Mette Axelsen

Postprandial hypertriglyceridemia and insulin resistance in normoglycemic first-degree relatives of patients with type 2 diabetes.

Microangiopathy and, in particular, macroangiopathy contribute to excess morbidity and early death in patients with type 2 diabetes (1). At diagnosis, patients with type 2 diabetes have a three- to fourfold greater risk for cardiovascular disease than nondiabetic persons (2, 3); in addition, approximately 40% have evidence of macroangiopathy (4). Therefore, diabetes may be only one of the underlying risk factors for macroangiopathic complications. Several factors associated with type 2 diabetes can be noted years before diagnosis, including decreased first-phase insulin secretion (5, 6) and an impaired metabolic effect of insulin (insulin resistance) (5, 7-9). Risk factors for macroangiopathy in patients with type 2 diabetes include an elevated fasting triglyceride level; a low high-density lipoprotein (HDL) cholesterol level; and accumulation of small, dense, low-density lipoprotein (LDL) particles, which are atherogenic and easily oxidized (10). More researchers now recognize that postprandial handling of triglyceride-rich lipoproteins is important for the propensity for atherosclerosis (10-12). Elevated postprandial triglyceride levels have been seen in persons with fasting hypertriglyceridemia (10, 12), persons who smoke (13, 14), and persons with type 2 diabetes (10). Although genetic predisposition for type 2 diabetes is associated with insulin resistance and impaired glucose disposal, fasting lipid levels usually remain normal at this early stage (8, 15). We assessed insulin sensitivity and postprandial triglyceride response in healthy first-degree male relatives of patients with type 2 diabetes and a group of carefully matched controls who had no known genetic predisposition for diabetes. Methods Participants Participants were recruited by advertisements in a local newspaper. Criteria for inclusion in our study were both parents or one parent and a sibling with type 2 diabetes; male sex (to exclude variation in insulin sensitivity during the menstrual cycle); normal glucose tolerance (16); a fasting triglyceride concentration less than 1.7 mmol/L; no evidence of hypertension, endocrine disease, or metabolic disease; and not smoking. The control group consisted of persons who did not have a known family history of diabetes but fulfilled the remaining criteria. Relatives and controls were pairwise matched for the following variables, expressed as mean SD: age (34 5 years compared with 34 4 years), body mass index (24.5 2.4 kg/m2 compared with 24.6 2.6 kg/m2), waist-to-hip ratio (0.89 0.07 compared with 0.88 0.05), and degree of physical activity (as assessed by interview). Thirteen persons who had two first-degree relatives with type 2 diabetes and 13 persons with no known family history of type 2 diabetes were included in the study. All participants gave informed consent, and the protocol was approved by the ethical committee of Gteborg University. Oral Glucose Tolerance Test All participants had a 75-g oral glucose tolerance test. Insulin Sensitivity Insulin sensitivity was measured by using the euglycemic clamp technique and insulin infusion rates of 10 mU/m2 body surface min -1 and 60 mU/m2 body surface min -1, as described in detail elsewhere (17). Insulin sensitivity was measured by using the rate of glucose infusion during steady-state hyperinsulinemia; this rate is expressed as glucose utilization (mg/kg lean body mass min -1). The insulin sensitivity index represents sensitivity in relation to the prevailing plasma insulin concentration. Lean body mass was calculated from measurements of naturally occurring potassium 40 in a whole-body counter. Meal Tolerance Test The 6-hour postprandial response to a standardized, mixed-meal test was determined as previously described (13) after the participants had fasted overnight. The energy content of the meal was 919 kcal (3.8 MJ); 33 g (14% of energy) were derived from protein, 51 g (49% of energy) were derived from fat, and 83 g (36% of energy) were derived from carbohydrates. The meal contained 30 g of saturated fat, 15 g of monounsaturated fat, and 3 g of polyunsaturated fat. Arterialized venous blood samples were collected from a heated forearm at the times indicated in the Figure for assessment of glucose, insulin, free fatty acids, and triglycerides. Postprandial lipoprotein and hepatic lipase activities were determined 6 hours before and 15 minutes after an intravenous injection of heparin, 100 U/kg of body weight (Lvens, Ballerup, Denmark). Figure. Metabolic variables during a meal tolerance test in 13 first-degree relatives of patients with type 2 diabetes ( white circles ) and 13 controls ( black circles ). A. B. C. D. P Blood Chemistry Glucose, insulin, and free fatty acid levels were determined as previously reported (17); other lipid levels were determined with an automated Cobas Mira analyzer (Hoffman-LaRoche, Basel, Switzerland). High-density lipoprotein cholesterol levels were measured by using the phosphotungstic acid-magnesium chloride precipitation method. Lipoprotein and hepatic lipase activities were determined as previously reported (17). Statistical Analysis Data were analyzed as individual values and as the area under the curve above zero or as the incremental area under the curve above baseline. Two-tailed values of statistical significance were evaluated by using the Student paired t-test. A P value less than 0.050 was considered statistically significant. Correlations were determined by using the Spearman rank test. StatView 4.5 (Abacus Concepts, Inc., Berkeley, California) was used for all statistical calculations. Role of the Funding Sources The funding sources were not involved in the collection, analysis, or interpretation of the data or in the decision to submit the manuscript for publication. Results The detailed results of the metabolic tests are shown in the Table. Table. Metabolic Variables in First-Degree Relatives of Patients with Type 2 Diabetes and in Controls Oral Glucose Tolerance Test The glucose and insulin concentrations during the oral glucose tolerance test were similar in relatives and controls. All participants had normal glucose tolerance. Insulin Sensitivity At the low insulin infusion rate, relatives had lower insulin sensitivity than controls when the euglycemic clamp was used (P=0.006). The difference at the high insulin infusion rate, however, was of borderline significance (P=0.051). Meal Tolerance Test Glucose concentrations before the meal (P=0.036) and 1 hour after the meal (P=0.039) were slightly but significantly higher in relatives than in controls (Figure, part A). Relatives had higher postprandial insulin levels 3 and 4 hours after the meal (Figure, part B). However, because of the variations, differences in the total 6-hour area under the curve and the incremental area under the curve for glucose and insulin during the meal tolerance test were not statistically significant (Table). Fasting triglyceride concentrations before the meal tolerance test were similar in relatives and controls (Table). However, the postprandial response, expressed as the 6-hour incremental area under the curve for triglycerides, was significantly increased by 50% in relatives (P=0.037) (Figure, part C). Relatives and controls had similar fasting concentrations before the meal; however, free fatty acid levels were 50% higher in relatives 1 hour after the meal (P=0.030) (Figure, part D). Fasting total cholesterol levels and HDL cholesterol levels did not differ significantly between the groups. Basal and heparin-released plasma lipase activities, assessed in 11 matched participants, were also similar (Table). Insulin sensitivity was significantly and negatively correlated to the fasting triglyceride concentrations (r s =0.52 [95% CI, 0.76 to 0.15]; P=0.011) and the postprandial triglyceride response (r s =0.46 [95% CI, 0.72 to 0.07]; P=0.026). The fasting HDL cholesterol levels were also negatively correlated to the fasting triglyceride concentrations (r s =0.60 [95% CI, 0.80 to 0.28]; P=0.003) and the postprandial triglyceride response (r s =0.44 [95% CI, 0.71 to 0.07]; P=0.027). Discussion In our study, male normoglycemic first-degree relatives of patients with type 2 diabetes exhibited an increased postprandial triglyceride response to a mixed meal, despite having normal fasting triglyceride levels. Because the relatives were carefully matched to the control group for potential confounding factors, such as sex, age, body mass index, and waist-to-hip ratio, the data suggest that the differences in postprandial triglyceride metabolism were caused by an inherited defect. This defect is probably linked to insulin resistance in the relatives. An increased and prolonged postprandial triglyceride response represents an atherogenic profile that is therefore present long before fasting hypertriglyceridemia or glucose intolerance becomes evident. As insulin resistance becomes exacerbated and free fatty acid levels become elevated by obesity (7), smoking (17), or an inherent progression to impaired glucose tolerance, the dyslipidemic features of the insulin resistance syndrome (that is, elevated fasting triglyceride levels and decreased HDL cholesterol levels) are consistently seen. The relation between postprandial lipid intolerance and fasting hypertriglyceridemia is well established (10, 12). The idea that atherosclerosis is linked to postprandial lipid metabolism was introduced by Zilversmit (11) approximately 20 years ago. Postprandial lipemia consists of a heterogeneous group of triglyceride-rich particles of different compositions and origins. It is not yet clear which lipoprotein particle or particles are related to the type of postprandial hyperlipidemia that is the major risk factor for coronary artery disease. However, evidence is accumulating that small chylomicrons; remnants of very-low-density lipoprotein (VLDL) particles; and easily oxidized small dense LDL particles are atherogenic (10, 12). In addition, in o

Low cellular IRS 1 gene and protein expression predict insulin resistance and NIDDM.

We examined the gene and protein expression of IRS 1 (insulin receptor substrate 1) in adipocytes from two groups of healthy individuals with an increased propensity for non‐insulin‐dependent diabetes mellitus (NIDDM): those with two first‐degree relatives with diabetes and another group with massive obesity. A low expression of IRS 1(<50% of the matched control group) was seen in «30% of both groups and these individuals were characterized by insulin resistance and its hallmarks: higher levels of insulin, glucose, and triglycerides. Two individuals with previously unknown NIDDM were diagnosed and both had low IRS 1 expression. Low IRS 1 protein expression was associated with low mRNA levels but not with the common Gly972Arg polymorphism of the IRS 1 gene. Taken together, our present and previous findings show that a low expression of IRS 1 in fat cells predicts insulin resistance and NIDDM. Furthermore, they support the likelihood that an impaired transcriptional activation may play a key role in the pathogenesis of NIDDM.—Carvalho, E., Jansson, P.‐A., Axelsen, M., Eriksson, J. W., Huang, X., Groop, L., Rondinone, C., Sjostrom, L., Smith, U. Low cellular IRS 1 gene and protein expression predict insulin resistance and NIDDM. FASEB J. 13, 2173–2178 (1999)

Lipid intolerance in smokers

Abstract. Objectives. Smokers have recently been shown to be insulin resistant and to exhibit several characteristics of the insulin resistance syndrome (IRS). In this study, we assessed fasting and postprandial lipid levels in healthy, normolipidaemic, chronic smokers and a matched group of non‐smoking individuals.

Breakfast glycaemic response in patients with type 2 diabetes : Effects of bedtime dietary carbohydrates

Objectives: Bedtime carbohydrate (CHO) intake in patients with type‐2 diabetes may improve glucose tolerance at breakfast the next morning. We examined the ‘overnight second‐meal effect’ of bedtime supplements containing ‘rapid’ or ‘slow’ CHOs.Design: Randomized cross‐over study with three test‐periods, each consisting of two days on a standardized diet, followed by a breakfast tolerance test on the third morning.Setting: The Lundberg Laboratory for Diabetes Research, Sahlgrenska University Hospital, Göteborg, Sweden.Subjects: Sixteen patients with type 2 diabetes on oral agents and/or diet.Interventions: Two different bedtime (22.00 h) CHO supplements (0.46 g available CHO/kg body weight) were compared to a starch‐free placebo (‘normal’ food regimen). The CHOs were provided as uncooked cornstarch (slow‐release CHOs) or white bread (rapid CHOs).Results: On the mornings after different bedtime meals we found similar fasting glucose, insulin, free fatty acid and lactate levels. However, the glycaemic response after breakfast was 21% less after uncooked cornstarch compared to placebo ingestion at bedtime (406±46 vs 511±61 mmol min 1−1, P<0.01). In contrast, it did not differ when the evening meal consisted of white bread (451±57 mmol min 1−1) compared to placebo. According to an in vitro analysis, uncooked cornstarch contained ∼4 times more slowly digestible starch as compared to white bread.Conclusions: A bedtime meal providing uncooked cornstarch improved breakfast tolerance the next morning while, in contrast, this was not found following a bedtime meal of white bread. The results are consistent, therefore, with the concept that an increased intake of slowly digestible carbohydrates exert an overnight second‐meal effect in patients with type 2 diabetes.Sponsorship: This study was supported by grants from the Swedish Medical Research Council (project 3506) and the Ingabritt and Arne Lundberg Foundation.

Children under the age of seven with diabetes are increasing their cardiovascular risk by their food choices

Early‐onset diabetes increases the risk of cardiovascular disease. This study examined the eating habits of children under 7 years of age with diabetes to see whether their diet increased that risk even further.

No acute effect of nateglinide on postprandial lipid and lipoprotein responses in subjects at risk for type 2 diabetes

To study the acute effect of nateglinide, an insulinotropic agent, on the postprandial triglyceride and lipoprotein responses in subjects at risk for type 2 diabetes.

Eating habits and physical activity: Health in Sweden: The National Public Health Report 2012. Chapter 8.

Although eating habits in Sweden have largely deteriorated since 1980, some improvements have been observed in the most recent years. Between 1980 and 2010, the consumption of sweets rose from 10 t ...

Sociodemographic determinants and health outcome variation in individuals with type 1 diabetes mellitus : A register-based study

Background Socioeconomic status, origin or demographic attributes shall not determine the quality of healthcare delivery, according to e.g. United Nations and European Union rules. Health equity has been defined as the absence of systematic disparities and unwarranted differences between groups defined by differences in social advantages. A study was performed to investigate whether this was applicable to type 1 diabetes mellitus (T1D) care in a setting with universal, tax-funded healthcare. Methods This retrospective registry-study was based on patient-level data from individuals diagnosed with T1D during 2010–2011 (n = 16,367) in any of seven Swedish county councils (covering ~65% of the Swedish population). Health equity in T1D care was analysed through multivariate regression analyses on absolute HbA1c level at one-year follow-up, one-year change in estimated glomerular filtration rate (eGFR) and one-year change in cardiovascular risk score, using selected sociodemographic dimensions as case-mix factors. Results Higher educational level was consistently associated with lower levels of HbA1c, and so was being married. Never married was associated with worse eGFR development, and lower educational level was associated with higher cardiovascular risk. Women had higher HbA1c levels than men, and glucose control was significantly worse in patients below the age of 25. Conclusion Patients’ sociodemographic profile was strongly associated with absolute levels of risk factor control in T1D, but also with an increased annual deterioration in eGFR. Whether these systematic differences stem from patient-related problems or healthcare organisational shortcomings is a matter for further research. The results, though, highlight the need for intensified diabetes management education and secondary prevention directed towards T1D patients, taking sociodemographic characteristics into account.

Cephalic phase of insulin secretion in response to a meal is unrelated to family history of type 2 diabetes

The pre-absorptive cephalic phase of insulin secretion is elicited during the first ten min of a meal and before glucose levels rise. Its importance for insulin release during the post-absorptive phase has been well documented in animals but its presence or importance in man has become increasingly controversial. We here examined the presence of an early cephalic phase of insulin release in 31 well matched individuals without (n = 15) or with (n = 16) a known family history of type 2 diabetes (first-degree relatives; FDR). We also examined the potential differences in individuals with or without impaired fasting (IFG) and impaired glucose tolerance (IGT). We here demonstrate that a cephalic phase of insulin secretion was present in all individuals examined and without any differences between control persons and FDR or IFG/IGT. However, the overall importance of the cephalic phase is conjectural since it was unrelated to the subsequent post-absorptive insulin release or glucose tolerance. One of the best predictors of the incremental cephalic phase of insulin release was fasting insulin level and, thus, a relation to degree of insulin sensitivity is likely. In conclusion, an early pre-absorptive and cephalic phase of insulin release is robustly present in man. However, we could not document any relation to family history of Type 2 diabetes nor to the post-absorptive phase and, thus, confirm its importance for subsequent degree of insulin release or glucose tolerance.