Jens Friis Bak

Regional differences in triglyceride breakdown in human adipose tissue : effects of catecholamines, insulin, and prostaglandin E2

Regional variation of adipose tissue triglyceride breakdown (lipolysis) has been suggested to play a role for the health consequences of some forms of obesity. Thus, in the present study we investigated the regulation of lipolysis in isolated adipocytes obtained from different fat depots in females. Intra-abdominal adipose tissue (omental) and subcutaneous abdominal adipose tissue were obtained from the same individuals undergoing abdominal surgery (n = 9); in addition, adipocytes from the subcutaneous gluteal region (n = 12) and from mammary adipose tissue (n = 5) were investigated. The lipolytic/antilipolytic properties of epinephrine (EPI), insulin, clonidine, and prostaglandin E2 (PGE2) were investigated. The most prominent observation was that EPI had none or only minor lipolytic effect in adipocytes from the subcutaneous regions, but significantly enhanced lipolysis by approximately 500% in omental adipocytes (P less than .001). In the presence of the alpha 2-adrenergic antagonist, yohimbine, EPI had similar stimulatory effects (fourfold to fivefold) in all fat depots. The antilipolytic compounds, insulin and clonidine, had greatly reduced antilipolytic properties in omental adipocytes as compared with subcutaneous adipocytes (P less than .01 and P less than .05, respectively). On the other hand, PGE2 had similar antilipolytic properties in adipocytes from the various depots. In conclusion, we found great regional variation in the regulation of lipolysis. Particularly, EPI was much more lipolytic in omental adipocytes than in subcutaneous adipocytes, mainly due to an enhanced functional alpha 2-receptor activity in subcutaneous adipocytes. These in vitro data suggest that free fatty acids (FFA) are more readily mobilized from omental adipose tissue than from subcutaneous adipose tissue.

Abdominal obesity is associated with insulin resistance and reduced glycogen synthase activity in skeletal muscle

Insulin resistance is commonly associated with obesity. The present study was performed to investigate the relative importance of total fat mass versus localization of adipose tissue in insulin-stimulated glucose disposal (Rd) and skeletal muscle glycogen synthase (GS) activity in obese individuals. Twenty obese women with an average body mass index (BMI) of 37.8 +/- 1.3 kg/m2 and a waist to hip ratio (WHR) ranging from 0.78 to 1.02 were examined during basal conditions and following hyperinsulinemia (hyperinsulinemic euglycemic clamp). To accurately determine body composition, the following three methods were used: anthropometric measurements, dual-energy x-ray absorptiometry scanning (DEXA-scan), and bioelectric impedance measurements. In addition, indirect calorimetry and muscle biopsy were performed. Insulin-stimulated glucose Rd was negatively correlated with WHR (R = -.52, P < .025) whereas there were no correlations with BMI or percent fat (R = .16, NS and R = .16, NS, respectively). Furthermore, a negative correlation between WHR and insulin stimulation of GS activity in skeletal muscle was found (R = -.62, P < .005). In contrast, BMI and percent fat were not correlated with the insulin effect on GS activity in skeletal muscle (R = .34, NS and R = -.35, NS, respectively). The concentration of nonesterified fatty acids (NEFA) during hyperinsulinemia was strongly correlated with WHR and abdominal localization of adipose tissue (determined by DEXA-scan; R = .60, P < .005 and R = .60, P < .007, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Diabetes prevalence and quality of diabetes care among Lebanese or Turkish immigrants compared to a native Danish population.

OBJECTIVES To describe Type 2 diabetes prevalence and care among Turkish (T) and Lebanese (L) immigrants as compared to native Danes (DK) in the county of Aarhus. METHOD Data from The National Health Service Registry, The Regional Laboratory Database and The Danish National Hospital Registry were collected from 2000 through 2003 to identify and describe known diabetes in a background population of 244.426 citizens in the age group of 40-70 years living in the County of Aarhus. RESULTS The age-standardised prevalence of Type 2 diabetes was 3.6% (DK), 18.9% (L) and 19.8% (T). In 2003, HbA1c was measured at least once in 84% (DK), 87% (L) and 83% (T) of the patients. In 2003, 72% (DK), 53% (L) and 51% (T) had an HbA1c <8% (p<0.05) and less than 50% of all groups had a total-cholesterol <5.0 mmol/l. In 39% (DK), 35% (L) and 37% (T) of the patients, no examination for retinopathy was registered during the period of 2000-2003. A cardiovascular diagnosis was registered in 27% (DK), 32% (L) and 33% (T) of the patients (p=NS). CONCLUSION Compared to native Danes, Lebanese and Turkish immigrants had a much higher prevalence of Type 2 diabetes and worse glycaemic regulation. The routine monitoring of diabetes care for native Danes, Lebanese or Turkish immigrants were similar. Overall, diabetes care is not satisfactory neither for native Danes, nor Lebanese or Turkish immigrants.

Epinephrine stimulates human muscle lipoprotein lipase activity in vivo

Lipoprotein lipase (LPL) is involved in lipoprotein metabolism and nutrient partitioning in both adipose tissue and skeletal muscle, and LPL activity is regulated by various hormones and the nutritional state. However, the action of catecholamines has not been thoroughly investigated in humans. Therefore, the effects of exogenous epinephrine on skeletal muscle LPL (SM-LPL) activity and whole-body lipid oxidation were studied. Muscle biopsies were obtained from eight healthy subjects before, during, and after epinephrine infusion. Somatostatin was infused to suppress endogenous insulin production and insulin was infused at a constant rate to maintain basal insulin levels throughout the study. After an equilibrium period (120 minutes), epinephrine (0.05 microg/kg/min) was infused for another 120 minutes. Epinephrine stimulated SM-LPL activity by 21.8%+/-6.8% above basal levels from 1.44+/-0.25 to 1.69+/-0.28 micromol free fatty acid (FFA)/h/g muscle (P<.02), increased plasma FFA 270% from 0.147 to 0.544 mmol/L (P<.05), and increased lipid oxidation 45% from 4.37 to 6.36 mg/kg/min (P<.05). The increase in SM-LPL activity was positively correlated with the increase in whole-body lipid oxidation (R=.75, P<.05). Finally, lipid oxidation and SM-LPL activity were negatively correlated with whole-body glucose oxidation. Overall, the results demonstrate that epinephrine is able to stimulate SM-LPL activity in humans, and thus may have opposite effects on adipose tissue and SM-LPL activity.

Kinetics of insulin binding and kinase activity of the partially purified insulin receptor from human skeletal muscle

The kinetics of insulin binding and kinase activity of soluble, partially purified insulin receptors from human skeletal muscle are considered. An equilibrium for insulin binding was obtained within 2 h at 37 degrees C. At lower temperatures the equilibrium for insulin binding was less clearly defined. Dissociation of 125I-labelled insulin was incomplete unless an excess amount of unlabelled insulin was added. Insulin-stimulatable autophosphorylation of the 95 kDa subunit was verified by gel electrophoresis. The kinase activity was measured with the synthetic polypeptide poly(Glu-Tyr(4:1] as a phosphoacceptor. The insulin receptor kinase activity correlated significantly (r = 0.92, P less than 0.0001) to the concentration of high-affinity insulin binding sites in the eluate. Autophosphorylation of the insulin receptor was necessary for the activation of the receptor kinase. When activated the receptor kinase activity was stable for at least 60 min at 21 degrees C with a pH optimum of approx. 7.8, similar to the pH optimum for insulin binding. The non-ionic detergent Triton X-100 inhibited the sensitivity of the receptor kinase to insulin. Insulin stimulated the Vmax of the kinase reaction about 3-fold, decreased the Km for ATP from 35 +/- 5 microM (mean +/- S.E.) to 8 +/- 1 microM (P less than 0.02) and induced a positive cooperativity to ATP with an increase in the Hill coefficient from 1.00 +/- 0.02 to 1.37 +/- 0.07 (P less than 0.05). According to the Hill plots, insulin itself showed no cooperativity with respect to receptor binding or kinase activation.

Insulin action and insulin secretion in identical twins with MODY: evidence for defects in both insulin action and secretion

To evaluate the pathogenetic mechanisms responsible for development of diabetes in the genetically inherited disease maturity-onset diabetes of the young (MODY), we have investigated a pair of identical twins (19 yr old) from a MODY family. One twin had nondiabetic fasting plasma glucose values but impaired glucose tolerance (IGT), whereas the other suffered from frank diabetes (fasting plasma glucose 12.5 mM). Differences in insulin secretion pattern and/or insulin action between the twins is supposed to be responsible for development of hyperglycemia in MODY. On the other hand, identical defects in insulin secretion and action in the twins may point to the primary genetic defect in MODY. Therefore, our aim was to investigate insulin secretion and insulin action in the twins to find these differences and similarities. We found that fasting plasma insulin and C-peptide values were slightly increased in the twins, whereas the responses of insulin and C-peptide to oral glucose tolerance tests (OGTT) and meals were similar in the twins and within normal range. The insulin responses to OGTT were, however, lower than expected from the glucose values, indicating a β-cell defect. Despite elevated plasma insulin levels, basal hepatic glucose output (HGO) was normal in the IGT twin but increased by 75% in the diabetic twin. The maximally inhibitory effect of insulin on HGO, when estimated at euglycemia, was normal in the IGT twin but reduced by 60% in the diabetic twin. Furthermore, the maximal insulin-mediated glucose uptake in peripheral tissues was reduced by 40% in the diabetic twin. lular defect that is responsible for the insulin resistance appears to be a reduced cellular insulin binding and, in surplus, a postreceptor defect in glucose metabolism in the diabetic twin. These data indicate that a cellular defect in insulin action at the postreceptor level may be responsible for the progression from a state of IGT to frank diabetes, whereas the genetic defect in MODY may be localized to the β-cells. A primary insulin-receptor defect, however, cannot be excluded.

Effects of sulfonylureas on adipocyte and skeletal muscle insulin action in patients with non-insulin-dependent diabetes mellitus

The effect of glibenclamide treatment on insulin action in isolated fat cells was studied in eight moderately obese patients with non-insulin-dependent diabetes mellitus (NIDDM). Insulin receptor binding and the effect of insulin on glucose transport and lipogenesis were determined before and after 3 months of glibenclamide therapy. At the end of the treatment period, mean daytime plasma glucose concentrations were reduced (10.8 +/- 0.4 versus 7.0 +/- 0.3 mmol/L, p less than 0.001) whereas mean daytime plasma insulin level was increased (40 +/- 12 versus 71 +/- 9 mU/L, p less than 0.001). Adipocyte insulin receptor binding as well as basal glucose transport and metabolism were unaffected by drug treatment. In contrast, insulin-stimulated glucose transport and lipogenesis were both significantly enhanced (p less than 0.05). These findings are comparable to those of another study involving seven moderately obese subjects with NIDDM who had biopsies of the lateral vastus muscle taken for measurement of insulin receptor function and glycogen synthase activity before and during 2 months of gliclazide treatment. In that study insulin receptors purified with wheatgerm agglutinin showed unchanged insulin binding and receptor kinase activity. Moreover, gliclazide had no impact on maximal glycogen synthase activity. However, under physiologic hyperinsulinemic conditions gliclazide therapy was associated with an increased sensitivity of glycogen synthase for its allosteric activation by glucose-6-phosphatase (p less than 0.04). In conclusion, sulfonylurea treatment of NIDDM enhances insulin-stimulated peripheral glucose utilization in part through a potentiation of insulin action on adipose tissue glucose transport and lipogenesis and skeletal muscle glycogen synthase.

Gliclazide and insulin action in human muscle

Sulfonylureas are widely used drugs in the treatment of NIDDM when diet treatment is unsuccessful. In addition to their pancreatic effects sulfonylureas have been reported to have insulin-like and insulin-potentiating actions in vitro with respect both to glucose transport and glycogen synthase activation in isolated adipocytes and hepatocytes from rats. Glycogen synthesis in muscle accounts for the major part of non-oxidative glucose metabolism during insulin stimulation. Treatment with gliclazide of patients with NIDDM has been shown to be associated with a potentiation of both insulin-mediated glucose disposal and insulin-stimulated glycogen synthase activity in skeletal muscle. Muscle insulin receptor binding or insulin receptor kinase activity was shown not to be affected by gliclazide treatment. Whether the improved insulin sensitivity and improved insulin action on skeletal muscle glycogen synthase during gliclazide treatment is due to a direct or an indirect action of the drug is discussed.

Impaired Glycogen Synthesis of Skeletal Muscle in Patients With Insulin-Resistant Diabetes Mellitus

T he etiological basis of the common form of non-insulin-dependent diabetes mellitus (NIDDM) is unknown but studies of high-risk populations emphasize a complex interplay of yet unidentified genetic susceptibility and nongenetic risk factors like sedentary life-style, obesity, fetal malnutrition, and aging.’ Based on the broad spectrum of NIDDM phenotypes, it is unlikely, however, that the genetic susceptibility is similar in all cases of NIDDM, and it may be hypothesized that the inherited component of NlDDM encompasses separate but interrelated risk genes for pancreatic B-cell dysfunction, insulin resistance, dyslipidemia, and android obesity. It is unknown if the nongenetic risk factors per se in some cases can cause NIDDM, but in most cases they are thought only to promote the disorder in genetically predisposed individuals. The pathophysiology of the overt NlDDM state is characterized by two dominant features: impaired insulin secretion and impaired whole-body insulin sensitivity.’ For years, controversy has existed whether impaired insulin secretion or insulin resistance is the triggering event leading to NIDDM. Much of tl

Increased insulin binding is not involved in the improved insulin effectiveness of gestational diabetics after hypoenergetic dieting

s controversy is due to studies of individuals with impaired glucose tolerance (IGT) or established NIDDM. Inclu-