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Diabetes, Obesity & Metabolism Dec 2023Donor hyperglycaemia following brain death has been attributed to reversible insulin resistance. However, our islet and pancreas transplant data suggest that other...
BACKGROUND
Donor hyperglycaemia following brain death has been attributed to reversible insulin resistance. However, our islet and pancreas transplant data suggest that other mechanisms may be predominant. We aimed to determine the relationships between donor insulin use and markers of beta-cell death and beta-cell function in pancreas donors after brain death.
METHODS
In pancreas donors after brain death, we compared clinical and biochemical data in 'insulin-treated' and 'not insulin-treated donors' (IT vs. not-IT). We measured plasma glucose, C-peptide and levels of circulating unmethylated insulin gene promoter cell-free DNA (INS-cfDNA) and microRNA-375 (miR-375), as measures of beta-cell death. Relationships between markers of beta-cell death and islet isolation outcomes and post-transplant function were also evaluated.
RESULTS
Of 92 pancreas donors, 40 (43%) required insulin. Glycaemic control and beta-cell function were significantly poorer in IT donors versus not-IT donors [median (IQR) peak glucose: 8 (7-11) vs. 6 (6-8) mmol/L, p = .016; C-peptide: 3280 (3159-3386) vs. 3195 (2868-3386) pmol/L, p = .046]. IT donors had significantly higher levels of INS-cfDNA [35 (18-52) vs. 30 (8-51) copies/ml, p = .035] and miR-375 [1.050 (0.19-1.95) vs. 0.73 (0.32-1.10) copies/nl, p = .05]. Circulating donor miR-375 was highly predictive of recipient islet graft failure at 3 months [adjusted receiver operator curve (SE) = 0.813 (0.149)].
CONCLUSIONS
In pancreas donors, hyperglycaemia requiring IT is strongly associated with beta-cell death. This provides an explanation for the relationship of donor IT with post-transplant beta-cell dysfunction in transplant recipients.
Topics: Humans; Islets of Langerhans Transplantation; Hyperglycemia; C-Peptide; Brain Death; Insulin; Tissue Donors; Cell Death; Cell-Free Nucleic Acids; MicroRNAs
PubMed: 37646197
DOI: 10.1111/dom.15248 -
Nutrients Oct 2023Diabetes mellitus represents a group of physiological dysfunctions characterized by hyperglycaemia resulting directly from insulin resistance (in the case of type 2...
Diabetes mellitus represents a group of physiological dysfunctions characterized by hyperglycaemia resulting directly from insulin resistance (in the case of type 2 diabetes mellitus-T2DM), inadequate insulin secretion/production, or excessive glucagon secretion (in type 1 diabetes mellitus-T1DM) [...].
Topics: Humans; Diabetes Mellitus, Type 2; Insulin; Glucagon; Blood Glucose; Diabetes Mellitus, Type 1
PubMed: 37836562
DOI: 10.3390/nu15194279 -
Physiological Research Dec 2023In order to understand the pathological changes associated with glucose homeostasis in old age, it is necessary to know the natural changes in the processing of...
In order to understand the pathological changes associated with glucose homeostasis in old age, it is necessary to know the natural changes in the processing of proinsulin to mature insulin. While there is abundant information about insulin production and function in diabetics, the situation in healthy adults and the elderly has surprisingly rarely been investigated. The aim of the study was to determine how proinsulin secretion changes in individuals with normal glucose tolerance during the process of natural aging. A total of 761 individuals (539 women, 222 men) aged 18-90 years with normal fasting glycemia (less than 5.6 mmol/l) were divided into five groups according to age. Body composition and levels of fasting blood glucose, proinsulin, insulin, and C-peptide were determined, and the ratios of proinsulin to both insulin and C-peptide were calculated. The homeostasis model of ?-cell function (HOMA F) and peripheral insulin resistance (HOMA R) were calculated. The effect of age was assessed using an ANOVA model consisting of the factors sex, age, and sex × age interaction. Statgraphics Centurion v. XVIII statistical software was used. Glycemia, insulin, C-peptide and HOMA R increased in both sexes up to 75 years. On the contrary, proinsulin levels as well as proinsulin/insulin and proinsulin/C-peptide ratios decreased with age up to 75 years. In normoglycemic and normotolerant people, both women and men, the aging process is associated with decreased insulin sensitivity compensated by potentiation of insulin production. In older age, there is also a gradual decrease in circulating proinsulin, which can be explained by its more efficient processing into active insulin by matured healthy beta cells.
Topics: Adult; Aged; Female; Humans; Male; Blood Glucose; C-Peptide; Insulin Resistance; Proinsulin; Aging; Adolescent; Young Adult; Middle Aged; Aged, 80 and over
PubMed: 38116775
DOI: 10.33549/physiolres.935181 -
Journal of Diabetes Science and... Jul 2023Recent in vitro experiments with patch pumps (PP) Omnipod (OP), Omnipod DASH (OP-D), A6 TouchCare (A6), and Accu-Chek Solo (ACS) have observed periodic fluctuations in...
Recent in vitro experiments with patch pumps (PP) Omnipod (OP), Omnipod DASH (OP-D), A6 TouchCare (A6), and Accu-Chek Solo (ACS) have observed periodic fluctuations in the delivered amount of insulin during basal rate and consecutive bolus delivery in some PP, calling for a more systematic characterization of these periodic delivery patterns. Here, it was found that during basal rate delivery of 1 U/h, some devices of OP, OP-D, and A6 showed deviations of up to ±30% from target delivery that consistently repeated every 5 hours, whereas ACS showed no clear periodicity with considerably lower deviations. Similar results were found during consecutive bolus delivery of 1 U, where deviations repeated consistently every five boluses in some devices of OP, OP-D, and A6. However, there was a large variability in the periodic delivery patterns between individual devices of the same PP model. Examining their pumping techniques indicated a connection between the insulin delivery mechanism and observed delivery patterns of the PP. However, the clinical impact of such patterns is unclear.
Topics: Humans; Insulin; Hypoglycemic Agents; Insulin Infusion Systems; Insulin, Regular, Human; Transdermal Patch
PubMed: 35466704
DOI: 10.1177/19322968221091843 -
Protein Science : a Publication of the... Apr 2024Primary defects in folding of mutant proinsulin can cause dominant-negative proinsulin accumulation in the endoplasmic reticulum (ER), impaired anterograde proinsulin...
Primary defects in folding of mutant proinsulin can cause dominant-negative proinsulin accumulation in the endoplasmic reticulum (ER), impaired anterograde proinsulin trafficking, perturbed ER homeostasis, diminished insulin production, and β-cell dysfunction. Conversely, if primary impairment of ER-to-Golgi trafficking (which also perturbs ER homeostasis) drives misfolding of nonmutant proinsulin-this might suggest bi-directional entry into a common pathological phenotype (proinsulin misfolding, perturbed ER homeostasis, and deficient ER export of proinsulin) that can culminate in diminished insulin storage and diabetes. Here, we've challenged β-cells with conditions that impair ER-to-Golgi trafficking, and devised an accurate means to assess the relative abundance of distinct folded/misfolded forms of proinsulin using a novel nonreducing SDS-PAGE/immunoblotting protocol. We confirm abundant proinsulin misfolding upon introduction of a diabetogenic INS mutation, or in the islets of db/db mice. Whereas blockade of proinsulin trafficking in Golgi/post-Golgi compartments results in intracellular accumulation of properly-folded proinsulin (bearing native disulfide bonds), impairment of ER-to-Golgi trafficking (regardless whether such impairment is achieved by genetic or pharmacologic means) results in decreased native proinsulin with more misfolded proinsulin. Remarkably, reversible ER-to-Golgi transport defects (such as treatment with brefeldin A or cellular energy depletion) upon reversal quickly restore the ER folding environment, resulting in the disappearance of pre-existing misfolded proinsulin while preserving proinsulin bearing native disulfide bonds. Thus, proper homeostatic balance of ER-to-Golgi trafficking is linked to a more favorable proinsulin folding (as well as trafficking) outcome.
Topics: Mice; Animals; Proinsulin; Protein Folding; Insulin; Endoplasmic Reticulum; Diabetes Mellitus; Insulin-Secreting Cells; Homeostasis; Disulfides
PubMed: 38511500
DOI: 10.1002/pro.4949 -
Diabetes Jul 2023The ability of insulin to stimulate glucose uptake in skeletal muscle is important for whole-body glycemic control. Insulin-stimulated skeletal muscle glucose uptake is...
The ability of insulin to stimulate glucose uptake in skeletal muscle is important for whole-body glycemic control. Insulin-stimulated skeletal muscle glucose uptake is improved in the period after a single bout of exercise, and accumulating evidence suggests that phosphorylation of TBC1D4 by the protein kinase AMPK is the primary mechanism responsible for this phenomenon. To investigate this, we generated a TBC1D4 knock-in mouse model with a serine-to-alanine point mutation at residue 711 that is phosphorylated in response to both insulin and AMPK activation. Female TBC1D4-S711A mice exhibited normal growth and eating behavior as well as intact whole-body glycemic control on chow and high-fat diets. Moreover, muscle contraction increased glucose uptake, glycogen utilization, and AMPK activity similarly in wild-type and TBC1D4-S711A mice. In contrast, improvements in whole-body and muscle insulin sensitivity after exercise and contractions were only evident in wild-type mice and occurred concomitantly with enhanced phosphorylation of TBC1D4-S711. These results provide genetic evidence to support that TBC1D4-S711 serves as a major point of convergence for AMPK- and insulin-induced signaling that mediates the insulin-sensitizing effect of exercise and contractions on skeletal muscle glucose uptake.
Topics: Female; Mice; Animals; Insulin; Glucose; AMP-Activated Protein Kinases; GTPase-Activating Proteins; Muscle, Skeletal; Insulin, Regular, Human; Phosphorylation; Muscle Contraction
PubMed: 37074686
DOI: 10.2337/db22-0666 -
Diabetes Jul 2023Inflammation-induced vascular insulin resistance is an early event in diet-induced obesity and contributes to metabolic insulin resistance. To examine whether exercise...
UNLABELLED
Inflammation-induced vascular insulin resistance is an early event in diet-induced obesity and contributes to metabolic insulin resistance. To examine whether exercise and glucagon-like peptide 1 (GLP-1) receptor agonism, alone or in combination, modulate vascular and metabolic insulin actions during obesity development, we performed a euglycemic insulin clamp in adult male rats after 2 weeks of high-fat diet feeding with either access to a running wheel (exercise), liraglutide, or both. Rats exhibited increased visceral adiposity and blunted microvascular and metabolic insulin responses. Exercise and liraglutide alone each improved muscle insulin sensitivity, but their combination fully restored insulin-mediated glucose disposal rates. The combined exercise and liraglutide intervention enhanced insulin-mediated muscle microvascular perfusion, reduced perivascular macrophage accumulation and superoxide production in the muscle, attenuated blood vessel inflammation, and improved endothelial function, along with increasing endothelial nucleus translocation of NRF2 and increasing endothelial AMPK phosphorylation. We conclude that exercise and liraglutide synergistically enhance the metabolic actions of insulin and reduce vascular oxidative stress and inflammation in the early stage of obesity development. Our data suggest that early combination use of exercise and GLP-1 receptor agonism might be an effective strategy in preventing vascular and metabolic insulin resistance and associated complications during the development of obesity.
ARTICLE HIGHLIGHTS
Inflammation-induced vascular insulin resistance occurs early in diet-induced obesity and contributes to metabolic insulin resistance. We examined whether exercise and GLP-1 receptor agonism, alone or in combination, modulate vascular and metabolic insulin actions during obesity development. We found that exercise and liraglutide synergistically enhanced the metabolic actions of insulin and reduced perimicrovascular macrophage accumulation, vascular oxidative stress, and inflammation in the early stage of obesity development. Our data suggest that early combination use of exercise and a GLP-1 receptor agonist might be an effective strategy in preventing vascular and metabolic insulin resistance and associated complications during the development of obesity.
Topics: Male; Rats; Animals; Liraglutide; Insulin Resistance; Glucagon-Like Peptide-1 Receptor; Insulin; Obesity; Diet, High-Fat; Insulin, Regular, Human; Inflammation
PubMed: 37074396
DOI: 10.2337/db22-0745 -
Journal of Endocrinological... Jun 2024The aim of this review is to evaluate the effects of new technology used in the management of diabetes mellitus (DM), including the use of continuous glucose monitoring... (Review)
Review
PURPOSE
The aim of this review is to evaluate the effects of new technology used in the management of diabetes mellitus (DM), including the use of continuous glucose monitoring (CGM) and the administration of insulin through continuous subcutaneous insulin infusion (CSII), on male and female sexual function.
METHODS
This narrative review was performed for all available prospective, retrospective and review articles, published up to June 2023 in PubMed. Data were extracted from the text and from the tables of the manuscript.
RESULTS
Sexual dysfunctions are an underestimated comorbidity of DM in both male and female. Although erectile dysfunction (ED) is recognized by the guidelines as a complication of DM, female sexual dysfunction (FSD) is poorly investigated in clinical setting. In addition to the complications of DM, the different types of therapies can also influence male and female sexual response. Furthermore, insulin therapy can be administered through multiple-daily injections (MDI) or a CSII. The new technologies in the field of DM allow better glycemic control which results in a reduction in the occurrence or aggravation of complications of DM. Despite this evidence, few data are available on the impact of new technologies on sexual dysfunctions.
CONCLUSIONS
The use of DM technology might affect sexual function due to the risk of a worse body image, as well as discomfort related to CSII disconnection during sexual activity. However, the use is related to an improved metabolic control, which, in the long-term associates to a reduction in all diabetes complications, including sexual function.
Topics: Humans; Sexual Health; Diabetes Mellitus; Sexual Dysfunction, Physiological; Male; Female; Blood Glucose Self-Monitoring; Insulin Infusion Systems; Insulin; Hypoglycemic Agents; Diabetes Complications
PubMed: 37987916
DOI: 10.1007/s40618-023-02237-7 -
Scientific Reports Dec 2023Insulin has long been associated with dementia. Insulin affecting the clearance of amyloid-β peptide and phosphorylation of tau in the CNS. Proinsulin is a precursor of...
Insulin has long been associated with dementia. Insulin affecting the clearance of amyloid-β peptide and phosphorylation of tau in the CNS. Proinsulin is a precursor of insulin and its elevated serum levels are associated with peripheral insulin resistance that may reduce brain insulin levels. Our study aimed to assess differences in serum proinsulin levels between normal and cognitive impairment groups. Prospective recruitment of elderly participants was initiated from October 2019 to September 2023. Patients were divided into "cognitive impairment" and "normal cognition" group. All participants had blood drawn and serum proinsulin was measured at baseline and 12 months. Neurocognitive testing was performed every 6 months. A total of 121 participants were recruited. Seventy-seven were in the normal cognition group and 44 in the cognitive impairment group. The glycemic control and prevalence of diabetes type 2 was similar between groups. Baseline serum proinsulin levels were higher in the cognitively impaired group compared to the normal group at baseline (p = 0.019) and correlated with worse cognitive scores. We identified cognitive status, age, and BMI as potential factors associated with variations in baseline proinsulin levels. Given the complex interplay between insulin and dementia pathogenesis, serum biomarkers related to insulin metabolism may exhibit abnormalities in cognitive impaired patients. Here we present the proinsulin levels in individuals with normal cognitive function versus those with cognitive impairment and found a significant difference. This observation may help identifying non-diabetic patients suitable for treatment with novel AD drugs that related to insulin pathway.
Topics: Humans; Aged; Proinsulin; Prospective Studies; Blood Glucose; Insulin; Cognitive Dysfunction; Biomarkers; Dementia
PubMed: 38105338
DOI: 10.1038/s41598-023-49479-2 -
Peptides Nov 2023The field of peptides exploded in the 1970's and has continued to be a major area of discovery. Among the early discoveries was that peptides administered peripherally... (Review)
Review
The field of peptides exploded in the 1970's and has continued to be a major area of discovery. Among the early discoveries was that peptides administered peripherally could affect brain functions. This led Kastin to propose that peptides could cross the blood-brain barrier (BBB). Although initially very controversial, Kastin, I, and others demonstrated not only that peptides can cross the BBB, but elucidated many fundamental characteristics of that passage. That work was in large part the basis of the 2022 Viktor Mutt Lectureship. Here, we review some of the early work with current updates on topics related to the penetration of peptides across the BBB. We briefly review mechanisms by which peripherally administered peptides can affect brain function without crossing the BBB, and then review the major mechanisms by which peptides and their analogs have been show to cross the BBB: transmembrane diffusion, saturable transport, and adsorptive transcytosis. Saturable transport systems are adaptable to physiologic changes and can be altered by disease states. In particular, the transport across the BBB of insulin and of pituitary adenylate cyclase activating polypeptide (PACAP) illustrate many of the concepts regarding peptide transport across the BBB.
Topics: Blood-Brain Barrier; Biological Transport; Pituitary Adenylate Cyclase-Activating Polypeptide; Insulin
PubMed: 37598757
DOI: 10.1016/j.peptides.2023.171079