Changes in Glucose Disposal and Cellular Insulin Binding in Obese Black Southern African Patients with Type 2 Diabetes Mellitus Before and After Sulphonylurea Therapy

Peripheral insulin action and cellular insulin binding were studied in 10 newly detected, obese, black, Southern African women with Type 2 diabetes mellitus before and after midterm oral sulphonylurea therapy and in five obese, non-diabetic controls. Glucose disposal (assessed by the euglycaemic insulin clamp technique) was significantly reduced in diabetic patients compared to control subjects (4.4 ± 0.5 vs 6.4 ± 0.5 mg kg^-1 min^-1, p < 0.05), and increased after 1 and 3 months of sulphonylurea therapy to 6.8 ± 0.6 mg kg^-1 min^-1 (p = 0.01) and 6.3 ± 0.7 mg kg^-1 min^-1 (p = 0.04), respectively. The major change in the binding kinetics of insulin to peripheral monocytes was an increase in the mean receptor concentration in the diabetic patients which was significant after 3 months of therapy (0.2 ± 0.08 to 0.6 ± 0.01 nM, p = 0.05). The basal plasma C-peptide concentration was significantly lower in the diabetic patients than in the controls and remained so following sulphonylurea therapy, despite significant reductions in fasting glucose and HbA_-1 concentrations. We conclude that newly diagnosed, obese, black Southern Africans with Type 2 diabetes showed diminished peripheral glucose disposal which increased following sulphonylurea therapy. This was accompanied by an increase in insulin receptor concentration but not with changes in basal insulin secretion.     

Preservation of Renal Haemodynamic Response to an Oral Protein Load in Non-insulin-dependent Diabetes Mellitus

Glomerular Filtration Rate (GFR) and Effective Renal Plasma Flow (ERPF) were determined, for 2h prior to and 3h following the ingestion of a 1.2 g kg^?1 meat meal, in seven normotensive normoalbuminuric Type 2 diabetic patients exhibiting good glycaemic control (fasting plasma glucose (mean ± SD): 7.2 ± 2.0 mmol l^?1; glycosylated haemoglobin: 8.1 ± 1.7%) and in nine normal subjects selected for similar basal GFR values. Baseline GFR and ERPF (corrected to 1.73 m² surface area) were 83 ± 10 and 410 ± 76 ml min^?1 for the Type 2 diabetic patients and 86 ± 11 and 405 ± 113 ml min^?1 for the normals. GFR increased by 38 ± 8 and 32 ± 15% in the diabetic patients and normals, to 108 ± 25 and 105 ± 26 ml min^?1 (p < 0.01 vs baseline). Peak ERPF was 501 ± 127 and 476 ± 119 ml min^?1 for the two respective groups (p < 0.01 vs baseline). Filtration fractions at peak GFR and EPRF values were unchanged from baseline for either groups. Fractional clearance of albumin for the Type 2 diabetic patients was unaltered by protein ingestion. Therefore, protein ingestion in Type 2 diabetes, as in normals, results in an acute elevation of GFR. Absolute and incremental changes in GFR were identical for the two groups. These data demonstrate a preserved capacity for renal vasodilatation in Type 2 diabetic patients despite their greater chronological age.     

Short Administration of Metformin Improves Insulin Sensitivity in Android Obese Subjects with Impaired Glucose Tolerance

In a double-blind, randomized, cross-over study, the metabolic effects of a short treatment with metformin (2 times 850 mg day^?1 for 2 days and 850 mg 1 h before evaluation) were compared to those of placebo in 15 obese subjects (BMI: 33.2 ± 0.9 kg m^?2), with abdominal distribution of adipose tissue and impaired glucose tolerance. An intravenous glucose tolerance test (0.3 g glucose kg^?1) was performed after each period of treatment. Areas under the curve (AUC_{0–180 min}) were calculated for plasma glucose, insulin, and C-peptide levels. Glucose tolerance was estimated by the coefficient of glucose assimilation (K_G). Insulin sensitivity (S_I) and glucose effectiveness (S_G) indices were calculated using Bergman's minimal model. Insulin secretion rate (ISR) was determined by deconvolution of plasma C-peptide levels and insulin metabolic clearance rate (MCR) was estimated by dividing AUC ISR by AUC insulin. Fasting plasma insulin levels were reduced after metformin (89.3 ± 15.9 vs 112.4 ± 24.3 pmol I^?1; p = 0.04). AUC glucose, K_G and S_G were similar in both tests. However, AUC insulin was reduced (39.7 ± 6.5 vs 51.8 ± 10.4 nmol min I^?1; p = 0.02), while S_I (6.98 ± 1.14 vs 4.61 ± 0.42 10^?5 min^?1 pmol^?1 I; p = 0.03) and insulin MCR (715 ± 116 vs 617 ± 94 ml min^?1 m^?2; p = 0.03) were increased after metformin. The demonstration that metformin rapidly improves insulin sensitivity should encourage further research to evaluate the long-term effects of metformin in android obese subjects with impaired oral glucose tolerance.     

Symptoms,Hormones, and Glucose Fluxes During a Gradual Hypoglycaemia Induced by Intraperitoneal vs Venous Insulin Infusion in Type I Diabetes

Intraperitoneal (IP) insulin infusion with programmable implantable pumps is associated with a reduction in hypoglycaemic events when compared to intensive diabetes management with subcutaneous insulin in patients with Type 1 diabetes mellitus. The mechanism may involve more physiological insulin kinetics, lower peripheral insulin levels or a specific hepatic action of portal insulin on hypoglycaemic counter regulation. To investigate the latter two hypotheses, we performed two hypoglycaemic clamps (controlled blood glucose decrement to 2.2 mmol l^?1) in random order in 12 Type 1 diabetic patients. Insulin was infused either IP or IV for 150 min, at rates chosen to generate similar peripheral insulin levels (1 mU/kg^?1 min^?1 IV or 2 mU/kg^?1 min^?1 IP, n = 6) to evaluate direct hepatic action, or at similar rates (1 mU/kg^?1 min^?1 IV and IP, n = 6) to evaluate IP indirect effects via lower peripheral insulinaemia. Hepatic glucose production and glucose utilization were measured by [6, 6 ²H] glucose dilution technique. Glucose production was lower (1.7 ± 0.4 vs 0.5 ± 0.4 mg kg^?1min^?1, p < 0.05), and utilization was similar at the end of the matched-insulinaemia IV and IP clamps, respectively. By contrast, glucose production was higher (1.7 ± 0.5 IV vs 2.7 ± 0.3 IP mg kg^?1 min^?1, p < 0.01) and glucose utilization lower (4.4 ± 1.0 IV vs 3.3 ± 0.2 IP mg kg^?1 min^?1, p < 0.05) with IP delivery at the end of the matched-dose clamps. Counterregulatory hormones and hypoglycaemic symptoms increased similarly in all clamps. In summary, IP insulin, when compared to IV insulin at similar delivery rates, but not at similar insulinaemia, is associated with a less negative glucose balance (glucose production-glucose utilization) during hypoglycaemia. Such a mechanism may play a role in the reduced hypoglycaemic risk seen with IP implantable pumps.     

The Acute Effect of Preprandial Exogenous and Endogenous Sulphonylurea-stimulated Insulin Secretion on Postprandial Glucose Excursions in Patients with Type 2 Diabetes

Sulphonylureas improve glucose tolerance by stimulating insulin secretion. Whether improved glucose tolerance results from enhanced early insulin release or greater total insulin secretion is not clear. Insulin responses to a test meal in Type 2 diabetic subjects with and without a single dose (2.5 mg) of oral and intravenous glipizide were, therefore, measured. Intravenous glipizide enhanced early insulin release more than oral glipizide (134% and 80% vs control; p<0.01), whereas total insulin release was equally improved (78% and 54% vs control; p<0.01). Despite slight differences in insulin release, there was no difference in glucose tolerance (median area under concentration curve (AUC); 66.6 vs 61.9 mmol × min I^?1; NS). The test meal was repeated after a bolus of intravenous insulin at the beginning of the meal. This allowed comparison of the effect of exogenous and endogenous insulin supply on postprandial glucose excursions. In spite of an early and fivefold larger rise in serum insulin after intravenous administration of the hormone than after intravenous glipizide (725% vs 134%; p<0.01), postprandial glucose was no better than after glipizide (median AUC; 87.8 vs 66.6 mmol × min I^?1; NS). In contrast, glucose tolerance was better after oral glipizide compared to intravenous insulin (median AUC; 61.9 vs 87.8 mmol × min I^?1; p<0.05). In conclusion, the total amount of insulin secreted seems more important than the timing of the insulin release for the postprandial glucose tolerance in Type 2 diabetic subjects. Neither endogenous nor peripheral pre-meal supply of insulin could normalize postprandial glucose excursions in patients with Type 2 diabetes.     

The Role of Plasma Non-esterified Fatty Acids During Exercise in Type 2 Diabetes Mellitus

Elevated fasting plasma non-esterified fatty acid (NEFA) levels have been reported in Type 2 diabetes. We examined whether such changes persist during low-grade exercise and influence carbohydrate metabolism. Eight Type 2 diabetic patients with moderate glycaemic control and eight healthy controls received the anti-lipolytic agent, acipimox, or placebo on separate occasions before exercising for 45 min at 35 % pre-determined V_o2max. Fasting plasma NEFA levels were similar (0.40 ± 0.06 (SEM) and 0.45 ± 0.05 mmol l^?1; healthy and Type 2 diabetic subjects) following placebo, and increased to comparable levels with exercise (0.73 ± 0.07 and 0.73 ± 0.10 mmol l^?1). Acipimox lowered basal NEFA levels (0.14 ± 0.03 and 0.28 ± 0.04 mmol I^?1; both p < 0.05 vs placebo), and prevented the rise with exercise. Blood glucose (p < 0.001) and serum insulin (p < 0.01) levels were higher in the Type 2 diabetic patients (vs controls) for both treatments. Whole body lipid oxidation increased from baseline to a comparable degree with exercise following placebo (3.2 ± 0.3 and 2.8 ± 0.3 mg kg^?1 min^?1; healthy and Type 2 diabetic subjects, both p < 0.02). Although less marked, the same was also observed following acipimox (2.0 ± 0.4 and 2.1 ± 0.5 mg kg^?1 min^?1; both p < 0.05). Carbohydrate oxidation increased with exercise in both subject groups, but with no significant difference between the treatments. Thus, the metabolic response to low-grade exercise was normal in Type 2 diabetic patients with moderate glycaemic control, but occurred against a background of hyperinsulinaemia. Plasma NEFA do not exert a major regulatory effect on carbohydrate metabolism during low-grade exercise.     

Cerebral Glucose Metabolism in Type 1 Diabetic Patients

To evaluate whether cerebral glucose metabolism is impaired in diabetes the [¹⁸F]–2–deoxy–2–fluoro-d-glucose method and positron emission tomography were used to determine the regional cerebral metabolic rate of glucose in 12 healthy subjects, 8 newly diagnosed Type 1 diabetic patients, 6 Type 1 diabetic subjects without peripheral neuropathy, and 7 Type 1 diabetic patients with symptomatic peripheral neuropathy, all of whom were men. In addition, multimodal evoked potentials were assessed. Cerebral glucose consumption was significantly reduced in the group with neuropathy as compared with the newly diagnosed diabetic patients and the healthy subjects (26.9 ± 1.0 vs 33.9 ± 1.9 and 32.5 ± 1.1 ±mol 100 g^-1 min^-1; p<0.05), while in the patients without neuropathy it was 30.2 ± 2.5 ±mol 100 g^-1 min^-1 (NS vs the remaining groups). There were no significant differences between the groups regarding brainstem auditory and visual evoked potentials. No relationship was noted between cerebral glucose metabolism and P300 latency of event-related potentials as an index of cognitive function, but there was an inverse correlation with age (r = -0.42; p < 0.05) and duration of diabetes (r = -0.67; p < 0.05). These results suggest that cerebral glucose metabolism is normal at the time of diagnosis of Type 1 diabetes, but may become altered with both increasing duration of diabetes and age in the absence of central conduction deficits or cognitive dysfunction. Diabetic neuropathy may constitute a possible additional correlate of reduced cerebral glucose consumption.     

Improved Blood Glucose Control by Insulin Therapy in Type 2 Diabetic Patients Has No Effect on Lipoprotein(a) Levels

The effects of improved blood glucose control by insulin therapy on lipoprotein(a) and other lipoproteins were studied in 54 patients with Type 2 diabetes (mean ± SD: age 67 ± 9 years, body mass index 26.1 ± 4.4 kg m^?2, median duration of diabetes 10 (range 1–37) years, 23 males, 31 females), who were poorly controlled despite diet and maximal doses of oral hypoglycaemic agents. After 6 months of insulin treatment, mean fasting blood glucose concentrations had decreased from 14.1 ± 2.2 mmol l^?1 to 8.4 ± 1.8 mmol l^?1 (p < 0.001), and HbA^1c had fallen from 11.1 ± 1.4 % to 8.2 ± 1.1 % (p < 0.001). Significant decreases of total and LDL cholesterol, triglycerides, apolipoprotein B, and free fatty acids were observed, while HDL-cholesterol and apoA1 increased by 10 %. Baseline serum Lp(a) levels were elevated compared to non-diabetic subjects of similar age (median 283, range 8–3050 mg I^?1, vs 101, range 8–1747 mg I^?1, p < 0.05), but did not change with insulin, and there was no correlation with the degree of metabolic improvement and changes in Lp(a) levels. It is concluded that improved blood glucose control by insulin therapy does not alter elevated Lp(a) levels in Type 2 diabetic patients, but has favourable effects on the other lipoproteins.     

Insulin sensitivity in alcoholics in a withdrawal state

Abstract. Insulin sensitivity in non-diabetic alcoholics in a withdrawal state was investigated using a euglycaemic clamp technique on two occasions with an interval of 1 week. Insulin was infused at a rate of 40 mU m^?2 min^?1 (n = 9) and 20 mU m^?2 min^?1 (n = 9). Hepatic glucose production was estimated with tritiated glucose in six subjects. The fasting glucose level at the first examination, 5.1 ± 0.2 mmol l^?1 exceeded that found at the second examination, 4.7 ± 0.1 mmol l^?1 (P < 0.05), although the C-peptide concentration was higher at the first examination (2.7 ± 0.3 vs. 1.6 ± 0.2 ng ml^?1: P < 0.001). Both glucose uptake (5.0 ± 0.6 vs 6.2 ± 0.7 mg kg^?1 min^?1: P < 0.05) and tissue sensitivity (M/I; 0.08 ± 0.02 vs. 0.1 ± 0.02 mg kg^?1 min^?1/mU l^?1; P < 0.05) increased between the first and second euglycaemic clamp (40 mU m^?2 min^?1). At the low insulin infusion rate (20 mU m^?2 min^?1), the tissue sensitivity to insulin increased (0.09 ± 0.01 vs. 0.13 ± 0.02 mg kg^?1 min^?1/mU l^?1; P < 0.05). Hepatic glucose production did not change during the examination period (2.2 ± 0.2 vs. 2.3 ± 0.1 mg kg^?1 min^?1), neither was there a change in the suppression of hepatic glucose output during hyperinsulinaemia (40 mU m^?2 min^?1). Our findings indicate that, in non-diabetic alcoholics, insulin sensitivity in peripheral tissues is decreased during the early part of a withdrawal period.     

Renal function and insulin sensitivity during simvastatin treatment in Type 2 (non-insulin-dependent) diabetic patients with microalbuminuria

Summary The effect of simvastatin (10–20 mg/day) on kidney function, urinary albumin excretion rate and insulin sensitivity was evaluated in 18 Type 2 (non-insulin-dependent) diabetic patients with microalbuminuria and moderate hypercholesterolaemia (total cholesterol ≥5.5 mmol·l⁻¹). In a double-blind, randomized and placebo-controlled design treatment with simvastatin (n=8) for 36 weeks significantly reduced total cholesterol (6.7±0.3 vs 5.1 mmol·l⁻¹ (p<0.01)), LDL-cholesterol (4.4±0.3 vs 2.9±0.2 mmol·l⁻¹ (p<0.001)) and apolipoprotein B (1.05±0.04 vs 0.77±0.02 mmol·l⁻¹ (p<0.01)) levels as compared to placebo (n=10). Both glomerular filtration rate (mean±SEM) (simvastatin: 96.6±8.0 vs 96.0±5.7 ml·min⁻¹·1.73 m⁻², placebo: 97.1±6.7 vs 88.8±6.0 ml·min⁻¹·1.73 m⁻²) (NS) and urinary albumin excretion rate (geometric mean x/÷ antilog SEM) (simvastatin: 18.4x/÷1.3vs 16.2 x/÷1.2 μg·min⁻¹, placebo 33.1 x/÷ 1.3 vs 42.7 x/÷ 1.3 μg·min⁻¹)(NS) were unchanged during the study. A euglycaemic hyperinsulinaemic clamp was performed at baseline and after 18 weeks in seven simvastatin-and nine placebo-treated patients. Isotopically determined basal and insulin-stimulated glucose disposal was similarly reduced before and during therapy in both the simvastatin (2.0±0.1 vs 1.9±0.1 (NS) and 3.1±0.6 vs 3.1±0.7 mg·kg⁻¹·min⁻¹ (NS)) and the placebo group (1.9±0.1 vs 1.8±0.1 (NS) and 4.1±0.6 vs 3.8±0.2 mg·kg⁻¹·min⁻¹ (NS)). No different was observed in glucose storage or glucose and lipid oxidation before and after treatment. Further, the suppression of hepatic glucose production during hyperinsulinaemia was not influenced by simvastatin (−0.7±0.8 vs −0.7±0.5 mg·kg⁻¹·min⁻¹ (NS)). In conclusion, despite marked improvement in the dyslipidaemia simvastatin had no impact on kidney function or urinary albumin excretion rate and did not reduce insulin resistance in these microalbuminuric and moderately hypercholesterolaemic Type 2 diabetic patients.     

Effect of insulin on renal sodium handling in hyperinsulinaemic Type 2 (non-insulin-dependent) diabetic patients with peripheral insulin resistance

Summary The sodium retaining effect of insulin was studied in ten Type 2 (non-insulin-dependent) diabetic patients (mean age 56 (43–73) years, mean body mass index 29.5 (24.2–33.7) kg/m²) and eight age-matched control subjects (mean age 57 (43–68) years, mean body mass index 23.4 (20.8–26.6) kg/m²). The renal clearances of ^99mTc-DTPA, lithium, sodium and potassium were measured over a basal period of 90 min. Then insulin was infused at a rate of 40 mU·mirr^–1·m^–2. After an equilibration period of 90 min, the clearance measurements were repeated during a new 90 min period. Blood glucose was clamped at the basal level (diabetic patients: 9.9±3.5, control subjects: 5.3±0.5 mmol/l) by a variable glucose infusion. Basal plasma insulin concentration was elevated in the diabetic patients (0.12±0.05 vs 0.05±0.02 pmol/ml, p<0.01). Insulin infusion resulted in comparable absolute increments in plasma insulin concentrations in the diabetic group and in the control group (0.44±0.13 vs 0.36±0.07 pmol/ml, NS). The metabolic clearance rate of glucose during the last 30 min of insulin infusion was lower in the diabetic patients (155±62 vs 320±69 ml·min^–1·m², p<0.01), reflecting peripheral insulin resistance. The decline in sodium clearance during insulin infusion was similar in diabetic subjects (1.8±1.1 vs 0.7±0.4 ml·min^–1·1.73 m^–2, p< 0.01) and in control subjects (1.7±0.3 vs 0.8±0.3 ml · min^–1 · 1.73 m^–2, p<0.01). The glomerular filtration rate and lithium clearance was unchanged, consequently calculated distal tubular fractional sodium reabsorption increased (diabetic patients: 92.9±4.1 vs 97.1±1.5, p<0.01, control subjects: 93.1±1.1 vs 96.5±0.6%, p< 0.01). Estimated extracellular fluid volume was 10% higher in the diabetic subjects (16.3±2.1 vs 14.8±2.01·1.73 m^–2, NS). In conclusion, the sodium retaining effect of insulin is preserved in Type 2 diabetic patients with peripheral insulin resistance. Insulin may contribute to sodium and fluid retention and thus to the increased frequency of hypertension in hyperinsulinaemic Type 2 diabetic patients.     

Increased Proximal Tubular Sodium Reabsorption in Hypertensive Patients with Type 2 Diabetes

Hyperinsulinaemia and sodium retention have been studied in 22 Type 2 diabetic patients (10 normotensive, 12 hypertensive) and 10 normal control subjects matched for age, sex, and body mass index. Exchangeable sodium was similar in the three groups. Plasma renin activity and plasma angiotensin II were lower in both groups of diabetic patients than in the normal control subjects (p<0.01). Plasma atrial natriuretic peptide was increased in the hypertensive patients (7.3 ± 1.1 vs normotensive 4.7 ± 1.1 pmol I^?1 and control 4.0 ± 0.2 pmol I^?1, p<0.01). Fractional lithium clearance, a measure of sodium clearance from the proximal tubule, was decreased (18.5 ± 1.4, p<0.01) and fractional excretion of sodium in the distal tubule was increased (6.66 ± 0.66, p<0.01) in untreated hypertensive diabetic patients compared with both normotensive diabetic patients (25.3 ± 1.6 and 3.96 ± 0.52 respectively) and normal control subjects (25.2 ± 2.9 and 3.31 ± 0.38, respectively). Fasting serum insulin was higher in hypertensive than in normotensive diabetic patients (18.5 ± 3.0 vs 10.7 ± 1.1 mU I^?1, p<0.01) and higher in both groups than in normal control subjects (5.6 ± 0.1 mU I^?1, both p<0.01). Creatinine clearance was higher in both groups of diabetic patients than in normal control subjects (p<0.05). Thus there appears to be increased proximal renal tubular sodium reabsorption in these hypertensive Type 2 diabetic patients, matched by a reduction in distal sodium reabsorption so that net sodium excretion was maintained. This was associated with fasting hyperinsulinaemia.     

Restoration of normal glucose tolerance in severely obese patients after bilio-pancreatic diversion: role of insulin sensitivity and beta cell function

Aims/hypothesis The aim of this study was to analyse the mechanisms underlying the improvement in glucose tolerance seen in morbidly obese patients undergoing bilio-pancreatic diversion (BPD).Subjects and methods We evaluated glucose tolerance (by OGTT), insulin sensitivity (euglycaemic–hyperinsulinaemic clamp and the OGTT index OGIS) and beta cell function (OGTT modelling analysis) in 32 morbidly obese (BMI=52±7 kg/m², mean±SD) patients (12 with NGT, 9 with IGT and 11 with type 2 diabetes), before and after BPD, and in 22 lean control subjects. Patients were studied before and from 7 days to 60 months after surgery.Results BPD improved glucose tolerance in all subjects, who after surgery all had normal glucose tolerance. Insulin sensitivity was restored to normal levels in all subjects (pre-BPD 341±79 ml min⁻¹ m⁻², post-BPD 511±57 ml min⁻¹ m⁻², lean 478±49 ml min⁻¹ m⁻²). The insulin sensitivity change was detectable within 10 days of BPD. At baseline, beta cell sensitivity to glucose was impaired in diabetic subjects (25 [18] pmol min⁻¹ m⁻² l mmol⁻¹, median [interquartile range]) compared with lean subjects (82 [98]; p≤0.05). After BPD, beta cell glucose sensitivity showed a tendency towards improvement but remained impaired in diabetic subjects (30 [62]; p<0.01 vs lean). Total insulin output decreased in parallel with the insulin sensitivity increase in all groups. In the whole patient group, mean OGTT glucose levels were inversely related to both insulin sensitivity and beta cell glucose sensitivity (r ²=0.67, partial r=−0.76 and −0.41, respectively). NEFAs, leptin and adiponectin were related to insulin sensitivity but could not explain the early improvement.Conclusions/interpretation Following BPD, glucose tolerance was restored mainly as a result of a rapid and large improvement in insulin sensitivity.     

Risk and mechanism of dexamethasone-induced deterioration of glucose tolerance in non-diabetic first-degree relatives of NIDDM patients

Summary We tested the hypothesis that glucose intolerance develops in genetically prone subjects when exogenous insulin resistance is induced by dexamethasone (dex) and investigated whether the steroid-induced glucose intolerance is due to impairment of beta-cell function alone and/or insulin resistance. Oral glucose tolerance (OGTT) and intravenous glucose tolerance tests with minimal model analysis were performed before and following 5 days of dex treatment (4 mg/day) in 20 relatives of non-insulin-dependent diabetic (NIDDM) patients and in 20 matched control subjects (age: 29.6 ± 1.7 vs 29.6 ± 1.6 years, BMI: 25.1 ± 1.0 vs 25.1 ± 0.9 kg/m²). Before dex, glucose tolerance was similar in both groups (2-h plasma glucose concentration (PG): 5.5 ± 0.2 [range: 3.2–7.0] vs 5.5 ± 0.2 [3.7–7.4] mmol/l). Although insulin sensitivity (Si) was significantly lower in the relatives before dex, insulin sensitivity was reduced to a similar level during dex in both the relatives and control subjects (0.30 ± 0.04 vs 0.34 ± 0.04 10^–4 min^–1 per pmol/l, NS). During dex, the variation in the OGTT 2-h PG was greater in the relatives (8.5 ± 0.7 [3.9–17.0] vs 7.5 ± 0.3 [5.7–9.8] mmol/l, F-test p < 0.05) which, by inspection of the data, was caused by seven relatives with a higher PG than the maximal value seen in the control subjects (9.8 mmol/l). These “hyperglycaemic” relatives had diminished first phase insulin secretion (?1) both before and during dex compared with the “normal” relatives and the control subjects (pre-dex ?1: 12.6 ± 3.6 vs 26.4 ± 4.2 and 24.6 ± 3.6 (p < 0.05), post-dex ?1: 22.2 ± 6.6 vs 48.0 ± 7.2 and 46.2 ± 6.6 respectively (p < 0.05) pmol · l^–1· min^–1 per mg/dl). However, Si was similar in “hyperglycaemic” and “normal” relatives before dex (0.65 ± 0.10 vs 0.54 ± 0.10 10−4 · min^–1 per pmol/l) and suppressed similarly during dex (0.30 ± 0.07 vs 0.30 ± 0.06 10−4 · min^–1 per pmol/l). Multiple regression analysis confirmed the unique importance of low pre-dex beta-cell function to subsequent development of high 2-h post-dex OGTT plasma glucose levels (R ² = 0.56). In conclusion, exogenous induced insulin resistance by dex will induce impaired or diabetic glucose tolerance in those genetic relatives of NIDDM patients who have impaired beta-cell function (retrospectively) prior to dex exposure. These subjects are therefore unable to enhance their beta-cell response in order to match the dex-induced insulin resistant state. [Diabetologia (1997) 40: 1439–1448] Received: 20 January 1997 and in final revised form: 17 July 1997     

Different Acute and Chronic Effects of Acipimox Treatment on Glucose and Lipid Metabolism in Patients with Type 2 Diabetes

To study whether therapeutic reduction of non-esterified fatty acids (NEFA) can be used to improve glucose metabolism, we administered the antilipolytic agent, acipimox, 250 mg four times daily for 4 weeks in eight obese Type 2 diabetic patients. Glucose and NEFA metabolism were assessed before and after treatment with a two-step euglycaemic hyperinsulinaemic clamp (0.25 and 1 ***mU kg^?1 min^?1 insulin) combined with infusions of [3–³H] glucose and [1–¹⁴C] palmitate. Three days of acipimox treatment reduced 24-h serum NEFA levels by 10%, but the difference disappeared after 4 weeks of treatment mainly due to a two-fold rise in morning NEFA concentrations (p < 0.01). After 3 days of acipimox treatment, fasting and 24-h plasma glucose and serum triglyceride concentrations were significantly reduced (p < 0.05), but no longer after 4 weeks of treatment. Despite the rebound rise in NEFA, acute administration of acipimox still inhibited both oxidative and non-oxidative NEFA metabolism in the basal state (p < 0.01 – 0.001) and during insulin infusion (p < 0.05 – 0.001). Inhibition of NEFA metabolism was associated with increased insulin-stimulated glucose uptake (from 3.56 ± 0.28 to 5.14 ± 0.67 μmol kg^?1 min^?1, p < 0.05), mainly due to stimulation of non-oxidative glucose disposal (from 1.74 ± 0.23 to 3.03 ± 0.53 μmol kg^?1 min^?1, p < 0.05). In conclusion, acipimox administered acutely inhibits NEFA appearance (lipolysis), which is associated with improved glucose uptake. However, after 4 weeks of treatment, the beneficial effects on NEFA and glucose metabolism are outweighed by a marked rebound rise in fasting NEFA concentrations. The results emphasize the problems using acipimox as a means to improve glucose tolerance in patients with Type 2 diabetes.     

Morphometric documentation of abnormal intramyocellular fat storage and reduced glycogen in obese patients with Type II diabetes

Aims/hypothesis. Insulin resistance of skeletal muscle has been associated with increased lipid availability. This study aimed to estimate volume fractions of intramyocellular triglyceride droplets and glycogen granules in skeletal muscle using electron microscopy and furthermore, relate these findings to insulin sensitivity and the level of circulating lipids. Methods. We compared 11 obese patients with Type II (non-insulin-dependent) diabetes mellitus and 11 obese normoglycaemic subjects matched for age and sex. Glucose metabolism was determined using the euglycaemic hyperinsulinaemic clamp technique (40 mU · m^–2· min^–1) coupled with indirect calorimetry and tritiated glucose. On the second day, using an automatic procedure, a fasting muscle biopsy was carried out and processed for electron microscopy. Volume fractions of intramyocellular structures were estimated by pointcounting on photographic pictures in a blinded manner. Results. Insulin-stimulated total glucose disposal rate was lower in the Type II diabetic subjects compared with the obese normoglycaemic subjects (4.96 ± 049 vs 10.35 ± 0.89 mg · min^–1· kg ffm^–1, p < 0.001) as was glucose storage (2.03 ± 0.50 vs 6.59 ± 0.83, p < 0.001). The electron microscopy study revealed that the diabetic subjects had higher intramyocellular amounts of triglyceride (1.43 ± 0.21 vs 0.39 ± 0.07 %, p < 0.001) and lower amounts of glycogen (3.53 ± 0.33 vs 6.94 ± 0.54 %, p < 0.001). Mitochondrial volume was identical indicating equal aerobic capacity. The fractional intramyocellular lipid volume was found to be positively associated with fasting NEFA (r = 0.63, p = < 0.05 and r = 0.79, p = < 0.05) and triglyceride (r = 0.74, p = 0.01 and r = 0.62, p < 0.05) in the obese diabetic and normoglycaemic cohorts respectively. Intramyocellular lipid content was negatively correlated to insulin sensitivity (r = –0.71, p < 0.02) in the obese diabetic group whereas no significant association was found in the obese normoglycaemic group. Conclusion/interpretation. This study shows that fat accumulates intramyocellulary while glycogen stores are simultaneously reduced in obese subjects with Type II (non-insulin-dependent) diabetes mellitus. Quantitatively, a major component of the excessive lipid accumulation could be secondary in origin, related to the diabetic state in itself, although a contribution from the altered insulin action cascade of obesity and diabetes cannot be excluded. In both groups significant positive relations were found between circulating and intramyocellular lipid. [Diabetologia (2001) 44: 824–833] Received: 6 December 2000 and in revised form: 16 March 2001     

Significant improvement of apolipoprotein B-containing lipoprotein metabolism by insulin treatment in patients with non-insulin-dependent diabetes mellitus

Aims/hypothesis. Patients with Type II (non-insulin-dependent) diabetes mellitus have multiple abnormalities in apolipoprotein B (apoB)-containing lipoprotein metabolism. These abnormalities are likely to play an important part in the development of premature atherogenesis in these patients. This stable isotope kinetic experiment was designed to study the effect of insulin therapy on apoB metabolism in poorly controlled Type II diabetic patients.¶Methods. Using L-[1-¹³C] leucine, we studied apoB metabolism in five control subjects without insulin resistance and in six poorly controlled Type II diabetic patients before and 2 months after the introduction of insulin therapy.¶Results. Insulin treatment induced a decrease of very low density lipoprotein apoB plasma concentration [121 ± 42 vs 158 ± 91 mg · l^{? 1}, p < 0.05 (control subjects: 48 ± 20)], related to an increased catabolism of very low density lipoprotein towards intermediate density lipoprotein or low density lipoprotein [0.20 ± 0.08 vs 0.14 ± 0.07 pool · h^{? 1}, p < 0.05 (control subjects: 0.36 ± 0.10)]. On the other hand, insulin treatment induced an acceleration of intermediate density lipoprotein apoB turn-over without changing its plasma concentration [77 ± 39 vs 61 ± 18 mg · l^{? 1}, (control subjects: 17 ± 3)], by increasing both its production rate [22.6 ± 9.2 vs 18.2 ± 9.6 mg · l^{? 1}· h^{? 1}, p < 0.05 (control subjects: 18.4 ± 3.2)] and its catabolic rate towards low density lipoprotein [0.34 ± 0.22 vs 0.22 ± 0.16 pool · h^{? 1}, p < 0.05 (control subjects: 1.02 ± 0.13)]. Likewise, insulin treatment increased low density lipoprotein apoB production rate [20.2 ± 7.4 vs 16.9 ± 7.7 mg · l^{? 1}· h^{? 1}, p < 0.05 (control subjects: 16.9 ± 2.3)] and restored a normal low density lipoprotein apoB fractional catabolic rate [0.022 ± 0.004 vs 0.018 ± 0.004 pool · h^{? 1}, p < 0.05 (control subjects: 0.025 ± 0.004)], resulting in a constant low density lipoprotein apoB plasma concentration [965 ± 485 vs 984 ± 558 mg · l^{? 1} (control subjects: 699 ± 106)].¶Conclusion/interpretation. Insulin treatment in Type II diabetes induces profound metabolic modifications of lipoprotein, resulting in significant decrease of the intravascular residence time of very low density lipoprotein, intermediate density lipoprotein and low density lipoprotein particles. This is likely to make these particles less harmful. [Diabetologia (2000) 43: 27–35]     

The Effect of Intensive Insulin Therapy on the Insulin-regulatable Glucose Transporter (GLUT4) Expression in Skeletal Muscle in Type 1 Diabetes

Studies in normal man and rodents have demonstrated that the expression of the dominant glucose transporter in skeletal muscle, GLUT4, is regulated by insulin at supraphysiological circulating levels. The present study was designed to determine whether intensified insulin replacement therapy for 24 h given to patients with Type 1 diabetes in poor metabolic control was associated with an adaptive regulation of GLUT4 mRNA and protein levels in vastus lateralis muscle. Nine Type 1 diabetic patients with a mean HbA_1c of 10.3% were included in the protocol. After intensified treatment with soluble insulin for 24 h the fasting plasma glucose concentration decreased from 20.8 ± 2.3 (SD) to 8.7 ± 2.3 mmol 1^?1 whereas the fasting serum insulin level increased from 0.06 ± 0.02 to 0.17 ± 0.09 nmol 1^?1 However, despite a 2.8-fold increase in serum insulin levels and more than a halving of the plasma glucose concentration for at least 15 h no significant alterations occurred in the amount of GLUT4 protein (0.138 ± 0.056, poor control vs 0.113 ± 0.026 arb. units, improved control, p = 0.16) or GLUT4 mRNA (96432 ± 44985, poor control vs 81395 ± 25461 arb. units, improved control, p = 0.54). These results suggest, that in spite of evidence that high insulin levels affect GLUT4 expression in muscle, changes in serum insulin within the physiological range do not play a major role in the short-term regulation of GLUT4 expression in Type 1 diabetic patients.     

Modulation of Glucose and Growth Hormone Responses to Meals and Exercise in Type 1 Diabetes by Cholinergic Muscarinic Blockade

Anticholinergic drugs suppress nocturnal and exercise-related growth hormone (GH) secretion in Type 1 diabetes; nocturnal GH suppression is associated with a fall in fasting plasma glucose levels. The aim of this study was to assess the effect of GH suppression on glucose levels following a period of meals and exercise in physiological pattern. Six Type 1 diabetic men recruited from the outpatient clinic were studied in random order at least 1 week apart. After an overnight fast subjects received two-thirds of their usual subcutaneous insulin and either 200 mg oral pirenzepine or placebo at time 0 min. Between 90 and 120 min subjects exercised continuously on an ergometric cycle. Standard meals or snacks were eaten at 30, 150, 270, and 390 min. Venous blood was collected from an indwelling cannula between 0 and 570 min. The mean incremental rise in plasma glucose after breakfast (δ peak/_{90 min}) was 2.6 ± 0.5 (mean ±SEM mmol l^?1 (pirenzepine) vs 4.5 ± 0.8 (placebo)), p < 0.05. Following exercise the fall in plasma glucose (δ gluc_{90–240 min}) was 6.4 ± 1.9 (pirenzepine) vs 2.0 ± 1.3 (placebo), p < 0.005. The exercise-related peak rise in GH was 12.6 ± 3.3 (pirenzepine) vs 28.5 ± 6.0 mU l^?1 (placebo), p = 0.08. Excluding one outlying result there was an inverse correlation between the integrated exercise-related increase in GH between 90 and 240 min and the fall in glucose over the corresponding time period (n = 11, r = ?0.75, p = 0.008). In conclusion suppression of exercise-related GH secretion by pirenzepine is associated with a subsequent lowering of plasma glucose levels. The smaller post-prandial glucose rise pre-exercise implies also a direct effect of pirenzepine on meal-related glucose tolerance in Type 1 diabetes.     

In vivo insulin action and muscle glycogen synthase activity in Type 2 (non-insulin-dependent) diabetes mellitus: effects of diet treatment

Summary Insulin resistant glucose metabolism is a key element in the pathogenesis of Type 2 (non-insulin-dependent) diabetes mellitus. Insulin resistance may be of both primary (genetic) and secondary (metabolic) origin. Before and after diet-induced improvement of glycaemic control seven obese patients with newly-diagnosed Type 2 diabetes were studied with the euglycaemic clamp technique in combination with indirect calorimetry and forearm glucose balance. Muscle biopsies were obtained in the basal state and again after 3 h of hyperinsulinaemia (200 mU/l) for studies of insulin receptor and glycogen synthase activities. Similar studies were performed in seven matched control subjects. Insulin-stimulated glucose utilization improved from 110±11 to 183±23 mg·m^–2·min^–1 (p<0.03); control subjects: 219+23 mg·m^–2·min^–1 (p=NS, vs post-diet Type 2 diabetes). Nonoxidative glucose disposal increased from 74±17 to 138+19 mg·m^–2·min^–1 (p<0.03), control subjects: 159±22 mg· m^–2·m^–1 (p=NS, vs post-diet Type 2 diabetic patients). Forearm blood glucose uptake during hyperinsulinaemia increased from 1.58±0.54 to 3.35±0.23 mol·l^–1·min^–1 (p<0.05), control subjects: 2.99±0.86 mol·l^–1·min^–1 (p=NS, vs post-diet Type 2 diabetes). After diet therapy the increase in insulin sensitivity correlated with reductions in fasting plasma glucose levels (r=0.97, p<0.001), reductions in serum fructosamine (r=0.77, p<0.05), and weight loss (r=0.78, p<0.05). Values of muscle glycogen synthase sensitivity to glucose 6-phosphate (A_0.5 for glucose 6-phosphate) were similar in the basal state. However, insulin stimulation of glycogen synthase was more pronounced after diet treatment (A_0.5: 0.43±0.06 (before) vs 0.30±0.04 mmol/l (after); p<0.03; control subjects: 0.22±0.03 mmol/l). Muscle insulin receptor binding and kinase activity were similar before and after diet treatment and comparable to values in the control group. The data suggest that impaired insulin stimulation of in vivo glucose turn-over and muscle glycogen synthase activity tend to be restored during successful diet treatment of patients with Type 2 diabetes.