Neuropsychological functioning in older people with type 2 diabetes: the effect of controlling for confounding factors.

AIMS AND METHODS: Neuropsychological functioning was examined in a group of 33 older (mean age 62.40 +/- 9.62 years) people with Type 2 diabetes (Group 1) and 33 non-diabetic participants matched with Group 1 on age, sex, premorbid intelligence and presence of hypertension and cardio/cerebrovascular conditions (Group 2). RESULTS: Data statistically corrected for confounding factors obtained from the diabetic group were compared with the matched control group. The results suggested small cognitive deficits in diabetic people's verbal memory and mental flexibility (Logical Memory A and SS7). No differences were seen between the two samples in simple and complex visuomotor attention, sustained complex visual attention, attention efficiency, mental double tracking, implicit memory, and self-reported memory problems. CONCLUSIONS: These findings indicate minimal cognitive impairment in relatively uncomplicated Type 2 diabetes and demonstrate the importance of control and matching for confounding factors.     

Clinical and Metabolic Characteristics of Type 1 and Type 2 Diabetes: An Epidemiological Study From the Närpes Community in Western Finland

Clinical and metabolic characteristics of all known Type 1 and Type 2 diabetic patients in a well-defined area in Western Finland are described. Retrospective data from the time of diagnosis and follow-up data were examined. Overall prevalence of diabetes was 25.4 cases per 1000 population. Patients were defined as having Type 1 or Type 2 diabetes based upon early insulin requirement and C-peptide levels. Applying these criteria 84% of the patients had Type 2 diabetes. Onset before the age of 40 years was observed in only 3% of Type 2 diabetic patients. This age limit therefore had a sensitivity of 97% and a specificity of 90% in correctly predicting Type 2 diabetes. At diagnosis, hypertension was observed in 2% of Type 1 and in 75% of Type 2 diabetic patients; the corresponding numbers at follow-up were 6 and 63%. At investigation, 27% of Type 1 and 22% of Type 2 diabetic patients had microalbuminuria. Retinopathy was observed in only 12% of Type 2 compared with 54% of Type 1 diabetic patients. The presence of retinopathy was associated with longer diabetes duration both among Type 1 and Type 2 diabetic patients. A significant decrease in C-peptide concentration was observed in Type 2 diabetic patients with increasing diabetes duration. The data therefore suggest that Type 2 diabetes is associated with a deterioration of beta-cell function with time.     

Comparison of the course to end-stage renal disease of Type 1 (insulin-dependent) and Type 2 (non-insulin-dependent) diabetic nephropathy

Summary Is the course leading to diabetic end-stage renal disease similar for Type 1 (insulin-dependent) and Type 2 (non-insulin-dependent) diabetes mellitus? We identified all diabetic end-stage renal disease patients starting renal replacement therapy from 1989 to 1991 in two urban counties in Texas. Three ethnic/racial groups were enrolled: Mexican Americans, non-Hispanic Whites, African Americans. Patients were interviewed and their medical records, both inpatient and out-patient, were abstracted for relevant diagnostic and therapeutic information. We attempted to obtain records as far back as the onset of diabetes or hypertension and from all physicians who had cared for the patient. An historical algorithm was used to determine diabetic type. Of the patients enrolled, 91 were Type 1 and 438 were Type 2 diabetic patients. Type 1 diabetic patients had higher mean glucose levels in the first 10 years of diabetes (16.3 vs 11.4 mmol/l) but lower systolic blood pressures (148 vs 157 mmHg). The duration of diabetes prior to end-stage renal disease was longer for Type 1 than Type 2 patients (22 vs 17 years). Type 1 diabetic patients were more likely to have other microvascular complications (retinopathy, neuropathy, gastroparesis), less likely to have coronary disease (myocardial infarction and congestive heart failure), and had similar rates of stroke and vascular surgery procedures (carotid endarterectomy, coronary artery bypass surgery, aortofemoral bypass). Type 1 and Type 2 diabetic patients were just as likely to have a first degree relative with hypertension (60.5 vs 65.5%). The late manifestations of end-stage renal disease were similar between the two groups (kidney size, proteinuria, slope of the inverse of creatinine, laboratory data prior to end-stage renal disease, reasons for starting dialysis). The course to end-stage renal disease may be different for Type 1 and Type 2 diabetes, with hyperglycaemia playing a more dominant role in Type 1 and hypertension playing a more dominant role for Type 2. The Type 1/Type 2 differences in patterns of other diabetic complications add weight to this hypothesis. However, the late course of the renal disease and the end result on the kidney is very similar.     

Depression in Croatian Type 2 diabetic patients: prevalence and risk factors. A Croatian survey from the European Depression in Diabetes (EDID) Research Consortium.

AIMS: To determine the prevalence rate of and risk factors for depression in Croatian Type 2 diabetic patients. METHODS: Depressive mood was examined in 384 randomly selected outpatients with Type 2 diabetes. Center for Epidemiological Studies Depression Scale (CES-D) and Structured Clinical Interview for DSM-IV Axis I Disorders (SCID) were used to identify depressive disturbances. The groups with CES-D > or = 16 and < 16 were compared with respect to demographic, psychological and clinical characteristics. Regression analysis was used to determine risk factors for depression. RESULTS: Of the examined patients, 22% had CES-D scores > or = 16, and in 33% of them clinical depression was confirmed by the psychiatric interview. Depressed patients compared with the non-depressed ones reported more diabetes-related problems and poorer well-being (t = 6.71, P < 0.001 and t = 11.98, P < 0.001, respectively). Multiple regression analysis indicated female gender, experienced support and the level of emotional well-being to predict depression (R = 0.74, F = 15.3, P < 0.001). CONCLUSIONS: The obtained data indicate that the prevalence rate in Croatian Type 2 diabetic patients is comparable to findings from other cultural settings. Depressive symptoms can be predicted by psychological rather than disease-related variables. Psychological care for diabetic patients may be necessary to prevent depressive symptomatology.     

Family histories of diabetes among Japanese patients with Type 1 (insulin-dependent) and Type 2 (non-insulin-dependent) diabetes

Summary Family histories of diabetes mellitus in first-degree relatives were compared in Japanese patients with Type 1 (insulin-dependent) and Type 2 (non-insulin-dependent) diabetes. The frequency of positive family histories for diabetes in first-degree relatives was 24% (13/55) in Type 1, 44% (281/631) in Type 2 (p<0.01 versus Type 1) and 47% (16/34) when the type of diabetes could not be classified. The prevalence of diabetes in siblings of Type 2 patients was higher than in Type 1 diabetic patients (p<0.01). Patients with Type 2 diabetes and definite obesity in the past had a lower frequency of a family history of diabetes (p<0.01) and a lower prevalence of diabetes in their parents (p<0.01) than did Type 2 patients without obesity. The highest rate of family history for diabetes was observed in non-obese Type 2 diabetic patients of early onset. Our data agree with the previously known higher frequency of familial diabetes in Type 2 compared with Type 1 diabetes, despite the fact that there are significant dissimilarities between Type 1 diabetes in Japanese and Caucasoid populations.     

Analysis of the association between diabetic nephropathy and polymorphisms in the aldose reductase gene in Type 1 and Type 2 diabetes mellitus.

AIMS: To investigate the association between polymorphisms of the aldose reductase gene and diabetic nephropathy in both Type 1 and Type 2 diabetes mellitus, and to carry out a meta-analysis of published results. METHODS: We have investigated the role of two aldose reductase polymorphisms in four independent cohorts of cases and controls (two each with Type 1 and Type 2 diabetes) drawn from two ethnic populations, including 471 patients with nephropathy and 494 control diabetic patients without nephropathy. A C/T transition at position -106, and a (CA)n microsatellite marker 2.1 kb from the start site of the aldose reductase gene were genotyped in nephropathic patients and non-nephropathic controls from each cohort. RESULTS: Carriage of the -106 T allele was significantly associated with diabetic nephropathy in three of the four study groups. The Mantel-Haenszel combined odds ratio was 2.22 (95% CI 1.69, 2.94), P = 1.05 x 10(-8). We found no evidence for association of the microsatellite marker with nephropathy, despite moderate levels of disequilibrium between the two markers. Meta-analysis of published data yielded no evidence for association of the microsatellite marker with diabetic nephropathy in Type 2 diabetes, but varying degrees of association with diabetic nephropathy in Type 1 diabetes. CONCLUSIONS: Meta-analyses provide more convincing evidence of a role for the ALR2-106 marker than for the microsatellite marker in diabetic nephropathy (DN). More studies are now required to confirm these results and to establish whether the ALR2-106 polymorphism has a functional role in DN.     

Calcaneal bone mineral density in patients with Charcot neuropathic osteoarthropathy: differences between Type 1 and Type 2 diabetes.

AIMS: To measure bone density and neuropathy in both feet in Type 1 and Type 2 patients with unilateral Charcot osteoarthropathy and controls. METHODS: Calcaneal bone density, temperature and vibration thresholds were compared between 17 Type 1 diabetic patients with osteoarthropathy and 47 Type 1 controls and between 18 Type 2 diabetic patients and 48 Type 2 controls. As well as the Charcot foot, the non-Charcot foot was studied to assess osteopenia at onset of osteoarthropathy. RESULTS: In Type 1 diabetes, bone density was reduced in the non-Charcot foot compared with controls [Z-score: -1.7 ({-1.9}-{-1.4}) vs. -0.2 ({-1.1}-{0.5}), P < 0.0001, median (interquartile range)]; but not in Type 2 diabetes [Z-score: 0.15 ({-0.45}-{0.85}) vs. 0.3 ({-0.5}-{0.9}), P = 0.675]. Bone density in the Charcot foot was lower compared with the non-Charcot foot in both Type 1 [Z-score: -2.0 ({-2.8}-{-1.4}) vs. -1.7 ({-1.9}-{-1.4}), P = 0.018] and Type 2 diabetes [Z-score: -0.2 ({-1.4}-{0.1}) vs. 0.3 ({-0.5}-{0.9}), P = 0.001]. In Type 1 diabetes, bone density of the non-Charcot foot was reduced compared with that in Type 2 (P < 0.0001). Body mass index was lower in Type 1 than in Type 2 Charcot patients (P = 0.007). Type 2 patients had high temperature (P = 0.001) and vibration thresholds (P < 0.0001) in the non-Charcot foot compared with Type 2 controls whereas Type 1 patients had a high temperature threshold (P = 0.01) but not vibration threshold compared with Type 1 controls (P = 0.077). CONCLUSION: Bone density was reduced in the non-Charcot foot in Type 1 but not in Type 2 diabetes. Type 2 patients had high temperature and vibration thresholds in contrast to Type 1 patients who had a high temperature threshold only.     

Psychosocial factors and diabetes-related outcomes following diagnosis of Type 1 diabetes in adults: the Edinburgh Prospective Diabetes Study.

AIMS: To examine prospectively the relationships between psychosocial variables and diabetes-related outcomes in adults with newly diagnosed Type 1 diabetes. METHODS: A total of 84 adults (48 male) with a median (range) age of 30.8 (17-51) years with newly diagnosed Type 1 diabetes were recruited for the study. Shortly after initial diagnosis each participant's personality, cognitive ability, and recent psychiatric distress were assessed. At 4 months (n = 69) and at 12 months (n = 66) after diagnosis diabetes-related outcomes were measured, including each respondent's knowledge of diabetes, satisfaction with diabetes treatment and diabetes-related quality of life. Glycated haemoglobin (HbA1c) was recorded at each clinic attendance. RESULTS: Social class (Spearman's correlation r = -0.30 and -0.28, respectively, P < 0.05) and scores on the National Adult Reading Test (r = 0.38 and 0.36, respectively, P < 0.01) were consistently associated with knowledge of diabetes at 4 months and at 12 months after diagnosis. Hierarchical regression revealed that alcohol consumption recorded at diagnosis and knowledge of diabetes at 4 months were independent predictors of glycaemic control at 12 months (adjusted r2 = 0.16). Total scores on the Diabetes Treatment Satisfaction Questionnaire (DTSQ) at 12 months were significantly predicted by age at diagnosis (adjusted r2 = 0.08). High neuroticism at diagnosis was consistently associated with poorer self-reported diabetes quality of life at 4 months and at 12 months after diagnosis (rs between -0.30 and -0.39, P < 0.05). CONCLUSIONS: Long-standing psychosocial factors have a significant influence on self-reported outcomes during the 12 months following diagnosis of Type 1 diabetes but may not be reliable predictors of glycaemic control. Further follow-up is necessary to determine the longer-term predictors of objective (e.g. glycaemic control) and subjective (e.g. quality of life) indicators of coping in people with diabetes.     

Epidemiology,development and treatment of end-stage renal failure in Type 2 (non-insulin-dependent) diabetic patients in Europe

Summary The aim of the present report was to compare the current patterns of incidence and prevalence of end-stage renal failure and mode of renal replacement therapy in patients with Type 1 (insulin-dependent) and Type 2 (non-insulin-dependent) diabetes mellitus in Europe. All Type 1 and Type 2 diabetic patients recorded on the Registry of the European Dialysis and Transplant Association as being alive on renal replacement therapy were analysed according to age, sex, geographic distribution, and mode of therapy (haemodialysis, peritoneal dialysis or renal transplantation). During 1990 3981 diabetic patients commenced renal replacement therapy in Europe, and at 31 December 1990 a total of 15, 197 diabetic patients were receiving treatment. One-third were reported to be Type 2 diabetic patients, but the true proportion is expected to be higher. Both male and female Type 2 diabetic patients were older than Type 1 patients. Major geographic variations were observed; annual acceptance of Type 2 diabetic patients for treatment was greatest in Austria (10.7 per million) and equal to Type 1 patients, whereas the number of Type 1 diabetic patients was four times that of Type 2 patients in Sweden, Finland and Norway. Overall, the majority of Type 2 diabetic patients (80%) were treated by haemodialysis, 14% by peritoneal dialysis, and 6% had a functioning renal transplant. However, transplantation was the preferred option in young patients (48% of 25–34 year olds) and in Sweden and Norway (45% of all Type 2 patients). On behalf of the European Dialysis and Transplant Association Registry     

Rates and risks for co-morbid depression in patients with Type 2 diabetes mellitus: results from a community-based study

Aims/hypothesis There is accumulating evidence that depression is common in people with Type 2 diabetes. However, most prevalence-studies are uncontrolled and could also be inaccurate from selection-bias, as they are conducted in specialized treatment settings. We studied the prevalence and risk factors of co-morbid depression in a community-based sample of older adults, comparing Type 2 diabetic patients with healthy control subjects.Methods A large (n=3107) community-based study in Dutch adults (55–85 years of age) was conducted. Pervasive depression was defined as a CES-D score greater than 15. Diagnosis of Type 2 diabetes was obtained from self-reports and data from general practitioners.Results A number of 216 patients (7%) were identified as having Type 2 diabetes. The prevalence of pervasive depression was increased in people with Type 2 diabetes and co-morbid chronic disease (20%) but not in patients with Type 2 diabetes only (8%), compared with the healthy control subjects (9%). Regression analyses in diabetic patients yielded that being single, being female, having functional limitations, receiving instrumental support and having an external locus of control were associated with higher levels of depression.Conclusions/interpretation The Results suggest that the prevalence of pervasive depression is increased in patients with Type 2 diabetes and co-morbid disease(s), but not in patients with Type 2 diabetes only. Functional limitations that often accompany co-morbid chronic disease could play an essential role in the development of depression in Type 2 diabetes. These findings can enable clinicians and researchers to identify high-risk groups and set up prevention and treatment programs.Abbreviations CES-D Centres for Epidemilologic Studies Depression Scale - LASA Longitudinal Aging Study Amsterdam     

Do subjective cognitive complaints correlate with cognitive impairment in systemic lupus erythematosus? A Danish outpatient study

This study examined the prevalence of cognitive impairment and its association with depressive symptoms and self-reported cognitive complaints in Danish outpatients with systemic lupus erythematosus (SLE). Fifty-seven consecutive female SLE-outpatients were examined with a comprehensive neuropsychological test-battery, a 20-item self-administered Perceived Deficits Questionnaire (PDQ) and a self-rated depression scale (Major Depression Inventory). Twenty-two patients (38.5%) were classified as cognitively impaired, mostly with deficits in executive functions and attention. Among cognitively impaired patients only 18.2% had significantly higher PDQ scores than the normal range. PDQ scores were highly correlated to depressive symptoms (r = 0.67, p < 0.001). Only two neuropsychological tests were significantly correlated with subjective cognitive complaints. When these variables and self-rated depression score were entered into a regression model both depression score and Symbol Digit Modalities Test performances were significantly associated with the PDQ score. In conclusion, cognitive impairments were common in this group of (mild) SLE outpatients, but the level of significant subjective cognitive complaints was low even among patients with cognitive impairment. Affective status may influence subjective experience of cognitive functions even more than cognitive functioning itself, and absence of subjective cognitive complaints did not exclude the presence of cognitive impairments.     

Relationship between B-cell function and HLA antigens in patients with Type 2 (non-insulin-dependent) diabetes

Summary In order to study the heterogeneity of Type 2 (non-insulin-dependent) diabetes, we determined HLA antigens and measured B-cell function as C-peptide response to intravenous glucagon in 217 patients with onset of non-ketotic diabetes after the age of 40 years. Their HLA frequencies were compared with those of Type 1 (insulin-dependent) diabetic patients and of healthy blood donors. The Type 1 diabetic patients showed a typical HLA pattern, with increased frequencies of B15, DR3, DR4, B8/B15 and DR3/DR4 and decreased frequencies of 137 and DR2. The Type 2 diabetic patients could be distinguished from blood donors by increased frequencies of Cw4, DR4, DR5 and DR3/DR4, and from Type 1 diabetic patients by increased frequencies of B7, DR2, DR5 and decreased frequency of A9, Bw22 and DR4. Age at onset and body mass index were unrelated to HLA antigens, but the Type 2 diabetic patients with HLA-Cw4, DR5 and DR6 showed a strong family history for Type 2 diabetes. Type 2 diabetic patients with HLA-B8, DR4, B8/B15 and DR3/DR4 showed significantly lower C-peptide concentrations (p < 0.05) than patients without these HLA antigens. In contrast, patients with DR5 and DRw8 presented with high C-peptide levels. Twelve patients who were positive for both DR3 and DR4 and 23 patients who were DR3/DR4 negative were followed with repeated C-peptide determinations during a period of three years. The C-peptide concentrations of the DR3/DR4 positive patients decreased during this period, whereas there was no change in C-peptide levels in the DR3/DR4 negative patients. In conclusion, B-cell function measured as C-peptide response to glucagon correlates with HLA antigens in patients with onset of diabetes after age 40. Impaired B-cell function seems to be associated with Type 1 diabetes-related HLA-antigens, whereas the presence of DR5 was associated with preserved B-cell function and a strong heredity for Type 2 diabetes. The results thus support the concept of heterogeneity in Type 2 diabetes. Admixture of patients with latent Type 1 diabetes can at least partially account for this heterogeneity.     

Autonomic neuropathy in Type 2 diabetic patients is associated with hyperinsulinaemia and hypertriglyceridaemia.

AIMS: To clarify whether parasympathetic neuropathy in Type 2 diabetic patients is associated with features of the insulin resistance syndrome. METHODS: Blood pressures, glycaemic control (HbA1c), plasma lipids, residual beta-cell function (fasting plasma C-peptide), autonomic nerve function, urinary albumin excretion and glomerular filtration rate (Cr-EDTA clearance) were evaluated in 82 Type 2 diabetic patients (age 63+/-years) 5 years after diagnosis of diabetes. RESULTS: Parasympathetic neuropathy (an abnormal age corrected E/I ratio) was found in 24/82 (29%) patients. After adjustment for body mass index (BMI), patients with parasympathetic neuropathy had elevated fasting plasma C-peptide (P < 0.001) and triglyceride (Tg) (P < 0.05) levels compared with patients without parasympathetic neuropathy. In addition, the age corrected E/I ratio correlated inversely with Tg (r=-0.31; P<0.01) and fasting plasma C-peptide (r=-0.32; P < 0.01) in the Type 2 diabetic patients. CONCLUSION: Autonomic neuropathy 5 years after diagnosis of Type 2 diabetes is associated with an unfavourable metabolic risk profile.     

Permanent neuropsychological impairment after recurrent episodes of severe hypoglycaemia in man

Summary Seventeen Type 1 (insulin-dependent) diabetic patients with a history of recurrent and severe hypoglycaemia and Type 1 diabetic patients with no severe hypoglycaemia were compared as regarded performances in tests of neuropsychological functioning. To test the hypothesis that recurrent severe hypoglycaemia gives rise to permanent cognitive impairment, the study group was selected among those patients who had met with repeated attacks over the last three years or more as identified by a questionnaire among almost 600 insulin-treated diabetic patients. The comparison group without known severe reactions were comparable to the study group with respect to type of diabetes, sex, age, age at onset, duration of diabetes, socio-economic parameters, and prevalence of neuropathy and retinopathy. The results indicate that Type 1 diabetic patients with recurrent severe hypoglycaemia scored lower than those without severe hypoglycaemia in tests of motor ability, short-term and associative memory and visuospatial tasks assessing ability in general problem-solving. Type 1 diabetic patients with severe hypoglycaemia also displayed a higher frequency of perspective reversals suggesting frontal-lobe involvement. These data can be interpreted in two ways. One interpretation implies that the cognitive impairment of Type 1 diabetic patients with severe hypoglycaemia reflects a selection factor, the other that recurrent episodes of severe hypoglycaemia result in permanent cognitive impairment.     

Peripheral blood level alterations of TIMP-1, MMP-2 and MMP-9 in patients with type 1 diabetes.

AIM: To determine the plasma levels of enzymes and inhibitors involved in extracellular matrix turnover in patients with Type 1 diabetes with normal renal function. METHODS: Plasma levels of matrix metalloproteinases 2 and 9 (MMP-2, MMP-9) and tissue inhibitor of metalloproteinase 1 (TIMP-1) were measured in 43 Type 1 diabetic subjects and age- and sex-matched controls. RESULTS: No significant difference in plasma MMP-2 between diabetic patients and controls was observed. MMP-9 was detected in the plasma of 15 diabetic patients (35%), but undetectable in all control subjects (P < 0.015). Plasma TIMP-1 concentrations were significantly elevated (P < 0.001) in diabetic patients compared to controls. There was no correlation observed between MMP-2, MMP-9 and TIMP-1 and similarly between MMP-2, MMP-9 and TIMP-1 and age, duration of diabetes, blood pressure and glycated haemoglobin (HbA1c). CONCLUSIONS: This study has demonstrated alterations in several plasma extracellular matrix modulators in the absence of significant vascular disease.     

Long-term (20 years) outcome and mortality of Type 1 diabetic patients in Soweto, South Africa.

AIMS: To assess the long-term (20 years) mortality, with causes of death, in a cohort of Type 1 diabetic patients resident in Soweto, South Africa. METHODS: A cohort of Type 1 diabetic patients attending the Diabetic Clinic of Baragwanath Hospital, Soweto were studied in 1982. They were followed over the subsequent 20 years, the final investigation being in 2002. Numbers dying during the period were recorded, as well as year of death and cause. The complication status of survivors was also assessed. RESULTS: Of the original cohort of 88 Type 1 patients, 21 died during the follow-up period. There were 39 lost to follow-up, giving a crude 20 years' mortality of 43%. Kaplan-Meier analysis showed mortality hazard of 33%. Of those dying, most (9/21) were as a result of renal failure. Other causes were hypoglycaemia (6), ketoacidosis (2), infection (2) and undetermined (2). Of the survivors, comparing data at 0 and 20 years' follow-up, there was a significant increase in rates of retinopathy (P<0.02) and hypertension (P<0.005), but not of other complications. CONCLUSIONS: This is the first long-term outcome study of Type 1 diabetes in sub-Saharan Africa. Although the mortality was substantial, it is similar to equivalent studies of United States (US) Afro-Americans with Type 1 diabetes. The major cause of death was renal failure related to diabetic nephropathy, and reflects lack of adequate facilities for renal replacement therapy. Despite the deprivation, poverty, political upheaval and recent AIDS epidemic in Soweto, Type 1 diabetes carries a reasonable long-term prognosis, and survivors are generally free of debilitating complications.     

Shared genetic susceptibility of Type 1 (insulin-dependent) and Type 2 (non-insulin-dependent) diabetes mellitus: contributions of HLA and haptoglobin

Summary Epidemiologic data suggest that having a parent with Type 2 (non-insulin-dependent) diabetes mellitus increases the risk for Type 1 (insulin-dependent) diabetes in siblings of a Type 1 diabetes proband. This increase in risk is consistent with a shared genetic susceptibility between Type 1 diabetes and Type 2 diabetes. We contrast genetic risk factors in three sets of families, consisting of (1) a single Type 1 diabetic child (proband) and non-diabetic parents, (2) multiple Type 1 diabetic siblings and non-diabetic parents, and (3) at least one Type 1 diabetic child and at least one Type 2 diabetic parent. Previous studies have demonstrated that HLA region genes, which elevate the risk in Type 1 diabetes, have no significant effect with respect to the risk for developing Type 2 diabetes. An earlier report cited a contribution by the haptoglobin locus to genetic susceptibility for Type 2 diabetes. We provide evidence that a high risk HLA antigen (HLA-DR3) is decreased to a greater extent in Type 1 patients with a Type 2 parent than in Type 1 patients in which the parents are not diabetic. The role of HLA-DR4 is maintained in these families, with an unexpectedly significant increased rate of transmission of the HLA-DR4 allele from Type 2 parent to Type 1 offspring. The role of haptoglobin in these families does not appear to be important, either with respect to association with diabetes or with respect to linkage with a secondary susceptibility locus. These results indicate that families with a Type 2 parent and Type 1 child, heavily determined by HLA-DR4 linked factors, may represent a homogeneous subset of diabetes susceptibility.     

Plasma N-terminal pro-brain natriuretic peptide in Type 1 diabetic patients with and without diabetic nephropathy.

AIMS: Plasma N-terminal pro-brain natriuretic peptide (NT proBNP) is produced and released from cardiac ventricles; it is elevated in patients with heart failure, hypertension and chronic renal failure. This study aimed to examine the plasma levels of NT proBNP and their relationship in Type 1 diabetic patients with and without diabetic nephropathy. METHODS: We developed a non-competitive immunoluminometric assay with in-house antibodies to the N- and C-terminal domains of NT proBNP. We compared NT proBNP levels between 47 normoalbuminuric patients (group 1), 12 microalbuminuric patients (group 2) and 12 patients with macroalbuminuria (group 3). RESULTS: There were significant differences in 24-h systolic and diastolic blood pressure, diabetes duration, serum creatinine, LDL-cholesterol and HbA1c between the three groups; other parameters did not differ significantly. NT proBNP (median and range) levels were 5 (0.75-68), 22 (0.75-82) and 23 (0.75-374) fmol/ml for groups 1-3, respectively. Log-transformed data of NT proBNP were used to compare all three groups (P=0.016). The Pearson correlation between NT proBNP and albuminuria (R=0.27; P=0.02) was positive; HbA1c (R=0.25; P=0.03) and age (R=0.33; P=0.005) correlated significantly as well. On the basis of multiple regression analysis, the adjusted difference remained significant between the three groups. CONCLUSIONS: This is the first demonstration that NT proBNP levels are significantly higher in Type 1 diabetic patients with albuminuria. This may be caused by a down-regulation of A-type guanylate cyclase-coupled natriuretic peptide receptors in renal tubules or by elevated NT proBNP levels leading to higher glomerular hydraulic pressure or higher capillary permeability and possibly increased albumin excretion. Further studies are required to investigate the potential role of NT proBNP in patients with diabetic nephropathy and such other co-morbidities as cardiovascular disease.     

Low acute insulin response to intravenous glucose. A sensitive but non-specific marker of early stages of Type 1 (insulin-dependent) diabetes

Summary Preventive treatment of Type 1 (insulin-dependent) diabetes presupposes early and accurate diagnosis of prediabetic states. The low acute insulin response to intravenous glucose has been proposed as a marker of both pre-Type 1 and pre-Type 2 (non-insulin-dependent) diabetes. In order to test the reliability of this marker for clinical detection of Type 1 diabetes we looked for this anomaly in 150 first degree relatives of Type 1 diabetic patients, 31 relatives of Type 2 diabetic patients and 39 young non-obese diabetic patients with mild or transient hyperglycaemia. The low acute insulin response was defined by a peak insulin value (sum of plasma insulin at 2 and 5 min after glucose load, 0.3 g/kg body weight) below 50 U/ml. It was observed in 12% of the relatives of Type 1 diabetic patients (2 of them became diabetic) and in 13% of the relatives of Type 2 diabetic patients. Reproducibility of the peak insulin value in 2 subsequent tests (r=0.749) was inadequate to interpret small variations in one individual. In the population of 39 diabetic patients, 10 subsequently developed typical Type 1 diabetes, 9 were low insulin responders. In the 29 patients who are still non-insulin-dependent 3 years later, the anomaly was found in the 3 islet cell antibody-positive subjects and 11 out of 26 patients with no detectable antibodies. In conclusion, low acute insulin response to glucose is a sensitive but non-specific marker of early stages of Type 1 diabetes as this anomaly is shared by both Type 2 and Type 1 diabetes.     

Frequency and Symptoms of Hypoglycaemia Experienced by Patients with Type 2 Diabetes Treated with Insulin

This study ascertained the prevalence of severe hypoglycaemia and loss of awareness of hypoglycaemia in patients with Type 2 diabetes treated with insulin. One hundred and four sequentially selected Type 2 diabetic patients were compared with 104 patients with Type 1 diabetes who were matched for duration of insulin therapy. The patients were interviewed using a standardized questionnaire. During treatment with insulin, 18 Type 2 patients had experienced fewer than two episodes of hypoglycaemia, while 86 had experienced two or more episodes; 80 (93%) reported normal awareness, six (7%) reported partial awareness, and none had absent awareness of hypoglycaemia. All 86 Type 1 diabetic patients matched to the 86 Type 2 patients had experienced multiple episodes of hypoglycaemia; 71 (83%) had normal awareness, 14 (16%) had partial awareness and one patient (1%) reported absent awareness of hypoglycaemia. The Type 1 patients who had altered awareness of hypoglycaemia had longer duration of diabetes and insulin therapy (normal awareness: 5 (1–17) years (median (range)) vs partial awareness: 9 (3–18) years, p < 0.01). Similarly, Type 2 patients with altered awareness had longer duration of diabetes (normal awareness: 11 (2–25) years vs partial awareness: 19 (8–24) years, p < 0.02) and had received insulin for longer (normal awareness: 3 (1–18) years vs partial awareness: 12 (6–17) years, p < 0.001). Severe hypoglycaemia in the preceding year had occurred with a similar prevalence in the Type 2 patients (9 (10%)) and Type 1 patients (14 (16%)), but was more frequent in those patients with partial awareness both in Type 1 patients (normal awareness: 3 (4%) vs partial awareness: 11 (73%), p < 0.001) and in Type 2 patients (normal awareness: 3 (4%) vs partial awareness: 6 (100%), p < 0.001). Although the symptoms of hypoglycaemia were idiosyncratic in individual Type 2 patients, the range and prevalence of specific symptoms were similar to those described by the patients with Type 1 diabetes.