Treating obesity in type 1 diabetes mellitus - review of efficacy and safety.

PURPOSE OF REVIEW: Obesity is an epidemic in the United States with serious concomitant co-morbid conditions; people living with type 1 diabetes mellitus (T1D) are not immune to the risk either. Weight gain in T1D is likely multifactorial, due to genetic, environmental and treatment-related factors. FDA-approved and other adjunctive weight loss therapies may benefit people living with T1D but there are risks to consider when providing recommendations or prescribing medications. RECENT FINDINGS: We performed a PubMed search of studies assessing clinical outcomes of both approved and off-label medications used in the treatment of type 1 diabetes. Search terms included 'type 1 diabetes, obesity' and the following: (1) metformin, (2) pramlintide, (3) glucagon-like peptide-1 (GLP-1) receptor agonists, (4) dual GLP-1 and gastric inhibitory polypeptide (GIP) agonists, (5) sodium-glucose cotransporter-2 (SGLT-2) inhibitors, (6) surgical treatment of obesity, (7) insulin pump, (8) insulin, (9) medical nutrition therapy, (10) diabetes self-management education, (11) exercise, (12) naltrexone-buproprion, (13) orlistat, and (14) phentermine-topiramate. SUMMARY: Weight loss treatments provide a wide-range of benefits in reducing both morbidity and mortality in those who are obese. Treatments also have varying adverse effect profiles which may impact T1D treatment. In this review, we aim to summarize study outcomes in people with T1D, including risks and benefits, of on- and off-label weight loss treatments.

Research design and baseline participant characteristics of the Resilient, Empowered, Active Living with Diabetes - Telehealth (REAL-T) Study: A randomized controlled trial for young adults with type 1 diabetes.

BACKGROUND: Type 1 diabetes (T1D) is a chronic condition affecting nearly 1.9 million people in the United States. Young adults (YAs) with T1D face unique challenges in managing their condition, experiencing poorer health and well-being than other age groups. The current study is evaluating the Resilient, Empowered, Active Living (REAL) intervention, previously shown to improve glucose levels and quality of life among YAs with diabetes, using telehealth delivery (REAL-T) to expand reach and accessibility. This paper reports on the methodology and baseline participant characteristics of the REAL-T study. METHODS: REAL-T is a two-arm randomized controlled trial that recruited 18-30 year olds with T1D via clinics and social media advertising. Data collection, which was adapted to be fully remote due to COVID-19, occurs every three months for one year. Participants receive either usual care or a 6-month telehealth occupational therapy intervention. The primary outcome is glycated hemoglobin (A1c); secondary outcomes include diabetes distress, quality of life, and continuous glucose monitor-derived measures. RESULTS: The study enrolled a diverse sample of 209 YAs with T1D. Analysis of baseline data indicates equivalence between the intervention and control groups. Study participants have notably higher diabetes distress and poorer mental well-being than similar populations. CONCLUSION: The REAL-T study successfully adapted to remote implementation during the COVID-19 pandemic. By examining long-term outcomes, mediating pathways, and cost-effectiveness, the study will contribute knowledge of the impact of tailored interventions for YAs with T1D, designed to reduce disparities and improve health and well-being in this population.

Microstructural brain tissue changes contribute to cognitive and mood deficits in adults with type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) patients show brain tissue changes in mood and cognitive regulatory sites, but the nature and extent of tissue injury and their associations with symptoms are unclear. Our aim was to examine brain tissue damage in T2DM over controls using mean diffusivity (MD) computed from diffusion tensor imaging (DTI), and assess correlations with mood and cognitive symptoms in T2DM. We collected DTI series (MRI), mood, and cognitive data, from 169 subjects (68 T2DM and 101 controls). Whole-brain MD-maps were calculated, normalized, smoothed, and compared between groups, as well as correlated with mood and cognition scores in T2DM subjects. Type 2 diabetes patients showed altered cognitive and mood functions over control subjects. Multiple brain sites in T2DM patients showed elevated MD values, indicating chronic tissue changes, including the cerebellum, insula, and frontal and prefrontal cortices, cingulate, and lingual gyrus. Associations between MD values and mood and cognition scores appeared in brain sites mediating these functions. Type 2 diabetes patients show predominantly chronic brain tissue changes in areas mediating mood and cognition functions, and tissue changes from those regions correlate with mood and cognitive symptoms suggesting that the microstructural brain changes may account for the observed functional deficits.

Barriers to Implementation of Teleretinal Diabetic Retinopathy Screening Programs Across the University of California.

Aim: To describe barriers to implementation of diabetic retinopathy (DR) teleretinal screening programs and artificial intelligence (AI) integration at the University of California (UC). Methods: Institutional representatives from UC Los Angeles, San Diego, San Francisco, Irvine, and Davis were surveyed for the year of their program's initiation, active status at the time of survey (December 2021), number of primary care clinics involved, screening image quality, types of eye providers, image interpretation turnaround time, and billing codes used. Representatives were asked to rate perceptions toward barriers to teleretinal DR screening and AI implementation using a 5-point Likert scale. Results: Four UC campuses had active DR teleretinal screening programs at the time of survey and screened between 246 and 2,123 patients at 1-6 clinics per campus. Sites reported variation between poor-quality photos (<5% to 15%) and average image interpretation time (1-5 days). Patient education, resource availability, and infrastructural support were identified as barriers to DR teleretinal screening. Cost and integration into existing technology infrastructures were identified as barriers to AI integration in DR screening. Conclusions: Despite the potential to increase access to care, there remain several barriers to widespread implementation of DR teleretinal screening. More research is needed to develop best practices to overcome these barriers.

Type 2 diabetes mellitus and cognitive function: understanding the connections.

PURPOSE OF REVIEW: To review the connection between type 2 diabetes and cognitive dysfunction, including its epidemiology, potential mechanisms of pathophysiology, risk factors, possible prevention, and treatment considerations. RECENT FINDINGS: Diabetes is a risk factor for mild cognitive decline, in addition to Alzheimer's disease and vascular dementia. Duration of diabetes, concomitant vascular or associated co-morbidities, hyper- and hypoglycemia may lead to worsening cognitive dysfunction. Unfortunately, there is a lack of evidence-based guidance on the prevention of cognitive dysfunction in the diabetes population. Studies of diabetes medications, including metformin, glucagon-like peptide-1 (GLP-1) receptor agonists, and sodium-glucose cotransporter-2 inhibitors (SGLT2) have shown some benefit with cardiovascular morbidity and may affect cognition. In the absence of clearly defined preventive tools, diabetes practice guidelines recommend annual cognitive screening as standard of care in adults with diabetes aged 65 years or older. SUMMARY: People living with diabetes are at risk for significant decline in cognitive function. Epidemiology and risk factors are well defined. Prevention and treatment strategies are limited and require further study.

Utilizing point-of-care A1c to impact outcomes - can we make it happen in primary care?

PURPOSE OF REVIEW: Hemoglobin A1c testing provides a marker of glycemic control and is the standard for diabetes risk assessment. According to the Centers for Disease Control (CDC), only 67.3-71.4% of diabetic patients between 2011 and 2016 had at least two A1c levels tested per year. Moreover, 27.8% had uncontrolled diabetes with an A1c of ≥8.0%, increasing the risk of microvascular complications. Lack of monitoring presents a significant barrier, and improving ease of testing could improve glycemic control. RECENT FINDINGS: Point-of-care (POC) A1c testing, obtained via capillary blood with results provided in 5-6 min, is available and used frequently in endocrine clinics. However, POC A1c testing is not standard in primary care, where 90% of type 2 diabetes patients are treated. Barriers include access and costs of POC A1c machines and standardization of testing in the primary care setting. Review of literature, however, suggests that POC A1c testing in primary care may lead to A1c reduction whereas being potentially cost-effective and strengths the patient-physician relationship. SUMMARY: POC A1c testing in primary care, if widely available and integrated into workflow, has the potential to positively impact diabetes care. Real-time feedback may change patient and physician behaviors, allowing earlier therapeutic intensification.

Adjunctive therapies in type 1 diabetes mellitus.

PURPOSE OF REVIEW: Insulin is the mainstay of treatment in people living with type 1 diabetes mellitus due to an immune-mediated loss of beta cells. Yet despite advances in insulin therapy and other technological advances, glycemic control remains difficult to achieve. Therefore, we aim to highlight risks and benefits of adjunctive therapies that may improve type 1 diabetes care. RECENT FINDINGS: We identified studies assessing clinical outcomes of adjunctive therapies that are both Food and Drug Administration (FDA)-approved and off-label in type 1 diabetes. Adjunctive therapies reviewed included metformin, pramlintide, glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter-2 inhibitors. SUMMARY: Although insulin is required in people living with type 1 diabetes mellitus, adjunctive therapies may positively impact glycemic control, reduce insulin requirements and lead to weight loss. In addition, the risk of hypoglycemia, gastrointestinal side effects and diabetes ketoacidosis may be increased with the use of these adjunctive therapies. Pramlintide is currently the only FDA-approved adjunctive therapy, whereas others require continued research to better understand risk-to-benefit ratio.

Poor Sleep Quality Linked to Decreased Brain Gray Matter Density in Adults with Type 2 Diabetes.

BACKGROUND: Poor sleep is common in adults with Type 2 Diabetes Mellitus (T2DM), which may contribute to brain tissue changes. However, the impact of sleep quality on brain tissue in T2DM individuals is unclear. We aimed to evaluate differential sleep quality with brain changes, and brain tissue integrity in T2DM patients. METHODS: Data were collected from 34 patients with T2DM and included sleep quality (assessed by the Pittsburgh Sleep Quality Index [PSQI], and high-resolution T1-weighted brain images using a 3.0-Tesla MRI scanner. Gray matter density (GMD) maps were compared between subjects with good vs poor sleep quality as assessed by PSQI (covariates: age, sex, BMI). RESULTS: Of 34 T2DM patients, 17 showed poor sleep quality. Multiple brain sites, including the hippocampus, cerebellum, prefrontal, amygdala, thalamus, hypothalamus, insula, cingulate, and temporal areas, showed reduced gray matter in T2DM patients with poor sleep quality over patients with good sleep quality. Negative associations emerged between PSQI scores and gray matter density in multiple areas. CONCLUSIONS: T2DM patients with poor sleep quality show brain tissue changes in sites involved in sleep regulation. Findings indicate that improving sleep may help mitigate brain tissue damage, and thus, improve brain function in T2DM patients.

Regional Brain Gray Matter Changes in Patients with Type 2 Diabetes Mellitus.

Patients with Type 2 diabetes mellitus (T2DM) show cognitive and mood impairment, indicating potential for brain injury in regions that control these functions. However, brain tissue integrity in cognition, anxiety, and depression regulatory sites, and their associations with these functional deficits in T2DM subjects remain unclear. We examined gray matter (GM) changes in 34 T2DM and 88 control subjects using high-resolution T1-weighted images, collected from a 3.0-Tesla magnetic resonance imaging scanner, and assessed anxiety [Beck Anxiety Inventory], depressive symptoms [Beck Depression Inventory-II], and cognition [Montreal Cognitive Assessment]. We also investigated relationships between GM status of cognitive and mood control sites and these scores in T2DM. Significantly increased anxiety (p = 0.003) and depression (p = 0.001), and reduced cognition (p = 0.002) appeared in T2DM over controls. Decreased GM volumes appeared in several regions in T2DM patients, including the prefrontal, hippocampus, amygdala, insular, cingulate, cerebellum, caudate, basal-forebrain, and thalamus areas (p < 0.01). GM volumes were significantly associated with anxiety (r = -0.456,p = 0.009), depression (r = -0.465,p = 0.01), and cognition (r = 0.455,p = 0.009) scores in regions associated with those regulations (prefrontal cortices, hippocampus, para hippocampus, amygdala, insula, cingulate, caudate, thalamus, and cerebellum) in T2DM patients. Patients with T2DM show brain damage in regions that are involved in cognition, anxiety, and depression control, and these tissue alterations are associated with functional deficits. The findings indicate that mood and cognitive deficits in T2DM patients has brain structural basis in the condition.

Prefrontal cortex brain damage and glycemic control in patients with type 2 diabetes.

BACKGROUND: This study examined brain tissue integrity in sites that controls cognition (prefrontal cortices; PFC) and its relationships to glycemic outcomes in adults with type 2 diabetes mellitus (T2DM). METHODS: We examined 28 T2DM patients (median age 57.1 years; median body mass index [BMI] 30.6 kg/m2 ;11 males) and 47 healthy controls (median age 55.0 years; median BMI 25.8 kg/m2 ; 29 males) for cognition (Montreal Cognitive Assessment [MoCA]), glycemic control (hemoglobin A1c [HbA1c]), and PFC tissue status via brain magnetic resonance imaging (MRI). High-resolution T1-weighted images were collected using a 3.0-Tesla MRI scanner, and PFC tissue changes (tissue density) were examined with voxel-based morphometry procedures. RESULTS: Reduced PFC density values were observed in T2DM patients compared to controls (left, 0.41 ± 0.02 mm3 /voxel vs 0.44 ± 0.02 mm3 /voxel, P < 0.001; right, 0.41 ± 0.03 mm3 /voxel vs 0.45 ± 0.02 mm3 /voxel, P < 0.001). PFC density values were positively correlated with cognition; left PFC region (r = 0.53, P = 0.005) and right PFC region (r = 0.56, P = 0.003), with age and sex as covariates. Significant negative correlations were found between PFC densities and HbA1c values; left PFC region (r = -0.39, P = 0.049) and right PFC region (r = -0.48, P = 0.01), with age and sex as covariates. CONCLUSIONS: T2DM patients showed PFC brain tissue damage, which is associated with cognitive deficits and poor glycemic control. Further research is needed to identify causal relationships between HbA1c, cognition, and brain changes in T2DM and to evaluate the impact of interventions to prevent brain tissue injury or neuroregeneration in this high-risk patient population, to eventually preserve or enhance cognition and improve glucose outcomes.

Efficacy of video-based education program in improving metabolic surgery perception among patients with obesity and diabetes.

BACKGROUND: Metabolic surgery remains underutilized despite its efficacy and safety. Poor perception of surgery has been cited as one of the major reasons. OBJECTIVES: Evaluate current patient perceptions about metabolic surgery and measure the impact a video-based education program has on changing the perceptions of patients diagnosed with obesity and type 2 diabetes. SETTING: A university hospital in the United States. METHODS: A prospective interventional study was performed at an endocrinology clinic. Patients were asked to complete surveys evaluating their perception of metabolic surgery before and after watching a short educational video. RESULTS: A total of 51 patients were recruited; almost all patients (98%) attempted weight loss in the past, and approximately 90.1% voiced dissatisfaction with their current weight. The video-based education program was effective in improving the patient's perception of the efficacy and safety with regard to surgery. In addition, the proportion of patients with overall positive impression toward metabolic surgery increased from 22.5% to 53.1% (P < .01) and those willing to undergo surgical consultation increased from 41.7% to 51.0% (P < .01). Among those that remained unwilling, fear of surgery in general was the most commonly voiced reason (31.4%), with safety (27.5%) and cost of metabolic surgery (27.5%) being equally concerning. CONCLUSIONS: Most patients with obesity and type 2 diabetes held negative impressions of metabolic surgery due to its perceived risk profile. A video-based educational intervention may improve patients' perception and increase their willingness for surgical referral. Future trials with a broader sample and longer follow-up could provide answers to its efficacy in increasing metabolic surgery accessibility.

Anti-PD-L1 therapy and the onset of diabetes mellitus with positive pancreatic autoantibodies.

An 84-year-old woman with metastatic squamous cell carcinoma of the nasopharynx and no history of diabetes was started on the antiprogrammed cell death ligand-1 (anti-PD-L1) antibody durvalumab. Four months later, she presented in diabetic ketoacidosis with glucose 488 mg/dL, anion gap 16, positive serum ketones and A1C9.1%. Antiglutamic acid decarboxylase 65 (GAD) antibody was 13 U/mL (normal, <0.5 U/mL), c-peptide 0.4 ng/dL (normal, 1.1-4.3 ng/mL) and glucose 142 mg/dL. A man with metastatic papillary urothelial carcinoma was treated with the PD-L1 inhibitor atezolizumab. He had no history of diabetes. Nine weeks after initiation, he developed fatigue and polyuria with blood glucose 336 mg/dL, c-peptide 0.6 ng/mL, A1C8.2% and GAD antibodies 28.4 U/mL (normal, <1 U/mL). Due to the diagnosis of autoimmune diabetes, both patients were treated with insulin. Autoimmune diabetes is a rare immune-related adverse effect of PD-L1 inhibitors. We present the first two cases with documented positive pancreatic autoantibodies.

Cross-sectional and Test-Retest Characterization of PET with [(18)F]FP-(+)-DTBZ for ß Cell Mass Estimates in Diabetes.

PURPOSE: The vesicular monoamine transporter, type 2 (VMAT2) is expressed by insulin producing ß cells and was evaluated as a biomarker of ß cell mass (BCM) by positron emission tomography (PET) with [(18)F]fluoropropyl-dihydrotetrabenazine ([(18)F]FP-(+)-DTBZ). PROCEDURES: We evaluated the feasibility of longitudinal pancreatic PET VMAT2 quantification in the pancreas in two studies of healthy controls and patients with type 1 or 2 diabetes. VMAT2 binding potential (BPND) was estimated voxelwise using a reference tissue method in a cross-sectional study, followed by assessment of reproducibility using a test-retest paradigm. Metabolic function was evaluated by stimulated c-peptide measurements. RESULTS: Pancreatic BPND was significantly decreased in patients with type 1 diabetes relative to controls and the test-retest variability was 9.4%. CONCLUSIONS: Pancreatic VMAT2 content is significantly reduced in long-term diabetes patients relative to controls and repeat scans are sufficiently reproducible to suggest the feasibility clinically VMAT2 measurements in longitudinal studies of new onset diabetes.

Differentiation of hypothalamic-like neurons from human pluripotent stem cells.

The hypothalamus is the central regulator of systemic energy homeostasis, and its dysfunction can result in extreme body weight alterations. Insights into the complex cellular physiology of this region are critical to the understanding of obesity pathogenesis; however, human hypothalamic cells are largely inaccessible for direct study. Here, we developed a protocol for efficient generation of hypothalamic neurons from human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) obtained from patients with monogenetic forms of obesity. Combined early activation of sonic hedgehog signaling followed by timed NOTCH inhibition in human ESCs/iPSCs resulted in efficient conversion into hypothalamic NKX2.1+ precursors. Application of a NOTCH inhibitor and brain-derived neurotrophic factor (BDNF) further directed the cells into arcuate nucleus hypothalamic-like neurons that express hypothalamic neuron markers proopiomelanocortin (POMC), neuropeptide Y (NPY), agouti-related peptide (AGRP), somatostatin, and dopamine. These hypothalamic-like neurons accounted for over 90% of differentiated cells and exhibited transcriptional profiles defined by a hypothalamic-specific gene expression signature that lacked pituitary markers. Importantly, these cells displayed hypothalamic neuron characteristics, including production and secretion of neuropeptides and increased p-AKT and p-STAT3 in response to insulin and leptin. Our results suggest that these hypothalamic-like neurons have potential for further investigation of the neurophysiology of body weight regulation and evaluation of therapeutic targets for obesity.

Human oocytes reprogram adult somatic nuclei of a type 1 diabetic to diploid pluripotent stem cells.

The transfer of somatic cell nuclei into oocytes can give rise to pluripotent stem cells that are consistently equivalent to embryonic stem cells, holding promise for autologous cell replacement therapy. Although methods to induce pluripotent stem cells from somatic cells by transcription factors are widely used in basic research, numerous differences between induced pluripotent stem cells and embryonic stem cells have been reported, potentially affecting their clinical use. Because of the therapeutic potential of diploid embryonic stem-cell lines derived from adult cells of diseased human subjects, we have systematically investigated the parameters affecting efficiency of blastocyst development and stem-cell derivation. Here we show that improvements to the oocyte activation protocol, including the use of both kinase and translation inhibitors, and cell culture in the presence of histone deacetylase inhibitors, promote development to the blastocyst stage. Developmental efficiency varied between oocyte donors, and was inversely related to the number of days of hormonal stimulation required for oocyte maturation, whereas the daily dose of gonadotropin or the total number of metaphase II oocytes retrieved did not affect developmental outcome. Because the use of concentrated Sendai virus for cell fusion induced an increase in intracellular calcium concentration, causing premature oocyte activation, we used diluted Sendai virus in calcium-free medium. Using this modified nuclear transfer protocol, we derived diploid pluripotent stem-cell lines from somatic cells of a newborn and, for the first time, an adult, a female with type 1 diabetes.

ß-cell dysfunction due to increased ER stress in a stem cell model of Wolfram syndrome.

Wolfram syndrome is an autosomal recessive disorder caused by mutations in WFS1 and is characterized by insulin-dependent diabetes mellitus, optic atrophy, and deafness. To investigate the cause of ß-cell failure, we used induced pluripotent stem cells to create insulin-producing cells from individuals with Wolfram syndrome. WFS1-deficient ß-cells showed increased levels of endoplasmic reticulum (ER) stress molecules and decreased insulin content. Upon exposure to experimental ER stress, Wolfram ß-cells showed impaired insulin processing and failed to increase insulin secretion in response to glucose and other secretagogues. Importantly, 4-phenyl butyric acid, a chemical protein folding and trafficking chaperone, restored normal insulin synthesis and the ability to upregulate insulin secretion. These studies show that ER stress plays a central role in ß-cell failure in Wolfram syndrome and indicate that chemical chaperones might have therapeutic relevance under conditions of ER stress in Wolfram syndrome and other forms of diabetes.

iPSC-derived ß cells model diabetes due to glucokinase deficiency.

Diabetes is a disorder characterized by loss of ß cell mass and/or ß cell function, leading to deficiency of insulin relative to metabolic need. To determine whether stem cell-derived ß cells recapitulate molecular-physiological phenotypes of a diabetic subject, we generated induced pluripotent stem cells (iPSCs) from subjects with maturity-onset diabetes of the young type 2 (MODY2), which is characterized by heterozygous loss of function of the gene encoding glucokinase (GCK). These stem cells differentiated into ß cells with efficiency comparable to that of controls and expressed markers of mature ß cells, including urocortin-3 and zinc transporter 8, upon transplantation into mice. While insulin secretion in response to arginine or other secretagogues was identical to that in cells from healthy controls, GCK mutant ß cells required higher glucose levels to stimulate insulin secretion. Importantly, this glucose-specific phenotype was fully reverted upon gene sequence correction by homologous recombination. Our results demonstrate that iPSC-derived ß cells reflect ß cell-autonomous phenotypes of MODY2 subjects, providing a platform for mechanistic analysis of specific genotypes on ß cell function.