatment of NIDDM is not particularly strong. Many of the early studies investigating the effects of exercise training on NIDDM could not demonstrate improvements in fasting plasma glucose and insulin levels, or glucose tolerance. The adequacy of the training programmes in many of these studies, however, is questionable. More recent studies using prolonged, vigorous exercise-training protocols have produced more favourable results. There are several important adaptations to exercise training that may be beneficial in the prevention and treatment of insulin resistance, impaired glucose tolerance and NIDDM. An increase in abdominal fat accumulation and loss of muscle mass are highly associated with the development of insulin resistance. Exercise training results in preferential loss of fat from the central regions of the body and should therefore contribute significantly in preventing or alleviating insulin resistance due to its development. Likewise, exercise training can prevent muscle atrophy and stimulate muscle development. Several months of weight training has been found to significantly lower the insulin response to a glucose challenge without affecting glucose tolerance, and to increase the rate of glucose clearance during a euglycaemic clamp. Muscle glucose uptake is equal to the product of the arteriovenous glucose difference and the rate of glucose delivery or muscle blood flow. While it has been known for many years that insulin will accelerate blood glucose extraction by insulin-sensitive peripheral tissues, recent evidence suggests that it can also acutely vasodilate skeletal muscle and increase muscle blood flow in a dose-dependent manner. A reduced ability of insulin to stimulate muscle blood flow is a characteristic of insulin-resistant obese individuals and individuals with NIDDM. Exercise training, however, has been found to help alleviate this problem, and substantially improve the control of insulin over blood glucose. Improvements in insulin resistance and glucose tolerance with exercise training are highly related to an increased skeletal muscle insulin action. This increased insulin action is associated with an increase in the insulin-regulatable glucose transporters, GLUT4, and enzymes responsible for the phosphorylation, storage and oxidation of glucose. Changes in muscle morphology may also be important following training. With exercise training there is an increase in the conversion of fast twitch glycolytic IIb fibres to fast twitch oxidative IIa fibres, as well as an increase in capillary density. IIa fibres have a greater capillary density and are more insulin-sensitive and -responsive than IIb fibres. Evidence has been provided that morphological changes in muscle, particularly the capillary density of the muscle, are associated with changes in fasting insulin levels and glucose tolerance. Furthermore, significant correlations between glucose clearance, muscle capillary density and fibre type have been found in humans during a euglycaemic clamp. Exercise training may also improve control over hepatic glucose production by increasin