Severe hypoglycaemia during treatment with sulphonylureas in patients with type 2 diabetes in the Capital Region of Denmark.

AIMS: Sulphonylureas (SU) are currently recommended as a well-established second line treatment in guidelines for type 2 diabetes (T2DM). In the Capital Region of Denmark 16,865 patients were given SU as part of their treatment of T2DM in 2010-2011. To what extent SU are associated with hospitalizations due to severe hypoglycaemic episodes, defined as episodes with a need for external assistance, was investigated. The prevalence and characteristics of these patients and potential risk factors were studied. METHODS: ICD-10 diagnosis codes were used to identify patients hospitalized due to hypoglycaemia and T2DM for a period of 2 years (2010-2011). Inclusion criteria were T2DM, hospitalization due to hypoglycaemia and treatment with SU as monotherapy or in combination with other glucose-lowering drugs except insulin treatment. RESULTS: We identified 161 patients fulfilling the inclusion criteria. Their mean age was 76 (53-97) years and 54% were males. Sixty percent of the patients had diabetic complications, including 19% with diabetic nephropathy. The major reason for severe hypoglycaemia was an unchanged dose of SU despite of a significant decline in food intake (45%). In 22% of the patients more than one reason was listed, most commonly a concomitant infection associated with decreased food intake and unchanged dose of SU. CONCLUSION: The incidence of hospital admission-requiring severe hypoglycaemia in patients treated with SU was 0.48 episodes per 100 patient-years of SU-treated patients. It was mainly older patients with diminished food intake, excessive alcohol use or other medications, concomitant infection, and with diabetic complications.

Heat-washout - an objective method for diagnosing neuropathy and atherosclerosis in diabetic patients.

BACKGROUND: The heat-washout method is an objective method that measures cutaneous blood flow rate (BFR) in ml (100 g. min)(-1), previously found useful for measuring toe BFR in non-diabetic patients with claudication. AIM: The method is used for evaluating the presence of a veno-arteriolar reflex (VAR) in the forefoot and signs of atherosclerosis in the first toe in type 2 diabetics. METHODS: Nine type 2 diabetics for +10 years, peripheral neuropathy, median age 62, and 9 healthy subjects without diabetes, median age 52 were examined for the presence of a VAR in the forefoot. A VAR was present when BFR decreased 25% or more with the foot 50 cm below heart level. Examinations for atherosclerosis were made in the pulp of the first toe. An increase in BFR of 50% or more with the foot 50 cm below heart level indicated the presence of atherosclerosis. RESULTS: The VAR was significantly attenuated in type 2 diabetics with neuropathy compared to controls, (P<0·01). Only one patient with known neuropathy and diabetes showed a reflex compared to eight out of nine controls (P<0·01). The VAR was correlated to the vibration perception threshold measured with biothesiometry (r = -0·661, P = 0·0003). Two patients with type 2 diabetes and neuropathy without clinical sign of peripheral artery disease (PAD) had an abnormal response similar to that seen in subjects with intermittent claudication. CONCLUSION: The heat-washout method seems useful as and objective method for evaluating as well the presence of a VAR as atherosclerosis in type 2 diabetics.

Musculoskeletal pain in patients with type 2 diabetes.

AIMS: The aims were to investigate the prevalence of musculoskeletal pain in patients with type 2 diabetes and demonstrate possible associated factors. METHODS: Nine hundred fifty-one patients completed a validated questionnaire used in The Danish Health and Morbidity Survey and results were compared to data for 2923 matched subjects from the Danish population. Musculoskeletal pain was self-reported Pain in the shoulder and neck; Low-back pain; and Pain in the arm, hand, knee and/or hip. RESULTS: Compared to the age, gender and region matched controls patients reported musculoskeletal pain 1.7-2.1 times as frequent (p<0.001). Pain was more frequently reported in women (p<0.001). Low-back pain and Pain in the arm, hand, knee and/or hip was associated with body mass index (p<0.005). Low-back pain was associated with a sedentary life style, impaired quality of life and reduced physical function (p<0.05). CONCLUSIONS: The prevalence of musculoskeletal pain was seriously increased in patients with type 2 diabetes. It was associated with body mass index, reduced quality of life, low physical function and the ability to be physical active. Focus on musculoskeletal pain in clinical practice is therefore of major importance in lifestyle interventions in type 2 diabetes.

Study rationale and design of the CIMT trial: the Copenhagen Insulin and Metformin Therapy trial.

BACKGROUND: Patients with type 2 diabetes (T2DM) have an increased mortality rate primarily because of macrovascular disease. Where T2DM patients cannot be managed sufficiently through diet, exercise and peroral antidiabetic drugs, that is when haemoglobin A1c (HbA1c) is above 7.0%, it is yet unknown whether a combination of metformin and insulin analogues is superior to insulin analogues alone. Nor is it known which insulin analogue regimen is the optimal. OBJECTIVE: The primary objective of this trial is to evaluate the effect of an 18-month treatment with metformin vs. placebo in combination with one of three insulin analogue regimens, the primary outcome measure being carotid intima-media thickness (CIMT) in T2DM patients. DESIGN: A randomized, stratified, multicentre trial having a 2 x 3 factorial design. The metformin part is double masked and placebo controlled. The insulin treatment is open. The intervention period is 18 months. PATIENT POPULATION: Nine hundred and fifty patients with T2DM and HbA1c > or = 7.5% on treatment with oral hypoglycaemic agents or on insulin treatment and deemed able, by the investigator, to manage once-daily insulin therapy with a long-acting insulin analogue. RANDOMIZATION: Central randomization stratified for age (above 65 years), previous insulin treatment and treatment centre. INTERVENTIONS: Metformin 1 g x two times daily vs. placebo (approximately 475 patients vs. 475 patients) in combination with insulin detemir before bedtime (approximately 315 patients) or biphasic insulin aspart 30 before dinner with the possibility to increase to two or three injections daily (approximately 315 patients) or insulin aspart before the main meals (three times daily) and insulin detemir before bedtime (approximately 315 patients). Intervention follows a treat-to-target principle in all six arms aiming for an HbA1c < or = 7.0%. OUTCOME MEASURES: Primary outcome measure is the change in CIMT from baseline to 18 months. Secondary outcome measures comprises the composite outcome of death, acute myocardial infarction, stroke or amputation assessed by an adjudication committee blinded to intervention, other cardiovascular clinical outcomes, average postprandial glucose increment from 0 to 18 months, hypoglycaemia and any inadvertent medical episodes. In addition, change in plaque formation in the carotids, HbA1c, cardiovascular biomarkers, body composition, progression of microvascular complications and quality of life will be assessed as tertiary outcome measures. TIME SCHEDULE: Patient enrolment started May 2008. Follow-up is expected to finish in March 2011. CONCLUSION: CIMT is designed to provide evidence as to whether metformin is advantageous even during insulin treatment and to provide evidence regarding which insulin analogue regimen is most advantageous with regard to cardiovascular disease.

[Treatment of diabetic patients with ischaemic heart disease]. / Behandling af diabetespatienter med iskaemisk hjertesygdom.

Patients with diabetes constitute a large group among patients with ischaemic heart disease, and their risk of repeated cardiovascular events is large. Due to this, there is increasing focus on intervention against the increased risk of cardiac morbidity and mortality in patients with diabetes. Subgroup analyses of patients with diabetes from studies on patients with ischaemic heart disease show that intervention with thrombolysis, aspirin, beta blockers, ACE inhibitors and statins have similar relative benefit among patients with diabetes, but because of the greater risk in these patients, the absolute benefit is increased. In spite of this, intervention is less common among patients with diabetes, a fact that should be corrected. Direct intervention targeted at the metabolic disorder in ischaemic heart disease has only been investigated in the DIGAMI study, where glucose/insulin treatment followed by long term treatment with insulin was compared to conventional treatment. The mortality was lower in the insulin treated group after one to four years of follow up, a promising result which is currently being investigated in the DIGAMI-2 study.

Serum levels of advanced glycation end products are associated with left ventricular diastolic function in patients with type 1 diabetes.

OBJECTIVE: Impairment of left ventricular diastolic function, possibly caused by increased collagen cross-linking of the cardiac muscle, is common in patients with type 1 diabetes even without coronary artery disease. Advanced glycation end products (AGEs) cross-link tissue collagen and are found within myocardial fibers. The aim of this study was to examine for a possible association between circulating AGEs and left ventricular cardiac function. RESEARCH DESIGN AND METHODS: Left ventricular diastolic and systolic function were assessed by M-mode and Doppler echocardiography in 52 patients with type 1 diabetes, age 40 +/- 13 (mean +/- SD) years, diabetes duration 17 +/- 13 years, and HbA1c 8.3 +/- 1.1%. Serum levels of AGEs and N epsilon-(carboxymethyl)lysine (CML) were measured by newly developed competitive immunoassays. RESULTS: A positive correlation was found between serum levels of AGEs and isovolumetric relaxation time (IVRT), r = 0.46 (P < 0.0008), and left ventricular diameter during diastole, r = 0.37 (P < 0.008). The systolic parameters did not correlate with serum levels of AGEs. Stepwise regression analysis showed that 21% of the IVRT variation could be explained by serum levels of AGEs (F = 11.4, P < 0.002), whereas serum levels of CML, HbA1c, albumin excretion rate, diabetes duration, and mean arterial blood pressure were of no importance. AGE levels were significantly increased in men compared with women (P < 0.03) and present or former smokers (P < 0.04). CONCLUSIONS: Increased serum levels of AGEs, unlike serum levels of CML, are associated with heart stiffness in patients with type 1 diabetes, possibly mediated by the cross-linking properties of AGEs.

The effect of metformin on blood pressure and metabolism in nondiabetic hypertensive patients.

OBJECTIVES: To study the effect of metformin on blood pressure and metabolism in nondiabetic hypertensives. DESIGN: A six-week single-blind placebo wash-out, followed by a double-blind placebo-controlled parallel group design with skew randomization (2:2:1) to metformin 850 mg b.i.d. (n = 10), metformin 500 mg b.i.d. (n = 10), or placebo b.i.d. (n = 5) for 12 weeks. Office blood pressure (oBP), ambulatory blood pressure (aBP), lipoproteins, and oral glucose tolerance (OGTT) were measured/performed before and during treatment. SUBJECTS: Sixteen male and nine female nondiabetic (OGTT) patients (median age 57 (39-74) years) with verified hypertension (White-coat excluded) for 4 (0-20) years. RESULTS: The possible effect of metformin treatment and dosage was tested with a two-factor analysis of variance. Treatment induced a significant decline in diastolic oBP, P < 0.05. This decline was, however, not significantly different comparing metformin and placebo. Systolic oBP, diastolic aBP, and systolic aBP showed no significant change by treatment. The decline in diastolic oBP was 5 mmHg in the pooled group of metformin-treated patients, P < 0.005. Different gender and the presence of obesity had no impact on the decline in diastolic oBP within this group. Changes in fasting C-peptide and fasting insulin during treatment were unrelated to blood pressure changes. High fasting insulin (> 60 pmol L[-1]) or high fasting C-peptide (> 1000 pmol L[-1]) at baseline did not favour an effect of metformin on diastolic oBP. Glucose metabolism and lipoproteins were unchanged in all groups. CONCLUSIONS: Although metformin treatment induced a decline in diastolic office blood pressure in nondiabetic hypertensives, the decline was not different from that during placebo treatment. Metformin had no significant effect on ambulatory blood pressure. Thus, metformin has, if any, only a minor clinically insignificant effect on blood pressure in nondiabetic hypertensives. The study does not support the hypothesis that circulating insulin is a major regulator of blood pressure in hypertension.

Proinsulin immunoreactivity in recent-onset IDDM: the significance of insulin antibodies and insulin autoantibodies.

OBJECTIVE: To study the natural history of fasting proinsulin immunoreactivity (PIM) during the first 30 months of IDDM and its relationship to fasting C-peptide and insulin antibodies. RESEARCH DESIGN AND METHODS: An incidence cohort of 204 consecutive newly diagnosed IDDM patients were followed prospectively, having blood drawn for measurements at diagnosis and at 1, 3, 6, 9, 12, 18, 24, and 30 months. A sensitive enzyme-linked immunosorbent assay was used for the determination of PIM. RESULTS: All patients had detectable fasting PIM in plasma at diagnosis, with a median value and interquartile range of 3.5 pmol/l (2.2-6.2). The median PIM level increased during the first months of IDDM to reach a peak at 9-12 months (9.9-10.3 pmol/l). PIM then declined gradually to 5.6 pmol/l (1.9-13.5) at 30 months without reaching baseline. PIM at each time point was widely scattered in a skewed log-normal distribution without signs of bimodality. After the onset of insulin treatment, median insulin antibody level increased and declined in a similar pattern. Both PIM and antibody level were significantly higher in children and adolescents compared with adults. However, stepwise multiple regression analysis showed that age was only of minor importance for the PIM variation during the study period. Insulin antibody level and fasting C-peptide were the major determinants at 3-30 months, accounting for approximately 40% of the variation (R2). Blood glucose was of minor importance, and insulin dose, HbA1c, and BMI were of no importance. The correlation between fasting PIM and fasting C-peptide improved (R2 doubled) if the insulin antibody level was accounted for. Further, the slope of the correlation curve between PIM and C-peptide increased threefold when antibody binding was > 4%. At diagnosis, insulin autoantibodies could be detected in 19% of the patients. Their presence predicted higher proinsulin at 1-3 months, a higher insulin dose the 1st year, and higher levels of insulin antibodies later in the study. CONCLUSIONS: Circulating insulin antibodies may affect the level of PIM in IDDM, probably by adding a pool of IgG-bound PIM thereby increasing half-life and plasma concentration. This may explain why C-peptide and PIM levels do not change in concert during the 1st years of IDDM. Unlike C-peptide, PIM can not therefore quantitate beta-cell secretion unless the presence of insulin antibodies is ruled out.

Creatinine height index and lean body mass in adult patients with insulin-dependent diabetes mellitus followed for 7 years from onset.

The 24-hour urinary creatinine excretion value can be used as an index of protein nutrition; the creatinine height index and lean body mass can be estimated from this value. On the basis of longitudinally measured 24-hour urinary creatinine excretions during the initial 7 years of type 1 diabetes in an incidence cohort of 147 adult patients, we studied creatinine height index and lean body mass and possible relationships to sequential measurements of glycated hemoglobin (HbA1c). The patients were divided into four groups according to their glycemic control during these 7 years: I, HbA1c < 7.4% (n = 37); II, HbA1c 7.4% to 8.2% (n = 37); III, HbA1c 8.3% to 8.9% (n = 38); IV, HbA1c > 8.9% (n = 35). One year after the onset of diabetes, height indices were as follows (% of normal values, median and quartiles): I, 104% (90 to 116); II, 101% (78 to 105); III, 121% (92 to 128); IV, 87% (78 to 109) ([IV] < [I to III]; p < .05). During the following 6 years no significant differences in height index were observed among the four groups of patients at any point in time. Slightly higher calculated lean body mass values were found in the most well-controlled patients, but otherwise no differences were found in lean body mass. It is concluded that, apart from the first year, indices of protein nutrition remain normal during the initial 7 years of type 1 diabetes, even in patients with poor glycemic control.

Monitoring the targets of the St Vincent Declaration and the implementation of quality management in diabetes care: the DIABCARE initiative. The DIABCARE Monitoring Group of the St Vincent Declaration Steering Committee.

The St Vincent Declaration, a joint initiative on diabetes care and research of the World Health Organization (Europe) and the International Diabetes Federation (Europe), includes 5-year targets for improvement in diabetes outcomes as a central tenet. Accordingly, the establishment of state of the art monitoring and control systems is urged as a basis for the implementation of quality management. As a prerequisite for both targets, a diabetes dataset (fields and definitions) has been agreed to allow common monitoring of diabetes throughout Europe. This dataset has been further developed as the foundation stone of DiabCare, an initiative for continuous quality development in diabetes care. In a formal consensus process using the Delphi method, over 130 European diabetologists from 21 countries contributed to the development of this dataset, which includes fields covering true patient outcomes, intermediate metabolic outcomes, markers of diabetes tissue damage, risk factors, pregnancy, and life-style. The tools for documentation of the quality of health status have been developed in three formats for use in different health care settings. These tools, the DiabCare Diabetes Dataset, the DiabCare Basic Information Sheet, and the DiabCare Computer Program, are designed to allow local feedback-driven improvement in the quality of care, but are also the subject of communication protocols to compare performance between centres, regions, and countries. Whether implemented with or without the benefits of modern information technology, these initiatives can be the basis for both monitoring the targets of the St Vincent Declaration and for implementation of continuing quality development in diabetes care.

Homogeneity in pattern of decline of beta-cell function in IDDM. Prospective study of 204 consecutive cases followed for 7.4 yr.

OBJECTIVE: To study the natural history of beta-cell function from onset of IDDM to expected deterioration of insulin (C-peptide) secretion and to identify different patterns of decline, if any. RESEARCH DESIGN AND METHODS: A cohort of 204 consecutive newly diagnosed IDDM (clinical criteria) patients were followed prospectively for 7.4 yr (range 6-9 yr), measuring fasting C-peptide at onset, 1, 3, 6, 9, 12, and then every 6 mo until 106 wk (range 104-135 wk). Then, postprandial C-peptide was measured. RESULTS: Fasting C-peptide was 0.17 nM (range 0.11-0.25 nM) at onset followed by an annual increase rate of 0.16 nM/yr (range 0.06-0.48 nM/yr) to a peak of 0.28 nM (range 0.23-0.34 nM/yr) after 25 wk (range 12-39 wk). The subsequent annual decline rate of fasting C-peptide was 0.08 (0.05-0.12) and of postprandial C-peptide 0.03 nM/yr (range 0.02-0.06 nM/yr). None of these parameters showed bimodality in their distribution. However, some parameters were important. In men, fasting C-peptide at onset was lower, but the initial C-peptide increase rate was more pronounced compared to women. Furthermore, insulin-free remission was related to higher C-peptide levels throughout the study. C-peptide was higher during the 1st yr of diabetes in subjects greater than 30 yr of age at onset compared with younger diabetic patients. Stepwise multiple regression analysis showed that age, male sex, and fasting C-peptide at onset were of some predictive value for the C-peptide levels at 5 yr. However, simple group comparisons revealed no significant differences. CONCLUSIONS: No major heterogeneity exists in the pattern of decline of beta-cell function in IDDM, although small differences in pattern could be identified in both sexes, in different age-groups, and in relation to achieving insulin-free remission.

[Functional hypoglycemia. Fancy or fact?]. / Funktionel hypoglykaemi. Fup eller fakta?

Idiopathic reactive or functional hypoglycemia is not a recognised disease entity. It is defined solely on the basis of a history of hypoglycemic symptoms in everyday life, which can be relieved by food intake. However, the general opinion is that functional hypoglycemia exists, but it is not a frequent condition. The coincidence of a low blood glucose nadir and hypoglycemic symptoms in the hypoglycemic phase of the oral glucose tolerance test is not diagnostic of functional hypoglycemia. Endocrine dysfunction has never been demonstrated. The logical approach to the problem is to study blood glucose values during everyday life and at the onset of symptoms. This has been done in two controlled studies using reliable monitoring techniques. Low blood glucose concentrations during attacks could only be demonstrated in one of the studies and only in some of the subjects. Furthermore, the pattern of recorded symptoms was independent of the measured levels. Thus, these patients are probably not hypoglycemic in the true sense of the word. In a recent controlled but unblinded study, a higher blood glucose threshold for the onset of hypoglycemic symptoms was demonstrated in a group of patients with functional hypoglycemia. This, combined with a highly refined diet poor in fibre and starch, could provide symptomatic oscillations of blood glucose levels. However, much more research is needed in this field, before any conclusions are drawn.

Elevated proinsulin levels related to islet cell antibodies in first-degree relatives of IDDM patients.

OBJECTIVE: To assess whether proinsulin levels are elevated in first-degree relatives of insulin-dependent diabetes mellitus (IDDM) patients and whether there is a relationship between proinsulin levels and the occurrence of immunological markers. RESEARCH DESIGN AND METHODS: Fasting proinsulin concentrations were measured in 85 first-degree relatives (54 siblings, 20 parents, 11 children) of IDDM patients and in 90 age- and weight-matched control subjects with no family history of diabetes mellitus. RESULTS: Fasting proinsulin levels (median, 25th, and 75th percentiles) were 8 pM (range 3.2-14 pM) in first-degree relatives and 1.7 pM (range 1.7-4 pM) in control subjects (P less than 0.0001). Proinsulin was significantly elevated in siblings (7.2 pM, range 3.8-15 pM; P less than 0.0001), parents (9.8 pM, range 6.4-13 pM; P less than 0.0001), and children (6.6 pM, range 1.8-12 pM, P = 0.04) compared with control subjects but without differences between these groups. Islet cell antibody positive (ICA+) IDDM relatives had significantly higher proinsulin levels than ICA- (16 pM; range 7.2-25 vs. 6.9 pM, range 3.1-12 pM; P = 0.02). There was no difference between individuals with and without insulin autoantibodies. No difference in proinsulin levels was observed if the relatives were subdivided according to HLA-DR sharing with the diabetic proband. CONCLUSIONS: Fasting proinsulin concentrations were raised not only in siblings but also in parents and children of IDDM patients. Because proinsulin is more elevated in ICA+ than in ICA- subjects, increased proinsulin levels could reflect minor beta-cell damage due to previous immunological attack.

Glycaemic thresholds for hypoglycaemic symptoms, impairment of cognitive function, and release of counterregulatory hormones in subjects with functional hypoglycaemia.

Nine patients with food-relieved hypoglycaemic symptoms, in whom insulinoma and other organic diseases presenting with hypoglycaemia had been ruled out, and nine matched controls, participated in the study. Subjects were studied during a 5-h controlled (Biostator) insulin-induced (1-2 mU kg-1 min-1) hypoglycaemic clamp. After 1 h of euglycaemia, we aimed to lower the glucose level in arterialized venous blood in a stepwise manner at 30-min intervals to 3.5, 3.0, and 2.0 mmol l-1, and to withhold these levels for a further 30 min. At euglycaemia and at the end of the latter steps, the visual reaction time and cognitive function (digit span, letter cancellation and trail making) were tested, together with recording symptoms and signs of hypoglycaemia. Counter-regulatory hormones were measured at 20-min intervals. In the patients, clinical signs and symptoms of hypoglycaemia developed at median blood glucose levels of 2.6-2.8 and 2.8-3.1 mmol l-1, respectively. By contrast, the blood glucose levels were 0.4-0.8 mmol l-1 lower in control subjects (P less than 0.05). Similarly, the median threshold for deterioration of visual reaction time was 2.8 mmol l-1 in patients and 2.1 mmol l-1 in controls (P less than 0.01). A similar trend was observed for the results of the neuropsychological tests. Visual reaction time deteriorated in all subjects, whereas the cognitive function of some of the subjects in each group remained unchanged during hypoglycaemia. The glycaemic thresholds for release of cortisol, glucagon and growth hormone were significantly higher in patients (P less than 0.05), whereas the thresholds for catecholamine release showed no significant difference from controls. Despite the comparable glucose infusion rates required to sustain each of the hypoglycaemic levels in the two groups, the control subjects achieved lower glucose levels, suggesting that there is resistance to insulin or glucose in functional hypoglycaemia. In conclusion, the present study suggests that the existence of a higher threshold for symptoms and signs, as well as for deterioration of brain function, may explain every-day hypoglycaemic symptoms, despite normal glucose levels, in subjects with functional hypoglycaemia. However, the hypothesis should be tested further using a blinded approach, including euglycaemic control studies.

Effects of octreotide on lipoproteins and endothelial function of type 1 (insulin-dependent) diabetic patients.

Hypersecretion of growth hormone (GH) is a characteristic feature of Type 1 diabetic patients. In healthy subjects growth hormone is able to induce an increase in endothelial cell proteins such as fibrinogen and von Willebrand factor. Plasma concentrations of such proteins, which are markers of cardiovascular risk, are elevated in diabetic patients with microalbuminuria, suggesting endothelial cell dysfunction. In a randomized prospective study we therefore evaluated the possible effects of 1 year's treatment with a somatostatin analogue, octreotide, on lipoproteins and on endothelial function in Type 1 diabetes mellitus. Seven patients were allocated to treatment with a continuous subcutaneous infusion of 400 micrograms octreotide per day. Seven patients served as a control group. During treatment a decrease in plasma LDL-cholesterol (2.62 (2.17-3.11) (median (range] vs 2.00 (1.89-2.96) mmol l-1, p less than 0.05) and serum apolipoprotein A-I (1.47 (1.25-1.60) vs 1.23 (1.13-1.90) g l-1, p less than 0.05) was observed in the treated group. Furthermore a probable reduction during treatment in plasma concentrations of von Willebrand factor (1.72 (0.84-3.04) vs 1.24 (0.94-1.82) U ml-1, p = 0.08) and fibrinogen (11.3 (7.3-25.3) vs 8.1 (7.5-11.8) mumol l-1, p = 0.06) was found, and after withdrawal of treatment an increase towards the initial levels was seen. The platelet count declined (326 (301-612) vs 217 (206-400) x 10(9) l-1, p less than 0.01) during octreotide treatment and remained depressed 2 months after withdrawal.

Effect of one year continuous subcutaneous infusion of a somatostatin analogue, octreotide, on early retinopathy, metabolic control and thyroid function in Type I (insulin-dependent) diabetes mellitus.

Growth hormone is assumed to be involved in the development of diabetic retinopathy. In a randomized study we evaluated the possible effects of one year treatment with a somatostatin (SRIH) analogue, octreotide, on early retinopathy and on metabolism in Type I (insulin-dependent) diabetes mellitus. Eleven patients were allocated to treatment with a continuous sc infusion of 400 micrograms octreotide per day and 9 served as controls. Only 7 patients from each group completed the study. Three octreotide-treated patients left the study owing to severe diarrhea. The subjects were evaluated at entry, after 2, 6 and 12 months treatment, and 2 months after withdrawal. Octreotide induced a decrease in GH secretion, expressed as the area under the 24 h serum GH profiles (p less than 0.05), and of the serum levels of IGF-I (p less than 0.05). The entire decline in GH levels occurred during the daytime, whereas the nocturnal levels were unaffected. Retinopathy, as assessed by determination of the blood retina barrier permeability, by colour fundus photography, and flurescein angiography was unchanged in both groups. Apart from a decline in insulin requirements, octreotide had no major effect on glycemic control, but induced a mild transient pituitary hypothyroidism, not clinically relevant. We conclude that treatment with octreotide for one year has modest effects on GH, IGF-I, and glucose metabolism, but has no significant effect on early retinopathy in Type I (insulin-dependent) diabetes.

Proinsulin and C-peptide at onset and during 12 months cyclosporin treatment of type 1 (insulin-dependent) diabetes mellitus.

An increased proinsulin to C-peptide molar ratio at the onset of Type 1 (insulin-dependent) diabetes mellitus has been suggested. We studied fasting proinsulin levels and proinsulin/C-peptide ratios in the newly diagnosed diabetic subjects participating in the Canadian/European placebo controlled cyclosporin study at entry, during the one year treatment period and six months of follow-up. Available entry data from 176 out of the 188 allocated patients were compared to 60 age and weight matched control subjects. Fasting proinsulin was significantly elevated in male patients compared to male control subjects (p less than 0.01), whereas the levels only tended to be elevated in female patients. The proinsulin/C-peptide ratio was three to fourfold elevated in the diabetic groups of both sexes, (p less than 0.001). Further, proinsulin and C-peptide were studied in 83 cyclosporin and 86 placebo-treated subjects during the trial and follow-up. An additional increase of proinsulin/C-peptide ratio was observed during the first three months of placebo treatment. It remained constantly high for nine months and then declined to entry level. This pattern was not seen in the cyclosporin-treated group, where the ratio was unchanged during the 12 months trial and follow-up. The effect of cyclosporin on the induction of non-insulin requiring remission was unrelated to fasting and glucagon stimulated C-peptide levels at entry, whereas 64% of the cyclosporin-treated against 28% of the placebo-treated subjects (p less than 0.01) went into remission if the proinsulin/C-peptide ratio at entry was above 0.024.(ABSTRACT TRUNCATED AT 250 WORDS)

Monitoring of blood glucose concentration in subjects with hypoglycaemic symptoms during everyday life.

OBJECTIVE: To study the persistence of hypoglycaemic symptoms, changes in blood glucose concentrations, and the relation between reported symptoms and measured blood glucose values in functional hypoglycaemia. DESIGN: Re-evaluation of symptoms in patients admitted consecutively with suspected hypoglycaemia followed by a case-control study. SETTING: The Steno Memorial Hospital in Gentofte, Denmark, which specialises in the diagnosis and treatment of and research on endocrine disorders, including hypoglycaemia. PATIENTS: 21 Subjects admitted consecutively with hypoglycaemic symptoms that were relieved by eating in whom insulinoma and other organic disorders presenting with hypoglycaemia had been ruled out. Twelve of these subjects with persistent symptoms entered the case-control study, as did a matched control group. INTERVENTIONS: Four days of monitoring blood glucose concentrations at home, six daily samples being taken in fixed relation to meals by the finger prick method. Extra samples were taken when symptoms occurred. MAIN OUTCOME MEASURES: Blood glucose concentration, glycated haemoglobin concentration, and within subject variation in measured values. RESULTS: After one to three years of observation 19 of the 21 subjects still had symptoms. Six out of 12 subjects experienced hypoglycaemic symptoms during the controlled study. Blood glucose concentration ranged from 3.7 mmol/l to 7.5 mmol/l during these episodes. Changes in blood glucose concentration, mean blood glucose concentrations at each time point, within subject variation in the measured values, and glycated haemoglobin concentration were not significantly different in all patients compared with the control subjects and in patients with symptoms during the study compared with controls. CONCLUSION: Hypoglycaemic symptoms during everyday life in apparently healthy subjects are persistent but are not related to chemical hypoglycaemia.

Diabetic ketoacidosis in Denmark: epidemiology, incidence rates, precipitating factors and mortality rates.

The epidemiology of uncontrolled diabetes mellitus was studied in an 11.2% sample of the Danish population (574,696 inhabitants) during a 24-month period. Some 175 admissions in ketoacidosis (heavy ketonuria and plasma bicarbonate below 21 mmol/l) were recorded. Based on prevalence rates from a socio-economically and ethnically comparable Danish county, the annual incidence rate was calculated to be 0.045 per diabetic. The incidence rate of moderate and severe episodes (bicarbonate less than 16 mmol/l) was 0.032 and of severe episodes only (bicarbonate less than 10 mmol/l) 0.017 per diabetic. The major risk group was female teenagers. The total annual frequency of recurrence was 8.7%: 48% of the male episodes were ketoacidosis (DKA) associated with onset of diabetes, against 30% of the female episodes (P = 0.02). All Danish diabetics were at the time of the survey (1978-79) treated with conventional insulin treatment. Annual incidence rate in these established diabetics was 0.028, i.e. three to five times less than reported during treatment with continuous subcutaneous insulin infusion. Mortality of DKA was low, 3.4%, and dependent upon age and precipitating factor but not upon the degree of acidosis. The overall annual mortality rate was 1.5 per 100 diabetics.