Impaired insulin action in newly diagnosed type 1 (insulin-dependent) diabetes mellitus

Summary Hepatic and peripheral insulin sensitivity were investigated in five newly diagnosed Type 1 (insulin-dependent) diabetic subjects before and after 1 week of twice daily insulin therapy. Eight weight-matched control subjects were also studied. Hepatic glucose production and glucose utilization were measured basally and during two sequential 2-h insulin (25 and 40 mU· kg^–1· h^–1)/glucose infusion periods. In the untreated hyperglycaemic diabetic patients hepatic glucose production was 16.3±2.6, 8.1±1.1 and 3.6±2.8|mol· kg^–1· min^–1 respectively for each of the three periods (mean±SEM), and fell with treatment to 12.5±1.4, 0.5±0.5 and 0.5±0.5 mol· kg^–1· min^–1. Hepatic glucose production for normal subjects was 13.4±0.7, 2.3±0.8 and <0.1 mol-kg^–1· min^–1. Glucose utilization was 12.7±1.4,18.2±0.7 and 22.1±3.4mol· kg^–1· min^–1 before treatment in the diabetic subjects, and 11.8±1.7, 20.9±3.3 and 30.1±3.6 after treatment. These values compare with those in the euglycaemic control subjects (13.4±0.7, 18.7±1.6 and 36.3±2.7 mol · kg^–1· min^–1). The pre-treatment metabolic clearance rate of glucose in all diabetic studies with insulin levels >30mU/l was 2.6 ±0.4 and rose to 3.9 ±0.5 ml· kg^–1· min^–1 following insulin therapy. This was significantly lower than in the control subjects (6.7±0.8 ml· kg^–1 · min^–1; p<0.005). Basal nonesterified fatty acid levels were high in the untreated, but normal in the treated diabetic subjects, and fell in response to insulin infusion. Basal -hydroxybutyrate levels were high in both diabetic groups, but also fell in response to insulin infusion. Erythrocyte insulin receptor binding was normal in the untreated diabetic subjects, and was not changed by treatment. Therefore, treatment of newly diagnosed Type 1 diabetic subjects with insulin reverses the hepatic insensitivity to insulin. In contrast, treatment only partially improves peripheral glucose disposal. Since erythrocyte insulin receptor binding is normal, it is likely that a post-receptor defect in peripheral glucose metabolism exists in Type 1 diabetic patients despite insulin therapy and good diabetic control for a period of 1 week.     

Isolated symptomatic peripheral neuropathy in type 1 insulin-dependent diabetes mellitus

Diabetic neuropathy is probably the most frequent of the chronic complications of diabetes, and is usually found in association with diabetic retinopathy and/or nephropathy. We report seven patients with long-standing insulin-dependent diabetes mellitus in whom symptomatic peripheral neuropathy was the first and only documented complication. The diagnosis of peripheral symmetrical neuropathy was based on the presence of symptoms and abnormal physical findings, confirmed with abnormal electrophysiological and/or vibratory and thermal threshold measurements. Diabetic retinopathy and nephropathy were absent. We conclude that in some type 1 insulin-dependent diabetic patients, similar to what has been reported in type 2 non-insulin-dependent diabetes, peripheral neuropathy may be the first chronic complication to become manifest. This observation provides additional evidence to suggest that each of the diabetic complications may have a different pathogenic mechanism.     

The relationship between the development and progression of microalbuminuria and arterial blood pressure in type 1 (insulin-dependent) diabetes mellitus.

OBJECTIVE: to investigate the association between urinary albumin excretion and arterial blood pressure in type 1 (insulin-dependent) diabetes. RESEARCH DESIGN AND METHODS: urinary albumin excretion and blood pressures were followed prospectively for a mean period of 26 months (range 18-29 months) in 46 young type 1 (insulin-dependent) diabetic subjects without overt nephropathy. Supine blood pressures (BP) were measured by a single observer using a random zero sphygmomanometer. Albumin excretion was assessed at baseline by a timed clinic excretion rate (AER; microalbuminuria = AER greater than 33 micrograms/min), and at follow-up in at least two urine specimens by the albumin/creatinine (A/Cr) ratio (micro-albuminuria = A/Cr greater than 3.7 mg/mmol). RESULTS: 39 subjects initially had normal AERs. Seven had developed microalbuminuria at follow-up: their mean BP rose from 114 +/- 13/62 +/- 13 to 119 +/- 7/77 +/- 5 mmHg (for diastolic BP, P less than 0.05), while there was no change in the mean BP in the remaining 32 patients. A rise in diastolic BP of greater than 10 mmHg occurred in five of the seven subjects who developed microalbuminuria, and in only seven of 32 who did not (P = 0.02). In the seven patients in whom microalbuminuria persisted (n = 3) or progressed to overt proteinuria (n = 4), BP increased from 123 +/- 12/70 +/- 14 to 139 +/- 12/88 +/- 10 mmHg (P less than 0.02 for both). CONCLUSIONS: this study has shown that BP is normal before the onset of microalbuminuria, and that a rise in diastolic BP accompanies the development or progression of microalbuminuria. The rate of rise in BP may be more important than the absolute level in defining 'hypertension' in young diabetic patients with microalbuminuria.     

Urinary transferrin excretion in type 1 (insulin-dependent) diabetes mellitus.

Urinary excretion of transferrin and albumin was studied by radioimmunoassay in 47 adult patients with Type 1 diabetes and 28 control subjects. Median (range) urinary transferrin excretion rate was significantly elevated in the diabetic group 0.58 (0.02-2663.3) micrograms min-1 compared with the control group 0.04 (0.01-0.28) micrograms min-1, p less than 0.001. Urinary transferrin:creatinine ratios (x 10(2)) were different in diabetic 47 (0.6-958.0) micrograms mmol-1 and control groups 0.7 (0.06-2.3) micrograms mmol-1, p less than 0.001). There were correlations between urinary transferrin and albumin excretion rates in diabetic (r = 0.78, p less than 0.001) and control groups (r = 0.81, p less than 0.05). Forty (85%) diabetic patients had elevated transferrin excretion rates, 18 (38.3%) had elevated albumin excretion rates. All diabetic patients with elevated albumin excretion rates had elevated transferrin excretion rates. Twenty-one (77.8%) of the patients with normal albumin excretion rates had elevated transferrin excretion rates. Urinary excretion of N-acetyl-beta-D-glucosaminidase was greater in diabetic patients than control subjects (142 vs 58 mumol h-1 l-1, p less than 0.001). There were correlation between transferrin and N-acetyl-beta-D-glucosaminidase excretion (r = 0.67, p less than 0.01) and albumin and N-acetyl-beta-D-glucosaminidase excretion (r = 0.63, p less than 0.01) in the diabetic group. Elevated urinary transferrin excretion rate may be a marker for renal dysfunction in diabetes mellitus.     

Plasma lipoprotein abnormalities in type 1 (insulin-dependent) diabetes mellitus

Lipoprotein abnormalities may well contribute to the increased risk of coronary heart disease, cerebrovascular disease and peripheral vascular disease observed in type 1 (insulin-dependent) diabetes mellitus. The spectrum of diabetes-associated changes in lipoprotein metabolism is discussed. The plasma levels of lipoprotein cholesterol and triglycerides are largely influenced by the degree of glycaemic control. With poor metabolic control, plasma cholesterol and triglycerides are frequently elevated. In contrast, in well-regulated patients without micro- and macrovascular complications lipid levels are generally normal or even favourable, although lipoprotein composition abnormalities can persist despite intensified insulin treatment. With the development of diabetic nephropathy the cardiovascular risk increases markedly and this complication is associated with increased concentrations of cholesterol and of the atherogenic lipoprotein species, lipoprotein(a), and low levels of high-density lipoprotein cholesterol. The rationale for treatment of lipid disorders in diabetes mellitus is based upon results of trials conducted primarily in non-diabetic populations. It is hoped that with increased recognition of dyslipidaemia and aggressive therapeutic measures the overkill in diabetes mellitus from macrovascular diseases will be reduced.     

The course and determinants of insulin action in Type 1 (insulin-dependent) diabetes mellitus

Summary The course and determinants of insulin action were investigated in 8 newly diagnosed Type 1 (insulin-dependent) diabetic patients, who were studied every 3 months for one year, and in three groups of 8 patients each with 5, 10 and 20 years diabetes, studied once. Fifteen healthy subjects matched for age, sex and body weight served as control subjects. Dose-response curves were constructed using sequential euglycaemic (5.0 mmol/l) clamps (insulin infusion rates: 0.5, 1.0, 2.0 and 5.0 mU·kg^–1·min^–1 in periods of 2h). After 1/2 month of insulin treatment, insulin responsiveness was normal, but sensitivity was decreased (ED₅₀ 70±7 mU/l (SEM) vs 54±4mU/l in control subjects, p<0.05). After 6 months, insulin sensitivity was improved (ED₅₀ 57±4 mU/l, p<0.01 vs 1/2 month and not significant (NS) vs control subjects); but after 9 and 12 months, it was reduced again, similarly to 0.5 month. Insulin responsiveness remained normal at all time-points. In the three groups of patients with longstanding diabetes, impaired insulin sensitivity with normal responsiveness was noted also (ED₅₀ 73±9 mU/l, p<0.02 vs control subjects). At 6, 9 and 12 months, glycaemic control (HbA₁) and insulin dose were inverse correlates for insulin action; in patients with longstanding disease, this was noted for HbA₁ and body weight, in control subjects for body weight. In conclusion, decreased insulin sensitivity re-develops in Type 1 diabetes within the first year following an initial improvement. Presumably, hyperglycaemia plays a role in the pathogenesis of this recurrence.     

The relationship of acute insulin sensitivity to the progression of vascular disease in long-term Type 1 (insulin-dependent) diabetes mellitus

Summary In 51 individuals with Type 1 (insulin-dependent) diabetes mellitus initially of more than 15 years' duration, the acute hypoglycaemic effect of intravenous insulin (0.11 IU/ kg) was related to outcome over 18 years. This acute insulin sensitivity, or glucose assimilation index, was reproducible over the period of study.At 18-year follow-up, initial low glucose assimilation index (<0.082 mmol·1^–1· min^–1 was significantly (p<0.01) associated with death from vascular disease. Low glucose assimilation index was similarly significantly (p<0.01) associated with progression of atherosclerotic disease, but not with microangiopathy alone. Hypertension (systolic blood pressure > 150mmHg and/or diastolic blood pressure > 95 mmHg) was the only other parameter significantly (p<0.01) related to outcome, but this relationship was no longer significant once glucose assimilation index had been taken into account. A linear logistic analysis confirmed that acute insulin sensitivity was independently associated with outcome. Neither initial clinical control of diabetes nor glycosylated haemoglobin level in the 26 survivors was related to vascular prognosis.     

Lipids,lipoproteins and apolipoproteins in type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetes mellitus

Summary Total plasma cholesterol, triglycerides, VLDL-C, VLDL-TG, HDL-C and the apoproteins A-I, A-II, B and D were measured in 111 male non-obese diabetic patients and in 90 male control subjects of similar age and body weight distribution. Forty-eight patients had Type 1 (insulin-dependent diabetes) and 63 had Type 2 (non-insulin-dependent diabetes); all were in stable metabolic control while following an appropriate diet and therapy with insulin or oral hypoglycemic agents. HDL-C, apoA-I, apoB and the apoA-I/apoA-II ratio were significantly increased in the Type 1 patients, whereas the VLDL-C/VLDL-TG and LDL-C/apoB ratios were decreased significantly. Type 2 diabetics showed low HDL-C and low apoA-I/apoA-II ratio, while the values of apoA-I, A-II, D and the VLDL-C/VLDL-TG ratio were significantly higher than in controls. Type 1 diabetics in ‘fair’ metabolic control presented higher values of TG, VLDL-C, VLDL-TG and apoB than patients in ‘good’ control: lower values of apoA-I and of the ratios apoA-I/apoA-II, apoA-I/apoB and LDL-C/apoB were recorded in the same subgroup. In Type 2 diabetics no significant differences were observed according to metabolic control, with the exception of a higher apo-D value in subjects in ‘fair’ control. The data obtained support the view that good metabolic control may be important for the prevention of a relevant derangement of lipoprotein components, particularly in Type 1 patients. Partially supported by grant No. 83.02521.56 fromConsiglio Nazionale delle Ricerche (CNR), Roma, Italy (Progetto Finalizzato di Medicina Preventiva e Riabilitativa).     

Insulin intervention in slowly progressive insulin-dependent (type 1) diabetes mellitus

OBJECTIVE: We tested the hypothesis that insulin therapy rather than sulfonylurea (SU) treatment is preferable to reverse or preserve beta-cell function among patients with slowly progressive insulin-dependent (type 1) diabetes (SPIDDM) or latent autoimmune diabetes in adults. METHODS: This multicenter, randomized, nonblinded clinical study screened 4089 non-insulin-dependent diabetic patients for glutamic acid decarboxylase autoantibodies (GADAb). Sixty GADAb-positive non-insulin-requiring diabetic patients with a 5-yr duration or shorter of diabetes were assigned to either the SU group (n = 30) or the insulin group (n = 30). Serum C-peptide responses to annual oral glucose tolerance tests were followed up for a mean of 57 months. The primary endpoint was an insulin-dependent state defined by the sum of serum C-peptide values during the oral glucose tolerance test (SigmaC-peptide) less than 4 ng/ml (1.32 nmol/liter). RESULTS: The progression rate to an insulin-dependent state in the insulin group (three of 30, 10%) was lower than that in the SU group (13 of 30, 43%; P = 0.003, log-rank). Longitudinal analysis demonstrated that SigmaC-peptide values were better preserved in the insulin group than in the SU group. Multiple regression analysis demonstrated that insulin treatment, a preserved C-peptide response, and a low GADAb titer at entry were independent factors in preventing progression to an insulin-dependent state. Subgroup analysis suggested that insulin intervention was highly effective for SPIDDM patients with high GADAb titers [> or =10 U/ml (180 World Health Organization U/ml)] and preserved beta-cell function [SigmaC-peptide > or = 10 ng/ml (3.31 nmol/liter)] at entry. No severe hypoglycemic episodes occurred during the study. CONCLUSIONS: Insulin intervention to preserve beta-cell function is effective and safe for patients with SPIDDM or latent autoimmune diabetes in adults.     

Insulin therapy in insulin-dependent (type I) diabetes mellitus.

Intensive insulin therapy is suitable for individuals who want optimal glucose control and the least fluctuation in glucose levels. It permits a greater flexibility in life style and the opportunity to vary, within certain limits, meal and exercise schedules and meal content. This therapeutic approach is modeled on physiologic insulin secretion, but shortcomings in the subcutaneous route of delivery hamper the ability to control precisely the glucose levels. The therapy is most successful when the user is motivated to do the glucose monitoring and carbohydrate counting and educated to make rational decisions about how to adjust the insulin doses.     

Muscle enzyme activity and insulin sensitivity in Type 1 (insulin-dependent) diabetes mellitus

Summary The mechanisms of insulin insensitivity in diabetes are poorly understood. We have therefore assessed the relationship between glucose disposal during a euglycaemic clamp, muscle glycogen formation, and the activities of insulin regulated enzymes within skeletal muscle in five Type 1(insulin-dependent) diabetic patients, both on conventional injection therapy (HbA₁ 11.0±1.0 (SD) %) and after 6 weeks continuous subcutaneous insulin infusion (HbA₁ 7.6±1.4%,p < 0.01). On both regimens, overnight euglycaemia before the clamp was maintained with an intravenous insulin infusion. The increase in clamp glucose requirements (insulin 0.1 U kg^–1·h^–1) between injection therapy and continuous subcutaneous insulin infusion was significant (6.2±0.9 (SE) to 7.0 ± 0.9 mg·kg^–1·min^–1,p<0.05), but small compared to differences between subjects. Glucose requirement remained lower than in control subjects (10.4 ± 0.7 mg·kg^–1·min^–1,p < 0.05). The increase in muscle glycogen with the clamp was slightly higher on continuous subcutaneous insulin infusion (9.5 ± 2.5 mg/g protein) than on injection therapy (8.5 ± 2.4 mg/g,p < 0.05), but less than in control subjects (17.9 ± 2.1 mg/g,p < 0.05). The expressed activity of glycogen synthase and pyruvate dehydrogenase increased significantly between fasting and the end of the clamps in the patients (p < 0.001 and < 0.005), but was not significantly different between the two treatment regimens. Expressed glycogen synthase activity at the end of the clamp was lower on both treatments than in control subjects (p < 0.05). Both enzyme activities were, however, highly correlated with glucose requirement between patients, (r=0.89–0.94,p<0.05-0.02), and glycogen synthase was similarly correlated in the control subjects (r = 0.84,p < 0.05). Patients had significantly different enzyme activities, glucose requirement, and glycogen stored by analysis of variance (p < 0.05-0.01). Correlation of each enzyme activity between subjects on the two treatment regimens was also high (r=0.94–0.98,p < 0.02–0.01). At the end of the clamp the enzyme activities were themselves closely related (injectionsr = 0.99,p < 0.001; infusionr = 0.88,p < 0.05), and glycogen synthase activity predicted muscle glycogen deposition (r=0.94–0.97,p < 0.02–0.01). We suggest that: (1) preceding metabolic control has a relatively small influence on whole body insulin sensitivity measured immediately after careful overnight control; (2) insulin sensitivity derived from glucose clamp data is strongly related to skeletal muscle glycogen deposition and skeletal muscle enzyme activities.     

Residual B-cell function in type 1 (insulin-dependent) diabetes mellitus: Its relation to clinical and metabolic features

Summary The aim of the present study was to investigate whether or not residual B-cell function could be related to insulin sensitivity as well as to duration of disease, insulin requirement, and indices of metabolic control in a population of Type 1 (insulin-dependent) diabetic patients. A positive correlation was found between fasting C-peptide and age at onset of diabetes, whereas a negative relationship occurred between C-peptide and duration of disease. Fasting C-peptide negatively correlated also to mean daily plasma glucose, 24-h glycosuria, and fasting free fatty acid concentration. Moreover, a negative correlation was found between C-peptide and daily insulin requirement. Conversely, a positive relationship occurred between C-peptide levels and the parameter we used for estimating insulin sensitivity, i.e. glucose disappearance rate after i.v. insulin injection. These results once more emphasize the importance of residual B-cell function in Type 1 (insulin-dependent) diabetes mellitus, and suggest that the residual endogenous insulin secretion might play an important role in glucose homeostasis of Type 1 diabetes by influencing the sensitivity to insulin. Supported by grant No. 83/02132.04 fromConsiglio Nazionale delle Ricerche (CNR), Roma, Italy.     

Enhanced hepatic insulin sensitivity,but peripheral insulin resistance in patients with Type 1 (insulin-dependent) diabetes

Summary Sensitivity to insulin in vivo was studied in 8 normal weight C-peptide negative Type 1 (insulin-dependent) diabetic patients (age 23±1 years, diabetes duration 6±2 years), and in 8 age, weight and sex matched healthy subjects, using the euglycaemic clamp and 3-³H-glucose tracer technique. Prior to the study diabetic patients were maintained normoglycaemic overnight by a glucose controlled insulin infusion. Sequential infusions of insulin in 3 periods of 2 h resulted in mean steady state insulin levels of 12±2 versus 11±1, 18±2 versus 18±2 and 28±3 versus 24±2 U/ml in diabetic patients and control subjects. Corresponding glucose utilization rates were 2.4±0.2 versus 2.4±0.1, 2.4±0.2 versus 3.0±0.3 and 2.9±0.3 versus 4.6±O.6 mg·kg^–1·min^–1, p<0.02. Portal insulin values in the three periods were calculated to 12±2 versus 25±3, 18±2 versus 32±3 and 28±3 versus 37±3 U/ml in the diabetic patients and control subjects using peripheral insulin and C-peptide concentrations and assuming a portal to peripheral insulin concentration gradient of 1 in diabetic patients and of 2.4 in control subjects. Corresponding glucose production rates were 2.5±0.2 versus 2.4±0.1, 1.6±0.1 versus 0.9±0.2 and 0.7±0.1 versus 0.4±0.2 mg·kg^–1·min^–1. Using this approach the insulin dose-response curve for the peripheral glucose utilization was right-ward shifted, while the dose-response curve for the hepatic glucose production as a function of portal insulin levels was left-ward shifted. We conclude that in vivo insulin action is increased in the liver but decreased in peripheral tissues in insulin treated Type 1 diabetic patients. Presumably these oppositely directed changes in insulin action are acquired defects, secondary to the present mode of peripheral insulin treatment.     

Effect of insulin on renal sodium handling and renal haemodynamics in insulin-dependent (type 1) diabetes mellitus patients

The effects of insulin on renal haemodynamics and renal sodium handling were studied in eight insulindependent (type 1) diabetic patients (aged 30±3 years). Seven healthy men (aged 38±4 years) served as controls. The type 1 diabetic patients were resistant to insulin-stimulated glucose disposal as estimated by a 45% lower metabolic (P<0.01) clearance of glucose as compared with controls. However, type 1 diabetic patients were still sensitive to the distal tubular antinatriuretic effect of insulin, as indicated by an increase in distal sodium reabsorption (95.5%±0.5% to 96.9%±0.4%;P<0.05) during insulin infusion compared with controls (95.5%±0.6% to 97.4%±0.3%;P<0.05). In control subjects insulin infusion was associated with 9% increases (P<0.05) in lithium clearance and in renal plasma flow, whereas no significant increases in lithium clearance and in renal plasma flow were observed in the type 1 diabetic patients. In both groups, the changes in renal plasma flow in response to insulin infusion were positively correlated with that in lithium clearance (r=0.80 andr=0.90, respectively;P<0.05?0.01). In conclusion, the present result demonstrates an intact distal tubular sodium retaining effect in conjunction with a blunted decrease in proximal tubular sodium reabsorption following insulin infusion, which could be the result of an impaired renal vasodilation in type 1 diabetes mellitus.     

The development of type 1 (insulin-dependent) diabetes mellitus: Two contrasting presentations

Genetic, immunological and viral factors have been implicated in pathogenesis of Type 1 diabetes mellitus. The development of Type 1 diabetes in two siblings of patients with Type 1 diabetes studied as part of a large epidemiological study, is described. One case, a 13-year-old male not sharing either HLA haplotype with his diabetic sister, had virtually normal glucose tolerance 80 days before symptomatic presentation. He showed serological evidence of infection by Coxsackie CB4 (at diagnosis) and influenza A virus (soon after diagnosis). The other case, a 15-year-old male, had impaired glucose tolerance for over 500 days (i.e., since the diagnosis of diabetes in his HLA-identical brother) before symptomatic presentation which was not associated with serological evidence of acute viral infection. The former case was negative for islet cell antibody (cytoplasmic) when first seen though positive at diagnosis, while the latter was positive throughout. These two cases suggest contrasting interactions of the main pathogenetic factors associated with Type 1 diabetes.