Course of HbA1c in non-diabetic pregnancy related to birth weight.

BACKGROUND: Despite good glycaemic control (according to the internationally accepted level of HbA1c < 7% (53.0 mmol/mol)) the incidence of macrosomia in pregnant women with diabetes is still very high. We measured HbA1c levels in each of the three trimesters of pregnancy in a cohort of healthy women to determine whether the upper reference level for good glycaemic control in diabetic pregnant females should be lower than the internationally accepted level. Secondly we investigated whether changes in HbA1c values in the course of pregnancy are associated with birth weight. METHODS: We determined HbA1c by high-performance liquid chromatography in 103 healthy pregnant women. The results were corrected with a method which was certified by the National Glycohaemoglobin Standardisation Program (NGSP) and standardised to the Diabetes Control and Complication trial reference assay. All women had a body mass index (BMI) < 30, none of the women had diabetes in the family in the first and/or second degree. The multiparous women had no history of macrosomia or small for gestational age infants. RESULTS: In the first trimester mean ± SD (range) HbA1c (n=93) was 4.7 ± 1.25% (27.9 ± 13.7 mmol/mol) (3.9-5.4% (19.1-35.5 mmol/mol)), in the second trimester (n=86) 4.6 ± 1.33% (26.8 ± 14.6 mmol/mol) (3.7-5.7% (16.9-38.8 mmol/mol)) and in the third trimester (n=71) 4.9 ± 1.39% (30.1 ± 15.2 mmol/mol) (4.0-6.0% (20.2-42.1 mmol/mol)). The calculated upper reference HbA1c values for the three trimesters were 5.4, 5.5 and 5.8% (35.5, 36.6 and 39.9 mmol/mol), respectively, compared with 6.5% (47.5 mmol/mol) in non-pregnant women in our hospital. We found a significant correlation between the differences of the first and second trimester HbA1c values and the birth weight percentiles (r=-0.251; p=0.032). All 44 women with a decrease in the HbA1c value from the first to the second trimester had a birth weight percentile ≤ 90. In the 30 women with no change or an increase in the HbA1c value from the first to the second trimester there was no relation between HbA1c values and birth weight percentiles, but seven of the 30 (23.3%) had a birth weight percentile of > 90. CONCLUSIONS: HbA1c is lower in all three trimesters of normal pregnancy compared with the level in non-pregnant women, and the change in HbA1c from the first to the second trimester predicts (the percentile of) birth weight. This could implicate that in order to prevent macrosomia in pregnant women with diabetes one should aim at lower HbA1c levels than the internationally accepted level, and at a decrease in HbA1c from the first to the second trimester.

Long-term follow-up of organ-specific antibodies and related organ dysfunction in type 1 diabetes mellitus.

OBJECTIVE: Diabetes mellitus type 1 (DM1) is associated with other autoimmune disorders. To our knowledge, there are no longitudinal data considering the long-term clinical relevance of organ-specific antibodies (OS-Ab) in DM1 patients. We performed a long-term retrospective longitudinal study in order to investigate the presence and diagnostic accuracy (positive predictive value: PPV and negative predictive value: NPV) of OS-Ab in DM1 patients. RESEARCH DESIGN AND METHODS: In a retrospective longitudinal study, the presence of OS-Ab and related organ function were analysed in 396 DM1 patients (184 F/212 M, age 44 ± 13 years, age at onset of DM1 21 ± 13 years), with a median follow-up time of 23 ± 10 years. RESULTS: OS-Ab frequencies at baseline were: antibodies against thyroglobulin (Tg-Ab) 4.3%, antibodies against thyroid peroxidase (TPO-Ab) 8.1%, Tg- and/or TPO-Ab 10.4%, antibodies against parietal cells (PCA) 5.8% and antibodies against adrenal cortex (ACA) 0.5%. The occurrence of (sub)clinical hypothyroidism was higher in patients with Tg-Ab (47%) or TPO-Ab (42%) than in those without these antibodies (6.2 and 5.1%, respectively, p<0.001). PPV and NPV for Tg-Ab were 0.60 and 0.88, respectively, for TPO -Ab 0.54 and 0.91. Also in patients with PCA, organ dysfunction occurred more often (61%) than in patients without PCA (9.7%, p<0.001). PPV for PCA was 0.61 and NPV 0.90. NPV and PPV for ACA could not be calculated because of the low prevalence. CONCLUSION: Long-term follow-up of 396 DM1 patients shows that the presence of thyroid antibodies and/ or parietal cell antibodies is clearly associated with dysfunction of the corresponding organ.

Prevalence and clinical significance of organ-specific autoantibodies in type 1 diabetes mellitus.

As diabetes mellitus type 1 (DM1) is associated with other autoimmune diseases, clinical tools are needed to diagnose and predict the occurrence of other autoimmune diseases in DM1. We performed a systematic search of the literature on the prevalence, and the diagnostic and prognostic significance of organ-specific autoantibodies in DM1, focusing on the most prevalent autoimmune diseases in DM1: Hashimoto's disease, autoimmune gastric disease, Addison's disease and coeliac disease. We found 163 articles that fulfilled our selection criteria. We analysed and compared the prevalence of autoantibodies in DM1 and control populations, studied the relation between antibody prevalence and age, gender, race and DM1 duration and studied the relation between the presence of autoantibodies and organ dysfunction. Because of the large variation in population characteristics and study design, a uniform conclusion on the relation of these autoantibody prevalences with age, gender, race, DM1 duration and target organ failure cannot be drawn easily. In addition, most studies reviewed used a cross-sectional design. Therefore, few data on the predictive value of the organ-specific antibodies in DM1 populations are present in these studies. Obviously, prospective studies are needed to fill this gap in knowledge. Despite these restrictions, the general picture from the present review is that the prevalence of the organ-specific autoantibodies is significantly higher in DM1 than in control populations. Given the relevant risk for organ failure in DM1 patients with autoantibodies against thyroid, gastric, adrenal and intestinal antigens, we recommend checking these autoantibodies in these patients at least once, for instance at the diagnosis of DM1. For detailed advice on assessing the different organ autoantibodies and function we refer to the summaries in the results section.

HbA1c in healthy, pregnant women.

AIM: Congenital malformations and macrosomia in infants of women with type 1 diabetes mellitus (DM1) still occur, even if diabetic control is considered 'good' (i.e. HbA1c below the nonpregnant upper reference value of 6.3%). We, therefore, measured HbA1c in healthy, pregnant women to determine whether the upper reference value for pregnant women should be lower than the nonpregnant value. METHODS: We investigated HbA1c, measured by high-performance liquid chromatography (HPLC), in two groups of healthy primigravid women. Group 1 (n=30; 30.0 +/- 5.3 (mean +/- sd) years; body mass index (BMI) before pregnancy 21.7 +/- 5.3 kg/m2) had a gestational age of 30 weeks (34.6 +/- 2.5) pregnant. None of the women had diabetes in the family in the first and/or second degree. RESULTS: Group 1 had an HbA1c of 4.3 +/- 0.3% (range 3.9-5.0) and in group 2 the HbA1c was 4.7 +/- 0.4% (range 3.6-5.9) (p < 0.001). No relation was found between HbA1C and BMI vs birth weight, corrected for gestational age, within the groups. CONCLUSIONS: Healthy, pregnant women had a low HbA1C, particularly in the first trimester of pregnancy. This might implicate that for prevention of congenital malformations and macrosomia in pregnant DM1 women and HbA1C should be below 5% in the first trimester of pregnancy and below 6% in the third trimester.

Blood glucose awareness training in Dutch type 1 diabetes patients: one-year follow-up.

BACKGROUND: American studies have shown positive effects of Blood Glucose Awareness Training (BGAT) on the recognition of hypoglycaemia. We evaluated the effects of BGAT among Dutch patients, and compared individual training with training in the original group format. METHODS: Fifty-nine type 1 diabetes patients participated in BGAT in either a group (n = 37) or an individual (n = 22) setting. Before and one year after training they performed up to 70 measurements, two to four a day, at home on a handheld computer. During each measurement they estimated their blood glucose (BG), indicated whether they would be participating in traffic and raised their BG on the basis of their estimation, and then measured their BG. The incidence of severe hypoglycaemia and traffic accidents was also assessed. RESULTS: BGAT had positive effects on hypoglycaemic awareness, decisions not to drive and to raise the blood glucose during hypoglycaemia, severe hypoglycaemic episodes and traffic accidents. The accuracy of BG estimations only improved after group training, while after individual training patients tended to measure more or more extremely high BG values. CONCLUSION: The training improved awareness of hypoglycaemia, and seems worthy of implementation in The Netherlands.

Blood Glucose Awareness Training in Dutch Type 1 diabetes patients. Short-term evaluation of individual and group training.

AIMS: The aims of the present study were: (i) to evaluate the effects of a Dutch translation and adaptation of Blood Glucose Awareness Training (BGAT-III) on blood glucose (bg) perception, glycaemic control, and decisions not to drive or to raise the bg during hypoglycaemia; (ii) to compare the effects of individual and group BGAT. METHODS: Fifty-nine patients with Type 1 diabetes participated in BGAT in either a group or an individual setting. Before and after BGAT, 39 (66%) of them completed 30-70 measurements on a hand-held computer (hhc). During every measurement, they estimated their bg, indicated whether they would drive or raise their bg on the basis of their estimation, and then measured their bg. RESULTS: Individual and group BGAT did not have significantly different effects (P = 0.35-0.98). Overall, BGAT did not significantly affect bg perception (P = 0.11-0.65). Before BGAT patients recognized a mean of 32% of their hypoglycaemic episodes, after BGAT a mean of 39% (P = 0.12). After BGAT, patients more often decided not to drive when their bg was low (P = 0.03). They tended to decide more often to raise their bg during hypoglycaemia (P = 0.09). CONCLUSIONS: The effects of BGAT were smaller than expected. Possible reasons for this negative outcome may be the adapted version of BGAT (shorter in duration), a lack of statistical power, or a difference between American and European samples in their reaction to BGAT.

Hyperlipidaemia is associated with increased insulin-mediated glucose metabolism, reduced fatty acid metabolism and normal blood pressure in transgenic mice overexpressing human apolipoprotein C1.

AIMS/HYPOTHESIS: Insulin resistance for glucose metabolism is associated with hyperlipidaemia and high blood pressure. In this study we investigated the effect of primary hyperlipidaemia on basal and insulin-mediated glucose and on non-esterified fatty acid (NEFA) metabolism and mean arterial pressure in hyperlipidaemic transgenic mice overexpressing apolipoprotein C1 (APOC1). Previous studies have shown that APOC1 transgenic mice develop hyperlipidaemia primarily because of an impaired hepatic uptake of very low density lipoprotein (VLDL). METHODS: Basal and hyperinsulinaemic (6 mU.kg-1.min-1), euglycaemic (7 mmol/l) clamps with 3(-)3H-glucose or 9,10(-)3H-palmitic acid infusions and in situ freeze clamped tissue collection were carried out. RESULTS: The APOC1 mice showed increased basal plasma cholesterol, triglyceride, NEFA and decreased glucose concentrations compared with wild-type mice (7.0 +/- 1.2 vs 1.6 +/- 0.1, 9.1 +/- 2.3 vs 0.6 +/- 0.1, 1.9 +/- 0.2 vs 0.9 +/- 0.1 and 7.0 +/- 1.0 vs 10.0 +/- 1.1 mmol/l, respectively, p < 0.05). Basal whole body glucose clearance was increased twofold in APOC1 mice compared with wild-type mice (18 +/- 2 vs 10 +/- 1 ml.kg-1.min-1, p < 0.05). Insulin-mediated whole body glucose uptake, glycolysis (generation of 3H2O) and glucose storage increased in APOC1 mice compared with wild-type mice (339 +/- 28 vs 200 +/- 11; 183 +/- 39 vs 128 +/- 17 and 156 +/- 44 vs 72 +/- 17 mumol.kg-1.min-1, p < 0.05, respectively), corresponding with a twofold to threefold increase in skeletal muscle glycogenesis and de novo lipogenesis from 3-(3)H-glucose in skeletal muscle and adipose tissue (p < 0.05). Basal whole body NEFA clearance was decreased threefold in APOC1 mice compared with wild-type mice (98 +/- 21 vs 314 +/- 88 ml.kg-1.min-1, p < 0.05). Insulin-mediated whole body NEFA uptake, NEFA oxidation (generation of 3H2O) and NEFA storage were lower in APOC1 mice than in wild-type mice (15 +/- 3 vs 33 +/- 6; 3 +/- 2 vs 11 +/- 4 and 12 +/- 2 vs 22 +/- 4 mumol.kg-1.min-1, p < 0.05) in the face of higher plasma NEFA concentrations (1.3 +/- 0.3 vs 0.5 +/- 0.1 mmol/l, p < 0.05), respectively. Mean arterial pressure and heart rate were similar in APOC1 vs wild-type mice (82 +/- 4 vs 85 +/- 3 mm Hg and 459 +/- 14 vs 484 +/- 11 beats.min-1). CONCLUSIONS/INTERPRETATION: 1) Hyperlipidaemic APOC1 mice show reduced NEFA and increased glucose metabolism under both basal and insulin-mediated conditions, suggesting an intrinsic defect in NEFA metabolism. Primary hyperlipidaemia alone in APOC1 mice does not lead to insulin resistance for glucose metabolism and high blood pressure.

Insulin receptor mRNA splicing and altered metabolic control in aged and mildly insulin-deficient rats.

Using reverse transcription-competitive polymerase chain reaction, we measured the abundance of the mRNAs encoding the two spliced isoforms of insulin receptor in aged and mildly insulin-deficient rats. Twelve-month-old rats were characterized by peripheral insulin resistance and decreased glucose tolerance. Mild insulin deficiency, obtained by neonatal streptozotocin treatment, was associated with glucose intolerance due to reduced glucose-stimulated insulin response. Both models were associated with a decrease in the relative abundance of the mRNA with exon 11 in liver, heart, adipose tissue, and tibialis muscle, whereas a slight increase was seen in the extensor digitorum longus and no change in the soleus muscle. In the three muscles, the expression of the form without exon 11 largely predominated (>90%). In heart and adipose tissue, the two isoforms were expressed at a similar level in control rats. In both tissues, the form without exon 11 increased in streptozotocin-treated rats, whereas the absolute level of the form with exon 11 decreased in old rats. Although a decreased level of the variant with exon 11 correlated with insulin resistance of whole body glucose uptake, our results indicated that changes in the expression of the insulin receptor variants were secondary events and thus not the cause of the insulin resistance in old and mildly insulin-deficient rats.

Pulsatile intravenous insulin replacement in streptozotocin diabetic rats is more efficient than continuous delivery: effects on glycaemic control, insulin-mediated glucose metabolism and lipolysis.

Short-term exposure of tissues to pulses of insulin generally leads to an enhancement of insulin action. We have investigated the possible beneficial effects of long-term near-physiological continuous vs pulsatile intravenous insulin treatment of insulin-deficient streptozotocin (70 mg/kg) diabetic rats on blood glucose control, in vivo insulin action and in vitro insulin action in isolated adipocytes. First, we determined the 24-h peripheral plasma insulin profiles in normal rats under precisely controlled mealfeeding conditions. Basal plasma insulin levels (40 +/- 9 microU/ml) oscillate with a periodicity of 11.9 +/- 0.9 min (p < 0.05), and an amplitude of 60 +/- 10%. Subsequently, the 24-h insulin profile was mimicked in diabetic (D) rats by a continuous (c) or pulsatile (p) (6-min double, 6-min off) insulin infusion rate for 2 weeks, using a programmable pumpswivel unit. Control (C) rats received vehicle treatment. In Cc, Dc, Cp and Dp daily urinary glucose loss and average plasma glucose levels were 0 +/- 0, 7.5 +/- 4.4, 0 +/- 0, 0.8 +/- 0.4 mmol and 6.7 +/- 0.2, 11.5 +/- 2.7, 6.6 +/- 0.1, 5.9 +/- 1.4 mmol/l, respectively. Hypoglycaemia (< 3 mmol/l) was observed in 10 and 20% of the blood samples collected from Dc and Dp rats, respectively. After 2 weeks of treatment, in vivo peripheral and hepatic insulin action was measured by the hyperinsulinaemic euglycaemic (6 mmol/l) clamp with [3-3H]-glucose infusion. Pre-clamp counter-regulatory hormone levels were similar among rats. Compared to Cc and Cp, Dc showed a reduction in insulin sensitivity and responsiveness for peripheral glucose uptake whereas Dp only showed a reduction in insulin sensitivity. Suppression of hepatic glucose production by insulin was similar among rats. After 2.5 weeks of treatment, epididymal adipocytes were isolated. Specific [125I]-insulin binding, basal and insulin-stimulated [U-14C]-glucose uptake and isoproterenol-stimulated glycerol output were comparable among rat adipocytes. The inhibition of glycerol output by insulin was identical in Cp and Dp (V(max) = 48.6 +/- 6.1 and 42.3 +/- 4.6%) but blunted in Dc vs Cc (V(max) = 8.2 +/- 4.6 vs 44.0 +/- 7.2%, p < 0.01) adipocytes, suggesting a post-binding defect in the antilipolytic action of insulin in Dc rats. In conclusion, long-term near-physiological pulsatile intravenous insulin replacement in insulin-deficient diabetic rats is more efficient than continuous delivery in reducing blood glucose, lowering glucosuria, increasing insulin sensitivity and inhibiting lipolysis.

Tissue-related changes in insulin receptor number and autophosphorylation induced by starvation and diabetes in rats.

Insulin action is subject to regulation at the level of the insulin receptor and at postreceptor levels. Starvation and diabetes are often associated with insulin resistance for glucose metabolism in various tissues. In muscle, fat, and liver, we examined whether changes in the functionality of the insulin receptor correlated with changes in insulin action in the starved and diabetic state. Insulin-stimulated receptor autophosphorylation reflects an early physiologic step in transmission of the insulin signal, and for that reason, changes in autophosphorylation activity of the insulin receptor were used as a marker to determine the functionality of the insulin receptor. Glycoprotein fractions prepared from skeletal muscle, diaphragm, epididymal fat, and liver of control, 3-day starved, short-term 3-day (S) diabetic (streptozotocin, 70 mg/kg intravenously), and long-term 6-month (L) diabetic (neonatal streptozotocin 100 micrograms/g intraperitoneally) rats were used in this study. Receptor activity was monitored by measuring insulin-stimulated [gamma-32P]adenosine triphosphate (ATP) receptor autophosphorylation. In addition, to obtain information about whether changes in receptor autophosphorylation are related to changes in receptor number, relative numbers of high-affinity insulin receptors were determined by affinity cross-linking of [125I]insulin to the receptor alpha-chain and quantitation of the yield of labeled receptor alpha-chain. Control, starved, S diabetic, and L diabetic rats had plasma insulin and glucose levels of 294 +/- 42, 90 +/- 24, 48 +/- 12, and 216 +/- 30 pmol/L and 6.7 +/- 0.2, 4.1 +/- 0.2, 23.3 +/- 0.7, and 21.6 +/- 2.9 mmol/L, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin-induced decline of plasma amino acid concentrations in obese subjects with and without non-insulin-dependent diabetes.

Obesity-associated hyperaminoacidemia is traditionally interpreted as a consequence of insulin resistance. We performed two different experiments to investigate the effects of both obesity-associated insulin resistance and the insulin resistance of non-insulin-dependent diabetes mellitus (NIDDM) on amino acid metabolism. In the first experiment, we measured postabsorptive amino acid concentrations and their decline in response to an oral carbohydrate load in 19 obese nondiabetic women and 19 normal-weight nondiabetic controls. Obese subjects were more resistant to insulin with respect to its effects on glucose metabolism than normal-weight controls, as calculated by the method described by Matthews. However, postabsorptive plasma concentrations of the so-called large neutral amino acids (LNAA), namely phenylalanine, tyrosine, valine, leucine, and isoleucine, and their decrease in response to carbohydrate consumption were similar in both groups. In the second experiment, we compared the decrease of plasma concentrations of LNAA during a euglycemic, hyperinsulinemic clamp in obese subjects with and without NIDDM. Peripheral glucose uptake (PGU) was more impaired in NIDDM subjects compared with obese controls. Furthermore, hepatic glucose production (HGP) was less attenuated by insulin infusion in NIDDM than in control subjects. Postabsorptive plasma LNAA concentrations were not different in the two groups. Values obtained in either group were not different from the postabsorptive concentrations in the normal-weight control subjects of experiment 1. All amino acid levels decreased substantially in response to insulin infusion. The magnitude of the decrease was not significantly different in the two groups, except for a slightly greater decrease of the plasma isoleucine concentration in obese control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Counterregulatory hormone responses during graded hyperinsulinemic euglycemia in conscious rats.

It has been suggested that hyperinsulinemia per se may affect the levels of some counterregulatory hormones in the absence of hypoglycemia. We studied the effect of graded hyperinsulinemia and concomitant increased glucose metabolism on the levels of counterregulatory hormones by means of the 5-step sequential hyperinsulinemic euglycemic clamp technique, combined with [3-3H]-glucose infusion, in conscious rats. Insulin infusion rates (IIR) of 0, 0.5, 1, 3, and 16 mU/min, resulted in steady-state plasma insulin levels (mean +/- SEM) of 24 +/- 4, 44 +/- 3, 98 +/- 8, 418 +/- 48, and 6626 +/- 361 microU/ml, peripheral glucose uptake (PGU) of 3.1 +/- 0.2, 3.6 +/- 0.3, 5.4 +/- 0.3, 9.2 +/- 0.4, and 12.4 +/- 0.2 mg/min and hepatic glucose production (HGP) of 3.1 +/- 0.2, 2.4 +/- 0.4, 0.8 +/- 0.3, -0.1 +/- 0.2, and -0.5 +/- 0.3 mg/min, respectively. Plasma glucagon levels were half maximally suppressed between IIRs of 0.5 and 1 mU/min and maximally suppressed at 3 mU/min. The suppression exactly paralleled the inhibition of HGP (r = 0.87 +/- 0.04, p < 0.02) but not the stimulation of PGU (r = -0.66 +/- 0.12, p = NS). This suggests that the inhibition of HGP by insulin is at least partially mediated by a simultaneous suppression of plasma glucagon levels. The adrenal hormones corticosterone and epinephrine were not influenced during the clamp.(ABSTRACT TRUNCATED AT 250 WORDS)

The cardiovascular risk factor plasminogen activator inhibitor type 1 is related to insulin resistance.

The cardiovascular risk factor plasminogen activator inhibitor type 1 (PAI-1) has been associated with abdominal obesity, hypertension, hypertriglyceridemia, hyperinsulinemia, glucose intolerance, and type II diabetes, conditions known to be linked with insulin resistance. To determine whether PAI-1 is related to insulin resistance, we studied nine obese nondiabetics and 10 obese type II diabetics by means of a sequential hyperinsulinemic euglycemic clamp study. Plasma PAI-1 antigen (Ag) correlated significantly with peripheral insulin resistance, represented by the insulin level at which peripheral glucose uptake (PGU) is half-maximal ([ED50PGU] r = .87, P < .001). Multiple regression analysis including indices of hepatic and peripheral insulin action, fasting plasma insulin levels, triglyceride levels, blood pressure (BP), waist to hip ratio (WHR), and body mass index (BMI) disclosed ED50PGU to account for 76% of the variance of PAI-1 Ag. We suggest that PAI-1 contributes to the increased cardiovascular risk encountered with insulin resistance.

Effect of high fat feeding on glucose tolerance in neonatally streptozotocin-treated rats at 3 and 6 months of age.

In the rat, a high fat intake is believed to be associated with an increased risk for the development of glucose intolerance by inducing insulin resistance. The aim of this study was to investigate whether reduced insulin production may also play a role. Rats were treated with 0, 30, 60, and 90 mg of streptozotocin (STZ)/kg of body weight on the day of birth (0, 30, 60, and 90 nSTZ rats). At 3 or 6 months of age, glucose tolerance was assessed by the intravenous glucose tolerance test (IVGTT). STZ dose-dependently decreased first- and second-phase insulin responses and correspondingly impaired glucose tolerance. Following a 3-week high fat diet (HFD: 60% of calories as corn oil), insulin responses were higher in control as well as in STZ-treated rats both at 3 and 6 months of age. In 3-month-old rats this was accompanied by unchanged or increased glucose levels following the glucose load, whereas in 6-month-old 0 and 30 nSTZ rats glucose tolerance was slightly improved. After 6 weeks of HFD in 6-month-old rats, glucose tolerance was impaired compared to that after 3 weeks of HFD despite higher insulin responses. Continuing the HFD for up to 12 weeks further impaired glucose tolerance, but insulin responses were decreased compared to those after 6 weeks of HFD. These results indicate that very low dose neonatal STZ administration impairs glucose tolerance through decreased overall insulin responses. This may possibly be due to a reduction of B-cell number rather than an alteration of B-cell function. No clear evidence exists that a high fat intake per se negatively influences glucose-induced insulin responses, but this may become apparent after longer periods of high fat feeding.

Fluoxetine increases insulin action in obese type II (non-insulin dependent) diabetic patients.

Insulin resistance contributes to the metabolic defects in non-insulin dependent diabetes mellitus (NIDDM). Anorectic agents have been shown to improve insulin action in NIDDM, irrespective of weight reduction. In a double-blind placebo-controlled cross-over study, we examined hepatic and peripheral insulin action by the sequential hyperinsulinaemic-euglycaemic clamp technique with infusion of 3-[3H]-glucose in eight obese NIDDM patients and in eight obese non-diabetics, matched for age, sex and body mass index. Body weight was kept constant. After 14 days of fluoxetine, 60 mg daily, in NIDDM half-maximal peripheral glucose uptake was achieved at a lower insulin level than after placebo (ED50pgu: 180.5 +/- 25.8 vs. 225.3 +/- 39.9 mU/l, P < 0.05), but not in non-diabetics (140 +/- 15.3 vs. 135.3 +/- 22.2 mU/l, n.s.). Maximal peripheral glucose uptake (Vmaxpgu) did not change significantly. Multivariate analysis disclosed no differences in the effect of fluoxetine between NIDDM and non-diabetics. When non-diabetics and NIDDM were considered together, only the most insulin-resistant individuals demonstrated a decrease in ED50pgu (P < 0.001). Likewise, only the individuals with the most outspoken hepatic insulin resistance demonstrated a decrease in insulin level, at which hepatic glucose production (HGP) is completely suppressed (HGP0) (P < 0.01). In conclusion, fluoxetine improves peripheral and hepatic insulin action in obese insulin-resistant subjects irrespective of its weight lowering effect.

Biological action of pancreatic amylin: relationship with glucose metabolism, diabetes, obesity and calcium metabolism.

Amylin, also called islet amyloid polypeptide (IAPP), or diabetes-associated peptide (DAP) is a recently discovered 37 amino acid polypeptide which has been shown to be co-secreted with insulin from the pancreatic beta-cell. The peptide turned out to be the major constituent of pancreatic amyloid deposits which are frequently found in the pancreas of type II diabetic patients. Therefore, a role for amylin in the aetiology of type II diabetes was hypothesized. To investigate this possibility, several studies have been performed to elucidate whether amylin is able to impair insulin secretion and action, two characteristic features of type II diabetes mellitus. These studies suggest that it is unlikely that amylin has a direct inhibitory effect on insulin secretion. Amyloid deposits, however, which are derived from the in situ polymerization and precipitation of amylin, may impair beta-cell function during type II diabetes by damaging and covering beta-cells. Furthermore, it has been shown that amylin has the potential to antagonize the action of insulin on glucose metabolism by increasing hepatic glucose production and by decreasing muscle, but not adipocyte glucose uptake. For these reasons, it has been suggested that amylin might be involved in the pathophysiology of type II diabetes and obesity, disease states which are characterized by abnormal beta-cell function and insulin resistance. In addition, amylin was shown to induce hypocalcaemia by inhibiting osteoclast-mediated bone resorption in a calcitonin-like manner. Therefore, amylin is likely to be involved in both the modulation of glucose and calcium metabolism.

Fluoxetine increases insulin action in obese nondiabetic and in obese non-insulin-dependent diabetic individuals.

Insulin resistance contributes to the metabolic defects in non-insulin-dependent diabetes mellitus (NIDDM). Anorectic agents have been shown to improve insulin action in NIDDM, irrespective of weight reduction. The serotonin-reuptake inhibiting agent fluoxetine has recently been recognized as an anorectic agent. The effect of fluoxetine on insulin action has not yet been determined. In a double blind placebo controlled crossover study, we examined hepatic and peripheral insulin action by the sequential hyperinsulinemic euglycemic clamp technique with infusion of 3-3H-glucose in eight obese NIDDM and in eight obese nondiabetics, matched for age, sex and body mass index. Body weight was kept constant. After 14 days of fluoxetine, 60 mg daily, in NIDDM half-maximal peripheral glucose uptake was achieved at a lower insulin level than after placebo (ED50pgu 180.5 +/- 25.8 vs 225.3 +/- 39.9 mU/l, P less than 0.05), but not in nondiabetics (140 +/- 15.3 vs 135.3 +/- 22.2 mU/l, n.s.). Maximal peripheral glucose uptake (Vmaxpgu) did not change significantly. Basal hepatic glucose production (HGP) was reduced after fluoxetine in both NIDDM (9.45 vs 10.37 mumol/kg/min) and in nondiabetics (8.57 vs 9.16 mumol/kg/min), although the difference was only significant in nondiabetics (P less than 0.05). Multivariate analysis disclosed no differences in the effect of fluoxetine between NIDDM and nondiabetics. When nondiabetics and NIDDM were considered together, only the most insulin-resistant individuals demonstrated a decrease in ED50pgu (P less than 0.001). Likewise, only the individuals with the most outspoken hepatic insulin resistance demonstrated a decrease in insulin level, at which hepatic glucose production is completely suppressed (HGP0) (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

In vivo insulin responsiveness for glucose uptake and production at eu- and hyperglycemic levels in normal and diabetic rats.

UNLABELLED: Whole body glucose uptake (BGU) and hepatic glucose production (HGP) at maximal plasma insulin concentrations (+/- 5000 microU/ml) were determined by eu- (EC) (6 mM) and hyperglycemic (HC) (20 mM) clamps (120 min), combined with [3-3H]glucose infusion, in normal and streptozotocin-treated (65 mg/kg) 3-day diabetic, conscious rats. In normal rats, during EC, BGU was 12.4 +/- 0.4 mg/min and during HC, when urinary glucose loss was 0.54 +/- 0.09 mg/min, BGU was 25.5 +/- 1.6 mg/min. However, throughout the final 60 min of HC, glucose infusion rate (GIR) was not constant but a linear decline in time (r = -0.99) of 17%, P less than 0.0001, was observed indicating a hyperglycemia-induced desensitization process. In diabetic rats, during EC, BGU was 7.7 +/- 0.3 mg/min and during HC, BGU was 15.5 +/- 1.4 mg/min. Throughout the final 60 min of HC, GIR was constant, suggesting that the hyperglycemia-induced desensitization process was already completed. In normal and diabetic rats, HGP was similar: during EC 0.2 +/- 0.5 mg/min and 0.1 +/- 0.5 mg/min, and during HC 0.4 +/- 0.4 mg/min and 0.5 +/- 0.6 mg/min, respectively. In vitro adipocyte and muscle insulin receptor studies showed normal to increased receptor number and increased receptor autophosphorylation in diabetic compared to normal rats. IN CONCLUSION: (i) 3-day diabetic rats show, at maximal plasma insulin concentrations, insulin resistance to BGU, but not to HGP. The resistance to BGU is equally present (reduction of 38%) at eu- and hyperglycemic levels as compared to normal rats. (ii) 3-day diabetic rats reveal no defect in adipocyte and muscle insulin receptor function. These data indicate that the diabetes induced insulin resistance for BGU is at the post-receptor level and due to a decreased maximal capacity (Vmax) for glucose uptake, with no change in affinity, or Km.

Whole body and hepatic insulin action in normal, starved, and diabetic rats.

In normal (N), 3-days starved (S), and streptozotocin-treated (65 mg/kg) 3-days diabetic (D) rats we examined the in vivo dose-response relationship between plasma insulin levels vs. whole body glucose uptake (BGU) and inhibition of hepatic glucose production (HGP) in conscious rats, as determined with the four-step sequential hyperinsulinemic euglycemic clamp technique, combined with [3-3H]glucose infusion. Twelve-hour fasting (basal) HGP was 3.0 +/- 0.2, 2.1 +/- 0.2, and 5.4 +/- 0.5 mg/min in N, S, and D rats, respectively. Next, all rats were clamped at matched glycemia (6 mM). Lowering plasma glucose in D rats from +/- 20 to 6.0 mM did not increase plasma norepinephrine, epinephrine, glucagon, and corticosterone levels. For BGU, insulin sensitivity was increased (70 +/- 11 microU/ml) in S and unchanged (113 +/- 21 microU/ml) in D compared with N rats (105 +/- 10 microU/ml). Insulin responsiveness was unchanged (12.4 +/- 0.8 mg/min) in S and decreased (8.5 +/- 0.8 mg/min) in D compared with N rats (12.3 +/- 0.7 mg/min). For HGP, insulin sensitivity was unchanged (68 +/- 10 microU/ml) in S and decreased (157 +/- 21 microU/ml) in D compared with N rats (71 +/- 5 microU/ml). Insulin responsiveness was identical among N, S, and D rats (complete suppression of HGP). In summary, 1) insulin resistance in D rats is caused by hepatic insensitivity and by a reduction in BGU responsiveness. 2) S rats show normal hepatic insulin action, but insulin sensitivity for BGU is increased. Therefore, S and D rats both suffering from a comparable catabolic state (10-15% body wt loss in 3 days) show opposite effects on in vivo insulin action. This indicates that in vivo insulin resistance in D rats is not caused by the catabolic state per se.