Jan Erik Henriksen

Decreased insulin activation of glycogen synthase in skeletal muscles in young nonobese Caucasian first-degree relatives of patients with non-insulin-dependent diabetes mellitus.

Insulin resistance in non-insulin-dependent diabetes is associated with a defective insulin activation of the enzyme glycogen synthase in skeletal muscles. To investigate whether this may be a primary defect, we studied 20 young (25 +/- 1 yr) Caucasian first-degree relatives (children) of patients with non-insulin-dependent diabetes, and 20 matched controls without a family history of diabetes. Relatives and controls had a normal oral glucose tolerance, and were studied by means of the euglycemic hyperinsulinemic clamp technique, which included performance of indirect calorimetry and muscle biopsies. Insulin-stimulated glucose disposal was decreased in the relatives (9.2 +/- 0.6 vs 11.5 +/- 0.5 mg/kg fat-free mass per (FFM) min, P less than 0.02), and was due to a decreased rate of insulin-stimulated nonoxidative glucose metabolism (5.0 +/- 0.5 vs 7.5 +/- 0.4 mg/kg fat-free mass per min, P less than 0.001). The insulin-stimulated, fractional glycogen synthase activity (0.1/10 mmol liter glucose-6-phosphate) was decreased in the relatives (46.9 +/- 2.3 vs 56.4 +/- 3.2%, P less than 0.01), and there was a significant correlation between insulin-stimulated, fractional glycogen synthase activity and nonoxidative glucose metabolism in relatives (r = 0.76, P less than 0.001) and controls (r = 0.63, P less than 0.01). Furthermore, the insulin-stimulated increase in muscle glycogen content over basal values was lower in the relatives (13 +/- 25 vs 46 +/- 9 mmol/kg dry wt, P = 0.05). We conclude that the defect in insulin activation of muscle glycogen synthase may be a primary, possibly genetically determined, defect that contributes to the development of non-insulin-dependent diabetes.

Insulin secretion, insulin action, and hepatic glucose production in identical twins discordant for non-insulin-dependent diabetes mellitus.

12 identical twin pairs discordant for non-insulin-dependent diabetes mellitus (NIDDM) were studied for insulin sensitivity (euglycemic insulin clamp, 40 mU/m2 per min), hepatic glucose production (HGP, [3-3H]glucose infusion), and insulin secretion (oral glucose tolerance test and hyperglycemic [12 mM] clamp, including glucagon administration). Five of the nondiabetic twins had normal and seven had impaired glucose tolerance. 13 matched, healthy subjects without a family history of diabetes were included as control subjects. The NIDDM twins were more obese compared with their non-diabetic co-twins. The nondiabetic twins were insulin resistant and had a delayed insulin and C-peptide response during oral glucose tolerance tests compared with controls. Furthermore, the nondiabetic twins had a decreased first-phase insulin response and a decreased maximal insulin secretion capacity during hyperglycemic clamping and intravenous glucagon administration. Nondiabetic twins and controls had similar rates of HGP. Compared with both nondiabetic twins and controls, the NIDDM twins had an elevated basal rate of HGP, a further decreased insulin sensitivity, and a further impaired insulin secretion pattern as determined by all tests. In conclusion, defects of both in vivo insulin secretion and insulin action are present in non- and possibly prediabetic twins who possess the necessary NIDDM susceptibility genes. However, all defects of both insulin secretion and glucose metabolism are expressed quantitatively more severely in their identical co-twins with overt NIDDM.

Twin study of genetic and environmental influences on adult body size, shape, and composition

OBJECTIVE: To investigate the genetic and environmental influences on adult body size, shape, and composition in women and men, and to assess the impact of age.MATERIALS AND METHODS: In this cross-sectional study of 325 female and 299 male like-sex healthy twin pairs, on average 38 y old (18–67 y), we determined zygosity by DNA similarity, and performed anthropometry and bioelectrical impedance analysis of body composition. The contribution to the total phenotypic variance of genetic, common environment, and individual environment was estimated in multivariate analysis using the FISHER program. Further, these variance components were analysed as linear functions of age.RESULTS: In both women and men genetic contributions were significant for all phenotypes. Heritability for body mass index was 0.58 and 0.63; for body fat%, 0.59 and 0.63; for total skinfolds, 0.61 and 0.65; for extremity skinfolds 0.65 and 0.62; for truncal skinfolds, 0.50 and 0.69; for suprailiac skinfolds, 0.49 and 0.48; for waist circumference, 0.48 and 0.61; for hip, 0.52 and 0.58; for lean body mass/height2, 0.61 and 0.56; and for height, 0.81 and 0.69, respectively. There was no strong evidence of common environmental effects under the assumptions of no nonadditive effect. The pattern of age trends was inconsistent. However, when significant there was a decrease in heritability with advancing age.DISCUSSION: These findings suggest that adult body size, shape, and composition are highly heritable in both women and men, although a decreasing tendency is seen with advancing age.

Mediating the effect of self-care management intervention in type 2 diabetes: A meta-analysis of 47 randomised controlled trials

OBJECTIVE To perform a meta-analysis assessing the effects of self-care management interventions in improving glycaemic control in type 2 diabetes by analysing the impact of different study characteristics on the effect size. METHODS A literature search in eight scientific databases up to November 2007 included original studies of randomised controlled trials involving adult patients diagnosed with type 2 diabetes and evaluating a self-care management intervention. RESULTS The 47 included studies yielded 7677 participants. The analysis showed a 0.36% (95% CI 0.21-0.51) improvement in glycaemic control in people who received self-care management treatment. In the univariate meta-regression sample size (effect size 0.42%, p=0.007) and follow-up period (effect size 0.49%, p=0.017) were identified to have significant effect on the effect size in favour of small studies and short follow-up. For type of intervention and duration of intervention there was a non-significant effect on effect size in favour of educational techniques and short interventions. CONCLUSION In type 2 diabetes, there are improvements in glycaemic control in people who receive self-care management treatment with a small advantage to intervention with an educational approach. PRACTICE IMPLICATIONS Further research on frequency and duration of intervention may provide useful information to identify the most effective regime.

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]

Correlations between insulin sensitivity and bone mineral density in non‐diabetic men

Aims To investigate relationships between bone mineral density (BMD), insulin secretion and insulin sensitivity, controlling for body composition, in view of data suggesting that hypoglycaemia leads to decreased osteoblast proliferation and a negative calcium balance and that insulin stimulates osteoblast differentiation and collagen synthesis, with no clear evidence if this response in impaired in insulin resistance.

Low dose spironolactone reduces blood pressure in patients with resistant hypertension and type 2 diabetes mellitus: a double blind randomized clinical trial

Background: The increased risk of cardiovascular morbidity and mortality associated with arterial hypertension is particularly pronounced in patients with type 2 diabetes mellitus. Blood pressure control is, therefore, decisively important but often not sufficiently achieved. Objective: The primary objective of this study was to evaluate the antihypertensive effect of low dose spironolactone added to triple therapy for resistant hypertension in patients with type 2 diabetes measured by ambulatory monitoring. Secondary objectives were to evaluate the effects on glycaemic control and urinary albumin excretion as well as adverse effects. Methods: In a multicentre, double-blind, randomized, placebo-controlled study 119 patients with blood pressure at or above 130/80 mmHg despite triple antihypertensive therapy were included. One tablet of 25 mg spironolactone or placebo was added to previous treatment and increased to two if blood pressure below 130/80 mmHg was not achieved after 4 weeks. Blood pressure was measured by ambulatory monitoring at baseline and after 16 weeks. Results: The study was completed by 112 patients, 57 randomized to spironolactone and 55 to placebo. Average daytime placebo-corrected blood pressure was reduced by 8.9 (4.7–13.2)/3.7 (1.5–5.8) mmHg. Also office blood pressure, night-time, 24-h and pulse pressures were reduced significantly. Urinary albumin/creatinine ratio was significantly reduced in the spironolactone group. Glycaemic control remained unchanged. Hyperkalemia was the most frequent adverse event leading to dose reduction in three cases and discontinuation in one, whereas gynaecomastia was not reported. Conclusion: Low dose spironolactone exerts significant BP and urinary albumin creatinine ratio lowering effects in high-risk patients with resistant hypertension and type 2 diabetes mellitus.

Left Ventricular Diastolic Function in Type 2 Diabetes Mellitus Prevalence and Association With Myocardial and Vascular Disease

Background—Although type 2 diabetes mellitus is a risk factor for developing congestive heart failure, the mechanism leading to heart failure is unclear. We examined the prevalence of left ventricular (LV) systolic and diastolic dysfunction in patients with type 2 diabetes mellitus in relation to vascular function and myocardial perfusion. Methods and Results—A prospective observational study of 305 patients with type 2 diabetes mellitus (diabetes duration, 4.5±5.3 years) referred consecutively to a diabetes clinic were screened for LV systolic and diastolic function by echocardiography. Vascular function was estimated using noninvasive estimation of pulse pressure, carotid arterial compliance, total arterial compliance, and valvulo-arterial impedance. The prevalences of LV diastolic dysfunction and left atrial (LA) volume index >32 mL/m2 were 40% and 32%, respectively. The prevalence of myocardial ischemia on myocardial perfusion scintigraphy was more frequent in patients with grade 2 diastolic dysfunction and LA volume index >32 mL/m2 compared with those having normal or grade 1 diastolic dysfunction (P=0.002) or LA volume index ≤32 mL/m2 (P<0.001), respectively. Predictors of grade 2 diastolic dysfunction and LA dilation were summed stress score on myocardial perfusion scintigraphy, total arterial compliance, and valvulo-arterial impedance, whereas pulse pressure and carotid arterial compliance were not, after adjusting for age, sex, and diabetes duration. On multivariable modeling, summed stress score (P<0.001) and valvulo-arterial impedance (P=0.027) remained predictors of grade 2 diastolic dysfunction, and only summed stress score (P<0.001) was a predictor of LA dilation. Conclusions—Abnormal LV filling is closely associated with abnormal myocardial perfusion on myocardial perfusion scintigraphy, whereas the association of LV filling with vascular function is less prominent. Clinical Trial Registration—The trial has been registered at www.clinicaltrial.gov with Identifier: NCT00298844.Background— Although type 2 diabetes mellitus is a risk factor for developing congestive heart failure, the mechanism leading to heart failure is unclear. We examined the prevalence of left ventricular (LV) systolic and diastolic dysfunction in patients with type 2 diabetes mellitus in relation to vascular function and myocardial perfusion. Methods and Results— A prospective observational study of 305 patients with type 2 diabetes mellitus (diabetes duration, 4.5±5.3 years) referred consecutively to a diabetes clinic were screened for LV systolic and diastolic function by echocardiography. Vascular function was estimated using noninvasive estimation of pulse pressure, carotid arterial compliance, total arterial compliance, and valvulo-arterial impedance. The prevalences of LV diastolic dysfunction and left atrial (LA) volume index >32 mL/m2 were 40% and 32%, respectively. The prevalence of myocardial ischemia on myocardial perfusion scintigraphy was more frequent in patients with grade 2 diastolic dysfunction and LA volume index >32 mL/m2 compared with those having normal or grade 1 diastolic dysfunction ( P =0.002) or LA volume index ≤32 mL/m2 ( P <0.001), respectively. Predictors of grade 2 diastolic dysfunction and LA dilation were summed stress score on myocardial perfusion scintigraphy, total arterial compliance, and valvulo-arterial impedance, whereas pulse pressure and carotid arterial compliance were not, after adjusting for age, sex, and diabetes duration. On multivariable modeling, summed stress score ( P <0.001) and valvulo-arterial impedance ( P =0.027) remained predictors of grade 2 diastolic dysfunction, and only summed stress score ( P <0.001) was a predictor of LA dilation. Conclusions— Abnormal LV filling is closely associated with abnormal myocardial perfusion on myocardial perfusion scintigraphy, whereas the association of LV filling with vascular function is less prominent. Clinical Trial Registration— The trial has been registered at www.clinicaltrial.gov with Identifier: [NCT00298844][1]. Received December 13, 2008; accepted October 20, 2009. # CLINICAL PERSPECTIVE {#article-title-2} [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00298844&atom=%2Fcirccvim%2F3%2F1%2F24.atom

Insulin resistance in skeletal muscles in patients with NIDDM.

Skeletal muscles in patients with non-insulin-dependent diabetes mellitus (NIDDM) are resistant to insulin; i.e., the effect of insulin on glucose disposal is reduced compared with the effect in control subjects. This defect has been found to be localized to the nonoxidative pathway of glucose disposal; hence, the deposition of glucose, as glycogen, is abnormally low. This defect may be inherited, because it is present in first-degree relatives to NIDDM patients two to three decades before they develop frank diabetes mellitus. The cellular defects responsible for the abnormal insulin action in NIDDM patients is reviewed in this article. The paper focuses mainly on convalent insulin signaling. Insulin is postulated to stimulate glucose storage by initiating a cascade of phosphorylation and dephosphorylation events, which results in dephosphorylation and hence activation of the enzyme glycogen synthase. Glycogen synthase is the key enzyme in regulation of glycogen synthesis in the skeletal muscles of humans. This enzyme is sensitive to insulin, but in NIDDM patients it has been shown to be completely resistant to insulin stimulation when measured at euglycemia. The enzyme seems to be locked in the glucose-6-phosphate (G-6-P)-dependent inactive D-form. This hypothesis is favored by the finding of reduced activity of the glycogen synthase phosphatase and increased activity of the respective kinase CAMP-dependent protein kinase. A reduced glycogen synthase activity has also been found in normoglycemic first-degree relatives of NIDDM patients, indicating that this abnormality precedes development of hyperglycemia in subjects prone to develop NIDDM. Therefore, this defect may be of primary genetic origin. However, it does not appear to be a defect in the enzyme itself, but rather a defect in the covalent activation of the enzyme system. Glycogen synthase is resistant to insulin but may be activated allosterically by G-6-P. This means that the defect in insulin activation can be compensated for by increased intracellular concentrations of G-6-P. In fact, we found that both hyperinsulinemia and hyperglycemia are able to increase the G-6-P level in skeletal muscles. Thus, insulin resistance in the nonoxidative pathway of glucose processing can be overcomed (compensated) by hyperinsulinemia and hyperglycemia. In conclusion, we hypothesize that insulin resistance in skeletal muscles may be a primary genetic defect preceding the diabetic state. The cellular abnormality responsible for that may be a reduced covalent insulin activation of the enzyme glycogen synthase. The compensation results in nearnormalization of glycogen synthesis, but the price diabetic subjects must pay to obtain this is hyperglycemia.

Variation in Absorption of NPH Insulin Due to Intramuscular Injection

To evaluate the importance of accidental intramuscular injection of NPH insulin, we measured disappearance rates of 125I-labeled NPH insulin (Protaphane) from subcutaneous and intramuscular injection sites in the thighs of 11 insulin-dependent diabetes mellitus patients. Both subcutaneous and intramuscular absorption rates were measured four times in each patient. NPH insulin was absorbed much faster when given intramuscularly than when given subcutaneously (T50% = 5.3 vs. 10.3 h, P < 0.0001). The intrapatient (day-to-day) coefficient of variation (C.V.) of T50% values (C.V. T50%) for subcutaneously injected NPH insulin in this study, where all injections were guided by ultrasound determination of the subcutaneous fat layer, was 18.4%. Intrapatient variation of absorption was significantly lower for subcutaneously than intramuscularly injected NPH insulin (C.V. T50% = 18.4 vs. 29.8%, P < 0.01) and was also lower than interpatient variation for subcutaneously injected insulin (C.V. T50% = 18.4 vs. 50%, P < 0.0001). The faster absorption rate and shorter duration of action, together with the higher day-to-day variation in absorption, led us to conclude that intramuscular injection of NPH insulin should be avoided.