Renal threshold for glucose in non-insulin-dependent diabetic patients.

Measurement of glycosuria is still widely used for home monitoring of glycaemia control in non-insulin-dependent diabetes (NIDDM). This method has been criticized because the renal threshold for glucose (RTglu) varies between subjects. In order to evaluate the validity of RTglu by measuring corresponding measurements of blood and urine glucose in NIDDM patients, we studied the blood/urine glucose relationship in 24 NIDDM patients. RTglu estimated from 75 contemporary blood and urine glucose concentrations measured at home by each patient (h-RTglu) was compared with RTglu measured by a hyperglycaemic glucose clamp (c-RTglu). H-RTglu and c-RTglu, being 7.6 mmol/1 (range 5.5-12.4) and 10.3 mmol/1 (6.2-12.3) respectively (P < 0.005), were weakly correlated (R(S) = 0.35, P = 0.15). In conclusion, c-RTglu varies two-fold between NIDDM patients. RTglu detected by home monitored urine and blood glucose determinations underestimates the true RTglu, probably due to the splay phenomenon. However, the method for detection of RTglu used by us seems of clinical relevance, since it reflects the individual blood glucose level at which glucose is detectable in the urine.

The effect of acute hyperglycemia on the plasma C-peptide response to intravenous glucagon or to a mixed meal in insulin-dependent diabetes mellitus.

The dose-response relationships between prestimulatory blood glucose concentration and the plasma C-peptide responses to stimulation with 1 mg of glucagon iv or a standard mixed meal were studied in 8 C-peptide positive patients with insulin-dependent diabetes mellitus. Hyperglycemia was maintained for 90 min before stimulation using a hyperglycemic clamp technique. Each test was performed at the steady state blood glucose levels approximately 5, approximately 12, and approximately 20 mmol/l. The glucose potentiation of the incremental plasma C-peptide area under the curve at the two levels of hyperglycemia in percent of the area at normoglycemia (median and range) was 343% (53-1053) (p less than 0.05) and 341% (267-1027) (p less than 0.05) after glucagon and 140% (76-227) (NS) and 251% (95-1700) (p less than 0.05) after the meal. The corresponding relative glucose potentiation of plasma C-peptide 6 min after stimulation with glucagon was 124% (100-427) (p less than 0.02) and 144% (100-209) (p less than 0.05). There was no significant difference in the degree of glucose potentiation at approximately 12 or approximately 20 mmol/l. Furthermore, there was no significant difference in the degree of glucose potentiation of the different estimated values of B-cell function. In conclusion, the plasma C-peptide responses to iv glucagon or to a standard test meal were markedly potentiated by acute hyperglycemia in insulin-dependent diabetes mellitus. No further potentiation was, however, obtained when the prestimulatory blood glucose concentration was raised above 12 mmol/l.(ABSTRACT TRUNCATED AT 250 WORDS)

Sulfonylureas. Why, which, and how?

Although controversies remain as to the usefulness of sulfonylureas, most evidence is in favor of their use in many if not patients with non-insulin-dependent diabetes mellitus. When used properly, sulfonylureas improve insulin secretion and action, and these effects may be maintained for years. If combined with hypocaloric dietary regulation, rapid- and short-acting sulfonylureas may help patients reach and maintain euglycemia without provoking chronic hyperinsulinemia or weight increase. There is no evidence that sulfonylurea treatment causes beta-cell exhaustion; instead, the antihyperglycemic effect helps improve beta-cell function. Sulfonylurea "failures" are often dietary failures or may be due to late introduction of these drugs, i.e., when beta-cell function is already attenuated. Desensitization of the insulinotropic effect of sulfonylureas may occur but might be avoided by discontinuous (less than 24 h/day) sulfonylurea exposure, i.e., once-daily administration of a short-acting sulfonylurea in a moderate dose. The most important adverse effect of sulfonylureas is long-lasting hypoglycemia, which may lead to permanent neurological damage and even death. This is mainly seen in elderly subjects who are exposed to some intercurrent event, e.g., acute energy deprivation or a drug interaction, i.e., aspirin. Long-acting sulfonylureas may be more likely to promote long-lasting hypoglycemia. The dose-response relationships of sulfonylureas have been poorly investigated, and sulfonylurea therapy should always be initiated and maintained at the lowest possible dose.

Acute actions of sulfonylurea drugs during long-term treatment of NIDDM.

The acute effect of sulfonylurea drugs during long-term treatment was evaluated in two separate studies. In the first study, the levels of plasma glucose, insulin, and C-peptide were measured after intake of 10 mg glyburide alone or together with a standardized mixed meal in 10 non-insulin-dependent diabetes mellitus (NIDDM) patients treated with 10-20 mg glyburide/day for greater than 2 yr. There was no acute effect of glyburide on the insulin and C-peptide responses to the meal or during continued fasting, indicating the absence of an acute insulinotropic action of glyburide during chronic treatment. The glucose increase after the meal was also unchanged, but a significant glucose reduction was found after glyburide intake during continued fasting, suggesting a sustained acute extrapancreatic (hepatic) effect. In the second study, the diurnal glycemic excursions in 8 NIDDM patients chronically and continuously (24 h/day) exposed to glipizide (2.5-7.5 mg 3 times/day) were similar when the drug was taken 30 min before each of the three main meals and when taken immediately before the meals. It is concluded that there is no acute insulinotropic action of sulfonylurea drugs during chronic continuous exposure, whereas an acute extrapancreatic action may prevail. During such exposure, there seems to be no clinical benefit in taking a sulfonylurea 30 min before rather than at the start of a meal.

Metabolic effect of islet B-cell function in insulin-treated diabetes.

We studied the relationship between endogenous insulin secretion and fasting levels of plasma free fatty acids (FFA), plasma acetoacetate plus plasma 3-hydroxybutyrate (total ketone bodies), blood glucose, and HbA1 in 132 diabetic outpatients treated with conventional insulin regimens. Patients were divided into four groups according to plasma C-peptide concentration after intravenous stimulation with glucagon: one group with C-peptide stimulation less than 0.06 nmol/l, one group with C-peptide stimulation 0.06- less than 0.32 nmol/l, one group with C-peptide stimulation 0.32- less than 0.60 nmol/l, and one group with C-peptide stimulation greater than 0.60 nmol/l. According to clinical criteria the prevalence of insulin-dependent diabetes mellitus was approximately 90% in patients with C-peptide stimulation less than 0.32 nmol/l, approximately 25% in patients with C-peptide stimulation from 0.32- less than 0.60 nmol/l, and approximately 10% in patients with C-peptide stimulation greater than 0.60 nmol/l. All metabolic variables were significantly higher in patients without detectable C-peptide in plasma when compared to values found in patients with C-peptide stimulation from 0.06- less than 0.32 nmol/l. These two patient groups also had similar peripheral plasma free insulin levels and were comparable according to age, sex, and body mass index.(ABSTRACT TRUNCATED AT 250 WORDS)

Sensitivity and reproducibility of urinary C-peptide as estimate of islet B-cell function in insulin-treated diabetes.

The aims of the present study were to evaluate the ability of urinary C-peptide determination to demonstrate presence of residual insulin secretion, and to evaluate the reproducibility of urinary C-peptide excretion in 125 insulin-treated diabetic patients. C-peptide was determined in two consecutive 24-h urine specimens and related to plasma C-peptide 6 min after the intravenous injection of 1 mg glucagon. The detection limit of C-peptide in plasma was defined analytically (greater than or equal to 0.02 nmol l-1) and from pancreatectomized patients (greater than or equal to 0.06 nmol l-1), and in urine only analytically (greater than or equal to 0.1 nmol l-1). If the analytical detection limit of plasma C-peptide was used as indicator of residual insulin secretion, islet B-cell function was preserved in all patients. In patients with stimulated plasma C-peptide levels from 0.02- less than 0.06 nmol l-1 no increase was found in plasma C-peptide values after stimulation with glucagon. This unresponsiveness of islet B-cells is in good agreement with the existence of a biological detection limit of C-peptide in plasma of 0.06 nmol l-1. Using this biological plasma C-peptide detection limit, 49 of 125 patients were without residual insulin secretion. In contrast to this, only 7 patients were diagnosed as C-peptide nonsecretors using the analytical detection limit of urinary C-peptide. Eighty-four per cent of patients considered to have Type 1 (insulin-dependent) diabetes with a duration of diabetes of more than 15 years had detectable C-peptide in the urine.(ABSTRACT TRUNCATED AT 250 WORDS)

Fasting plasma C-peptide, glucagon stimulated plasma C-peptide, and urinary C-peptide in relation to clinical type of diabetes.

Many patients with Type 2 (non-insulin-dependent) diabetes mellitus are treated with insulin in order to control hyperglycaemia. We studied fasting plasma C-peptide, glucagon stimulated plasma C-peptide, and 24 h urinary C-peptide in relation to clinical type of diabetes in 132 insulin treated diabetic subjects. Patients were classified clinically as Type 1 (insulin-dependent) diabetic subjects in the presence of at least two of the following criteria: 1) significant ketonuria, 2) insulin treatment started within one year after diagnosis, 3) age of diagnosis less than or equal to 40 years, and 4) weight below 110% of ideal weight of the same age and sex. Eighty patients were classified as Type 1 and 52 as Type 2 diabetic subjects. A second classification of patients into 6 C-peptide classes was then performed. Class I consisted of patients without islet B-cell function. Class II-VI had preserved islet B-cell function and were separated according to the 20%, 40%, 60% and 80% C-peptide percentiles. The two classifications of patients were compared by calculating the prevalence of clinical Type 1 and Type 2 diabetes in each of the C-peptide classes. This analysis showed that patients with a fasting plasma C-peptide value less than 0.20 nmol/l, a glucagon stimulated plasma C-peptide value less than 0.32 nmol/l, and a urinary C-peptide value less than 3.1 nmol/l, or less than 0.54 nmol/mmol creatinine/24 h, or less than 5.4 nmol/24 h mainly were Type 1 diabetic patients; while patients with C-peptide levels above these values mainly were Type 2.(ABSTRACT TRUNCATED AT 250 WORDS)

The beta-cell response to glucagon and mixed meal stimulation in non-insulin dependent diabetes.

The aim of this study was to evaluate the correlations of the C-peptide and insulin responses after stimulation with glucagon intravenously as well as the 24-h urinary excretion of C-peptide to the C-peptide response to a standard mixed meal in 30 patients with non-insulin dependent diabetes mellitus (NIDDM). Fasting plasma C-peptide as well as the C-peptide and insulin responses to glucagon, showed similar but only modest correlations with the C-peptide response to the meal. Urinary C-peptide showed no correlation with the C-peptide response to the meal, but correlated modestly with fasting plasma C-peptide (r = 0.55, p less than 0.01). The C-peptide and insulin responses after meal stimulation correlated modestly inversely with HbA1. In conclusion, measurement of C-peptide in fasting state, as well as measurements of C-peptide and insulin after glucagon stimulation, only modestly predict the C-peptide response to physiologic stimulation in NIDDM. Twenty-four-hour urinary C-peptide excretion does not predict this response. Patients with NIDDM seem to show a better metabolic control if they have a more pronounced beta-cell response to physiologic stimulation.

Insulin requirement in non-insulin-dependent diabetes mellitus: relation to simple tests of islet B-cell function and insulin sensitivity.

Evaluation of simple tests of islet B-cell function and insulin sensitivity as predictors of metabolic control was performed during 3 months of insulin withdrawal in 25 insulin-treated diabetic subjects. All patients had a glucagon stimulated plasma C-peptide concentration above 0.33 nmol/l and a fasting plasma C-peptide concentration above 0.20 nmol/l a few days before insulin withdrawal. Insulin sensitivity was measured as the glucose disappearance rate (k) during an intravenous insulin tolerance test. Two patients were considered insulin-requiring due to high fasting blood glucose levels (greater than 20 mmol/l) and two patients due to an increase in glycosylated haemoglobin of more than 1.1% (greater than approximately 3SD) in combination with weight loss. None of the remaining patients had a significant increase in glycosylated haemoglobin. An inverse correlation was found between stimulated C-peptide levels and insulin sensitivity (r = 0.41, p less than 0.05). Fasting and stimulated C-peptide concentrations of 0.40 and 0.70 nmol/l, respectively, separated non-insulin-requiring patients from a group consisting of both insulin- and non-insulin-requiring patients. At these C-peptide levels the predictive value of a positive test was 100% while the predictive value of a negative test was as low as 33% or 27% depending on whether fasting or stimulated C-peptide concentration was used. Including the k value in the prediction only increased the predictive values of negative tests to 40% and 33%, respectively.

Interaction of ethanol and glipizide in humans.

The hypoglycemic effect of 2.5 mg glipizide and the potentiation of this effect by ethanol were studied in 10 normal-weight nondiabetic subjects. The reductions in blood glucose concentrations were similar in time of onset and extent (2 mM) whether glipizide was taken alone or in combination with ethanol. However, the return of blood glucose toward fasting level was delayed by ethanol. Beta-Cell secretory activity, evaluated from the concentrations of insulin and C-peptide, was unchanged by ethanol. The serum glipizide concentrations were reproducible within subjects, whereas there was a considerable interindividual variation. This heterogeneity in the rise in glipizide concentration was strongly correlated with blood glucose fall and insulin secretion. Thus, ethanol can prolong but does not augment the hypoglycemia induced by glipizide. The heterogeneity in glipizide concentration seems to be caused by an interindividual variation in kinetics.

Reproducibility of beta-cell function estimates in non-insulin-dependent diabetes mellitus.

We evaluated the reproducibility of different estimates of endogenous insulin secretion in 30 patients with non-insulin-dependent diabetes mellitus (NIDDM). Fasting blood glucose concentration was similar on the 2 days of study. The coefficients of variation of fasting plasma C-peptide, plasma C-peptide 6 min after the injection of 1 mg i.v. glucagon, and the increment in plasma C-peptide after glucagon were 16.0, 14.8 and 24.1%, respectively. The coefficients of variation of the corresponding plasma insulin values were 19.2, 24.8, and 34.8%, respectively. The coefficient of variation of 24-h urinary C-peptide excretion was 22.1%. Because fasting plasma C-peptide correlated closely with plasma C-peptide 6 min after glucagon (test 1: r = .70, P less than .01; test 2: r = .76, P less than .01), it seems that these two values can be used equally well as assessment of beta-cell function in NIDDM. In conclusion, fasting plasma insulin, fasting plasma C-peptide, and plasma C-peptide 6 min after glucagon stimulation showed a similar and acceptable degree of reproducibility. Plasma insulin 6 min after glucagon and increments in plasma insulin and C-peptide, as well as urinary C-peptide, seem to be less reproducible.

Correlations between fasting plasma C-peptide, glucagon-stimulated plasma C-peptide, and urinary C-peptide in insulin-treated diabetics.

This study correlated fasting plasma C-peptide (CP), plasma CP 6 min after stimulation with 1 mg glucagon i.v., and the mean of three 24-h urinary excretions of C-peptide (UCP)/creatinine in 132 insulin-treated diabetics. Patients were divided into three groups: group 1, stimulated CP less than 0.06 nM (n = 51); group 2, stimulated CP 0.06-0.60 nM (n = 48); and group 3, stimulated CP greater than 0.60 nM (n = 33). In all patients fasting CP was closely correlated to stimulated CP (r = .988, P less than .001), whereas the correlations between UCP and both fasting CP (r = .904, P less than .001) and stimulated CP r = .902, P less than .001) were slightly less pronounced. The associations between UCP and both fasting CP (r = .716, P less than .001) and stimulated CP (r = .731, P less than .001) were modest in group 2, and even more so in group 3 (r = .557, P less than .001 and r = .641, P less than .001, respectively). In conclusion, fasting CP is closely correlated to glucagon-stimulated CP in insulin-treated diabetics and can probably be used equally well in the assessment of beta-cell function. The associations between UCP and both fasting and glucagon-stimulated CP are less pronounced, especially in patients with well-preserved beta-cell function.

Prevalence of fasting hyperglycemia and known non-insulin-dependent diabetes mellitus classified by plasma C-peptide: Fredericia survey of subjects 60-74 yr old.

A Danish population of 5699 individuals (60-74 yr old) was screened by fasting blood glucose (FBG) and interviewed about known diabetes. The distribution of FBG in individuals not known to have diabetes showed no sex difference or significant variation with age. Fasting hyperglycemia (FH), defined as FBG greater than or equal to mM in subjects without a history of diabetes, was found in 1.7% of men and women. Known diabetes (KD) had a prevalence of 3.9 and 5.0% in men and women, respectively. The prevalence rates of FH and KD increased significantly with age. In the two subgroups, plasma C-peptide was measured after overnight fasting and subsequently 6 min after an intravenous injection of glucagon. Based on the distribution of the C-peptide concentrations in non-insulin-treated KD subjects, lower limits for non-insulin-dependent diabetes mellitus (NIDDM) of 0.30 pmol/ml for fasting C-peptide and 0.60 pmol/ml for stimulated C-peptide were arbitrarily chosen. According to these cutoff points, only 38.5% of KD subjects treated with insulin had insulin-dependent diabetes mellitus, corresponding to 9.3% of all KD subjects. After exclusion of these patients, the prevalence of recognized NIDDM was 3.5% in men and 4.5% in women. All FH subjects except one had C-peptide values in the NIDDM interval. A close agreement between fasting and glucagon-stimulated C-peptide was seen. In epidemiological studies with an expected high prevalence of NIDDM, we propose to use fasting C-peptide for classification of patients with insulin-treated diabetes.

ELISA for human proinsulin.

A micro enzyme-linked-immunosorbent-assay (ELISA) for monitoring circulating human proinsulin (hPI) was developed. A micro test plate was coated with guinea pig anti-insulin antibody. As labelling system peroxidase-labelled F(ab1)2-fragments of a guinea pig anti-human-C-peptide was used. The detection limit in buffer (95% level) was 0.6 pmol/l corresponding to 0.06 fmol/incubation well and to 1.2 pmol/l in serum, since samples were diluted 50%. Standard operating range was from 0-160 pmol/l. Interassay variation was 9% estimated from two human control materials (assayed within the range 6-9 pmol/l and 9-14 pmol/l, respectively). Insulin in samples did not interfere in concentrations below 400 pmol/l. Human C-peptide, porcine, and bovine proinsulins did not cross-react even at 10 000 pmol/l. In 38 healthy fasting subjects a reference range less than 1.2-13 pmol/l with a median of 4.1 pmol/l was found. Serum from total pancreatectomised patients showed values below the detection limit. The value from a patient with an insulinoma was 263 pmol/l. When stored at -20 degrees C human proinsulin appeared stable in serum or plasma for at least 9 mth. This ELISA, although among the most sensitive immunoassays for human proinsulin, is still not sensitive enough to measure the concentrations expected in samples from IDDM patients in the fasting state. In spite of this the method is useful in characterising beta-cell function in stimulated situations, as well as in the diagnosis of insulinoma.

The effect of residual beta-cell function on the development of diabetic retinopathy.

The effect of residual B-cell function on retinopathy was evaluated in a cross-sectional study of 533 insulin-dependent diabetic patients (disease duration 0 to 45 years). One hundred and fifty-three patients with residual B-cell function, as evaluated by stimulated plasma C-peptide concentration, had lower prevalence of retinopathy than patients without B-cell function. The patients with B-cell function had a shorter duration of diabetes and were older at onset, but there was no difference in age at the time of the study. When patients with similar duration of diabetes were compared, no differences in the degrees of retinopathy could be demonstrated between patients with and without B-cell function. These results indicate that residual B-cell function does not protect against or delay the development of diabetic microvascular lesions.

C-peptide: an index of insulin secretion.

Insight into the natural history of beta cell function in IDDM patients obtained by C-peptide measurements is reviewed. It is argued that residual insulin secretion of metabolic importance is present in all IDDM patients during the initial course of the disease. After some months, beta cell function reaches its maximum; thereafter it declines at different rates dependent on the age at onset of diabetes and, possibly, on the presence of ICA and HLA-antigens. As many as 15% of IDDM patients retain life-long beta cell function that persists at approximately 10% of that observed in nondiabetic individuals. The residual endogenous insulin secretion is characterized by reduced capacity, as well as abnormal insulin secretory kinetics; these defects in residual insulin secretion can be modulated by changes in metabolic regulation as well as by immunosuppression during the initial course of the disease.

The effect of insulin deprivation on fasting levels of 5000 dalton gastric inhibitory polypeptide in type 1 (insulin-dependent) diabetics.

To investigate whether metabolic decompensation has an effect on gastric inhibitory polypeptide (GIP), 8 fasting male type 1 diabetics were deprived of insulin for 12 h. An overnight insulin infusion aiming at normoglycaemia was stopped at 08.00 h. During the following 12 h blood glucose increased from 7.0 +/- 0.4 to 14.9 +/- 1.0 mmol/l, P less than 0.01, 3-hydroxy-butyrate from 0.18 +/- 0.07 to 4.00 +/- 0.74 nmol/1, P less than 0.01, and immunoreactive GIP (IR-GIP) from 16.7 +/- 2.6 to 21.9 +/- 2.9 pmol/1, P less than 0.05. The antiserum employed, R65, only measures 5000 dalton IR-GIP. The final IR-GIP concentrations were not significantly different from fasting IR-GIP concentrations in 13 normal male subjects (17.4 +/- 1.5 pmol/1). Short term insulin deprivation therefore is associated with a slight increase in fasting IR-GIP concentrations. Whether this modest increase in IR-GIP significantly enhances insulin secretion is unknown.

Beta-cell function and diabetic control in insulin dependent diabetes melletus.

Beta-cell function, as evaluated from plasma C-peptide measurements, is found in all insulin dependent diabetic patients the first months of disease and in about 15% of patients with more than 15 years of treatment. The beta-cells are capable of modulating their secretory activity in response to changes in blood glucose. Even a minimal residual insulin secretion is of metabolic significance.