humulin-s and Insulin-Resistance

Alzheimer's disease (AD) is the main type of dementia and is a disease with a profound socioeconomic burden due to the lack of effective treatment. In addition to genetics and environmental factors, AD is highly associated with metabolic syndrome, defined as the combination of hypertension, hyperlipidemia, obesity and type 2 diabetes mellitus (T2DM). Among these risk factors, the connection between AD and T2DM has been deeply studied. It has been suggested that the mechanism linking both conditions is insulin resistance. Insulin is an important hormone that regulates not only peripheral energy homeostasis but also brain functions, such as cognition. Insulin desensitization, therefore, could impact normal brain function increasing the risk of developing neurodegenerative disorders in later life. Paradoxically, it has been demonstrated that decreased neuronal insulin signalling can also have a protective role in aging and protein-aggregation-associated diseases, as is the case in AD. This controversy is fed by studies focused on neuronal insulin signalling. However, the role of insulin action on other brain cell types, such as astrocytes, is still unexplored. Therefore, it is worthwhile exploring the involvement of the astrocytic insulin receptor in cognition, as well as in the onset and/or development of AD.

Topics: Alzheimer Disease; Brain; Diabetes Mellitus, Type 2; Humans; Insulin; Insulin Resistance; Insulin, Regular, Human; Metabolic Syndrome; Risk Factors

Physiologic insulin secretion consists of an oscillating pattern of secretion followed by distinct trough periods that stimulate ligand and receptor activation. Apart from the large postprandial bolus release of insulin, β cells also secrete small amounts of insulin every 4-8 min independent of a meal. Insulin resistance is associated with a disruption in the normal cyclical pattern of insulin secretion. In the case of type-2 diabetes, β-cell mass is reduced due to apoptosis and β cells secrete insulin asynchronously. When ligand/receptors are constantly exposed to insulin, a negative feedback loop down regulates insulin receptor availability to insulin, creating a relative hyperinsulinemia. The relative excess of insulin leads to insulin resistance (IR) due to decreased receptor availability. Over time, progressive insulin resistance compromises carbohydrate metabolism, and may progress to type-2 diabetes (T2D). In this review, we discuss insulin resistance pathophysiology and the use of dynamic exogenous insulin administration in a manner consistent with more normal insulin secretion periodicity to reverse insulin resistance. Administration of insulin in such a physiologic manner appears to improve insulin sensitivity, lower HgbA1c, and, in some instances, has been associated with the reversal of end-organ damage that leads to complications of diabetes. This review outlines the rationale for how the physiologic secretion of insulin orchestrates glucose metabolism, and how mimicking this secretion profile may serve to improve glycemic control, reduce cellular inflammation, and potentially improve outcomes in patients with diabetes.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Humans; Insulin; Insulin Resistance; Insulin, Regular, Human; Ligands

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

A daily habit of yogic practice or walking, along with an oral hypoglycemic agent (OHA) could be beneficial for better control of type 2 diabetes mellitus (T2DM). We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to find out the efficiency of yoga or walking on glycemic control in T2DM.. The present systematic review and meta-analysis were completed according to the PRISMA guidelines. The risk of bias in included studies was evaluated, by using the revised Cochrane risk-of-bias tool for randomized trials. Meta-analysis was implemented using RevMan software. Forest plots were used to illustrate the study findings and meta-analysis results.. Sixteen studies were included in this systematic review, where 1820 participants were allocated to one of the following interventions: yoga, walking, and without any regular exercise (control group). Participants were between 17-75 years of age. Compared to the control group, the yoga group had a significant reduction in fasting blood glucose (FBG) by 31.98 mg/dL (95% CI = -47.93 to -16.03), postprandial blood glucose (PPBG) by 25.59 mg/dL (95% CI = -44.00 to -7.18], glycosylated hemoglobin (HbAlc) by 0.73% (95% CI = -1.24 to -0.22), fasting insulin by 7.19 μIU/mL (95% CI = -12.10 to -2.28), and homeostatic model assessment for insulin resistance (HOMA-IR) by 3.87 (95% CI = -8.40 to -0.66). Compared to the control group, the walking group had a significant reduction in FBG by 12.37 mg/dL (95% CI = -20.06 to -4.68) and HbA1c by 0.35% (95% CI = -0.70 to -0.01). Compared to the walking group, the yoga group had a significant reduction in FBG by 12.07 mg/dL (95% CI = -24.34 to - 0.20), HbA1c by 0.20% (95% CI = -0.37 to -0.04), fasting insulin by 10.06 μIU/mL (95% CI = -23.84 to 3.71) and HOMA-IR by 5.97 (95% CI = -16.92 to 4.99).. Yoga or walking with OHA has positive effects on glycemic control. For the management of T2DM, yoga has relatively more significant effects on glycemic control than walking.Review registration number: PROSPERO registration number CRD42022310213.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Glycemic Control; Humans; Insulin; Insulin Resistance; Insulin, Regular, Human; Walking; Yoga

In the 1950's, Dr. I. Arthur Mirsky first recognized the possible importance of insulin degradation changes to the pathogenesis of type 2 diabetes. While this mechanism was ignored for decades, insulin degradation is now being recognized as a possible factor in diabetes risk. After Mirsky, the relative importance of defects in insulin release and insulin resistance were recognized as risk factors. The hyperbolic relationship between secretion and sensitivity was introduced, as was the relationship between them, as expressed as the disposition index (DI). The DI was shown to be affected by environmental and genetic factors, and it was shown to be differentiated among ethnic groups. However, the importance of differences in insulin degradation (clearance) on the disposition index relationship remains to be clarified. Direct measure of insulin clearance revealed it to be highly variable among even normal individuals, and to be affected by fat feeding and other physiologic factors. Insulin clearance is relatively lower in ethnic groups at high risk for diabetes such as African Americans and Hispanic Americans, compared to European Americans. These differences exist even for young children. Two possible mechanisms have been proposed for the importance of insulin clearance for diabetes risk: in one concept, insulin resistance per se leads to reduced clearance and diabetes risk. In a second and new concept, reduced degradation is a primary factor leading to diabetes risk, such that lower clearance (resulting from genetics or environment) leads to systemic hyperinsulinemia, insulin resistance, and beta-cell stress. Recent data by Chang and colleagues appear to support this latter hypothesis in Native Americans. The importance of insulin clearance as a risk factor for metabolic disease is becoming recognized and may be treatable.

Topics: Blood Glucose; Child; Child, Preschool; Diabetes Mellitus, Type 2; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Insulin-Secreting Cells; Insulin, Regular, Human

Prevalence of type 2 diabetes increased from 2.5% of the US population in 1990 to 10.5% in 2018. This creates a major public health problem, due to increases in long-term complications of diabetes, including neuropathy, retinopathy, nephropathy, skin ulcers, amputations, and atherosclerotic cardiovascular disease. In this review, we evaluated the scientific basis that supports the use of physiologic insulin resensitization. Insulin resistance is the primary cause of type 2 diabetes. Insulin resistance leads to increasing insulin secretion, leading to beta-cell exhaustion or burnout. This triggers a cascade leading to islet cell destruction and the long-term complications of type 2 diabetes. Concurrent with insulin resistance, the regular bursts of insulin from the pancreas become irregular. This has been treated by the precise administration of insulin more physiologically. There is consistent evidence that this treatment modality can reverse the diabetes-associated complications of neuropathy, diabetic ulcers, nephropathy, and retinopathy, and that it lowers HbA1c. In conclusion, physiologic insulin resensitization has a persuasive scientific basis, significant treatment potential, and likely cost benefits.

Topics: Diabetes Mellitus, Type 2; Glycated Hemoglobin; Humans; Insulin Resistance; Insulin Secretion; Insulin, Regular, Human; Pancreas

Exercise profoundly influences glycemic control by enhancing muscle insulin sensitivity, thus promoting glucometabolic health. While prior glycogen breakdown so far has been deemed integral for muscle insulin sensitivity to be potentiated by exercise, the mechanisms underlying this phenomenon remain enigmatic. We have combined original data from 13 of our studies that investigated insulin action in skeletal muscle either under rested conditions or following a bout of one-legged knee extensor exercise in healthy young male individuals (n = 106). Insulin-stimulated glucose uptake was potentiated and occurred substantially faster in the prior contracted muscles. In this otherwise homogenous group of individuals, a remarkable biological diversity in the glucometabolic responses to insulin is apparent both in skeletal muscle and at the whole-body level. In contrast to the prevailing concept, our analyses reveal that insulin-stimulated muscle glucose uptake and the potentiation thereof by exercise are not associated with muscle glycogen synthase activity, muscle glycogen content, or degree of glycogen utilization during the preceding exercise bout. Our data further suggest that the phenomenon of improved insulin sensitivity in prior contracted muscle is not regulated in a homeostatic feedback manner from glycogen. Instead, we put forward the idea that this phenomenon is regulated by cellular allostatic mechanisms that elevate the muscle glycogen storage set point and enhance insulin sensitivity to promote the uptake of glucose toward faster glycogen resynthesis without development of glucose overload/toxicity or feedback inhibition.

Topics: Glucose; Glycogen; Glycogen Synthase; Humans; Insulin; Insulin Resistance; Insulin, Regular, Human; Isophane Insulin, Human; Male; Muscle, Skeletal

Male hypogonadism is a disorder characterized by low levels of the hormone testosterone and patients may also have insulin sensitivity (IS) or insulin resistance (IR), such that they show different clinical complications and different metabolic pathways. In this review, we compare metabonomic differences observed between these two groups before and after testosterone therapy (TRT) in order to obtain information on whether the two hormones testosterone and insulin are synergistic or antagonistic. IS hypogonadism uses glucose as the main biofuel, while IR activates gluconeogenesis by the degradation of branched-chain amino acids. The Krebs (TCA) cycle is active in IS but connected with glutaminolysis, while in IR the TCA cycle stops at citrate, which is used for lipogenesis. In both cases, the utilization of fatty acids for energy (β-oxidation) is hampered by lower amounts of acetylcarnitine, although it is favored by the absence of insulin in IR. Increased free fatty acids (FFAs) are free in the blood in IS, while they are partially incorporated in triglycerides in IR. Thus, upon TRT, the utilization of glucose is increased more in IS than in IR, revealing that in IR there is a switch from preferential glucose oxidation to lipid oxidation. However, in both cases, a high production of lactate and acetyl-CoA is the final result, with these levels being much higher in IR. Lactate is used in IS in the glucose-lactate cycle between the liver and muscle to produce energy, while in IR lactate and acetyl-CoA are biotransformed into ketone bodies, resulting in ketonuria. In conclusion, the restoration of testosterone values in hypogonadism gives better results in IS than in IR patients: in IS, TRT restores most of the metabolic pathways, while in IR TRT impairs insulin, and when insulin is inactive TRT activates an ancestral molecular mechanism to produce energy. This evidence supports the hypothesis that, over time, hypogonadism switches from IS to IR, and in the latter case most of the insulin-related metabolisms are not reactivated, at least within 60 days of TRT. However, testosterone therapy in both IS and IR might be of benefit given supplementation with metabolites that are not completely restored upon TRT, in order to help restore physiological metabolisms. This review underlines the importance of using a systems biology approach to shed light on the molecular mechanisms of related biochemical pathways involving insulin and testosterone.

Topics: Acetyl Coenzyme A; Glucose; Humans; Hypogonadism; Insulin; Insulin Resistance; Insulin, Regular, Human; Lactates; Male; Testosterone

Alzheimer's disease (AD) is a global concern and has become a major public health event affecting human health. Insulin is a metabolic hormone secreted mainly by the peripheral tissue pancreas. In recent years, more and more evidence has proved that insulin regulates various functions of the brain. The hippocampus, one of the earliest brain regions affected by AD, is widely distributed with insulin receptors. Studies have shown that type 2 diabetes mellitus, characterized by insulin resistance, is closely related to AD, which has drawn extensive attention to the relationship between hippocampal insulin signaling and AD. Therefore, we provide an overview of intranasal insulin administration on memory and its underlying mechanism. We also highlight the molecular link between hippocampal insulin resistance and AD and provide a theoretical basis for finding new therapeutic targets for AD in clinical practice.

Topics: Alzheimer Disease; Diabetes Mellitus, Type 2; Hippocampus; Humans; Insulin; Insulin Resistance; Insulin, Regular, Human

"Brittle diabetes" was first used to describe a life "disrupted by episodes of hypoglycemia or hyperglycemia." Early descriptions focused on small case reports of mostly young women with psycho-social instability, recurrent diabetic ketoacidosis, poor patient compliance or maladaptation. We redefine "brittle diabetes" as occurring in four specific life stages each with distinct characteristics and associated conditions resulting in severely erratic glycemic control and poor outcomes. Once identified however these factors can often be reversed or significantly mitigated. The first group includes younger patients with associated psychiatric diseases such as bulimia and depression which require specific therapy and are treatable. A second group includes individuals who have another underlying medical condition resulting in disruption of insulin sensitivity or glucose utilization which must be sought. A third group, the largest we believe, has "geriatric type 1 diabetes" and develops severe glycemic instability due to frailty, chronic renal failure, dementia, vision loss, loss of counterregulation and other diseases of aging which lead to unintentional omission of insulin, insulin dosing errors and increasing insulin sensitivity. The fourth group, now seen around the world, suffers lack of insulin access and associated food insecurity. All four of these groups are described.

Topics: Diabetes Mellitus, Type 1; Diabetic Ketoacidosis; Female; Humans; Hypoglycemia; Insulin; Insulin Resistance; Insulin, Regular, Human

As patients with diabetes continue to have greater problems with obesity, the need for more medications and higher doses of insulin has increased. Some patients are so insulin resistant that they require U-500 insulin.. All insulins carry the risk of hypoglycemia. Despite being the most potent insulin available, the methodology for describing U-500 insulin administration varies. This paper examines the properties of U-500 insulin and suggests a unified method of defining how it is administered.. A literature search for English language articles that reference U-500 insulin was performed. The 51 articles, and additional websites as applicable, were independently reviewed.. Now that U-500 insulin has a specific syringe and a pen, all patients who use this should be converted to one of these two devices. The insulin dose should be described as the number of units administered.. U-500 insulin is a potent formulation and carries the risk of hypoglycemia. A unified method of administration is now available, and the description of its use should reflect the number of units administered.

Topics: Diabetes Mellitus; Humans; Hypoglycemic Agents; Injections; Insulin Resistance; Insulin, Regular, Human; Medication Errors; Obesity; Patient Education as Topic

The rise in prevalence of obesity and diabetes has created a challenge in managing increasing numbers of patients who require high doses of insulin. This article reviews the published literature on the properties of U-500 insulin and its use in clinical practice. U-500 insulin is likely to have a longer time to peak effect and a longer duration of action than similar doses of U-100 insulin. Evidence for its use in clinical practice rests on retrospective case series, which suggests that the use of U-500 insulin either by multiple daily injections or a continuous subcutaneous insulin infusion is effective in improving glycaemic control. To prevent insulin dosing and administration errors, great care must be taken in providing staff and patient education, and in developing policies for the management of patients on U-500 insulin who are admitted to hospital.

Topics: Blood Glucose; Cost-Benefit Analysis; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Evidence-Based Medicine; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Injections, Subcutaneous; Insulin Infusion Systems; Insulin Resistance; Insulin, Regular, Human; Male; Obesity; Patient Education as Topic; Treatment Outcome

This study strove to investigate the hypothesis that a low dosage of myo-inositol supplementation might decrease the likelihood of gestational diabetes in overweight, pregnant women.. A randomized, double-blind, controlled trial was performed on 60 eligible overweight, pregnant women, at 12-14 weeks of gestation, at two Iranian obstetric clinics. The participants were divided into two groups based on blocked randomization. The myo-inositol group received 2000 mg plus 400 μg folic acid daily and the control group received 400 μg of folic acid daily from 14-24 gestational weeks. The occurrence of gestational diabetes was determined based on 75-g 2-hour oral glucose tolerance test (OGTT) at 24-28 gestational weeks, which was the primary outcome of the study. The secondary outcomes were: the evaluation of insulin therapy, insulin resistance and lipid profile, gestational weight gain, and fetal and maternal outcomes.. The incidence of gestational diabetes in myo-inositol group was noticeably minimized compared to that in the control group (RR=0.29, 95% CI: 0.09-0.94, P=0.037). There were no differences between the two groups in terms of fasting blood sugar, fasting insulin, homeostasis model assessment-estimated insulin resistance (HOMA-IR), insulin therapy, and triglyceride. There was no report of severe adverse drug reactions.. The absolute risk reduction and the number-needed-to-treat for gestational diabetes were 26.8% (95% CI: 5.6-48) and 3.7 (95% CI: 2.1-18.0), respectively. Hence, it can be concluded that approximately one out of every four overweight pregnant women receiving myo-inositol benefitted from its daily intake.

Topics: Diabetes, Gestational; Dietary Supplements; Female; Folic Acid; Humans; Inositol; Insulin Resistance; Insulin, Regular, Human; Iran; Overweight; Pregnancy; Pregnant Women

Antipsychotics (APs) are the cornerstone of treatment for schizophrenia (SCZ) but are unfortunately associated with serious metabolic adverse effects including weight gain and type 2 diabetes. The pathophysiology of AP-induced metabolic dysfunction is largely undetermined. Brain insulin resistance has been posited to be at the cross-roads of many cognitive and metabolic disorders, and disruption of central insulin action has emerged as a possible explanatory mechanism underlying AP induced metabolic dysfunction. Previous studies suggest that change in neuroimaging-based parameters with intranasal insulin administration can be leveraged to investigate brain insulin resistance. In this proof-of-concept study, we will utilize neural signatures of insulin action in the brain to examine if APs disrupt brain insulin signaling. It is hypothesized that: 1) intranasal insulin (INI), but not intranasal placebo (INP), will change cerebral blood flow and resting state connectivity, as well as increase glutamate levels in the striatum and dorsolateral prefrontal cortex; 2) oral olanzapine (OLA), but not oral placebo (PL), will inhibit the effect of INI on these parameters. Thirty-two healthy volunteers will undergo a single blind, cross-over design, wherein all participants receive the following four treatment combinations, 2-6 weeks apart, in a random sequence: INP + PL, INP + OLA, INI + PL, and INI + OLA. Participants will undergo an MRI-based assay of brain insulin resistance 15 minutes after administering 160 IU INI or INP. The scanning protocol includes resting and task-based functional MRI, arterial spin labelling, and proton magnetic resonance spectroscopy. Demonstrating that OLA can acutely induce brain insulin resistance is clinically relevant to metabolic health in SCZ. Evidence of brain insulin resistance induced by acute AP dosing can inform the early use of adjunctive insulin sensitizers for the treatment of metabolic comorbidities associated with AP treatment in severe mental illness. Trial registration ClinicalTrials.gov Registration: NCT03741478.

Topics: Antipsychotic Agents; Brain; Cross-Over Studies; Diabetes Mellitus, Type 2; Humans; Insulin; Insulin Resistance; Insulin, Regular, Human; Magnetic Resonance Imaging; Olanzapine; Single-Blind Method

Initiation and titration of human regular U-500 insulin (U-500R) with a dosing algorithm of either thrice daily (TID) or twice daily (BID) improved glycemic control with fewer injections in patients with type 2 diabetes treated with high-dose, high-volume U-100 insulin. The objective of this analysis was to compare patient-reported outcomes between U-500R TID and BID treatment groups in this titration-to-target randomized, clinical trial.. In this 24-week, open-label, parallel trial, 325 patients were randomized to TID (n = 162) or BID (n = 163) U-500R after a 4-week lead-in period (screening). The Treatment Related Impact Measure-Diabetes (TRIM-D) and EQ-5D-5L questionnaires were administered at screening, baseline/randomization, and endpoint (24 weeks). The Visual Analog Scale-Injection Site Pain (VAS-ISP) was assessed at baseline/randomization, 12 weeks, and endpoint.. The TRIM-D showed statistically significant improvements in overall scores from baseline to endpoint for both BID and TID groups, most domains in the TID group, and all domains in the BID group. The BID group achieved better scores than the TID patients in overall and in treatment burden, daily life, and compliance domains (p < .05). EQ-5D-5L index scores showed no statistically significant differences for TID and BID groups (and no differences between TID and BID groups) from baseline to endpoint. VAS-ISP scores improved for both treatment groups (-5.60 TID; -6.47 BID; p < .05 for both) from baseline to endpoint.. U500 can be successfully titrated for improved glycemic control using BID and TID regimens with diabetes-specific Patient-Reported Outcomes showing improvements in both arms; however, BID had better scores than TID in overall, treatment burden, daily life, and compliance domains.. These secondary analyses are based on the study first received January 22, 2013 and reported in Clinical Trial Registry No.: NCT01774968 .

Topics: Adult; Aged; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Hypoglycemic Agents; Insulin Resistance; Insulin, Regular, Human; Male; Medication Adherence; Middle Aged; Patient Reported Outcome Measures; Quality of Life

To compare the efficacy and safety of 2 dosing regimens for human regular U-500 insulin (U-500R, 500 units/mL) replacing high-dose U-100 insulins with or without oral antihyperglycemic drugs in patients with inadequately controlled type 2 diabetes (T2D).. We conducted a 24-week, open-label, parallel trial in 325 patients (demographics [means]: age, 55.4 years; diabetes duration, 15.2 years; body mass index, 41.9 kg/m(2); glycated hemoglobin [HbA1c], 8.7%; U-100 insulin dose, 287.5 units administered in 5 injections/day [median; range, 2 to 10]). Patients were randomized to thrice-daily (TID, n = 162) or twice-daily (BID, n = 163) U-500R after a 4-week lead-in period. The primary outcome was HbA1c change from baseline.. After 24 weeks, both treatments demonstrated significant HbA1c reductions (TID, -1.12%; BID, -1.22%; both, P<.001) and clinical equivalence (difference, -0.10%; 95% confidence interval, -0.33 to 0.12%; noninferiority margin, 0.4%). Comparable increases in total daily U-500R dose (TID, 242.7 to 343.1 units; BID, 249.0 to 335.0 units) were observed. Incidence and rate of documented symptomatic hypoglycemia (≤70 mg/dL) were lower for TID versus BID (P = .003 and P = .02, respectively); severe hypoglycemia was similar between treatments. Weight gain was similar in both groups (TID, 5.4 kg; BID, 4.9 kg).. Initiation and titration of U-500R using either algorithm (TID or BID) improves glycemic control effectively and safely with fewer injections in patients with T2D treated with high-dose/high-volume U-100 insulin. These results provide clinicians with a practical framework for using U-500R in severely insulin-resistant patients with suboptimally controlled T2D.

Topics: Diabetes Mellitus, Type 2; Drug Administration Schedule; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Insulin Resistance; Insulin, Regular, Human; Male; Middle Aged; Treatment Outcome

Dietary n-3 polyunsaturated fatty acids, including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), prevent insulin resistance and stimulate mitochondrial biogenesis in rodents, but the findings of translational studies in humans are thus far ambiguous. The aim of this study was to evaluate the influence of EPA and DHA on insulin sensitivity, insulin secretion, and muscle mitochondrial function in insulin-resistant, nondiabetic humans using a robust study design and gold-standard measurements.. Thirty-one insulin-resistant adults received 3.9 g/day EPA+DHA or placebo for 6 months in a randomized double-blind study. Hyperinsulinemic-euglycemic clamp with somatostatin was used to assess hepatic and peripheral insulin sensitivity. Postprandial glucose disposal and insulin secretion were measured after a meal. Measurements were performed at baseline and after 6 months of treatment. Abdominal fat distribution was evaluated by MRI. Muscle oxidative capacity was measured in isolated mitochondria using high-resolution respirometry and noninvasively by magnetic resonance spectroscopy.. Compared with placebo, EPA+DHA did not alter peripheral insulin sensitivity, postprandial glucose disposal, or insulin secretion. Hepatic insulin sensitivity, determined from the suppression of endogenous glucose production by insulin, exhibited a small but significant improvement with EPA+DHA compared with placebo. Muscle mitochondrial function was unchanged by EPA+DHA or placebo.. This study demonstrates that dietary EPA+DHA does not improve peripheral glucose disposal, insulin secretion, or skeletal muscle mitochondrial function in insulin-resistant nondiabetic humans. There was a modest improvement in hepatic insulin sensitivity with EPA+DHA, but this was not associated with any improvements in clinically meaningful outcomes.

Topics: Adult; Antimetabolites; Blood Glucose; Deoxyglucose; Docosahexaenoic Acids; Double-Blind Method; Eicosapentaenoic Acid; Glucose Clamp Technique; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Insulin, Regular, Human; Liver; Male; Meals; Mitochondria, Muscle; Postprandial Period

To assess β-cell function and insulin sensitivity following improvement in glycemic control in severely insulin-resistant patients with poorly controlled type 2 diabetes (T2D).. A subset of patients in a 24-week, open-label, randomized trial comparing thrice-daily (n = 14/162) versus twice-daily (n = 11/163) human regular U-500 insulin (U-500R) underwent mixed meal tolerance testing at baseline and endpoint. Baseline characteristics were similar between treatment groups (combined means: age, 54.0 years; diabetes duration, 13.6 years; body mass index, 38.8 kg/m(2); glycated hemoglobin [HbA1c], 8.3%; U-100 insulin dose, 287.6 units/day, 2.6 units/kg/day). Primary outcome measure was ratio of area under the curve (AUC) for C-peptide to glucose (AUCC-peptide/AUCglucose) at 24-week endpoint.. Change from baseline HbA1c, daily U-500R dose, and weight were -1.17% (P = .0002), +80.8 units (P = .0003), and +5.9 kg (P = .33), respectively. β-Cell function significantly improved after 24 weeks of U-500R therapy in combined treatment groups. The AUCC-peptide/AUCglucose increased 34.0% (ratio of least-squares geometric mean, 1.34; 95% confidence interval, 1.18 to 1.52; P = .0001). Integral of total insulin secretion rate increased from 27.0 to 33.7 nmol/m(2), and glucose sensitivity improved from 18.3 to 24.0 pmol/min/m(2)/mM (both, P = .02). Matsuda index improved from 0.8 to 1.3 (P = .008).. Despite long-standing diabetes and poor glycemic control at baseline, functional recovery of β-cells was observed with improved glycemic control in these severely insulin-resistant patients with T2D, possibly due to alleviation of glucotoxicity.

Topics: Adult; Aged; Blood Glucose; Calibration; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Dosage Calculations; Female; Humans; Hypoglycemic Agents; Insulin Resistance; Insulin-Secreting Cells; Insulin, Regular, Human; Male; Middle Aged; Severity of Illness Index; Time Factors

Diabetes remission is frequent after biliopancreatic diversion (BPD) in morbidly obese patients with type 2 diabetes (T2D). Data, mechanisms, and clinical indications in nonobese T2D patients are scanty.. The objective of the study was to assess remission and investigate insulin sensitivity and β-cell function after BPD in nonobese patients with long-standing T2D.. This was a clinical research study comparing 15 T2D patients (aged 55 ± 1 years, duration of 16 ± 2 years, body mass index of 28.3 ± 0.6 kg/m², glycosylated hemoglobin 8.6% ± 1.3%) with 15 gender-, age-, and body mass index-matched nondiabetic controls. Before surgery and 2 months and 1 year later, a 3-hour oral glucose tolerance test, a 5-hour mixed-meal test, and a 3-hour euglycemic clamp were performed.. The intervention included a BPD (distal gastrectomy, proximal ileum anastomosed to remaining stomach, biliopancreatic limb anastomosed to ileum 50 cm from the ileocecal valve).. Glycemia improved in all patients, but remission (glycosylated hemoglobin < 6.5% and normal oral glucose tolerance test) occurred in 6 of 15 patients. Insulin resistance (19.8 ± 0.8 μmol · min⁻¹ · kg(ffm)⁻¹, P < .001 vs 40.9 ± 5.3 of controls) resolved already at 2 months (34.2 ± 2.8) and was sustained at 1 year (34.7 ± 1.6), although insulin-mediated suppression of endogenous glucose production remained impaired. In contrast, β-cell glucose sensitivity (19 [12] pmol · min⁻¹ · m⁻² · mM⁻¹ vs 96 [73] of controls, P < .0001) rose (P = .02) only to 31 [26] at 1 year and was lower in nonremitters (16 [18]) than remitters (46 [33]).. In nonobese patients with long-standing T2D, BPD improves metabolic control but induces remission in only approximately 40% of patients. Peripheral insulin sensitivity is restored early after surgery and similarly in remitters and nonremitters, indicating a weight-independent effect of the operation. The initial extent of β-cell incompetence is the main predictor of the metabolic outcome.

Topics: Bariatric Surgery; Biliopancreatic Diversion; Body Mass Index; Diabetes Mellitus, Type 2; Female; Gluconeogenesis; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Insulin, Regular, Human; Italy; Liver; Male; Middle Aged; Overweight; Recombinant Proteins; Remission Induction; Weight Loss

To examine the effect of intensive glycemic control therapy (IT) on insulin sensitivity and β-cell function in newly diagnosed type 2 diabetic patients compared with subjects with normal glucose tolerance (NGT) and those with impaired glucose tolerance (IGT).. Forty-eight newly diagnosed type 2 diabetic patients were randomly assigned to IT for 2 weeks and followed up for 1 year. Intravenous glucose tolerance tests were conducted in NGT, IGT, and diabetic subjects. Blood glucose and insulin were measured before and after IT and at the 1-year follow-up.. IT lowered the homeostasis model assessment (HOMA) for insulin resistance (IR) significantly, from 3.12 ± 1.4 (mean ± SD) to 1.72 ± 0.8, a level comparable to the IGT (1.96 ± 1.1) and NGT (1.37 ± 0.6) subjects in the remission group; however, no HOMA-IR improvement was observed in nonremission subjects. HOMA-β in the remission group was improved (mean, interquartile range) from 18.4 (8.3-28.5) to 44.6 (32.1-69.1) and acute insulin response of insulin (AIRins) from 1.50 ± 0.22 to 1.83 ± 0.19 μIU/mL after IT, but was still significantly lower than those in NGT individuals (HOMA-β: 86.4 [56.7-185.2], P < 0.01; AIRins: 2.54 ± 0.39 μIU/mL, P < 0.01). After IT and at 1 year, the hyperbolic relationship between HOMA-β and HOMA sensitivity of remission subjects shifted close to that of IGT subjects.. IT in newly diagnosed type 2 diabetes not only partially restored β-cell function but also greatly restored insulin sensitivity. Compared with IGT and NGT subjects, β-cell function was less restored than insulin sensitivity after IT in the remission subjects.

Topics: Adult; Diabetes Mellitus, Type 2; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin-Secreting Cells; Insulin, Isophane; Insulin, Regular, Human; Isophane Insulin, Human; Male; Middle Aged

To assess the diurnal patterns of postprandial glucose tolerance and insulin sensitivity, 19 subjects with type 2 diabetes (8 women; 60 ± 11 years; BMI 32 ± 5 kg/m2) and 19 anthropometrically matched subjects with no diabetes (ND; 11 women; 53 ± 12 years; BMI 29 ± 5 kg/m2) were studied during breakfast (B), lunch (L), and dinner (D) with identical mixed meals (75 g carbohydrates) on 3 consecutive days in a randomized Latin square design. Three stable isotopes of glucose were ustilized to estimate meal fluxes, and mathematical models were used in estimating indices of insulin action and β-cell function. Postmeal glucose excursions were higher at D versus B and at D versus L in type 2 diabetes (P < 0.05), while in ND they were higher at D versus B (P = 0.025) and at L versus B (P = 0.04). The insulin area under the curve was highest at B compared with L and D in type 2 diabetes, while no differences were observed in ND. Disposition index (DI) was higher at B than at L (P < 0.01) and at D (P < 0.001) in ND subjects, whereas DI was low with unchanging pattern across B-L-D in individuals with type 2 diabetes. Furthermore, between-meal differences in β-cell responsivity to glucose (F) and insulin sensitivity (SI) were concurrent with changes in the DI within groups. Fasting and postmeal glucose, insulin, and C-peptide concentrations, along with estimates of endogenous glucose production (EGP), Rd, SI, F, hepatic extraction of insulin, insulin secretion rate, extracted insulin, and DI, were altered in type 2 diabetes compared with ND (P < 0.011 for all). The data show a diurnal pattern of postprandial glucose tolerance in overweight otherwise glucose-tolerant ND individuals that differs from overweight individuals with type 2 diabetes. The results not only provide valuable insight into management strategies for better glycemic control in people with type 2 diabetes, but also improved understanding of daytime glucose metabolism in overweight individuals without impaired glucose tolerance or overt diabetes.

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 2; Female; Glucose; Humans; Insulin; Insulin Resistance; Insulin, Regular, Human; Meals; Middle Aged; Overweight

The etiology of insulin resistance (IR) in Type 1 Diabetes (T1D) is unclear; however, intramyocellular lipids (IMCL) are likely contributors. While exercise lessens IR and IMCL content; T1D patients elevate glycemia to offset exercise-induced hypoglycemic risk. The preferred treatment for T1D patients is tight glucose management through intensive insulin therapy (IIT); however, IIT is accompanied with a sedentary lifestyle. The purpose of this study was to examine IR development and IMCL in combined exercise (DARE; aerobic/resistance) and IIT-treated T1D animals. 76 rats were divided into control sedentary (C), diabetic sedentary (CD), diabetes sedentary intensive insulin therapy (DIT) and DARE groups. Following streptozotocin (STZ), glycemia was maintained at either 9-15 mM (CD, DARE) or 5-9 mM (DIT) using insulin. DARE alternated between running and weighted climbing for 12 weeks. Results demonstrate that DARE exhibited reduced onset of IR compared with C, DIT and CD, indicated by increased glucose infusion rate (hyperinsulinemic-euglycemic-clamp). A shift in lipid metabolism was evident whereby diacylglycerol was elevated in DIT compared to DARE, while triacylglycerol was elevated in DARE. These findings indicate enhanced IMCL metabolism and the sequestration of fat as neutral triacylglycerol leads to reduced IR in DARE. In contrast, IIT and sedentary behavior leads to diacylglycerol accumulation and IR.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 1; Diglycerides; Disease Models, Animal; Exercise; Glucose; Insulin; Insulin Resistance; Insulin, Regular, Human; Lipid Metabolism; Muscle, Skeletal; Rats; Triglycerides

Topics: Blood Glucose; Humans; Insulin; Insulin Resistance; Insulin, Regular, Human

Sleeve gastrectomy (SG) successfully recovers metabolic homeostasis in obese humans and rodents while also resulting in the normalization of insulin sensitivity and insulinemia. Reduced insulin levels have been attributed to lower insulin secretion and increased insulin clearance in individuals submitted to SG. Insulin degradation mainly occurs in the liver in a process controlled, at least in part, by the insulin-degrading enzyme (IDE). However, research has yet to explore whether liver IDE expression or activity is altered after SG surgery. In this study, C57BL/6 mice were fed a chow (CTL) or high-fat diet (HFD) for 10 weeks. Afterward, the HFD mice were randomly assigned to two groups: sham-surgical (HFD-SHAM) and SG-surgical (HFD-SG). Here, we confirmed that SG improves glucose-insulin homeostasis in obese mice. Additionally, SG reduced insulinemia by reducing insulin secretion, assessed by the analysis of plasmatic C-peptide content, and increasing insulin clearance, which was evaluated through the calculation of the plasmatic C-peptide:insulin ratio. Although no changes in hepatic IDE activity were observed, IDE expression was higher in the liver of HFD-SG compared with HFD-SHAM mice. These results indicate that SG may be helpful to counteract obesity-induced hyperinsulinemia by increasing insulin clearance, likely through enhanced liver IDE expression.

Topics: Animals; C-Peptide; Diet, High-Fat; Gastrectomy; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Insulin, Regular, Human; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Weight Loss

High-throughput proteomics allows researchers to simultaneously explore the roles of thousands of biomarkers in the pathophysiology of diabetes. We conducted proteomic association studies of incident type 2 diabetes and physiologic responses to an intravenous glucose tolerance test (IVGTT) to identify novel protein contributors to glucose homeostasis and diabetes risk. We tested 4,776 SomaScan proteins measured in relation to 18-year incident diabetes risk in participants from the Cardiovascular Health Study (N = 2,631) and IVGTT-derived measures in participants from the HERITAGE Family Study (N = 752). We characterize 51 proteins that were associated with longitudinal diabetes risk, using their respective 39, 9, and 8 concurrent associations with insulin sensitivity index (SI), acute insulin response to glucose (AIRG), and glucose effectiveness (SG). Twelve of the 51 diabetes associations appear to be novel, including β-glucuronidase, which was associated with increased diabetes risk and lower SG, suggesting an alternative pathway to insulin for glucose disposal; and plexin-B2, which also was associated with increased diabetes risk, but with lower AIRG, and not with SI, indicating a mechanism related instead to pancreatic dysfunction. Other novel protein associations included alcohol dehydrogenase-1C, fructose-bisphosphate aldolase-B, sorbitol dehydrogenase with elevated type 2 diabetes risk, and a leucine-rich repeat containing protein-15 and myocilin with decreased risk.. Plasma proteins are associated with the risk of incident diabetes in older adults independent of various demographic, lifestyle, and biochemical risk factors. These same proteins are associated with subtle differences in measures of glucose homeostasis earlier in life. Proteins that are associated with lower insulin sensitivity in individuals without diabetes tend to be associated with appropriate compensatory mechanisms, such as a stronger acute insulin response or higher glucose effectiveness. Proteins that are associated with future diabetes risk, but not with insulin insensitivity, tend to be associated with lower glucose effectiveness and/or impaired acute insulin response.

Topics: Aged; Blood Glucose; Diabetes Mellitus, Type 2; Glucose; Homeostasis; Humans; Insulin; Insulin Resistance; Insulin, Regular, Human; Proteomics

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

Gangliosides, sialic acid-containing glycosphingolipids, are widely involved in regulations of signal transductions to control cellular functions. It has been suggested that GM3, the simplest structure among gangliosides, is involved in insulin resistance, whereas it remains unclear whether insulin signaling diminished by GM3 actually aggravates the pathological conditions in metabolic disorders. Moreover, the functional roles of gangliosides in the regulation of insulin signaling have not yet been fully elucidated in liver or hepatocytes despite that it is one of the major insulin-sensitive organs. To understand physiological roles of GM3 in metabolic homeostasis in liver, we conducted a high fat diet (HFD) loading experiment using double knockout (DKO) mice of GM2/GD2 synthase and GD3 synthase, which lack all gangliosides except GM3, as well as wild-type (WT) mice. DKO mice were strikingly resistant to HFD-induced hepatosteatosis, and hepatic lipogenesis-related molecules including insulin signaling components were down-regulated in HFD-fed DKO. Furthermore, we established primary hepatocyte cultures from DKO and WT mice, and examined their responses to insulin in vitro. Following insulin stimulation, DKO hepatocytes expressing GM3 showed attenuated expression and/or activations in the downstream components compared with WT hepatocytes expressing GM2. While insulin stimulation induced lipogenic proteins in hepatocytes from both genotypes, their expression levels were lower in DKO than in WT hepatocytes after insulin treatment. All our findings suggest that the modified gangliosides, i.e., a shift to GM3 from GM2, might exert a suppressive effect on lipogenesis by attenuating insulin signaling at least in mouse hepatocytes, which might result in protection of HFD-induced hepatosteatosis.

Topics: Animals; Diet, High-Fat; G(M2) Ganglioside; G(M3) Ganglioside; Gangliosides; Insulin; Insulin Resistance; Insulin, Regular, Human; Mice; Signal Transduction

Prior studies provided evidence that low-density lipoprotein (LDL)-cholesterol-lowering statins reduce cardiovascular events while conveying an increased risk of type 2 diabetes. The aim of this study was to investigate the association between LDL levels and both insulin sensitivity and insulin secretion in a cohort of 356 adult first-degree relatives of patients with type 2 diabetes.. Insulin sensitivity was assessed by euglycemic hyperinsulinemic clamp and first-phase insulin secretion was measured by both intravenous glucose tolerance test (IVGTT) and OGTT.. LDL-cholesterol levels were not independently associated with insulin-stimulated glucose disposal. After adjusting for several potential confounders, LDL-cholesterol concentration exhibited a positive independent association with acute insulin response (AIR) during IVGTT and with the OGTT derived Stumvoll first-phase insulin secretion index. When insulin release was adjusted for the underlying degree of insulin sensitivity, using the disposition index (AIR × insulin-stimulated glucose disposal), β-cell function was significantly associated with LDL-cholesterol levels, even after further adjusting for several potential confounders.. The present results suggest that LDL cholesterol is a positive modulator of insulin secretion. The deterioration in glycemic control observed during treatment with statins might thus be explained by an impairment in insulin secretion due to the cholesterol-lowering effect of statins.

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 2; Glucose; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Insulin; Insulin Resistance; Insulin, Regular, Human; Lipoproteins, LDL

Plasma levels of angiopoietin-like protein 8 (ANGPTL8) are regulated by feeding and they increase following glucose ingestion. Because both plasma glucose and insulin increase following food ingestion, we aimed to determine whether the increase in plasma insulin and glucose or both are responsible for the increase in ANGPTL8 levels.. ANGPTL8 levels were measured in 30 subjects, 14 with impaired fasting glucose (IFG), and 16 with normal fasting glucose (NFG); the subjects received 75g glucose oral Glucose tolerance test (OGTT), multistep euglycaemic hyperinsulinemic clamp and hyperglycaemic clamp with pancreatic clamp.. Subjects with IFG had significantly higher ANGPTL8 than NGT subjects during the fasting state (p < 0.05). During the OGTT, plasma ANGPTL8 concentration increased by 62% above the fasting level (p < 0.0001), and the increase above fasting in ANGPTL8 levels was similar in NFG and IFG individuals. During the multistep insulin clamp, there was a dose-dependent increase in plasma ANGPTL8 concentration. During the 2-step hyperglycaemic clamp, the rise in plasma glucose concentration failed to cause any change in the plasma ANGPTL8 concentration from baseline.. In response to nutrient ingestion, ANGPTL8 level increased due to increased plasma insulin concentration, not to the rise in plasma glucose. The incremental increase above baseline in plasma ANGLPTL8 during OGTT was comparable between people with normal glucose tolerance and IFG.

Topics: Angiopoietin-Like Protein 8; Blood Glucose; Eating; Fasting; Glucose; Glucose Intolerance; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Insulin, Regular, Human; Nutrients; Peptide Hormones; Prediabetic State

To determine the potential impact of the cross-reactivity of insulin glargine U-100 and its metabolites on insulin sensitivity and β-cell measures in people with type 2 diabetes.. Using liquid chromatography-mass spectrometry (LC-MS), we measured concentrations of endogenous insulin, glargine and its two metabolites (M1 and M2) in fasting and oral glucose tolerance test-stimulated plasma from 19 participants and fasting specimens from another 97 participants 12 months after randomization to receive the insulin glargine. The last dose of glargine was administered before 10:00 PM the night before testing. Insulin was also measured on these specimens using an immunoassay. We used fasting specimens to calculate insulin sensitivity (Homeostatic Model Assessment 2 [HOMA2]-S%; QUICKI index; PREDIM index) and β-cell function (HOMA2-B%). Using specimens following glucose ingestion, we calculated insulin sensitivity (Matsuda ISI[comp] index) and β-cell response (insulinogenic index [IGI], and total incremental insulin response [iAUC] insulin/glucose).. In plasma, glargine was metabolized to form the M1 and M2 metabolites that were quantifiable by LC-MS; however, the analogue and its metabolites cross-reacted by less than 100% in the insulin immunoassay. This incomplete cross-reactivity resulted in a systematic bias of fasting-based measures. By contrast, because M1 and M2 did not change following glucose ingestion, a bias was not observed for IGI and iAUC insulin/glucose.. Despite glargine metabolites being detected in the insulin immunoassay, dynamic insulin responses can be used to assess β-cell responsiveness. However, given the cross-reactivity of the glargine metabolites in the insulin immunoassay, fasting-based measures of insulin sensitivity and β-cell function are biased.

Topics: Blood Glucose; Chromatography, Liquid; Diabetes Mellitus, Type 2; Glucose; Humans; Insulin; Insulin Glargine; Insulin Resistance; Insulin, Regular, Human; Mass Spectrometry

Insulin action in the brain influences cognitive processes, peripheral metabolism and eating behaviour. However, the influence of age and peripheral insulin sensitivity on brain insulin action remains unclear.. We used intranasal administration of insulin and functional magnetic resonance imaging in a randomized, placebo-controlled within-subject design in 110 participants (54 women, body mass index 18-49 kg/m. We found significant negative associations between age and insulin action in the hippocampus (β = -0.215; p = .017) and caudate nucleus (β = -0.184; p = .047); and between peripheral insulin sensitivity and insulin action in the amygdala (β = -0.190, p = .023). Insulin action in the insular cortex showed an interaction effect between age and peripheral insulin sensitivity (β = -0.219 p = .005). Furthermore, women showed the strongest negative association between age and hippocampal insulin action, while men showed the strongest associations with peripheral insulin sensitivity and age in reward-related brain regions.. We could show a region-specific relationship between brain insulin responsiveness, age and peripheral insulin sensitivity. Our findings underline the need to study brain insulin action in both men and women and further substantiate that brain insulin sensitivity is a possible link between systemic metabolism and neurocognitive functions.

Topics: Adult; Aged; Brain; Female; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Insulin, Regular, Human; Male; Middle Aged; Young Adult

Sex-specific differences exist in insulin secretion (ISec) and sensitivity (IS) in humans. However, current fasting indices used to estimate them, such as HOMA and QUICKI, are not sex-specific. We aimed to develop sex-specific models to improve the prediction of ISec and IS by fasting measures in adults with overweight/obesity. A post hoc analysis was conducted on baseline data of two clinical trials completed between 2010 and 2020 (37 men and 61 postmenopausal women, 45-73 years, BMI > 25 kg/m

Topics: Adult; Blood Glucose; C-Peptide; Female; Glucose; Humans; Insulin; Insulin Resistance; Insulin Secretion; Insulin, Regular, Human; Male; Obesity; Overweight

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.. 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: Animals; Diet, High-Fat; Glucagon-Like Peptide-1 Receptor; Inflammation; Insulin; Insulin Resistance; Insulin, Regular, Human; Liraglutide; Male; Obesity; Rats

The year 2021 marked the centenary of the discovery of insulin [...].

Topics: Humans; Insulin; Insulin Resistance; Insulin, Regular, Human; Metabolic Diseases

Biliverdin reductase-A (BVRA) is involved in the regulation of insulin signaling and the maintenance of glucose homeostasis. Previous research showed that BVRA alterations are associated with the aberrant activation of insulin signaling in dysmetabolic conditions. However, whether BVRA protein levels change dynamically within the cells in response to insulin and/or glucose remains an open question. To this aim, we evaluated changes of intracellular BVRA levels in peripheral blood mononuclear cells (PBMC) collected during the oral glucose tolerance test (OGTT) in a group of subjects with different levels of insulin sensitivity. Furthermore, we looked for significant correlations with clinical measures. Our data show that BVRA levels change dynamically during the OGTT in response to insulin, and greater BVRA variations occur in those subjects with lower insulin sensitivity. Changes of BVRA significantly correlate with indexes of increased insulin resistance and insulin secretion (HOMA-IR, HOMA-β, and insulinogenic index). At the multivariate regression analysis, the insulinogenic index independently predicted increased BVRA area under curve (AUC) during the OGTT. This pilot study showed, for the first time, that intracellular BVRA protein levels change in response to insulin during OGTT and are greater in subjects with lower insulin sensitivity, supporting the role of BVR-A in the dynamic regulation of the insulin signaling pathway.

Topics: Blood Glucose; Glucose; Humans; Insulin; Insulin Resistance; Insulin, Regular, Human; Leukocytes, Mononuclear; Pilot Projects

To evaluate changes in insulin physiology in euglycemic pregnancy and gestational diabetes mellitus (GDM).. Participants underwent oral glucose tolerance tests at ≤15 weeks' gestation (early pregnancy), 24-32 weeks' gestation (mid-late pregnancy), and 6-24 weeks postpartum. We evaluated longitudinal changes in insulin secretory response (log Stumvoll first-phase estimate) and insulin sensitivity (log Matsuda index) using linear mixed models. We then evaluated participants who met GDM criteria in early pregnancy (early GDM) and mid-late pregnancy (classic GDM) separately from those without GDM. We derived the pregnancy insulin physiology (PIP) index to quantify β-cell compensation for insulin resistance.. Among 166 participants, 21 had early GDM and 24 developed classic GDM. Insulin sensitivity was reduced slightly in early pregnancy (β = -0.20, P < 0.001) and substantially in mid-late pregnancy (β = -0.47, P < 0.001) compared with postpartum. Insulin secretory response (adjusted for insulin sensitivity) was augmented in early pregnancy (β = 0.16, P < 0.001) and mid-late pregnancy (β = 0.16, P = 0.001) compared with postpartum. Compared with postpartum, the PIP index was augmented in early pregnancy (β = 215, P = 0.04) but not mid-late pregnancy (β = 55, P = 0.64). Early GDM was distinguished by a substantial reduction in early pregnancy insulin sensitivity (β = -0.59, P < 0.001) compared with postpartum. Both early and classic GDM lacked evidence of early pregnancy augmentation of insulin secretory response (adjusted for insulin sensitivity) and the PIP index (P > 0.1 vs. postpartum). Early pregnancy PIP index predicted GDM independent of participant characteristics (area under the curve without PIP index 0.70 [95% CI 0.61-0.79], area under the curve with PIP index 0.87 [95% CI 0.80-0.93]).. β-Cell function is enhanced in early pregnancy. Deficient first-trimester β-cell function predicts GDM.

Topics: Blood Glucose; Diabetes, Gestational; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Insulin, Regular, Human; Postpartum Period; Pregnancy

Pediatric obesity is a growing health care burden. Understanding how the metabolic phenotype of youth with obesity may modify the effect of intestinal fermentation on human metabolism is key to designing early intervention.. To assess whether adiposity and insulin resistance in youth may be associated with colonic fermentation of dietary fibers and its production of acetate, gut-derived hormone secretion, and adipose tissue lipolysis.. Cross-sectional study of youths aged 15 to 22 years with body mass index in the 25th to 75th percentile or higher than the 85th percentile for age and sex throughout the New Haven County community in Connecticut. Recruitment, studies, and data collection occurred from June 2018 to September 2021. Youths were assigned to a lean, obese insulin sensitive (OIS), or obese insulin resistant (OIR) group. Data were analyzed from April 2022 to September 2022.. Participants consumed 20 g of lactulose during a continuous 10-hour sodium d3-acetate intravenous infusion to measure the rate of appearance of acetate in plasma.. Plasma was obtained hourly to measure acetate turnover, peptide tyrosine tyrosine (PYY), ghrelin, active glucagon-like peptide 1 (GLP-1), and free fatty acids (FFA).. A total of 44 youths participated in the study (median [IQR] age, 17.5 [16.0-19.3] years; 25 [56.8%] were female; 23 [52.3%] were White). Consequent to lactulose ingestion, there was a reduction of plasma FFA, an improvement of adipose tissue insulin sensitivity index, an increase in colonic acetate synthesis, and an anorexigenic response characterized by an increased plasma concentration of PYY and active GLP-1 and a reduction of ghrelin in the subgroups. Compared with the lean and OIS groups, the OIR group showed a less marked median (IQR) rate of acetate appearance (OIR: 2.00 [-0.86 to 2.69] μmol × kg-1 × min-1; lean: 5.69 [3.04 to 9.77] μmol × kg-1 × min-1; lean vs OIR P = .004; OIS: 2.63 [1.22 to 4.52] μmol × kg-1 × min-1; OIS vs OIR P = .09), a blunted median (IQR) improvement of adipose insulin sensitivity index (OIR: 0.043 [ 0.006 to 0.155]; lean: 0.277 [0.220 to 0.446]; lean vs OIR P = .002; OIS: 0.340 [0.048 to 0.491]; OIS vs OIR P = .08), and a reduced median (IQR) PYY response (OIR: 25.4 [14.8 to 36.4] pg/mL; lean: 51.3 [31.6 to 83.3] pg/mL; lean vs OIR P = .002; OIS: 54.3 [39.3 to 77.2] pg/mL; OIS vs OIR P = .011).. In this cross-sectional study, lean, OIS, and OIR youth demonstrated different associations between colonic fermentation of indigestible dietary carbohydrates and the metabolic response, with OIR youth showing minimal metabolic modifications as compared with the other 2 groups.. ClinicalTrials.gov Identifier: NCT03454828.

Topics: Adolescent; Child; Cross-Sectional Studies; Female; Fermentation; Ghrelin; Humans; Insulin; Insulin Resistance; Insulin, Regular, Human; Lactulose; Male; Pediatric Obesity; Tyrosine

Healthy non-obese insulin resistant (IR) individuals are at higher risk of metabolic syndrome. The metabolic signature of the increased risk was previously determined. Physical activity can lower the risk of insulin resistance, but the underlying metabolic pathways remain to be determined. In this study, the common and unique metabolic signatures of insulin sensitive (IS) and IR individuals in active and sedentary individuals were determined. Data from 305 young, aged 20-30, non-obese participants from Qatar biobank, were analyzed. The homeostatic model assessment of insulin resistance (HOMA-IR) and physical activity questionnaires were utilized to classify participants into four groups: Active Insulin Sensitive (ISA, n = 30), Active Insulin Resistant (IRA, n = 20), Sedentary Insulin Sensitive (ISS, n = 21) and Sedentary Insulin Resistant (SIR, n = 23). Differences in the levels of 1000 metabolites between insulin sensitive and insulin resistant individuals in both active and sedentary groups were compared using orthogonal partial least square discriminate analysis (OPLS-DA) and linear models. The study indicated significant differences in fatty acids between individuals with insulin sensitivity and insulin resistance who engaged in physical activity, including monohydroxy, dicarboxylate, medium and long chain, mono and polyunsaturated fatty acids. On the other hand, the sedentary group showed changes in carbohydrates, specifically glucose and pyruvate. Both groups exhibited alterations in 1-carboxyethylphenylalanine. The study revealed different metabolic signature in insulin resistant individuals depending on their physical activity status. Specifically, the active group showed changes in lipid metabolism, while the sedentary group showed alterations in glucose metabolism. These metabolic discrepancies demonstrate the beneficial impact of moderate physical activity on high risk insulin resistant healthy non-obese individuals by flipping their metabolic pathways from glucose based to fat based, ultimately leading to improved health outcomes. The results of this study carry significant implications for the prevention and treatment of metabolic syndrome in non-obese individuals.

Topics: Blood Glucose; Exercise; Glucose; Humans; Insulin; Insulin Resistance; Insulin, Regular, Human; Metabolic Syndrome; Obesity

Diet modulates the development of insulin resistance during aging. This includes tissue-specific alterations in insulin signaling and mitochondrial function, which ultimately affect glucose homeostasis. Exercise stimulates glucose clearance and mitochondrial lipid oxidation and also enhances insulin sensitivity (IS). It is not well known how exercise interacts with age and diet in the development of insulin resistance. To investigate this, oral glucose tolerance tests with tracers were conducted in mice ranging from 4 to 21 months of age, fed a low-fat diet (LFD) or high-fat diet (HFD) with or without life-long voluntary access to a running wheel (RW). We developed a computational model to derive glucose fluxes, which were commensurate with independent values from steady-state tracer infusions. Values for an IS index derived for peripheral tissues (IS-P) and one for the liver (IS-L) were steeply decreased by aging and an HFD. This preceded the age-dependent decline in the mitochondrial capacity to oxidize lipids. In young animals fed an LFD, RW access enhanced the IS-P concomitantly with the muscle β-oxidation capacity. Surprisingly, RW access completely prevented the age-dependent IS-L decrease; however this only occurred in animals fed an LFD. Therefore, this study indicates that endurance exercise can improve the age-dependent decline in organ-specific IS if paired with a healthy diet.. Exercise is a known strategy to improve insulin sensitivity (IS), whereas aging and a lipid-rich diet decrease IS. Using a tracer-based oral glucose tolerance test, we investigated how exercise, age, and diet interact in the development of tissue-specific insulin resistance. Exercise (voluntary access to a running wheel) mainly improved IS in animals fed a low-fat diet. In these animals, exercise improved peripheral IS only at young age but fully prevented the age-dependent decline of hepatic IS. The prevention of age-dependent decline in IS by exercise is tissue-specific and blunted by a lipid-rich diet.

Topics: Animals; Diet, High-Fat; Glucose; Glucose Tolerance Test; Insulin; Insulin Resistance; Insulin, Regular, Human; Lipids; Mice; Mice, Inbred C57BL

Acute coronary syndrome (ACS) is a major cardiovascular problem due to its high hospitalization and mortality rates. One of the risk factors for atherosclerosis that leads to ACS is insulin resistance (IR) which plays a role in the pathogenesis and development of cardiovascular events. This study aims to determine the relationship between IR and in-hospital outcomes in non-diabetic patients with ACS.. This was a cohort study conducted from January-June 2021. Insulin resistance was assessed using the Admission insulin resistance index (AIRI). This measurement was performed once during the patient's admission, and then the outcome was observed during hospitalization. The observed in-hospital outcomes were composite outcomes; namely, heart failure, arrhythmia, cardiogenic shock, and death. The statistical tests used were ANOVA, independent T and Chi-Square tests. Statistical test results were considered significant if. There is an association between AIRI and composite outcomes. Patients with IR have 5.5 times the risk of developing heart failure.

Topics: Acute Coronary Syndrome; Cohort Studies; Female; Heart Failure; Hospitalization; Hospitals; Humans; Insulin; Insulin Resistance; Insulin, Regular, Human; Male

There is limited research regarding insulin dosing changes following adoption of plant-based diets. We conducted a nonrandomized crossover trial utilizing two plant-based diets (Dietary Approaches to Stop Hypertension, or DASH, and Whole Food, Plant-Based, or WFPB) to assess acute changes in insulin requirements and associated markers among individuals with insulin-treated type 2 diabetes.. Participants (n = 15) enrolled in a 4-week trial with sequential, one-week phases: Baseline, DASH 1, WFPB, and DASH 2. Each diet was ad libitum and meals were provided.. Compared to baseline, daily insulin usage was 24%, 39%, and 30% lower after DASH 1, WFPB, and DASH 2 weeks respectively (all p < 0.01). Insulin resistance (HOMA-IR) was 49% lower (p < 0.01) and the insulin sensitivity index was 38% higher (p < 0.01) at the end of the WFPB week before regressing toward baseline during DASH 2. Total, LDL, and HDL cholesterol, leptin, urinary glucose, and hsCRP decreased to a nadir at the end of the WFPB week before increasing during DASH 2.. Adopting a DASH or WFPB diet can result in significant, rapid changes in insulin requirements, insulin sensitivity, and related markers among individuals with insulin-treated type 2 diabetes, with larger dietary changes producing larger benefits.

Topics: Diabetes Mellitus, Type 2; Diet; Diet, Vegetarian; Dietary Approaches To Stop Hypertension; Humans; Hypertension; Insulin; Insulin Resistance; Insulin, Regular, Human

Defining the regulators of cell metabolism and signaling is essential to design new therapeutic strategies in obesity and NAFLD/NASH. E3 ubiquitin ligases control diverse cellular functions by ubiquitination-mediated regulation of protein targets, and thus their functional aberration is associated with many diseases. The E3 ligase Ube4A has been implicated in human obesity, inflammation, and cancer. However, its in vivo function is unknown, and no animal models are available to study this novel protein.. A whole-body Ube4A knockout (UKO) mouse model was generated, and various metabolic parameters were compared in chow- and high fat diet (HFD)-fed WT and UKO mice, and in their liver, adipose tissue, and serum. Lipidomics and RNA-Seq studies were performed in the liver samples of HFD-fed WT and UKO mice. Proteomic studies were conducted to identify Ube4A's targets in metabolism. Furthermore, a mechanism by which Ube4A regulates metabolism was identified.. Although the body weight and composition of young, chow-fed WT and UKO mice are similar, the knockouts exhibit mild hyperinsulinemia and insulin resistance. HFD feeding substantially augments obesity, hyperinsulinemia, and insulin resistance in both sexes of UKO mice. HFD-fed white and brown adipose tissue depots of UKO mice have increased insulin resistance and inflammation and reduced energy metabolism. Moreover, Ube4A deletion exacerbates hepatic steatosis, inflammation, and liver injury in HFD-fed mice with increased lipid uptake and lipogenesis in hepatocytes. Acute insulin treatment resulted in impaired activation of the insulin effector protein kinase Akt in liver and adipose tissue of chow-fed UKO mice. We identified the Akt activator protein APPL1 as a Ube4A interactor. The K63-linked ubiquitination (K63-Ub) of Akt and APPL1, known to facilitate insulin-induced Akt activation, is impaired in UKO mice. Furthermore, Ube4A K63-ubiquitinates Akt in vitro.. Ube4A is a novel regulator of obesity, insulin resistance, adipose tissue dysfunction and NAFLD, and preventing its downregulation may ameliorate these diseases.

Topics: Adipose Tissue, Brown; Animals; Female; Homeostasis; Humans; Inflammation; Insulin; Insulin Resistance; Insulin, Regular, Human; Male; Mice; Non-alcoholic Fatty Liver Disease; Obesity; Proteomics; Proto-Oncogene Proteins c-akt; Ubiquitin-Protein Ligases

Inflammation can trigger hyperglycemia in people with type 1 diabetes (T1D). Vaccines purposefully intend to cause an acute immunogenic response, and booster vaccines may cause even more potent immunologic responses. However, the effects of vaccines on glycemic control and insulin requirements in the days immediately post-vaccination remains poorly understood. The aim of this study was to examine the changes in glycemic control and insulin usage immediately preceding and following a COVID-19 booster vaccine among adults with T1D.. In this prospective cohort study of adults with T1D, participants wore blinded Dexcom G6 Pro continuous glucose monitors for 10 days. After a baseline period, participants received a COVID-19 booster vaccine, and subsequent changes in glycemic indices were evaluated.. Among the 21 enrolled participants, 38% received a Moderna and 62% Pfizer-BioNTech booster. Compared to baseline (162.9 ± 44.1 mg/dL), mean glucose was significantly increased at Day 2 (172.8 ± 47.0 mg/dL; p = 0.04) and Day 3 (173.1 ± 45.0 mg/dL; p = 0.02) post-vaccination. Insulin resistance was also increased on Day 2 (p = 0.03). There were no differences in outcome metrics between booster vaccine manufacturers.. These results suggest that adults with type 1 diabetes may experience transient mild glycemic elevations after receiving a COVID-19 booster vaccination. Studies examining the effects of other vaccines are warranted.

Topics: Adult; COVID-19; COVID-19 Vaccines; Diabetes Mellitus, Type 1; Glucose; Humans; Insulin; Insulin Resistance; Insulin, Regular, Human; Pilot Projects; Prospective Studies

Hyperglycaemia in Type 1 diabetes (T1D) results from an absolute insulin deficiency. However, insulin resistance (IR) may exacerbate glycaemic instability in T1D and contribute to long-term cardiovascular complications. We previously showed that IR in teenagers with obesity is associated with sex-dependent derangements in the catabolism of branched-chain amino acids (BCAA) and fatty acids. Here we hypothesized that byproducts of BCAA and fatty acid metabolism may serve as biomarkers or determinants of glycaemic control and IR in prepubertal or early pubertal children with T1D.. Metabolites, hormones and cytokines from fasting blood samples were analysed in 28 children (15 females, 13 males; age 6-11 years) with T1D. Principal components analysis (PCA) and multiple linear regression models were used to correlate metabolites of interest with glycaemic control, total daily insulin dose (TDD, units/kg/d), adiponectin and the triglyceride (TG) to high-density lipoprotein (HDL) ratio.. Males and females were comparable in age, BMI-z, insulin sensitivity, glycaemic control, inflammatory markers, BCAAs and C2/C3/C5-acylcarnitines. The majority of components retained in PCA were related to fatty acid oxidation (FAO) and BCAA catabolism. HbA1c correlated positively with Factor 2 (acylcarnitines, incomplete FAO) and Factor 9 (fasting glucose). TDD correlated negatively with C3 and C5 and Factor 10 (BCAA catabolism) and positively with the ratio of C2 to C3 + C5 and Factor 9 (fasting glucose).. These findings suggest that glucose intolerance in prepubertal or early pubertal children with T1D is accompanied by incomplete FAO while TDD is associated with preferential catabolism of fats relative to amino acids.

Topics: Amino Acids, Branched-Chain; Child; Diabetes Mellitus, Type 1; Factor IX; Fatty Acids; Female; Glucose; Glycemic Control; Humans; Insulin; Insulin Resistance; Insulin, Regular, Human; Male

Scant West African data on non-alcoholic fatty liver disease (NAFLD) means there is little representation of this population in the modelling used to derive biomarkers and predictive indices for risk stratification of patients for the presence of hepatic steatosis. This study evaluates the performance of the fatty liver index (FLI), hepatic steatosis index (HSI) and triglyceride-glucose (TyG) index and its derivatives in predicting ultrasound detected NAFLD in a locally resident population of Ghanaian participants.. A post hoc analysis of data from a cross sectional assessment of NAFLD and cardiovascular risk was performed. Data from 210 participants without significant alcohol intake, or secondary causes of fatty liver and not on steatogenic drugs was evaluated. A structured questionnaire had been used to collect demographic data, medical and drug history. Anthropometry, blood sampling for liver chemistry and fasting lipids were performed. Hepatic steatosis was detected by ultrasonography. A retrospective analysis involving multivariate binary logistic regression assessed FLI, HIS, TyG (and its derivatives) as predictors of NAFLD with p < .05 considered statistically significant. Sensitivity, specificity, predictive values, likelihood ratios were calculated and accuracy of the proxies evaluated from area under the receiver operating characteristics curve (AUROC). All the biomarkers and indices were significantly associated with NAFLD (p ≤ .001). All the lipid and fatty liver indices assessed performed acceptably as predictors of NAFLD. FLI (AUC = 0.8, 95% CI [0.74-0.87]), TyG-WC (AUC = 0.81, 95% CI [0.75-0.88]) and TyG-WHtR (AUC = 0.81, 95% CI [0.74-0.88]) performed best at predicting NAFLD. Whilst in all cases the markers had good specificity (>90%) they lacked sufficient sensitivity with FLI having the highest sensitivity of 36.7%. Their overall accuracy was greater than 70% in each case.. The overall accuracy of HSI, FLI, TyG index and its derivatives (TyG WHtR, TyG BMI, TyG WC) was acceptable for predicting NAFLD in this population. Given their performance in this study and in light of their low cost, accessibility, easy interpretation and non-invasive nature; they are suitable tools for screening in the Ghanaian population.

Topics: Biomarkers; Cross-Sectional Studies; Ghana; Glucose; Humans; Insulin; Insulin Resistance; Insulin, Regular, Human; Non-alcoholic Fatty Liver Disease; Retrospective Studies; Triglycerides

Model predictive control (MPC) has become one of the most popular control strategies for automated insulin delivery (AID) in type 1 diabetes (T1D). These algorithms rely on a prediction model to determine the best insulin dosing every sampling time. Although these algorithms have been shown to be safe and effective for glucose management through clinical trials, managing the ever-fluctuating relationship between insulin delivery and resulting glucose uptake (aka insulin sensitivity, IS) remains a challenge. We aim to evaluate the effect of informing an AID system with IS on the performance of the system.. The University of Virginia (UVA) MPC control-based hybrid closed-loop (HCL) and fully closed-loop (FCL) system was used. One-day simulations at varying levels of IS were run with the UVA/Padova T1D Simulator. The AID system was informed with an estimated value of IS obtained through a mixed meal glucose tolerance test. Relevant controller parameters are updated to inform insulin dosing of IS. Performance of the HCL/FCL system with and without information of the changing IS was assessed using a novel performance metric penalizing the time outside the target glucose range.. Feedback in AID systems provides a certain degree tolerance to changes in IS. However, IS-informed bolus and basal dosing improve glycemic outcomes, providing increased protection against hyperglycemia and hypoglycemia according to the individual's physiological state.. The proof-of-concept analysis presented here shows the potentially beneficial effects on system performance of informing the AID system with accurate estimates of IS. In particular, when considering reduced IS, the informed controller provides increased protection against hyperglycemia compared with the naïve controller. Similarly, reduced hypoglycemia is obtained for situations with increased IS. Further tailoring of the adaptation schemes proposed in this work is needed to overcome the increased hypoglycemia observed in the more resistant cases and to optimize the performance of the adaptation method.

Topics: Algorithms; Blood Glucose; Blood Glucose Self-Monitoring; Diabetes Mellitus, Type 1; Glucose; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Infusion Systems; Insulin Resistance; Insulin, Regular, Human

Diabetes may feature impaired insulin kinetics, which could be aggravated by altered hepatic metabolism and glycemic control. Thus, we examined insulin clearance and its possible determinants in individuals with recent-onset diabetes.. Participants of the German Diabetes Study (GDS) with type 1 diabetes (T1D) (n = 306), type 2 diabetes (T2D) (n = 489), or normal glucose tolerance (control [CON]) (n = 167) underwent hyperinsulinemic-euglycemic clamps for assessment of whole-body insulin sensitivity (M value) and insulin clearance (ICCLAMP). Insulin clearance rates were further calculated during intravenous glucose tolerance tests (ICIVGTT) and mixed-meal tests (ICMMT). Hepatocellular lipid content (HCL) was quantified with 1H-MRS.. Both T1D and T2D groups had lower ICCLAMP (0.12 ± 0.07 and 0.21 ± 0.06 vs. 0.28 ± 0.14 arbitrary units [a.u.], respectively, all P < 0.05) and ICMMT (0.71 ± 0.35 and 0.99 ± 0.33 vs. 1.20 ± 0.36 a.u., all P < 0.05) than CON. In T1D, ICCLAMP, ICIVGTT, and ICMMT correlated negatively with HbA1c (all P < 0.05). M value correlated positively with ICIVGTT in CON and T2D (r = 0.199 and r = 0.178, P < 0.05) and with ICMMT in CON (r = 0.176, P < 0.05). HCL negatively associated with ICIVGTT and ICMMT in T2D (r = -0.005 and r = -0.037) and CON (r = -0.127 and r = -0.058, all P < 0.05). In line, T2D or CON subjects with steatosis featured lower ICMMT than those without steatosis (both P < 0.05).. Insulin clearance is reduced in both T1D and T2D within the first year after diagnosis but correlates negatively with liver lipid content rather in T2D. Moreover, insulin clearance differently associates with glycemic control and insulin sensitivity in each diabetes type, which may suggest specific mechanisms affecting insulin kinetics.

Topics: Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glycemic Control; Humans; Insulin; Insulin Resistance; Insulin, Regular, Human; Lipids; Liver

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

The high-dose large-volume insulin injections that may become necessary during pregnancy due to marked pregnancy-induced insulin resistance may result in suboptimal therapeutic effectiveness. Use of U-500 insulin, a concentrated insulin formulation, has been suggested during pregnancy. However, the pharmacokinetic properties of U-500 insulin monotherapy can impede achievement of strict pregnancy glycemic targets. We propose a novel regimen for treatment of severe pregnancy-induced insulin resistance that enables precise delivery of U-500 basal insulin therapy through continuous subcutaneous insulin infusion (CSII) while maintaining the desired kinetics of prandial rapid-acting U-100 insulin therapy. This combination approach, guided by continuous glucose monitoring data, enabled achievement of pregnancy glycemic targets while reducing basal insulin requirements by approximately one-third. We report our method for (1) conversion to U-500 insulin delivery through CSII during pregnancy and (2) conversion from U-500 basal insulin delivery through CSII to U-100 intravenous insulin infusion therapy at delivery, to offer clinicians who encounter similar challenging scenarios a novel approach to diabetes management during pregnancy in the setting of marked insulin resistance.

Topics: Blood Glucose; Blood Glucose Self-Monitoring; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Injections, Subcutaneous; Insulin; Insulin Infusion Systems; Insulin Resistance; Insulin, Regular, Human; Prediabetic State; Pregnancy

Insulin deficiency (ID) and resistance (IR) contribute to progression from normal glucose tolerance to diabetes to insulin requirement although their relative contributions in young-onset diabetes is unknown.. We examined the associations of HOMA2 using fasting plasma glucose and C-peptide in Chinese aged 20-50 years with (1) progression to type 2 diabetes (T2D) in participants without diabetes in a community-based cohort (1998-2013) and (2) glycaemic deterioration in patients with T2D in a clinic-based cohort (1995-2014). We defined ID as HOMA2-%B below median and insulin IR as HOMA2-IR above median.. During 10-year follow-up, 62 (17.9%) of 347 community-dwelling participants progressed to T2D. After 8.6 years, 291 (48.1%) of 609 patients with T2D had glycaemic deterioration. At baseline, progressors for T2D had higher HOMA2-IR, while in patients with T2D, progressors for glycaemic deterioration had higher HOMA2-IR and lower HOMA2-%B than non-progressors. The non-ID/IR group and the ID/IR group had an adjusted odds ratios of 2.47 (95% CI: 1.28, 4.94) and 5.36 (2.26, 12.79), respectively, for incident T2D versus the ID/non-IR group. In patients with T2D, 50% of the ID/IR group required insulin at 6.7 years versus around 11 years in the non-ID/IR or ID/non-IR, and more than 15 years in the non-ID/non-IR group. Compared with the latter group, the adjusted hazard ratios were 2.74 (1.80, 4.16) in the ID/non-IR, 2.73 (1.78, 4.19) in the non-ID/IR and 4.46 (2.87, 6.91) in the ID/IR group (p-interaction = 0.049).. In young Chinese adults, IR and ID contributed to progression to T2D and glycaemic deterioration.

Topics: Adult; Blood Glucose; China; Diabetes Mellitus, Type 2; Humans; Insulin; Insulin Resistance; Insulin, Regular, Human; Middle Aged

Kidney insulin clearance, proposed to be the main route of extra-hepatic insulin clearance, occurs in tubular cells following glomerular filtration and peritubular uptake, a process that may be impaired in people with type 2 diabetes (T2D) and/or impaired kidney function. Human studies that investigated kidney insulin clearance are limited by the invasive nature of the measurement. Instead, we evaluated relationships between whole-body insulin clearance, and gold-standard measured kidney function and insulin sensitivity in adults with T2D and normal kidney function.. We determined insulin, inulin/iohexol and para-aminohippuric acid (PAH) clearances during a hyperinsulinemic-euglycemic clamp to measure whole-body insulin clearance and kidney function. Insulin sensitivity was expressed by glucose infusion rate (M value). Associations between whole-body insulin clearance, kidney function and insulin sensitivity were examined using univariable and multivariable linear regressions models.. We investigated 44 predominantly male (77%) T2D adults aged 63 ± 7, with fat mass 34.5 ± 9 kg, lean body mass 63.0 ± 11.8 kg, and HbA1c 7.4 ± 0.6%. Average whole-body insulin clearance was 1188 ± 358 mL/min. Mean GFR was 110 ± 22 mL/min, mean ERPF 565 ± 141 mL/min, and M value averaged 3.9 ± 2.3 mg/min. Whole-body insulin clearance was positively correlated with lean body mass, ERPF and insulin sensitivity, but not with GFR. ERPF explained 6% of the variance when entered in a nested multivariable linear regression model op top of lean body mass (25%) and insulin sensitivity (15%).. In adults with T2D and normal kidney function, whole-body insulin clearance was predicted best by lean body mass and insulin sensitivity, and to a lesser extent by ERPF. GFR was not associated with whole-body insulin clearance. In contrast to prior understanding, this suggests that in this population kidney insulin clearance may not play such a dominant role in whole-body insulin clearance.

Topics: Adult; Diabetes Mellitus, Type 2; Female; Glomerular Filtration Rate; Humans; Insulin; Insulin Resistance; Insulin, Regular, Human; Kidney; Male; Renal Plasma Flow

A growing body of evidence suggests that intrapancreatic fat is associated with diabetes, but whether distribution of intrapancreatic fat across the regions of the pancreas has a pathophysiologic role is unknown. The aim of this study was to investigate the differences in intrapancreatic fat deposition between the head, body, and tail of the pancreas, as well as the relationship between regional intrapancreatic fat deposition and diabetes status and insulin traits. A total of 368 adults from the general population underwent MRI on a 3 Tesla scanner, and intrapancreatic fat was manually quantified in duplicate. Statistical models included adjustment for age, sex, ethnicity, BMI, and liver fat. Intrapancreatic fat deposition in the head, body, and tail of the pancreas did not differ significantly in adjusted models in either the overall cohort or the three subgroups based on diabetes status. HOMA of insulin resistance and fasting insulin were significantly positively associated with fat in the tail and body of the pancreas. There was no significant association between regional intrapancreatic fat and HOMA of β-cell function. The association of increased intrapancreatic fat deposition in the tail and body regions with increased insulin resistance may have an important role in the early identification of patients at risk for developing insulin resistance and diseases that stem from it.

Topics: Adult; Diabetes Mellitus; Humans; Insulin; Insulin Resistance; Insulin, Regular, Human; Pancreas

To examine the determinants and metabolic impact of the reduction in fasting and postload insulin levels after a low n-6 to n-3 polyunsaturated fatty acid (PUFA) ratio diet in obese youth.. Insulin secretion and clearance were assessed by measuring and modelling plasma insulin and C-peptide in 17 obese youth who underwent a nine-point, 180-minute oral glucose tolerance test (OGTT) before and after a 12-week, eucaloric low n-6:n-3 polyunsaturated fatty acid (PUFA) ratio diet. Hepatic fat content was assessed by repeated abdominal magnetic resonance imaging.. Insulin clearance at fasting and during the OGTT was significantly increased after the diet, while body weight, glucose levels, absolute and glucose-dependent insulin secretion, and model-derived variables of β-cell function were not affected. Dietary-induced changes in insulin clearance positively correlated with changes in whole-body insulin sensitivity and β-cell glucose sensitivity, but not with changes in hepatic fat. Subjects with greater increases in insulin clearance showed a worse metabolic profile at enrolment, characterized by impaired insulin clearance, β-cell glucose sensitivity, and glucose tolerance, and benefitted the most from the diet, achieving greater improvements in glucose-stimulated hyperinsulinaemia, insulin resistance, and β-cell function.. We showed that a 12-week low n-6:n-3 PUFA ratio diet improves hyperinsulinaemia by increasing fasting and postload insulin clearance in obese youth, independently of weight loss, glucose concentrations, and insulin secretion.

Topics: Adolescent; Blood Glucose; Diet; Fatty Acids, Omega-3; Glucose; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Insulin, Regular, Human; Obesity

The role of hepatoportal glucose sensors is poorly understood in the context of insulin resistance.. We assessed the effects of glucose infusion in the portal vein on insulin tolerance in 2 rat models of insulin resistance, and the role of capsaicin sensitive nerves in this signal.. Male Wistar rats, 8 weeks old, weighing 250-275 g, were used. Insulin and glucose tolerance were assessed following a 4-hour infusion of either glucose or saline through catheterization in the portal vein in 3 paradigms. In experiment 1, for diet-induced insulin resistance, rats were fed either a control diet (energy content: proteins = 22.5%, carbohydrates = 64.1%, and lipids = 13.4%) or a high-fat diet (energy content: proteins = 15.3%, carbohydrates = 40.3%, and lipids =44.4%) for 4 months. In experiment 2, for centrally induced peripheral insulin resistance, catheters were inserted in the carotid artery to deliver either an emulsion of triglycerides [intralipid (IL)] or saline towards the brain for 24 hours. In experiment 3, for testing the role of capsaicin-sensitive nerves, experiment 2 was repeated following a periportal treatment with capsaicin or vehicle.. In experiment 1, when compared to rats fed the control diet, rats fed the high-fat diet exhibited decreased insulin and glucose tolerance (P ≤ 0.05) that was restored with a glucose infusion in the portal vein (P ≤ 0.05). In experiment 2, infusion of a triglyceride emulsion towards the brain (IL rats) decreased insulin and glucose tolerance and increased hepatic endogenous production when compared to saline-infused rats (P ≤ 0.05). Glucose infusion in the portal vein in IL rats restored insulin and glucose tolerance, as well as hepatic glucose production, to controls levels (P ≤ 0.05). In experiment 3, portal infusion of glucose did not increase insulin tolerance in IL rats that received a periportal pretreatment with capsaicin.. Stimulation of hepatoportal glucose sensors increases insulin tolerance in rat models of insulin resistance and requires the presence of capsaicin-sensitive nerves.

Topics: Animals; Blood Glucose; Capsaicin; Emulsions; Glucose; Insulin; Insulin Resistance; Insulin, Regular, Human; Liver; Male; Nerve Fibers; Portal Vein; Rats; Rats, Wistar; Triglycerides

Insulin resistance is a metabolic disorder characterized by the decreased response to insulin in muscle, liver, and adipose cells. This condition remains a complex phenomenon that involves several genetic defects and environmental stresses. In the present study, we investigated the mechanism of known phytochemical constituents of Tinospora crispa and its interaction with insulin-resistant target proteins by using network pharmacology, molecular docking, and molecular dynamics (MD) simulation. Tinoscorside A, Makisterone C, Borapetoside A and B, and β sitosterol consider the main phytoconstituents of Tinospora crispa by its binding with active sites of main protein targets of insulin resistance potential therapy. Moreover, Tinoscorside A was revealed from the docking analysis as the ligand that binds most strongly to the target protein, PI3K. This finding was strengthened by the results of MD simulation, which stated that the conformational stability of the ligand-protein complex was achieved at 15 ns and the formation of hydrogen bonds at the active site. In conclusion, Tinospora crispa is one of the promising therapeutic agent in type 2 diabetes mellitus management. Regulation in glucose homeostasis, adipolysis, cell proliferation, and antiapoptosis are predicted to be the critical mechanism of Tinospora crispa as an insulin sensitizer.

Topics: Diabetes Mellitus, Type 2; Humans; Insulin; Insulin Resistance; Insulin, Regular, Human; Ligands; Molecular Docking Simulation; Molecular Dynamics Simulation; Network Pharmacology; Plant Extracts; Tinospora

In the setting of obesity and insulin resistance, glycemia is controlled in part by β-cell compensation and subsequent hyperinsulinemia. Weight loss improves glycemia and decreases hyperinsulinemia, whereas weight cycling worsens glycemic control. The mechanisms responsible for weight cycling-induced deterioration in glucose homeostasis are poorly understood. Thus, we aimed to pinpoint the main regulatory junctions at which weight cycling alters glucose homeostasis in mice. Using in vivo and ex vivo procedures we show that despite having worsened glucose tolerance, weight-cycled mice do not manifest impaired whole-body insulin action. Instead, weight cycling reduces insulin secretory capacity in vivo during clamped hyperglycemia and ex vivo in perifused islets. Islets from weight-cycled mice have reduced expression of factors essential for β-cell function (Mafa, Pdx1, Nkx6.1, Ucn3) and lower islet insulin content, compared with those from obese mice, suggesting inadequate transcriptional and posttranscriptional response to repeated nutrient overload. Collectively, these data support a model in which pancreatic plasticity is challenged in the face of large fluctuations in body weight resulting in a mismatch between glycemia and insulin secretion in mice.

Topics: Animals; Blood Glucose; Diet; Glucose; Hyperinsulinism; Insulin; Insulin Resistance; Insulin Secretion; Insulin, Regular, Human; Islets of Langerhans; Mice; Obesity; Weight Cycling

Long-term glucagon receptor (GCGR) agonism is associated with hyperglycemia and glucose intolerance, while acute GCGR agonism enhances whole-body insulin sensitivity and hepatic AKTSer473 phosphorylation. These divergent effects establish a critical gap in knowledge surrounding GCGR action. mTOR complex 2 (mTORC2) is composed of seven proteins, including RICTOR, which dictates substrate binding and allows for targeting of AKTSer473. We used a liver-specific Rictor knockout mouse (RictorΔLiver) to investigate whether mTORC2 is necessary for insulin receptor (INSR) and GCGR cross talk. RictorΔLiver mice were characterized by impaired AKT signaling and glucose intolerance. Intriguingly, RictorΔLiver mice were also resistant to GCGR-stimulated hyperglycemia. Consistent with our prior report, GCGR agonism increased glucose infusion rate and suppressed hepatic glucose production during hyperinsulinemic-euglycemic clamp of control animals. However, these benefits to insulin sensitivity were ablated in RictorΔLiver mice. We observed diminished AKTSer473 and GSK3α/βSer21/9 phosphorylation in RictorΔLiver mice, whereas phosphorylation of AKTThr308 was unaltered in livers from clamped mice. These signaling effects were replicated in primary hepatocytes isolated from RictorΔLiver and littermate control mice, confirming cell-autonomous cross talk between GCGR and INSR pathways. In summary, our study reveals the necessity of RICTOR, and thus mTORC2, in GCGR-mediated enhancement of liver and whole-body insulin action.

Topics: Animals; Glucose; Glucose Intolerance; Homeostasis; Hyperglycemia; Insulin; Insulin Resistance; Insulin, Regular, Human; Liver; Mechanistic Target of Rapamycin Complex 2; Mice; Mice, Inbred C57BL; Mice, Knockout; Proto-Oncogene Proteins c-akt; Rapamycin-Insensitive Companion of mTOR Protein; Receptor, Insulin; Receptors, Glucagon; TOR Serine-Threonine Kinases

Background: The liver has the capacity to regulate glucose metabolism by altering the insulin clearance rate (ICR). The decreased fasting insulin concentrations and enhanced prandial hyperinsulinemia after Roux-en-Y gastric-bypass (GB) surgery and sleeve gastrectomy (SG) are well documented. Here, we investigated the effect of GB or SG on insulin kinetics in the fasting and fed states. Method: ICR was measured (i) during a mixed-meal test (MMT) in obese non-diabetic GB (n = 9) and SG (n = 7) subjects and (ii) during a MMT combined with a hyperinsulinemic hypoglycemic clamp in the same GB and SG subjects. Five BMI-matched and non-diabetic subjects served as age-matched non-operated controls (CN). Results: The enhanced ICR during the fasting state after GB and SC compared with CN (p < 0.05) was mainly attributed to augmented hepatic insulin clearance rather than non-liver organs. The dose-response slope of the total insulin extraction rate (InsExt) of exogenous insulin per circulatory insulin value was greater in the GB and SG subjects than in the CN subjects, despite the similar peripheral insulin sensitivity among the three groups. Compared to the SG or the CN subjects, the GB subjects had greater prandial insulin secretion (ISR), independent of glycemic levels. The larger post-meal ISR following GB compared with SG was associated with a greater InsExt until it reached a plateau, leading to a similar reduction in meal-induced ICR among the GB and SG subjects. Conclusions: GB and SG alter ICR in the presence or absence of meal stimulus. Further, altered ICR after bariatric surgery results from changes in hepatic insulin clearance and not from a change in peripheral insulin sensitivity.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Fasting; Gastrectomy; Gastric Bypass; Humans; Insulin; Insulin Resistance; Insulin, Regular, Human; Obesity, Morbid

Hypogonadic subjects with insulin resistance (IR) showed different metabonomic profiles compared to normo-insulinemic subjects (IS). Testosterone replacement therapy (TRT) may have a different impact on the metabolisms of those with the presence or absence of insulin resistance. We evaluated the changes in the metabolism of IR hypogonadic patients before and after 60 days of TRT. The metabonomic plasma profiles from 20 IR hypogonadal patients were recorded using ultra-high-performance liquid chromatography (UHPLC) and high-resolution mass spectrometry (HRMS). Plasma metabolites, before and after 60 days of TRT, were compared. In hypogonadic patients, carnosine, which is important for improving performance during exercise, increased. Conversely, proline and lysine-amino acids involved in the synthesis of collagen-reduced. Triglycerides decreased and fatty acids (FFAs) increased in the blood as a consequence of reduced FFA β-oxidation. Glycolysis slightly improved, while the Krebs cycle was not activated. Gluconeogenesis (which is the main energy source for hypogonadal IR before TRT) stopped after treatment. As a consequence, lactate and acetyl CoA increased significantly. Both lactate and acetyl CoA were metabolized into ketone bodies which increased greatly, also due to leucine/isoleucine degradation. Ketone bodies were derived predominantly from acetyl CoA because the reaction of acetyl CoA into ketone bodies is catalyzed by mtHMGCoA synthase. This enzyme is inhibited by insulin, which is absent in IR patients but overexpressed following testosterone administration. Ketosis is an alternative route for energy supply and provides the same metabolic effects as insulin but at the metabolic or primitive control level, which bypasses the complex signaling pathway of insulin. After treatment, the hypogonadic patients showed clinical symptoms related to ketonuria. They presented similarly to those following a ketogenic diet, the so-called 'keto flu'. This must be taken into account before the administration of TRT to hypogonadic patients.

Topics: Acetyl Coenzyme A; Humans; Hypogonadism; Insulin; Insulin Resistance; Insulin, Regular, Human; Ketone Bodies; Ketosis; Lactates; Testosterone

Gut microbiome studies have documented depletion of butyrate-producing taxa in type 2 diabetes. We analyzed associations between butyrate-producing taxa and detailed measures of insulin homeostasis, whose dysfunction underlies diabetes in 224 non-Hispanic Whites and 129 African Americans, all of whom completed an oral glucose tolerance test. Stool microbiome was assessed by whole-metagenome shotgun sequencing with taxonomic profiling. We examined associations among 36 butyrate-producing taxa (n = 7 genera and 29 species) and insulin sensitivity, insulin secretion, disposition index, insulin clearance, and prevalence of dysglycemia (prediabetes plus diabetes, 46% of cohort), adjusting for age, sex, BMI, and race. The genus Coprococcus was associated with higher insulin sensitivity (β = 0.14; P = 0.002) and disposition index (β = 0.12; P = 0.012) and a lower rate of dysglycemia (odds ratio [OR] 0.91; 95% CI 0.85-0.97; P = 0.0025). In contrast, Flavonifractor was associated with lower insulin sensitivity (β = -0.13; P = 0.004) and disposition index (β = -0.11; P = 0.04) and higher prevalence of dysglycemia (OR 1.22; 95% CI 1.08-1.38; P = 0.0013). Species-level analyses found 10 bacteria associated with beneficial directions of effects and two bacteria with adverse associations on insulin homeostasis and dysglycemia. Although most butyrate producers analyzed appear to be metabolically beneficial, this is not the case for all such bacteria, suggesting that microbiome-directed therapeutic measures to prevent or treat diabetes should be targeted to specific butyrate-producing taxa rather than all butyrate producers.

Topics: Blood Glucose; Butyrates; Diabetes Mellitus, Type 2; Homeostasis; Humans; Insulin; Insulin Resistance; Insulin, Regular, Human; Microbiota

South Asian women have a higher risk of type 2 diabetes after gestational diabetes mellitus (GDM) than Nordic women; however, the mechanisms behind this difference remain unclear. We investigated insulin sensitivity, β-cell function, and hepatic insulin clearance in 179 South Asian and 108 Nordic women ∼17 months after GDM (mean age 35.3 years, BMI 29.1 kg/m2) by oral glucose tolerance test using deconvolution of C-peptide kinetics. Thirty-one percent of South Asian and 53% of Nordic participants were normoglycemic at the time of measurement. South Asian women had higher areas under the curve (AUCs) for glucose, prehepatic insulin, and peripheral insulin and lower insulin sensitivity, disposition index, and fasting hepatic insulin clearance than Nordic women. In the group with prediabetes or diabetes, South Asian women had similar AUCs for glucose and prehepatic insulin but a higher AUC for peripheral insulin, lower disposition index, and lower fasting hepatic insulin clearance than Nordic women. The waist-to-height ratio mediated ∼25-40% of the ethnic differences in insulin sensitivity in participants with normoglycemia. Overall, our novel data revealed that South Asian women with normoglycemia after GDM showed lower insulin secretion for a given insulin resistance and lower hepatic insulin clearance than Nordic women. South Asian women are at high risk of developing type 2 diabetes after GDM, and preventive efforts should be prioritized.

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 2; Diabetes, Gestational; Female; Glucose; Humans; Insulin; Insulin Resistance; Insulin, Regular, Human; Kinetics; Pregnancy

The D3-Creatine (D3Cr) dilution method is a direct and accurate measure of skeletal muscle mass. In this study, we examined the association of D3Cr muscle mass with measures of insulin-glucose homeostasis in community dwelling postmenopausal women. Additionally, we examined association of sarcopenic obesity, defined as low D3Cr muscle mass and high percent body fat, with fasting plasma glucose, insulin, hemoglobin A1c and insulin resistance. Insulin resistance was measured by the homeostatic measure of insulin resistance (HOMA-IR). This pilot study included 74 participants (mean age = 82.3 years) from the Women's Health Initiative-Buffalo site. The D3Cr method was initiated at a clinic visit and used to measure muscle mass via remote urine sample collection. Descriptive and graphical approaches and age-adjusted linear regression models were used to analyze study data. We examined muscle mass as an absolute value (kg) and scaled to body weight (D3Cr muscle mass/kg). There was an inverse relationship between skeletal muscle mass, and impaired insulin-glucose homeostasis. Women with low muscle mass had higher levels of insulin (uIU/mL; β = -0.40; 95% CI: -0.79, -0.01), fasting plasma glucose (mg/dL; β = -0.1; 95% CI: -0.2, 0.03), HbA1c (%; β = -2.30; 95% CI: -5.7, 1.1), and calculated homeostatic model of insulin resistance, HOMA-IR, (β = -1.49; 95% CI: -2.9, -0.1). Sarcopenic obesity was common in this population of women; 41% of participants were categorized as having low muscle mass and high percent body fat. Results demonstrate that D3Cr muscle mass is independently associated with measures of insulin-glucose homeostasis, but obesity is a stronger predictor of insulin resistance than muscle mass.

Topics: Blood Glucose; Body Mass Index; Creatine; Female; Humans; Insulin; Insulin Resistance; Insulin, Regular, Human; Muscles; Obesity; Pilot Projects; Sarcopenia

Adipose insulin-resistant but normal weight phenotype has not been reported and hence was characterized in young Japanese women.. Body composition, a broad range of cardiometabolic health and dietary intake were cross-sectionally measured in 166 normal weight young Japanese women. They were grouped into tertile of adipose tissue-insulin resistance (AT-IR) index (fasting insulin×free fatty acids) and analyzed by analysis of variance and then Bonferroni's multiple comparison procedure.. Body mass index averaged <21 kg/m. Adipose insulin-resistant but normal weight phenotype may be associated with increased sympathetic nervous system and low-grade systemic inflammation in addition to glucose and lipid dysmetabolism through mechanisms unrelated to adiposity in young Japanese women.

Topics: Adiposity; Blood Glucose; C-Reactive Protein; East Asian People; Fasting; Female; Heart Rate; Humans; Insulin; Insulin Resistance; Insulin, Regular, Human; Obesity; Triglycerides

To determine the extent to which the presence of acanthosis nigricans confers additional risk for insulin resistance, in addition to obesity alone (body mass index, BMI) within a young, overweight, UK population.. Retrospective data were collected to compare the degree of insulin resistance within a sample of 94 young people with acanthosis nigricans, and a matched cohort of 94 participants with obesity alone. Insulin resistance was assessed by fasting glucose, fasting insulin and Homeostatic Model Assessment of insulin resistance (HOMA-IR) score (a mathematical model derived to measure insulin resistance).. The acanthotic and control group were well matched for age, BMI, BMI SDS and sex, although the groups were not matched for ethnicity. The acanthotic group showed a significantly greater median fasting insulin (215 pmol/L), mean fasting glucose (4.7 mmol/L) and median HOMA-IR score (6.4), compared with the control group (126 pmol/L, 4.5 mmol/L and 3.7, respectively). The presence of acanthosis nigricans as an indicator of insulin resistance was found to have a positive predictive value of 81% (within this study population).. Individuals with both acanthosis nigricans and obesity had significantly greater degrees of insulin resistance than individuals with obesity alone. The findings support the potential for acanthosis nigricans as a visible marker of type 2 diabetes in young people.

Topics: Acanthosis Nigricans; Case-Control Studies; Diabetes Mellitus, Type 2; Glucose; Humans; Insulin; Insulin Resistance; Insulin, Regular, Human; Obesity; Overweight; Retrospective Studies; United Kingdom

Pancreatic and duodenal homeobox factor-1 (. HOMA-beta (homeostatic model assessment beta-cell function) was significantly lower in the high-risk group than in the low-risk group for all subjects (72.9±54.2% vs 107.0±63.5%, p<0.05). Glucose levels and glucose area under the curve (AUC) were not significantly different between both the risk groups. The insulin levels at 60 and 120 min and the insulin AUC after MTT were remarkably lower in the high-risk group than those in the low-risk group for all subjects (AUC 75.7±36.7 vs 112.7±59.5, p<0.05). High-risk subjects with type 2 diabetes had significantly lower insulin levels at 30 and 60 min and insulin AUC than low-risk subjects. Non-diabetic high-risk subjects depicted significantly lower insulin levels at 120 and 180 min. There were negligible differences in insulin resistance between the risk groups.. These results suggest that the

Topics: Diabetes Mellitus, Type 2; East Asian People; Genes, Homeobox; Genome-Wide Association Study; Glucose; Humans; Insulin; Insulin Resistance; Insulin Secretion; Insulin, Regular, Human; Polymorphism, Genetic

To evaluate multiple determinants of the longitudinal change in insulin clearance (IC) in subjects at high risk for type 2 diabetes (T2D).. Adults (n=492) at risk for T2D in the Prospective Metabolism and Islet Cell Evaluation cohort, a longitudinal observational cohort, had four visits over 9 years. Values from oral glucose tolerance tests collected at each assessment were used to calculate the ratios of both fasting C peptide-to-insulin (IC. IC declined by 20% over the 9-year follow-up period (p<0.05). Primary GEE results indicated that non-European ethnicity, as well as increases in baseline measures of waist circumference, white cell count, and alanine aminotransferase, was associated with declines in IC. Our findings suggest that non-European ethnicity and components of the metabolic syndrome, including central obesity, non-alcoholic fatty liver disease, and subclinical inflammation, may be related to longitudinal declines in IC.

Topics: Biomarkers; Blood Glucose; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Insulin Resistance; Insulin, Regular, Human; Islets of Langerhans; Longitudinal Studies; Male; Middle Aged; Prediabetic State; Prognosis; Prospective Studies

In recent years, the possibility of using intranasally administered insulin to treat Alzheimers disease and other cognitive disorders has been widely studied. At the same time, the possibility of its use in the treatment of diabetes mellitus is practically not investigated, which is due to the insufficient study of the molecular mechanisms of its action on the hormonal and metabolic status of the organism. The review discusses literature data and the results of our own research on the role of insulin in the central regulation of energy homeostasis, as well as on the experience of using intranasally administered insulin to correct eating disorders and metabolic and hormonal dysfunctions developing under conditions of experimental diabetes mellitus and metabolic syndrome. In studies involving healthy volunteers, various effects of intranasally administered insulin were shown, including effects on cognitive function, eating behavior and weight loss, and the gender specificity of its action was found. In the course of numerous studies of intranasally administered insulin in animal models of diabetes mellitus, not only stabilization of carbohydrate homeostasis was shown, but also a positive effect in the form of restoration of the functional activity of insulin signaling pathways in the hypothalamus and other parts of the brain. We have presented and analyzed data on the systemic effects of intranasally administered insulin in rodents with experimental models of diabetes mellitus, as well as in healthy individuals.. В последние годы широко изучается возможность применения интраназально вводимого инсулина для лечения болезни Альцгеймера и других когнитивных расстройств. В то же время практически не исследуется возможность его применения в рамках терапии сахарного диабета, что во многом связано с недостаточной изученностью молекулярных механизмов его действия на гормональный и метаболический статусы организма. В обзоре обсуждаются данные литературы и результаты собственных исследований о роли инсулина в центральной регуляции энергетического гомеостаза, а также об опыте применения интраназально вводимого инсулина для коррекции нарушений пищевого поведения и метаболических и гормональных дисфункций, развивающихся в условиях экспериментального сахарного диабета и метаболического синдрома. В исследованиях с участием здоровых добровольцев были показаны различные эффекты интраназально вводимого инсулина, в том числе влияние на когнитивные функции, пищевое поведение и снижение массы тела, а также обнаружена гендерная специфичность его действия. В ходе многочисленных исследований интраназально вводимого инсулина на животных моделях сахарного диабета были показаны не только стабилизация углеводного гомеостаза, но и положительное действие в виде восстановления функциональной активности инсулиновых сигнальных путей в гипоталамусе и других отделах мозга. Нами представлены и проанализированы данные о системных эффектах интраназально вводимого инсулина у грызунов с экспериментальными моделями сахарного диабета, а также у здоровых индивидуумов.

Topics: Animals; Diabetes Mellitus, Experimental; Insulin; Insulin Resistance; Insulin, Regular, Human; Metabolic Syndrome

Topics: Humans; Insulin; Insulin Resistance; Insulin, Regular, Human; Liver; Non-alcoholic Fatty Liver Disease

Topics: Humans; Insulin; Insulin Resistance; Insulin, Regular, Human; Liver; Non-alcoholic Fatty Liver Disease

Purpose The purpose of this article is to provide recommendations to the diabetes educator/expert prescriber team for the use of human regular U-500 insulin (U-500R) in patients with severely insulin-resistant type 2 diabetes, including its initiation and titration, by utilizing dosing charts and teaching materials translated from a recent U-500R clinical trial. Conclusions Clinically relevant recommendations and teaching materials for the optimal use and management of U-500R in clinical practice are provided based on the efficacy and safety results of and lessons learned from the U-500R clinical trial by Hood et al, current standards of practice, and the authors' clinical expertise. This trial was the first robustly powered, randomized, titration-to-target trial to compare twice-daily and three-times-daily U-500R dosing regimens. Modifications were made to the initiation and titration dosing algorithms used in this trial to simplify dosing strategies for the clinical setting and align with current glycemic targets recommended by the American Diabetes Association. Leveraging the expertise, resources, and patient interactions of the diabetes educator who can provide diabetes self-management education and support in collaboration with the multidisciplinary diabetes team is strongly recommended to ensure patients treated with U-500R receive the timely and comprehensive care required to safely and effectively use this highly concentrated insulin.

Topics: Adult; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Female; Health Educators; Humans; Hypoglycemic Agents; Insulin Resistance; Insulin, Regular, Human; Male; Patient Care Team; Patient Education as Topic; Randomized Controlled Trials as Topic; Translational Research, Biomedical

Topics: Developmental Disabilities; Diabetes Mellitus; Diet; Humans; Hyperinsulinism; Hypoglycemic Agents; Insulin Resistance; Insulin, Regular, Human; Male; Metformin; Middle Aged

Insulin effects reportedly involve reactive oxygen species (ROS) and oxidative stress in vitro, but skeletal muscle oxidative stress is an emerging negative regulator of insulin action following high-fat feeding. NEFA may enhance oxidative stress and insulin resistance. We investigated the acute impact of insulin with or without NEFA elevation on muscle ROS generation and insulin signalling, and the potential association with altered muscle mitochondrial function.. We used hyperinsulinaemic-euglycaemic clamping, 150 min, without or with lipid infusion to modulate plasma NEFA concentration in lean rats.. Insulin and glucose (Ins) infusion selectively enhanced xanthine oxidase-dependent muscle ROS generation. Ins with lipid infusion (Ins+NEFA) lowered whole-body glucose disposal and muscle insulin signalling, and these effects were associated with high muscle mitochondrial ROS generation and activation of the proinflammatory nuclear factor-κB inhibitor (IκB)-nuclear factor-κB (NFκB) pathway. Antioxidant infusion prevented NEFA-induced systemic insulin resistance and changes in muscle mitochondrial ROS generation, IκB-NFκB pathway and insulin signalling. Changes in insulin sensitivity and signalling were independent of changes in mitochondrial enzyme activity and ATP production, which, in turn, were not impaired by changes in ROS generation under any condition.. Acute muscle insulin effects include enhanced ROS generation through xanthine oxidase. Additional NEFA elevation enhances mitochondrial ROS generation, activates IκB-NFκB and reduces insulin signalling. These alterations are not associated with acute reductions in mitochondrial enzyme activity and ATP production, and are reversed by antioxidant infusion. Thus, NEFA acutely cause systemic and muscle insulin resistance by enhancing muscle oxidative stress through mitochondrial ROS generation and IκB-NFκB activation.

Topics: Animals; Antioxidants; Diet, High-Fat; Fatty Acids, Nonesterified; Hypoglycemic Agents; I-kappa B Proteins; Infusions, Intravenous; Insulin Resistance; Insulin, Regular, Human; Male; Mitochondria, Muscle; Muscle, Skeletal; NF-kappa B; Oxidative Stress; Random Allocation; Rats; Rats, Wistar; Reactive Oxygen Species; Signal Transduction; Xanthine Oxidase

Obesity and its associated disorders constitute a growing epidemic across the world. Numerous studies have demonstrated the presence of systemic oxidative stress in patients with obesity. In this study, we show the effects of oxidative stress present in the blood from obese patients on recombinant human insulin. Insulin was incubated with whole blood (WB) from overweight subjects (OW), obese 1 patients (O1), or normal weight volunteers (NW) (n=16 for each group). Whole blood from OW and O1, unlike WB from NW, increased the carbonyl content of insulin; however, only whole blood from O1 patients increased the amount of formazan present in the hormone. Interestingly, the incubation of insulin with WB from O1 provoked a decrease in the hypoglycemic activity of the hormone (18%), an effect due to insulin polymerization. In addition, we showed that the formation of the insulin polymer generated the formation of new epitopes and the development of a new immunogenicity. These observations show that oxidative stress present in the WB of O1 patients can result in abolition of the biological activity of insulin and contribute to the development of an immune response to the hormone.

Topics: Adult; Animals; Antigen-Antibody Reactions; Biomarkers; Body Mass Index; Female; Formazans; Humans; Hypoglycemic Agents; Insulin Resistance; Insulin, Regular, Human; Mice; Obesity; Overweight; Oxidation-Reduction; Oxidative Stress; Polymerization; Protein Carbonylation; Recombinant Proteins; Young Adult