Effects of improved glycaemic control maintained for 3 months on cognitive function in patients with Type 2 diabetes.

BACKGROUND AND AIM: In a previous study we failed to find beneficial short-term effects of improved glycaemic control on cognitive functioning in patients with Type 2 diabetes mellitus. A subgroup of the entire sample was tested again to examine the effect of longer-lasting improvement of metabolic control on cognitive functioning. METHODS: The cognitive performance of 26 patients with Type 2 diabetes was assessed at baseline and 3 months after discharge. Thirteen controls were tested at the similar time-points. Attention/concentration, psychomotor speed, verbal fluency, verbal memory and depressive symptoms were assessed. Improved glycaemic control was generally achieved with insulin therapy (20/26). RESULTS: At baseline, there was a trend for diabetic patients to perform worse than controls. Both groups improved significantly over 3 months in several measures. However, diabetic patients did not improve more than controls. CONCLUSIONS: In individuals with long-standing Type 2 diabetes, previous reports of improved cognitive capacity following restoration and maintenance of near-normoglycaemia were not confirmed. This might relate to the type of anti-diabetic therapy.

Short-term effects of improved glycemic control on cognitive function in patients with type 2 diabetes.

BACKGROUND: According to numerous studies, type 2 diabetes is associated with mild cognitive dysfunction, and there is some evidence suggesting favorable effects of improved metabolic control on the mental capability of elderly diabetic patients. OBJECTIVE: To compare patients with type 2 diabetes to normal controls with respect to cognitive performance and to investigate the consequences of glycemic adjustment. METHODS: 53 patients with type 2 diabetes, most of them in secondary failure on oral antidiabetic drugs, but free from conditions which may cause brain dysfunction, were included (mean age 58.8 +/- 6.1 years, duration of disease 12.0 +/- 6.4 years). They were examined prior to (t1), and following (t2) glycemic adjustment with a time interval of approximately 2 weeks. 29 non-diabetic controls, comparable with regard to age, gender, education and verbal intelligence were examined twice with a corresponding time interval. Cognitive performance was assessed by well-standardized tests with a focus on attention/concentration, psychomotor speed, verbal fluency and verbal memory; mood status by two self-rating scales. Restoration of glycemic control included insulin treatment in the majority of patients (46/53). RESULTS: Diabetic subjects scored significantly lower in all cognitive tests used, while they did not differ from controls in mood status. From t1 to t2 they improved in those tests measuring attention/concentration, and psychomotor speed. With regard to similar changes in controls, we interpret these improvements as practice effects rather than the consequence of altered metabolic control. CONCLUSION: In a sample of patients with long-standing type 2 diabetes we could not confirm previous reports of improved cognitive capacity with restoration of glycemic control. Further studies on the effects of changes in control of blood glucose on cognitive performance in type 2 diabetes should be conducted with special regard to drugs used to lower blood glucose.

A polymorphism in the gene for the atrial natriuretic peptide and diabetic nephropathy. Diabetic Nephropathy Study Group.

BACKGROUND: Atrial natriuretic peptide is involved in blood pressure regulation via its vasodilating and natriuretic actions. Since diabetic nephropathy and hypertension are closely related, ANP is a reasonable candidate gene for diabetic nephropathy (DN). METHODS: We genotyped 410 patients with type I diabetes (without DN n = 307; with DN n = 103) and 658 patients with type II diabetes (without DN n = 464; with DN n = 194). In the patients the duration of diabetes was at least 10 years. Diabetic nephropathy was defined as urinary albumin excretion of > or = 30 mg/24 h. The HpaII polymorphism in intron 2 of the ANP gene was determined using PCR amplification followed by restriction digest. Alleles were separated on agarose gels stained with ethidium bromide. RESULTS: We compared genotype distribution and allele frequencies between patients with and without nephropathy. No significant difference was observed either in type I (allele frequency without DN H1, 0.02/H2, 0.98 vs with DN H1, 0.05/H2, 0.95; P = 0.132) or in type II diabetes (allele frequency without DN H1, 0.04/H2, 0.96 vs with DN H1, 0.05/H2, 0.95; P = 0.551). CONCLUSIONS: The polymorphism in the gene for the atrial natriuretic peptide does not seem to play a major role in the development of diabetic nephropathy in either type I or in type II diabetes.

Abnormal pulsatile secretion of growth hormone in non-insulin-dependent diabetes mellitus.

OBJECTIVE: Studies of GH secretion in patients with non-insulin dependent diabetes mellitus (NIDDM) have produced conflicting results. We aimed to differentiate the effects of obesity and metabolic control on pulsatile GH secretion in patients with NIDDM. DESIGN: Blood sampling every 15 min from 22.00 hours to 08.00 hours after a fasting period of at least 3 h. PATIENTS: 13 male NIDDM patients, 9 healthy control subjects matched for age and BMI, and 6 lean subjects matched for age. MEASUREMENTS: Measurement of GH by a novel ultrasensitive chemiluminescence assay. Analysis of concentration vs time profiles by a multiparameter deconvolution technique. RESULTS: GH burst frequency was increased in the NIDDM (0.82 +/- 0.28 h-1) compared with both control groups (lean: 0.6 +/- 0.11; obese: 0.56 +/- 0.19). GH burst mass was decreased in patients (1.57 +/- 0.98 micrograms/l.min) and in obese controls (1.46 +/- 1.44) compared to lean controls (3.71 +/- 3.88). These differences resulted in a significantly higher nocturnal pulsatile GH secretion rate in the lean compared to the obese controls, whereas in the patient group enhanced GH burst frequency compensated for reduced burst mass. The characteristics of GH secretion were not related to nocturnal or early morning blood glucose concentrations. However, GH secretion rate was correlated positively with HbA1c (r = 0.57; P = 0.04), and negatively with plasma C peptide concentrations. CONCLUSIONS: The specific increase in GH burst frequency previously described in insulin-dependent diabetes mellitus is also present in NIDDM. However, GH hypersecretion does not occur because GH burst mass is reduced in proportion to the degree of obesity. The effect of diabetes on the hypothalamic control of GH release appears to be determined by the quality of long-term glycaemic control.

Persistent GAD 65 antibodies in longstanding IDDM are not associated with residual beta-cell function, neuropathy or HLA-DR status.

Persistent humoral autoimmunity to the enzyme glutamic acid decarboxylase (GAD) has been described in a substantial proportion of patients with insulin-dependent diabetes mellitus (IDDM) of long duration. The source of the stimulus for this autoimmune reactivity is still unknown. Because the GAD 65 isoform is mainly expressed in pancreatic beta-cells and in the nervous system we investigated in the present study of the largest number of well characterized patients with longstanding IDDM (n = 105; median duration: 21 years; range: 10-46 years) the presence of autoantibodies to GAD 65 and their relationship to a residual C-peptide response or peripheral and autonomic neuropathy. Additionally we studied the HLA-DR status relative to GAD 65 antibodies in 86 out of the 105 individuals. One hundred healthy control subjects and 100 recent onset IDDM patients were also studied for GAD 65 antibodies. GAD 65 antibodies were detected in a radioligand-binding-assay with recombinant human GAD 65 and were present in 32% of the long-term diabetic patients, 82% of the recent onset IDDM patients and in 3% of the healthy control subjects. A preserved C-peptide response to i.v. glucagon (Hendriksen criteria) was observed in 23% of the long-term IDDM patients. Autonomic neuropathy and peripheral neuropathy was identified using criteria based on both symptoms and formal testing giving a frequency of 67% vs 79%. The HLA specific DR 4/X was observed in 47% and HLA-DR 3/X in 22% of the long-term IDDM patients. Patients who were heterozygous for DR3/DR4 were found in 23% of the cases. GAD 65 antibodies were significantly less frequent in the long-term IDDM patients compared to recent onset IDDM (p < 0.001), and diabetes duration showed a significant negative correlation with GAD 65 antibody index levels (r = 0.22, p < 0.01). Interestingly, GAD 65 antibodies were not significantly correlated either with residual beta-cell function or neuropathy and no particular HLA-DR status was associated with persistent GAD 65 antibodies. In conclusion neither residual beta-cell function nor diabetic neuropathy or a certain HLA-DR specificity are exclusively associated with persistent autoimmunity directed to GAD 65 in longstanding IDDM. The stimulus for the persistent humoral immune response and its significance for the disease process and its complications remain to be established.

Pathogenesis and course of renal disease in IDDM/NIDDM: differences and similarities.

In the past the opinion prevailed that renal prognosis was less adverse in non-insulin-dependent diabetes mellitus (NIDDM) as compared with insulin-dependent diabetes mellitus (IDDM). This notion has to be revised in the light of recent evidence, based on epidemiologic data of NIDDM patients reaching endstage renal failure and a comparison of the cumulative prevalence of proteinuria and renal failure, respectively, in NIDDM as compared with IDDM. It has also been established that initial renal hemodynamic changes are quite comparable in NIDDM and in IDDM. It follows that past complacency about the renal sequelae of NIDDM is no longer justified and that preventive measures to interfere with the development of diabetic nephropathy are similarly important in NIDDM and IDDM.

[Nephropathy and hypertension in type II diabetes]. / Nephropathie und Hypertonie bei Typ-II-Diabetes.

BACKGROUND: In Germany nephropathy in patients with type II diabetes has become the most frequent single cause of uremia requiring renal replacement therapy. This calls for effective measures of prevention. DIABETIC NEPHROPATHY AND HYPERTENSION: In patients with established diabetic nephropathy, hypertension is the most important pathogenetic factor which is susceptible to therapeutic intervention. Some pathogenetic mechanisms are discussed which impact on antihypertensive therapy. Interaction between hypertension and diabetic nephropathy is analyzed. CONCLUSION: Diabetic nephropathy in patients with type II diabetes has become the most frequent cause of endstage renal failure in Germany. Preventive measures, i. e. near normal glycemia and particularly antihypertensive treatment, have been proven to interfere with progression of renal failure in diabetic nephropathy. Early recognition is possible by testing for urinary albumin (microalbuminuria). In patients with diabetic nephropathy, blood pressure should be lowered to values well within the range of normotension by dietary salt restriction and antihypertensive drug therapy.

Excess of DD homozygotes in haemodialysed patients with type II diabetes. The Diabetic Nephropathy Study Group.

The role of the insertion/deletion polymorphism of the angiotensin-converting enzyme (ACE) gene in the genesis of diabetic nephropathy has been controversial. It has recently been proposed that progression occurs more rapidly in individuals with diabetic and non-diabetic renal disease who are homozygous for the D allele. We studied 658 patients with type II diabetes, 347 without diabetic nephropathy and 311 with various stages of diabetic nephropathy, and determined the I/D polymorphism of the ACE gene. Patients at the extremes of renal risk, i.e. normotensive patients without antihypertensive treatment and without nephropathy (n = 144), vs patients on dialysis (n = 61), differed with respect to genotype (DD 36.8% vs 57.4%; P = 0.007) and allele frequencies (D 0.59 vs 0.76; P < 0.001). In contrast, patients with and without presumed nephropathy as assessed by albuminuria did not differ with respect to DD genotype. In conclusion, in this study, which was limited by sample size, patients with the highest renal risk more frequently had the DD genotype. This would be compatible with a greater risk of (or rate of) progression to end-stage renal failure.

Altered action of angiotensin II in patients with type 2 diabetes mellitus of recent onset.

OBJECTIVE: Angiotensin II (Ang II) increases insulin sensitivity in healthy volunteers. This effect is thought to be mediated, at least in part, by an increase in skeletal muscle blood flow. In the past it had been documented that some biological actions of Ang II are altered in diabetes. We addressed the issue of whether this is also true for its action on insulin sensitivity. DESIGN AND METHODS: Twelve healthy volunteers (aged 43+/-9 years) and 15 patients with type 2 diabetes mellitus (NIDDM) of recent onset (aged 45+/-9 years) were allocated in random order in a double-blind placebo-controlled design to be administered a sham infusion or an infusion of 2 ng Ang II/kg per min. Insulin-stimulated glucose uptake (the M value) was measured with the euglycaemic clamp technique, leg muscle blood flow (MBF) with plethysmography, blood pressure with a Dinamap device, and glomerular filtration rate and effective renal plasma flow with the steady-state inulin (Cin) and p-aminohippurate (CPAH) clearance methods, respectively. RESULTS: In volunteers the mean M-value after Ang II infusion (10.1+/-1.5 mg/kg per min) was significantly higher (P < 0.01) than that after sham infusion (8.2+/-0.9 mg/kg per min). In contrast, in diabetic patients it was not significantly different with Ang II (6.1+/-1.3 mg/kg per min) and sham infusion (5.5+/-1.2 mg/kg per min). The difference in the mean absolute increase in the M value (deltaM) between groups was significant (P< 0.02). The Ang II-induced increase in MBF under euglycaemic conditions was attenuated in diabetic patients (from 15.0+/-3.5 to 15.5+/-3.9 ml/100 ml per min, NS) compared with volunteers (from 16.8+/-3.3 to 19.1+/-3.7 ml/100 ml per min, P< 0.01). Again, the difference between the mean absolute increases in MBF (deltaMBF) in the groups was significant (P < 0.01). A significant correlation was found between deltaMBF and deltaM (r= 0.62, P<0.01). The absolute acute increase in mean arterial blood pressure with Ang II was similar in diabetic patients and volunteers. Mean Cin, CPAH and fractional sodium excretion values were significantly lower and renal vascular resistances and filtration fractions higher during the Ang II than they were during the placebo clamp period. This was observed in patients as well as in healthy subjects, but the effects of Ang II on renal haemodynamics and sodium handling were more pronounced in diabetic patients. CONCLUSIONS: In patients with NIDDM of recent onset the stimulatory effect of Ang II on insulin sensitivity and on skeletal muscle blood flow is attenuated. In contrast, the effects of Ang II on renal perfusion and sodium handling are more pronounced in patients with NIDDM than they are in healthy subjects.

Renal findings in patients with short-term type 2 diabetes.

Under semiambulatory conditions, 85 consecutive patients with the diagnosis of Type 2 diabetes of short duration (excluding patients with islet cell antibodies or maturity onset diabetes of the young) were admitted to a self-control training program and were examined in this study. A comprehensive renal assessment was performed, including evaluation of albumin excretion rate (AER), renal hemodynamics, blood pressure (BP) profile, and indicators of genetic risk. AER > or = 30 mg/24 h was found in 13 (15%) of patients; in two of these patients, AER was > or = 300 mg/24 h. By logistic regression, high HbA1, current smoking, and BP parameters were significantly correlated with an increased risk of microalbuminuria (MA). In a multiple linear regression model, accounting for 57% of total variance, HbA1, ERPF, and current smoking were significantly correlated with AER. Median GFR (Cin(inulin clearance) 136 mL/min per 1.73m2; range, 94 to 194) and ERPF (Cpah(para-aminohippuric acid clearance) 733; range, 451 to 1328) were significantly higher in patients than in control subjects (upper 95th percentile, 131 and 706 mL/min per 1.73m2, respectively). In a multiple linear regression model, explaining 27% of total variance, age, AER, gender, and fasting blood glucose were significantly correlated to GFR. According to the criteria of average daytime BP > or = 135/85 mm Hg or 24-h BP > or = 130/80 mm Hg, 60% of patients were hypertensive (HT). Sixty-one percent of all patients (including 50% of the untreated normotensive patients) were "nondippers", i.e., < 15% nighttime decrease of mean arterial pressure. Either HT or nondipping was found in 79% of all patients, so that only 21% had a completely normal blood pressure profile. Ninety-four percent of untreated hypertensive patients had no MA. First-degree relatives of patients with MA compared with patients without MA had more frequent cardiovascular events (69% versus 31%). The risk of MA in diabetic patients with positive family history was amplified by poor glycemic control. MA, but not hypertension, was marginally related to K(m) of Na+/Li+ countertransport. It was concluded that (1) microalbuminuria is found in 15% of patients newly presenting with Type 2 diabetes; (2) a high proportion of patients exhibit hyperfiltration; (3) according to ambulatory BP only, 21% of patients have a completely normal circadian BP profile; (4) a family history of cardiovascular events interacts with glycemic control to increase the risk of MA.

Angiotensinogen gene M235T polymorphism is not associated with diabetic nephropathy. The Diabetic Nephropathy Study Group.

BACKGROUND: There is agreement that a family history of hypertension (HT), is a predictor for the risk of diabetic nephropathy (DN) in patients with type 2 diabetes, and possibly also type 1 diabetes. It follows that genes related to the risk of hypertension must also be considered candidate genes for DN. The 235T allele of the angiotensinogen gene was found to be related to primary HT. METHODS: To examine whether it is predictive for DN as well, we examined the angiotensinogen gene polymorphism in 230 healthy local controls, 423 patients with type 1 diabetes (n = 180 with DN; n = 243 without DN) and 663 patients with type 2 diabetes (n = 310 with DN; n = 353 without DN). The angiotensinogen gene M235T polymorphism was determined using PCR amplification. RESULTS: The following results were obtained (i) no significant difference of genotype distribution (type 1: MM/MT/TT (%) 27.6/57.2/15.2 vs 27.2/56.1/16.7 (P = 0.92); type 2; MM/MT/TT (%) 31.7/48.2/2/20.1 vs. 32.9/46.8/20.3 (P = 0.93) or allele frequencies (type 1: M 0.56 vs. 0.55 (P = 0.795); type 2; M 0.56 vs. 0.56 (P = 0.86)) was found, between diabetic patients with or without DN, (ii) no difference was found between normotensive and hypertensive diabetic patients. CONCLUSION: The data argue against a role of the angiotensinogen gene M235T polymorphism in the manifestation of diabetic nephropathy or hypertension in diabetic patients.

Plasma thrombomodulin: a marker for microvascular complications in diabetes mellitus.

Thrombomodulin (TM), a marker of endothelial cell damage was studied in 183 patients with diabetes mellitus and different stages of complications. Thrombomodulin plasma levels correlated with duration of diabetes in patients with type I and type II diabetes. Thrombomodulin levels were higher in patients with increasing numbers of complications (nephropathy, retinopathy, arterio-occlusive disease, neuropathy). Neither the presence of retinopathy, nor neuropathy alone significantly increased plasma thrombomodulin in patients with similar urinary albumin concentration. The plasma level of thrombomodulin was more prominent in hypertensive than normotensive patients. Multivariate analysis showed that albuminuria is the factor which influences the most the increase of thrombomodulin in serum of diabetic patients.

Nephropathy of type II diabetes mellitus.

In recent years there has been a dramatic increase of almost epidemic proportions in the incidence of patients with type II diabetes mellitus who reach end-stage renal failure and enter renal replacement programmes. This is mainly due to the greater prevalence and better survival of patients with type II diabetes and diabetic nephropathy. Against this background measures to prevent the appearance and progression of diabetic nephropathy are of immense interest. Apart from the undoubted role of hyperglycaemia, the importance of genetic determinants of nephropathy has recently been recognized. Factors of proven or suspected efficacy in attenuating progression include: hypertension, hyperglycaemia, smoking and proteinuria. The role of dietary protein intake is less well documented. Nephropathy in type II diabetes has become the single most common cause of end-stage renal failure in Germany and is today a major challenge to clinical nephrology.

[Thrombomodulin is a marker of microvascular, but not for macrovascular endothelial cell damage]. / Thrombomodulin ist ein Marker für mikrovaskuläre, aber nicht für makrovaskuläre Endothelzellschädigung.

UNLABELLED: Plasma levels of thrombomodulin are increased in diseases associated with microangiopathia. The target of this study was to examine whether plasma thrombomodulin is also influenced by macroangiopathia. There was no variation of plasma thrombomodulin in a sample of 183 diabetic patients with or without peripheral arterio-occlusive disease of the lower limbs. In a second sample of 33 patients with peripheral arteriosclerosis of the lower limbs, without any indication of diabetes, plasma levels of thrombomodulin were not significantly increased compared to a control group. Since thrombomodulin is also found in thrombocytes, we analysed whether plasma thrombomodulin levels were influenced by platelet activation. Neither platelet activation after hyperthermal limb perfusion not the PGE1-treatment showed any effect on plasma thrombomodulin level. CONCLUSION: Thrombomodulin is a marker for microvascular but not for macrovascular endothelial cell damage.

Renal involvement in type II diabetes.

The incidence and prevalence of renal failure from type II diabetes have been seriously underestimated in the past. Currently, the incidence of uremia in patients with type II diabetes has increased continuously in Europe and the United States, mainly because of better patient survival (ie, they now live until nephropathy develops) and possibly because of a rising prevalence of type II diabetes in the general population (ie, more patients are at risk of developing nephropathy). Generally, renal hemodynamics and glomerular lesions are similar in type I and type II diabetes, but glomerular histology is more diverse in type II diabetes. Given the high prevalence of diabetes and renal failure from various causes in the elderly, coexistence of the two (even in the absence of glomerulosclerosis) occurs in approximately 20% of uremic type II diabetic patients. The development of nephropathy is controlled by strong genetic determinants, but these have not been further characterized.

Prospective randomized two-years clinical study comparing additional metformin treatment with reducing diet in type 2 diabetes.

After a 2 weeks hospital treatment with a strong dietary regime 100 patients not sufficiently controlled (blood glucose fasting 120-180, pp 180-250 mg/100 ml), were randomly allocated to a purely dietary therapy or to a diet-metformin-combination for a duration of 2 years. After 1 and 2 years the patients were rehospitalized for an accurate evaluation. Additionally, HbA1 was controlled every 3 months, in case of problems after shorter periods. If HbA1 exceeded 10% for more than 4 weeks the patients were hospitalized for 5 days in order to decide whether the deterioration of metabolic control was due to the patients' non-compliance to treatment or to treatment failure. During 2 years of observation 30 patients were withdrawn from the treatment for external reasons. 13 patients (6 diet, 7 metformin + diet) were non-compliant with diet, 3 further patients were not metformin-compliant. Therapeutic failures were confirmed in 4 diet patients, none of the metformin + diet patients failed to respond to treatment. After excluding all these patients there was a group of 29 diet and 25 metformin + diet patients with a similar development of criteria of metabolic control during 2 years. Lipid levels deteriorated in the dietary group more noticeably than during additional metformin treatment although without reaching a statistically significant level, though. The stimulated C-peptide was significantly reduced by metformin in comparison to diet only, which supports former findings of an insulin-lowering effect of the drug.