Renal functional reserve in IDDM patients

Summary The aim of this study was to determine whether renal functional reserve (RFR) is altered in insulin-dependent diabetic (IDDM) patients according to the stage of diabetic nephropathy. RFR was examined in 33 IDDM patients in similar glycaemic and metabolic control and compared to 12 healthy control subjects, during eight 1 h clearance periods prior to, during and after a 3-h stimulation by amino acid infusion (4.5 mg · kg⁻¹· min⁻¹). RFR was calculated as the difference between stimulated and baseline glomerular filtration rates (GFR). In 14 early normotensive diabetic patients with normal urinary albumin excretion, mean baseline GFR (133 ± 3 ml · min⁻¹· 1.73 m⁻²) was higher whereas RFR (10 ± 4 ml · min⁻¹· 1.73 m⁻²) was lower (p < 0.05) than in control subjects (113 ± 4 and 28 ± 2 ml · min⁻¹· 1.73 m⁻², respectively). In 10 normotensive patients who had lived with IDDM for 16 years and who had microalbuminuria, baseline GFR and RFR (109 ± 7 and 24 ± 6 ml · min⁻¹· 1.73 m⁻², respectively) were similar to those in control subjects. In 9 patients who had suffered IDDM for 23 years and had developed macroalbuminuria and hypertension, baseline GFR (78 ± 8 ml · min⁻¹· 1.73 m⁻²) was lower than in control subjects (p < 0.05) and RFR (8 ± 4 ml · min⁻¹· 1.73 m⁻²) was not significant. In addition, renal vascular resistance decreased significantly during infusion (p < 0.05) in microalbuminuric normotensive patients as well as in control subjects (by 9 ± 4 and 11 ± 4 mm Hg · l⁻¹· min⁻¹· 1.73 m⁻², respectively) but not in normoalbuminuric normotensive or macroalbuminuric hypertensive patients. These results indicate that microalbuminuric normotensive patients retain a normal RFR, whereas RFR is reduced or suppressed at two opposite stages of the disease: in normoalbuminuric normotensive patients with a high GFR and in macroalbuminuric hypertensive patients with a decreased GFR. This dissimilar impairment reveals permanent glomerular hyperfiltration in both early IDDM without nephropathy and IDDM with overt diabetic nephropathy, but not in IDDM with incipient nephropathy. [Diabetologia (1998) 41: 86–93] Received: 12 February 1997 and in final revised form: 28 August 1997     

Effects of insulin on renal haemodynamics and the proximal and distal tubular sodium handling in healthy subjects

Summary The effects of insulin on renal haemodynamics and renal sodium handling were studied in 10 healthy males. Using the euglycaemic insulin clamp technique, insulin was infused on separate days resulting in two levels of hyperinsulinaemia (41 ± 3 and 90 ± 7 mU/1, respectively). Renal haemodynamics and the proximal and distal tubular sodium handling were studied using inulin, para-amino-hippuric acid, sodium and lithium clearances. Low- and high-dose insulin infusions were followed by a fall in sodium clearance from 1.6 ± 0.1 ml/min to 1.2 ± 0.1 and 1.0 ± 0.1 ml/min, respectively. Both levels of hyperinsulinaemia resulted in increased distal tubular sodium reabsorption. The distal antinatriuretic effect of insulin was associated with dose- and time-dependent decline in proximal tubular sodium reabsorption. The changes in proximal tubular sodium handling occurred without any significant changes in natriuretic factors, such as renal dopamine and plasma atrial natriuretic peptide levels. However, hyperinsulinaemia resulted in time- and dose-dependent increases in renal plasma flow, and renal vasodilatation could, possibly via changes in renal interstitial pressure, have contributed to the fall in the proximal tubular sodium reabsorption. The results also suggest that decreased proximal sodium reabsorption may be a compensatory mechanism counteracting the insulin-induced sodium retention.     

Effect of insulin on renal sodium handling in hyperinsulinaemic Type 2 (non-insulin-dependent) diabetic patients with peripheral insulin resistance

Summary The sodium retaining effect of insulin was studied in ten Type 2 (non-insulin-dependent) diabetic patients (mean age 56 (43–73) years, mean body mass index 29.5 (24.2–33.7) kg/m²) and eight age-matched control subjects (mean age 57 (43–68) years, mean body mass index 23.4 (20.8–26.6) kg/m²). The renal clearances of ^99mTc-DTPA, lithium, sodium and potassium were measured over a basal period of 90 min. Then insulin was infused at a rate of 40 mU·mirr^–1·m^–2. After an equilibration period of 90 min, the clearance measurements were repeated during a new 90 min period. Blood glucose was clamped at the basal level (diabetic patients: 9.9±3.5, control subjects: 5.3±0.5 mmol/l) by a variable glucose infusion. Basal plasma insulin concentration was elevated in the diabetic patients (0.12±0.05 vs 0.05±0.02 pmol/ml, p<0.01). Insulin infusion resulted in comparable absolute increments in plasma insulin concentrations in the diabetic group and in the control group (0.44±0.13 vs 0.36±0.07 pmol/ml, NS). The metabolic clearance rate of glucose during the last 30 min of insulin infusion was lower in the diabetic patients (155±62 vs 320±69 ml·min^–1·m², p<0.01), reflecting peripheral insulin resistance. The decline in sodium clearance during insulin infusion was similar in diabetic subjects (1.8±1.1 vs 0.7±0.4 ml·min^–1·1.73 m^–2, p< 0.01) and in control subjects (1.7±0.3 vs 0.8±0.3 ml · min^–1 · 1.73 m^–2, p<0.01). The glomerular filtration rate and lithium clearance was unchanged, consequently calculated distal tubular fractional sodium reabsorption increased (diabetic patients: 92.9±4.1 vs 97.1±1.5, p<0.01, control subjects: 93.1±1.1 vs 96.5±0.6%, p< 0.01). Estimated extracellular fluid volume was 10% higher in the diabetic subjects (16.3±2.1 vs 14.8±2.01·1.73 m^–2, NS). In conclusion, the sodium retaining effect of insulin is preserved in Type 2 diabetic patients with peripheral insulin resistance. Insulin may contribute to sodium and fluid retention and thus to the increased frequency of hypertension in hyperinsulinaemic Type 2 diabetic patients.     

Effects of insulin on kidney function and sodium excretion in healthy subjects

Summary Insulin action on kidney function was evaluated in 8 healthy subjects, (mean age 27 years) using the euglycaemic clamp technique. Insulin was infused at rates of 0, 20 and 40 mU·min^–1·m^–2 over consecutive periods of 120 min resulting in plasma insulin concentrations of 8±2, 29±7 and 66±14 mU/l. The renal clearance of ⁵¹Cr-EDTA, lithium, sodium and potassium was determined during the last 90 min of each period. Sodium clearance declined with increasing plasma insulin concentrations (1.3±0.4, 1.0±0.3 and 0.5±0.2 ml·min^–1·1.73 m^–2, p<0.001), while glomerular filtration rate (108±21, 104±21 and 108±20ml·min^–1·1.73 m^–2) and lithium clearance (a marker of fluid flow rate from the proximal tubules) 29±5, 29±4 and 30±4 ml·min^–1·1.73 m^–2) remained unchanged. Calculated proximal tubular reabsorption of sodium and water was unchanged, while calculated distal fractional sodium reabsorption increased (95.5±1.5, 96.4±1.2 and 98.1±0.7%, p<0.001). Potassium clearance and plasma potassium concentration declined, whereas plasma aldosterone and plasma renin concentrations were unchanged. In conclusion, elevation of plasma insulin concentration within the physiological range has a marked antinatriuretic action. This effect is located distally to the proximal renal tubules.     

149例慢性肾衰患者血脂水平及其与肾功能的相关性

目的探讨血脂水平对慢性肾衰患者肾功能的影响。方法检测149例慢性肾衰患者（观察组）和30例健康献血者（对照组）血脂[TG、TC、HDL—C、LDL—C、血肌酐（SCr）]水平,并分析上述指标与肾小球滤过率（GFR）的相关性。结果观察组TG、TC轻度升高,HDL—C明显下降,LDL—C明显升高。GFR与TG、TC无明显相关性,而与HDL-C水平呈明显正相关（r=0．21,P〈0．05）,与LDL—C水平呈显著负相关（r=-0．29,P〈0．01）。结论慢性肾衰患者存在明显的血脂代谢异常;其可能是加快肾脏功能损伤的重要危险因素。     

The acute effect of insulin on renal haemodynamics and protein excretion in diabetics

Summary The effect of IV injection of 7 to 8 I. U. of insulin on renal haemodynamics and on urinary excretion of beta-2-microglobulin and of albumin was examined in 5 juvenile diabetics. Plasma glucose decreased from a mean value of 250 mg/100 ml to 117 mg/100 ml during the first 85 min after insulin. None of the patients had symptoms of hypoglycaemia and plasma adrenaline did not increase. There was no change in arterial blood pressure after insulin whereas pulse rate increased from 66/min to a maximum of 75/min. Glomerular filtration rate (GFR) and renal plasma flow (RPF) were decreased by 9 per cent and 13 per cent, respectively, during the first 90 min after insulin (2p < 0.01). There was also a statistically significant decrease in urine flow and urine secretion of several electrolytes, while filtration fraction remained almost constant. IV insulin decreased urinary excretion of beta-2-microglobulin and increased albumin excretion (2 p < 0.05). The albumin excretion induced by insulin is most likely due to increased amounts of filtered albumin, the mechanism of which remains unexplained.     

Acute mental stress impairs insulin sensitivity in IDDM patients

Summary The effect of acute mental stress on insulin sensitivity was evaluated in ten IDDM patients, studied on two occasions (test day and control day) in random order and separated by a period of 1–3 weeks. Mental stress was evoked by a modified filmed version of Stroop's CWT for 20 min. On the control day, the patients were resting quietly during the corresponding period. Insulin sensitivity was estimated by an insulin (0.4 mU · kg^–1 · min^–1)-glucose (4.5 mg · kg^–1 · min^–1)-infusion test (IGIT) for 6.5 h. Mental stress evoked significant responses for adrenaline, cortisol and GH, their respective peak values being 0.27 ± 0.05 nmol/l, 426 ± 27 nmol/l and 7.6 ± 1.8 g/l, as well as increases in systolic and diastolic blood pressure and pulse rate The steady-state blood glucose levels, i.e. the mean blood glucose levels 3–6.5 h after the start of the IGIT, were significantly higher after stress, compared with those on the control day, 10.6 ± 1.5 vs 8.7 ± 1.4 mmol/l, p = 0.01, demonstrating impairment of the insulin sensitivity by mental stress. It is concluded that acute mental stress induces a state of insulin resistance in IDDM patients, which can be demonstrated by an IGIT to appear 1 h after maximal stress and to last more than 5 h.Abbreviations IDDM Insulin-dependent diabetes mellitus - GH growth hormone - IGIT insulin-glucose-infusion test - CWT colour-word test - AUC area under the curve     

The effect of six months continuous subcutaneous insulin infusion on kidney function and size in insulin-dependent diabetics

Glomerular filtration rate (GFR), renal plasma flow (RPF), kidney volume, and urinary albumin excretion rate were measured in 24 insulin-dependent diabetics, aged 29 +/- 7 years (mean +/- S.D.) of 8 +/- 4 years duration, randomly allocated to either continuous subcutaneous insulin infusion (CSII) (n = 12) or unchanged conventional insulin treatment (CIT) (n = 12). Glomerular filtration rate, renal plasma flow, and kidney volume were identical in the two groups at the start of the study, although significantly increased above normal values. During the 6 months CSII treatment a reduction of the GFR from 145 +/- 21 to 132 +/- 14 ml/min (2p = 2.4%) was seen, no change was observed in the CIT group while in both groups RPF and kidney volume remained unchanged. Urinary albumin excretion rate was normal or near normal in both groups and remained unchanged. Thus improved glycaemic control in insulin-dependent diabetics studied before the onset of microalbuminuria is associated with improved (reduced) GFR. Nephromegaly does not improve with 6 months CSII treatment. Whether it would improve with more prolonged treatment is uncertain.     

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

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

The effect of low-dose dopamine on renal haemodynamics in patients with type 1 (insulin-dependent) diabetes does not differ from normal individuals

Summary It is well known that patients with Type 1 (insulin-dependent) diabetes exhibit both increased glomerular filtration rate and effective renal plasma flow, which can be found even when these patients are well controlled. Usually this is attributed to a decrease in renal vascular resistance and/or to enlarged kidney size and glomerular volume. Among the factors which govern glomerular filtration rate, renal plasma flow is most important. Renal plasma flow increases if renal vascular resistance decreases. The latter might exist in insulin-dependent diabetes mellitus because of either a predominantly afferent or a predominantly efferent vasodilatation. Dopamine is an agent which causes predominantly efferent vasodilatation. Therefore, the effects of infusing a low dose of dopamine on glomerular filtration rate and effective renal plasma flow in 12 well-controlled patients with Type I (insulin-dependent) diabetes and 28 healthy volunteers were compared to investigate whether the increased glomerular filtration rate in Type 1 diabetes is caused by an efferent vasodilatation. The median increase in glomerular filtration rate during dopamine infusion amounted to 13.0% in diabetic patients and 12.5% in healthy control subjects (n. s.). It is concluded that the elevated glomerular filtration rate in well-controlled Type 1 diabetes is not caused by a predominantly efferent vasodilatation.     

Cyclic AMP-phosphodiesterases inhibitor improves sodium excretion in rats with cirrhosis and ascites.

BACKGROUND: The mechanisms responsible for renal dysfunction and sodium retention in cirrhosis remain unclear. Cyclic AMP (cAMP) regulates sodium reabsorption in the proximal nephron. This study investigates the role of cAMP metabolism in renal dysfunction in cirrhosis. METHODS: Renal function was studied by the clearance technique in anesthetized control and cirrhotic rats with or without ascites. cAMP phosphodiesterase (PDE) activity was measured in the renal cortex in vitro. Moroever, the effects on renal function of the intravenous administration of cAMP and rolipram, a powerful and specific cAMP-PDE4 inhibitor, were evaluated. RESULTS: In control and in non-ascitic cirrhotic rats, cAMP administration significantly increased sodium and phosphate excretions, but did not change these excretions in cirrhotic rats with ascites. cAMP-PDE activity was higher in ascitic than in control rats (P < 0.05). Rolipram infusion significantly increased sodium and phosphate excretion only in cirrhotic rats with ascites. CONCLUSION: These results suggest that increased renal cAMP-PDE activity is responsible for resistance to the natriuretic effects of cAMP in cirrhosis and plays a role in the development of ascites.     

Monitoring kidney function in diabetic nephropathy

Summary Progression in diabetic nephropathy is usually determined by repeated measurements of glomerular filtration rate and expressed as rate of decline in glomerular filtration rate. Our aim was to evaluate the agreement between rate of decline in glomerular filtration rate estimated from the Cockroft-Gault formula: (140-age)^*K^*body weight^* (1/S-creatinine) and measured by the plasma clearance of ⁵¹CrEDTA. All insulin-dependent diabetic patients with diabetic nephropathy followed-up for at least 5 years with at least 5 simultaneous measurements of glomerular filtration rate, s-creatinine, and weight were included in the study. Forty-three patients (32 male/11 female), age 31 (18–61) years were enrolled. Observation period: 6.6 (5.1–9.9) years and number of investigations per patient 6 (5–16) (median(range)). Baseline glomerular filtration rate (ml/min) was 97 (30) measured and 107 (37) estimated (mean(SD))(p<0.001) and the 95% limits of agreement were –42.0 to 20.8 ml/min. Measured and estimated glomerular filtration rate correlated significantly (r = 0.91, p<0.00001). Rate of decline in kidney function ml · min^–1 · year^–1 was 4.7 (3.3) measured and 4.8 (3.5) estimated (mean(SD)) (NS), but the 95% limits of agreement showed a wide range –3.9 to 3.5 ml · min^–1 · year^–1. A significant correlation between rate of decline in measured and estimated glomerular filtration rate was present (r = 0.84, p<0.00001). In conclusion, glomerular filtration rate is overestimated by the Cockroft-Gault formula. The mean rates of decline in glomerular filtration rate are comparable, but the limits of agreement are wide, which make the Cockroft-Gault method unacceptable for clinical purposes, i.e. monitoring progression in kidney function in the individual patient. However, the estimated glomerular filtration rate may be used for comparison of groups in observational studies and in clinical trials with a long observation period.Abbreviations GFR Glomerular filtration rate - ⁵¹Cr-ED-TA ⁵¹Chromium ethylene diamine tetra-acetic acid - IDDM insulin-dependent diabetes mellitus     

Relation of kidney size to kidney function in early insulin-dependent diabetes

Summary Renal function and renal size have been studied in ten early insulin-dependent diabetic patients and in ten matched control subjects. Glomerular filtration rate, renal plasma flow and radiological kidney size were determined in each subject. Glomerular filtration rate and renal plasma flow were increased in diabetics (mean ± SD: 169.6± 16.1 and 690.1±52.6ml/min/1.73 m², respectively) compared with controls (120.6±9.7 and 605.9±67.2 ml/min/1.73m²; p < 0.001 and p <0.01). Calculated kidney weight corrected to 1.73 m² of body surface area was elevated in diabetics (385.2±29.0 g) with respect to controls (277.5±17.5 g; p <0.001). No significant differences were found between diabetics and control subjects when glomerular filtration rate was expressed per gram calculated kidney weight, while renal plasma flow was significantly lower in diabetics than control subjects when so expressed (p <0.01). A positive correlation was found between glomerular filtration rate, renal plasma flow and kidney size in both controls and diabetics (p < 0.01 in all cases). These findings support the conclusion that in the early state of diabetes glomerular hyperfunction is related to enlargement of the kidneys and augmented renal plasma flow.     

Exercise-induced hypoglycaemia and subcutaneous insulin infusion

To assess whether exercise-induced hypoglycaemia could be prevented by interruption of insulin infusion (3 h) we studied diabetic patients treated with continuous subcutaneous insulin infusion (CSII). The studies were performed in 7 insulin-dependent diabetics (aged 31.4 +/- 4.8 (mean +/- SD) years, duration of diabetes 16.9 +/- 5.4 years), after an overnight fast and in the afternoon, 4 h after the last pre-meal bolus injection (exercise and control period). Bicycle exercise (45 min at 60% of maximum oxygen consumption) was started 30 min after the insulin infusion was stopped. During exercise there was a more pronounced decline in blood glucose in the afternoon (2.2 +/- 0.3 mmol/l, mean +/- SEM) than in the morning (1.4 +/- 0.4 mmol/l) (p less than 0.01). This corresponded to higher mean levels of free insulin during exercise in the afternoon (20 +/- 4.5 mU/I vs 12.0 +/- 1.0 mU/l, in the morning). Interruption of insulin delivery for 3 h resulted in a moderate increase of blood glucose, a gradual decrease of free insulin, and a moderate increase in free fatty acids and beta-hydroxybutyrate. During exercise in the afternoon 3 diabetics suffered from symptomatic hypoglycaemia (BG less than 2.8 mmol/l). In contrast with most of the other patients they showed no decline of free insulin during exercise. Thus even after interruption of basal rate insulin infusion moderate postprandial exercise may lead to hypoglycaemia if there is relative hyperinsulinism.     

肝病时肾损伤和肾功能不全评估的若干问题

病毒性肝炎和肝硬化等肝病患者的肾损伤和肾功能不全总体上可分为急性肾损伤(AKI)、慢性肾病和慢加急性肾病。AKI又分为1期(风险期)、2期(损伤期)和3期(衰竭期)。肝肾综合征传统上分为Ⅰ和Ⅱ型,近年提出还存在伴有肾器质性损伤的Ⅲ型。肝病伴肾病一词被用来描述肝硬化背景下任何类型的肾疾病。目前临床上判断肝病时肾功能状态相对敏感和准确的生化指标包括估算的肾小球滤过率、单位时间内血清肌酐的升幅、血清胱抑素C水平等,尿微量白蛋白水平等对早期发现肾病也有重要价值。肝病病因、严重程度、感染等并发症、营养状态、治疗药物以及基础肾病等均可能与肝病状态下的肾损伤和肾功能不全相关,应注意辨别。     

Renal function and insulin sensitivity during simvastatin treatment in Type 2 (non-insulin-dependent) diabetic patients with microalbuminuria

Summary The effect of simvastatin (10–20 mg/day) on kidney function, urinary albumin excretion rate and insulin sensitivity was evaluated in 18 Type 2 (non-insulin-dependent) diabetic patients with microalbuminuria and moderate hypercholesterolaemia (total cholesterol ≥5.5 mmol·l⁻¹). In a double-blind, randomized and placebo-controlled design treatment with simvastatin (n=8) for 36 weeks significantly reduced total cholesterol (6.7±0.3 vs 5.1 mmol·l⁻¹ (p<0.01)), LDL-cholesterol (4.4±0.3 vs 2.9±0.2 mmol·l⁻¹ (p<0.001)) and apolipoprotein B (1.05±0.04 vs 0.77±0.02 mmol·l⁻¹ (p<0.01)) levels as compared to placebo (n=10). Both glomerular filtration rate (mean±SEM) (simvastatin: 96.6±8.0 vs 96.0±5.7 ml·min⁻¹·1.73 m⁻², placebo: 97.1±6.7 vs 88.8±6.0 ml·min⁻¹·1.73 m⁻²) (NS) and urinary albumin excretion rate (geometric mean x/÷ antilog SEM) (simvastatin: 18.4x/÷1.3vs 16.2 x/÷1.2 μg·min⁻¹, placebo 33.1 x/÷ 1.3 vs 42.7 x/÷ 1.3 μg·min⁻¹)(NS) were unchanged during the study. A euglycaemic hyperinsulinaemic clamp was performed at baseline and after 18 weeks in seven simvastatin-and nine placebo-treated patients. Isotopically determined basal and insulin-stimulated glucose disposal was similarly reduced before and during therapy in both the simvastatin (2.0±0.1 vs 1.9±0.1 (NS) and 3.1±0.6 vs 3.1±0.7 mg·kg⁻¹·min⁻¹ (NS)) and the placebo group (1.9±0.1 vs 1.8±0.1 (NS) and 4.1±0.6 vs 3.8±0.2 mg·kg⁻¹·min⁻¹ (NS)). No different was observed in glucose storage or glucose and lipid oxidation before and after treatment. Further, the suppression of hepatic glucose production during hyperinsulinaemia was not influenced by simvastatin (−0.7±0.8 vs −0.7±0.5 mg·kg⁻¹·min⁻¹ (NS)). In conclusion, despite marked improvement in the dyslipidaemia simvastatin had no impact on kidney function or urinary albumin excretion rate and did not reduce insulin resistance in these microalbuminuric and moderately hypercholesterolaemic Type 2 diabetic patients.     

Effect of 14 days' subcutaneous administration of the human amylin analogue,pramlintide (AC137), on an intravenous insulin challenge and response to a standard liquid meal in patients with IDDM

Summary Individuals with insulin-dependent diabetes mellitus (IDDM or type 1 diabetes) are deficient in both insulin and amylin, peptides secreted by the beta cell. We have investigated the effects of amylin replacement therapy employing the human amylin analogue, pramlintide (25, 28, 29-pro-human amylin, previously referred to as AC137), upon the responses to a standardized insulin infusion (40 mU · kg^–1 · h^–1) for 100 min and a liquid Sustacal meal (360 kcal) in 84 healthy IDDM patients. Following baseline evaluations, patients were randomly assigned to receive subcutaneous injections of placebo, 30, 100 or 300 g pramlintide 30 min before meals for 14 days. There was no meaningful difference between adverse events reported by the 30-g pramlintide and the placebo groups, but ten subjects withdrew due to nausea, eight of these in the 300-g dose group. Peak plasma pramlintide concentrations for the 30-g group were 21±3 and 29±5 pmol/l on Days 1 and 14, respectively. These values are similar to postprandial plasma amylin concentrations in normal volunteers. The plasma glucose, free insulin, glucagon, epinephrine and norepinephrine concentrations during the insulin infusion test before and after therapy were identical in each of the groups. Prior to pramlintide therapy, Sustacal ingestion produced a 4.0–4.8 mmol/l rise in plasma glucose concentrations in each of the groups. Pramlintide therapy reduced postprandial hyperglycaemia as reflected by the 3-h incremental AUC_glucose (AUC_glucose above or below fasting glucose concentration) Day 1 vs Day 14: 30 g, 322±92 vs –38±161 mmol/l · min, p=0.010; 100 g, 317±92 vs –39±76 mmol/l · min, p=0.001; and 300 g, 268±96 vs –245±189 mmol/l · min, p=0.077. Thus, pramlintide therapy with these regimens did not appear to impair either in vivo insulin action or the counter-regulatory response to hypoglycaemia but did show a clear effect of blunting postprandial hyperglycaemia following a standardized meal.Abbreviations IDDM Insulin-dependent diabetes mellitus - AUC_glucose area under the plasma glucose concentration curve - ANOVA analysis of variance     

Effects of dietary sodium on blood pressure in IDDM patients with nephropathy

Summary The objectives of the study were to assess the effects of moderate sodium restriction on blood pressure in insulin-dependent diabetic (IDDM) patients with nephropathy and high normal or mildly hypertensive blood pressure (primary objective), and to document possible associated changes of exchangeable body sodium, body volumes, components of the renin-angiotensin-aldosterone system, atrial natriuretic peptide, and catecholamines (secondary objective). Sixteen patients with untreated systolic blood pressure 140 <160 mmHg and/or diastolic blood pressure 85 <100 mmHg were included in a double-blind, randomized, placebo-controlled trial. After a 4-week run-in period on their usual diet and a 2-week dietary training period to reduce sodium intake to about 90 mmol/day, eight patients received 100 mmol/day sodium supplement (group 2) and eight patients a matching placebo (group 1) for 4 weeks while continuing on the reduced-sodium diet. Patients were examined at weekly intervals. Main response variables were mean values of supine and sitting systolic and diastolic blood pressure as measured in the clinic and by the patients at home. The differences in blood pressure between the beginning and the end of the blinded 4-week study period were calculated and the differences in changes between the two patient groups were regarded as the main outcome parameters. During the blinded 4-week study period, average urinary sodium excretion was 92±33 (mean ± SD) mmol/day in group 1 and 199±52 mmol/day in group 2 (p=0.0002). The differences in blood pressure changes between the two patient groups were 3.9(–1.2 to 9) mmHg [mean (95% confidence intervals)] for systolic home blood pressure, 0.9(–3.7 to 5.5) mmHg for diastolic home blood pressure, 4.9(–3.3 to 13.1) mmHg for clinic systolic blood pressure and 5.3(1 to 9.7 mmHg, p=0.02) for clinic diastolic blood pressure. Combining all patients, there were relevant associations between changes of urinary sodium excretion and blood volume (Spearman correlation coefficient r=0.57), blood pressure and angiotensin II (diastolic: r=–0.7; systolic: r=–0.48), and exchangeable body sodium and renin activity (r=–0.5). In conclusion, in this study of IDDM patients with nephropathy and high normal or mildly hypertensive blood pressure, a difference in sodium intake of about 100 mmol/day for a period of 4 weeks led to a slight reduction of clinic diastolic blood pressure. Studies including larger numbers of patients with various stages of nephropathy and hypertension are needed to definitely clarify the effects of sodium restriction in IDDM.Abbreviations ACE Angiotensin converting enzyme - ANP atrial natriuretic peptide - CV coefficient of variation - GFR glomerular filtration rate - RPF renal plasma flow - PAH paraaminohippuric acid     

High prevalence of risk factors for cardiovascular disease in parents of IDDM patients with albuminuria

Summary Life expectancy is shorter in the subset of insulin-dependent diabetic (IDDM) patients who are susceptible to kidney disease. Familial factors may be important. In this study the prevalence of cardiovascular disease mortality and morbidity and of risk factors for cardiovascular disease was compared in the parents of 31 IDDM patients with elevated albumin excretion rate (AER > 45 μg/min; group A) with that of parents of 31 insulin-dependent diabetic patients with normoalbuminuria (AER < 20 μg/min; group B). The two diabetic patient groups were matched for age and duration of disease. Information on deceased parents was obtained from death certificates and clinical records and morbidity for cardiovascular disease was ascertained using the World Health Organization questionnaire and Minnesota coded ECG. Hyperlipidaemia was defined as serum cholesterol higher than 6 mmol/l and/or plasma triglycerides higher than 2.3 mmol/l and/or lipid lowering therapy; arterial hypertension as systolic blood pressure higher than 140 mmHg and/or diastolic blood pressure higher than 90 mmHg and/or antihypertensive treatment. The percentage of dead parents was similar in the two groups (26 vs 20 % for parents of group A vs group B, respectively), but the parents of the diabetic patients with elevated AER had died at a younger age (58 ± 10 vs 70 ± 14 years; p < 0.05). Parents of diabetic patients with nephropathy had a more than three times greater frequency of combined mortality and morbidity for cardiovascular disease than that of the parents of diabetic patients without nephropathy (26 vs 8 %; odds ratio 3.96, 95 % CI 1.3 to 12.2; p < 0.02). Living parents of group A had a higher prevalence of arterial hypertension (42 vs 14 % p < 0.01) and hyperlipidaemia (49 vs 26 % p < 0.05) as well as higher levels of lipoprotein (a) [median (range) 27.2 (1–107) vs 15.6 (0.2–98) mg/dl; p < 0.05]. They also had reduced insulin sensitivity [insulin tolerance test: median (range) K_itt index: 3.7 (0.7–6.2) vs 4.8 (0.7–6.7)% per min; p < 0.05]. In the families of IDDM patients with elevated AER there was a higher frequency of risk factors for cardiovascular disease as well as a predisposition to cardiovascular disease events. This may help explain, in part, the high prevalence of cardiovascular disease mortality and morbidity in those IDDM patients who develop nephropathy. [Diabetologia (1997) 40: 1191–1196] Received: 4 March 1997 and in revised form: 9 May 1997     

Diabetes susceptibility at IDDM2 cannot be positively mapped to the VNTR locus of the insulin gene

Summary An inconsistency has come to light between the conclusion of Lucassen et al. that IDDM2 (11p15.5) must lie within a 4.1 kilobase (kb) segment at the insulin (INS) locus and their own data showing statistically significant associations between insulin-dependent diabetes mellitus (IDDM) and markers beyond the boundaries of that segment. We present data from an independent study of 201 IDDM patients and 107 non-diabetic control subjects that also show significant association with a marker 5 of the INS locus. Patients and control subjects were genotyped at INS/+1140 A/C (a surrogate for the variable number tandem repeat (VNTR) polymorphism in the regulatory part of the INS gene) and a marker 5 of the tyrosine hydroxylase (TH) gene, TH/pINS500-RsaI, making it 10 kb 5 of the VNTR. Homozygotes for INS/+1140 allele + were significantly more frequent among IDDM patients than among control subjects (73 vs 45%, p<0.001) giving an odds ratio of 3.3 (95% confidence interval (CI): 2.0–5.3). A very similar association was found for homozygotes for the TH/RsaIallele + (53 vs 31%, p<0.001) giving an odds ratio of 2.6 (95% CI 1.6–4.2). By multilocus analysis, the TH/RsaI allele + identified a subset of INS/+1140 alleles + haplotypes that are more specifically associated with IDDM (odds ratio = 5.4, 95% CI 2.9–10.4) than allele +1140 + as a whole. In conclusion, the segment of chromosome 11 that is associated with IDDM spans, at least, the INS and TH loci. No legitimate claim can be made that IDDM2 corresponds to the VNTR polymorphism at the INS locus until the correct boundaries for IDDM2 have been defined and other loci within them have been excluded as determinants of IDDM.Abbreviations IDDM Insulin-dependent diabetes mellitus - INS insulin locus - VNTR variable number of tandem repeats - TH tyrosine hydroxylase - IGF-2 insulin-like growth factor-2 - DGGE denaturing gradient gel electrophoresis