Human C-peptide in normal and diabetic subjects

Concentrations of human C-peptide, IRI (immunoreactive insulin) and glucose were determined during oral glucose tolerance test (1.75 g glucose/kg ideal body weight) in 14 normal persons (N), 9 maturity-onset diabetics (DI) and 10 insulin-requiring diabetics (DII) never treated with insulin and in 3 formerly insulin treated diabetics. The mean fasting levels of C-peptide and IRI in the first three groups were: N: 0.37 +/- 0.02 nM and 0.048 +/- 0.009 nM, DI: 0.86 +/- 0.17 nM and 0.11 +/- 0.029 nM, DH: 0.37 +/- 0.04 nM and 0.063 +/- 0.009 nM. One hour after oral glucose ingestion, the respective values increased to: N: 2.53 +/- 0.20 nM and 0.52 +/- 0.077 nM, DI: 2.49 +/- 0.31 nM and 0.49 +/- 0.11 nM, DH: 0.49 +/- 0.05 nM and 0.11 +/- 0.014 nM. Although secreted from the pancreas in equimolar concentrations, the molar ratio of C-peptide to insulin in peripheral blood was about 7 in the fasting state, falling to about 5 in the glucose stimulated condition. Maturity-onset diabetics had higher fasting levels of C-peptide than normal subjects, in agreement with the IRI levels. Three patients previously treated with insulin and having insulin antibodies showed C-peptide responses significantly below the normal range. In one of these patients, the test was repeated 9 months later when the insulin antibodies had disappeared, and the C-peptide response observed at that time was much higher. It is suggested that insulin antibodies cause an impaired IRI - and consequently C-peptide response - by constantly removing insulin from the granules in the B-cell. In normal humans the peripheral C-peptide responses to the oral glucose load showed less relative variation than do the insulin responses. Therefore, a radioimmunoassay for C-peptide in addition to the assay for insulin will provide supplementary information on insulinsecretion.     

C-Peptide in children with juvenile diabetes

Summary Serum C-peptide, insulin-binding IgG and total insulin (IRI) were determined in 96 juvenile diabetics aged 4–21 years, with onset of diabetes at the age of 1–16 years and with 2–17 years' duration of diabetes. Thirty-four patients (35.4%) had detectable levels of C-peptide ( 0.04 pmol/ml). Compared to non-diabetic adults, 19 had values below the normal range, 12 showed values within the normal range (0.18–0.63 pmol/ml) and 3 rated above normal. There was a negative correlation between the fasting C-peptide concentration and the degree of ketonuria at the onset of diabetes and a positive correlation between C-peptide levels and the incidence of postinitial remission periods. Patients without detectable C-peptide had significantly higher levels of insulin antibodies than those who had detectable levels of C-peptide. The possibility of a relationship between the intensity of the initial treatment of diabetes and the preservation of the B-cell function is discussed, as well as the possibility of insulin antibodies being a cause of B-cell exhaustion.     

A 2-year pilot trial of continuous subcutaneous insulin infusion versus intensive insulin therapy in patients with newly diagnosed type 1 diabetes (IMDIAB 8)

In a pilot study, the metabolic effects of continuous subcutaneous insulin infusion (CSII) versus intensive subcutaneous insulin therapy (ISIT) started at diagnosis in patients with Type 1 diabetes and continued for a 2-year period were evaluated and compared. Twenty-three patients (between 12 and 35 years old, mean +/- SD 18.4 +/- 9 years) were randomized into two treatment groups (CSII vs. ISIT), and both received supplemental nicotinamide (NA), 25 mg/kg of body weight. CSII was started immediately after admission to the hospital. Parameters of metabolic control [insulin dose, hemoglobin A1c (HbA1c), and C-peptide] were evaluated for a 2-year follow-up period. Data are presented for a total of 19 patients who remained in the study for its duration. Two years after diagnosis, mean +/- SD HbA1c was 6.3 +/- 0.5% and 6.2 +/- 0.3% for the CSII and ISIT groups, respectively (p=not significant). Compared with baseline values, an increase of baseline C-peptide of 38% for the CSII group and 27% for the ISIT group was observed; however, the difference between the groups was not significant. The insulin requirement for the entire duration of the study, but not at entry and 3 months, was significantly higher in CSII compared with ISIT patients (0.62 +/- 0.4 IU/kg/day vs. 0.3 +/- 0.4 IU/kg/day, respectively; p<0.01). After trial completion patients on CSII continued with this mode of therapy. Implementation of CSII as well as ISIT at diagnosis of Type 1 diabetes and continuation for 2 years thereafter achieved similar and optimal metabolic control, but more insulin was required with the CSII group. Both types of intensive insulin therapy combined with NA are able to preserve C-peptide secretion or even increase baseline levels for up to 2 years after diagnosis.     

Enhancement of B-cell secretion by blood glucose normalization in type 2 diabetes is associated with fasting C-peptide levels

OBJECTIVES: To investigate (i) the variability of beneficial effects achieved by short-term near-normalization of blood glucose in type 2 diabetes patients, and (ii) the relationship of beneficial effects to individual characteristics of diabetes. DESIGN: Arginine-induced insulin and glucagon release tested at two glucose levels before and after 3 days of intensive insulin treatment. SETTING: The Department of Endocrinology and Diabetology, Karolinska Hospital, Stockholm, Sweden. SUBJECTS: Type 2 diabetes patients with poor metabolic control sampled from an area-based population of diabetes patients. RESULTS: Levels of fasting blood glucose declined from 15.0 +/- 0.9 to 8.5 +/- 0.7 mmol L-1, C-peptide from 0.81 +/- 0.06 to 0.49 +/- 0.05 nmol L-1 and percent proinsulin (of total IRI) from 7.8 +/- 1.0 to 3.2 +/- 0.6%. At comparable glucose levels arginine-induced insulin secretion was enhanced 46.3 +/- 19.5% (range -36 to 220%). Enhancement correlated with extent of blood glucose normalization and also with fasting C-peptide levels and with overweight. Arginine-induced glucagon secretion was nonsignificantly depressed (17.2 +/- 7.4%, range -59 to 29%). Insulin sensitivity assessed by M:I ratio was increased by a median of 95%. CONCLUSIONS: In type 2 diabetes patients reversibility of the effects of poor metabolic control on B-cell function is variable. Variability is related to B-cell mass in individual patients with type 2 diabetes.     

HLA-types,C-peptide and insulin antibodies in juvenile diabetes

Summary HLA-types were determined in 102 juvenile diabetics. HLA-B8 was found in 39 patients (RR 2.64; p < 0.01) and HLA-BW15 in 32 patients (RR 1.33; n.s.). HLA-B7 was found in 14 patients (RR 0.40; p < 0.05). There were no correlations between HLA-B8 or BW15 and family history of diabetes, occurrence of infection before onset of diabetes, ketonuria at onset or the age at onset of diabetes. Serum C-peptide, insulin binding capacity of IgG and total serum insulin, IRI, were determined in 94 patients who had had diabetes for more than two years and who were beyond the remission period. Measurable amounts of C-peptide were found in 33 patients (34.7%). There was no evidence of a relationship between any particular HLA-antigen and the B-cell function except for an increased incidence of detectable C-peptide in patients with HLA-B18 and a tendency to a decreased incidence of detectable C-peptide in patients with the combination HLA-B8, W15. Only four patients (4.3%) were lacking insulin antibodies. HLA-BW15 positive patients had higher levels of insulin antibodies than other groups, while HLA-B7 positive patients had lower levels. The results suggest that HLA-B7 and HLA-B 18 might be associated with a different and perhaps milder form of juvenile diabetes.This work was supported by the Swedish Medical Research Council no 16X-3557 and no 19X-04 528, by the Swedish Diabetic Association and by the Medical Faculty, Linköping University, Sweden     

Altered C-peptide/insulin molar ratios and glucose turnover rates after stimulation in nondiabetic offsprings of type II diabetic patients

We evaluated the serum glucose/insulin/C-peptide dynamics and C-peptide/insulin molar ratios during sequential standard meal and intravenous (IV) glucagon testing for 240 minutes in eight genetically predisposed but nondiabetic female offsprings of type II diabetic patients and seven weight-matched, normal female controls. Glucose turnover rates and metabolic clearance rates of glucose (MCRG) were also determined isotopically by the D-[3-3H]glucose infusion technique. All the subjects had normal fasting serum glucose and glycosylated hemoglobin (HbA1) values. After meal ingestion, mean serum glucose concentrations were not different except for 120 to 180 minute values, which were significantly higher in the offsprings v controls. After intravenous glucagon infusion, percent maximum increments of glucose were no different. Mean basal immunoreactive insulin (IRI) levels were significantly (P less than 0.02) higher in the nondiabetic offsprings v controls. Following meal ingestion, mean IRI rose to a peak at 40 minutes in both groups, but values were significantly (P less than 0.001) higher in the offsprings v controls. After glucagon administration, the percent maximum increment was significantly (P less than 0.05) lower in the offsprings v controls. Despite exaggerated IRI levels in the offsprings, the mean fasting and stimulated C-peptide levels were identical in both groups throughout the study period. Basal and stimulated C-peptide/IRI molar ratios were quantitatively lower but qualitatively no different in the nondiabetic offsprings v controls throughout the study period. Mean basal hepatic glucose output (HGO) was higher but not statistically different in the offsprings compared with the controls (2.10 +/- 0.28 v 1.65 +/- 0.15 mg/kg X min).(ABSTRACT TRUNCATED AT 250 WORDS)     

C-peptide and insulin ratio in patients with juvenile dyspituitarism in varying symptomatology]

Altogether 24 adolescents with pubertal juvenile dyspituitarism (PJD) were investigated in the course of an oral GTT for 3 hours. The patients were divided into 3 groups: (1) with liver dysfunction and normal BP; (2) with normal liver and arterial hypertension; (3) with normal BP and normal liver function. The levels of glycemia, immunoreactive insulin, C-peptide and a molar C-peptide/insulin ratio were measured. All the examinees were characterized by basal and stimulated hyperinsulinemia against a background of a normal C-peptide value, the absence of a tendency to IRI reduction by the end of the GTT. A decrease in the C-peptide/IRI ratio was marked in the 1st group. One of the reasons of hyperinsulinemia in PJD in parallel with high insulin secretory pancreatic function can be a decrease in the metabolic clearance of liver insulin, especially noticeable in patients with hepatocyte dysfunction.     

Infusion of synthetic human C-peptide does not affect plasma glucose, serum insulin, or plasma glucagon in healthy subjects

We studied six healthy male subjects to determine whether a four-hour infusion of synthetic human C-peptide sufficient to achieve mean (+/- SD) peripheral plasma concentrations of 1.3 +/- 0.7 pmol/mL affected plasma glucose, serum insulin, or plasma glucagon. Subjects were studied in a fasting state and following an oral glucose load during four-hour 0.9% NaCl (control) and C-peptide (mean dose: 70 nmol) infusions. No differences were observed between saline and C-peptide infusions for mean values of fasting plasma glucose (94 +/- 6 v 87 +/- 5 mg/dL), serum insulin (3 +/- 1 v 2 +/- 1 microU/mL), or plasma glucagon (124 +/- 65 v 112 +/- 70 pg/dL). Following oral glucose ingestion no differences were detected between saline and C-peptide infusions for mean peak values of plasma glucose (168 +/- 18 v 168 +/- 31) and serum insulin (59 +/- 6 v 57 +/- 21) or mean nadir values of plasma glucagon (80 +/- 73 v 75 +/- 70). There was a slight delay in the insulin rise following oral glucose on the C-peptide infusion day, but differences between mean values for individual sampling times were not statistically significantly different.     

Continuous subcutaneous insulin infusion (CSII) versus conventional injection therapy in newly diagnosed diabetic children: two-year follow-up of a randomized, prospective trial

The effect of continuous subcutaneous insulin infusion (CSII), begun at diagnosis, on blood glucose control and endogenous insulin production was studied in a group of consecutively referred newly diagnosed diabetic children. In a random order, 15 children started CSII (age 9.5 +/- 4.2 (+/- SD) years) and 15 conventional injection therapy (age 7.0 +/- 3.6 years). For 2 years HbA1 and urinary C-peptide were measured monthly, C-peptide responses to glucagon 6-monthly, and insulin antibodies every 3 months. None of the patients requested change of therapy during the study period, but at 28 months 1 adolescent girl changed to injection therapy from CSII. Severe hypoglycaemia was observed once in each group, but ketoacidosis only once, in the injection therapy group. From 2 months after diagnosis onwards the CSII group had significantly lower HbA1 levels. Urinary and plasma C-peptide levels did not differ between the two groups and similar insulin doses were used throughout the study. At the end of the 2 years of therapy, the CSII group had significantly lower insulin antibody levels. The observations suggest that CSII is well accepted in newly diagnosed children and improves metabolic control, but does not prolong endogenous insulin production.     

Serum C-peptide concentrations and their value in evaluating the usefulness of insulin therapy in elderly diabetics

Serum C-peptide concentrations were determined in 121 elderly subjects: 25 nondiabetic controls aged 69-86 years, and 96 type 2 (noninsulin-dependent diabetes mellitus) diabetics aged 64-96 years. Forty-seven of the diabetics were treated with tablets, 35 with insulin, and 14 with diet alone. Fasting serum C-peptide concentrations (nmol/l; mean +/- SD) were 0.51 +/- 0.20 for controls; 0.60 +/- 0.16 for diabetics on diet alone; 0.72 +/- 0.33 for diabetics on tablets and 0.46 +/- 0.23 for diabetics on insulin (p less than 0.001 for diabetics on tablets vs. controls and diabetics on tablets vs. diabetics on insulin). The glucagon-stimulated C-peptide concentrations were similar in all groups; the increment after glucagon was less in the diabetic patients on tablets or on insulin than in the nondiabetics. In 10 patients on insulin treatment and with fasting C-peptide of 0.24-1.46 nmol/l an attempt was made to withdraw insulin. In 4 subjects the transfer to tablets was possible. Serum C-peptide level did not predict the outcome of the attempt to change the therapy, but the possibility of an adequate dietary regimen seemed to be important. The results demonstrate a wide range of basal C-peptide concentrations in elderly diabetics on different treatments, which may indicate varying pathogenetic contributions of insulin deficiency and resistance in these patients. Our observations emphasize the necessity for regular re-evaluation of the therapeutic management of elderly diabetic patients.     

C-peptide and glucagon profiles in minority children with type 2 diabetes mellitus

The present study was conducted to determine the extent of insulin deficiency and glucagon excess in the hyperglycemia of type 2 diabetes in children. The incidence of type 2 diabetes mellitus in children and adolescents has increased substantially over the past several years. Because insulin and glucagon action both regulate blood glucose concentration, we studied their responses to mixed meals in children with type 2 diabetes. Subjects were 24 patients with type 2 diabetes compared with 24 controls, aged 9--20 yr (predominantly African-Americans), matched for body mass index and sexual maturation. All of those with diabetes were negative for antibodies to glutamic acid decarboxylase. Plasma glucose, glucagon, and serum C-peptide concentrations were measured at 0, 30, 60, 90, and 120 min after a mixed liquid meal (Sustacal) ingestion (7 mL/kg body weight; maximum, 360 mL). The area under the curve (AUC) was calculated by trapezoidal estimation. The incremental C-peptide (Delta CP) in response to the mixed meal was calculated (peak -- fasting C-peptide). The plasma glucose AUC was significantly greater in patients than in controls (mean +/- SEM, 1231 +/- 138 vs. 591 +/- 13 mmol/L x min; P < 0.001). The Delta CP was significantly lower in those with diabetes than in controls (1168 +/- 162 vs. 1814 +/- 222 pmol/L; P < 0.02). Glucagon responses did not differ between the two groups. Hyperglycemia is known to inhibit glucagon secretion. Therefore, our patients with substantial hyperglycemia would be expected to have decreased glucagon responses compared with controls and are thus relatively hyperglucagonemic. Patients were divided into poorly and well controlled subgroups (glycosylated hemoglobin A(1c), > or =7.2% and <7.2%, respectively). There were no significant differences in the Delta CP and glucagon responses between these two subgroups. We next analyzed the data in terms of duration of diabetes (long term, > or =1 yr; short term, <1 yr). The CP was significantly lower in long- vs. short-term patients (768 +/- 232 vs. 1407 +/- 199 pmol/L; P < 0.05). The plasma glucagon AUC was significantly higher in the long- vs. short-term patients (9029 +/- 976 vs. 6074 +/- 291 ng/L x min; P < 0.001). Hemoglobin A(1c) did not differ between long- vs. short-term patients. Our results indicate that relative hypoinsulinemia and hyperglucagonemia represent the pancreatic beta- and alpha-cell dysfunctions in children with type 2 diabetes. The severity of both beta- and alpha-cell dysfunctions appears to be determined by the duration of diabetes.     

Insulin and C-peptide responses to 75 g oral glucose load in the healthy man

Plasma insulin and C-peptide levels in the fasting state and after a 2-h 75 g oral glucose tolerance test (OGTT) in a large number of healthy subjects are reported. 247 volunteers (134 males, 113 females), aged 13-69 years, who had a negative history of diabetes, no history of significant disease, normal physical examination, normal body weight, normal glucose tolerance, normal blood tests, and who were taking no drugs were studied. Results, mean +/- SEM (range): fasting glucose concentration = 4.64 +/- 0.03 mmol/l (3.10 - 6.10), 1-h glucose concentration = 5.23 +/- 0.10 mmol/l (2.20 - 9.90), 2-h glucose concentration = 4.11 +/- 0.06 mmol/l (2.00 - 6.80); fasting insulin level = 0.088 +/- 0.002 nmol/l (0.03 - 0.28), 1-h insulin level = 0.45 +/- 0.01 nmol/l (0.06 - 1.63), 2-h insulin level = 0.24 +/- 0.01 nmol/l (0.05 - 1.12); fasting C-peptide concentration = 0.60 +/- 0.01 nmol/l (0.14 - 1.34), 1-h C-peptide concentration = 2.17 +/- 0.05 (0.63 - 8.56), 2-h C-peptide concentration = 1.77 +/- 0.04 nmol/(0.35 - 5.74). Fasting insulin and fasting C-peptide concentrations correlated to post-glucose insulin and C-peptide concentrations, respectively. At each sampling-point insulin concentration correlated to C-peptide concentration. After glucose ingestion, both insulin and C-peptide plasma levels correlated significantly with the corresponding glucose levels. During fasting, C-peptide but no insulin level correlated to glucose level.(ABSTRACT TRUNCATED AT 250 WORDS)     

Elevated circulating adiponectin in type 1 diabetes is associated with long diabetes duration

OBJECTIVE: To study circulating adiponectin concentrations in relation to diabetes duration and endogenous insulin secretion in patients with type 1 diabetes. PATIENTS: Patients with haemoglobin A1c (HbA1c) < 6% (reference range 3.6-5.4%) were selected for the study. Twenty-two men and 24 women [age 41.3 +/- 13.8 years (mean +/- SD), diabetes duration 4 months to 52 years] participated. Healthy controls (15 women and nine men, age 41.3 +/- 13.0 years) were also included. Overnight fasting serum samples were analysed for adiponectin, HbA1c, C-peptide and lipoproteins. RESULTS: Significant positive associations were found between adiponectin concentrations and diabetes duration in univariate and multiple regression analyses. Serum adiponectin averaged 9.7 +/- 5.3 [median 8.1, interquartile range (IQR) 3.6] mg/l in patients with diabetes duration less than 10 years and 17.8 +/- 10.7 (median 14.7, IQR 7.5) mg/l in patients with longer duration (P = 0.0001). Among the patients, 24 were without detectable (< 100 pmol/l) and 22 with detectable C-peptide levels (185 +/- 91 pmol/l). C-peptide levels in controls averaged 492 +/- 177 pmol/l. HbA1c was 5.7 +/- 0.6% in patients without detectable C-peptide and 5.6 +/- 0.4% in patients with detectable C-peptide (ns). Serum adiponectin was higher in patients without detectable C-peptide than in patients with detectable C-peptide [17.3 +/- 11.1 vs. 10.6 +/- 5.8 mg/l (P < 0.005)] and in the controls [10.1 +/- 2.9 mg/l (P < 0.001 vs. patients without detectable C-peptide)]. CONCLUSIONS: The increase in circulating adiponectin concentrations in patients with type 1 diabetes appears to be strongly associated with long diabetes duration, irrespective of the metabolic control. Among other factors, a putative role for residual beta-cell function in the regulation of circulating adiponectin levels can be considered but we did not find sufficient evidence for this in the present study.     

Nicotinamide increases C-peptide secretion in patients with recent onset type 1 diabetes

Nicotinamide, a poly-(ADP-ribose) synthetase inhibitor, has been shown in animal models to induce islet B-cell regeneration. An open controlled trial was therefore carried out for 1 year in 36 patients with recent onset (less than 4 weeks symptoms) Type 1 diabetes. Twenty-three patients were treated with nicotinamide (200 mg daily) in addition to insulin, and 13 control patients were treated with insulin alone. Metabolic and immunological variables at entry were similar in the two groups. A significant increase of stimulated plasma C-peptide levels compared to diagnosis was observed only in the nicotinamide treated group (1.4 +/- 0.3 (+/- SE) micrograms l-1 at diagnosis vs 2.4 +/- 0.4 at 6 months, p less than 0.04; and 3.0 +/- 0.5 at 1 year, p less than 0.01). Patients receiving nicotinamide had lower glycosylated haemoglobin levels at 6 months and 1 year compared to the control group (p less than 0.04 and p less than 0.03, respectively) although insulin dose was lower. Small doses of nicotinamide may be successful in improving metabolic control in recent onset Type 1 diabetes, probably by increasing residual islet B-cell function.     

C-peptide replacement improves weight gain and renal function in diabetic rats

AIM: Recent experimental and clinical data suggest that C-peptide replacement during type 1 diabetes exerts beneficial effects on diabetic nephropathy. The aim of this study was to determine if physiological C-peptide administration in replacement dose during 28 days had beneficial effects on metabolic status and renal functions in type-1 diabetic rats. METHODS: Four groups of rats were investigated: a non diabetic group treated with buffer (C group, n=6), three streptozotocin diabetic-induced groups treated with either buffer (D group, n=6), insulin (D-I group, n=6) or rat homologous C-peptide (D-C group, n=6). Weight gain was measured every week. All animals were housed in metabolic cages on day 28 for assessment of metabolic data. Blood and urine samples were collected to allow measurement of plasmatic osmolality, C-peptide concentration, sodium, and glucose losses and proteinuria. Glomerular filtration rate (GFR) was determined by creatinine clearance. RESULTS: All streptozotocin-treated animals were diabetic. Glycaemic control (mg/dl), was markedly improved in D-I (133+/-65) when compared with either D (547+/-49, P<0.05) or D-C (520+/-48, P<0.05) groups. Conversely, weight gain during the study, was improved in D-I and D-C as compared with D animals (135+/-13 and 41+/-18 vs 18+/-21 respectively), despite different glycaemic control. Diabetes-induced glomerular hyperfiltration (ml/min/kg), urinary protein leakage (g/kg/day), and Na urinary losses (mmol/100 g/day) respectively, were significantly (P<0.05) reduced in D-C (3.95+/-0.6; 0.08+/-0.06; 1.5+/-0.9) in comparison with D (4.95+/-0.8; 0.18+/-0.16; 3.7+/-2.1) and D-I (5+/-0.9; 0.19+/-0.11; 2.7+/-0.8) animals. Plasmatic osmolality was significantly increased in D group whereas there were no differences between C group and D-C group. Food and water intakes, urinary volume as well as urinary glucose losses were not significantly different between D-C and D groups. CONCLUSIONS: C-peptide administration in replacement dose to streptozotocin diabetic rats induces weight gain regardless hyperglycaemia or glycosuria. Diabetic animals supplemented with C-peptide exhibit better renal function resulting in reduced urinary sodium waste and protein excretion together with reduction of the diabetes-induced glomerular hyperfiltration.     

Diurnal variation of blood ketone bodies in insulin-dependent diabetes mellitus and noninsulin-dependent diabetes mellitus patients: the relationship to serum C-peptide immunoreactivity and free insulin

We examined whether the rise in ketone body concentration around midnight and in the early morning was due to the lack of free insulin (IRI) or excess of insulin counterregulatory hormones such as human growth hormone (hGH), cortisol and glucagon in noninsulin-dependent diabetes mellitus (NIDDM) and insulin-dependent diabetes mellitus (IDDM) patients and whether the monitoring of blood ketone body concentration was clinically useful as an index of metabolic control for deciding to increase or decrease the insulin dose in the treatment of diabetes mellitus. Serum levels of 3-hydroxybutyrate (3-OHBA), acetoacetate (AcAc) and 3-OHBA/AcAc ratio before breakfast were significantly increased in insulin-treated NIDDM patients with well-controlled fasting plasma glucose levels and IDDM patients compared to those in normal subjects. Mirror image diurnal changes were found between serum concentrations of 3-OHBA and serum C-peptide or free IRI in normal subjects and NIDDM patients treated with diet alone or sulfonylurea during the 24-hour daily profiles. However, there were no correlations between 3-OHBA and free IRI in the NIDDM patients treated with insulin and IDDM patients who had a much larger increase in the mean concentration of serum 3-OHBA at 6 a.m. caused by a low concentration of free IRI. Counterregulatory hormones were not increased in IDDM patients compared to normal subjects in the early morning. Cortisol/free IRI and hGH/free IRI molar ratios were significantly increased in NIDDM and IDDM patients compared to normal subjects in the early morning, but glucagon/free IRI molar ratio was not changed between IDDM and normal subjects. In conclusion, the early morning rising of ketone body concentration in insulin-treated diabetic patients, particularly IDDM patients, is due to the absolute lack of free IRI and/or the relative lack of free IRI to the levels of hGH or cortisol, and the monitoring of 3-OHBA is clinically useful as a more sensitive index of metabolic control.     

The effect of short-term basal insulin supplementation with human ultralente insulin on diurnal glycemic control in NIDDM patients

The effect of short-term insulin treatment with a long-acting insulin preparation, Ultratard HM (U-HM) was investigated in eight non-insulin-dependent diabetes mellitus (NIDDM) patients whose previous glycemic control using diet was judged unsatisfactory. The treatment consisted of one daily pre-breakfast injection of U-HM (0.3 IU/kg) for 8 days. Glycemic control, assessed by mean plasma glucose (PG) daily profile and M-value, was improved significantly after U-HM treatment (mean PG and M-value, before: 223 +/- 19 mg/dl, 38.2; on the last day of U-HM: 151 +/- 11 mg/dl, 16.3; P less than 0.001; P less than 0.05). Serum insulin (IRI) reached a peak at 14:30 h during U-HM treatment, and mean IRI level increased during U-HM treatment (before: 14.0 +/- 2.8; during U-HM: 19.9 +/- 2.7 microU/ml). The mean C-peptide (CP) level decreased during U-HM treatment. Daily urinary CP excretion also decreased during U-HM treatment (before: 52.7 +/- 4.2; during U-HM: 34.8 +/- 4.2 micrograms/24 h). The data indicated that a single daily injection of U-HM was effective to improve whole-day glycemic control in NIDDM patients.     

Persistent insulin secretion,assessed by plasma C-peptide estimation in long-term juvenile diabetics with a low insulin requirement

Summary In order to investigate whether patients with long-standing juvenile diabetes mellitus (onset of diabetes before the age of 30) and a low daily insulin requirement (< 0.50 units/kg body weight) still have functioning B-cells, plasma C-peptide was determined after stimulation (OGTT and glucagon/ tolbutamide) in 64 patients with diabetes of more than 18 years' duration (mean 31 years). Measurable endogenous insulin production was found in 24% of the patients. The prevalence of severe retinopathy was lower in the secretors than in the non-secretor group. There was no difference in insulin antibody concentration between the two groups. Furthermore, the insulin requirement in the secretor group was relatively constant during the course of diabetes. Metabolic control was similar in both groups. It is concluded that a persisting but low activity of endogenous insulin production can be found in many long-term juvenile diabetics with a low insulin requirement, while others without any residual betacell function develop a low insulin requirement for unknown reasons.     

Heterogeneity of non-insulin-dependent diabetes expressed as variability in insulin sensitivity, beta-cell function and cardiovascular risk profile.

AIMS: The present study investigated the variability in insulin sensitivity and beta-cell function and their relationship to anti-glutamic acid decarboxylase (GAD) positivity and the metabolic syndrome in a group of patients with non-insulin-dependent diabetes mellitus (NIDDM). METHODS: Fifty-four subjects aged 59.5 +/- 6.1 (mean +/- SD) years with NIDDM for 7.9 +/- 3.9 years referred to hospital due to poor glycaemic control, were investigated. Insulin sensitivity was determined by the euglycaemic hyperinsulinaemic glucose clamp technique as the glucose disposal rate relative to the insulin level obtained (GDRI), and also estimated with the homeostasis model assessment (HOMA-S). beta-cell function was measured by assaying the fasting and glucagon-stimulated C-peptide levels and with the HOMA-B. RESULTS: The insulin sensitivity varied 18-fold between subjects when estimated with the clamp and six-fold when estimated with HOMA-S, and was lower the more criteria for the metabolic syndrome present (P = 0.0001 by anova). The beta-cell function varied four-fold when measured as stimulated C-peptide, and eight-fold when estimated with the HOMA-B. The levels of fasting C-peptide and HOMA-B values tended to be lower in anti-GAD+ (n = 11) than in anti-GAD-subjects (P = 0.06 and P = 0.08, respectively). From previously published coronary risk charts, we estimated the 10-year risk of a coronary heart disease (CHD) event to be > 20% in 17 of 39 patients free from cardiovascular disease at the time of study, 16 of whom qualified for a diagnosis of the metabolic syndrome. CONCLUSIONS: The wide variations in insulin sensitivity and beta-cell function found among subjects with NIDDM support the notion that the disorder is highly heterogeneous. Reduced insulin sensitivity was clearly related to the metabolic syndrome and an increased risk for CHD.     

Urinary C-peptide as an index of unstable glycemic control in insulin-dependent diabetes mellitus (IDDM)

In order to investigate whether urinary C-peptide (UCP) excretion can be a useful index of insulin-dependent diabetes mellitus (IDDM) with unstable glycemic control, UCP was measured in nine IDDM patients with unstable glycemic control, nine IDDM patients with stable glycemic control, and 12 non-insulin-dependent diabetic (NIDDM) patients treated with insulin. The UCPs in overnight urine (U1) and fasting single void urine (U2) in IDDM patients with unstable glycemic control were significantly lower than those in IDDM patients with stable glycemic control (U1: 0.03 +/- 0.03 vs 0.24 +/- 0.20 nmol/mmol-Creatinine, U2: 0.02 +/- 0.01 vs 0.20 +/- 0.20 nmol/mmol-Cr, mean +/- SD, both P less than 0.01). The UCPs in U1 and U2 in both groups of IDDM were significantly lower than those in NIDDM (U1: 0.97 +/- 0.52, U2: 0.73 +/- 0.41 nmol/mmol-Cr, both P less than 0.01). The UCPs in U1 and U2 significantly correlated with incremental C-peptide response to intravenous glucagon injection and with glycemic stability assessed by the standard deviation of 10 previous fasting plasma glucose levels. These results suggest that UCP reflects their residual insulin secretory capacity and that UCP can be a useful index which distinguishes patients with unstable IDDM from those with stable diabetes mellitus.