Hans J. Arnqvist

Declining incidence of nephropathy in insulin-dependent diabetes mellitus.

BACKGROUND The high relative mortality among patients with insulin-dependent diabetes mellitus results mainly from diabetic nephropathy. The cumulative incidence of nephropathy of 25 to 30 percent among patients who had had diabetes for 25 years remained stable from 1950 to the early 1980s. In a population study, we assessed recent trends in the incidence of diabetic nephropathy. METHODS We studied all 213 patients in whom insulin-dependent diabetes mellitus was diagnosed before the age of 15 years between 1961 and 1980 in a district in southeastern Sweden. Ninety-two percent of the patients were followed from the onset of diabetes to 1991 or to death. Patients with persistent albuminuria (positive Albustix test) were considered to have diabetic nephropathy. Glycosylated hemoglobin was measured periodically in all patients, beginning in 1980. RESULTS The cumulative incidence of persistent albuminuria after 25 years of diabetes decreased from 30.0 percent among the patients in whom diabetes developed in the period 1961 to 1965 to 8.9 percent among those in whom it developed from 1966 to 1970 (P = 0.01). After 20 years of diabetes, the cumulative incidence decreased from 28.0 percent among the patients in whom diabetes developed from 1961 to 1965 to 5.8 percent among those in whom it developed from 1971 to 1975 (P = 0.01). Persistent albuminuria has not yet developed in any patient in whom diabetes was diagnosed in the period 1976 to 1980. The average glycosylated hemoglobin value decreased from 7.4 percent in the period 1980 to 1985 to 7.0 percent from 1986 to 1991 (P < 0.001). The mean glycosylated hemoglobin value was higher in the patients with persistent albuminuria than the patients with no albuminuria (8.1 percent vs. 7.1 percent, P < 0.001). CONCLUSIONS During the past decade the cumulative incidence of diabetic nephropathy, as manifested by persistent albuminuria, among patients who have had diabetes for 25 years has decreased substantially, probably as a result of improved glycemic control.

Declining incidence of severe retinopathy and persisting decrease of nephropathy in an unselected population of Type 1 diabetes— the Linköping Diabetes Complications Study

Aims/hypothesisIn a previous study conducted over the last decades we found a decreased incidence of nephropathy but unchanged incidence of severe retinopathy among patients with Type 1 diabetes diagnosed in childhood and with 20 years duration of diabetes. The aim of our current study was to investigate the incidence 5 to10 years later in the same population.MethodsWe studied all 269 patients in whom Type 1 diabetes was diagnosed in childhood between 1961 and 1985 in a district in southeastern Sweden. Ninety-one percent were monitored for retinopathy until at least 1997 and 95% were monitored for nephropathy. Severe retinopathy was defined as laser-treated retinopathy and nephropathy as persistent proteinuria. Survival analysis was used and the patients divided into five cohorts according to the time of onset of diabetes.ResultsThe cumulative proportion of severe retinopathy had declined (p=0.006). After 25 years it was 47% (95% CI 34–61), 28% (15–40) and 24% (12–36) in the cohorts 1961 to 1965, 1966 to 1970 and 1971 to 1975 respectively. After 30 years it was 53% (40–66) and 44% (28–59) in the oldest cohorts. The cumulative proportion of nephropathy after 25 years duration was 30% (18–42), 8% (1–16) and 13% (4–23) in the cohorts 1961 to 1965, 1966 to 1970 and 1971 to 1975 respectively. After 30 years, it was 32% (20–44) and 11% (2–20) for the oldest cohorts (p<0.0001).Conclusions/interpretationIn an unselected population with Type 1 diabetes diagnosed in childhood, modern diabetes care markedly reduced the incidence of severe retinopathy and nephropathy.

A comparison a amitriptyline and maprotiline in the treatment of painful polyneuropathy in diabetics and nondiabetics.

OBJECTIVE To compare amitriptyline and maprotiline in the treatment of painful polyneuropathy in diabetics and nondiabetics. DESIGN A double-blind, crossover trial of treatment with amitriptyline, maprotiline, and placebo. Treatment was given in randomized order for periods of 4 weeks. Each period was separated by a 1-week washout. The final dose was 75 mg/day for both amitriptyline and maprotiline. PATIENTS Thirty-seven patients with diabetic and nondiabetic painful polyneuropathy. OUTCOME MEASURES The treatment effects were assessed by daily ratings of pain intensity on a 10-step verbal scale (0 = no pain and 10 = worst thinkable pain) and at the end of each treatment period by a global rating of the analgesic effect on a 5-step verbal scale (pain relief scale). For the assessment of depression, the Comprehensive Psychopathological Rating Scale (CPRS) was used. RESULTS Using the global assessment of pain relief at the end of each treatment period, 22 of 33 patients reported reduced pain on amitriptyline treatment compared with 14 of 33 patients on maprotiline treatment and 8 patients on placebo treatment (p < .0001 and p < .05 for amitriptyline and maprotiline, respectively, against placebo). Amitriptyline was slightly better than maprotiline (p < .05) [tested by repeated measures analysis of variance (ANOVA)]. The order in which treatments occurred and the diagnosis of diabetes or nondiabetes did not have any significant effect on the global rating of pain relief. The mean values of the daily ratings of pain intensity showed that pain was more severe in the evenings than in the mornings and that diabetic patients reported worse pain than nondiabetics at baseline. The mean values of pain reduction as assessed with the 10-step verbal scale during the 4th week of treatment showed that amitriptyline and maprotiline were significantly better than placebo in relieving the pain (p < .0001 and p < .01, respectively, post hoc test according to Scheffé). However, there was no significant difference between the pain reduction of amitriptyline compared with maprotiline when assessing pain reduction with the 10-step verbal scale during the 4th treatment week. Nor was there a significant difference between diabetics and nondiabetics with regard to the effect of the drugs. The clinical effect was not significantly correlated to plasma concentration of either amitriptyline and its active metabolite nortriptyline or maprotiline in the global or daily assessments. The effect of treatment was not correlated to any particular pain quality nor to the intensity of pain. Depression was noted in three patients who completed the medication trial, but the effect of treatment of pain and depression did not clearly correlate. The adverse side effects of amitriptyline and maprotiline were common, and in 5 patients the medication had to be discontinued because of severe side effects. CONCLUSION From the present results and the literature, it is concluded that tricyclic antidepressants with a pharmacologic profile similar to amitriptyline are the most effective drugs in the treatment of polyneuropathy pain in both diabetic and nondiabetic patients.

Binding and biological effects of insulin, insulin analogues and insulin-like growth factors in rat aortic smooth muscle cells. Comparison of maximal growth promoting activities

SummaryBinding and growth promoting effects of insulin, insulin analogues modified in the B chain, proinsulin, insulin-like growth factor-I and -II were studied in cultured rat aortic smooth muscle cells. Specific binding of125I-insulin was 0.9±0.2% of total 125I-insulin added, and the IC50-value was estimated to 8.9 pmol/1. The insulin analogue B10 Asp tended to be more potent than insulin in displacing 125I-insulin, B28 Asp was equipotent, B9 Asp/B27 Glu was approximately 100 times less potent and insulin-like growth factor-I more than 1000 times less potent than insulin. Specific binding of 125I-insulin-like growth factor-I after 4 h incubation at 10 °C was five times higher than the specific binding of insulin (4.4±0.4% of total 125I-insulin-like growth factor-I added), and the IC50-value was 0.3 nmol/l. Insulin was approximately 500 times less potent than insulin-like growth factor-I in displacing 125I-insulin-like growth factor-I. The insulin analogue B10 Asp was slightly more potent and analogue B28 Asp was equipotent with insulin. Analogue B9 Asp/B27 Glu was ten times less potent and proinsulin was more than ten times less potent than insulin. The order of potency was similar for 3H-thymidine incorporation into DNA: insulin-like growth factor-I > B10 Asp > insulin-like growth factor-II > insulin > B28 Asp > B9 Asp/B27 Glu > proinsulin. The maximal effect of insulin-like growth factor-I on 3H-thymidine incorporation was 71±16% higher than the maximal effect of insulin. The maximal effect of insulin-like growth factor-II was at least as high as the effect of insulin-like growth factor-I. Furthermore, the maximal effect of B10 Asp was 62±10% higher than the maximal effect of insulin. Insulin-like growth factor-I and B10 Asp tended to increase cell number more than insulin. In conclusion, this study shows that insulin analogues interact with different potencies with receptors for insulin and insulin-like growth factor-I in vascular smooth muscle cells and that insulin-like growth factors and the insulin analogue B10 Asp have more pronounced growth effects than insulin. Substitution of the amino acid Asp for His at position B10 in insulin makes the molecule more similar to insulin-like growth factor-I, chemically and probably also biologically.

Hypoglycaemia and Cardiac Arrhythmias in Patients with Type 2 Diabetes Mellitus

Improved blood glucose control by insulin treatment in patients with Type 2 (non‐insulin dependent) diabetes mellitus increases the risk for hypoglycaemic episodes. Our objective was to investigate if hypoglycaemia causes electrocardiographic changes and cardiac arrhythmias in patients with Type 2 diabetes. Six insulin‐treated patients with Type 2 diabetes and no known cardiac disease took part in the study. Hypoglycaemia was induced by insulin infusion aiming at a plasma glucose ≥ 2.0 mmol I−1 or hypoglycaemic symptoms. All patients experienced hypoglycaemic symptoms. The median lowest arterial plasma glucose was 2.0 mmol I−1. Arterial plasma adrenaline concentration increased from 0.4 ± 0.1 (mean ± SE) to 6.9 ±0.3 nmol I−1 (p < 0.001) while serum potassium was lowered from 4.1 ± 0.3 mmol I−1 to 3.5 ± 0.2 mmol I−1 (p < 0.001). The heart rate increased significantly during hypoglycaemia except in one patient who developed hypoglycaemic symptoms and a severe bradyarrhythmia at a plasma glucose of 4.4 mmol I−1. One patient developed frequent ventricular ectopic beats during hypoglycaemia while four patients showed no arrhythmia. ST‐depression in ECG leads V2 and V6 was observed during hypoglycaemia in five patients (p < 0.05) and four patients developed flattening of the T‐wave.

Kidney IGF-I mRNA in initial renal hypertrophy in experimental diabetes in rats

SummaryIt has recently been demonstrated that immunoassayable kidney insulin-like growth factor I concentration increases 24–48 h after induction of diabetes, preceding the initial renal hypertrophy. To elucidate whether this increase is due to increased local production we studied rat kidney insulin-like growth factor I gene expression during the first four days after induction of streptozotocin diabetes. Eighteen hours after injection with streptozotocin the diabetic animals were divided into two groups, one of which was treated with insulin, and daily for four days animals from each group were taken out for investigation. After four days the wet kidney weight had increased from baseline by 20% (from 687±23 to 827±6mg (mean±SEM), p < 0.01) in the untreated diabetic group, while no significant increase occurred in the insulin-treated group (687±23 vs 732±21 mg, NS). Kidney insulin-like growth factor I increased rapidly from baseline, the rise amounting to 52% after 48 h (from 271±11 to 411±32 ng/g, p < 0.01) with a decline to control level on day four in the untreated diabetic group. Kidney insulin-like growth factor I remained unchanged in the insulin-treated diabetic group. Insulin-like growth factor I mRNA was measured by solution-hybridization assay. No differences were found in kidney insulin-like growth factor I mRNA between the two diabetic groups over the study period, while in liver, insulin-like growth factor I mRNA tended to be lower on day four in diabetic rats when compared to insulin-treated rats (p=0.07). These results show that the increase in kidney insulin-like growth factor I during initial renal hypertrophy in experimental diabetes is not associated with an elevated level of kidney insulin-like growth factor I mRNA and suggest that other, possibly translational, mechanisms are responsible for insulin-like growth factor accumulation in the kidney.

Serum leptin concentrations in a normal population and in GH deficiency: Negative correlation with testosterone in men and effects of GH treatment

To study relationships between leptin and factors regulating body composition as well as metabolic risk factors. Furthermore, to study the effects of GH on leptin.

In vivo proliferation of rat vascular smooth muscle in relation to diabetes mellitus insulin-like growth factor I and insulin

SummaryThe roles of diabetes mellitus, insulin-like growth factor I and insulin in vascular smooth muscle proliferation in vivo were studied. Proliferation was induced by endothelial injury (balloon catheterization) of rat aorta, and was measured as 3H-thymidine incorporation into DNA. Levels of insulin-like growth factor I mRNA and insulin-like growth factor I receptor mRNA were measured with a solution hybridization assay. The increase in DNA synthesis was most pronounced 2 days after injury in both normal and diabetic rats and declined thereafter, but DNA synthesis in aortas from diabetic rats was lower throughout the time period studied. Levels of insulin-like growth factor I mRNA and the receptor mRNA were both increased in balloon catheterized aortas, and time-course studies showed an increase in receptor mRNA prior to the increase in insulin-like growth factor I mRNA. Diabetic rats were treated with equimolar concentrations of insulin (35 nmol/day) or insulin-like growth factor I (31 nmol/day) for 5 days. Insulin-like growth factor I increased DNA synthesis in injured aortas 2 days after injury without improving blood glucose, whereas the effect of insulin was associated with a decrease in blood glucose levels. In conclusion, vascular smooth muscle proliferation is impaired by diabetes and stimulated by insulin treatment. Insulin-like growth factor I infusion stimulates vascular smooth muscle proliferation without affecting bloo glucose, and gene expressions of insulin-like growth factor I and its receptor are increased in proliferating vascular smooth muscle, indicating that insulin-like growth factor I is involved in vascular smooth muscle proliferation in vivo.

Male predominance of type 1 (insulin-dependent) diabetes mellitus in young adults : results from a 5-year prospective nationwide study of the 15-34 year age group in Sweden

SummaryThe incidence of diabetes mellitus in Sweden in the 15–34 year age group was prospectively studied on a nationwide basis, beginning 1 January 1983. A total of 1,214 male and 720 female cases of newly-diagnosed (excluding gestational) diabetes were reported over a 5-year period. This corresponds to an incidence of 20.5 per 100,000/year in male subjects and 12.7 per 100,000/year in female subjects. Most cases were classified as Type 1 (insulin-dependent) diabetes, with an incidence of 15.9 in males and 8.6 in females. The incidence of Type 1 diabetes decreased gradually with age, while the incidence of Type 2 (non-insulin-dependent) diabetes increased. A male predominance was found in all age groups, with a male-to-female ratio of 1.8∶1 for Type 1 diabetes and 1.3∶1 for Type 2 diabetes. Maximum blood glucose concentration at diagnosis was significantly higher in males than in females in both Type 1 and Type 2 diabetic subjects. In contrast, the percent desirable weight was significantly higher in females, both in Type 1 and Type 2 diabetic subjects. The difference in diabetes incidence therefore cannot be attributed to any methodological error. The present finding of a marked male predominance after puberty in Type 1 diabetes in an ethnically quite homogeneous population supports the hypothesis that environmental risk factors and life-style are important for the development of the disease.

Good glycemic control remains crucial in prevention of late diabetic complications – the Linköping Diabetes Complications Study

Background:  Several intervention studies have convincingly demonstrated the importance of good glycemic control to avoid long‐term diabetic complications, but the importance of other risk factors remains controversial. We previously reported a markedly reduced incidence of severe retinopathy and nephropathy during the past decades in an unselected population of type 1 diabetes mellitus diagnosed in childhood. The aim of the present study was to analyze possible risk factors, which could explain the improved prognosis.