Effects of insulin vs. glibenclamide in recently diagnosed patients with type 2 diabetes: a 4-year follow-up.

AIM: To compare effects of early insulin vs. glibenclamide treatment on beta-cell function, metabolic control and quality of life (QL) in recently diagnosed patients with type 2 diabetes. METHODS: Forty-nine patients with type 2 diabetes diagnosed 0-2 years before inclusion were randomized to two daily injections of premixed 30% soluble and 70% NPH insulin or glibenclamide at six diabetic clinics in Sweden. C-peptide-glucagon tests were performed yearly after 3 days of withdrawal of treatment. RESULTS: Thirty-four patients completed 4 years of study. Daily dose of insulin was increased from 20.4 +/- 1.8 U at year 1 to 26.1 +/- 2.9 U at year 4 (p = 0.005). Glibenclamide dosage increased from 2.7 +/- 0.4 mg at year 1 to 4.5 +/- 0.8 mg at year 4 (p = 0.02). Weight increased more in insulin than in glibenclamide treated (+4.4 +/- 0.8 vs. +0.3 +/- 1.0 kg, p < 0.005). Following short-term withdrawal of treatment, the C-peptide responses to glucagon were significantly higher in the insulin vs. glibenclamide group at years 1 (p < 0.01) and 2 (p < 0.02). HbA1c improved identical during the first year but thereafter deteriorated in the glibenclamide group (p < 0.005 for difference at year 4). Ratios of proinsulin to insulin were higher during treatment in glibenclamide- vs. insulin-treated patients after year 2. QL after 4 years as measured by the MOS 36-item Short-Form Health Survey (SF-36) form was not significantly altered. CONCLUSIONS: In a 4-year perspective, beta-cell function deteriorated in both groups. However, deterioration occurred faster in the glibenclamide group, indicating that alleviating demands on secretion by insulin treatment is beneficial.

Effects of C-peptide on forearm blood flow and brachial artery dilatation in patients with type 1 diabetes mellitus.

Recent studies suggest that C-peptide increases blood flow in both exercising and resting forearm in patients with type 1 diabetes. Now we have studied the effect of C-peptide administration on endothelial-mediated and non-endothelial-mediated arterial responses as well as central haemodynamics in 10 patients with type 1 diabetes in a placebo-controlled double-blind study. Euglycaemia was maintained with an i.v. insulin infusion before and during the study. A high-resolution ultrasound technique and Doppler echocardiography were used to assess haemodynamic functions. Brachial artery blood flow and brachial artery diameter were measured in the basal state, 1 and 10 min after reactive hyperaemia and 4 min after sublingual glyceryl trinitrate administration (GTN; endothelial-independent vasodilatation), both before and after the end of 60-min C-peptide (6 pmol kg-1 min-1) or saline infusion periods. Echocardiographic measurements were also performed before and at the end of the infusion periods. Seven healthy age-matched males served as controls for vascular studies. The patients showed a blunted brachial dilatation after reactive hyperaemia in comparison with the healthy controls (2.1 +/- 0.5% vs. 9.3 +/- 0.3%, P < 0.001), indicating a disturbed endothelial function. C-peptide infusion compared with saline resulted in increased basal blood flow (33 +/- 6%, P < 0.001) and brachial arterial dilatation (4 +/- 1%, P < 0.05). Left ventricular ejection fraction seemed to be improved (5 +/- 2%, P < 0.05) at the end of C-peptide infusion compared with placebo. The vascular response to reactive hyperaemia and GTN was not affected by C-peptide infusion. Our results demonstrate that physiological concentrations of C-peptide increase resting forearm blood flow, brachial artery diameter and left ventricular systolic function in patients with type 1 diabetes.

Beneficial effects of C-peptide on incipient nephropathy and neuropathy in patients with Type 1 diabetes mellitus.

AIMS: Recent studies have indicated that proinsulin C-peptide shows specific binding to cell membrane binding sites and may exert biological effects when administered to patients with Type 1 diabetes mellitus. This study was undertaken to determine if combined treatment with C-peptide and insulin might reduce the level of microalbuminuria in patients with Type 1 diabetes and incipient nephropathy. METHODS: Twenty-one normotensive patients with microalbuminuria were studied for 6 months in a double-blind, randomized, cross-over design. The patients received s.c. injections of either human C-peptide (600 nmol/24 h) or placebo plus their regular insulin regimen for 3 months. RESULTS: Glycaemic control improved slightly during the study and to a similar extent in both treatment groups. Blood pressure was unaltered throughout the study. During the C-peptide treatment period, urinary albumin excretion decreased progressively on average from 58 microg/min (basal) to 34 microg/min (3 months, P < 0.01) and it tended to increase, but not significantly so, during the placebo period. The difference between the two treatment periods was statistically significant (P < 0.01). In the 12 patients with signs of autonomic neuropathy prior to the study, respiratory heart rate variability increased by 21 +/- 9% (P < 0.05) during treatment with C-peptide but was unaltered during placebo. Thermal thresholds were significantly improved during C-peptide treatment in comparison to placebo (n = 6, P < 0.05). CONCLUSION: These results indicate that combined treatment with C-peptide and insulin for 3 months may improve renal function by diminishing urinary albumin excretion and ameliorate autonomic and sensory nerve dysfunction in patients with Type 1 diabetes mellitus.

Splanchnic exchange of insulin-like growth factor binding protein-1 (IGFBP-1), IGF-I and acid-labile subunit (ALS) during normo- and hyper-insulinaemia in healthy subjects.

OBJECTIVE: The main source of circulating IGF-I, insulin like growth factor binding protein-1 (IGFBP-1) and acid-labile subunit (ALS) is considered to be the liver, but their production rates have not been determined in healthy individuals. Thus, the splanchnic exchange of IGFBP-1, IGF-I, ALS and glucose were studied. STUDY DESIGN: In five overnight fasting healthy, normal weight men (mean age 29 +/- 1 years) blood samples were taken from a hepatic vein, a brachial artery and a peripheral vein in the basal state and during 3 h i.v. infusion of insulin (1.0 mU/kg/min). Normoglycaemia was maintained with a variable glucose infusion and splanchnic blood flow was determined using a constant rate indicator infusion technique. RESULTS: The basal net splanchnic glucose output amounted 0.96 +/- 0. 09 mmol/min and the splanchnic production of IGFBP-1 was 7 +/- 2 microg/min. There was a net splanchnic uptake of IGF-I (7 +/- 2 microg/min) in the basal state, while no significant splanchnic exchange of ALS was found. During the insulin infusion, insulin concentration increased from 78 +/- 12 to 660 +/- 30 pmol/l, resulting in a complete inhibition of splanchnic glucose production after 40 min of infusion. Splanchnic IGFBP-1 production rose initially to 13 +/- 4 microg/min (P < 0.05) and then gradually decreased and was completely inhibited at 180 min (P < 0.05). Insulin infusion influenced neither ALS nor IGF-I splanchnic exchange. CONCLUSION: Splanchnic production of IGFBP-1 in the basal state was demonstrated and it is completely inhibited after 180 min of hyperinsulinaemia. In contrast to what is generally held, there was no net splanchnic production of IGF-I in the basal state or during insulin stimulation.

Brain substrate utilisation during acute hypoglycaemia.

AIMS/HYPOTHESIS: Our study was undertaken to examine directly the utilisation of glucose and alternative substrates, in particular amino acids, during hypoglycaemia. METHODS: Catheters were positioned in the jugular venous bulb and an artery in six healthy subjects in the overnight fasted state. Arterio-venous differences for glucose, amino acids, lactate and pyruvate were measured in the basal state, during hyperinsulinaemic euglycaemia and during hyperinsulinaemic hypoglycaemia. The subjects were studied on two different occasions, once during intravenous infusion of amino acids and once during infusion of saline. RESULTS: In the basal state the fractional extraction of glucose across the brain was 10 +/- 2%, glucose uptake accounted for 106 +/- 5% of the brain's oxidative metabolism. There was a small release of lactate and pyruvate. During hyperinsulinaemia glucose uptake continued to account for the entire fuel requirement of the brain. Hyperaminoacidaemia did not result in net amino acid uptake by the brain. During hypoglycaemia (2.4 +/- 0.2 mmol/l) fractional extraction of glucose by the brain increased (p < 0.01) and glucose uptake accounted for 90 +/- 15% of the brain's oxidative metabolism. Uptake of amino acids, lactate or pyruvate could not be detected. CONCLUSION/INTERPRETATION: 1) Brain fractional extraction of glucose increases during hypoglycaemia, 2) hyperinsulinaemia does not change fractional extraction of glucose by the brain, 3) augmented availability of amino acids does not result in brain amino acid uptake during euglycaemia or hypoglycaemia and 4) under the present study conditions glucose remains the major substrate for cerebral metabolism during hypoglycaemia; lactate or pyruvate uptake by the brain can not be detected.

Influence of circulating epinephrine and norepinephrine on insulin-like growth factor binding protein-1 in humans.

The aim of the present study was to investigate the influence of circulating epinephrine (Epi) and norepinephrine (Norepi) on serum insulin-like growth factor binding protein-1 (IGFBP-1) concentrations. Healthy men received 0.3 nmol.kg.min Epi iv (n = 6), 0.5 nmol.kg.min Norepi iv (n = 7), or saline (n = 5) during 30 min. Arterial blood samples were obtained before, during, and 120 min after infusion. During the catecholamine infusion arterial Epi and Norepi plasma concentrations reached 6.35 +/- 0.53 and 15.65 +/- 2.71 nmol/L, respectively, which resulted in significant increases in glucose concentrations. When Epi was infused, IGFBP-1 increased from 45 +/- 6 micrograms/L to 76 +/- 10 micrograms/L (P < 0.05) 60 min after the infusion. Epi was also followed by increases in insulin, C-peptide, and glucagon. Norepi resulted in a slight increase in circulating IGFBP-1 (43 +/- 6 to 54 +/- 8 nmol/L, NS). The findings suggest that Epi, at plasma concentrations similar to those reached during physical stress, stimulates the production of IGFBP-1 in humans.

Insulin mediators in man: effects of glucose ingestion and insulin resistance.

Insulin mediators (inositol phosphoglycans) have been shown to mimic insulin action in vitro and in intact mammals, but it is not known which mediator is involved in insulin action under physiological conditions, nor is it known whether insulin resistance alters the mediator profile under such conditions. We therefore investigated the effects of glucose ingestion on changes in the bioactivity of serum inositol phosphoglycan-like substances (IPG) in healthy men and insulin resistant (obese, non-insulin-dependent diabetic) men. Two classes of mediators were partially purified from serum before and after glucose ingestion. The first was eluted from an anion exchange resin with HCl pH 2.0, and bioactivity was determined by activation of pyruvate dehydrogenase in vitro. The second was eluted with HCl pH 1.3, and bioactivity was determined by inhibition of cyclic AMP-dependent protein kinase. In healthy men, the bioactivity of the pH 1.3 IPG was not altered by glucose ingestion, whereas bioactivity of the pH 2.0 IPG increased to approximately 120% of the pre-glucose ingestion value at 60-240 min post-glucose ingestion (p < 0.05 vs pre-glucose). There was no change in either IPG after glucose ingestion in the insulin-resistant group. These data suggest that the pH 2.0 IPG plays an important role in mediating insulin's effect on peripheral glucose utilization in man under physiological conditions. The data further show, for the first time, a defective change in the bioactivity of an insulin mediator isolated from insulin-resistant humans after hyperinsulinaemia, suggesting that inadequate generation/release of IPGs is associated with insulin resistance.

C-peptide revisited--new physiological effects and therapeutic implications.

Recent studies have demonstrated that replacement of C-peptide to normal physiological concentrations in insulin-dependent diabetic (IDDM) patients on a short-term basis (1-3 h) results in decreased glomerular hyperfiltration, augmented glucose utilization and improved autonomic nervous function. More prolonged administration (1-3 months) of C-peptide to IDDM patients is accompanied by improvements in both renal and autonomic nervous function. Moreover, both in-vitro and in-vivo studies indicate that C-peptide may have a role in the regulation of insulin secretion. The effects of C-peptide may in part be explained by its ability to stimulate Na+,K(+)-ATPase activity. In conclusion, the combined findings indicate that C-peptide is a biologically active hormone. The possibility that C-peptide therapy in IDDM patients may be beneficial should be considered.

C-peptide improves autonomic nerve function in IDDM patients.

In order to determine the possible influence of C-peptide on nerve function, 12 insulin-dependent diabetic (IDDM) patients with symptoms of diabetic polyneuropathy were studied twice under euglycaemic conditions. Tests of autonomic nerve function (respiratory heart rate variability, acceleration and brake index during tilting), quantitative sensory threshold determinations, nerve conduction studies and clinical neurological examination were carried out before and during a 3-h i.v. infusion of either C-peptide (6 pmol.kg-1.min-1) or physiological saline solution in a double-blind study. Plasma C-peptide concentrations increased from 0.11 +/- 0.02 to 1.73 +/- 0.04 nmol/l during C-peptide infusion. Clinical neurological examination quantitative sensory threshold evaluations and nerve conduction measurements failed to detect significant changes between C-peptide and saline study periods. Respiratory heart rate variability increased significantly from 13 +/- 1 to 20 +/- 2% during C-peptide infusion (p < 0.001), reaching normal values in five of the subjects; control studies with saline infusion did not alter the heart rate variability (basal, 14 +/- 2; saline, 15 +/- 2%). A reduced brake index value was found in seven patients and increased significantly during the C-peptide infusion period (4.6 +/- 1.0 to 10.3 +/- 2.2%, p < 0.05) but not during saline infusion (5.9 +/- 2 to 4.1 +/- 1.1%, NS). It is concluded that short-term (3-h) infusion of C-peptide in physiological amounts may improve autonomic nerve function in patients with IDDM.

Protein dynamics in whole body and in splanchnic and leg tissues in type I diabetic patients.

To elucidate the mechanism of insulin's anticatabolic effect in humans, protein dynamics were evaluated in the whole-body, splanchnic, and leg tissues in six C-peptide-negative type I diabetic male patients in the insulin-deprived and insulin-treated states using two separate amino acid models (leucine and phenylalanine). L-(1-13C,15N)leucine, L-(ring-2H5)phenylalanine, and L-(ring-2H2) tyrosine were infused intravenously, and isotopic enrichments of [1-13C,15N]-leucine, (13C)leucine, (13C)ketoisocaproate, (2H5)phenylalanine, [2H4]tyrosine, (2H2)tyrosine, and 13CO2 were measured in arterial, hepatic vein, and femoral vein samples. Whole-body leucine flux, phenylalanine flux, and tyrosine flux were decreased (< 0.01) by insulin treatment, indicating an inhibition of protein breakdown. Moreover, insulin decreased (< 0.05) the rates of leucine oxidation and leucine transamination (P < 0.01), but the percent rate of ketoisocaproate oxidation was increased by insulin (P < 0.01). Insulin also reduced (< 0.01) whole-body protein synthesis estimated from both the leucine model (nonoxidative leucine disposal) and the phenylalanine model (disposal of phenylalanine not accounted by its conversion to tyrosine). Regional studies demonstrated that changes in whole body protein breakdown are accounted for by changes in both splanchnic and leg tissues. The changes in whole-body protein synthesis were not associated with changes in skeletal muscle (leg) protein synthesis but could be accounted for by the splanchnic region. We conclude that though insulin decreases whole-body protein breakdown in patients with type I diabetes by inhibition of protein breakdown in splanchnic and leg tissues, it selectively decreases protein synthesis in splanchnic tissues, which accounted for the observed decrease in whole-body protein synthesis. Insulin also augmented anabolism by decreasing leucine transamination.

Effect of insulin on the hepatic production of insulin-like growth factor-binding protein-1 (IGFBP-1), IGFBP-3, and IGF-I in insulin-dependent diabetes.

Insulin-like growth factors (IGFs) circulate attached to binding proteins (IGFBPs). Only the unbound form of IGF is suggested to be biological active. The main source of circulating IGF-I and IGFBP-1 is considered to be the liver, but that of circulating IGFBP-3 is not known. IGF-I and IGFBP-3 are GH dependent, whereas IGFBP-1 is insulin regulated. The aim of the present study was to examine the effect of insulin on the hepatic secretion of IGFBP-1, IGFBP-3, and IGF-I. Seven insulin-dependent diabetic patients in whom insulin was withheld for 12 h were studied in the overnight fasted state. Blood was sampled simultaneously from the hepatic vein, a peripheral vein, and an artery before and during insulin infusion for 3 h. The basal IGFBP-1 levels in the peripheral vein were several-fold elevated (249 +/- 44 micrograms/L) compared to those in healthy subjects (37 +/- 2 micrograms/L). Fasting IGFBP-1 concentrations were inversely correlated to the insulin levels (r = -0.918; P < 0.001). The mean IGF-I concentration (175 +/- 17 micrograms/L; -1.62 +/- 0.38 SD score) was decreased compared with that in age-matched healthy subjects. The basal IGFBP-3 levels in the peripheral vein (4.50 +/- 0.33 mg/L) were within the normal range. There was a significant correlation in the hepatic vein between fasting IGF-I and IGFBP-3 levels (r = 0.928; P < 0.001). Basal splanchnic IGFBP-1 production was 18 +/- 7 micrograms/min, whereas no basal net exchanges of IGF-I or IGFBP-3 were observed across the splanchnic area. Insulin inhibited splanchnic IGFBP-1 production within 120 min and glucose output within 20 min. Serum IGF-I, but not IGFBP-3, concentrations increased significantly during the insulin infusion. In summary, this study demonstrates the existence of considerable IGFBP-1 production from the liver during insulinopenia and the complete blocking of splanchnic IGFBP-1 production and increases in serum levels of IGF-I by insulin despite no effect on IGFBP-3 levels. Thus, insulin may play a role in determining the bioavailability of IGF-I.

Insulin absorption, glucose homeostasis, and lipolysis in IDDM during mental stress.

OBJECTIVE: To study the effects of mental stress on the absorption kinetics of insulin and on glucose homeostasis and lipolysis in insulin-dependent diabetes mellitus (IDDM). RESEARCH DESIGN AND METHODS: Nine IDDM patients were exposed to the Stroop color word conflict test (CWT) during 40 min after injection of 125I-labeled soluble human insulin (10 U) into the abdomen. Adipose tissue blood flow (133Xe-clearance) was determined concomitantly to elucidate the importance of blood flow for insulin absorption during CWT. The effect of the CWT was followed by measurement of arterial levels of catecholamines and as blood pressure and heart-rate responses. Lipolysis was measured as arterial glycerol levels, and ketone body levels were monitored by determination by beta-hydroxybutyrate. RESULTS: Although insulin absorption (residual 125I-radioactivity and plasma free insulin levels) and the arterial levels of glucose and beta-hydroxybutyrate were not significantly changed by the CWT, arterial glycerol and norepinephrine levels and adipose tissue blood flow were approximately doubled, and epinephrine levels increased fourfold. Heart rate increased approximately 35 beats/min and mean blood pressure approximately 25 mmHg. CONCLUSIONS: The results suggest that intense mental stress of 40 min duration does not alter the absorption of subcutaneously injected insulin, glucose homeostasis, or ketone body levels in patients with IDDM, despite a considerable increase in blood flow and lipolysis.

Insulin-induced hypoglycaemia and absorption of injected insulin in diabetic patients.

The effect of insulin-induced hypoglycaemia (soluble insulin 1 mU kg-1 min-1 IV) on the absorption of 125I-labelled soluble insulin (10 U SC) from thigh was studied in 10 insulin-treated Type 1 diabetic patients on a test and a control day. Disappearance of 125I was followed by external gamma counting. Adipose tissue blood flow was measured concomitantly using the 133Xe-clearance technique. Arterial plasma levels of glucose, insulin, adrenaline and noradrenaline were determined intermittently. Hypoglycaemia occurred at a glucose level of 2.2 +/- 0.1 (+/- SE) mmol l-1 after 58 +/- 6 min. Peak levels of adrenaline (6.44 +/- 1.62 nmol l-1) and noradrenaline (2.29 +/- 0.39 nmol l-1) were found 10 min later. During the 30-min period after onset of hypoglycaemia, adipose tissue blood flow increased 132 +/- 45% (p less than 0.05) but the disappearance rate of 125I-insulin was unchanged. Thus, insulin absorption was unaltered in connection with hypoglycaemia in Type 1 diabetic patients, in contrast to the depression previously reported in healthy subjects, despite similar increases in adipose tissue blood flow.

Insulin absorption and subcutaneous blood flow in normal subjects during insulin-induced hypoglycemia.

We studied the effects of insulin-induced hypoglycemia on the absorption of 10 U 125I-labeled soluble human insulin injected sc in the thigh in 10 normal subjects. The disappearance of 125I from the injection site was followed by external gamma-counting. Subcutaneous blood flow (ATBF) was measured concomitantly with the 133Xe washout technique. The plasma glucose nadir [mean, 2.0 +/- 0.1 (+/- SE) mmol/L] occurred at 33 +/- 3 min and resulted in maximal arterial plasma epinephrine concentrations of approximately 6 nmol/L. From 30 min before to 60 min after the glucose nadir the [125I]insulin absorption rate was depressed compared to that during normoglycemia. The first order disappearance rate constants were reduced by approximately 50% (P less than 0.01) during the first 30-min interval after the glucose nadir. During the same period ATBF increased by 100% (P less than 0.05). The results suggest that in normal subjects the absorption of soluble insulin from a sc depot is depressed in connection with hypoglycemia, despite considerably elevated ATBF.