Lipohypertrophy in Elderly Insulin-Treated Patients With Type 2 Diabetes.

BACKGROUND: The number of older adults with insulin-treated diabetes mellitus (DM) is steadily increasing worldwide. Errors in the insulin injection technique can lead to skin lipohypertrophy (LH), which is the accumulation of fat cells and fibrin in the subcutaneous tissue. While lipohypertrophic lesions/nodules (LHs) due to incorrect insulin injection techniques are very common, they are often flat and hardly visible and thus require thorough deep palpation examination and ultrasonography (US) for detection. Detection is crucial because such lesions may eventually result in poor diabetes control due to their association with unpredictable insulin release patterns. Skin undergoes fundamental structural changes with aging, possibly increasing the risk for LH. We have therefore investigated the effect of age on the prevalence of LHs and on factors potentially associated with such lesions. METHODS: A total of 1227 insulin-treated outpatients with type 2 DM (T2DM) referred to our diabetes centers were consecutively enrolled in the study. These patients underwent a thorough clinical and US evaluation of the skin at injection sites, as previously described, with up to 95% concordance betweenthe clinical and US screening techniques. Of these 1227 patients, 718 (59%) had LH (LH+) and 509 (41%) were LH-free (LH-). These patients were then assigned to two age class groups (≤ 65 years and > 65 years), and several clinical features, diabetes complication rates, and injection habits were investigated. RESULTS: Comparison of the two age subgroups revealed that 396 (48%) and 322 (79%) patients in the younger and older groups, respectively, had LHs (p < 0.001). Compared to the younger subgroup, the older subgroup displayed a higher LH rate in the abdomen (52.9 vs. 38.3%; p < 0.01) and a lower rate in the arms (25.4 vs. 35.8%; p < 0.05), thighs (26.7 vs. 33.4%; p < 0.05), and buttocks (4.9 vs. 26.2%; p < 0.01). In older subjects, the most relevant parameters were: habit of injecting insulin into LH nodules (56 vs. 47% [younger subjects]; p < 0.01), rate of post-injection leakage of insulin from injection site (drop-leaking rate; 47 vs. 39% [younger subjects]; p < 0.05), and rate of painful injections (5 vs. 16% [younger subjects]; p < 0.001). Multivariate analysis showed a stronger association between LH and poor habits, as well as between several clinical parameters, among which the most relevant were hypoglycemic events and glycemic variability. DISCUSSION: The higher rate of post-injection drop-leaking and pain-free injections might find an explanation in skin changes typically observed in older adults, including lower thickness, vascularity and elasticity, and a more prominent fibrous texture, all of which negatively affect tissue distensibility. Consequently, in addition to the well-known association between aging skin impaired drug absorption rate, aging skin displays a progressively decreasing ability to accommodate large volumes of insulin-containing fluid. CONCLUSIONS: The strong association between LH rate and hypoglycemic events plus glycemic variability suggests the need (1) to take specific actions to prevent and control the high risk of acute cardiovascular events expected to occur in older subjects in the case of hypoglycemic events, and (2) to identify suitable strategies to fulfill the difficult task of performing effective educational programs specifically targeted to the elderly. TRIAL REGISTRATION: Trial registration number 172-11:12.2019, Scientific and Ethical Committee of Campania University "Luigi Vanvitelli", Naples, Italy).

Insulin-Induced Skin Lipohypertrophy in Type 2 Diabetes: a Multicenter Regional Survey in Southern Italy.

INTRODUCTION: Lipohypertrophies (LHs) due to incorrect insulin injection techniques have been described in the literature for decades. Their rate averages 38%, but this is still controversial because of the vast range reported by different publications, most of which fail to describe the selected detection protocol and therefore are not entirely reliable. We still need to identify the real LH rate, and only consistently using a standardized method in a large cohort of insulin-treated (IT) patients make this possible. METHODS: Our group performed thorough clinical skin examinations on patients suffering from type 2 diabetes mellitus (T2DM): 1247 IT T2DM outpatients were examined according to a standardized protocol, previously published elsewhere, as well as an ultrasound scan of the same skin areas to assess the degree of concordance between the two methods and to evaluate the demographic, clinical, and behavioral risk factors (RF) as well as metabolic consequences of identified LHs. RESULTS: The concordance between the two methods was 99%. Identified risk factors for LHs were needle reuse, failure to rotate injection sites, and ice-cold insulin injections. High HbA1c values, wide glycemic variability, and longstanding proneness to hypoglycemia with a high rate of ongoing hypoglycemic events proved to be significantly associated with LHs, too; the same applied to cardiovascular and renal complications as well as to living alone and being retired. CONCLUSIONS: Based on a strict well-structured methodology, our data confirmed what has already been reported in the literature on factors leading to, or associated with, LHs and, for the first time in adults, indicated cryotrauma from ice-cold insulin injections and specific social conditions as factors facilitating LH occurrence. HCPs should therefore plan a yearly clinical examination of all injection sites to improve patient quality of life through better glucose control and a reduced rate of hypoglycemic events. TRIAL REGISTRATION: Trial registration no. 127-11.01.2019, approved by the Scientific and Ethics Committee of Campania University "Luigi Vanvitelli," Naples, Italy.

A randomized, open-label, comparative, crossover trial on preference, efficacy, and safety profiles of lispro insulin u-100 versus concentrated lispro insulin u-200 in patients with type 2 diabetes mellitus: a possible contribution to greater treatment adherence.

BACKGROUND: Several outstanding pharmacological advances making innovative drugs sophisticateddevices available during the last few years. Nevertheless too many patients still disappointingly fail to meetthe metabolic targets suggested by current guidelines. Incorrect insulin administration techniques may greatly affect metabolic control in T2DM people. The aim of our study was to compare glycemic control associated with a concentrated insulin analog preparation (U-200 lispro) in people with T2DM to the one observed with standard U-100 lispro. The secondary endpoint of our study was patients' preference and performance ratings of U-200 lispro. METHODS: 126 patients with T2DM were enrolled. They were also assessed for limited joint mobility syndrome (LJMS),defined as limitation in at least two anatomical areas of the dominant upper extremity. After a 4-weekstructured insulin injection education period. Half of them were randomized to U-100 lispro, half to U-200 and after 12 weeks they were switched to the other preparation for 12 weeks. At the end a questionnaire was also administered to investigate patient preference. RESULTS: No significant variation in fasting blood glucose, HbA1c, severe or mild hypoglycemic rate and daily fast-acting insulin analog dose was observed with U-100 lispro while U-200 lispro treatment was associated with a significant improvement of all the above mentioned parameters and with around 20% decrease in insulin requirement. Moreover patients' answers to the questionnaire pointed out a higher preference for U-200 lispro for continuing treatment due to fewer difficulties completing injection. DISCUSSION: The explanation of better metabolic results with the U-200 device might be the lower inner piston inertia and volume and shorter duration of a complete injection. CONCLUSIONS: Checking for LJIMS before insulin prescription could be adopted as a standard practiceaimed at choosing the most suitable device for patient's specific characteristics and abilities. The use of U-200 lispro might improve treatment adherence and metabolic control. This would also result intocost reduction by saving about half the amount of pens per year and of time spent to both fill prescriptionand dump the pharmacy.

Increased serum osteoprotegerin values in long-lived subjects: different effects of inflammation and bone metabolism.

AIM: To evaluate serum osteoprotegerin (OPG) concentrations in relation to age-dependent changes in serum markers of bone metabolism and systemic inflammation. METHODS: Two-hundred and eighty-three healthy subjects were evaluated for plasma estimated creatinine clearance (Cr-clearance), C-reactive protein (CRP), bone alkaline phosphatase, C-telopeptides of type-1 collagen (CrossLaps), nuclear factor-kappaB ligand (RANKL) and OPG concentrations. RESULTS: In adult subjects (82 cases aged between 27 and 64 years) serum OPG concentrations were significantly and independently correlated with RANKL and Cr-clearance (R(2): 0.29), but not with CRP and biochemical markers of bone metabolism. In old subjects who were between 65 and 84 years of age (52 cases) serum OPG concentrations were significantly higher as compared with the adult subjects and correlated independently and significantly with serum RANKL, Cr-clearance and CrossLaps values (R(2): 0.63). The highest OPG values were found in the long-lived subjects (149 cases with ages between 85 and 110 years) who also showed increased serum CrossLaps and CRP concentrations as compared with the younger subjects. However, in the long-lived subjects serum OPG concentrations were significantly and independently correlated with Cr-clearance and CRP (R(2): 0.45) but not with CrossLaps values. CONCLUSIONS: These data would suggest that different factors might be responsible for the age-dependent enhancement of OPG production. Bone metabolism would seem to be the most important factor influencing serum OPG concentrations in old subjects under 85 years of age, whereas in long-lived subjects the circulating values of this cytokine seem to be mainly correlated with serum CRP which could be a marker of inflammation and cardiovascular risk.

Recombinant human TSH modulates in vivo C-telopeptides of type-1 collagen and bone alkaline phosphatase, but not osteoprotegerin production in postmenopausal women monitored for differentiated thyroid carcinoma.

UNLABELLED: In women monitored for thyroid carcinoma, short-term stimulation with rhTSH induced an acute decrease in serum C-telopeptides of type-1 collagen and an increase in serum BALP levels without any effect on OPG production. The inhibitory effect of TSH on bone resorption occurred only in postmenopausal women who showed low BMD and a high bone turnover rate as an effect of L-thyroxine suppressive therapy. INTRODUCTION: It has been recently shown that thyrotropin (TSH) has an inhibitory activity on skeletal remodeling in in vitro conditions. Here, we have aimed at evaluating whether TSH has similar effects in vivo. For this purpose, we have evaluated the sequential profile of serum bone metabolism markers during acute stimulation with recombinant human TSH (rhTSH) in thyroidectomized women monitored for thyroid carcinoma. MATERIALS AND METHODS: The study group included 66 thyroidectomized patients, of whom 38 were premenopausal and 28 postmenopausal, who underwent routine rhTSH-assisted whole body radioactive iodine scanning for differentiated thyroid carcinoma. The patients were sequentially evaluated for TSH, free triiodothyronine (FT3), free thyroxine (FT4), bone alkaline phosphatase (BALP), C-telopeptides of type-1 collagen (CrossLaps), and osteoprotegerin (OPG) levels during rhTSH stimulation. The samples were drawn just before and 2 and 7 days after the first administration of rhTSH. BMD was evaluated by ultrasonography at baseline. Seventy-one healthy women (41 premenopausal and 30 postmenopausal) acted as a control group. RESULTS AND CONCLUSIONS: At study entry, all patients had subclinical thyrotoxicosis as effect of L-thyroxine (L-T4) treatment. The patients had higher serum CrossLaps and OPG levels and lower BMD than healthy subjects. Postmenopausal patients showed comparable serum FT4 and FT3 concentrations with those found in premenopausal patients. However, postmenopausal patients showed higher serum CrossLaps (p < 0.001), OPG (p = 0.03), and BALP (p < 0.001) levels and lower BMD (p < 0.001) than those measured in premenopausal patients. Two days after the first administration of rhTSH, all patients had serum TSH values >100 mUI/liter. At this time, serum CrossLaps levels decreased significantly (p < 0.001) and BALP values increased (p = 0.001) with respect to the baseline values in postmenopausal but not in premenopausal patients. rhTSH did not induce any significant change in serum OPG values either in premenopausal or in postmenopausal patients. One week after the first rhTSH administration, serum CrossLaps values decreased again to values comparable with those measured at baseline, whereas serum BALP values remained high. This study shows that subclinical thyrotoxicosis is accompanied by high bone turnover rate with an increase in serum OPG levels compared with euthyroid healthy subjects. Acute increase in serum TSH levels is accompanied by a reversible inhibition of bone resorption. This effect is characterized by a decrease in serum CrossLaps and an increase in BALP levels without any evident effect on OPG production. The activity of TSH occurs specifically in postmenopausal women in whom the negative effects of L-T4 suppressive therapy on bone mass and metabolism are more marked compared with premenopausal women.

Effects of increased thyroxine dosage pre-conception on thyroid function during early pregnancy.

OBJECTIVE: To compare the effects of pregnancy on the serum free thyroxine (FT4) levels in two cohorts of primary hypothyroid women treated with different levothyroxine (L-T4) doses before gestation. DESIGN AND METHOD: Twenty-five women with compensated hypothyroidism of different aetiology (thyroidectomized and Hashimoto's thyroiditis) were enrolled in this prospective study. The women were receiving substitutive doses of L-T4 and were anticipating pregnancy. They were assigned to two groups: 14 patients (group I) were switched to partially suppressive treatment while 11 patients (group II) continued the same therapeutic regimen. RESULTS: Pre-conceptional thyroid function evaluation demonstrated significantly higher FT4 and lower TSH in group I (P<0.001, for both hormones) and comparable free 3,5,3'-triiodothyronine (FT3) levels. The first post-conception thyroid function evaluation occurred at a median time of 6 (5-8) and 7 (5-9) weeks of gestation, for groups I and II respectively (P<0.05); all women in group I showed adequate serum FT4 levels while three patients in group II showed low-normal FT4 levels and one case was below normal levels. Statistical analysis demonstrated significantly higher frequencies (0% vs 36.4%; P<0.05) of low-normal FT4 levels in patients receiving substitutive doses of L-T4. None of the Hashimoto's-affected patients showed low or low-normal serum FT4 levels regardless of their therapeutic regimen. CONCLUSION: Our results suggest that in hypothyroid women anticipating pregnancy (with serum TSH in the lower quartile of normal range), the pre-conception adjustment of L-T4 doses may result in adequate maternal thyroid function up to the first post-conception evaluation. The procedure seems safe and inexpensive; it may be a worthwhile treatment, at least in thyroidectomized women, in view of the well-known potential effects of even marginal maternal thyroid hypofunction on the subsequent IQ of the progeny.

Recombinant human thyrotropin reduces serum vascular endothelial growth factor levels in patients monitored for thyroid carcinoma even in the absence of thyroid tissue.

In this study, we have investigated in vivo the time-dependent effects of TSH on vascular endothelial growth factor (VEGF) production in patients monitored for thyroid carcinoma. Serum VEGF, thyroglobulin (Tg), and TSH levels were assayed at baseline and 6, 24, 30, 48, 72, and 96 h and 1 wk after administration of recombinant human TSH (rhTSH) in 45 thyroidectomized patients affected by differentiated thyroid carcinoma. At baseline, the patients with metastasis (18 cases) showed serum Tg and VEGF values significantly higher than those seen in the cured patients (27 cases). During rhTSH stimulation, the mean VEGF levels decreased significantly in both patient groups. In 60% of patients with metastasis, VEGF nadir occurred at the same time as serum TSH reached the highest values, whereas in 85.7% of the cured patients VEGF decreased after the TSH peak (P = 0.003). In conclusion, we demonstrate for the first time that short-term administration of rhTSH in patients monitored for differentiated thyroid carcinoma induces a significant reduction in serum VEGF values even in the absence of thyroid tissue. This result would suggest that TSH may be able in vivo to regulate VEGF production from tissues other than the thyroid gland.

Grey-scale analysis allows a quantitative evaluation of thyroid echogenicity in the patients with Hashimoto's thyroiditis.

OBJECTIVE: In the present study we have performed a grey-scale quantitative analysis of thyroid echogenicity in the patients affected by Hashimoto's thyroiditis (HT), obtaining a numerical estimate of the degree of hypoechogenicity associated with the appearance of thyroid dysfunction. MATERIALS AND METHODS: The study group included 89 patients with serum positivity for thyroglobulin (TgAb) and/or peroxidase (TPOAb) antibodies. Ultrasound (US) evaluation of thyroid gland and biochemical assay of serum thyrotropin (TSH), free-thyroxine (FT4) and free-triiodiothyronyne (FT3) were performed in all patients, and in 40 healthy subjects enrolled as control group. Thyroid echogenicity was compared with that of the surrounding neck muscles, using the grey-scale histogram analysis. The echogenicity was expressed in grey-scales (GWE). RESULTS: In HT patients, the mean of thyroid echogenicity was lower when compared to the normal thyroid (61.9 +/- 8.3 GWE vs. 71.9 +/- 3.1 GWE; P = 0.01). In all HT patients the lowest limit of thyroid echo distribution was in the echogenicity range of the surrounding muscle, the overlapping ranging between 3.4% and 95.0% (mean +/- SD 48.4 +/- 20.9%). The extension of like-muscle hypoechogenicity into the thyroid gland was significantly correlated with serum TSH values (r = 0.37; P < 0.001), serum FT4 values (r = -0.60; P < 0.001), and serum TPOAb values (r = 0.31; P = 0.004). Nobody was hypothyroid when the hypoechogenicity was less than 38.0%, whereas hypothyroidism occurred in all cases with hypoechogenicity of more than 68.9%. The receiving operating characteristic curve demonstrated that 48.3% was the best cut-off for identifying hypothyroid patients with sensitivity, specificity and diagnostic accuracy of 88.9%, 86.3% and 87.6%, respectively. CONCLUSIONS: In conclusion, the grey-scale quantitative analysis has provided a measure of thyroid hypoechogenicity associated with the appearance of hypothyroidism during the course of HT. The results of the present study would encourage the application of the computerized grey-scale analysis as complementary tool to US evaluation in the patients affected by HT.