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Background We investigated the concordance between glucose effectiveness (SG) and insulin sensitivity (SI), derived from the unmodified dynamic non-insulin-assisted intravenous glucose tolerance test (IVGTT) implemented by SGMM and SIMM; simulation analysis and modelling/conversational interaction (SAAM/CONSAM) versus the eu/hyperglycaemic basal insulinaemic and the euglycaemic hyperinsulinaemic clamp (SGCLAMP and SICLAMP). Methods Twenty-seven of 30 normoglycaemic subjects completed a (1) euglycaemic hyperinsulinaemic clamp, (2) 6-h eu/hyperglycaemic near-normoinsulinaemic pancreatic clamp with hyperglycaemia present over the final 2 h of the clamp (Day 2 study), (3) identical clamp to (2) but with euglycaemia maintained over the entire 6 h (Day 3 study) and (4) IVGTT. SGCLAMP was calculated in two ways based on data from study (2) alone (Day 2 SGCLAMP210–240′) or from data from study day (2) and (3) (Day 2–3 SGCLAMP330–360′). Results SGMM was unrelated to the magnitude of endogenous insulin release (AIR). The single-day (Day 2) and two-day (Day 2 and 3) SGCLAMP protocols correlated (r = 0.72, p = 0.003), but SGCLAMP210–240′ was significantly (p = 0.001) higher than SGCLAMP330–360′. Employing the Day 2 and 3 SGCLAMP protocol, the whole body SGCLAMP330–360′ was similar to SGMM (1.80 ± 0.82 versus 1.73 ± 0.58 dL/min) and correlated (r = 0.45, p < 0.02). SGCLAMP210–240′ did not correlate with SGMM (r = 0.24). SIMM and SICLAMP were similar (0.093 ± 0.060 versus 0.087 ± 0.029 dL/min per mU/L) and correlated (r = 0.76, p < 0.001). Conclusions The time-dependent increase in glucose disposal observed during a prolonged 6-h clamp significantly influences the estimation of SGCLAMP, and significant concordance coefficients are observed between SGMM, and SGCLAMP330–360′, and SIMM and SICLAMP. Copyright © 2010 John Wiley & Sons, Ltd.

BACKGROUND: Insulin resistance was found in some but not in all previous studies of non-diabetic first degree relatives of Type 2 diabetic patients. Small study groups, ethnic differences and/or non-optimal techniques may explain the conflicting results. AIM: To study the impact of a family history of Type 2 diabetes on insulin action in a large group of non-diabetic Europeans using the 'gold standard' euglycaemic hyperinsulinaemic clamp technique. METHODS: Non-diabetic subjects (n = 235) with a positive family history of Type 2 diabetes (FH+) and 564 subjects with no family history of diabetes (FH-) were recruited from The European Group of Insulin Resistance (EGIR) database. This database includes measurements of insulin action using the insulin clamp technique (1 mU/kg per min) in normal glucose-tolerant individuals from 20 different European centres. In a subset of subjects the measurements were performed in combination with indirect calorimetry (n = 80 vs. 213 with and without family history of Type 2 diabetes). RESULTS: The body mass index (BMI) was slightly higher in FH+ compared with FH- (26.7 +/- 4.6 vs. 25.1 +/- 4.7 kg/m(2); P < 0.02). After correction for covariates according to differences between investigators and subject characteristics including BMI (multiple regression analysis), insulin-stimulated glucose disposal was lower in FH+ compared with FH- (P < 0.00001). Insulin-stimulated glucose oxidation was slightly increased in FH+ compared with FH-, and insulin-stimulated non-oxidative glucose metabolism was consequently markedly reduced in FH+ compared with FH- (P < 0.0005). CONCLUSION: Insulin resistance is present in European non-diabetic relatives of Type 2 diabetic patients. The insulin resistance is independent of degree of obesity and is restricted solely to the pathway of non-oxidative glucose metabolism. (Less)

Acute administration of the antilipolytic nicotinic acid analog acipimox to patients with noninsulin-dependent diabetes mellitus (NIDDM) is associated with increased peripheral and hepatic insulin sensitivity. However, long term acipimox treatment (250 mg, 3 times/24 h) of NIDDM patients does not improve blood glucose control, possibly due to rebound lipolysis. The current study assessed the influence of intensified acipimox administration (125 mg, 12 times/24 h) on diurnal plasma profiles of glucose, insulin, nonesterified FFA (NEFA), and triglycerides during a 3-day period. Eight NIDDM patients [mean age, 58.9 yr (range, 46-68); mean body mass index, 31.4 kg/m2 (range, 24.9-39.6)] were included in a randomized, double blind, placebo-controlled, cross-over study. Blood samples were collected every second hour during the study. The acipimox and placebo treatments were separated by a 2-week washout period. Acipimox treatment was associated with reduced diurnal mean plasma concentrations of NEFA [0.26 +/- 0.03 (+/- SEM) vs. 0.63 +/- 0.06 mmol/L; P < 0.001], triglycerides (1.74 +/- 0.21 vs. 2.10 +/- 0.18 mmol/L; P < 0.03), glucose (12.7 +/- 1.0 vs. 15.8 +/- 1.2 mmol/L; P < 0.002), and insulin (157 +/- 21 vs. 207 +/- 27 pmol/L; P < 0.05). However, despite the overall reduction in mean NEFA, during acipimox treatment NEFA increased from days 1-3 (0.18 +/- 0.03 vs. 0.34 +/- 0.04 mmol/L; P < 0.001), whereas plasma glucose (13.4 +/- 1.2 vs. 12.3 +/- 0.9 mmol/L; P < 0.03) and plasma insulin (168 +/- 23 vs. 148 +/- 17 pmol/L; P < 0.04) decreased steadily from days 1-3 during active treatment. In conclusion, inhibition of lipolysis using the intensified acipimox treatment regiment was associated with a pronounced blood glucose- and plasma insulin-lowering effect. However, minor rebound effects of lipolysis occurred in some patients despite the presence of allegedly effective acipimox levels. This suggests that caution should be employed concerning long term use of acipimox as a hypoglycemic agent in NIDDM patients.

Previous animal and human studies have indicated that nociceptive thresholds are decreased by acute hyperglycemia. The results of these studies may be challenged due to methodological problems. We therefore conducted a double-blind, controlled, cross-over study on the effect of acute hyperglycemia on nociceptive and non-nociceptive thresholds in 10 type 1 (insulin-dependent) diabetic patients (diabetes < 5 years) without symptoms or clinical signs of peripheral neuropathy. During an overnight fast, blood glucose concentration was normalized by refract insulin injections. Then, blood glucose was kept at 6 mmol/1 for 3 h by an intravenous infusion of glucose and insulin. On one study day, blood glucose was kept at 6 mmol/1 for a further 3 h and on another day, blood glucose was elevated to 12 mmol/1 during 0.5 h by additional glucose infusion and kept at that level for 2.5 h. Sensory testing was carried out twice during the initial 3 h with euglycemia and 3 times during the following period with either hyper- or euglycemia. The test procedure included determination of pain detection and pain tolerance thresholds to heat (wrists) and pressure (fingers) as well as detection thresholds to warmth/cooling (wrist), vibration (finger), and mechanical (wrist) stimulation. The changes in neither nociceptive nor non-nociceptive thresholds showed any statistically significant differences between the 2 study days. The pressure pain detection and tolerance thresholds showed, however, minor decreases at each of the test days, probably due to cutaneous sensitization caused by the repeated measurements. Compared to baseline, the pressure pain thresholds decreased significantly on the day with hyperglycemia. None of the other thresholds showed such changes. It cannot be excluded that more pronounced or longer term hyperglycemia can cause changes in sensibility. We conclude that acute hyperglycemia (12 mmol/1) does not cause major changes in nociceptive or non-nociceptive thresholds in the upper extremity, however, pressure pain thresholds was reduced significantly with hyper glycemia.

With the aim of investigating glucose-mediated glucose disposal (glucose effectiveness [GE]) in 15 (3 female and 12 male subjects) insulin-resistant normoglycemic relatives of patients with type 2 diabetes (DM2), and 15 age-, sex-, and BMI-matched control subjects without a family history of DM2, we performed 2 studies: 1) a 5-h euglycemic near-normoinsulinemic pancreatic clamp with somatostatin (360 microg/h), insulin (0.25 mU x kg(-1) x min(-1)), glucagon (0.5 ng x kg(-1) x min(-1)), growth hormone (6 ng x kg(-1) x min(-1)), and tritiated glucose infusion and indirect calorimetry; and 2) on a separate day, an identical 5-h clamp but at hyperglycemia (approximately 12 mmol/l) over the last 2 h. Fasting plasma insulin (PI) concentrations were elevated in the relatives compared with control subjects (49 +/- 6 vs. 32 +/- 5 pmol/l, P < 0.04), whereas plasma glucose (PG) was not (5.6 +/- 0.1 vs. 5.5 +/-0.1 mmol/l). At the end (i.e., 4.5-5.0 h) of the euglycemic clamp (PG, 6.1 +/- 0.4 vs. 5.6 +/- 0.1 mmol/l; PI, 78 +/- 5 vs. 73 +/-6 pmol/l), peripheral glucose uptake (Rd(euglycemia)) was decreased in the relatives (2.93 +/- 0.08 vs. 3.70 +/-0.23 mg x min(-1) x kg(-1) fat free mass [FFM], P < 0.005), due to a decreased nonoxidative glucose disposal (0.83 +/-0.21 vs. 1.62 +/- 0.19 mg x min(-1) x kg(-1) FFM, P < 0.01), but hepatic glucose production (HGP) was increased (1.97 +/-0.19 vs. 1.50 +/- 0.13 mg x min(-1) x kg(-1) FFM, P < 0.05). At the matched end of the hyperglycemic clamp (PG, 12.7 +/-0.2 vs. 12.6 +/- 0.2 mmol/l; PI, 87 +/- 5 vs. 78 +/- 7 pmol/l), peripheral glucose disposal (Rd(hyperglycemia)) (5.52 +/- 0.22 vs. 5.92 +/- 0.29 mg x min(-1) x kg(-1) FFM, NS), nonoxidative glucose disposal (2.93 +/- 0.18 vs. 2.78 +/- 0.25 mg x min(-1) x kg(-1) FFM, NS), and HGP(hyperglycemia) (1.20 +/- 0.09 vs. 1.37 +/-0.23 mg x min(-1) x kg(-1) FFM, NS) were all identical. When the effectiveness of glucose itself on glucose uptake and production [(Rd(hyperglycemia) - Rd(euglycemia))/deltaPG and (HGP(euglycemia)- HGP(hyperglycemia))/deltaPG] was calculated, the relatives had a 22% increase in peripheral uptake (0.022 +/- 0.002 vs. 0.018 +/- 0.002 mg x min(-1) x kg(-1) FFM per mg/dl), due to a significantly increased nonoxidative glucose metabolism and enhanced suppression of HGP (0.0076 +/- 0.0021 vs. 0.0011 +/- 0.0022 mg x min(-1) x kg(-1) FFM per mg/dl, P < 0.05). In conclusion, in insulin-resistant relatives of DM2 patients, whole-body glucose-mediated glucose disposal is increased by GE enhancement of the muscle nonoxidative glucose pathway and by GE enhancement of the suppression of HGP. These mechanisms may represent a compensatory mechanism to the ongoing insulin resistance of these relatives.

OBJECTIVE: To evaluate the effect of clinically obtainable improvements in metabolic control in patients with type 1 diabetes on biochemical cardiovascular risk factors. RESEARCH DESIGN AND METHODS: Blood and 24-h urinary samples were obtained from 49 patients with type 1 diabetes before and after a run-in period and after 3 months of intervention, with frequent adjustment of insulin dosage according to measured blood glucose concentrations. RESULTS: The intervention caused a mean insulin dosage increment of 10%, a 20% decrease in fasting plasma glucose concentration, a 10% decrease in albumin corrected serum fructosamine, and a somewhat lesser decrease in HbAlc.A 14% decrease in the renal excretion of magnesium (Mg) was observed, but without a change in average serum Mg concentration. Serum HDL cholesterol increased 4%, and serum triglycerides decreased 10% as an average. Looking at individual patients, the decrease in serum triglycerides correlated with both the change in serum total Mg concentration and with the increase in insulin dosage. Using the change in serum total Mg concentration and in insulin dosage as independent variables in a multiple regression analysis, the coefficient of correlation with the decrease in serum triglycerides was 0.52. CONCLUSIONS: Moderate but clinically obtainable improvement of metabolic control in patients with type 1 diabetes seems to reduce the loss of Mg, increase serum HDL cholesterol, and decrease serum triglycerides. The decrease in serum triglycerides was associated with the change in serum total Mg concentration. These reductions in Mg loss and serum triglycerides might reduce the risk of developing cardiovascular disease in patients with type 1 diabetes.

Skeletal muscles in patients with non-insulin-dependent diabetes mellitus (NIDDM) are resistant to insulin; i.e., the effect of insulin on glucose disposal is reduced compared with the effect in control subjects. This defect has been found to be localized to the nonoxidative pathway of glucose disposal; hence, the deposition of glucose, as glycogen, is abnormally low. This defect may be inherited, because it is present in first-degree relatives to NIDDM patients two to three decades before they develop frank diabetes mellitus. The cellular defects responsible for the abnormal insulin action in NIDDM patients is reviewed in this article. The paper focuses mainly on convalent insulin signaling. Insulin is postulated to stimulate glucose storage by initiating a cascade of phosphorylation and dephosphorylation events, which results in dephosphorylation and hence activation of the enzyme glycogen synthase. Glycogen synthase is the key enzyme in regulation of glycogen synthesis in the skeletal muscles of humans. This enzyme is sensitive to insulin, but in NIDDM patients it has been shown to be completely resistant to insulin stimulation when measured at euglycemia. The enzyme seems to be locked in the glucose-6-phosphate (G-6-P)-dependent inactive D-form. This hypothesis is favored by the finding of reduced activity of the glycogen synthase phosphatase and increased activity of the respective kinase CAMP-dependent protein kinase. A reduced glycogen synthase activity has also been found in normoglycemic first-degree relatives of NIDDM patients, indicating that this abnormality precedes development of hyperglycemia in subjects prone to develop NIDDM. Therefore, this defect may be of primary genetic origin. However, it does not appear to be a defect in the enzyme itself, but rather a defect in the covalent activation of the enzyme system. Glycogen synthase is resistant to insulin but may be activated allosterically by G-6-P. This means that the defect in insulin activation can be compensated for by increased intracellular concentrations of G-6-P. In fact, we found that both hyperinsulinemia and hyperglycemia are able to increase the G-6-P level in skeletal muscles. Thus, insulin resistance in the nonoxidative pathway of glucose processing can be overcomed (compensated) by hyperinsulinemia and hyperglycemia. In conclusion, we hypothesize that insulin resistance in skeletal muscles may be a primary genetic defect preceding the diabetic state. The cellular abnormality responsible for that may be a reduced covalent insulin activation of the enzyme glycogen synthase. The compensation results in nearnormalization of glycogen synthesis, but the price diabetic subjects must pay to obtain this is hyperglycemia.