Glenn M. Ward

Pulsatile insulin has greater hypoglycemic effect than continuous delivery.

The relative hypoglycemic effects of pulsatile versus steadily infused insulin have been examined in six normal subjects in whom pancreatic insulin output was suppressed by somatostatin-14. Soluble insulin was infused continuously overnight on one occasion and on another occasion the same quantity was given in pulses of 2-min duration with a gap of 11 min. The mean plasma glucose concentrations were lower when pulsed insulin was given [mean for the last hour: 4.66 ± 0.08 mmol/L (±SEM) versus 5.53 ± 0.06 mmol/L (±SEM) for steady infusion], diverging significantly (P < 0.05 paired t test) 7 h after the start of the study. The specific binding of 125I(A14)mono-iodo-insulin to monocytes was greater after pulsed insulin (2.9% with pulsed versus 2.4% with steadily infused insulin at tracer-only point; P < 0.02 paired t test). Thus, intravenous insulin has greater hypoglycemic effect when pulsed, possibly mediated by greater insulin receptor binding.

The Mediterranean diet improves hepatic steatosis and insulin sensitivity in individuals with non-alcoholic fatty liver disease

BACKGROUND & AIMS Non-alcoholic fatty liver disease (NAFLD) affects up to 30% of the population and signifies increased risk of liver fibrosis and cirrhosis, type 2 diabetes, and cardiovascular disease. Therapies are limited. Weight loss is of benefit but is difficult to maintain. We aimed at examining the effect of the Mediterranean diet (MD), a diet high in monounsaturated fatty acids, on steatosis and insulin sensitivity, using gold standard techniques. METHODS Twelve non-diabetic subjects (6 Females/6 Males) with biopsy-proven NAFLD were recruited for a randomised, cross-over 6-week dietary intervention study. All subjects undertook both the MD and a control diet, a low fat-high carbohydrate diet (LF/HCD), in random order with a 6-week wash-out period in- between. Insulin sensitivity was determined with a 3-h hyperinsulinemic-euglycemic clamp study and hepatic steatosis was assessed with localized magnetic resonance (1)H spectroscopy ((1)H-MRS). RESULTS At baseline, subjects were abdominally obese with elevated fasting concentrations of glucose, insulin, triglycerides, ALT, and GGT. Insulin sensitivity at baseline was low (M=2.7 ± 1.0 mg/kg/min(-1)). Mean weight loss was not different between the two diets (p=0.22). There was a significant relative reduction in hepatic steatosis after the MD compared with the LF/HCD: 39 ± 4% versus 7 ± 3%, as measured by (1)H-MRS (p=0.012). Insulin sensitivity improved with the MD, whereas after the LF/HCD there was no change (p=0.03 between diets). CONCLUSIONS Even without weight loss, MD reduces liver steatosis and improves insulin sensitivity in an insulin-resistant population with NAFLD, compared to current dietary advice. This diet should be further investigated in subjects with NAFLD.

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 (Ø1) both before and during dex compared with the “normal” relatives and the control subjects (pre-dex Ø1: 12.6 ± 3.6 vs 26.4 ± 4.2 and 24.6 ± 3.6 (p < 0.05), post-dex Ø1: 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 (R2 = 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]

A Simple Method for Quantitation of Insulin Sensitivity and Insulin Release from an Intravenous Glucose Tolerance Test

Both insulin secretion and insulin sensitivity are important in the development of diabetes but current methods used for their measurements are complex and cannot be used for epidemiological surveys. This study describes a simplified approach for the estimation of first phase insulin release and insulin sensitivity from a standard 40‐min intravenous glucose tolerance test (IVGTT), and compares these parameter estimations with the sophisticated minimal model analysis of a frequently sampled 3‐h IVGTT and the euglycaemic clamp technique. For the simplified IVGTT, first phase insulin release was measured as the insulin area above basal post glucose load unit−1 incremental change (i.e. peak rise) in plasma glucose over 0–10 min, and insulin sensitivity as a rate of glucose disappearance (Kg) unit−1 insulin increase above basal from 0–40 min post‐glucose load in 18 subjects who were studied twice, either basally or in a perturbed pathophysiological state (i.e. pre‐ and post‐ultramarathon race, n = 5; pre‐ and post‐20 h pulsatile hyperinsulinaemia, n = 8; pre‐ and post‐thyrotoxic state, n = 5). A further 12 subjects were compared by IVGTT, and glucose clamp. In addition, seven dogs were studied three times by IVGTT during normal saline infusion and after short‐term (1/2 hour) or long‐term (72 hour) adrenaline infusions. First phase insulin release and insulin sensitivity estimated from the simplified IVGTT as calculated by the two methods correlated closely (rs = 0.89 and rs = 0.87, respectively), although less precisely in markedly insulin‐resistant subjects and the slopes and y intercepts of the linear regression lines were similar in the basal and perturbed states. Insulin sensitivity measured by the shortened 40 min IVGTT and glucose clamp techniques were also comparable for the whole group (rs = 0.85), and for hypoinsulinaemic‐glucose intolerance subjects (rs = 0.96). It is concluded that the shortened simple IVGTT method is practical, gives reliable simultaneous estimates of glucose tolerance, first phase insulin secretion and insulin sensitivity in a diverse group of individuals with normal to moderately impaired glucose tolerance, and therefore may be useful in population surveys where prolonged, multiple blood sampling test procedures are not possible.

Effects of Prolonged Pulsatile Hyperinsulinemia in Humans: Enhancement of Insulin Sensitivity

Prolonged near-physiological pulsatile insulin infusion has a greater hypoglycemie effect than continuous insulin infusion. We have previously shown that continuous hyperinsulinemia induces insulin insensitivity. This study examines the mechanisms responsible for the greater hypoglycemie effect of pulsatile insulin administration, in particular, whether prolonged pulsatile hyperinsulinemia induces insulin insensitivity. Basally and 1 h after cessation of a 20-h pulsatile infusion of insulin (0.5 mU · kg−1 · min−1), eight nondiabetic human subjects were assessed for 1) glucose turnover with [3-3H]glucose, 2) insulin sensitivity by minimal-model analysis of intravenous glucose tolerance tests, and 3) monocyte insulin-receptor binding. The time-averaged plasma insulin levels were 30 ± 5 mU/L (mean ± SE) during the infusion, which was similar to the levels achieved in our previous continuous hyperinsulinemia study. However, the average rate of glucose infusion to maintain euglycemia was 55% greater than in the previous study. Hepatic glucose production was -5.2 ±1.4 μmol · kg −1 · min−1 during the infusion but returned to preinfusion levels 1 h after the infusion was stopped. Insulin sensitivity (Si) and glucose tolerance (rate of glucose disappearance, Kg) showed changes opposite in direction to our previous continuous hyperinsulinemia study (pre- vs. postinfusion Kg 1.5 ± 0.1 vs. 1.7 ± 0.2 min−1 × 102, NS; pre- vs. postinfusion S, 8.4 ± 2.3 vs. 11.8 ± 3.7 min−1 · mU1 · L × 104 P < 0.05). There was no change in glucose-mediated glucose disposal (2.0 ± 0.2 vs. 2.3 ± 0.4 min−1 × 102) or pancreatic β-cell responsiveness (1st phase, 1.8 ± 0.2 vs. 2.2 ± 0.4 μU · ml−1 · min−1 · mg−1 · dl; 2nd phase, 9.9 ± 1.0 vs. 16.6 ± 3.5 μU · ml−1 · min∼−2 · mg−1 · dl). Monocyte insulin-receptor binding showed a postinfusion decrease. Plasma nonesterified fatty acids were profoundly suppressed during the infusion (0.05 ± 0.01 mM) and remained significantly (P < 0.05) suppressed 1 h postinfusion (0.21 ± 0.06 mM) compared with preinfusion (0.54 ± 0.08 mM). We conclude that despite a reduction in monocyte insulin-receptor binding, prolonged moderate pulsatile hyperinsulinemia, in contrast to equivalent continuous hyperinsulinemia, induced enhancement of insulin sensitivity, causing a greater hypoglycemie effect and greater suppression of plasma nonesterified-fatty acid levels.

Gliclazide Therapy Is Associated with Potentiation of Postbinding Insulin Action in Obese, Non-insulin-dependent Diabetic Subjects

Six obese, non-insulin-dependent diabetic subjects were studied before and 3 mo after treatment with the sulfonylurea gliclazide, 40–80 mg b.i.d. Fasting plasma glucose fell significantly from 13.4 ±1.6 (SEM) to 8.6 ±1.2 mmol/L, accompanied by a significant reduction from 40.6 ± 3.7 to 29.8 ± 2.8 mM · h of the plasma glucose response to 75 g oral glucose. Fasting plasma insulin showed a nonsignificant increase from 24.8 ± 2.0 to 31.3 ± 2.3 mU/L. The percent specific binding of tracer 125I-insulin to erythrocytes and monocytes did not change significantly (from 9.8 ± 1.7 to 8.5 ± 0.7 for erythrocytes and 1.7 ± 0.3 to 1.6 ± 0.4 for monocytes). Glucose utilization was measured at three levels of insulin infusion (40, 100, and 300 mU/ kg/h) by the euglycemic clamp technique. Overall there was a significant (P < 0.05) increase in the disappearance rate (Rd) and metabolic clearance rate (MCRg) for glucose at the two higher insulin infusion rates (MCRg: 3.3 ± 0.7 to 5.1 ± 0.7 and 5.9 ± 0.9 to 7.9 ± 0.9 ml/kg/min), but not at the lowest infusion rate (MCRg: 3.6 ± 0.8 to 3.3 ± 0.6). Thus, the chronic hypoglycemic effect of gliclazide in obese diabetic subjects was associated with an improvement in insulin-mediated glucose utilization at high plasma insulin concentrations. This enhanced effect of insulin after gliclazide treatment was not accompanied by increased monocyte or erythrocyte insulin binding, which suggests that it was due to potentiation of postbinding insulin-sensitive pathways.

Fenfluramine Increases Insulin Action in Patients With NIDDM

These studies examined the effect of fenfluramine on insulin action and insulin secretion in healthy subjects and patients with non-insulin-dependent diabetes mellitus (NIDDM). In the first study, a double-blind crossover design was used in healthy subjects to compare the effect of short-term fenfluramine therapy (60 mg orally for 3 days) with placebo. Insulin secretion and whole-body insulin sensitivity (determined by frequently sampled intravenous glucose tolerance tests with analysis by the minimal-model method) were unchanged by fenfluramine. In the second study, involving patients with NIDDM inadequately controlled on submaximal to maximal doses of oral hypoglycemic agents, a double-blind crossover strategy was used to compare baseline studies (conducted after a run-in period) with fenfluramine (60 mg orally) or placebo for 4 wk. There was a signficant fall in fasting blood glucose after therapy with fenfluramine compared with the baseline study period (13.0 ± 1.2 vs. 8.4 ± 0.89 mM, mean ± SE, P < .01) with no significant fall in fasting serum insulin (20± 2 vs. 24 ± 3 (μU/ml) or C-peptide (1.3 ± 0.2 vs. 1.3 ± 0.1 nM). During euglycemichyperinsulinemic (1 mU · kg−1 · min−1) clamp studies there was a significant increase in insulin action from 12.7± 2.3 to 17.3 ± 1.8 min−1 103 μU · ml1 (P < .05), although clamp insulin levels were lower after fenfluramine treatment (136 ± 14 vs. 96 ± 9 μU/ml−1, P < .02), reflecting an enhanced metabolic clearance rate for insulin (12.7 ± 1.5 vs. 20.1 ± 2.1 ml · kg−1 · min−1 P < .025). When insulin action was normalized for the prevailing insulin level during the clamp, the increase of insulin action/in concentration was more marked (0.11 ± 0.22 to 0.22 ±0.04 min−1 103μU · ml−1 <.005). The insulin secretory response to arginine was unchanged from 21 ± 4 to 22 ± 6 μU/ml at similar levels of glycemia. Chronic fenfluramine therapy can lower fasting plasma glucose and increase insulin sensitivity without affecting insulin secretion in patients with NIDDM. Acute fenfluramine treatment in healthy individuals has no effect on glucose metabolism. We conclude that in patients with inadequately controlled NIDDM, fenfluramine may serve as a useful adjunct to sulfonylurea therapy.

INSULIN SECRETION, INSULIN SENSITIVITY AND GLUCOSE‐MEDIATED GLUCOSE DISPOSAL IN THYROTOXICOSIS: A MINIMAL MODEL ANALYSIS

In order to evaluate simultaneously in thyrotoxic subjects the relative contributions of insulin secretion, insulin‐sensitivity (SI) and glucose‐mediated (SG) glucose disposal to overall glucose tolerance, seven non‐obese patients with thyrotoxicosis were studied by the minimal model analysis of the frequently sampled intravenous glucose tolerance test, before and > 1 month after being rendered euthyroid, and compared with eight healthy control subjects. Basal glucose, C‐peptide and glucagon levels were similar in all groups but, in the toxic and euthyroid states, basal insulin levels were significantly elevated compared to the control group (11.2 ±2‐0 and 7.9± 1‐1 vs 5.1 ±0.6 μU/ml, mean±SE, P<0.02). FFA levels were raised in the thyrotoxic subjects prior to treatment (0.95 ±0.11 vs 0.68 ± 0.08 and 054 ± 008 mmol/1, P <0.0). Glucose tolerance (Kg) was reduced in the thyrotoxic subjects compared to the euthyroid state (1.16 ± 0.12 vs 1.44 ± 0.13 per min, P <0.025) and control group (1.44± 1.0 per min, 0.05

Multicenter Australian trial of islet transplantation: Improving accessibility and outcomes

Whilst initial rates of insulin independence following islet transplantation are encouraging, long‐term function using the Edmonton Protocol remains a concern. The aim of this single‐arm, multicenter study was to evaluate an immunosuppressive protocol of initial antithymocyte globulin (ATG), tacrolimus and mycophenolate mofetil (MMF) followed by switching to sirolimus and MMF. Islets were cultured for 24 h prior to transplantation. The primary end‐point was an HbA1c of <7% and cessation of severe hypoglycemia. Seventeen recipients were followed for ≥12 months. Nine islet preparations were transported interstate for transplantation. Similar outcomes were achieved at all three centers. Fourteen of the 17 (82%) recipients achieved the primary end‐point. Nine (53%) recipients achieved insulin independence for a median of 26 months (range 7–39 months) and 6 (35%) remain insulin independent. All recipients were C‐peptide positive for at least 3 months. All subjects with unstimulated C‐peptide >0.2 nmol/L had cessation of severe hypoglycemia. Nine of the 17 recipients tolerated switching from tacrolimus to sirolimus with similar graft outcomes. There was a small but significant reduction in renal function in the first 12 months. The combination of islet culture, ATG, tacrolimus and MMF is a viable alternative for islet transplantation.

Impaired glucose tolerance after endurance exercise is associated with reduced insulin secretion rather than altered insulin sensitivity

Paired frequently sampled intravenous glucose tolerance tests (FSIGT) were performed on five highly trained athletes within 2 hours of completing a 6-day ultramarathon run (E) and after 2 weeks of complete rest (R). Severe exercise increased free fatty acid (FFA) levels (E 1.2 +/- 0.16 v 0.42 +/- 0.07 mmol/L, P < .01) and norepinephrine levels (E 573 +/- 141 v 224 +/- 33 pg/mL, P < .01), with only moderate reductions in glucose tolerance (glucose disappearance [Kg] E 1.06 +/- 0.2 v R 1.7 +/- 0.3 min-1 x 10(2), P < .05). The minimal model analysis of FSIGT data using the method of Bergman et al (Endocr Rev 6:45-86, 1985) showed a reduced second-phase insulin secretion ([phi 2] E 5.2 +/- 1.3 v 13 +/- 2.2 microU/mL.min-2 per mg/dL, P < .05) and glucose disposition index ([SI x phi 2] E 33.8 +/- 10 v 73.9 +/- 11 mg-1.dL.min-3 x 10(4), P < .02). Insulin sensitivity (SI) and glucose-mediated glucose disposal (SG) were unchanged (SI E 6.9 +/- 1.0 v 6.0 +/- 0.6 min-1 per microU/mL x 10(4); SG E 1.8 +/- 0.6 v 1.4 +/- 0.3 min-1 x 10(2)). Reduced glucose tolerance after prolonged extreme physical exercise was accompanied by reduced phi 2 and not by alterations of SI or SG, despite the marked increase of FFA levels. Elevated norepinephrine levels, reflecting activation of the sympathetic noradrenergic system, was also associated with the reduction in Kg. The reduction in phi 2 would promote mobilization of FFA, the predominant metabolic substrate in these endurance events.