Human pancreatic islet function at the onset of Type 1 (insulin-dependent) diabetes mellitus

Summary Viable human pancreatic islets isolated from a recent-onset Type 1 (insulin-dependent) diabetic patient were used to perform in vitro studies. Pre-proinsulin mRNA and insulin content, as well as insulin response were analysed. Insulin response to glucose and forskolin was completely absent in diabetic islets, as compared to control islets. Insulin content was reduced to only one-third of control values (395.0±3.5 vs 989.0±46.3 U/islet) and 20.7±3.9% of islets from the diabetic pancreas contained insulin-positive cells in immunofluorescence studies. Northern blot analysis revealed a severe reduction in the content of pre-proinsulin mRNA in diabetic pancreatic tissue. Our results indicate that although markedly decreased, beta cells in human pancreatic islets at the onset of Type 1 diabetes are still present. Never-theless, pancreatic islet function is disproportionately impaired with a complete absence of an insulin response.     

Risk for developing Type 1 (insulin-dependent) diabetes mellitus and the presence of islet 64K antibodies

Summary First-degree relatives of Type 1 (insulin-dependent) diabetic patients are at increased risk for developing clinical diabetes. The presence of islet cell or insulin autoantibodies further identifies relatives at greater risk, but not all immunologic-marker-positive relatives progress to disease. Beta-cell dysfunction, however, seems to be more prevalent than clinical Type 1 diabetes, since stable subclinical pancreatic Beta-cell dysfunction may occur. Antibodies against a M_r 64,000 (64K) islet Beta-cell protein, identified as glutamic acid decarboxylase, have been reported both at and several years prior to the clinical onset of Type 1 diabetes. We measured 64K antibodies in first-degree relatives with varying degrees of Beta-cell dysfunction and risk for subsequent Type 1 diabetes to determine whether 64K antibodies improve the predictive power of islet cell antibodies and/or insulin autoantibodies. In the Seattle Family Study first-degree relatives of Type 1 diabetic patients are followed prospectively using detailed Beta-cell function tests, insulin sensitivity, quantitative evaluation of islet cell antibodies and fluid phase assay insulin autoantibodies. 64K antibodies were measured using dog islets. Relatives were selected, based on Beta-cell function to represent individuals at high (n=6) and low (n=30) risk for subsequent Type 1 diabetes. The 30 low-risk individuals followed-up for 78 months, had stable Beta-cell function, and six (20%) were negative for all autoantibodies, ten (33%) were positive for insulin autoantibodies, 16 (53%) were islet cell antibody positive while six (20%) were positive for 64K antibodies. In contrast, of the six subjects with progressively declining Beta-cell function who are therefore at high risk, two of whom have already developed Type 1 diabetes, two (33%) were positive for insulin autoantibodies, four (67%) were islet cell antibody positive, while all six (100%) were positive for 64K antibodies. We conclude that antibodies to the M_r 64,000 islet protein correlate with progressive Beta-cell dysfunction more closely than either islet cell antibodies or insulin autoantibodies, but can sometimes be present in individuals whose Beta-cell function remains stable over several years.     

Prevention or delay of Type 1 (insulin-dependent) diabetes mellitus in children using nicotinamide

Summary A controlled trial of oral nicotinamide to prevent the onset of diabetes mellitus in high risk children was conducted in two centres. The selection criteria were age less than 16 years, islet cell antibody 80 IUs, and first phase insulin release < 5th percentile. All of eight untreated control subjects have developed diabetes, whereas only 1 of 14 treated children has diabetes to date. This data suggests that nicotinamide has an effect in preventing Type 1 (insulin-dependent) diabetes and that randomized controlled studies are now indicated.     

Proinsulin autoantibodies are more closely associated with Type 1 (insulin-dependent) diabetes mellitus than insulin autoantibodies

Summary The disease association of autoantibodies to proinsulin and insulin was compared in patients with Type 1 (insulin-dependent) diabetes mellitus and first-degree relatives. Following the recommendation of the Fourth International Workshop on the Standardization of insulin autoantibodies, autoantibodies were determined by fluid-phase radioimmunoassay using equimolar concentrations of mono¹²⁵I-A14-insulin or -proinsulin to detect insulin or proinsulin autoantibodies, respectively. A higher prevalence of proinsulin autoantibodies vs insulin autoantibodies was found in 97 patients with Type 1 diabetes prior to insulin treatment (34.0 % vs 22.7 %, p< 0.05) and in 16 islet cell antibody-positive relatives (43.8% vs 31.3%, NS). There was only one serum positive for insulin and proinsulin autoantibodies in 110 islet cell antibody-negative first degree relatives (0.9 %). None of 88 normal sera contained proinsulin autoantibodies or insulin autoantibodies. There was a close correlation of proinsulin autoantibody and insulin autoantibody titres in individual sera (r=0.95, p< 0.01) due to crossreaction of all insulin autoantibodies with proinsulin. However, some proinsulin autoantibodies did not crossreact with insulin. Background binding in normal sera was lower for proinsulin autoantibodies. We conclude that proinsulin autoantibodies have a higher association to acute Type 1 diabetes than insulin autoantibodies.Part of this work was presented at the 26th Annual Meeting of the EASD in Copenhagen, 10^th–13^th September 1990     

Acute insulin response to intravenous glucose,glucagon and arginine in some subjects at risk for Type 1 (insulin-dependent) diabetes mellitus

Summary The relationships between first-phase insulin secretion to i.v. glucagon and i.v. arginine were studied in 19 healthy adult volunteers (Group I) and in 21 subjects at risk for Type 1 (insulin-dependent) diabetes mellitus with either a normal (n=11; Group II a) or a low insulin response to i.v. glucose (n=10; Group II b). Groups I and II a displayed similar insulin responses to the three secretagogues. In contrast, Group II b demonstrated lower insulin responses to both glucagon and arginine than control subjects (p}<0.007 and (p}<0.04 respectively) orthan normo-responders to glucose (#x007D;<0.007 and p<0.04 respectively). In Group II b however, arginine-stimulated insulin release was increased compared to the response to glucose (p}<0.006), while glucagon and glucose led to non-statistically different responses. Five low-responders developed Type 1 diabetes. As a group, they displayed lower responses to glucagon and to arginine than subjects who up to now have not developed the disease (p<0.05 and p<0.0003 respectively). In the subjects who progressed to diabetes, the responses to glucose and glucagon were similarly blunted. In the low-responders who have not developed the disease, no statistical difference could be detected between mean responses to glucagon and glucose, but four out of these five subjects had a glucagon-stimulated response within the control range and higher than their corresponding response to glucose. Arginine led to a higher stimulation than glucose, in subgroups that either progressed to diabetes (p<0.006) or did not (p<0.002). Finally, low-responders who did not develop diabetes displayed similar responses to both glucagon and arginine than normo-responders to glucose. A progressive decrease of arginine-stimulated insulin response may be a later event during pre-Type 1 diabetes than a blunted response to glucose, while a loss of glucagon-stimulated insulin release may be intermediate. Diminished response to all secretagogues may offer better prediction than a low response to glucose alone.     

Autoantibodies to the insulin receptor are infrequent findings in Type 1 (insulin-dependent) diabetes mellitus of recent onset

Summary To determine whether autoantibodies to the insulin receptor may represent markers of Type 1 (insulin-dependent) diabetes, the prevalence of such antibodies was investigated in sera of 60 newly diagnosed untreated Type 1 diabetic patients. A sensitive assay, based on enzyme linked immunosorbent assay has been set up which detects antibodies to the insulin receptor irrespective of their potentially inhibiting effect on insulin binding. Moreover, this method allows easy determination of the immunoglobulin class involved in the anti-receptor activity. Among the 60 sera examined, only one was found to contain anti-insulin receptor autoantibodies (IgG class). In view of our data, we conclude that autoantibodies to the insulin receptor are infrequent findings in Type 1 diabetes of recent onset.     

Urinary kallikrein excretion in Type 1 (insulin-dependent) diabetes mellitus

Summary Kidney haemodynamics appear to change after the early phases of diabetic nephropathy: increases in glomerular filtration rate and in renal plasma flow have been widely reported, while kidney size is increased. As the renal kallikrein-kinin system has been demonstrated to regulate kidney blood circulation, we have evaluated the excretion of urinary kallikrein in 87 Type 1 (insulin-dependent) diabetic patients with and without hyperfiltration. Urinary kallikrein excretion was measured in 24-h urine collections. The esterolytic activity was determined by fluorimetric assay. The excretion of urinary kallikreins was significantly higher in hyperfiltering patients (472±125 esterase units/24 h) than in normofiltering (168±77 esterase units/24 h) and control subjects (151±39 esterase units/24 h), p<0.001. Furthermore, we observed a positive correlation between urinary kallikrein excretion and glomerular filtration rate (r=0.785). These data suggest that variations of kallikrein and kinin concentrations may play a role in the alteration of renal haemodynamics in Type 1 diabetes. It is possible that the kinin-kallikrein system, the renin-angiotensin system and the prostaglandins may interact to determine the haemodynamic alterations which are present in the diabetic disease.     

Incidence of Type 1 (insulin-dependent) diabetes mellitus in Catalonia, Spain

Summary The incidence of Type 1 (insulin-dependent) diabetes mellitus was prospectively evaluated in Catalonia, Spain in patients up to 30 years of age during the period 1987–1990. The population at risk (0–29 years) consisted of 2,690,394 inhabitants (total population of Catalonia 5,978,638). All the cases were independently identified from four sources: endocrinologists, sales of blood glucose monitors and insulin pen injectors, diabetes societies and diabetic summer camps. The degree of ascertainment was 90.1 %. The overall observed incidence rate was 10.7 per 100,000 per year, being 11.5 per 100,000 per year in the 0–14 age group. The incidence in males (12.0 per 100,000 per year) was higher than in females (9.3 per 100,000 per year), with a male/female ratio of 1.36/l. The sex differences were only present in cases over 14 years of age. Age specific incidence rates per 100,000 per year were 4.4 (confidence interval 95%: 3.2–5.7) in the age group 0–4, 9.9 (8.5–11.4) in 5–9, 17.5 (15.7–19.4) in 10–14, 11.4 (9.9–13.0) in 15–19, 11.3 (9.7–13.0) in 20–24 and 8.5 (7.2–9.9) in 25–29. There was a seasonal onset pattern, with the highest incidence in winter (December–February). We conclude that the incidence of Type 1 diabetes observed in Catalonia during the period 1987–1990 is higher than that recently reported in other Mediterranean countries. This study offers the first standardized data on Type 1 diabetes incidence in Catalonia, including cases up to 30 years, and contributes to the knowledge of the epidemiology of diabetes in South Europe.     

The significance of the concordance rate for Type 1 (insulin-dependent) diabetes in identical twins

Summary We studied prospectively 49 non-diabetic identical twins of recently-diagnosed Type 1 (insulin-dependent) diabetic patients for up to 24 years (median 9 years). During this time 15 developed Type 1 diabetes. Actuarial analysis indicates that by 12 years 34% of the twins will have developed Type 1 diabetes and that thereafter only another 2% will do so. Inevitable bias in ascertainment of the twins makes it likely that the true figure is less. We conclude that factors which are not genetically determined must be important in the pathogenesis of the disease. The rates of developing Type 1 diabetes in the co-twins declines sharply in the years after diagnosis of the index twin, which suggests that the initiation of the process leading to Type 1 diabetes occurs within a finite, and not a prolonged, period.     

Type 1 (insulin-dependent) diabetes mellitus diagnosed during pregnancy: a clinical and prognostic study

Summary The study concerns the clinical outcome and later prognosis (regarding permanent insulin treatment) of patients who develop insulin-dependent diabetes mellitus during pregnancy (which is different from gestational diabetes). Sixty-three such patients (27±1 (SEM) years old) were delivered at the Copenhagen Centre for Diabetes and Pregnancy during the years 1966–1980. Obstetric complications such as toxaemia were seen in 9.5% of these study patients and the perinatal mortality was 6.3%, both percentages being higher than in the general population (1.1%,p<10^–7 and 1.0%,p<10^–3, respectively), but similar to those observed in patients with Type 1 diabetes diagnosed before pregnancy. In contrast, the frequency of malformations was 1.6%, the same as in the general population (1.4%), but lowerthan that seen in patients with long-standing diabetes (8.3%,p<0.05). At follow-up examination 8±1 years after diagnosis all patients were diabetic; 77% were insulin treated, having no or virtually no residual B-cell function, and were clearly Type 1 diabetic patients. After delivery 80% of the patients had a remission period (median 256 days) without insulin treatment. This remission period was absent or shortest in patients with the following characteristics (p0.03): low age, first parity, not overweight, and high blood glucose level at diagnosis. These prognostic parameters should be considered in obligatory, clinical follow-up plans for such patients.     

Distinct cytoplasmic islet cell antibodies with different risks for Type 1 (insulin-dependent) diabetes mellitus

Summary The cytoplasmic islet cell antibody patterns of sera from islet cell antibody positive non-diabetic and diabetic endocrine autoimmune patients, and newly-diagnosed Type 1 (insulin-dependent) diabetic patients were characterised using four layer immunofluorescence with monoclonal antiproinsulin or anti-glucagon antibodies. Two distinct islet cell antibody types were identified. One gave a diffuse cytoplasmic staining in both Beta and Alpha cells (whole islet pattern), and was not affected by pre-incubation with rat brain homogenate. The other had a granular appearance with staining restricted predominantly to Beta cells (selective islet pattern) and was completely inhibited by pre-incubation with rat brain homogenate. Some sera appeared to have a mixed islet pattern, in which glucagon-positive cells gave a weaker cytoplasmic staining than proinsulin-positive cells. The granular selective pattern was found in sera from 19 (79%) of 24 non-diabetic endocrine autoimmune patients, in two (22%) endocrine autoimmune patients who developed Type 1 diabetes (p<0.0001 vs non-diabetic endocrine autoimmune patients), and in none of 19 newly-diagnosed diabetic patients. The whole islet pattern was found only in sera from patients who had, or who subsequently progressed to, Type 1 diabetes. This study has identified a novel islet cell antibody specificity and demonstrates that in islet cell antibody positive endocrine autoimmune patients, only islet cell antibodies which stain both Beta and Alpha cells are associated with progression to Type 1 diabetes.     

Clinical pattern of childhood Type 1 (insulin-dependent) diabetes mellitus in the Sudan

Summary During a 10-year period, 101 children with Type 1 (insulin-dependent) diabetes mellitus were admitted to the Department of Paediatrics of the University Hospital in Khartoum, Sudan. The age distribution of the patients showed a steady increase from age one to ten years followed by a sharper increase around puberty. A higher number of cases were diagnosed during the cooler compared to the warmer months of the year (p<0.05). Family history of Type 1 diabetes was reported in 14.9% of patients. Diabetic ketoacidosis was a presenting symptom in 82 patients (81.2%) and 93 patients (92.1%) have had at least two documented episodes of ketoacidosis during the follow-up period. Almost all patients were treated with bovine insulin given as a single dose per day. An initial remission period was not observed in any of the patients. Four years after diagnosis, the average daily dose of insulin used by the patients was greater than 2.0 U/kg body weight and the mean HbA_1C was 13.4% (reference value 5.3–6.7%). Seventeen patients (16.8%) were known to have died during 399 person-years of observation resulting in a mortality rate of 42.6 per 1000 person-years of follow-up. Another 29 patients (28.7%) for no apparent reason did not attend a follow-up examination after discharge from hospital. Some of these patients might have died in other hospitals or at home. The study emphasizes the need for urgent measures to increase public awareness of diabetes and to improve methods of case-finding and management of diabetic patients.     

Increased aortic stiffness in patients with Type 1 (insulin-dependent) diabetes mellitus

Summary The biomechanical properties of aortic samples from patients with Type 1 (insulin-dependent) diabetes mellitus and age- and sex-matched control subjects were analysed using a materials testing machine. The specimens were prepared from tissue outside areas of visible atherosclerosis in order to discriminate between primary Type 1 diabetic alterations in the aortae and secondary changes due to increased atherosclerosis. We paid special attention to the correction of biomechanical parameters for differences in wall thickness and registration of specimen length values. In the Type 1 diabetic aortae a marked reduction was found in the extensibility and an increase in their stiffness. The reduced extensibility was correlated significantly to the duration of Type 1 diabetes. The pronounced alterations in the mechanical properties could not be explained by the increase in the wall thickness which was observed among the Type 1 diabetic patients and the alterations could not be correlated to the grade of atherosclerosis in the thoracic aorta. The results of the present study, therefore, strongly suggest that Type 1 diabetic patients develop alterations in the arterial connective tissue independent of the presence of atherosclerosis. Such primary alterations in the vessel wall may play a role in the pathogenesis of large vessel disease among these patients.     

Lessons from the NOD mouse for the pathogenesis and immunotherapy of human Type 1 (insulin-dependent) diabetes mellitus

Summary Suitable animal models of human Type 1 (insulin-dependent) diabetes mellitus have long been sought, in particular a model that would permit detailed histological and immunological investigation of changes in the islet preceding the metabolic disorder. This would allow hypotheses as to pathogenesis of the condition to be examined and interventions such as immunotherapy to be tested. The most widely studied models include the low-dose streptozotocin induced diabetic mouse and the BB rat, but both differ in important respects from the human disease. In this review we describe one highly successful model, the non obese diabetic mouse. Selected aspects of pathogenesis and immunotherapy are presented and analogies with human Type 1 diabetes discussed.     

Prevalence of hypertension in Type 1 (insulin-dependent) diabetes mellitus

Summary The prevalence of hypertension in a representative sample (n=10202) of the Danish general population aged 16–59 years was assessed to 4.4% based on three blood pressure readings. In Type 1 (insulin-dependent) diabetic patients of similar age (n=1703) the prevalence was determined in a similar way to 14.7% (p<0.00001). The excess prevalence in Type 1 diabetic patients was due to hypertension in patients with incipient and clinical nephropathy as the prevalence of hypertension among diabetic patients with normal urinary albumin excretion (essential hypertension) was 3.9%, similar to that observed in the general population. The patients with Type 1 diabetes and essential hypertension had higher systolic (146±19 vs 133±18 mmHg, p<0.00001) and diastolic blood pressure (87±12 vs 79±7mmHg, p<0.00001), but less changes in the eye background than patients with incipient nephropathy (urinary albumin excretion 30–300 mg/24 h) (p<0.03), indicating that the two groups were also different with respect to other microangiopathic lesions. Patients with essential hypertension were defined as having a normal urinary albumin excretion before and during antihypertensive treatment (if any). They were followed-up for a 58 (6–234) month period. We confirmed that hypertension is more common among Type 1 diabetic patients than in the general population and found the prevalence of essential hypertension similar in Type 1 diabetic patients to the non-diabetic population. This supports our hypothesis that hypertension is very unlikely to be the cause of diabetic nephropathy.     

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.     

Islet-cell antibodies as predictors of the later development of Type 1 (insulin-dependent) diabetes

Summary To determine the value of islet-cell antibodies, both complement-fixing and non-complement-fixing, in predicting the later development of Type 1 (insulin-dependent) diabetes, we studied different groups of identical twins. Twelve twins have developed diabetes and 11 of these had non-complement-Fixing islet-cell antibodies before diagnosis, and eight out of nine tested had complement-fixing islet-cell antibodies. Of the twins who have remained non-diabetic for many years and are now unlikely to develop diabetes, twelve have had non-complement-fixing islet-cell antibodies at some stage but only four have ever had complement-fixing antibodies. In 29 non-diabetic co-twins tested within 5 years of the diagnosis of diabetes in the affected twin the presence of islet-cell antibodies, especially complement-fixing, predicted the progression to frank diabetes with a high specificity (100%), sensitivity (88%) and predictive value (100%). In pairs remaining discordant the antibodies were found more frequently in the diabetic than the non-diabetic twin. We conclude that the presence of islet-cell antibodies is not genetically determined and can occur without progression to diabetes. However, the presence of islet-cell antibodies, especially complement-fixing, in non-diabetic twins tested soon after the diagnosis of their co-twin, indicates a high risk for the development of diabetes.     

Different genetic backgrounds for malnutrition-related diabetes and Type 1 (insulin-dependent) diabetes mellitus in South Indians

Summary HLA-DRB, -DQA and -DQB genes were studied in ten South Indian malnutrition-related diabetic patients, ten Type 1 (insulin-dependent) diabetic patients and 45 control subjects, by TaqI restriction fragment length polymorphism analysis. The DR7,DQw9 haplotype was found to be frequent in patients with malnutrition-related diabetes (p<0.01). The DRw17,DQw2 haplotype was overrepresented in the patients with Type 1 diabetes compared to control subjects (p<0.05). In vitro amplification of the polymorphic second exon of DQB genes by the polymerase chain reaction technique was performed on DNA from 10 malnutrition-related diabetic patients, 10 Type 1 diabetic patients and 13 control subjects, as they belong to a new population. Hybridization with sequence-specific oligonucleotide probes for DQB1 alleles showed homozygosity of aspartic acid at position 57 in 7 of 10 malnutrition-related diabetic patients compared to 2 of 10 Type 1 diabetic (p<0.05) and 15 of 45 control subjects (p<0.05). Homozygosity of non-aspartic acid at position 57 was present in 7 of 10 Type 1 diabetic compared to 0 of 10 malnutrition-related diabetic patients (p<0.005) and 3 of 45 control subjects (p<0.05). This study has confirmed the association of DQB1 57 non-asp in South Indians with Type 1 diabetes. In addition, our data clearly show that the genetic background of malnutrition-related diabetes mellitus is different from that of Type 1 diabetes.     

Determination and kinetic analysis of non-insulin mediated glucose uptake in Type 1 (insulin-dependent) diabetes mellitus

Summary In man, total glucose uptake is the sum of insulin mediated glucose uptake and non-insulin mediated glucose uptake. The latter pathway has not been examined in Type 1 (insulin-dependent) diabetes mellitus. In order to assess non-insulin mediated glucose uptake in Type 1 diabetes, we measured steady-state rates of glucose uptake during glucose clamps at 5.27, 9.71 and 12.5 mmol/l using low (0.25 mU· kg^–1·min^–1), intermediate (0.75 mU·kg^–1·min^–1) and high (1.50 mU·kg^–1·min^–1) insulin infusion rates in 10 subjects with Type 1 diabetes. For insulin infusion rates of 0.25, 0.75 and 1.50 mU·kg^–1·min^–1 as plasma glucose rose from 5.27 to 9.71 mmol/l, total glucose uptake increased by 35, 43 and 52 percent respectively (p<0.05 for each insulin infusion rate). For all three insulin infusion rates, there was no significant increase in total glucose uptake as plasma glucose increased from 9.71 to 12.5 mmol/l. At each glycaemic level, glucose uptake correlated significantly with plasma free insulin (r=0.81, p<0.01 at 5.71 mmol/l; r=0.84, p<0.01 at 9.71 mmol/l; r=0.73, p<0.02 at 12.5 mmol/l). Linear regression analysis to a point corresponding to plasma free insulin equalling zero, yielded values for non-insulin mediated glucose uptake (mmol·kg^–1·min^–1) of 0.11,0.14,0.18 at plasma glucose of 5.27, 9.7 and 12.5 mmol/l respectively. Thus, increasing plasma glucose concentrations were associated with increasing rates of non-insulin mediated glucose uptake. For each insulin infusion rate used, the percent of total glucose uptake accounted for by non-insulin mediated glucose uptake remained independent of plasma glucose concentration, but decreased as insulin infusion rate increased. During the insulin infusion at 0.25 mU·kg^–1·min^–1, this percentage ranged from 83.7 to 91.4%. Analysis of glucose uptake data derived for theoretical plasma insulin levels of 0, 40, 80 and 160 U/ml yielded linear Eadie-Hofstee plots (r=– 0.83 to – 0.99), suggesting that insulin increased Vmax but did not alter Km. Hence, in these subjects with Type 1 diabetes, glucose uptake, both insulin mediated and non-insulin mediated can be described by Michaelis-Menten kinetics. Comparison of values obtained for Vmax and Km in the present studies of Type 1 diabetes with those obtained from non-diabetic subjects indicates that non-insulin dependent glucose uptake in Type 1 diabetes is quantitatively similar to that of non-diabetic subjects.     

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

Summary 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<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<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 cyclosporintreated 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<0.01) went into remission if the proinsulin/C-peptide ratio at entry was above 0.024. If the ratio was below 0.024 at entry, 42% and 33% went into non-insulin requiring remission, respectively (NS). We conclude that fasting proinsulin to C-peptide molar ratio is elevated at the onset of Type 1 diabetes mellitus. A further plateaushape elevation lasting nine months was seen during the remission period. Cyclosporin seems to inhibit or delay this development. The proinsulin/C-peptide ratio at diagnosis may show to be of value in the prediction of remission during cyclosporin treatment.Prepared by the authors for The Canadian/European Diabetes Study Group.