Diagnosing Osteoporosis in Diabetes-A Systematic Review on BMD and Fractures.

PURPOSE OF REVIEW: Recently, the American Diabetes Association updated the 2024 guidelines for Standards of Care in Diabetes and recommend that a T-score of - 2.0 in patients with diabetes should be interpreted as equivalent to - 2.5 in people without diabetes. We aimed to evaluate the most recent findings concerning the bone mineral density (BMD)-derived T-score and risk of fractures related to osteoporosis in subjects with diabetes. RECENT FINDINGS: The dual-energy X-ray absorptiometry (DXA) scan is the golden standard for evaluating BMD. The BMD-derived T-score is central to fracture prediction and signifies both diagnosis and treatment for osteoporosis. However, the increased fracture risk in diabetes is not sufficiently explained by the T-score, complicating the identification and management of fracture risk in these patients. Recent findings agree that subjects with type 2 diabetes (T2D) have a higher T-score and higher fracture risk compared with subjects without diabetes. However, the actual number of studies evaluating the direct association of higher fracture risk at higher T-score levels is scant. Some studies support the adjustment based on the 0.5 BMD T-score difference between subjects with T2D and subjects without diabetes. However, further data from longitudinal studies is warranted to validate if the T-score treatment threshold necessitates modification to prevent fractures in subjects with diabetes.

The associations of sodium-glucose cotransporter-2 inhibitors versus dipeptidyl peptidase-4 inhibitors as add-on to metformin with fracture risk in patients with type 2 diabetes mellitus.

AIM: To investigate whether sodium-glucose cotransporter-2 (SGLT2) inhibitor use as compared to dipeptidyl peptidase-4 (DPP-4) inhibitor use as add-on to metformin is associated with the risk of any fracture or major osteoporotic fractures (MOFs). METHODS: A cohort study using the Clinical Practice Research Datalink (CPRD) Aurum database was conducted. All patients aged 18 years and older with a first-ever prescription for a DPP-4 inhibitor or an SGLT2 inhibitor as add-on to metformin between January 1, 2013 and June 30, 2020 were selected. Patients starting with SGLT2 inhibitors were matched (up to 1:3) on propensity scores to patients starting with DPP-4 inhibitors. Propensity scores were calculated based on sex, age, body mass index, comorbidities, comedication and lifestyle factors. Cox proportional hazard models were used to estimate the risk of fracture with SGLT2 inhibitor use as compared to DPP-4 inhibitor use. RESULTS: A total of 13 807 SGLT2 inhibitor users (age 55.4 ± 10.6 years, 36.7% female) were included in this study, matched with 28 524 DPP-4 inhibitor users (age 55.4 ± 8.0 years, 36.4% female). The risk of any fracture with current SGLT2 inhibitor use was similar compared with current DPP-4 inhibitor use (adjusted hazard ratio [aHR] 1.09, 95% confidence interval [CI] 0.91-1.31), as was the risk of MOFs (aHR 0.89, 95% CI 0.64-1.22) and the risk of fractures at any of the individual MOF sites. Additionally, no association was found with duration of SGLT2 inhibitor use (longest duration >811 days) for any of the individual SGLT2 inhibitor agents, or after stratification by sex and age. CONCLUSION: Use of SGLT2 inhibitors was not associated with the risk of any fracture, MOFs or fracture at the individual MOF sites when compared to DPP-4 inhibitor use.

Osteoglycin and Bone-a Systematic Review.

PURPOSE OF REVIEW: Bone turnover is a regulated process. Osteoglycin is suggested to have an important impact on bone function but may also affect cardiovascular and metabolic functions. This review investigates the action of osteoglycin in bone as well as its potential endocrine effects. RECENT FINDINGS: Osteoglycin is expressed by several tissues including bone and muscle. Some studies suggest that osteoglycin increases osteoblast differentiation whereas others suggest that osteoglycin decreases osteoblast differentiation. Thus, findings on the influence of osteoglycin in bone are conflicting. A recent study found increased bone mass in osteoglycin deficient mice. Another study reported that osteoglycin is a marker of low bone mineral density and vertebral fractures in women with type 2 diabetes. Furthermore, clinical studies link osteoglycin to insulin resistance and cardiovascular disease. Osteoglycin may be a novel marker of a muscle, pancreatic, and bone axis. However, current evidence is limited and further research investigating osteoglycin in both a pre-clinical and a clinical setting is needed.

Differential regulation of lipid and protein metabolism in obese vs. lean subjects before and after a 72-h fast.

Increased availability of lipids may conserve muscle protein during catabolic stress. Our study was designed to define 1) intracellular mechanisms leading to increased lipolysis and 2) whether this scenario is associated with decreased amino acid and urea fluxes, and decreased muscle amino acid release in obese subjects under basal and fasting conditions. We therefore studied nine lean and nine obese subjects twice, after 12 and 72 h of fasting, using measurements of mRNA and protein expression and phosphorylation of lipolytic and protein metabolic signaling molecules in fat and muscle together with whole body and forearm tracer techniques. Obese subjects displayed increased whole body lipolysis, decreased urea production rates, and decreased forearm muscle protein breakdown per 100 ml of forearm tissue, differences that persisted after 72 h of fasting. Lipolysis per fat mass unit was reduced in obese subjects and, correspondingly, adipose tissue hormone-sensitive lipase (HSL) phosphorylation and mRNA and protein levels of the adipose triglyceride lipase (ATGL) coactivator CGI58 were decreased. Fasting resulted in higher HSL phosphorylations and lower protein levels of the ATGL inhibitor G0S2. Muscle protein expressions of mammalian target of rapamycin (mTOR) and 4EBP1 were lower in obese subjects, and MuRf1 mRNA was higher with fasting in lean but not obese subjects. Phosphorylation and signaling of mTOR decreased with fasting in both groups, whereas ULK1 protein and mRNA levels increased. In summary, obese subjects exhibit increased lipolysis due to a large fat mass with blunted prolipolytic signaling, together with decreased urea and amino acid fluxes both in the basal and 72-h fasted state; this is compatible with preservation of muscle and whole body protein.

Serum osteoglycin is stable during various glycemic challenges in healthy men.

PURPOSE: Osteoglycin is hypothesized to be metabolically active and may enhance insulin action. We hypothesized that osteoglycin levels increase during hyperglycemia as a physiological response to enhance the effects of insulin. METHODS: Eight healthy males were included in a cross-over study consisting of three study days following an 8 h fast. First, we performed an oral glucose tolerance test (OGTT); second, an isoglycemic intravenous glucose infusion (IIGI); and third, a control period consisting of a three hour fast. We analyzed blood samples for circulating osteoglycin levels during the study days. Repeated measures ANOVA was performed to compare levels of s-osteoglycin between OGTT, IIGI, and the fasting control. RESULTS: There were no differences in baseline osteoglycin levels among study days (p > 0.05). We observed no significant changes neither in absolute s-osteoglycin levels by time (p = 0.14) nor over time by study day (p = 0.99). Likewise, we observed no significant changes in percentage s-osteoglycin levels neither by time (p = 0.11) nor over time by study day (p = 0.89). CONCLUSION: We found that s-osteoglycin levels were stable for three hours during OGTT, IIGI, and fasting in healthy males. Based on the present study, circulating s-osteoglycin levels may be measured independently of fasting or non-fasting conditions. Furthermore, circulating physiological levels of glucose and insulin did not affect s-osteoglycin levels.

Discrepancies in type of first major osteoporotic fracture and anti-osteoporotic therapy in elderly people with type 2 diabetes mellitus: A retrospective Danish cohort study.

OBJECTIVE: Subjects with diabetes mellitus have an increased risk of fractures. We aimed to identify discrepancies in the first type of major osteoporotic fracture (MOF) and anti-osteoporotic therapy between subjects with type 2 diabetes (T2D) and subjects without diabetes. Methods and research design. We conducted a retrospective national cohort study by access to all discharge diagnoses (ICD-10 system) and redeemed drug prescriptions (ATC classification system). We included all subjects alive and Danish citizens in 2010 and identified subjects with T2D diagnosed after the age of 50 between 1998 and 2018. Only subjects with a MOF after the index date were included in the main analysis. The type of MOF was identified by diagnosis codes and categorized into Humerus, Forearm, Spine, and Hip. Multinomial logistic regression modeling was used to assess the predicted probability changes in MOF type between T2D and control subjects. Data on first anti-osteoporotic therapy after the MOF was assessed by redeemed drug prescriptions. Mortality and time to therapy after the MOF were evaluated by cox proportional hazards. RESULT: We included 26,588 subjects with T2D and 97,982 subjects without diabetes. The mean age was age 69.33 (±10.34) for T2D and 69.85 (±10.19) for control subjects. The cohort was primarily females (67 %). Subjects with T2D had a higher probability of hip (3.98 % [95 % CI 3.29; 4.67]) and humerus (2.82 % [95 % CI 2.17; 3.46]) fractures as the first MOF compared to control subjects. However, the probability of forearm fractures as the first MOF was 6.77 % (95 % CI 6.08; 7.46) lower among subjects with T2D. The multiple adjusted hazard ratio for anti-osteoporotic treatment after the first MOF was 0.80 (95 % CI 0.77; 0.88) for T2D compared to controls among treatment-naïve subjects. CONCLUSION: Forearm fractures were the most frequent type of MOF and were more prevalent in control subjects. Subjects with T2D had a significantly higher probability of hip and humerus fractures as the first MOF but had a 20 % lower chance of anti-osteoporotic treatment afterwards.

Effects of Incretin Therapy on Skeletal Health in Type 2 Diabetes-A Systematic Review.

Diabetes poses a significant risk to bone health, with Type 1 diabetes (T1D) having a more detrimental impact than Type 2 diabetes (T2D). The group of hormones known as incretins, which includes gastric inhibitory peptide (GIP) and glucagon-like peptide 1 (GLP-1), play a role in regulating bowel function and insulin secretion during feeding. GLP-1 receptor agonists (GLP-1 RAs) are emerging as the primary treatment choice in T2D, particularly when atherosclerotic cardiovascular disease is present. Dipeptidyl peptidase 4 inhibitors (DPP-4is), although less potent than GLP-1 RAs, can also be used. Additionally, GLP-1 RAs, either alone or in combination with GIP, may be employed to address overweight and obesity. Since feeding influences bone turnover, a relationship has been established between incretins and bone health. To explore this relationship, we conducted a systematic literature review following the PRISMA guidelines. While some studies on cells and animals have suggested positive effects of incretins on bone cells, turnover, and bone density, human studies have yielded either no or limited and conflicting results regarding their impact on bone mineral density (BMD) and fracture risk. The effect on fracture risk may vary depending on the choice of comparison drug and the duration of follow-up, which was often limited in several studies. Nevertheless, GLP-1 RAs may hold promise for people with T2D who have multiple fracture risk factors and poor metabolic control. Furthermore, a potential new area of interest is the use of GLP-1 RAs in fracture prevention among overweight and obese people. Based on this systematic review, existing evidence remains insufficient to support a positive or a superior effect on bone health to reduce fracture risk in people with T2D. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Risk of Major Adverse Cardiovascular Events, Severe Hypoglycemia, and All-Cause Mortality in Postpancreatitis Diabetes Mellitus Versus Type 2 Diabetes: A Nationwide Population-Based Cohort Study.

OBJECTIVE: Postpancreatitis diabetes mellitus (PPDM) is a frequent complication of pancreatitis and associates with poor glycemic control. We investigated the risk of adverse diabetes-related outcomes in PPDM compared with type 2 diabetes. RESEARCH DESIGN AND METHODS: In this Danish population-based cohort study, we included adults (>18 years) with incident PPDM or type 2 diabetes between 1998 and 2018 through national health registries. PPDM was further divided into acute (PPDM-A) and chronic (PPDM-C) subtypes. We ascertained risk of major adverse cardiovascular events (MACE), severe hypoglycemia, and all-cause mortality as well as incidence rates of severe hypoglycemia. We compared risk and incidence rates across diabetes subgroups using multivariate Cox and Poisson regression analyses. RESULTS: We identified 383,325 people with incident type 2 diabetes, 3,418 with PPDM-A, and 2,461 with PPDM-C. Compared with type 2 diabetes, PPDM-C was associated with increased risks of severe hypoglycemia (hazard ratio [HR] 5.27, 95% CI 4.62-6.00, P < 0.001) and all-cause mortality (HR 1.54, 95% CI 1.45-1.64, P < 0.001). Similar patterns were observed for people with PPDM-A. Incidence rate ratios (IRRs) for severe hypoglycemia were increased in both PPDM-C (IRR 7.38, 95% CI 6.75-8.08, P < 0.001) and PPDM-A (IRR 3.76, 95% CI 3.36-4.21, P < 0.001) compared with type 2 diabetes. Findings were consistent in an analysis restricted to people on insulin and in an analysis including pancreatitis patients without diabetes as comparator group. CONCLUSIONS: Compared with type 2 diabetes, PPDM is associated with excess risk of adverse diabetes-related outcomes. This has important implications for management.

SGLT2 inhibitor treatment is not associated with an increased risk of osteoporotic fractures when compared to GLP-1 receptor agonists: A nationwide cohort study.

Background: Type 2 diabetes mellitus (T2D) is associated with an increased fracture risk. It is debated whether sodium-glucose cotransporter 2 (SGLT2) inhibitors influence fracture risk in T2D. We aimed to investigate the risk of major osteoporotic fractures (MOF) with SGLT2 inhibitors compared to glucagon-like peptide 1 (GLP-1) receptor agonists when used as add-on therapies to metformin. Methods: We conducted a population-based cohort study using Danish national health registries. Diagnoses were obtained from discharge diagnosis codes (ICD-10 and ICD-8-system) from the Danish National Patient Registry, and all redeemed drug prescriptions were obtained from the Danish National Prescription Registry (ATC classification system). Subjects treated with metformin in combination with either SGLT2 inhibitors or GLP-1 receptor agonists were identified and enrolled from 2012 to 2018. Subjects were then propensity-score matched 1:1 based on age, sex, and index date. Major osteoporotic fractures (MOF) were defined as hip, vertebral, humerus, or forearm fractures. A Cox proportional hazards model was utilized to estimate hazard rate ratios (HR) for MOF, and survival curves were plotted using the Kaplan-Meier estimator. Results: In total, 27,543 individuals treated with either combination were identified and included. After matching, 18,390 individuals were included in the main analysis (9,190 in each group). Median follow-up times were 355 [interquartile range (IQR) 126-780] and 372 [IQR 136-766] days in the SGLT2 inhibitor and GLP-1 receptor agonist group, respectively. We found a crude HR of 0.77 [95% CI 0.56-1.04] for MOF with SGLT2 inhibitors compared to GLP-1 receptor agonists. In the fully adjusted model, we obtained an unaltered HR of 0.77 [95% CI 0.56-1.05]. Results were similar across subgroup- and sensitivity analyses. Conclusion: These results suggest that SGLT2 inhibitors have no effect on fracture risk when compared to GLP-1 receptor agonists. This is in line with results from previous studies.

The risk of major osteoporotic fractures with GLP-1 receptor agonists when compared to DPP-4 inhibitors: A Danish nationwide cohort study.

Background: Type 2 diabetes mellitus (T2D) is associated with an increased fracture risk. There is little evidence for the effects of glucagon-like peptide 1 receptor agonists (GLP-1RA) on fracture risk in T2D. We aimed to investigate the risk of major osteoporotic fractures (MOF) for treatment with GLP-1RA compared to dipeptidyl peptidase 4 inhibitors (DPP-4i) as add-on therapies to metformin. Methods: We conducted a population-based cohort study using Danish national health registries. Diagnoses were obtained from discharge diagnosis codes (ICD-10 and ICD-8-system) from the Danish National Patient Registry, and all redeemed drug prescriptions were obtained from the Danish National Prescription Registry (ATC classification system). Subjects treated with metformin in combination with either GLP-1RA or DPP-4i were enrolled from 2007 to 2018. Subjects were propensity-score matched 1:1 based on age, sex, and index date. MOF were defined as hip, vertebral, humerus, or forearm fractures. A Cox proportional hazards model was utilized to estimate hazard rate ratios (HR) for MOF, and survival curves were plotted using the Kaplan-Meier estimator. In addition, Aalen's Additive Hazards model was applied to examine additive rather than relative hazard effects while allowing time-varying effects. Results: In total, 42,816 individuals treated with either combination were identified and included. After matching, 32,266 individuals were included in the main analysis (16,133 in each group). Median follow-up times were 642 days and 529 days in the GLP-1RA and DPP-4i group, respectively. We found a crude HR of 0.89 [0.76-1.05] for MOF with GLP-1RA compared to DPP-4i. In the fully adjusted model, we obtained an unaltered HR of 0.86 [0.73-1.03]. For the case of hip fracture, we found a crude HR of 0.68 [0.49-0.96] and a similar adjusted HR. Fracture risk was lower in the GLP-1RA group when examining higher daily doses of the medications, when allowing follow-up to continue after medication change, and when examining hip fractures, specifically. Additional subgroup- and sensitivity analyses yielded results similar to the main analysis. Conclusion: In our primary analysis, we did not observe a significantly different risk of MOF between treatment with GLP-1RA and DPP-4i. We conclude that GLP-1RA are safe in terms of fracture.

Use of sodium-glucose co-transporter 2 inhibitors, changes in body mass index and risk of fracture: A population-based cohort study.

AIMS: Sodium-glucose co-transporter-2 (SGLT-2) inhibitor-induced weight loss might play a role in the debated elevated fracture risk with these agents. The aim of the current study was to investigate the association between SGLT-2 inhibitor use, changes in body mass index (BMI) and fracture risk. METHODS: A retrospective cohort study was conducted using data from the UK Clinical Practice Research Datalink (CPRD) GOLD (2013-2018). The study population (N = 34,960) consisted of adults with diabetes initiating a sulphonylurea or SGLT-2 inhibitor. Cox proportional hazards models estimated hazard ratios (HRs) for major osteoporotic fracture with SGLT-2 inhibitor use versus sulphonylurea use, stratified by change in BMI, average daily dose and cumulative dose. Analyses were adjusted for age, sex, lifestyle variables, comorbidities, and concomitant drug use. RESULTS: SGLT-2 inhibitor use was not associated with an increased fracture risk compared to sulphonylurea use (adjusted HR 1.19; 95% confidence interval (CI): 0.80-1.79). This finding remained consistent after stratification by BMI change. However, the highest cumulative dose category was associated with an increased fracture risk (adjusted HR: 2.10, 95 %CI: 1.11-3.99). CONCLUSION: SGLT-2 inhibitor use was not associated with increased osteoporotic fracture risk, irrespective of change in BMI. However, a high cumulative dose could be an important risk factor.

Prevalent Morphometrically Assessed Vertebral Fractures in Individuals With Type 2 Diabetes, Prediabetes and Normal Glucose Metabolism: The Maastricht Study.

BACKGROUND: Type 2 diabetes (T2D) is frequently reported to be associated with an increased fracture risk. Epidemiological data on prevalent morphometric vertebral fractures (VFs) in T2D are sparse and even less is known in the prediabetic state. PURPOSE: To determine the association between prevalence and severity of morphometric VFs and glucose metabolism state: normal glucose metabolism (NGM), impaired glucose metabolism (prediabetes) or T2D. METHODS: This study included cross-sectional data from 3625 participants of the Maastricht Study who had a vertebral fracture assessment on lateral Dual Energy X-Ray Absorptiometry images. VFs were classified based on morphometric assessment into mild, moderate and severe VFs (respectively 20-24%, 25-39% or ≥40% reduction in expected vertebral body height). Logistic regression models were used to investigate the association between glucose metabolism status and the prevalence and severity of VFs. Analyses were adjusted for subject characteristics and life-style factors. RESULTS: T2D individuals were older (62.8 ± 7.5 years old) and less often female (30.5%) compared to the NGM group (57.7 ± 8.5 years old, and 58.8% female, respectively). At least one mild, moderate or severe prevalent VF was found in 8.6% of the men and 2.2% of the women in the T2D group, in 9.4% and 8.4% in the prediabetes group and in 9.1% and 4.8% in the NGM group, respectively. After adjustment T2D in women was associated with a lower probability of having a prevalent VF compared to NGM [adjusted OR 0.25 (95% CI 0.09-0.65)], while this was not the case for prediabetes. Furthermore, women with T2D had a significantly lower probability of a prevalent moderate or severe VF [adjusted OR 0.32 (95% CI 0.11-0.96)]. In men there was no significant association between T2D or prediabetes and prevalent VFs. CONCLUSION: Women with T2D had a lower probability of prevalent VFs compared to women with a normal glucose metabolism, while this was not the case for men with T2D and participants with prediabetes.

Alendronate Use and Risk of Type 2 Diabetes: A Nationwide Danish Nested Case-Control Study.

Objective: A link has been proposed between glucose homeostasis and bone metabolism. Bisphosphonates are first-line treatment of osteoporosis, and we aimed to investigate whether the risk of developing type 2 diabetes was associated with prior use of alendronate. Research Design and Methods: We conducted a population-based nested case-control study through access to all discharge diagnoses (ICD-10 system) from the National Danish Patient Registry along with all redeemed drug prescriptions (ATC classification system) from the Health Service Prescription Registry. All cases with a diagnosis of type 2 diabetes between 2008 and 2018 were matched on sex and age with 3 randomly selected controls by incidence-density sampling. Exposure was defined as ever use of alendronate and further grouped as effective and compliant use. ORs were calculated by conditional logistic regression analysis with adjustment for several confounders and test for trend for dose-response relationship. Results: We included 163,588 patients with type 2 diabetes and 490,764 matched control subjects with a mean age of 67 years and 55% male subjects. The odds of developing type 2 diabetes were lower among ever users of alendronate (multiple adjusted OR: 0.64 [95% CI 0.62-0.66]). A test for trend suggested a dose-response relationship between longer effective use of alendronate and lower risk of type 2 diabetes. Conclusion: These results suggest a possible protective effect of alendronate in a dose-dependent manner against development of type 2 diabetes.

The Efficacy of Alendronate Versus Denosumab on Major Osteoporotic Fracture Risk in Elderly Patients With Diabetes Mellitus: A Danish Retrospective Cohort Study.

Objective: Patients with diabetes mellitus have an increased risk of fractures; however, the underlying mechanism is largely unknown. We aimed to investigate whether the risk of major osteoporotic fractures in diabetes patients differs between subjects initiated with alendronate and denosumab, respectively. Methods and Research Design: We conducted a retrospective nationwide cohort study through access to all discharge diagnoses (ICD-10 system) from the National Danish Patient Registry along with all redeemed drug prescriptions (ATC classification system) from the Health Service Prescription Registry. We identified all subjects with a diabetes diagnosis between 2000 and 2018 and collected data on the first new prescription of anti-osteoporotic treatment between 2011 and 2018. Exposure was defined as either alendronate or denosumab treatment initiated after diabetes diagnosis. Outcome information was collected by identification of all major osteoporotic fracture (MOF) diagnoses, i.e., hip, spine, forearm, and humerus, from exposure until 2018 or censoring by emigration or death. The risk of fracture was calculated as hazard ratios (HR) using multiply adjusted Cox proportional models with death as a competing risk. Results: We included 8,745 subjects initiated with either alendronate (n = 8,255) or denosumab (n = 490). The cohort consisted of subjects with a mean age of 73.62 (SD ± 9.27) years, primarily females (69%) and suffering mainly from type 2 diabetes (98.22%) with a median diabetes duration at baseline of 5.45 years (IQR 2.41-9.19). Those in the denosumab group were older (mean 75.60 [SD ± 9.72] versus 73.51 [SD ± 9.23] years), had a higher proportion of women (81% versus 68%, RR 1.18 [95% CI 1.13-1.24], and were more comorbid (mean CCI 2.68 [95% CI 2.47-2.88] versus 1.98 [95% CI 1.93-2.02]) compared to alendronate initiators. In addition, denosumab users had a higher prevalence of previous fractures (64% versus 46%, RR 1.38 [95% CI 1.28-1.48]). The adjusted HR for any MOF after treatment initiation with denosumab was 0.89 (95% CI 0.78-1.02) compared to initiation with alendronate. Conclusion: The risk of incident MOF among subjects with diabetes was similar between those initially treated with alendronate and denosumab. These findings indicate that the two treatment strategies are equally effective in preventing osteoporotic fractures in subjects with diabetes.

Associations of Circulating Osteoglycin With Bone Parameters and Metabolic Markers in Patients With Diabetes.

Objective: Circulating osteoglycin may facilitate the crosstalk between bone and pancreas to empower adaptation of bone mass to whole body energy balance. We aimed to examine whether osteoglycin is associated with bone and metabolic parameters and if osteoglycin levels differ between patients with type 1 and 2 diabetes (T1D and T2D). Design and methods: A cross-sectional study of 190 patients with diabetes mellitus and stable hemoglobin A1c (HbA1c) (97 T1D and 93 T2D) was conducted. S-osteoglycin was analyzed by ELISA. Unpaired t-tests were performed to test differences between patients with T1D and T2D and linear regression analyses were performed to investigate associations between osteoglycin, glycemic markers, bone turnover markers and characteristics. Results: S-osteoglycin did not differ between patients with T1D and T2D (p=0.10). No associations were present between osteoglycin and age, gender, microvascular complications, HbA1c, or plasma glucose in T1D or T2D patients (p>0.05 for all). S-osteoglycin was not associated with levels of bone turnover markers (C-terminal cross-linked telopeptide of type-I collagen (CTX), P-procollagen type 1 amino terminal propeptide (P1NP), P-osteocalcin (OC), P-sclerostin, S-osteoprotegerin (OPG) or S-Receptor Activator of Nuclear factor Kappa beta Ligand (RANKL)) in neither T1D or T2D patients (p>0.05 for all). Conclusion: Osteoglycin levels were similar in T1D and T2D patients. Osteoglycin did not correlate with glucose, HbA1c or any other biochemical marker of bone turnover. Thus, we did not find evidence supporting the existence of an osteoglycin-bone-pancreas axis. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT01870557.

Glucose-Lowering Therapy in Patients With Postpancreatitis Diabetes Mellitus: A Nationwide Population-Based Cohort Study.

OBJECTIVE: Postpancreatitis diabetes mellitus (PPDM) is a type of secondary diabetes that requires special considerations for management. The main objective was to examine prescription patterns of glucose-lowering therapy among adults with PPDM compared with type 1 and type 2 diabetes. RESEARCH DESIGN AND METHODS: In a Danish nationwide population-based cohort study, we identified all individuals with adult-onset diabetes in the period 2000-2018 and categorized them as having type 1 diabetes, type 2 diabetes, or PPDM. We ascertained diabetes incidence rates, clinical and demographic characteristics, and classifications and prescription patterns of glucose-lowering therapy and compared these parameters across diabetes subgroups. RESULTS: Among 398,456 adults with new-onset diabetes, 5,879 (1.5%) had PPDM, 9,252 (2.3%) type 1 diabetes, and the remaining type 2 diabetes (96.2%). The incidence rate of PPDM was 7.9 (95% CI 7.7-8.1) per 100,000 person-years versus 12.5 (95% CI 12.2-12.7) for type 1 diabetes (incidence rate ratio 0.6 [95% CI 0.6-0.7]; P < 0.001). A sizeable proportion of patients with PPDM were classified as having type 2 diabetes (44.9%) and prescribed sulfonylureas (25.2%) and incretin-based therapies (18.0%) that can potentially be harmful in PPDM. In contrast, 35.0% of patients never received biguanides, which are associated with a survival benefit in PPDM. Increased insulin requirements were observed for patients with PPDM compared with type 2 diabetes (hazard ratio 3.10 [95% CI 2.96-3.23]; P < 0.001) in particular for PPDM associated with chronic pancreatitis (hazard ratio 4.30 [95% CI 4.01-4.56]; P < 0.001). CONCLUSIONS: PPDM is a common type of secondary diabetes in adults but is often misclassified and treated as type 2 diabetes, although PPDM requires special considerations for management.

Prolonged fasting-induced metabolic signatures in human skeletal muscle of lean and obese men.

Insulin resistance is a well-known physiological adaptation to prolonged fasting in healthy skeletal muscle. Obesity is associated with insulin resistance and metabolic inflexibility in skeletal muscle, and a pronounced increase in the risk of metabolic complications. Under the hypothesis that the metabolic traits of insulin resistance associated with prolonged fasting are different from insulin resistance associated with obesity, we examined nine obese and nine lean participants during 12 and 72h of fasting, respectively. Insulin resistance in obese participants was associated with impaired insulin signaling, and reduced levels of glucose-6-phosphate and TCA-cycle intermediates. 72h of fasting in lean participants reduced insulin-stimulated glucose uptake to levels similar to obese participants fasted for 12h. This was associated with increased lipid oxidation, but not accumulation of diacylglycerol or acylcarnitines and impairment of insulin signaling. Prolonged fasting was associated with pronounced increases in ß-hydroxybutyrate and ß- hydroxybutyrylcarnitine levels in skeletal muscle suggesting augmented ketone body metabolism. Fasting induced insulin resistance may be a consequence of substrate competition. The underlying mechanism behind insulin resistance in obesity is thus not comparable to the physiological adaptations in skeletal muscle induced by prolonged fasting in lean participants.

Pronounced expression of the lipolytic inhibitor G0/G1 Switch Gene 2 (G0S2) in adipose tissue from brown bears (Ursus arctos) prior to hibernation.

Prior to hibernation, the brown bear (Ursus arctos) exhibits unparalleled weight gain. Unlike humans, weight gain in bears is associated with lower levels of circulating free fatty acids (FFA) and increased insulin sensitivity. Understanding how free-ranging brown bears suppress lipolysis when gaining weight may therefore provide novel insight toward the development of human therapies. Blood and subcutaneous adipose tissue were collected from immobilized free-ranging brown bears (fitted with GPS-collars) during hibernation in winter and from the same bears during the active period in summer in Dalarna, Sweden. The expression of lipid droplet-associated proteins in adipose tissue was examined under the hypothesis that bears suppress lipolysis during summer while gaining weight by increased expression of negative regulators of lipolysis. Adipose triglyceride lipase (ATGL) expression did not differ between seasons, but in contrast, the expression of ATGL coactivator Comparative gene identification-58 (CGI-58) was lower in summer. In addition, the expression of the negative regulators of lipolysis, G0S2 and cell-death inducing DNA fragmentation factor-a-like effector (CIDE)C markedly increased during summer. Free-ranging brown bears display potent upregulation of inhibitors of lipolysis in adipose tissue during summer. This is a potential mechanism for increased insulin sensitivity during weight gain and G0S2 may serve as a target to modulate insulin sensitivity.