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Open access

Bledar Daka, Thord Rosen, Per Anders Jansson, Lennart Råstam, Charlotte A Larsson, and Ulf Lindblad

Objectives

Obesity is associated with low levels of sex hormone-binding globulin (SHBG). While the reason is not fully understood, we aimed to study the association between serum insulin and levels of SHBG in a random population.

Design and methods

Between 2001 and 2005, a random sample of 2816 participants aged 30–74 years were enrolled in a cross-sectional survey in the South-west of Sweden. Fasting blood samples were collected and an oral glucose tolerance test (OGTT) was conducted in all subjects without known diabetes. Diabetes mellitus was defined according to criteria from WHO, and clinical characteristics were used to discriminate between type 1 (T1D) and type 2 diabetes (T2D). Analyses of SHBG were successful in 2782 participants (98%), who thus constituted the current study population.

Results

We found significant inverse association between levels of SHBG and fasting serum insulin in both genders (men: β=−0.090, P=0.001; women: β=−0.197, P<0.001), which was independent of differences in age and BMI. The associations remained when also differences in fasting plasma glucose were accounted for (men: β=−0.062, P=0.022; women: β=−0.176, P≤0.001). Subjects with T1D exhibited higher levels of SHBG than both T2D (men: δ=15.9 nmol/l, P<0.001; women: δ=71.1 nmol/l, P<0.001) and non-diabetic subjects (men: δ=15.1 nmol/l, P<0.001; women: δ=72.9 nmol/l, P<0.001) independent of age, BMI and fasting glucose levels.

Conclusion

These findings are consistent with high levels of SHBG in T1D, and correspondingly low levels in T2D subjects, suggesting an inhibitory effect of insulin on the SHBG production in the liver.

Open access

Magdalene K Montgomery and Nigel Turner

Mitochondrial dysfunction has been implicated in the development of insulin resistance (IR); however, a large variety of association and intervention studies as well as genetic manipulations in rodents have reported contrasting results. Indeed, even 39 years after the first publication describing a relationship between IR and diminished mitochondrial function, it is still unclear whether a direct relationship exists, and more importantly if changes in mitochondrial capacity are a cause or consequence of IR. This review will take a journey through the past and summarise the debate about the occurrence of mitochondrial dysfunction and its possible role in causing decreased insulin action in obesity and type 2 diabetes. Evidence is presented from studies in various human populations, as well as rodents with genetic manipulations of pathways known to affect mitochondrial function and insulin action. Finally, we have discussed whether mitochondria are a potential target for the treatment of IR.

Open access

Melinda Kertész, Szilárd Kun, Eszter Sélley, Zsuzsanna Nagy, Tamás Kőszegi, and István Wittmann

Background

Type 2 diabetes is characterized, beyond the insulin resistance, by polyhormonal resistance. Thyroid hormonal resistance has not yet been described in this population of patients. Metformin is used to decrease insulin resistance, and at present, it is assumed to influence the effect of triiodothyronine, as well.

Methods

In this open-label, pilot, hypothesis-generating, follow-up study, 21 patients were included; all of them were euthyroid with drug naïve, newly diagnosed type 2 diabetes. Before and after 4 weeks of metformin therapy, fructosamine, homeostasis model assessment for insulin resistance (HOMA-IR), thyroid hormones, T3/T4 ratio, and TSH, as well as blood pressure and heart rate using ambulatory blood pressure monitor were measured. We also conducted an in vitro study to investigate the possible mechanisms of T3 resistance, assessing T3-induced Akt phosphorylation among normal (5 mM) and high (25 mM) glucose levels with or without metformin treatment in a human embryonal kidney cell line.

Results

Metformin decreased the level of T3 (P < 0.001), the ratio of T3/T4 (P = 0.038), fructosamine (P = 0.008) and HOMA-IR (P = 0.022). All these changes were accompanied by an unchanged TSH, T4, triglyceride, plasma glucose, bodyweight, blood pressure, and heart rate. In our in vitro study, T3-induced Akt phosphorylation decreased in cells grown in 25 mM glucose medium compared to those in 5 mM. Metformin could not reverse this effect.

Conclusion

Metformin seems to improve T3 sensitivity in the cardiovascular system in euthyroid, type 2 diabetic patients, the mechanism of which may be supracellular.

Open access

Selina Mäkinen, Neeta Datta, Yen H Nguyen, Petro Kyrylenko, Markku Laakso, and Heikki A Koistinen

Objectives

Simvastatin use is associated with muscular side effects, and increased risk for type 2 diabetes (T2D). In clinical use, simvastatin is administered in inactive lipophilic lactone-form, which is then converted to active acid-form in the body. Here, we have investigated if lactone- and acid-form simvastatin differentially affect glucose metabolism and mitochondrial respiration in primary human skeletal muscle cells.

Methods

Muscle cells were exposed separately to lactone- and acid-form simvastatin for 48 h. After pre-exposure, glucose uptake and glycogen synthesis were measured using radioactive tracers; insulin signalling was detected with Western blotting; and glycolysis, mitochondrial oxygen consumption and ATP production were measured with Seahorse XFe96 analyzer.

Results

Lactone-form simvastatin increased glucose uptake and glycogen synthesis, whereas acid-form simvastatin did not affect glucose uptake and decreased glycogen synthesis. Phosphorylation of insulin signalling targets Akt substrate 160 kDa (AS160) and glycogen synthase kinase 3β (GSK3β) was upregulated with lactone-, but not with acid-form simvastatin. Exposure to both forms of simvastatin led to a decrease in glycolysis and glycolytic capacity, as well as to a decrease in mitochondrial respiration and ATP production.

Conclusions

These data suggest that lactone- and acid-forms of simvastatin exhibit differential effects on non-oxidative glucose metabolism as lactone-form increases and acid-form impairs glucose storage into glycogen, suggesting impaired insulin sensitivity in response to acid-form simvastatin. Both forms profoundly impair oxidative glucose metabolism and energy production in human skeletal muscle cells. These effects may contribute to muscular side effects and risk for T2D observed with simvastatin use.

Open access

Jothydev Kesavadev, Pradeep Babu Sadasivan Pillai, Arun Shankar, Gopika Krishnan, and Sunitha Jothydev

Objective

To compare the effect of sitagliptin (100 mg) vs glimepiride (1–3 mg) as add-on therapy in Indian type 2 diabetes (T2DM) patients on treatment with insulin and metformin (SWIM study).

Research design and methods

This 24-week, controlled, open-label study randomized T2DM patients (n = 440) receiving a stable dose of metformin and insulin combination therapy to sitagliptin (100 mg) or glimepiride (1–3 mg) as add-on therapy. Baseline HbA1c was ≥7.3% and ≤8.5%. After a 6-week titration period for glimepiride (dose titrated every 2 weeks by 1 mg up to a maximum of 3 mg daily), patients were continued for 18 weeks on their respective tolerable doses of glimepiride (ranging from 1 mg to 3 mg) or sitagliptin (100 mg) along with metformin and insulin.

Results

Greater reductions in HbA1c and TDD of insulin were achieved with sitagliptin compared to glimepiride. HbA1c targets and reductions in TDD were achieved by more patients on sitagliptin than on glimepiride. Reductions in both body weight and BMI were also noted among patients on sitagliptin when compared to those on glimepiride, and more hypoglycemic events occurred with glimepiride treatment than with sitagliptin.

Conclusions

Sitagliptin (100 mg), when compared to glimepiride (1–3 mg), bestowed beneficial effects to T2DM patients in terms of achieving greater glycemic control and also brought significant reductions in total daily dose of insulin required, bodyweight, BMI and hypoglycemic events. Overall, the results suggest that sitagliptin (100 mg) is a superior agent over glimepiride (1–3 mg) as an add-on to insulin–metformin therapy among Asian Indians with T2DM.

Open access

Frederique Van de Velde, Marlies Bekaert, Anja Geerts, Anne Hoorens, Arsène-Hélène Batens, Samyah Shadid, Margriet Ouwens, Yves Van Nieuwenhove, and Bruno Lapauw

Purpose

Obese subjects with nonalcoholic fatty liver disease (NAFLD) are more prone to develop additional metabolic disturbances such as systemic insulin resistance (IR) and type 2 diabetes. NAFLD is defined by hepatic steatosis, lobular inflammation, ballooning and stage of fibrosis, but it is unclear if and which components could contribute to IR.

Objective

To assess which histological components of NAFLD associate with IR in subjects with obesity, and if so, to what extent.

Methods

This cross-sectional study included 78 obese subjects (mean age 46 ± 11 years; BMI 42.2 ± 4.7 kg/m2). Glucose levels were analysed by hexokinase method and insulin levels with electrochemiluminescence. Homeostasis model assessment-estimated insulin resistance (HOMA-IR) was calculated. Liver biopsies were evaluated for histological components of NAFLD.

Results

A positive association between overall NAFLD Activity Score and HOMA-IR was found (r s = 0.259, P = 0.022). As per individual components, lobular inflammation and fibrosis stage were positively associated with HOMA-IR, glucose and insulin levels (P < 0.05), and HOMA-IR was higher in patients with more inflammatory foci or higher stage of fibrosis. These findings were independent of age, BMI, triglyceride levels, diabetes status and sex (all P < 0.043). In a combined model, lobular inflammation, but not fibrosis, remained associated with HOMA-IR.

Conclusion

In this group of obese subjects, a major contributing histological component of NAFLD to the relation between NAFLD severity and IR seems to be the grade of hepatic lobular inflammation. Although no causal relationship was assessed, preventing or mitigating this inflammatory response in obesity might be of importance in controlling obesity-related metabolic disturbances.

Open access

Xiuzhen Zhang, Dan Xu, Ping Xu, Shufen Yang, Qingmei Zhang, Yan Wu, and Fengyi Yuan

Introduction

Metformin has been demonstrated to enhance cardioprotective benefits in type 1 diabetes (T1DM). Although glycemic variability (GV) is associated with increased risk of CVD in diabetes, there is a scarcity of research evaluating the effect of metformin on GV in T1DM.

Objectives

In the present study, the effects of adjuvant metformin therapy on GV and metabolic control in T1DM were explored.

Patients and methods

A total of 65 adults with T1DM were enrolled and subjected to physical examination, fasting laboratory tests, and continuous glucose monitoring, and subsequently randomized 1:1 to 3 months of 1000–2000 mg metformin daily add-on insulin (MET group, n = 34) or insulin (non-MET group, n = 31). After, baseline measurements were repeated.

Results

The mean amplitude of glycemic excursions was substantially reduced in MET group, compared with non-MET group (–1.58 (–3.35, 0.31) mmol/L vs 1.36 (–1.12, 2.24) mmol/L, P = 0.004). In parallel, the largest amplitude of glycemic excursions (–2.83 (–5.47, –0.06) mmol/L vs 0.45 (–1.29, 4.48) mmol/L, P = 0.004), the s.d. of blood glucose (–0.85 (–1.51, 0.01) mmol/L vs –0.14 (–0.68, 1.21) mmol/L, P = 0.015), and the coefficient of variation (–6.66 (–15.00, 1.50)% vs –1.60 (–6.28, 11.71)%, P = 0.012) all demonstrated improvement in the MET group, compared with the non-MET group. Significant reduction in insulin dose, BMI, and body weight was observed in patients in MET, not those in non-MET group.

Conclusion

Additional metformin therapy improved GV in adults with T1DM, as well as improving body composition and reducing insulin requirement. Hence, metformin as an adjunctive therapy has potential prospects in reducing the CVD risk in patients with T1DM in the long term.

Open access

Alessandro Ciresi, Stefano Radellini, Valentina Guarnotta, Maria Grazia Mineo, and Carla Giordano

Objective

To evaluate the impact of gender on the clinical and metabolic parameters in prepubertal growth hormone deficiency (GHD) children at diagnosis and during GH treatment (GHT).

Design

The data of 105 prepubertal children (61 males, 44 females, mean age 6.8 ± 0.7 years) affected by idiopathic GHD were retrospectively evaluated.

Methods

Body height, BMI, waist circumference (WC), IGF-I, HbA1c, lipid profile, fasting and after-OGTT glucose and insulin levels, insulin sensitivity and secretion indices were evaluated at baseline and after 24 months of GHT.

Results

At baseline, no significant difference was found in all clinical, hormonal and metabolic parameters between males and females. After 24 months of GHT, both males and females showed a significant increase in height (both P < 0.001), BMI (both P < 0.001), WC (P < 0.001 and P = 0.004, respectively), IGF-I (both P < 0.001), fasting glucose (P < 0.001 and P = 0.001, respectively), fasting insulin (both P < 0.001) and Homa-IR (both P < 0.001), with a concomitant significant decrease in insulin sensitivity index (ISI) (both P < 0.001) and oral disposition index (DIo) (P = 0.001 and P < 0.001, respectively). At 24 months of GHT, females showed significantly higher BMI (P = 0.027), lower ISI (P < 0.001) and DIo (P < 0.001), in concomitance with a significant greater change from baseline to 24 months of BMI (P = 0.013), WC (P < 0.001), ISI (P = 0.002) and DIo (P = 0.072), although the latter does not reach statistical significance.

Conclusions

Twenty-four months of GHT in prepubertal children leads to different metabolic outcomes according to gender, with a greater reduction in insulin sensitivity in females, regardless of auxological and hormonal parameters. Therefore, prepubertal GHD females should probably need a more proper monitoring in clinical practice.

Open access

Krzysztof C Lewandowski, Justyna Płusajska, Wojciech Horzelski, Ewa Bieniek, and Andrzej Lewiński

Background

Though insulin resistance (IR) is common in polycystic ovary syndrome (PCOS), there is no agreement as to what surrogate method of assessment of IR is most reliable.

Subjects and methods

In 478 women with PCOS, we compared methods based on fasting insulin and either fasting glucose (HOMA-IR and QUICKI) or triglycerides (McAuley Index) with IR indices derived from glucose and insulin during OGTT (Belfiore, Matsuda and Stumvoll indices).

Results

There was a strong correlation between IR indices derived from fasting values HOMA-IR/QUICKI, r = −0.999, HOMA-IR/McAuley index, r = −0.849 and between all OGTT-derived IR indices (e.g. r = −0.876, for IRI/Matsuda, r = −0.808, for IRI/Stumvoll, and r = 0.947, for Matsuda/Stumvoll index, P < 0.001 for all), contrasting with a significant (P < 0.001), but highly variable correlation between IR indices derived from fasting vs OGTT-derived variables, ranging from r = −0.881 (HOMA-IR/Matsuda), through r = 0.58, or r = −0.58 (IRI/HOMA-IR, IRI/QUICKI, respectively) to r = 0.41 (QUICKI/Stumvoll), and r = 0.386 for QUICKI/Matsuda indices. Detailed comparison between HOMA-IR and IRI revealed that concordance between HOMA and IRI was poor for HOMA-IR/IRI values above 75th and 90th percentile. For instance, only 53% (70/132) women with HOMA-IR >75th percentile had IRI value also above 75th percentile. There was a significant, but weak correlation of all IR indices with testosterone concentrations.

Conclusions

Significant number of women with PCOS can be classified as being either insulin sensitive or insulin resistant depending on the method applied, as correlation between various IR indices is highly variable. Clinical application of surrogate indices for assessment of IR in PCOS must be therefore viewed with an extreme caution.

Open access

Giorgio Bedogni, Andrea Mari, Alessandra De Col, Sofia Tamini, Amalia Gastaldelli, and Alessandro Sartorio

Few data are available on the association between serum lipids and insulin secretion (ISEC) in children. We evaluated the association of triglycerides (TG), HDL cholesterol (HDL-C) and LDL cholesterol (LDL-C) with ISEC in 1150 non-diabetic obese children and adolescents using multivariable robust median regression. The following models were employed: (1) IGI or incAUCR as the ISEC response variable; (2) QUICKI, OGIS, the Stumvoll index or the Matsuda insulin sensitivity index as the insulin sensitivity (ISEN) predictor; (3) TG, HDL-C and LDL-C as the predictors of interest; (4) 120-min glucose, age, sex and body mass index as confounders. LDL-C and TG were not associated with ISEC in any model. In three out of four IGI models, an increase of 1 interquartile range (IQR) of HDL-C was associated with a decrease of median incAUCR ranging from −9 (robust 95% CI −17 to −2) to −8 (−14 to −1) pmol/mmol. In two out of four incAUCR models, an increase of 1 IQR of HDL-C was associated with a decrease of median IGI ranging from −8 (−15 to −1) to −7 (−11 to −2) pmol/mmol. TG and LDL-C are not associated and HDL-C is inversely associated with ISEC in obese children and adolescents.