Michael Roden

Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans: a 1H NMR spectroscopy study

Summary Recent muscle biopsy studies have shown a relation between intramuscular lipid content and insulin resistance. The aim of this study was to test this relation in humans by using a novel proton nuclear magnetic resonance (1H NMR) spectroscopy technique, which enables non-invasive and rapid ( ∼ 45 min) determination of intramyocellular lipid (IMCL) content. Normal weight non-diabetic adults (n = 23, age 29 ± 2 years, BMI = 24.1 ± 0.5 kg/m2) were studied using cross-sectional analysis. Insulin sensitivity was assessed by a 2-h hyperinsulinaemic ( ∼ 450 pmol/l)-euglycaemic ( ∼ 5 mmol/l) clamp test. Intramyocellular lipid concentrations were determined by using localized 1H NMR spectroscopy of soleus muscle. Simple linear regression analysis showed an inverse correlation (r = –0.692, p = 0.0017) between intramyocellular lipid content and M-value (100–120 min of clamp) as well as between fasting plasma non-esterified fatty acid concentration and M-value (r = –0.54, p= 0.0267). Intramyocellular lipid content was not related to BMI, age and fasting plasma concentrations of triglycerides, non-esterified fatty acids, glucose or insulin. These results show that intramyocellular lipid concentration, as assessed non invasively by localized 1H NMR spectroscopy, is a good indicator of whole body insulin sensitivity in non-diabetic, non-obese humans. [Diabetologia (1999) 42: 113–116]

Hepatic glucose metabolism in humans: its role in health and disease

The liver is mainly responsible for maintaining normal concentrations of blood glucose by its ability to store glucose as glycogen and to produce glucose from glycogen breakdown or gluconeogenic precursors. During the last decade, new techniques have made it possible to gain further insight into the turnover of hepatic glucose and glycogen in humans. Hepatic glycogen varies from approximately 200 to approximately 450 mM between overnight fasted and postprandial conditions. Patients with type-1 diabetes (T1DM), type 2 diabetes (T2DM) or partial agenesis of the pancreas exhibit increased endogenous glucose production and synthesize only 25-45% of hepatic glycogen compared with non-diabetic humans. This defect can be partly restored in T1DM by combined long- and short-term optimized treatment with insulin. In T2DM, increased gluconeogenesis was identified as the main cause of elevated glucose production and fasting hyperglycaemia. These patients also exhibit augmented intracellular lipid accumulation which could hint at a link between deranged glucose and lipid metabolism in insulin-resistant states.

Lipid-dependent control of hepatic glycogen stores in healthy humans

Aims/hypothesis. Non-esterified fatty acids and glycerol could stimulate gluconeogenesis and also contribute to regulating hepatic glycogen stores. We examined their effect on liver glycogen breakdown in humans.¶Methods. After an overnight fast healthy subjects participated in three protocols with lipid/heparin (plasma non-esterified fatty acids: 2.2 ± 0.1 mol/l; plasma glycerol: 0.5 ± 0.03 mol/l; n = 7), glycerol (0.4 ± 0.1 mol/l; 1.5 ± 0.2 mol/l; n = 5) and saline infusion (control; 0.5 ± 0.1 mol/l; 0.2 ± 0.02 mol/l; n = 7). Net rates of glycogen breakdown were calculated from the decrease of liver glycogen within 9 h using 13C nuclear magnetic resonance spectroscopy. Endogenous glucose production was measured with infusion of D-[6,6-2H2]glucose.¶Results. Endogenous glucose production decreased by about 25 % during lipid and saline infusion (p < 0.005) but not during glycerol infusion (p < 0.001 vs lipid, saline). An increase of plasma non-esterified fatty acids or glycerol reduced the net glycogen breakdown by about 84 % to 0.6 ± 0.3 μmol · kg–1· min–1 (p < 0.001 vs saline: 3.7 ± 0.5 μmol · kg–1· min–1) and by about 46 % to 2.0 ± 0.4 μmol · kg–1· min–1 (p < 0.01 vs saline and lipid), respectively. Rates of gluconeogenesis increased to 11.5 ± 0.8 μmol · kg–1· min–1 (p < 0.01) and 12.8 ± 1.0 μmol · kg–1· min–1 (p < 0.01 vs saline: 8.2 ± 0.7 μmol · l–1· min–1), respectively.¶Conclusion/interpretation: An increase of non-esterified fatty acid leads to a pronounced inhibition of net hepatic glycogen breakdown and increases gluconeogenesis whereas glucose production does not differ from the control condition. We suggest that this effect is not due to increased availability of glycerol alone but rather to lipid-dependent control of hepatic glycogen stores. [Diabetologia (2001) 44: 48–54]

Inherited Platelet Glycoprotein Polymorphisms and a Risk for Coronary Heart Disease in Young Central Europeans

Among central Europeans polymorphisms of GPIIIa, GPIb, GPIIb, and GPIa named human platelet antigen-1 (HPA-1), -2, -3, and -5 are the clinically most relevant systems in which alloimmunization occurs. These genetically determined polymorphisms of glycoproteins may render platelets sensible for plaque formation and thus could increase risk for coronary artery disease (CAD). We therefore determined gene frequencies of HPA-1, -2, -3, and -5 in European patients suffering from CAD (n = 92; median age, 46 years) or CAD accompanied by diabetes mellitus (DM) (n = 30; median age, 60 years, DM I/II, 5/25) and compared the data obtained with those in DM patients without CAD (n = 80; median age, 43 years; DM I/II, 53/27) and a control group (newborns, n = 906). Triglyceride and cholesterin levels as well as the percentage of smokers was significantly higher in the CAD group compared with the diabetics without DM (p < 0.005). No significant difference of the frequencies of any HPA-type between CAD patients with or without DM, diabetics, or controls could be detected. This was also true when evaluating a subgroup of patients aged 45 years or younger. To include a mutual influence of the described HPA-polymorphisms, we condensed the four HPA genotypes to joint glycoprotein variants. Again the same frequencies were found in patient groups and controls, when analyzing the five most common condensed joint glycoprotein variants. The analysis of the combined published studies shows that the pooled HPA-1 allele frequencies are identical in controls and CAD patients. Thus, no significant association between the polymorphisms of any of the studied HPA systems and the development of CAD can be found in central Europeans.

Transcapillary insulin transfer in human skeletal muscle

Background Transcapillary insulin transfer is considered a rate‐limiting step in insulin action at supraphysiological insulin concentrations. However, it remains unclear whether this concept also applies for physiological conditions.

Acute troglitazone action in isolated perfused rat liver

The thiazolidinedione compound, troglitazone, enhances insulin action and reduces plasma glucose concentrations when administered chronically to type 2 diabetic patients. To analyse to what extent thiazolidinediones interfere with liver function, we examined the acute actions of troglitazone (0.61 and 3.15 μM) on hepatic glucose and lactate fluxes, bile secretion, and portal pressure under basal, insulin‐ and/or glucagon‐stimulated conditions in isolated perfused rat livers. During BSA‐free perfusion, high dose troglitazone increased basal (P<0.01), but inhibited glucagon‐stimulated incremental glucose production by ∼75% (10.0±2.5 vs control: 40.0±7.2 μmol g liver−1, P<0.01). In parallel, incremental lactate release rose ∼6 fold (13.1±5.9 vs control: 2.2±0.8 mmol g liver−1, P<0.05), while bile secretion declined by ∼67% [0.23±0.02 vs control: 0.70±0.05 mg g liver−1 min−1), P<0.001]. Low dose troglitazone infusion did not enhance the inhibitory effect of insulin on glucagon‐stimulated glucose production, but rapidly increased lactate release (P<0.0005) and portal venous pressure (+0.17±0.07 vs +0.54±0.07 cm buffer height, P<0.0001). These results indicate that troglitazone exerts both insulin‐like and non‐insulin‐like hepatic effects, which are blunted by addition of albumin, possibly due to troglitazone binding.

Acute and Chronic Exposure to Tumor Necrosis Factor-α Fails to Affect Insulin-Stimulated Glucose Metabolism of Isolated Rat Soleus Muscle1

To better understand the effects of tumor necrosis factor-α (TNFα) on insulin sensitivity, direct interaction of the peptide with freshly isolated rat soleus muscle strips was investigated. Muscles were exposed to TNFα at concentrations ranging from 0.01–5 nmol/liter. Rates of insulin-stimulated (5 or 100 nmol/liter) glucose metabolism were determined after periods of TNFα preexposure of 30 min, 6 h, and 24 h. Independent of exposure time, TNFα failed to exert any significant effect on rates of 3H-2-deoxy-glucose transport (stimulation by 100 nmol/liter insulin after preincubation without vs. with 5 nmol/liter TNFα, cpm/mg·h: 30 min, 779 ± 29 vs. 725 ± 29; 6 h, 652 ± 56 vs. 617 ± 60; 24 h, 911± 47 vs. 936 ± 31) or glucose incorporation into glycogen (μmol/g·h: 30 min, 5.19 ± 0.22 vs. 5.25 ± 0.41; 6 h, 2.08 ± 0.10 vs. 2.09 ± 0.17; 24 h, 2.51 ± 0.21 vs. 2.41 ± 0.26). In parallel, TNFα neither affected insulin-stimulated rates of glucose oxidation (CO2 production) and anaerobic glycolysis (lactate release), ...

Acute non-insulin-like stimulation of rat muscle glucose metabolism by troglitazone in vitro

1 The direct short‐term effects of troglitazone on parameters of glucose metabolism were investigated in rat soleus muscle strips. 2 In muscle strips from Sprague‐Dawley rats, troglitazone (3.25 μmol l−1) increased basal and insulin‐stimulated glucose transport by 24% and 41%, respectively (P<0.01 each). 3 In the presence of 5 nmol l−1 insulin, stimulation of glucose transport by 3.25 μmol l−1 troglitazone was accompanied by a 36% decrease in glycogen synthesis, while glycolysis was increased (112% increase in lactate production) suggesting a catabolic response of intracellular glucose handling. 4 Whereas insulin retained its stimulant effect on [3H]‐2‐deoxy‐glucose transport in hypoxia‐stimulated muscle (by 44%; c.p.m. mg−1 h−1: 852±77 vs 1229±75, P<0.01), 3.25 μmol l−1 troglitazone failed to increase glucose transport under hypoxic conditions (789±40 vs 815±28, NS) suggesting that hypoxia and troglitazone address a similar, non‐insulin‐like mechanism. 5 No differences between troglitazone and hypoxia were identified in respective interactions with insulin. 6 Troglitazone acutely stimulated muscle glucose metabolism in a hypoxia/contraction‐like manner, but it remains to be elucidated whether this contributes to the long‐term antidiabetic and insulin enhancing potential in vivo or is to be regarded as an independent pharmacological effect.

Effects of islet amyloid polypeptide on hepatic insulin resistance and glucose production in the isolated perfused rat liver

SummaryThe impact of (pancreatic) islet amyloid polypeptide on glucose metabolism and insulin sensitivity was examined in isolated rat livers perfused in a non-recirculating system. Continuous infusion of 10−7mol/l islet amyloid polypeptide affected neither basal nor glucagon (10−9 mol/l)-stimulated glucose output by livers from fed rats, but it did increase the hepatic cyclic AMP release within 44 min (7.91±12.07 vs control: 0.07±0.03 pmol·100 g body weight−1). The effect of the peptide on the ability of insulin to inhibit glucagon-induced hepatic glycogenolysis was measured in three experimental groups (n = 6). As expected glucagon (7×10−11 mol/l) increased integral hepatic glucose release within 84 min (763.4±161.7 vs −25.7±73.2 μmol · 100 g body weight−1 in the control group, p<0.001), while insulin (100 mU/l) decreased the glucagon-stimulated glucose production (395.2±180.0 μmol·100 g body weight−1, p<0.01). Simultaneous infusion of 10−7 mol/l islet amyloid polypeptide however, was not able to reverse insulin-dependent inhibition of glucagon-stimulated hepatic glucose output (370.0±102.5 μmol·100 g body weight−1, NS) or to enhance lactate-induced gluconeogenesis of livers from 24 h fasted rats (n = 8). The glucose production stimulated by 10−9 mol/l glucagon was slightly greater in islet amyloid polypeptide-pre-treated livers than in a control group without addition of islet amyloid polypeptide (5 min: 3.60±3.36 vs 1.67±1.28 μmol·min−1·100 g body weight−1). These results suggest that islet amyloid polypeptide neither directly affects hepatic glycogenolysis nor causes insulin resistance to hormone-sensitive glucose production, but may increase the size of the hepatic glycogen pool by enhancing gluconeogenesis.

Diabetes mellitus – Definition, Klassifikation und Diagnose

ZusammenfassungDiabetes mellitus bezeichnet eine Gruppe von heterogenen Erkrankungen, deren gemeinsamer Befund die Erhöhung der Blutglukose ist. Die gegenwärtigen Klassifikationen von Diabetes mellitus Typ 1–4 werden beschrieben und die wesentlichen Merkmale von Typ 1 und Typ 2 Diabetes werden zur besseren Unterscheidung dieser Diabetestypen gegenübergestellt. Darüber hinaus werden die Kriterien für die korrekte biochemische Diagnose unter Nüchtern-Bedingungen und im oralen Glukosetoleranz-Test sowie die Anwendung des Hämoglobin A1c (HbA1c) zusammengefasst. Diese Daten bilden die Grundlage der Empfehlungen der Österreichischen Diabetes-Gesellschaft für die klinische Praxis der Diabetesbehandlung.SummaryDiabetes mellitus comprises of a group of heterogeneous disorders, which have an increase in blood glucose concentrations in common. The current classifications for diabetes mellitus type 1–4 are described and the main features of type 1 and type 2 diabetes are compared to allow for better discrimination between these diabetes types. Furthermore, the criteria for the correct biochemical diagnosis during fasting and oral glucose tolerance tests as well as the use of hemoglobin A1c (HbA1c) are summarized. These data form the basis of the recommendations of the Austrian Diabetes Association for the clinical praxis of diabetes treatment.