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.     

Validation of the low dose short insulin tolerance test for evaluation of insulin sensitivity

OBJECTIVES The assessment of insulin sensitivity requires an accurate and reproducible technique. The short insulin tolerance test is a simple and rapid method for screening large numbers of subjects when the fasting glucose level is normal. Conventionally, an insulin dose of 0·1 units/kg is used, but this may result in symptomatic hypoglycaemia in healthy thin subjects who are insulin sensitive. In order to overcome this problem we have employed a lower dose of insulin and have studied the reproducibility of this modified technique comparing it with the euglycaemic hyperinsulinaemic clamp. DESIGN Subjects were studied on two separate occasions, once by a short insulin tolerance test and on a second occasion by either a euglycaemic hyperinsulinaemic clamp (insulin infusion of 40 mU/m²/min) or a repeat short insulin tolerance test. PATIENTS Eleven healthy subjects were studied twice with a short insulin tolerance test. A further 10 healthy subjects received a short insulin tolerance test on one day and a euglycaemic hyperinsulinaemic clamp study on another occasion. MEASUREMENTS Insulin sensitivity was measured in the short insulin tolerance test using the slope of arterialized blood glucose concentration from 3 to 15 minutes after an intravenous bolus of short-acting insulin, 0·05 units/kg body weight. In the clamp study, insulin sensitivity was derived from the average amount of glucose infused at steady state (M) and the mean plasma insulin level (l). RESULTS In the short insulin tolerance test no subject developed symptomatic or biochemical hypoglycaemia, defined as a blood glucose < 2·2 mmol/l. The (mean ± SEM) insulin sensitivities for the 11 subjects studied twice were 174±10 and 179±11 μmol/l/min with a coefficient of variation of 6·9±2·6%. There was a close correlation between insulin sensitivity derived from the short insulin tolerance test and that obtained from the euglycaemic clamp studies (so-called M/l ratio) in the same subjects (r= 0·81; P < 0·005). CONCLUSION The short insulin tolerance test employing 0·05 units/kg insulin is a safe, valid and reproducible method for the assessment of insulin sensitivity.     

Whole-body Glucose Metabolism in Obese Patients with Type 2 Diabetes Mellitus: the Impact of Hypertension and Strict Blood Glucose Control

We have examined the impact of hypertension and blood glucose control on insulin sensitivity in obese Type 2 (non-insulin-dependent) diabetic patients. Glucose metabolism in the basal state and in response to insulin was examined using the euglycaemic, hyperinsulinaemic (2 mU kg^?1 min^?1) clamp technique in combination with 3-[3H]-glucose infusion and indirect calorimetry in 60 obese Type 2 diabetic patients (30 normotensive patients and 30 hypertensive patients on antihypertensive treatment) and 10 obese normotensive control subjects. In the basal state and during hyperinsulinaemia, glucose disposal rates (total, oxidative, and nonoxidative) were similar in Type 2 diabetic patients with or without hypertension (230 ± 83 vs 270 ± 114 mg m^?2min^?1 (NS), 83 ± 28 vs 95 ± 7 mg m^?2 min^?1 (NS), 148 ± 70 vs 180 ± 89 mg m^?2 min^?1 (NS), treated hypertensive vs normotensive subjects, respectively). However, compared to obese control subjects (403 ± 65 mg m^?2 min^?1) both groups of diabetic patients had significantly decreased insulin-stimulated glucose disposal rates (p < 0.005). Even in a subset of Type 2 diabetic patients with long-term (> 6 months) near normal blood glucose control (HbA_1c < 6.1 %) significant defects were detectable in whole-body glucose and lipid metabolism when compared to control subjects. These results indicate that treated hypertension does not significantly aggravate the insulin insensitivity that is already present in Type 2 diabeted mellitus. Furthermore, Type 2 diabetic patients with long-term good metabolic control continue to demonstrate insulin insensitivity in peripheral tissues.     

Post-marathon Paradox in IDDM: Unchanged Insulin Sensitivity in Spite of Glycogen Depletion

Acute physical exercise usually enhances insulin sensitivity. We examined the effect of a competitive 42 km marathon run on glucose uptake and lipid oxidation in 7 runners with insulin-dependent diabetes mellitus (IDDM), aged 36 ± 3 yr, BMI 23.9 ± 0.5 kg m⁻², VO_{2 max} 46 ± 1 ml kg⁻¹ min⁻¹, HbA_1c 7.7 ± 0.3 %, duration of diabetes 16 ± 5 yr, runtime 3 h 47 ± 8 min. On the marathon day, they reduced pre-race insulin doses by 26 ± 8 %, and ingested 130 ± 33 g carbohydrate before, 91 ± 26 g during, and 115 ± 20 g after the race. During the run, blood glucose concentration fell from 14.4 ± 2.0 to 7.4 ± 3.0 mmol l⁻¹ (p < 0.05) and serum insulin from 51 ± 8 to 33 ± 8 pmol l⁻¹ (p < 0.05). Serum NEFA increased by 4-fold (p < 0.05), but fell to the normal level by next morning. Muscle glycogen content was 56 % lower (p < 0.05) and glycogen synthase fractional activity 40 % greater (p < 0.05) in the morning after the marathon as compared to the resting control day. In spite of glycogen depletion, whole body glucose disposal (euglycaemic insulin clamp) was unchanged, while glucose oxidation (indirect calorimetry) was decreased by 49 % (p < 0.05) and lipid oxidation increased by 41 % (p < 0.01). There was an inverse correlation between the rates of lipid oxidation and glucose uptake after the marathon (r = −0.75; p < 0.05). In conclusion: after successfully managed marathon running in patients with IDDM, insulin sensitivity was not increased in spite of low glycogen content and enhanced glycogen synthase activity after marathon, probably because of increased lipid oxidation. © 1997 by John Wiley & Sons, Ltd.     

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.     

AMP-activated protein kinase (AMPK)α2 plays a role in determining the cellular fate of glucose in insulin-resistant mouse skeletal muscle

Aims/hypothesis

We determined whether: (1) an acute lipid infusion impairs skeletal muscle AMP-activated protein kinase (AMPK)α2 activity, increases inducible nitric oxide synthase (iNOS) and causes peripheral insulin resistance in conscious, unstressed, lean mice; and (2) restoration of AMPKα2 activity during the lipid infusion attenuates the increase in iNOS and reverses the defect in insulin sensitivity in vivo.

Methods

Chow-fed, 18-week-old C57BL/6J male mice were surgically catheterised. After 5 days they received: (1) a 5 h infusion of 5 ml? kg^?1?h^?1 Intralipid?+?6 U/h heparin (Lipid treatment) or saline (Control); (2) Lipid treatment or Control, followed by a 2 h hyperinsulinaemic–euglycaemic clamp (insulin clamp; 4 mU kg^?1?min^?1); and (3) infusion of the AMPK activator, 5-aminoimidazole-4-carboxamide 1-β-d-ribofuranoside (AICAR) (1 mg kg^?1?min^?1), or saline during Lipid treatment, followed by a 2 h insulin clamp. In a separate protocol, mice producing a muscle-specific kinase-dead AMPKα2 subunit (α2-KD) underwent an insulin clamp to determine the role of AMPKα2 in insulin-mediated muscle glucose metabolism.

Results

Lipid treatment decreased AMPKα2 activity, increased iNOS abundance/activation and reduced whole-body insulin sensitivity in vivo. AICAR increased AMPKα2 activity twofold; this did not suppress iNOS or improve whole-body or tissue-specific rates of glucose uptake during Lipid treatment. AICAR caused a marked increase in insulin-mediated glycogen synthesis in skeletal muscle. Consistent with this latter result, lean α2-KD mice exhibited impaired insulin-stimulated glycogen synthesis even though muscle glucose uptake was not affected.

Conclusions/interpretation

Acute induction of insulin resistance via lipid infusion in healthy mice impairs AMPKα2, increases iNOS and causes insulin resistance in vivo. However, these changes do not appear to be interrelated. Rather, a functionally active AMPKα2 subunit is required for insulin-stimulated muscle glycogen synthesis.     

Lack of acute effect of amylin (islet associated polypeptide) on insulin sensitivity during hyperinsulinaemic euglycaemic clamp in humans

Summary It is suggested that amylin (islet associated polypeptide), co-secreted with insulin from the pancreatic beta cells acts as a circulating hormone which opposes the action of insulin on muscle and increases hepatic glucose production. We have tested the effect of amylin in human subjects on postabsorptive glucose homeostasis and on insulin sensitivity using the euglycaemic hyperinsulinaemic clamp. The amylin used opposed insulin-mediated glucose disposal in rat soleus muscle at concentrations of 10 nmol/l. Seven subjects were studied on two occasions and infused with either amylin or placebo for 6 h, initially when postabsorptive and then during a euglycaemic hyperinsulinaemic clamp. Mean plasma amylin concentrations during the first 3 h were 2006±327 pmol/l during amylin infusion and 20±9 pmol/l during the control infusion. Amylin infusion had no effect on postabsorptive plasma concentrations of insulin (control: 32±16 vs amylin: 25±8 pmol/l) or glucose (5.1±0.1 vs 5.3±0.1 mmol/l). During the clamp, amylin concentrations were 1636 ±422 pmol/l when it was infused and 24±6 during control infusions. Plasma glucose and insulin concentrations were well matched during the control and amylin infusions (glucose: 4.7±0.1 vs 4.8±0.1 mmol/l; insulin: 198±37 vs 195±22 pmol/l). Exogenous glucose infusion rates were a mean of 13 % lower than control values during the amylin infusion but were not statistically different (p =0.17). Therefore, an approximately 100-fold elevation of plasma amylin concentration failed to consistently alter glucose metabolism. Our data suggest that amylin does not act as a circulating hormone to influence glucose metabolism in humans. [Diabetologia (1994) 37: 166–169] Received: 1 June 1993 and in revised form: 16 August 1993     

Time–action Profile of Inhaled Insulin

We compared the pharmacodynamics of insulin after inhalation of 99 U microcrystalline solid insulin and subcutaneous injection of 10 U regular insulin and intravenous injection of 5 U regular insulin. The time–action profiles of the three insulin administrations were studied in 11 healthy volunteers using the euglycaemic glucose clamp technique. The insulins were administered to each volunteer on three separate occasions in random order. Onset of action, assessed as glucose infusion rate, after insulin inhalation was substantially more rapid than after subcutaneous injection and half-maximal action was reached earlier (31 ± 17 vs 54 ± 12 min; p < 0.001). Maximal metabolic response was reached earlier after insulin inhalation in comparison to subcutaneous injection (108 ± 49 vs 147 ± 53 min; p < 0.001). The maximal glucose infusion rate after inhalation of insulin was lower than after subcutaneous insulin injection (6.2 ± 2.4 vs 9.1 ± 2.5 mg kg⁻¹ min⁻¹; p < 0.001). The glucose infusion rates in the first 60 min after inhalation were significantly greater than after insulin injection (area under the glucose infusion rate curve: 0.23 ± 0.12 vs 0.13 ± 0.08 g kg⁻¹ 60 min⁻¹; p < 0.001). However, the total metabolic effect after inhalation was significantly lower than after insulin injection (1.44 ± 0.68 vs 1.90 ± 0.47 g kg⁻¹ 360 min⁻¹; p < 0.001). Relative effectiveness of inhaled insulin calculated with regard to the data from the intravenous insulin application was 9.5 ± 4.1 % and of the subcutaneous insulin application was 7.6 ± 2.9 %. With its rapid onset of action, inhaled insulin might have potential for clinical use. © 1997 by John Wiley & Sons, Ltd.     

Insulin resistant subjects lack islet adaptation to short-term dexamethasone-induced reduction in insulin sensitivity

Aims/hypothesis. To establish whether islet compensation to deterioration of insulin action depends on inherent insulin sensitivity. Methods. We examined insulin and glucagon secretion after iv arginine (5 g) at fasting, 14 and greater than 25 mmol/l glucose concentrations before and after lowering of insulin sensitivity by oral dexamethasone (3 mg twice daily for 2 1/2 days) in 10 women with normal glucose tolerance, aged 58 or 59 years. Five women had high insulin sensitivity as shown by euglycaemic, hyperinsulinaemic clamp (99 ± 12 nmol glucose · kg body weight^–1· min^–1/pmol insulin · l^–1; means ± SD) whereas five women had low insulin sensitivity (34 ± 15 nmol glucose · kg body weight^–1· min^–1/pmol insulin · l^–1). Results. Dexamethasone reduced insulin sensitivity in both groups. Fasting insulin concentration increased by dexamethasone in high insulin sensitivity (72 ± 10 vs 49 ± 9 pmol/l, p = 0.043) but not in low insulin sensitivity (148 ± 63 vs 145 ± 78 pmol/l) whereas the fasting glucose concentration increased in low insulin sensitivity (6.5 ± 0.8 vs 5.8 ± 0.6 mmol/l, p = 0.043) but not in high insulin sensitivity (5.3 ± 0.8 vs 5.3 ± 0.6 mmol/l). Fasting glucagon concentration was not changed. Plasma insulin concentrations after raising glucose to 14 and more than 25 mmol/l and the insulin response to arginine at more than 25 mmol/l glucose were increased by dexamethasone in high insulin sensitivity (p < 0.05) but not changed by dexamethasone in low insulin sensitivity. Furthermore, in high but not in low insulin sensitivity, dexamethasone reduced the glucagon response to arginine (p = 0.043). Conclusion/interpretation. The results show that adaptation in islets function to dexamethasone-induced short-term reduction in insulin sensitivity is lacking in subjects with low inherent insulin sensitivity. [Diabetologia (1999) 42: 936–943] Received: 26 January 1999 and in revised form: 1 March 1999     

Co-existence of severe insulin resistance and hyperinsulinaemia in pre-adolescent obese children

Summary To determine the time course of changes in insulin action and secretion that occur early during the development of obesity, we studied children before the onset of puberty. The reason for choosing the prepubertal stage of development is that it is metabolically characterized by both a high sensitivity to insulin and low glucose stimulated insulin responses. Fifteen obese preadolescents (8 male/7 female, age 10 ± 0.4 years, body mass index (BMI) 31 ± 1.2 kg/m² Tanner Stage I) with a duration of obesity of less than 5 years and 10 non-obese preadolescents (6 male/4 female, age 10 ± 0.4 years, BMI 18 ± 0.9 kg/m²) matched for gender were studied. In a cross-sectional analysis, we compared responses in obese preadolescents, with those in obese adolescents and obese adults with a longer duration of obesity. The euglycaemic hyperinsulinaemic clamp with 1-¹³C-glucose (Hot Ginf) and indirect calorimetry were used to quantitate insulin action and the hyperglycaemic clamp used to assess beta-cell function. Insulin-stimulated glucose uptake measured at two physiological levels of hyperinsulinaemia ( ∼ 180 and 480 pmol) was reduced by 20 and 45 % in all three groups of obese compared to non-obese subjects (p < 0.01). Defects in oxidative and non-oxidative glucose metabolism were observed in all three groups of obese subjects at the higher insulin infusion rate. The ability of insulin to inhibit lipid oxidation was impaired in all three obese groups at both levels of hyperinsulinaemia. Increases in basal and glucose-stimulated insulin levels during the hyperglycaemic clamp mirrored the reductions in glucose uptake during the insulin clamp in all obese groups. These results indicate that insulin resistance and hyperinsulinaemia co-exist in preadolescent children with moderate to severe obesity. [Diabetologia (1996) 39: 1489–1497] Received: 23 March 1996 and in revised form: 16 July 1996     

Insulin resistance and coronary artery disease

Summary The purpose of the present study was to quantitate insulin-mediated glucose disposal in normal glucose tolerant patients with angiographically documented coronary artery disease (CAD) and to define the pathways responsible for the insulin resistance. We studied 13 healthy, normal weight, normotensive subjects with angiographically documented CAD and 10 age-, weight-matched control subjects with an oral glucose tolerance test and a 2-h euglycaemic insulin (40 mU · m⁻²· min⁻¹) clamp with tritiated glucose and indirect calorimetry. Lean body mass was measured with tritiated water. All CAD and control subjects had a normal oral glucose tolerance test. Fasting plasma insulin concentration (66 ± 6 vs 42 ± 6 pmol/l, p < 0.05) and area under the plasma insulin curve following glucose ingestion (498 ± 54 vs 348 ± 42 pmol · l⁻¹· min⁻¹, p < 0.001) were increased in CAD vs control subjects. Insulin-mediated whole body glucose disposal (27.8 ± 3.9 vs 38.3 ± 4.4 μmol · kg fat free mass (FFM)⁻¹· min⁻¹, p < 0.01) was significantly decreased in CAD subjects and this was entirely due to diminished non-oxidative glucose disposal (8.9 ± 2.8 vs 20.0 ± 3.3 μmol · kg FFM⁻¹· min⁻¹, p < 0.001). The magnitude of insulin resistance was positively correlated with the severity of CAD (r = 0.480, p < 0.05). In the CAD subjects basal and insulin-mediated rates of glucose and lipid oxidation were normal and insulin caused a normal suppression of hepatic glucose production. In conclusion, subjects with angiographically documented CAD are characterized by moderate-severe insulin resistance and hyperinsulinaemia and should be included in the metabolic and cardiovascular cluster of disorders that comprise the insulin resistance syndrome or ’syndrome X'. [Diabetologia (1996) 39: 1345–1350] Received: 6 February 1996 and in revised form: 29 May 1996     

A vascular mechanism for high-sodium-induced insulin resistance in rats

Aims/hypothesis

High sodium (HS) effects on hypertension are well established. Recent evidence implicates a relationship between HS intake and insulin resistance, even in the absence of hypertension. The aim of the current study was to determine whether loss of the vascular actions of insulin may be the driving factor linking HS intake to insulin resistance.

Methods

Sprague Dawley rats were fed a control (0.31% wt/wt NaCl) or HS (8.00% wt/wt NaCl) diet for 4 weeks and subjected to euglycaemic–hyperinsulinaemic clamp (10 mU min^?1 kg^?1) or constant-flow pump-perfused hindlimb studies following an overnight fast. A separate group of HS rats was given quinapril during the dietary intervention and subjected to euglycaemic–hyperinsulinaemic clamp as above.

Results

HS intake had no effect on body weight or fat mass or on fasting glucose, insulin, endothelin-1 or NEFA concentrations. However, HS impaired whole body and skeletal muscle glucose uptake, in addition to a loss of insulin-stimulated microvascular recruitment. These effects were present despite enhanced insulin signalling (Akt) in both liver and skeletal muscle. Constant-flow pump-perfused hindlimb experiments revealed normal insulin-stimulated myocyte glucose uptake in HS-fed rats. Quinapril treatment restored insulin-mediated microvascular recruitment and muscle glucose uptake in vivo.

Conclusions/interpretation

HS-induced insulin resistance is driven by impaired microvascular responsiveness to insulin, and is not due to metabolic or signalling defects within myocytes or liver. These results imply that reducing sodium intake may be important not only for management of hypertension but also for insulin resistance, and highlight the vasculature as a potential therapeutic target in the prevention of insulin resistance.     

Counterregulatory Hormone Responses and Symptoms During Hypoglycaemia Induced by Porcine,Human Regular Insulin,and Lys(B28), Pro(B29) Human Insulin Analogue (Insulin Lispro) in Healthy Male Volunteers

Lys(B28)Pro(B29) human insulin analogue (Lispro) is a newly developed monomeric insulin analogue with a rapid onset and short duration of action. The aim of the study was to compare the thresholds for the counterregulatory responses during a stepwise euglycaemic/hypoglycaemic clamp for insulin lispro (LP), human (H), and porcine (P) insulin in a randomized order in 12 healthy male volunteers (age 22.4 ± 1.7 years, BMI 21.9 ± 1.7 kg m⁻²). A euglycaemic period of 2 h was followed by three hypoglycaemic levels of 60 min each: from 150–210 min at 3.5 mmol l⁻¹, 240–300 min at 3.0 mmol l⁻¹, and 330–390 min at 2.5 mmol l⁻¹. Plasma insulin levels during the 50 mU kg⁻¹ h⁻¹ infusions and blood glucose levels were not significantly different. The glucose requirements (mean ± SD) during the last part of the euglycaemic period (90–120 min) tended to be higher during LP compared to those during H and P; 2239 ± 702 and 1929 ± 769, 1957 ± 725 mg kg⁻¹, P = 0.067, respectively. The thresholds (blood glucose level at which a sustained elevation of the counterregulatory hormones as compared to the mean at normoglycaemia level 4.0 mmol l⁻¹ , occurs) for the various hormones were very similar during LP, H, and P insulin infusions and occurred at 253.8 ± 56.7, 256.3 ± 55.3 and 257.5 ± 70.0 min for adrenaline; 241.4 ± 80.3, 260.5 ± 82.5 and 225.0 ± 75.9 min for noradrenaline; 307.5 ± 65.5, 304.1 ± 74.1 and 322.5 ± 40.4 min for cortisol; 263.8 ± 50.3, 255.0 ± 63.6 and 249.6 ± 50.9 min for growth hormone; 236.3 ± 78.2, 200.0 ± 73.1 and 226.3 ± 65.5 for pancreatic polypeptide. The autonomic and neuroglycopenic symptoms were elicited at 240 and 300 min, respectively. In conclusion, our data indicate a tendency to a higher biological activity of approximately 10 % for Lispro insulin. During a stepwise euglycaemic/hypoglycaemic clamp, the counterregulatory hormone responses to insulin lispro, human insulin, and porcine insulin were similar. © 1997 by John Wiley & Sons, Ltd.     

Acute Effect of Insulin on Autonomic Regulation of the Cardiovascular System: A Study by Heart Rate Spectral Analysis

Insulin is suggested to have direct effects on the cardiovascular system but these are not well described. We assessed the possible influence of insulin on autonomic control of heart function. A 2-h hyperinsulinaemic euglycaemic clamp was performed in 10 healthy women (mean age 21.7 ± 1.3 years), at two different insulin infusion rates: 80 mU m⁻² and 400 mU m⁻² min⁻¹, in 7 and 3 subjects, respectively. Saline alone was infused in 4 controls. Power spectral analysis (PSA) of heart rate was recorded before and after 90–120 min of insulin infusion, as were blood pressure and heart rate. Although there were no significant changes in heart rate or blood pressure, PSA showed marked reductions of high frequency (HF) bands after insulin (2.60 ± 0.12 vs 2.09 ± 0.16 log ms², p < 0.005), as at both low and high infusion rates (2.46 ± 0.13 to 2.14 ± 0.23 log ms², p < 0.05, and 2.92 ± 0.18 to 1.98 ± 0.06 log ms², p < 0.01, respectively). There were no significant changes of low frequency (LF) bands. Densities at LF and HF did not change significantly in control studies. As HF and LF are considered to reflect parasympathetic and mainly sympathetic control respectively, our observation of an increased LF/HF ratio (0.13 ± 0.10 vs 0.63 ± 0.13, p < 0.005) may be considered an index of relative sympathetic predominance induced by insulin infusion. We conclude that insulin affects the cardiovascular system, reducing vagal influence on the heart and inducing a relative hypersympathetic tone.     

A comparison between enalapril and captopril on insulin sensitivity in normotensive healthy volunteers

Background: Captopril has been shown to improve insulin sensitivity in insulin resistant hypertensive individuals and enalapril has been shown to improve insulin sensitivity in a small group of healthy volunteers, but there has been no direct comparison of the effects of the different angiotensin converting enzyme inhibitors (ACEIs) on insulin sensitivity in either insulin sensitive or insulin insensitive populations. Aim: To compare the impact of two different ACEIs (captopril and enalapril) on insulin mediated glucose uptake in normotensive, non-obese, insulin sensitive subjects. Method: A single blind cross-over study comparing captopril (6.25 mg twice daily) and enalapril (5 mg once daily) for 28 days with a 28 day washout period between drugs. Insulin mediated glucose uptake was measured by means of the euglycaemic hyperinsulinaemic clamp at the start and completion of each period of drug therapy. Results: Both drugs resulted in elevations of fasting insulin levels (mean difference ± SEM for combined data, 2.7 ± 1.8; p < 0.05) and a reduction in insulin mediated glucose uptake (mean difference for combined data, - 0.72 ± 0.37 mg/kg¹ minute^-1; p= 0.056). Results were similar for both agents and suggest a class effect. Conclusions: The increase in fasting insulin levels, and reduction in insulin mediated glucose uptake in this study are in contrast to findings in obese and hypertensive subjects, and indicate that studies of insulin sensitivity of ACEIs in non-obese, normotensive subjects are inappropriate for predicting likely effects in clinical practice. (Aust NZ J Med 1993; 23: 652–655.)     

Dissociation between insulin sensitivity of glucose uptake and endothelial function in normal subjects

Summary Insulin increases limb blood flow in a time- and dose-dependent manner. This effect can be blocked by inhibiting nitric oxide synthesis. These data raise the possibility that insulin resistance is associated with endothelial dysfunction. To examine whether endothelial function and insulin sensitivity are interrelated we quantitated in vivo insulin-stimulated rates of whole body and forearm glucose uptake at a physiological insulin concentration (euglycaemic hyperinsulinaemic clamp, 1 mU · kg^–1· min^–1 insulin infusion for 2 h) and on another occasion, in vivo endothelial function (blood flow response to intrabrachial infusions of sodium nitroprusside, acetylcholine, and N-monomethyl-l-arginine) in 30 normal male subjects. Subjects were divided into an insulin-resistant (IR) and an insulin-sensitive (IS) group based on the median rate of whole body glucose uptake (31 ± 2 vs 48 ± 1 μmol · kg^–1· min^–1, p < 0.001). The IR and IS groups were matched for age, but the IR group had a slightly higher body mass index, percentage of body fat and blood pressure compared to the IS group. The IR group also had diminished insulin-stimulated glucose extraction (p < 0.05) compared to the IS group, while basal and insulin-stimulated forearm blood flow rates were identical. There was no difference between the IR and IS groups in the forearm blood flow response to endothelium-dependent (acetylcholine and N-monomethyl-l-arginine) or -independent (sodium nitroprusside) vasoactive drugs. In conclusion, the ability of insulin to stimulate glucose uptake at physiological insulin concentrations and endothelium-dependent vasodilatation are distinct phenomena and do not necessarily coexist. [Diabetologia (1996) 39: 1477–1482] Received: 31 May 1996 and in revised form: 10 July 1996     

Intramuscular versus subcutaneous injection of soluble and lispro insulin: comparison of metabolic effects in healthy subjects

The aim of this study was to compare the glucodynamic effects of soluble insulin and the rapid acting insulin analogue insulin lispro after subcutaneous (s.c.) and intramuscular (i.m.) injection. Twelve healthy male volunteers (age 26.8 ± 1.7 years, BMI 23.2 ± 2.3 kg m⁻²; mean ± SD) participated in this single-centre, open-labelled, euglycaemic glucose clamp study on four different days. Soluble insulin or insulin lispro (0.2 U kg⁻¹) were injected s.c. or i.m. into the thigh by syringe. The glucodynamic effects were assessed by registering the glucose infusion rates necessary to maintain blood glucose at 5.0 mmol l⁻¹ for the subsequent 420 min. Intramuscular injection of soluble insulin led to an earlier peak of metabolic action when compared to s.c. administered soluble insulin (t_max 138 ± 29 vs 179 ± 34 min; p < 0.05). The maximal metabolic effect and metabolic activity during the first 2 h after i.m. and s.c. injection of soluble insulin were comparable (GIR_max 9.7 ± 2.3 vs 7.8 ± 2.3 mg kg⁻¹ min⁻¹; n.s., AUC_{0–120 min} 0.60 ± 0.18 vs 0.50 ± 0.15 g kg⁻¹ 120 min; n.s.). Subcutaneous administration of insulin lispro led to a metabolic effect resembling that induced by i.m. application of soluble insulin (t_max 116 ± 26 vs 138 ± 29 min; n.s., GIR_max 11.1 ± 2.3 mg vs 9.7 ± mg kg⁻¹ min⁻¹; n.s.). However, the overall metabolic response during the first 2 h after injection was higher with s.c. insulin lispro (AUC_{0–120 min} 0.81 ± 0.26 vs 0.60 ± 0.18 g kg⁻¹ 120 min; p < 0.05). The glucodynamic activity of i.m. applied insulin lispro was comparable to that of lispro s.c.. Following i.m. injection of soluble insulin, the metabolic activity peaked more rapidly than with s.c. administration. In contrast, the metabolic effect of insulin lispro was similar with either route. The time–action profile of i.m. injected soluble insulin lies between that of s.c. applied soluble insulin and insulin lispro. © 1998 John Wiley & Sons, Ltd.     

In vivo effects of glucosamine on insulin secretion and insulin sensitivity in the rat: Possible relevance to the maladaptive responses to chronic hyperglycaemia

Summary We tested the hypothesis that glucosamine, a putative activator of glucose toxicity in vitro through acceleration of the hexosamine pathway, may determine in vivo the two key features of glucose toxicity in diabetes, namely, peripheral insulin resistance and decreased insulin secretion. Two groups of awake rats were studied either with intraarterial administration of glucosamine (5 mol·kg^–1· min^–1) or saline. Insulin secretion was determined after arginine, glucose (hyperglycaemic clamp), and arginine/glucose infusions, while insulin-mediated glucose metabolism was assessed by the euglycaemic hyperinsulinaemic clamp in combination with [3-³H]-glucose infusion. Glucosamine had no effects on arginine-induced insulin secretion both at euglycaemia and hyperglycaemia, but significantly (40–50%) impaired glucose-induced insulin secretion (both first and second phases). During euglycaemic hyperinsulinaemic clamp studies, glucosamine decreased glucose uptake by 30%, affecting glycolysis (estimated from ³H₂O rate of appearance) and muscle glycogen synthesis (calculated from accumulation of [³H]-glucosyl units in muscle glycogen) to a similar extent. Muscle glucose 6-phosphate concentration was markedly reduced in the glucosamine-infused rats, suggesting an impairment in glucose transport/phosphorylation. Therefore, an increase in hexosamine metabolism in vivo: 1) inhibits glucose-induced insulin secretion, and 2) reduces insulin stimulation of both glycolysis and glycogen synthesis, thereby mimicking in normal rats the major alterations due to glucose toxicity in diabetes.Abbreviations GFAT Glutamine:fructose 6-phosphate amidotransferase - UDP-N-acetylglucosamine uridine-diphospho-N-acetylglucosamine     

Impaired glucose tolerance (IGT) is associated with reduced insulin-induced suppression of glucagon concentrations

Aims/hypothesis: We aimed to examine whether impaired glucose tolerance is associated with reduced suppression of glucagon concentrations. Methods: Eighty-four non-diabetic women of Caucasian origin and 61 years of age, of whom 48 had normal glucose tolerance (NGT) and 36 had IGT, underwent a 75 g OGTT and a hyperinsulinaemic, euglycaemic clamp with measurement of glucagon, insulin and glucose concentrations. Results: At 2 h after 75 g oral glucose, glucagon concentrations were reduced by 7.1 ± 1.1 ng/l in NGT vs 8.0 ± 1.4 ng/l in IGT, (NS). However, the 2 h reductions in glucagon per mmol/l increase in 2 h glucose or per pmol/l increase in 2 h insulin were both impaired in IGT (p = 0.002 and p = 0.043, respectively) because the 2 h increases in glucose and insulin were higher in IGT than in NGT. Furthermore, suppression of glucagon concentrations during a euglycaemic clamp at hyperinsulinaemic concentrations (NGT: 607 ± 19 pmol/l, IGT: 561 ± 21 pmol/l) was lower in IGT (13.6 ± 1.6 ng/l) than in NGT (23.1 ± 1.2 ng/l; p < 0.001). The suppression of glucagon concentrations during the hyperinsulinaemic, euglycaemic clamp correlated with insulin sensitivity (r = 0.24, p = 0.027) and with the 2 h glucose value during the OGTT (r = –0.52, p < 0.001). Conclusion/interpretation: Impaired glucose tolerance is associated with reduced insulin-induced suppression of glucagon secretion, which could be caused by A-cell insulin resistance. Inappropriately high glucagon secretion could therefore contribute to the metabolic perturbations in IGT. [Diabetologia (2001) 44: 1998–2003] Received: 15 May 2001 and in revised form: 13 July 2001     

Estimated Glucose Requirement Following Massive Insulin Overdose in a Patient with Type 1 Diabetes

A well-documented case of a 35-year-old male Type 1 diabetic patient who was admitted as an emergency after having injected 1500 international units (IU) of insulin (750 IU regular insulin,750 IU NPH-insulin) subcutaneously as a suicidal attempt is reported. Computing disappearance rates of glucose from its infused amounts necessary to maintain euglycaemia during 65 h after the insulin injection in analogy to experimental hyperinsulinaemic euglycaemic clamp examinations, a glucose consumption of 55.6 μmol kg^?1 min^?1 was found at peak serum insulin concentrations of about 14400 pmol I^?1. The insulin-induced glucose dynamics resemble closely those seen in healthy persons and Type 1 diabetic subjects during a 10 mU kg^?1 min^?1 euglycaemic clamp. This information may be useful in the handling of similar cases of insulin intoxication.