Prandial glucose effectiveness and fasting gluconeogenesis in insulin-resistant first-degree relatives of patients with type 2 diabetes.

Impaired glucose effectiveness (i.e., a diminished ability of glucose per se to facilitate its own metabolism), increased gluconeogenesis, and endogenous glucose release are, together with insulin resistance and beta-cell abnormalities, established features of type 2 diabetes. To explore aspects of the pathophysiology behind type 2 diabetes, we assessed in a group of healthy people prone to develop type 2 diabetes (n = 23), namely first-degree relatives of type 2 diabetic patients (FDR), 1) endogenous glucose release and fasting gluconeogenesis measured using the 2H2O technique and 2) glucose effectiveness. The FDR group was insulin resistant when compared with an age-, sex-, and BMI-matched control group without a family history of type 2 diabetes (n = 14) (M value, clamp: 6.07 +/- 0.48 vs. 8.06 +/- 0.69 mg x kg(-1) lean body weight (lbw) x min(-1); P = 0.02). Fasting rates of gluconeogenesis (1.28 +/- 0.06 vs. 1.41 +/- 0.07 mg x kg(-1) lbw x min(-1); FDR vs. control subjects, P = 0.18) did not differ in the two groups and accounted for 53 +/- 2 and 60 +/- 3% of total endogenous glucose release. Glucose effectiveness was examined using a combined somatostatin and insulin infusion (0.17 vs. 0.14 mU x kg(-1) x min(-1), FDR vs. control subjects), the latter replacing serum insulin at near baseline levels. In addition, a 360-min labeled glucose infusion was given to simulate a prandial glucose profile. After glucose infusion, the integrated plasma glucose response above baseline (1,817 +/- 94 vs. 1,789 +/- 141 mmol/l per 6 h), the ability of glucose to simulate its own uptake (1.50 +/- 0.13 vs. 1.32 +/- 0.16 ml x kg(-1) lbw x min(-1)), and the ability of glucose per se to suppress endogenous glucose release did not differ between the FDR and control group. In conclusion, in contrast to overt type 2 diabetic patients, healthy people at high risk of developing type 2 diabetes are characterized by normal glucose effectiveness at near-basal insulinemia and normal fasting rates of gluconeogenesis.

Evidence of an increased number of type IIb muscle fibers in insulin-resistant first-degree relatives of patients with NIDDM.

Insulin resistance is a common feature in first-degree relatives of NIDDM patients. To explore the mechanism(s) behind this condition in more detail, a percutaneous muscle biopsy (vastus lateralis) was performed in 25 first-degree relatives of NIDDM patients and 21 control subjects to examine muscle fiber composition and capillary density. Insulin-stimulated glucose disposal (Rd) was determined employing a hyperinsulinemic-(insulin infusion rate 0.6 mU x kg[-1] x min[-1]) euglycemic clamp. Rd (5.76 +/- 0.35 vs. 8.06 +/- 0.36 mg x kg lean body weight [LBW]-1 x min[-], P < 0.001) and estimated VO2max (49.3 +/- 2.8 vs. 57.2 +/- 3.5 mg x kg LBW[-1] x min[-1], 0.05 < P < 0.10) were decreased in the relatives. The number of type IIb fibers (29.5 +/- 2.5 vs. 21.0 +/- 2.8%, P < 0.05) was increased in the relatives, whereas no significant differences were found in other fiber types or capillary density between the groups. Correlations were observed between number of type I fibers (positive), number of type IIb fibers (negative), and capillary density (positive) versus Rd as well as estimated VO2max (P < 0.05). In a multiple linear regression analysis with Rd as a dependent variable, estimated VO2max, family history of NIDDM, and number of type IIb fibers (P < 0.001, r2 = 0.64) significantly determined the level of Rd, whereas capillary density did not. In conclusion, insulin-resistant first-degree relatives of NIDDM patients are characterized by an increased number of type IIb muscle fibers. Whether this finding reflects a reduced physical activity level and fitness in the relatives or is of primary genetic origin remains to be determined.

Glucagon-like peptide 1 increases mass but not frequency or orderliness of pulsatile insulin secretion.

Glucagon-like peptide 1 (GLP-1) is a peptide hormone that is released from the gut after luminal stimulation. The hormone is a potent insulin secretagogue and is a potential novel pharmaceutical adjuvant in the treatment of NIDDM. Insulin is secreted as a series of punctuated secretory bursts superimposed on a basal insulin release. Recently, the contribution of these secretory bursts to overall insulin secretion has been evaluated, and studies using catheterization across the pancreas in a canine model and studies using deconvolution in humans have revealed that the majority of insulin is released during these secretory bursts. Moreover, the main regulation of insulin secretion is through perturbation of mass and frequency of these secretory bursts. The mode of delivery of insulin into the circulation seems important for insulin action, and it is therefore important to know the impact of a potential therapeutic insulin secretagogue on the mode of insulin secretion. To assess the effects of GLP-1 on the mass, frequency, amplitude, and overall contribution of pulsatile insulin secretion, we used a recently validated deconvolution model to examine these variables before and during infusion of GLP-1 in eight healthy men (age 28 +/- 2 years; BMI 24 +/- 2 kg/m2). At a constant glucose infusion (2.5 mg x kg-1 x min-1), near-steady state was reached at 75 min, and sampling was performed every minute at t = 75-115 and 145-185 min. At t = 115 min, an infusion of saline or GLP-1 (50 pmol x kg-1 x min-1) was given. The regularity of insulin secretion was measured by approximate entropy, a recently developed mathematical statistic, applied herein to assess the regularity in a hormone concentration time series. After GLP-1 infusion, there was an abrupt increase in the peripheral concentrations of serum C-peptide (696 +/- 65 vs. 1,538 +/- 165 pmol/l) and insulin (49 +/- 8 vs. 138 +/- 21 pmol/l) concentrations. This increase was mainly due to an increase in the pulsatile component of insulin secretion that was achieved by a fourfold increase in secretory burst mass (28.2 +/- 4.4 vs. 100.1 +/- 15.8 pmol x l-1 x pulse-1; P < 0.001), and amplitude (12.7 +/- 2.2 vs. 4.3 +/- 7.7 pmol x l-1 x min-1; P < 0.002), whereas the secretory burst frequency was not affected by GLP-1 (11.5 +/- 0.7 vs. 12.6 +/- 0.6 pulses/h; P = 0.4). As a consequence, the detected contribution of pulsatile to overall insulin secretion was increased from 56 +/- 4 to 77 +/- 4% (P < 0.005). The orderliness of the insulin release process was not deteriorated by short-term GLP-1 infusion as assessed by approximate entropy (1.19 +/- 0.04 vs. 1.18 +/- 0.04; P = 0.7).

Muscle fiber composition and capillary density in Turner syndrome: evidence of increased muscle fiber size related to insulin resistance.

OBJECTIVE: To assess muscle fiber composition and capillary density in Turner syndrome, a condition linked with insulin resistance and increased frequency of type 2 diabetes, and link these findings with insulin sensitivity and physical fitness. RESEARCH DESIGN AND METHODS: A total of 10 patients with Turner syndrome who were off hormone replacement therapy (aged 32.7 +/- 8.9 years) and a control group of 14 normal women (aged 35.6 +/- 9.3 years) were studied. None of the participants had diabetes or any family history of type 2 diabetes. An oral glucose tolerance test was performed, and insulin sensitivity was assessed by homeostasis model assessment (HOMA) and a composite whole-body insulin sensitivity index (ISI(comp)). Physical fitness was assessed, and a muscle biopsy was obtained. RESULTS: Women with Turner syndrome were insulin resistant, as seen by a lower ISI(comp) (P = 0.003) and increased glucose (P < 0.0005) and insulin (P = 0.01) levels at 120 min. Impaired glucose tolerance was present in most Turner syndrome patients (6 of 10), but not in the control subjects. Women with Turner syndrome had an increased size of type IIa fibers (P = 0.01), whereas the size of their type I and IIa fibers were comparable with the control group. The groups did not differ in percentage of type I, Iia, or IIx fibers, and there was no difference in the capillary density. Significant correlations were found among ISI(comp), the HOMA index (R(HOMA)), and the mean area of type IIa fibers (ISI(comp): r = -0.632, P = 0.002; R(HOMA): r = 0.570, P = 0.006). Furthermore, capillaries/type IIa fibers correlated significantly with ISI(comp) (r = -0.618, P = 0.01). There were no significant correlations between VO(2max) and muscle fiber composition. CONCLUSIONS: Healthy women with Turner syndrome are characterized by impaired glucose tolerance, insulin resistance, low physical capacity, and enlarged type IIa muscle fibers, indicating diminished oxygen and substrate supply for metabolic processes. These findings could be indicative of a prediabetic state.

Glucose metabolism, lipid metabolism, and cardiovascular risk factors in adult Turner's syndrome. The impact of sex hormone replacement.

OBJECTIVE: To examine glucose metabolism, blood pressure, physical fitness, and lipid metabolism in adult untreated women with Turner's syndrome compared with a group of normal women and to examine the effects of female sex hormone substitution on these factors. RESEARCH DESIGN AND METHODS: A total of 26 patients with Turner's syndrome were examined before and during sex hormone replacement with 17 beta-estradiol and norethisterone, and an age-matched control group (n = 24) was examined once. A frequently sampled intravenous glucose tolerance test was applied with minimal model assessment. We also performed an oral glucose tolerance test, measurement of 24-h ambulatory blood pressure, and assessment of physical fitness and lipid metabolism. RESULTS: Insulin sensitivity (SI) and glucose effectiveness (SG) were similar in Turner's syndrome patients and control subjects, whereas the acute insulin response (P = 0.03) was lower in Turner's syndrome patients, and no change was seen during sex hormone treatment. Abnormal glucose tolerance was found in 50% of Turner's syndrome patients before and 78% during treatment with sex hormones. Fat-free mass (FFM; P = 0.0005) and physical fitness (P = 0.002) were lower in Turner's syndrome subjects compared with control subjects. During treatment, an increase in FFM (P = 0.001) and physical fitness (P = 0.02) was seen in Turner's syndrome patients. Blood pressure was increased in Turner's syndrome, and a decrease was seen in diastolic blood pressure during treatment with sex hormones. CONCLUSIONS: Turner's syndrome is associated with glucose intolerance, diminished first-phase insulin response, elevated blood pressure, reduced FFM, and physical fitness. Sex hormone administration causes a deterioration in glucose tolerance, increases FFM and physical fitness, and has beneficial effects on blood pressure. The deleterious effect on glucose tolerance may be mediated by norethisterone, a gestagen known to have androgenic effects.

Acute effects of the human amylin analog AC137 on basal and insulin-stimulated euglycemic and hypoglycemic fuel metabolism in patients with insulin-dependent diabetes mellitus.

Amylin has been reported to decrease glycogen storage in rodent skeletal muscles and produce insulin resistance in intact rats. To test the acute effect of a human amylin analog (AC137) on glucose metabolism in man, seven IDDM patients were infused in a randomized, double blind, cross-over study with AC137 (100 micrograms/h, n = 1; 50 micrograms/h, n = 6) or placebo for 330 min during a two-step euglycemic clamp (insulin infusion rates, 0.2 and 0.6 mU/kg.min; basal and hyperinsulinemic period, respectively) followed by a hyperinsulinemic hypoglycemic clamp (insulin infusion rate, 1.5 mU/kg.min; hypoglycemic period). During euglycemia, no differences were found in glucose disposal (step 1, 2.43 +/- 0.20 vs. 2.03 +/- 0.26; step 2, 4.28 +/- 0.54 vs. 4.11 +/- 0.45 mg/kg.min; AC137 vs. placebo, mean +/- SEM), arteriovenous substrate balances across the forearm, or hepatic glucose production. During hypoglycemia, glucose fluxes were also similar. However, lactate release from the forearm was more pronounced (P < 0.05) with the analog than with placebo (area under the curve, -11.2 +/- 4.6 vs. -1.4 +/- 2.2 mmol/min.L). Despite similar plasma glucose nadirs (2.7 +/- 0.0 vs. 2.6 +/- 0.1 mmol/L; AC137 vs. placebo), circulating cortisol and GH rose to significantly higher levels during hypoglycemia with the amylin analog (P < 0.05). In conclusion, acute administration of the amylin analog AC137 did not influence insulin-stimulated glucose metabolism during euglycemic conditions. During imposed hypoglycemia, lactate release from skeletal muscle was, however, enhanced, and the rise in cortisol and GH was augmented.

The effect of two frequent amino acid variants of the hepatocyte nuclear factor-1alpha gene on estimates of the pancreatic beta-cell function in Caucasian glucose-tolerant first-degree relatives of type 2 diabetic patients.

The objective of the present study was to investigate whether the frequent amino acid polymorphisms, Ile/Leu27 and Ser/Asn487, of the hepatocyte nuclear factor-1alpha gene were associated with alterations in glucose-induced serum C-peptide and serum insulin responses among glucose-tolerant first-degree relatives of type 2 diabetic patients. The study comprised 2 independent Danish cohorts. Among 74 unrelated type 2 diabetic relatives, 12 homozygous carriers of the Ile/Leu27 polymorphism had a 32% decrease in the 30-min serum C-peptide level (P = 0.01), as well as a 39% decrease in the 30-min serum insulin level (P = 0.02) during an oral glucose tolerance test. Ten homozygous carriers of the Ile/Leu27 variant did, however, not differ from wild-type carriers, with respect to the acute circulating insulin and serum C-peptide responses during an i.v. glucose tolerance test in the same study cohort. In a larger (more than 3-fold) study group of 230 glucose tolerant offspring of 62 type 2 diabetic probands, 33 homozygous carriers of the Ile/Leu27 variant did not differ, with respect to either serum insulin and serum C-peptide levels during an oral glucose tolerance test or acute serum insulin and serum C-peptide responses during an i.v. glucose tolerance test. We therefore consider the former positive finding as a statistical type I error. There were no differences in the above mentioned variables between carriers of the Ser/Asn487 polymorphism and wild-type carriers within any of the 2 study populations. Nor did carriers of combined genotypes, i.e. carriers of both the Ile/Leu27 and the Ser/Asn487 variants, show any associations with the examined variables. In conclusion, the Ile/Leu27 and Ser/ Asn487 polymorphisms of the hepatocyte nuclear factor-1alpha gene have apparently no major impact on the pancreatic beta-cell function, after an oral and i.v. glucose challenge, in Caucasian first-degree relatives of type 2 diabetic patients.

Amylin receptor agonists: a novel pharmacological approach in the management of insulin-treated diabetes mellitus.

Amylin is a peptide hormone which is co-secreted with insulin from the pancreatic beta-cell. Type 1 diabetic individuals and some Type 2 diabetic individuals are characterised by amylin deficiency. Animal experiments have revealed several actions of amylin on intermediary metabolism, of these some have been demonstrated to be of potential physiological relevance in humans. In particular amylin appears to have important actions in controlling prandial glucose homeostasis. The peptide hormone inhibits postprandial glucagon secretion and delays gastric emptying thereby modifying postprandial hyperglycaemia in diabetic individuals which presumably adds to overall glycaemic control without a concomitant increase in the number of severe hypoglycaemic episodes. Moreover, amylin acts as a satiety agent. Amylin replacement may therefore improve glycaemic control in diabetes mellitus. However, human amylin exhibits physicochemical properties predisposing the peptide hormone to aggregate and form amyloid fibres, which makes it unsuitable for pharmacological use. A stable analogue, pramlintide, with actions and pharmacokinetic and pharmacodynamic properties similar to the native peptide has therefore been developed. The efficacy and safety of pramlintide administration to diabetic individuals have been tested in a large number of clinical trials. It is the aim of this review to describe possible (patho)physiological actions of amylin as demonstrated in animal and human models, to discuss the background for potential amylin (analogue) replacement in diabetes mellitus and to review results from clinical trials with the amylin receptor analogue pramlintide.

Increased circulating leptin concentrations in insulin-resistant first-degree relatives of patients with non-insulin-dependent diabetes mellitus: relationship to body composition and insulin sensitivity but not to family history of non-insulin-dependent diabetes mellitus.

OBJECTIVE: To explore a possible association between serum concentration of leptin, insulin sensitivity and non-insulin-dependent diabetes mellitus (NIDDM). DESIGN: Forty first-degree relatives of NIDDM patients and 35 control subjects matched for age, gender and body mass index underwent a hyperinsulinaemic (insulin infusion rate 0.6 mU/kg per min) euglycaemic clamp combined with indirect calorimetry. Serum leptin was measured in fasting blood samples obtained before the clamp. RESULTS: All subjects had a normal oral glucose tolerance test. Insulin-stimulated glucose uptake (M) was decreased in the relatives compared with the control subjects (4.58 +/- 0.27 versus 6.06 +/- 0.25 mg/kg per min, P < 0.001). Conversely, serum leptin was increased in the relatives (9.6 x/divided by 1.1 versus 6.1 x/divided by 1.2 ng/ml (geometric mean x/divided by antilog S.E.M.), P < 0.05). A positive correlation was observed between circulating levels of leptin and percentage body fat (P < 0.001) and inverse correlations were found between leptin, M (P < 0.01), maximal aerobic capacity (VO2 max) (P < 0.01), and energy expenditure (P < or = 0.01) in both groups. In multiple linear regression analysis, percentage body fat, gender and M significantly determined the level of leptin (r2 = 0.71, P < 0.001) whereas family history of NIDDM and VO2 max did not. CONCLUSION: Serum leptin is increased in insulin-resistant offspring of NIDDM patients. The association between leptin, anthropometric measures and insulin sensitivity is, however, comparable with that of a control group. The increased concentrations of serum leptin in the relatives appear to be associated with the insulin resistance, but not with a family history of NIDDM.

Circulating levels of incretin hormones and amylin in the fasting state and after oral glucose in GH-deficient patients before and after GH replacement: a placebo-controlled study.

OBJECTIVE: Hyperinsulinemia in association with GH excess is considered a compensatory response to insulin resistance, but the possibility of alternative insulinotropic mechanisms has not been investigated in vivo. It is also unknown how GH influences the secretion from pancreatic beta-cells of amylin, a peptide which regulates prandial glucose homeostasis and may be linked to development of beta-cell dysfunction. We therefore measured plasma concentrations of two gut insulinotropic hormones, glucagon-like peptide 1 (GLP-1) and glucose-dependent insulin-releasing peptide (GIP), and total as well as non-glycosylated amylin, in 24 GH-deficient adults before and after 4 months of GH replacement (daily evening injections of 2 IU GH/m). DESIGN: Double-blind, placebo-controlled, parallel study. METHODS: All participants underwent an oral glucose tolerance test (OGTT) at 0 and 4 months. RESULTS: A 33% suppression of fasting GLP-1 concentrations was measured in the GH group at 4 months (P=0.02), whereas a non-significant increase occurred in the placebo group (P=0.08). Fasting levels of GIP and amylin did not change significantly after 4 months in either group. The incremental response in GLP-1 during the OGTT was significantly lower after GH treatment as compared with both baseline (P=0.02) and the response in the placebo group (P=0. 03). The stimulation of GIP secretion following OGTT was similar on all occasions. The OGTT-induced incremental response in non-glycosylated amylin was moderately elevated after GH treatment as compared with placebo (P=0.05). Plasma concentrations of glucose and insulin, both in the fasting state and after the OGTT, were higher after GH treatment, but the ratio between amylin and insulin remained unchanged. CONCLUSIONS: GH-induced hyperinsulinemia is accompanied by proportionate elevations in amylin concentrations and a blunting of gut GLP-1 secretion. The mechanisms underlying the suppression of GLP-1 remain to be elucidated.

No seasonal variation of insulin sensitivity and glucose effectiveness in men.

Insulin resistance is of pathogenetic importance for the development of non-insulin-dependent diabetes mellitus (NIDDM). However, not much is known about the variation in insulin sensitivity in the individual over longer periods. Consequently, we measured insulin sensitivity (Si) and glucose effectiveness (Sg) in healthy young men (N = 10) 5 times over a period of 15 months using a frequently sampled intravenous glucose tolerance test (FSIVGTT) with minimal-model analysis (study of seasonality). The maximal aerobic capacity (V(O2)max), fat-free mass, body mass index (BMI), and 24-hour ambulatory blood pressure (BP) were also assessed. Furthermore, we performed a study designed to evaluate the day-to-day variation in Si and Sg (study of day-to-day variation). Here, we studied Si and Sg in healthy young men (n = 8) within 2 weeks. In the study of seasonality, the coefficient of variation (CV) for Si was 24.0%, whereas the CV for Sg was 26.0%. Anticipating a seasonal variation in Si following a sine curve with a cycle length of 1 year and an unknown phase and amplitude, we tested this hypothesis with a multiple linear regression model that allows for different levels of Si between individuals, and failed to detect any impact due to this. Si (mean +/- SD, 1.17 +/- 0.28 x 10(-4) x min(-1) x pmol/L(-1), P = .38), Sg (0.023 +/- 0.006 min(-1), P= .71), fasting insulin (21.2 +/- 7.3 pmol/L, P= .98), V(O2)max (3.8 +/- 0.6 L/min, P= .13), and fat-free mass (64.9 +/- 2.5 kg, P = .92) were constant over time. In the study of day-to-day variation, we found a CV for Si of 17.3% and a CV for Sg of 23.3%. In conclusion, we found that the variations in Si and Sg were slightly higher than those found in studies performed to establish the day-to-day variation. However, no significant seasonal variation in Si and Sg was evident in this group of healthy young lean caucasian men. Consequently, indices of Si and Sg obtained at different times of the year appear comparable.

Assessment of insulin secretion in relatives of patients with type 2 (non-insulin-dependent) diabetes mellitus: evidence of early beta-cell dysfunction.

To examine beta-cell function in glucose-tolerant offspring of type 2 diabetic families, 41 insulin-resistant (hyperinsulinemic-euglycemic clamp, P < .001) first-degree relatives and 32 controls underwent oral (OGTT) and intravenous (IVGTT) glucose tolerance tests and a constant intravenous glucose infusion (4.0 or 4.5 mg/kg/min) with blood sampling every minute for insulin determinations. Insulin concentration time-series were analyzed with complementary mathematical models (deconvolution and autocorrelation analysis, approximate entropy [ApEn], and coefficient of variation [CV] for a 6-point moving average, together with a combined index for regularity and stationarity [RaS] based on the last 2 measures). During the OGTT, the area under the curve (AUC) for plasma glucose was moderately (11%) but significantly (P < .01) elevated in the relatives despite a trend for increased serum insulin (AUC, P = .14). The acute-phase serum insulin response (IVGTT) did not differ between groups (2,055 +/- 330 v 1,766 +/- 229 pmol/L x 10 min, P = .84) but was inappropriately low (individually, P < .05 v control group) for the degree of insulin resistance in 16 relatives. Deconvolution analysis of the insulin time-series did not uncover differences in either the intersecretory pulse interval (5.8 +/- 0.2 v5.7 +/- 0.2 min/pulse) or the fractional secretory burst amplitude (133% +/- 10% v 116% +/- 7% over basal) between the 2 groups. Similarly, significant autocorrelation coefficients were observed in a comparable number of relatives and control subjects (P = .74). In contrast, the RaS index was significantly higher (ie, insulin time-series was more irregular and nonstationary) in the relatives (0.221 +/- 0.194) than in the controls (-0.318 +/- 0.176, P < .05), primarily attributed to the pattern of insulin secretion in relatives with a strong genetic burden. In conclusion, nonstationary and disorderly insulin secretion patterns during glucose stimulation and a low acute-phase serum insulin response associated with significant insulin resistance suggest early beta-cell regulatory dysfunction in individuals genetically predisposed to type 2 diabetes mellitus prior to any evident alterations in insulin secretory burst frequency or mass.

The amylin analog pramlintide improves glycemic control and reduces postprandial glucagon concentrations in patients with type 1 diabetes mellitus.

To explore further the effects of the human amylin analog pramlintide on overall glycemic control and postprandial responses of circulating glucose, glucagon, and metabolic intermediates in type 1 diabetes mellitus, 14 male type 1 diabetic patients were examined in a double-blind, placebo-controlled, crossover study. Pramlintide (30 microg four times daily) or placebo were administered for 4 weeks, after which a daytime blood profile (8:30 AM to 4:30 PM) was performed. Serum fructosamine was decreased after pramlintide (314+/-14 micromol/L) compared with placebo (350+/-14 micromol/L, P = .008). On the profile day, the mean plasma glucose (8.3+/-0.7 v 10.2+/-0.8 mmol/L, P = .04) and postprandial concentrations (incremental areas under the curve [AUCs] from 0 to 120 minutes) were significantly decreased during pramlintide administration (P < .01 for both) despite comparable circulating insulin levels (359+/-41 v 340+/-35 pmol/L). Mean blood glycerol values were reduced (0.029+/-0.004 v 0.040+/-0.004 mmol/L, P = .01) and blood alanine levels were elevated (0.274+/-0.012 v 0.246+/-0.008 mmol/L, P = .03) after pramlintide versus placebo. Blood lactate concentrations did not differ during the two regimens. During pramlintide administration, the AUC (0 to 120 minutes) for plasma glucagon after breakfast was diminished (P = .02), and a similar trend was observed following lunch. In addition, peak plasma glucagon concentrations 60 minutes after breakfast (45.8+/-7.3 v 72.4+/-8.0 ng/L, P = .005) and lunch (47.6+/-9.0 v 60.9+/-8.2 ng/L, P = .02) were both decreased following pramlintide. These data indicate that pramlintide (30 microg four times daily) is capable of improving metabolic control in type 1 diabetics. This may relate, in part, to suppression of glucagon concentrations. Longer-term studies are required to ascertain whether these findings are sustained over time.

Effects of hyperinsulinaemia and hypoglycaemia on circulating leptin levels in healthy lean males.

Current knowledge of the regulatory mechanisms of leptin synthesis and release is limited. To elucidate the role of short-term hyperinsulinaemia and hypoglycaemia on circulating levels of leptin, 7 healthy lean men underwent a 360-min hyperinsulinaemic (insulin infusion rate: 1.5 mU/kg/min) clamp in two conditions: (i) during 360 min of euglycaemia and (ii) during 120 min of euglycaemia followed by 240 min of graded hypoglycaemia (nadir 2.9 +/- 0.1 mmol/l). During hyperinsulinaemic euglycaemia, serum leptin levels were initially stable and then rose gradually after 180 min to a peak value of 147 +/- 7% of baseline (ANOVA, p < 0.01). During the hypoglycaemic clamp, the leptin profile differed from that of euglycaemic conditions (p < 0.01) since the increase was postponed and reduced. In both clamp studies, leptin dynamics contrasted with the changes in a control study performed in 7 other men whose serum leptin fell significantly (p < 0.05) to 77 +/- 4% of baseline values during a 360-min fast (following overnight fasting). It is concluded that hyperinsulinaemia for more than 3 h increases circulating levels of leptin in lean males, whereas hyperinsulinaemia with concomitant hypoglycaemia leads to transient suppression. The exact nature of the underlying mechanisms, e.g. changes in levels of insulin, glucose, various substrates, glucose turnover and/or counterregulatory hormones, remains to be determined.

[Substrate metabolism in untreated and treated thyrotoxicosis]. / Substratomsaetning ved tyreotoksikose før og efter medicinsk behandling.

Accelerated metabolism is a hallmark of thyrotoxicosis, but the underlying biochemical mechanisms are incompletely understood. In order to elucidate these metabolic events further, we studied 12 patients with newly diagnosed diffuse (10 patients) or nodular (two patients) toxic goitre (ten women, two men; age 42.8 +/- 3.2 yr; BMI: 21.6 +/- 0.7 kg/m2) before ("TOX") and after ("TRE") 11.2 +/- 1.0 weeks treatment with methimazole and compared these patients to a control group ("CTR") of 11 subjects (nine women, two men; age 40.5 +/- 3.9 yr; BMI 22.5 +/- 1.0 kg/m2). All were studied for three hours in the basal state, using indirect calorimetry, isotope dilution for measurement of glucose turnover and the forearm technique for assessment of muscle metabolism. Prior to treatment patients with thyrotoxicosis were characterized by: Increased (p < 0.05) levels of T3 (3.75 +/- 0.23 [TOX], 1.89 +/- 0.08 [TRE] and 1.75 +/- 0.11 [CTR] nmol/l), resting energy expenditure (130.5 +/- 3.5 [TOX], 107.7 +/- 2.7 [TRE] and 106.3 +/- 3.1 [CTR] percent of predicted), protein oxidation (0.67 +/- 0.03 [TOX], 0.54 +/- 0.06 [TRE] and 0.46 +/- 0.05 [CTR] mg/kg/min), lipid oxidation (1.34 +/- 0.08 [TOX], 1.00 +/- 0.06 [TRE] and 1.02 +/- 0.04 [CTR] mg/kg/min), endogenous glucose production (2.51 +/- 0.13 [TOX], 1.86 +/- 0.12 [TRE] and 1.85 +/- 0.12 [CTR] mg/kg/min), non-oxidative glucose turnover (1.28 +/- 0.16 [TOX], 0.75 +/- 0.18 [TRE] and 0.71 +/- 0.11 [CTR] mg/kg/min) and a 50% increase in total forearm blood flow. Glucose oxidation (1.23 +/- 0.09 [TOX], 1.13 +/- 0.10 [TRE] and 1.13 +/- 0.09 [CTR] mg/kg/min), exchange of substrates in the muscles of the forearm and circulating levels of insulin, C-peptide, growth hormone or glucagon were not influenced by hyperthyroidism. Propranolol (20 mg thrice daily) given to seven of the patients for two days did not affect circulating levels of thyroid hormones, energy expenditure or glucose turnover rates. These results suggest that all major fuel sources contribute to the hypermetabolism of thyrotoxicosis and that augmented non-oxidative glucose metabolism may further aggravate the condition. All abnormalities recede with medical treatment of the disease.

[Insulin resistance among relatives of patients with NIDDM. Significance of physical fitness and muscle metabolism]. / Insulinresistens hos slaegtninge til patienter med NIDDM. Betydning af fysisk traeningstilstand og muskelmetabolisme.

To explore the possible role of a reduced physical fitness for the diminished insulin sensitivity in first-degree relatives of NIDDM patients, 21 relatives and 22 matched control subjects were examined employing a hyperinsulinaemic (insulin infusion rate 0.6 mU/kg/min) euglycaemic clamp combined with the isotope dilution technique (3-3H-glucose), the forearm technique and indirect calorimetry. During hyperinsulinaemia glucose disposal (Rd) was significantly diminished in the relatives (p < 0.01). Maximal oxygen uptake (VO2 max) was 15% lower in the relatives than in the controls (p = 0.03). There was a highly significant correlation between Rd and VO2 max in both groups. In multiple linear regression analyses with Rd as the dependent variable VO2 max significantly determined the level of Rd (p < 0.01), whereas forearm blood flow and anthropometric data did not. We concluded that the insulin resistance in healthyfirst degree relatives of patients with NIDDM is associated with a diminished physical work capacity. Whether this finding is ascribable to environmental or genetic factors remains to be determined.

Increased adiposity and reduced adipose tissue mRNA expression of uncoupling protein-2 in first-degree relatives of type 2 diabetic patients: evidence for insulin stimulation of UCP-2 and UCP-3 gene expression in adipose tissue.

The mitochondrial uncoupling proteins (UCP-2 and UCP-3), which have been suggested to be involved in the development of obesity by controlling the energy expenditure (EE), were studied in 22 healthy first-degree relatives (FDRs) of patients with type 2 diabetes and 13 body mass index (BMI)- and age-matched healthy control subjects. Abdominal subcutaneous adipose tissue biopsies were obtained before and after 150-min hyperinsulinaemic clamp (average serum insulin 250 pM). Basal adipose tissue UCP-2 mRNA levels in the FDR group were significantly lower than that in the control group. After the hyperinsulinaemic clamp, adipose tissue UCP-2 mRNA levels were increased by 32% in the control group (p < 0.05) and 32% in the FDR group (p < 0.05). The basal adipose tissue UCP-3 mRNA level was similar in the two groups and increased in both the groups during hyperinsulinaemia (p < 0.001). Dual energy X-ray absorptiometry showed that despite similar BMI the FDR group had significantly higher fat mass (FM) per cent compared to that of the control group (p < 0.01). The UCP-2 mRNA expression was inversely correlated with the amount of adipose tissue (r = -0.53, p < 0.001), and multiple regression analysis revealed that only the amount of FM was independently correlated with basal UCP-2 mRNA levels, whereas age, gender nor family history of type 2 diabetes contributed independently to the variation in UCP-2 mRNA levels. No differences in EE were observed between the two groups, and no association between EE and UCP mRNA expression was found. In conclusion, we have demonstrated that adipose tissue UCP-2 and UCP-3 mRNA levels are significantly increased during a 150-min hyperinsulinaemic clamp. The UCP-2 mRNA levels were expressed at a significantly lower level FDR to type 2 diabetes compared to control subjects. However, in multiple regression analysis controlling for amount of adipose tissue, the difference between the two groups disappeared. Thus, only the amount of adipose tissue contributed independently to the variation in UCP-2 mRNA expression.

Mortality after hip fracture: results of operation within 12 h of admission.

This retrospective study was undertaken to evaluate the mortality and morbidity of patients undergoing hip fracture surgery within 12 h of admission, compared with surgery more than 12 h after admission, the patients had no acute medical conditions that required preoperative treatment. Mortality rates were based on survival of the patients up to 1 year after surgery. For patients with fractures of the femoral neck, and in whom surgery was performed within 12 hours of admission, the mortality rate was significantly lower from 5 months after the operation. Time of surgery did not influence the mortality of patients with trochanteric fractures. It is suggested that a fractured neck of the femur in an otherwise fit elderly patient should be regarded as a surgical emergency.

Glucose turnover, fuel oxidation and forearm substrate exchange in patients with thyrotoxicosis before and after medical treatment.

OBJECTIVE: Accelerated metabolism is a hallmark of thyrotoxicosis, but the underlying biochemical mechanisms are incompletely understood and the majority of studies have investigated normal subjects rendered only modestly hyperthyroid for a brief period of time. We have therefore studied a group of thyrotoxic patients using several different techniques. DESIGN: Twelve patients with newly diagnosed diffuse (10 patients) or nodular (2 patients) toxic goitre (10 women, 2 men; age 42.8 +/- 3.2 years; BMI 21.6 +/- 0.7 kg/m2) before ('pretreatment') and after ('treated') 11.2 +/- 1.0 weeks treatment with methimazole and compared these patients to a control group ('control') of 11 subjects (9 women, 2 men; age 40.5 +/- 3.9 years; BMI 22.5 +/- 1.0 kg/m2). All were studied for 3 hours in the basal state, using indirect calorimetry, isotope dilution for the measurement of glucose turnover and the forearm technique for assessment of muscle metabolism. RESULTS: Prior to treatment patients with thyrotoxicosis were characterized by increased (P < 0.05) levels of T3 (3.75 +/- 0.23 nmol/l (pretreatment), 1.89 +/- 0.08 (treated) and 1.75 +/- 0.11 (control)), resting energy expenditure (130.5 +/- 3.5 (pretreatment), 107.7 +/- 2.7 (treated) and 106.3 +/- 3.1 (control), % of predicted), protein oxidation (0.67 +/- 0.03 (pretreatment), 0.54 +/- 0.06 (treated) and 0.46 +/- 0.05 (control), mg/kg/min), lipid oxidation (1.34 +/- 0.08 (pretreatment), 1.00 +/- 0.06 (treated) and 1.02 +/- 0.04 (control), mg/kg/min), endogenous glucose production (2.51 +/- 0.13 (pretreatment), 1.86 +/- 0.12 (treated) and 1.85 +/- 0.12 (control), mg/kg/min), non-oxidative glucose turnover (1.28 +/- 0.16 (pretreatment), 0.75 +/- 0.18 (treated) and 0.71 +/- 0.11 (control), mg/kg/min) and a 50% increase in total forearm blood flow. Glucose oxidation (1.23 +/- 0.09 (pretreatment), 1.13 +/- 0.10 (treated) and 1.21 +/- 0.11 (control) mg/kg/min), exchange of substrates in the muscles of the forearm and circulating levels of insulin, C-peptide, growth hormone or glucagon were not influenced by hyperthyroidism. Propranolol (20 mg thrice daily) given to 7 of the patients for 2 days did not affect circulating levels of thyroid hormones, energy expenditure or glucose turnover rates. CONCLUSIONS: These results suggest that all major fuel sources contribute to the hypermetabolism of thyrotoxicosis and that augmented non-oxidative glucose metabolism may further aggravate the condition. All abnormalities diminish with medical treatment of the disease.