humulin-s and Cardiovascular-Diseases

Despite enormous global efforts within clinical research and medical practice to reduce cardiovascular disease(s) (CVD), it still remains the leading cause of death worldwide. While genetic factors clearly contribute to CVD etiology, the preponderance of epidemiological data indicate that a major common denominator among diverse ethnic populations from around the world contributing to CVD is the composite of Western lifestyle cofactors, particularly Western diets (high saturated fat/simple sugar [particularly high fructose and sucrose and to a lesser extent glucose] diets), psychosocial stress, depression, and altered sleep/wake architecture. Such Western lifestyle cofactors are potent drivers for the increased risk of metabolic syndrome and its attendant downstream CVD. The central nervous system (CNS) evolved to respond to and anticipate changes in the external (and internal) environment to adapt survival mechanisms to perceived stresses (challenges to normal biological function), including the aforementioned Western lifestyle cofactors. Within the CNS of vertebrates in the wild, the biological clock circuitry surveils the environment and has evolved mechanisms for the induction of the obese, insulin-resistant state as a survival mechanism against an anticipated ensuing season of low/no food availability. The peripheral tissues utilize fat as an energy source under muscle insulin resistance, while increased hepatic insulin resistance more readily supplies glucose to the brain. This neural clock function also orchestrates the reversal of the obese, insulin-resistant condition when the low food availability season ends. The circadian neural network that produces these seasonal shifts in metabolism is also responsive to Western lifestyle stressors that drive the CNS clock into survival mode. A major component of this natural or Western lifestyle stressor-induced CNS clock neurophysiological shift potentiating the obese, insulin-resistant state is a diminution of the circadian peak of dopaminergic input activity to the pacemaker clock center, suprachiasmatic nucleus. Pharmacologically preventing this loss of circadian peak dopaminergic activity both prevents and reverses existing metabolic syndrome in a wide variety of animal models of the disorder, including high fat-fed animals. Clinically, across a variety of different study designs, circadian-timed bromocriptine-QR (quick release) (a unique formulation of micronized bromocriptine-a dopamine D2 receptor

Topics: Animals; Brain; Bromocriptine; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dopamine; Dopamine Agonists; Insulin; Insulin Resistance; Insulin, Regular, Human; Metabolic Syndrome

The association between FTO rs9939609 and obesity is modified by physical activity (PA) and/or insulin sensitivity (IS). We aimed to assess whether these modifications are independent, to assess whether PA and/or IS modify the association between rs9939609 and cardiometabolic traits, and to elucidate underlying mechanisms.. Genetic association analyses comprised up to 19,585 individuals. PA was self-reported, and IS was defined based on inverted HOMA insulin resistance index. Functional analyses were performed in muscle biopsies from 140 men and in cultured muscle cells.. The BMI-increasing effect of the FTO rs9939609 A allele was attenuated by 47% with high PA (β [SE], -0.32 [0.10] kg/m2, P = 0.0013) and by 51% with high IS (-0.31 [0.09] kg/m2, P = 0.00028). Interestingly, these interactions were essentially independent (PA, -0.20 [0.09] kg/m2, P = 0.023; IS, -0.28 [0.09] kg/m2, P = 0.0011). The rs9939609 A allele was also associated with higher all-cause mortality and certain cardiometabolic outcomes (hazard ratio, 1.07-1.20, P > 0.04), and these effects tended to be weakened by greater PA and IS. Moreover, the rs9939609 A allele was associated with higher expression of FTO in skeletal muscle tissue (0.03 [0.01], P = 0.011), and in skeletal muscle cells, we identified a physical interaction between the FTO promoter and an enhancer region encompassing rs9939609.. Greater PA and IS independently reduced the effect of rs9939609 on obesity. These effects might be mediated through altered expression of FTO in skeletal muscle. Our results indicated that PA and/or other means of increasing insulin sensitivity could counteract FTO-related genetic predisposition to obesity.

Topics: Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Body Mass Index; Cardiovascular Diseases; Exercise; Genetic Predisposition to Disease; Genotype; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Insulin, Regular, Human; Male; Obesity; Polymorphism, Single Nucleotide

To describe glucose-lowering drugs prescribing pattern in a large population of older diabetics from 2010 to 2021.. Using linkable administrative health databases, we included patients aged 65-90 years treated with glucose-lowering drugs. Prevalence rate of drugs was collected within each study year. A stratified analysis by gender, age and coexistence of cardiovascular disease (CVD) was conducted.. A total of 251 737 and 308 372 patients were identified in 2010 and 2021, respectively. Use of metformin (68.4% to 76.6%), DPP-4i (1.6% to 18.4%), GLP-1-RA (0.4% to 10.2%), SGLT2i (0.6% to 11.1%) increased, while sulfonylureas (53.6% to 20.7%) and glinides (10.5% to 3.5%) decreased over time. Metformin, glitazones, GLP1-RA, SGLT2i and DPP4i (except for 2021) usage decreased with aging, in contrast to sulfonylureas, glinides and insulin. The coexistence of CVD was associated with a higher prescription of glinides, insulin, DPP-4i, GLP1-RA and SGLT2i, particularly in 2021.. We found a significant increase in the prescriptions of GLP-1 RA and SGLT2i in older diabetics, mainly in those with CVD. However, drugs without CV benefits including sulfonylureas and DPP-4i continued to be highly prescribed in older patients. There is still room to improve the management in this population according to recommendations.

Topics: Aged; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Humans; Hypoglycemic Agents; Insulin; Insulin, Regular, Human; Metformin; Sodium-Glucose Transporter 2 Inhibitors; Sulfonylurea Compounds

We investigated whether lean insulin-resistant individuals manifest increased cardiometabolic risk.. 2,341 (51.8% females) healthy 16-23-year-old subjects were categorized as lean or overweight/obese; and insulin-sensitive or insulin-resistant, and compared.. In both sexes, lean insulin-sensitive and insulin-resistant subjects displayed similar measures of obesity (e.g., males, waist-to-height ratio: lean insulin-sensitive: 0.42 ± 0.03, lean insulin-resistant: 0.43 ± 0.03, overweight/obese insulin-sensitive: 0.49 ± 0.05, overweight/obese insulin-resistant: 0.53 ± 0.06). Lean insulin-sensitive individuals were more insulin-sensitive compared with their overweight/obese peers; insulin-resistant groups presented similar insulin-sensitivity (males, the Quantitative insulin-sensitivity check index (QUICKI): lean insulin-sensitive: 0.354 ± 0.022, lean insulin-resistant: 0.304 ± 0.013, overweight/obese insulin-sensitive: 0.343 ± 0.019, overweight/obese insulin-resistant: 0.299 ± 0.015). The two-factor analysis of variance indicated an independent effect of insulin sensitivity, overweight/obesity, and their interaction on the continuous metabolic syndrome score (p < 0.001, all; males, lean insulin-sensitive: 1.87 ± 0.35, lean insulin-resistant: 2.14 ± 0.42, overweight/obese insulin-sensitive: 2.15 ± 0.40, overweight/obese insulin-resistant: 2.75 ± 0.69). C-reactive protein, leukocyte count, and glomerular filtration rate in both sexes; uric acid, asymmetric dimethyl-arginine, and soluble vascular adhesion protein-1 in males; and soluble receptor for advanced glycation end-products in females were independently associated with insulin resistance. Among phenotypes associated with low QUICKI, the distribution of insulin-resistant individuals was random.. Later clinical consequences of insulin resistance in lean subjects remain to be elucidated in longitudinal studies.

Topics: Body Mass Index; Cardiovascular Diseases; Cross-Sectional Studies; Female; Humans; Insulin; Insulin Resistance; Insulin, Regular, Human; Male; Obesity; Overweight; Receptor for Advanced Glycation End Products; Retrospective Studies; Young Adult

We aimed to determine if severe hypoglycemia (SH) independently increases the risk of hospitalization for heart failure (hHF) in type 2 diabetes, regardless of the prevalent or incident cardiovascular disease (CVD).. This was a nationwide population-based propensity score-matched study using Korean National Health Insurance Service data (2002-2018). The hazards of hHF were compared in individuals who experienced SH (n = 8,965) and 1:3 matched controls, among adults with diabetes using oral anti-diabetes medications (OADs) with or without insulin and without previous hHF at baseline.. During 236,417 person-years, 1,189 cases of hHF occurred. The hazard of hHF was higher in individuals with SH compared to matched controls (adjusted hazard ratio [aHR] 1.503, 95 % confidence interval [CI] 1.324-1.707). The increase in aHR remained significant when excluding participants with prevalent or incident major adverse cardiovascular events (MACE; aHR 1.352, 95 % CI 1.228-1.622) and any CVD (aHR 1.342, 95 % CI 1.025-1.756). Two or more SH events were associated with further increase in hHF risk.. SH was associated with increased risks of hHF among adults with diabetes using OAD with or without insulin. The increased risk was attenuated but remained significant in those without prevalent or incident MACE or CVDs.

Topics: Adult; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Heart Failure; Hospitalization; Humans; Hypoglycemia; Insulin; Insulin, Regular, Human; Risk Factors

The comparative cardiovascular safety of analogue and human insulins in adults with type 2 diabetes who initiate insulin therapy in usual care settings has not been carefully evaluated using machine learning and other rigorous analytic methods.. To examine the association of analogue vs human insulin use with mortality and major cardiovascular events.. This retrospective cohort study included 127 600 adults aged 21 to 89 years with type 2 diabetes at 4 health care delivery systems who initiated insulin therapy from January 1, 2000, through December 31, 2013. Machine learning and rigorous inference methods with time-varying exposures were used to evaluate associations of continuous exposure to analogue vs human insulins with mortality and major cardiovascular events. Data were analyzed from September 1, 2017, through June 30, 2018.. On the index date (first insulin dispensing), participants were classified as using analogue insulin with or without human insulin or human insulin only.. Overall mortality, mortality due to cardiovascular disease (CVD), myocardial infarction (MI), stroke or cerebrovascular accident (CVA), and hospitalization for congestive heart failure (CHF) were evaluated. Marginal structural modeling (MSM) with inverse probability weighting was used to compare event-free survival in separate per-protocol analyses. Adjusted and unadjusted hazard ratios and cumulative risk differences were based on logistic MSM parameterizations for counterfactual hazards. Propensity scores were estimated using a data-adaptive approach (machine learning) based on 3 nested covariate adjustment sets. Sensitivity analyses were conducted to address potential residual confounding from unmeasured differences in risk factors across delivery systems.. The 127 600 participants (mean [SD] age, 59.4 [12.6] years; 68 588 men [53.8%]; mean [SD] body mass index, 32.3 [7.1]) had a median follow-up of 4 quarters (interquartile range, 3-9 quarters) and experienced 5464 deaths overall (4.3%), 1729 MIs (1.4%), 1301 CVAs (1.0%), and 3082 CHF hospitalizations (2.4%). There were no differences in adjusted hazard ratios for continuous analogue vs human insulin exposure during 10 quarters for overall mortality (1.15; 95% CI, 0.97-1.34), CVD mortality (1.26; 95% CI, 0.86-1.66), MI (1.11; 95% CI, 0.77-1.45), CVA (1.30; 95% CI, 0.81-1.78), or CHF hospitalization (0.93; 95% CI, 0.75-1.11).. Insulin-naive adults with type 2 diabetes who initiate and continue treatment with human vs analogue insulins had similar observed rates of major cardiovascular events, CVD mortality, and overall mortality.

Topics: Adult; Aged; Aged, 80 and over; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Female; Heart Failure; Humans; Hypoglycemic Agents; Insulin; Insulin, Regular, Human; Male; Middle Aged; Myocardial Infarction; Proportional Hazards Models; Retrospective Studies; Risk Factors; Stroke; Young Adult

Few studies are available evaluating the impact of rapid-acting insulin analogues on long-term diabetes outcomes. Our aim was to compare the use of rapid-acting insulin analogues versus human regular insulin in relation to the occurrence of diabetic complications in a cohort of diabetic patients through the analysis of administrative databases.. A population-based cohort study was conducted using administrative data from four local health authorities in the Abruzzo Region (900,000 inhabitants). Diabetic patients free of macrovascular disease at baseline and treated either with human regular insulin or rapid-acting insulin analogues were followed for a maximum of 3 years. The incidence of diabetic complications was ascertained by hospital discharge claims. Hazard ratios (HRs) and 95% CIs of any diabetic complication and macrovascular, microvascular and metabolic complications were estimated separately using Cox proportional hazard models adjusted for patients' characteristics and anti-diabetic drug use. Propensity score matching was also used to adjust for significant difference in the baseline characteristics between the two treatment groups.. A total of 2,286 patients were included: 914 receiving human regular insulin and 1,372 rapid-acting insulin analogues. During the follow-up, 286 (31.3%) incident events occurred in the human regular insulin group and 235 (17.1%) in the rapid-acting insulin analogue group. After propensity score-based matched-pair analyses, rapid-acting insulin analogues users had a HR of 0.73 (0.58-0.92) for any diabetes-related complication and HRs of 0.73 (0.55-0.93) and 0.55 (0.32-0.96) for macrovascular and metabolic complications respectively, as compared with human regular insulin users. No difference between the two groups was found for microvascular complications.. Our findings suggest that the use of rapid-acting insulin analogues is associated with a lower risk of cardiovascular and metabolic complications compared with human regular insulin use.

Topics: Aged; Aged, 80 and over; Cardiovascular Diseases; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Insulin, Regular, Human; Insulin, Short-Acting; Male; Middle Aged; Proportional Hazards Models; Retrospective Studies

Topics: Cardiovascular Diseases; Diabetes Complications; Diabetes Mellitus, Type 2; Follow-Up Studies; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin Aspart; Insulin, Regular, Human; Postprandial Period; Randomized Controlled Trials as Topic