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Aims/Introduction: Imeglimin is a recently approved oral antidiabetic agent that improves insulin resistance, and promotes insulin secretion from pancreatic β‐cells. Here, we investigated the effects of imeglimin on glucagon secretion from pancreatic α‐cells. Materials and Methods: Experiments were carried out in high‐fat, high‐sucrose diet‐fed mice. The effects of imeglimin were examined using insulin and glucose tolerance tests, glucose clamp studies, and measurements of glucagon secretion from isolated islets. Glucagon was measured using both the standard and the sequential protocol of Mercodia sandwich enzyme‐linked immunosorbent assay; the latter eliminates cross‐reactivities with other proglucagon‐derived peptides. Results: Plasma glucagon, insulin and glucagon‐like peptide‐1 levels were increased by imeglimin administration in high‐fat, high‐sucrose diet‐fed mice. Glucose clamp experiments showed that the glucagon increase was not caused by reduced blood glucose levels. After both single and long‐term administration of imeglimin, glucagon secretions were significantly enhanced during glucose tolerance tests. Milder enhancement was observed when using the sequential protocol. Long‐term administration of imeglimin did not alter α‐cell mass. Intraperitoneal imeglimin administration did not affect glucagon secretion, despite significantly decreased blood glucose levels. Imeglimin did not enhance glucagon secretion from isolated islets. Imeglimin administration improved fatty liver by suppressing de novo lipogenesis through decreasing sterol regulatory element binding protein‐1c and carbohydrate response element binding protein and their target genes, while enhancing fatty acid oxidation through increasing carnitine palmitoyltransferase I. Conclusions: Overall, the present results showed that imeglimin enhances glucagon secretion through an indirect mechanism. Our findings also showed that glucagon secretion promoted by imeglimin could contribute to improvement of fatty liver through suppressing de novo lipogenesis and enhancing fatty acid oxidation. [ABSTRACT FROM AUTHOR]

Accurate measurements of glycaemic control and the underpinning regulatory mechanisms are vital in human physiology research. Glycaemic control is the maintenance of blood glucose concentrations within optimal levels and is governed by physiological variables including insulin sensitivity, glucose tolerance and β‐cell function. These can be measured with a plethora of methods, all with their own benefits and limitations. Deciding on the best method to use is challenging and depends on the specific research question(s). This review therefore discusses the theory and procedure, validity and reliability and any special considerations of a range common methods used to measure glycaemic control, insulin sensitivity, glucose tolerance and β‐cell function. Methods reviewed include glycosylated haemoglobin, continuous glucose monitors, the oral glucose tolerance test, mixed meal tolerance test, hyperinsulinaemic euglycaemic clamp, hyperglycaemic clamp, intravenous glucose tolerance test and indices derived from both fasting concentrations and the oral glucose tolerance test. This review aims to help direct understanding, assessment and decisions regarding which method to use based on specific physiology‐related research questions. [ABSTRACT FROM AUTHOR]

Aim: Experimental hypoglycaemia blunts the counterregulatory hormone and symptom responses to a subsequent episode of hypoglycaemia. In this study, we aimed to assess the associations between antecedent exposure and continuous glucose monitoring (CGM)‐recorded hypoglycaemia during a 1‐week period and the counterregulatory responses to subsequent experimental hypoglycaemia in people with type 1 diabetes. Materials and Methods: Forty‐two people with type 1 diabetes (20 females, mean ± SD glycated haemoglobin 7.8% ± 1.0%, diabetes duration median (interquartile range) 22.0 (10.5‐34.9) years, 29 CGM users, and 19 with impaired awareness of hypoglycaemia) wore an open intermittently scanned CGM for 1 week to detect hypoglycaemic exposure before a standardized hyperinsulinaemic‐hypoglycaemic [2.8 ± 0.1 mmol/L (50.2 ± 2.3 mg/dl)] glucose clamp. Symptom responses and counterregulatory hormones were measured during the clamp. The study is part of the HypoRESOLVE project. Results: CGM‐recorded hypoglycaemia in the week before the clamp was negatively associated with adrenaline response [β −0.09, 95% CI (−0.16, −0.02) nmol/L, p =.014], after adjusting for CGM use, awareness of hypoglycaemia, glycated haemoglobin and total daily insulin dose. This was driven by level 2 hypoglycaemia [<3.0 mmol/L (54 mg/dl)] [β −0.21, 95% CI (−0.41, −0.01) nmol/L, p =.034]. CGM‐recorded hypoglycaemia was negatively associated with total, autonomic, and neuroglycopenic symptom responses, but these associations were lost after adjusting for potential confounders. Conclusions: Recent exposure to CGM‐detected hypoglycaemia was independently associated with an attenuated adrenaline response to experimental hypoglycaemia in people with type 1 diabetes. [ABSTRACT FROM AUTHOR]

Physical activity is effective for preventing and treating type 2 diabetes, but some individuals do not achieve metabolic benefits from exercise ("non-responders"). We investigated non-responders in terms of insulin sensitivity changes following a 12-week supervised strength and endurance exercise program. We used a hyperinsulinaemic euglycaemic clamp to measure insulin sensitivity among 26 men aged 40–65, categorizing them into non-responders or responders based on their insulin sensitivity change scores. The exercise regimen included VO2max, muscle strength, whole-body MRI scans, muscle and fat biopsies, and serum samples. mRNA sequencing was performed on biopsies and Olink proteomics on serum samples. Non-responders showed more visceral and intramuscular fat and signs of dyslipidaemia and low-grade inflammation at baseline and did not improve in insulin sensitivity following exercise, although they showed gains in VO2max and muscle strength. Impaired IL6-JAK-STAT3 signalling in non-responders was suggested by serum proteomics analysis, and a baseline serum proteomic machine learning (ML) algorithm predicted insulin sensitivity responses with high accuracy, validated across two independent exercise cohorts. The ML model identified 30 serum proteins that could forecast exercise-induced insulin sensitivity changes. [ABSTRACT FROM AUTHOR]

This research letter discusses the absence of a glucose-lowering effect in glucose clamp procedures with a long-acting insulin analogue. The study analyzed data from three euglycemic glucose clamp studies involving insulin glargine U100 administered subcutaneously in people with type 1 diabetes. The results showed that a small percentage of clamp procedures did not require glucose infusion, indicating a near equilibrium between endogenous glucose production and glucose uptake. The authors suggest that arithmetic means should be used for the analysis of pharmacodynamic outcomes in biosimilar insulin studies. [Extracted from the article]

The article discusses a study which compared continuous positive airway pressure (CPAP) treatment with nasal dilator strip (NDS) control in pregnant individuals with gestational diabetes mellitus (GDM). Topics include assessment of adherence to CPAP by downloading CPAP usage reports every two weeks, analysis of glucose profiles, and primary analysis of CGM data using multiple imputation.

Background: Recognizing insulin resistance (IR) in children remains challenging due to uncertain IRI-HOMA cut-offs and unclear recommendations for evaluating IR based on OGTT. In our study, we compare the effectiveness of IRI-HOMA and IRI-Belfiore (OGTT-based) in detecting IR and its metabolic complications in children. Methods: The analysis included 553 children who were hospitalized at the Department of Endocrinology and Metabolic Diseases of the Polish Mother's Memorial Hospital Research Institute (PMMH-RI) in Lodz, Poland, between 2002 and 2018 due to various reasons—of these, 67.5% were girls. All underwent OGTT for glucose and insulin assessment. IR diagnosis relied on IRI-HOMA and IRI-Belfiore. IR based on IRI-HOMA was evaluated using three criteria: (A) >2.5; (B) >2.67 in boys and >2.22 in girls before puberty and >5.22 and >3.82 during puberty, respectively; (C) >95th percentile according to charts for IRI-HOMA in children. Results: Prepubertal children exhibited significantly lower IRI-HOMA and IRI-Belfiore than their pubertal counterparts (p < 0.00005). IRI-HOMA and IRI-Belfiore values positively correlated with age and BMI SDS value (p < 0.000001 for all calculations). As many as 26% to 46.9% of children with normal IRI-HOMA showed elevated IRI-Belfiore, with notably higher levels of triglycerides, a lower HDL cholesterol fraction, and a lower HDL/total cholesterol ratio in this subgroup. Conclusions: A notable proportion of children exhibited elevated IRI-Belfiore levels despite having normal IRI-HOMA values. This suggests the possibility of peripheral IR preceding hepatic IR in children—omitting an OGTT may therefore lead to overlooking cases of IR. Children diagnosed with IR via OGTT displayed significantly poorer lipid profiles compared to those without IR (characterized by normal values in both IRI-HOMA and IRI-Belfiore). This underscores the ability of OGTT-derived IR indices to identify individuals at risk of developing complications associated with obesity and IR before the onset of metabolic syndrome (MS) symptoms. If IR is already detected in children based on fasting glucose and insulin levels (IRI-HOMA), further evaluation may not be warranted, as OGTT results often simply confirm the diagnosis. [ABSTRACT FROM AUTHOR]

Residual beta cells are present in most patients with longstanding type 1 diabetes but it is unknown whether these beta cells react normally to different stimuli. Moreover a defect in proinsulin conversion and abnormal alpha cell response are also part of the islet dysfunction. A three-phase [euglycemia, hyperglycemia, and hyperglycemia + glucagon-like peptide 1 (GLP-1)] clamp was performed in patients with longstanding type 1 diabetes. Intravenous arginine boluses were administered at the end of each phase. On another day, a mixed meal stimulation test with a subsequent intravenous arginine bolus was performed. C-peptide was detectable in a subgroup of subjects at baseline (2/15) or only after stimulation (3/15). When detectable, C-peptide increased 2.9-fold [95% CI: 1.2–7.1] during the hyperglycemia phase and 14.1-fold [95% CI: 3.1–65.2] during the hyperglycemia + GLP-1 phase, and 22.3-fold [95% CI: 5.6–89.1] during hyperglycemia + GLP-1 + arginine phase when compared with baseline. The same subset of patients with a C-peptide response were identified during the mixed meal stimulation test as during the clamp. There was an inhibition of glucagon secretion (0.72-fold, [95% CI: 0.63–0.84]) during the glucose clamp irrespective of the presence of detectable beta cell function. Proinsulin was only present in a subset of subjects with detectable C-peptide (3/15) and proinsulin mimicked the C-peptide response to the different stimuli when detectable. Residual beta cells in longstanding type 1 diabetes respond adequately to different stimuli and could be of clinical benefit. NEW & NOTEWORTHY: If beta cell function is detectable, the beta cells react relatively normal to the different stimuli except for the first phase response to intravenous glucose. An oral mixed meal followed by an intravenous arginine bolus can identify residual beta cell function/mass as well as the more commonly used glucose potentiated arginine-induced insulin secretion during a hyperglycemic clamp. [ABSTRACT FROM AUTHOR]

Aims: To investigate the pharmacokinetic/pharmacodynamic properties of once‐weekly insulin icodec in individuals with type 1 diabetes (T1D). Materials and Methods: In this randomized, open‐label, two‐period crossover trial, 66 individuals with T1D (age 18–64 years; glycated haemoglobin ≤75 mmol/mol [≤ 9%]) were to receive once‐weekly icodec (8 weeks) and once‐daily insulin glargine U100 (2 weeks) at individualized fixed equimolar total weekly doses established during up to 10 weeks' run‐in with glargine U100 titrated to pre‐breakfast plasma glucose (PG) of 4.4–7.2 mmol/L (80–130 mg/dL). Insulin aspart was used as bolus insulin. Blood sampling for icodec pharmacokinetics was performed from the first icodec dose until 35 days after the last dose. The glucose infusion rate at steady state was assessed in glucose clamps (target 6.7 mmol/L [120 mg/dL]) at 16–52 h and 138–168 h after the last icodec dose and 0–24 h after the last glargine U100 dose. Icodec pharmacodynamics during 1 week were predicted by pharmacokinetic‐pharmacodynamic modelling. Hypoglycaemia was recorded during the treatment periods based on self‐measured PG. Results: Icodec reached pharmacokinetic steady state on average within 2–3 weeks. At steady state, model‐predicted daily proportions of glucose infusion rate during the 1‐week dosing interval were 14.3%, 19.6%, 18.3%, 15.7%, 13.1%, 10.6% and 8.4%, respectively. Rates and duration of Level 2 hypoglycaemic episodes (PG <3.0 mmol/L [54 mg/dL]) were 32.8 versus 23.9 episodes per participant‐year of exposure and 33 ± 25 versus 30 ± 18 min (mean ± SD) for icodec versus glargine U100. Conclusions: The pharmacokinetic/pharmacodynamic properties of icodec suggest its potential to provide basal coverage in a basal‐bolus insulin regimen in people with T1D. [ABSTRACT FROM AUTHOR]

The article offers information on the incretin effect (IE) and its role in regulating β cell functional response and insulin secretion dynamics. Topics include the impact of IE reduction in type 2 diabetes, a study using surgical removal of β cell mass as a model for diabetes development, and findings suggesting that preexisting defects in β cell response to incretins predict the risk of developing impairments in glucose tolerance after β cell mass reduction.

Metabolic tests are vital to determine in vivo insulin sensitivity and glucose metabolism in preclinical models, usually rodents. Such tests include glucose tolerance tests, insulin tolerance tests, and glucose clamps. Although these tests are not standardized, there are general guidelines for their completion and analysis that are constantly being refined. In this review, we describe metabolic tests in rodents as well as factors to consider when designing and performing these tests. [ABSTRACT FROM AUTHOR]

OBJECTIVE: β-Cell dysfunction and insulin resistance magnify the risk of kidney injury in type 2 diabetes. The relationship between these factors and intraglomerular hemodynamics and kidney oxygen availability in youth with type 2 diabetes remains incompletely explored. RESEARCH DESIGN AND METHODS: Fifty youth with type 2 diabetes (mean age ± SD 16 ± 2 years; diabetes duration 2.3 ± 1.8 years; 60% female; median HbA1c 6.4% [25th, 75th percentiles 5.9, 7.6%]; BMI 36.4 ± 7.4 kg/m2; urine albumin-to-creatinine ratio [UACR] 10.3 [5.9, 58.0] mg/g) 21 control participants with obesity (OCs; age 16 ± 2 years; 29% female; BMI 37.6 ± 7.4 kg/m2), and 20 control participants in the normal weight category (NWCs; age 17 ± 3 years; 70% female; BMI 22.5 ± 3.6 kg/m2) underwent iohexol and p-aminohippurate clearance to assess glomerular filtration rate (GFR) and renal plasma flow, kidney MRI for oxygenation, hyperglycemic clamp for insulin secretion (acute C-peptide response to glucose [ACPRg]) and disposition index (DI; ×103 mg/kg lean/min), and DXA for body composition. RESULTS: Youth with type 2 diabetes exhibited lower DI (0.6 [0.0, 1.6] vs. 3.8 [2.4, 4.5] × 103 mg/kg lean/min; P < 0.0001) and ACPRg (0.6 [0.3, 1.4] vs. 5.3 [4.3, 6.9] nmol/L; P < 0.001) and higher UACR (10.3 [5.9, 58.0] vs. 5.3 [3.4, 14.3] mg/g; P = 0.003) and intraglomerular pressure (77.8 ± 11.5 vs. 64.8 ± 5.0 mmHg; P < 0.001) compared with OCs. Youth with type 2 diabetes and OCs had higher GFR and kidney oxygen availability (relative hyperoxia) than NWCs. DI was associated inversely with intraglomerular pressure and kidney hyperoxia. CONCLUSIONS: Youth with type 2 diabetes demonstrated severe β-cell dysfunction that was associated with intraglomerular hypertension and kidney hyperoxia. Similar but attenuated findings were found in OCs. [ABSTRACT FROM AUTHOR]

Background: Hypoglycaemia has been shown to induce a systemic pro-inflammatory response, which may be driven, in part, by the adrenaline response. Prior exposure to hypoglycaemia attenuates counterregulatory hormone responses to subsequent hypoglycaemia, but whether this effect can be extrapolated to the pro-inflammatory response is unclear. Therefore, we investigated the effect of antecedent hypoglycaemia on inflammatory responses to subsequent hypoglycaemia in humans. Methods: Healthy participants (n = 32) were recruited and randomised to two 2-h episodes of either hypoglycaemia or normoglycaemia on day 1, followed by a hyperinsulinaemic hypoglycaemic (2.8 ± 0.1 mmol/L) glucose clamp on day 2. During normoglycaemia and hypoglycaemia, and after 24 h, 72 h and 1 week, blood was drawn to determine circulating immune cell composition, phenotype and function, and 93 circulating inflammatory proteins including hs-CRP. Results: In the group undergoing antecedent hypoglycaemia, the adrenaline response to next-day hypoglycaemia was lower compared to the control group (1.45 ± 1.24 vs 2.68 ± 1.41 nmol/l). In both groups, day 2 hypoglycaemia increased absolute numbers of circulating immune cells, of which lymphocytes and monocytes remained elevated for the whole week. Also, the proportion of pro-inflammatory CD16+-monocytes increased during hypoglycaemia. After ex vivo stimulation, monocytes released more TNF-α and IL-1β, and less IL-10 in response to hypoglycaemia, whereas levels of 19 circulating inflammatory proteins, including hs-CRP, increased for up to 1 week after the hypoglycaemic event. Most of the inflammatory responses were similar in the two groups, except the persistent pro-inflammatory protein changes were partly blunted in the group exposed to antecedent hypoglycaemia. We did not find a correlation between the adrenaline response and the inflammatory responses during hypoglycaemia. Conclusion: Hypoglycaemia induces an acute and persistent pro-inflammatory response at multiple levels that occurs largely, but not completely, independent of prior exposure to hypoglycaemia. Clinical Trial information Clinicaltrials.gov no. NCT03976271 (registered 5 June 2019). [ABSTRACT FROM AUTHOR]

The article discusses the historical context and scientific understanding of diabetes, focusing on the interplay between pancreatic β cell function and insulin resistance, as elucidated by the hyperbolic law of glucose tolerance. Topics include the distinction between type 1 and type 2 diabetes, the debate over the primary pathogenetic defect in type 2 diabetes, and the application of the hyperbolic curve in studying glucose regulation and predicting disease onset.

The carotid bodies (CBs) have been implicated in glucose abnormalities in obesity via elevation of activity of the sympathetic nervous system. Obesity-induced hypertension is mediated by insulin receptor (INSR) signaling and by leptin, which binds to the leptin receptor (LEPRb) in CB and activates transient receptor potential channel subfamily M member 7 (TRPM7). We hypothesize that in mice with diet-induced obesity, hyperglycemia, glucose intolerance, and insulin resistance will be attenuated by the CB denervation (carotid sinus nerve dissection, CSND) and by knockdown of Leprb, Trpm7, and Insr gene expression in CB. In series of experiments in 75 male diet-induced obese (DIO) mice, we performed either CSND (vs. sham) surgeries or shRNA-induced suppression of Leprb, Trpm7, or Insr gene expression in CB, followed by blood pressure telemetry, intraperitoneal glucose tolerance and insulin tolerance tests, and measurements of fasting plasma insulin, leptin, corticosterone, glucagon and free fatty acids (FFAs) levels, hepatic expression of gluconeogenesis enzymes phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G-6-Pase) mRNA and liver glycogen levels. CSND decreased blood pressure, fasting blood glucose levels and improved glucose tolerance without any effect on insulin resistance. CSND did not affect any hormone levels and gluconeogenesis enzymes, but increased liver glycogen level. Genetic knockdown of CB Leprb, Trpm7, and Insr had no effect on glucose metabolism. We conclude that CB contributes to hyperglycemia of obesity, probably by modulation of the glycogen-glucose equilibrium. Diabetogenic effects of obesity on CB in mice do not occur via activation of CB Leprb, Trpm7, and Insr. [ABSTRACT FROM AUTHOR]

Background: Hepatic insulin clearance (HIC) is an important pathophysiology of type 2 diabetes mellitus (T2DM). HIC was reported to decrease in patients with type 2 diabetes and metabolic syndrome. HIC is originally calculated by post-load insulin and C-peptide from the oral glucose tolerance test (OGTT). However, OGTT or meal tolerance tests are a burden for patients, and OGTT is not suitable for overt diabetes due to the risk of hyperglycemia. If we can calculate the HIC from the fasting state, it is preferable. We hypothesized that fasting HIC correlates with postprandial HIC in both participants with T2DM and without diabetes. We investigated whether fasting HIC correlates with postprandial HIC in overt T2DM and nondiabetes subjects (non-DM) evaluated by using glucose clamp and meal load. Methods: We performed a meal tolerance test and hyperinsulinemic–euglycemic clamp in 70 subjects, 31 patients with T2DM and 39 non-DM subjects. We calculated the postprandial C-peptide AUC-to-insulin AUC ratio as the postprandial HIC and the fasting C-peptide-to-insulin ratio as the fasting HIC. We also calculated whole-body insulin clearance from the glucose clamp test. Results: The fasting HIC significantly correlated with postprandial HIC in T2DM (r_S = 0.82, P < 0.001). Nondiabetes subjects also showed a significant correlation between fasting and postprandial HIC (r_S = 0.71, P < 0.001). Fasting HIC in T2DM was correlated with BMI, HbA1c, gamma-glutamyl transpeptidase, HOMA-IR, HOMA-beta, M/I, and whole-body insulin clearance. Fasting HIC in nondiabetes subjects was correlated with HOMA-IR and HOMA-beta. Conclusions: These results suggest that fasting HIC is strongly correlated with postprandial HIC in both overt T2DM and non-DM patients, as evaluated by the meal test and glucose clamp method. Fasting HIC could be a convenient marker of HIC. [ABSTRACT FROM AUTHOR]

Coronary artery calcification (CAC) is positively and independently associated with cardiovascular disease (CVD) in patients undergoing maintenance hemodialysis (MHD). Insulin resistance is independently associated with CAC and is an important risk factor for CVD. The triglyceride–glucose (TyG) index is a reliable biomarker of insulin resistance. This cross-sectional, observational study aimed to investigate the relationship between the TyG index and CAC in asymptomatic non-diabetic patients undergoing MHD. The quantitative coronary artery calcification score (CACS) was calculated and expressed using the Agatston score. The TyG index was calculated as ln [fasting triglyceride (mg/dL) × fasting glucose (mg/dL)/2]. Multiple Poisson regression analysis, Spearman correlation analysis, and receiver operating characteristic (ROC) curves were used to investigate the relationship between the TyG index and CAC. The 151 patients were divided into three groups according to the tertiles of the TyG index. With an increase in the TyG index, the CACS significantly increased (Spearman's rho = 0.414, p < 0.001). Poisson regression analysis indicated that the TyG index was independently related to the presence of CAC (prevalence ratio, 1.281 [95% confidence interval, 1.121–1.465], p < 0.001). Furthermore, ROC curve analysis showed that the TyG index was of value in predicting the CAC in asymptomatic non-diabetic patients undergoing MHD, with an area under the curve of 0.667 (p = 0.010). The TyG index is independently related to the presence of CAC in asymptomatic, non-diabetic patients undergoing MHD. [ABSTRACT FROM AUTHOR]

Aim: For the successful approval and clinical prescription of insulin biosimilars, it is essential to show pharmacokinetic (PK) and pharmacodynamic (PD) bioequivalence to the respective reference products sourced from the European Union and the United States. Methods: Three phase 1, randomized, double‐blind, three‐period crossover trials compared single doses of the proposed biosimilar insulin analogues aspart (GL‐Asp, n = 36), lispro (GL‐Lis, n = 38) and glargine (GL‐Gla, n = 113), all manufactured by Gan & Lee pharmaceuticals, to the respective EU‐ and US‐reference products in healthy male participants (GL‐Asp and GL‐Lis) or people with type 1 diabetes (GL‐Gla). Study participants received 0.2 U/kg (aspart and lispro) or 0.5 U/kg (glargine) of each treatment under automated euglycaemic clamp conditions. The clamp duration was 12 h (aspart and lispro) or 30 h (glargine). Primary PK endpoints were the total area under the PK curves (AUCins.total) and maximum insulin concentrations (Cins.max). Primary PD endpoints were the total area under the glucose infusion rate curve (AUCGIR.total) and maximum glucose infusion rate (GIRmax). Results: Bioequivalence to both EU‐ and US‐reference products were shown for all three GL insulins. Least squares mean ratios for the primary PK/PD endpoints were close to 100%, and both 90% and 95% confidence intervals were within 80%–125% in all three studies. There were no noticeable differences in the safety profiles between test and reference insulins, and no serious adverse events were reported for the GL insulins. Conclusion: GL‐Asp, GL‐Lis and GL‐Gla are bioequivalent to their EU‐ and US‐reference products. [ABSTRACT FROM AUTHOR]

Aims: To characterize the pharmacokinetic and pharmacodynamic properties of once‐weekly insulin icodec in type 2 diabetes (T2D). Materials and Methods: In an open‐label trial, 46 individuals with T2D (18‐75 years; body mass index 18.0‐38.0 kg/m2; glycated haemoglobin ≤75 mmol/mol [≤9%]; basal insulin‐treated) received subcutaneous once‐weekly icodec for ≥8 weeks at individualized doses, aiming at a pre‐breakfast plasma glucose concentration of 4.4 to 7.0 mmol/L (80‐126 mg/dL) on the last three mornings of each weekly dosing interval. Frequent blood sampling to assess total serum icodec concentration (ie, albumin‐bound and unbound) occurred from first icodec dose until 35 days after last dose. Icodec trough concentrations following initiation of once‐weekly dosing were predicted by pharmacokinetic modelling. During the final 3 weeks of icodec treatment, while at steady state, the icodec glucose‐lowering effect was assessed in three glucose clamps (target 7.5 mmol/L [135 mg/dL]): 0 to 36, 40 to 64 and 144 to 168 h post‐dose, thus covering the initial, middle and last part of the 1‐week dosing interval. Glucose‐lowering effect during a complete dosing interval was predicted by pharmacokinetic‐pharmacodynamic modelling. Results: Model‐predicted icodec steady state was attained after 3 to 4 weeks. At steady state, model‐predicted daily proportions of glucose‐lowering effect on days 1 to 7 of the 1‐week dosing interval were 14.1%, 16.1%, 15.8%, 15.0%, 14.0%, 13.0% and 12.0%, respectively. Icodec duration of action was at least 1 week in all participants. Once‐weekly icodec was overall safe and well tolerated in the current trial. Conclusions: The pharmacokinetic and pharmacodynamic characteristics of icodec in individuals with T2D support its potential as a once‐weekly basal insulin. [ABSTRACT FROM AUTHOR]

OBJECTIVE: 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. RESEARCH DESIGN AND METHODS: 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. RESULTS: 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). CONCLUSIONS: 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. [ABSTRACT FROM AUTHOR]

Individuals with type 1 diabetes have an impaired glucagon counterregulatory response to hypoglycemia. Sodium-glucose cotransporter (SGLT) inhibitors increase glucagon concentrations. We evaluated whether SGLT inhibition restores the glucagon counterregulatory hormone response to hypoglycemia. Adults with type 1 diabetes (n = 22) were treated with the SGLT2 inhibitor dapagliflozin (5 mg daily) or placebo for 4 weeks in a randomized, double-blind, crossover study. After each treatment phase, participants underwent a hyperinsulinemic-hypoglycemic clamp. Basal glucagon concentrations were 32% higher following dapagliflozin versus placebo, with a median within-participant difference of 2.75 pg/mL (95% CI 1.38-12.6). However, increased basal glucagon levels did not correlate with decreased rates of hypoglycemia and thus do not appear to be protective in avoiding hypoglycemia. During hypoglycemic clamp, SGLT2 inhibition did not change counterregulatory hormone concentrations, time to recovery from hypoglycemia, hypoglycemia symptoms, or cognitive function. Thus, despite raising basal glucagon concentrations, SGLT inhibitor treatment did not restore the impaired glucagon response to hypoglycemia. We propose that clinical reduction in hypoglycemia associated with these agents is a result of changes in diabetes care (e.g., lower insulin doses or improved glycemic variability) as opposed to a direct, physiologic effect of these medications on α-cell function.

Aim: To determine the duration and the extension of the pro‐inflammatory response to hypoglycaemia both in people with type 1 diabetes and healthy controls. Materials and Methods: Adults with type 1 diabetes (n = 47) and matched controls (n = 16) underwent a hyperinsulinaemic‐euglycaemic hypoglycaemic (2.8 ± 0.1 mmoL/L [49.9 ± 2.3 mg/dL]) glucose clamp. During euglycaemia, hypoglycaemia, and 1, 3 and 7 days later, blood was drawn to determine immune cell phenotype, monocyte function and circulating inflammatory markers. Results: Hypoglycaemia increased lymphocyte and monocyte counts, which remained elevated for 1 week. The proportion of CD16+ monocytes increased and the proportion of CD14+ monocytes decreased. During hypoglycaemia, monocytes released more tumour necrosis factor‐α and interleukin‐1β, and less interleukin‐10, after ex vivo stimulation. Hypoglycaemia increased the levels of 19 circulating inflammatory proteins, including high sensitive C‐reactive protein, most of which remained elevated for 1 week. The epinephrine peak in response to hypoglycaemia was positively correlated with immune cell number and phenotype, but not with the proteomic response. Conclusions: Overall, despite differences in prior exposure to hypoglycaemia, the pattern of the inflammatory responses to hypoglycaemia did not differ between people with type 1 diabetes and healthy controls. In conclusion, hypoglycaemia induces a range of pro‐inflammatory responses that are sustained for at least 1 week in people with type 1 diabetes and healthy controls. [ABSTRACT FROM AUTHOR]

Triglyceride-based indices have gained much attention over the past few years. Relation of triglyceride – glucose (TyG) index with insulin resistance and diabetic macrovascular complications was thoroughly studied; nevertheless its relation to microvascular complications is still unclear. This provoked us to carry out the present study. This cross-sectional study included 500 patients with type 2 diabetes (T2DM), who were enrolled from the outpatient clinic of the Diabetes and Metabolism Unit at Alexandria Main University Hospital. The equations utilized to calculate triglycerides-related indices were: TyG ratio = fasting triglycerides (mg/dL)/fasting glucose (mg/dL), and TyG index = logarithm of [fasting triglyceride (mg/dl) x fasting glucose (mg/dl)/2]. The diagnostic criteria set by the American Diabetes Association were followed to diagnose diabetic microvascular complications. In patients with T2DM, TyG index was significantly higher in patients with diabetic retinopathy, diabetic kidney disease, and diabetic peripheral neuropathy compared to those without complications (p < 0.001). TyG index was significantly positively correlated to diabetes duration, as well as triglyceride/high density lipoprotein ratio in the total sample (p < 0.001). TyG index is an easy, cheap, and available marker for detection of microvascular complications in patients with T2DM. [ABSTRACT FROM AUTHOR]

The effectiveness of therapy in patients with diabetes depends on the correct use of the insulin injection technique. However, despite many established recommendations and evidence that an effective insulin injection technique is essential to improve glycaemic control and minimise the risk associated with diabetes, there is still a need to identify impediments to the insulin injection technique among patients and create awareness among patients and healthcare professionals about the importance of the optimisation of insulin injection techniques. This review focuses on the recent advancements in delivery devices, insulin injection technique teaching methods, monitoring, and complication management and highlights regional best practices and recommendations for optimising injection techniques to improve diabetes outcomes. [ABSTRACT FROM AUTHOR]

Intramyocellular lipid content (IMCL) is elevated in insulin-resistant humans, but it changes over time, and relationships with comorbidities remain unclear. We examined IMCL during the initial course of diabetes and its associations with complications. Participants of the German Diabetes Study (GDS) with recent-onset type 1 (n = 132) or type 2 diabetes (n = 139) and glucose-tolerant control subjects (n = 128) underwent 1H-MRS to measure IMCL and muscle volume, whole-body insulin sensitivity (hyperinsulinemic-euglycemic clamps; M-value), and cycling spiroergometry (VO2max). Subgroups underwent the same measurements after 5 years. At baseline, IMCL was ∼30% higher in type 2 diabetes than in other groups independently of age, sex, BMI, and muscle volume. In type 2 diabetes, the M-value was ∼36% and ∼62% lower compared with type 1 diabetes and control subjects, respectively. After 5 years, the M-value decreased by ∼29% in type 1 and ∼13% in type 2 diabetes, whereas IMCL remained unchanged. The correlation between IMCL and M-value in type 2 diabetes at baseline was modulated by VO2max. IMCL also associated with microalbuminuria, the Framingham risk score for cardiovascular disease, and cardiac autonomic neuropathy. Changes in IMCL within 5 years after diagnosis do not mirror the progression of insulin resistance in type 2 diabetes but associate with early diabetes-related complications. Article Highlights: Intramyocellular lipid content (IMCL) can be elevated in insulin-resistant humans, but its dynamics and association with comorbidities remain unclear. Independently of age, sex, body mass, and skeletal muscle volume, IMCL is higher in recent-onset type 2, but not type 1 diabetes, and remains unchanged within 5 years, despite worsening insulin resistance. A degree of physical fitness modulates the association between IMCL and insulin sensitivity in type 2 diabetes. Whereas higher IMCL associates with lower insulin sensitivity in people with lower physical fitness, there is no association between IMCL and insulin sensitivity in those with higher degree of physical fitness. IMCL associates with progression of microalbuminuria, cardiovascular disease risk, and cardiac autonomic neuropathy. [ABSTRACT FROM AUTHOR]

Objective: Insulin resistance is characterized by ectopic fat accumulation leading to cardiac diastolic dysfunction and nonalcoholic fatty liver disease. The objective of this study was to determine whether treatment with the peroxisome proliferator‐activated receptor‐α (PPARα) agonist ciprofibrate has direct effects on cardiac and hepatic metabolism and can improve insulin sensitivity and cardiac function in insulin‐resistant volunteers. Methods: Ten insulin‐resistant male volunteers received 100 mg/d of ciprofibrate and placebo for 5 weeks in a randomized double‐blind crossover study. Insulin‐stimulated metabolic rate of glucose (MRgluc) was measured using dynamic 18F‐fluorodeoxyglucose‐positron emission tomography (18F‐FDG‐PET). Additionally, cardiac function, whole‐body insulin sensitivity, intrahepatic lipid content, skeletal muscle gene expression, 24‐hour blood pressure, and substrate metabolism were measured. Results: Whole‐body insulin sensitivity, energy metabolism, and body composition were unchanged after ciprofibrate treatment. Ciprofibrate treatment decreased insulin‐stimulated hepatic MRgluc and increased hepatic lipid content. Myocardial net MRgluc tended to decrease after ciprofibrate treatment, but ciprofibrate treatment had no effect on cardiac function and cardiac energy status. In addition, no changes in PPAR‐related gene expression in muscle were found. Conclusions: Ciprofibrate treatment increased hepatic lipid accumulation and lowered MRgluc, without affecting whole‐body insulin sensitivity. Furthermore, parameters of cardiac function or cardiac energy status were not altered upon ciprofibrate treatment. [ABSTRACT FROM AUTHOR]

Purpose: Findings concerning the effects of almond consumption on glucose metabolism are inconsistent which might relate to body weight gain. The effects of long-term almond consumption on glucose metabolism are investigated in a free-living setting without detailed dietary instructions in males and females with overweight/obesity and prediabetes. Methods: Forty-three participants volunteered in this randomized, cross-over trial with a 5-months control and intervention period and a 2-months wash-out. In the intervention period participants daily consumed 50 g whole almonds. At the end of both periods insulin sensitivity was assessed by a hyperinsulinemic euglycemic clamp, and postprandial glucose responses, and 48 h continuous glucose concentrations were measured. Results: Almond consumption significantly decreased insulin sensitivity (P = 0.002), and increased postprandial glucose concentrations (P = 0.019), as well as fasting insulin concentrations (P = 0.003) as compared to the control period. The AUCs for 24 h glucose concentrations were not significantly different between control and intervention (P = 0.066). Almond consumption also significantly increased BMI (P = 0.002), and waist circumference (P = 0.013), supported by the concurrent increased energy intake (P = 0.031). The effects on glucose metabolism could only partly be explained by the observed weight gain as the almond effect remained after correcting for BMI changes. Conclusions: In participants with prediabetes, long-term almond consumption showed adverse effects on insulin sensitivity and glucose metabolism. As almonds seemed not to have fully replaced other food items, it might be necessary to provide more supporting guidelines on how to incorporate energy-dense nuts into healthy diets to prevent type 2 diabetes development. Clinical Trial Registration: This clinical trial was registered in February 2018 as NCT03419702. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the contributions of two factors potentially impairing glucagon response to insulin-induced hypoglycemia (IIH) in insulin-deficient diabetes: 1) loss of paracrine disinhibition by intra-islet insulin and 2) defects in the activation of the autonomic inputs to the islet. Plasma glucagon responses during hyperinsulinemic-hypoglycemic clamps ([Formula: see text]40 mg/dL) were assessed in dogs with spontaneous diabetes (n = 13) and in healthy nondiabetic dogs (n = 6). Plasma C-peptide responses to intravenous glucagon were measured to assess endogenous insulin secretion. Plasma pancreatic polypeptide, epinephrine, and norepinephrine were measured as indices of parasympathetic and sympathoadrenal autonomic responses to IIH. In 8 of the 13 diabetic dogs, glucagon did not increase during IIH (diabetic nonresponder [DMN]; ∆ = -6 ± 12 pg/mL). In five other diabetic dogs (diabetic responder [DMR]), glucagon responses (∆ = +26 ± 12) were within the range of nondiabetic control dogs (∆ = +27 ± 16 pg/mL). C-peptide responses to intravenous glucagon were absent in diabetic dogs. Activation of all three autonomic responses were impaired in DMN dogs but remained intact in DMR dogs. Each of the three autonomic responses to IIH was positively correlated with glucagon responses across the three groups. The study conclusions are as follows: 1) Impairment of glucagon responses in DMN dogs is not due to generalized impairment of α-cell function. 2) Loss of tonic inhibition of glucagon secretion by insulin is not sufficient to produce loss of the glucagon response; impairment of autonomic activation is also required. 3) In dogs with major β-cell function loss, activation of the autonomic inputs is sufficient to mediate an intact glucagon response to IIH.NEW & NOTEWORTHY In dogs with naturally occurring, insulin-dependent (C-peptide negative) diabetes mellitus, impairment of glucagon responses is not due to generalized impairment of α-cell function. Loss of tonic inhibition of glucagon secretion by insulin is not sufficient, by itself, to produce loss of the glucagon response. Rather, impaired activation of the parasympathetic and sympathoadrenal autonomic inputs to the pancreas is also required. Activation of the autonomic inputs to the pancreas is sufficient to mediate an intact glucagon response to insulin-induced hypoglycemia in dogs with naturally occurring diabetes mellitus. These results have important implications that include leading to a greater understanding and insight into the pathophysiology, prevention, and treatment of hypoglycemia during insulin treatment of diabetes in companion dogs and in human patients.

Background: Habitually skipping breakfast may promote the initiation and progression of gastrointestinal (GI) cancers, which have never been systematically explored in large-scale prospective studies. Methods: We prospectively examined the effects of breakfast frequency on the occurrence of GI cancers among 62,746 participants. The hazard ratios (HRs) and 95% confidence intervals (95% CIs) of GI cancers were calculated by Cox regression. The CAUSALMED procedure was used to perform the mediation analyses. Results: During a median follow-up of 5.61 (5.18 ~ 6.08) years, 369 incident GI cancer cases were identified. Participants who consumed 1–2 times breakfasts per week exhibited an increased risk of stomach (HR = 3.45, 95% CI: 1.06–11.20) and liver cancer (HR = 3.42, 95% CI: 1.22–9.53). Participants who did not eat breakfast had an elevated risk of esophageal (HR = 2.72, 95% CI: 1.05–7.03), colorectal (HR = 2.32, 95% CI: 1.34–4.01), liver (HR = 2.41, 95% CI: 1.23–4.71), gallbladder, and extrahepatic bile duct cancer (HR = 5.43, 95% CI: 1.34–21.93). In the mediation effect analyses, BMI, CRP, and TyG (fasting triglyceride-glucose) index did not mediate the association between breakfast frequency and the risk of GI cancer incidence (all P for mediation effect > 0.05). Conclusions: Habitually skipping breakfast was associated with a greater risk of GI cancers including esophageal, gastric, colorectal, liver, gallbladder, and extrahepatic bile duct cancer. Trial Registration: Kailuan study, ChiCTR–TNRC–11001489. Registered 24 August, 2011-Retrospectively registered, http://www.chictr.org.cn/showprojen.aspx?proj=8050 [ABSTRACT FROM AUTHOR]

Background: Empagliflozin reduces the risk of cardiovascular disease (CVD) in patients with type 2 diabetes (T2DM) and high cardiovascular risk via mechanisms which have not been fully explained. The mechanisms of such benefit have not been fully understood, and whether empagliflozin can be safely administered as first-line treatment in patients with CVD at the initial stages of glycaemic perturbations remains to be established. We investigated the effects of empagliflozin on insulin resistance, insulin sensitivity and β-cell function indexes in patients with a recent acute coronary event and newly detected dysglycaemia, i.e., impaired glucose tolerance (IGT) or T2DM. Methods: Forty-two patients (mean age 67.5 years, 19% females) with a recent myocardial infarction (n = 36) or unstable angina (n = 6) and newly detected dysglycaemia were randomized to either empagliflozin 25 mg daily (n = 20) or placebo (n = 22). Patients were investigated with stress-perfusion cardiac magnetic resonance imaging before randomization, 7 months after the start of study drug and 3 months following its cessation. Indexes of insulin resistance, sensitivity and β-cell function were calculated based on glucose and insulin values from 2-hour oral glucose tolerance tests (OGTT) and fasting C-peptide. The differences in glucose, insulin, C-peptide, mannose levels and indexes between the two groups were computed by repeated measures ANOVA including an interaction term between the treatment allocation and the time of visit. Results: After 7 months, empagliflozin significantly decreased glucose and insulin values during the OGTT, whereas C-peptide, mannose and HbA1c did not differ. Empagliflozin significantly improved insulin sensitivity indexes but did not impact insulin resistance and β-cell function. After cessation of the drug, all indexes returned to initial levels. Insulin sensitivity indexes were inversely correlated with left ventricular mass at baseline. Conclusions: Empagliflozin improved insulin sensitivity indexes in patients with a recent coronary event and drug naïve dysglycaemia. These findings support the safe use of empagliflozin as first-line glucose-lowering treatment in patients at very high cardiovascular risk with newly diagnosed dysglycaemia. Trial registration number: EudraCT number 2015-004571-73. [ABSTRACT FROM AUTHOR]

Aim: To establish the pharmacokinetic (PK) and pharmacodynamic (PD) equivalence of proposed biosimilar Insulin N (Biocon's Insulin‐N; Biocon Biologics Ltd., Bangalore, India) and US‐licensed Humulin® N (Humulin‐N; Eli Lilly and Company, Indianapolis, IN, USA) in healthy subjects. Materials and Methods: This was a phase‐1, single‐centre, double‐blind, randomized, three‐period, six‐sequence, partially replicated, crossover, 24‐h euglycaemic clamp study. Overall, 90 healthy subjects were randomized, of whom 85 completed the study. The subjects received either two single doses of Biocon's Insulin‐N and a single dose of Humulin‐N or two single doses of Humulin‐N and a single dose of Biocon's Insulin‐N subcutaneously at a dose of 0.4 IU/kg. The primary PK endpoints were the area under the insulin concentration‐time curve from 0 to 24 h (AUCins.0‐24h) and the maximum insulin concentration (Cins.max). The primary PD endpoints were the area under the glucose infusion rate (GIR) curve from 0 to 24 h (AUCGIR.0‐24h) and the maximum GIR (GIRmax). Results: Biocon's Insulin‐N was found to be equivalent to Humulin‐N for the primary PK (geometric 90% confidence interval for the least squares mean ratio: AUCins.0‐24h, 100.98%‐115.66% and Cins.max, 95.91%‐110.16%) and PD endpoints (intra‐subject variability ≥0.294; 95% upper confidence interval [(μT – μR)2 − θσ2WR] <0; point estimates of geometric least squares mean ratio: AUCGIR.0‐24h, 104.61% and GIRmax, 100.81%). The safety profile of Biocon's Insulin‐N was similar to that of Humulin‐N, and no serious adverse events were reported. Conclusion: PK and PD equivalence was shown between Biocon's Insulin‐N and Humulin‐N in healthy subjects, and both treatments were well tolerated and considered safe. [ABSTRACT FROM AUTHOR]

Polycystic ovary syndrome (PCOS) can induce fertility and metabolism disorders, which may increase the prevalence of glucose metabolism disorders and cause health hazards to women and their offspring. We aim to evaluate the effect of maternal preconception glucose metabolism on neonatal birthweight in PCOS women undergoing IVF/ICSI cycles. We retrospectively analyzed 269 PCOS women who delivered 190 singletons and 79 twins via IVF/ICSI at a reproductive center. The effects of maternal preconception glucose metabolism indicators on singleton and twin birthweight were evaluated using generalized linear models and generalized estimate equations, respectively. The potential nonlinear associations were evaluated using generalized additive models. The analyses were further stratified by maternal preconception BMI and delivery mode to evaluate the possible interaction effects. Among PCOS women, maternal preconception fasting plasma glucose (FPG) and glycohemoglobin (HbA1c) had significant negative associations with singleton birthweight (all p for trends = 0.04). We also found an overweight-specific association between elevated maternal preconception 2 h plasma insulin (2hPI) and twin birthweight (p for interactions = 0.05) and a caesarean-specific association between maternal preconception HbA1c and singleton birthweight (p for interactions = 0.02) in PCOS women. Maternal preconception glucose metabolism may affect neonatal birthweight, suggesting the importance of preconception glucose and insulin management for PCOS women. Further large prospective cohorts and animal studies are needed to confirm these findings and investigate the potential mechanisms. [ABSTRACT FROM AUTHOR]

BackgroundSome studies have suggested that in people with type 2 diabetes, Roux-en-Y gastric bypass has therapeutic effects on metabolic function that are independent of weight loss.MethodsWe evaluated metabolic regulators of glucose homeostasis before and after matched (approximately 18%) weight loss induced by gastric bypass (surgery group) or diet alone (diet group) in 22 patients with obesity and diabetes. The primary outcome was the change in hepatic insulin sensitivity, assessed by infusion of insulin at low rates (stages 1 and 2 of a 3-stage hyperinsulinemic euglycemic pancreatic clamp). Secondary outcomes were changes in muscle insulin sensitivity, beta-cell function, and 24-hour plasma glucose and insulin profiles.ResultsWeight loss was associated with increases in mean suppression of glucose production from baseline, by 7.04 μmol per kilogram of fat-free mass per minute (95% confidence interval [CI], 4.74 to 9.33) in the diet group and by 7.02 μmol per kilogram of fat-free mass per minute (95% CI, 3.21 to 10.84) in the surgery group during clamp stage 1, and by 5.39 (95% CI, 2.44 to 8.34) and 5.37 (95% CI, 2.41 to 8.33) μmol per kilogram of fat-free mass per minute in the two groups, respectively, during clamp stage 2; there were no significant differences between the groups. Weight loss was associated with increased insulin-stimulated glucose disposal, from 30.5±15.9 to 61.6±13.0 μmol per kilogram of fat-free mass per minute in the diet group and from 29.4±12.6 to 54.5±10.4 μmol per kilogram of fat-free mass per minute in the surgery group; there was no significant difference between the groups. Weight loss increased beta-cell function (insulin secretion relative to insulin sensitivity) by 1.83 units (95% CI, 1.22 to 2.44) in the diet group and by 1.11 units (95% CI, 0.08 to 2.15) in the surgery group, with no significant difference between the groups, and it decreased the areas under the curve for 24-hour plasma glucose and insulin levels in both groups, with no significant difference between the groups. No major complications occurred in either group.ConclusionsIn this study involving patients with obesity and type 2 diabetes, the metabolic benefits of gastric bypass surgery and diet were similar and were apparently related to weight loss itself, with no evident clinically important effects independent of weight loss. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT02207777.).

ABSTRACT Objectives: To validate the homeostasis model assessment (HOMA) of insulin resistance (IR) as a surrogate to the hyperglycemic clamp to measure IR in both pubertal and postpubertal adolescents, and determine the HOMA-IR cutoff values for detecting IR in both pubertal stages. Subjects and methods: The study sample comprised 80 adolescents of both sexes (aged 10-18 years; 37 pubertal), in which IR was assessed with the HOMA-IR and the hyperglycemic clamp. Results: In the multivariable linear regression analysis, adjusted for sex, age, and waist circumference, the HOMA-IR was independently and negatively associated with the clamp-derived insulin sensitivity index in both pubertal (unstandardized coefficient – B = −0.087, 95% confidence interval [CI] = −0.135 to −0.040) and postpubertal (B = −0.101, 95% CI, −0.145 to −0.058) adolescents. Bland-Altman plots showed agreement between the predicted insulin sensitivity index and measured clamp-derived insulin sensitivity index in both pubertal stages (mean = −0.00 for pubertal and postpubertal); all P > 0.05. The HOMA-IR showed a good discriminatory power for detecting IR with an area under the receiver operator characteristic curve of 0.870 (95% CI, 0.718-0.957) in pubertal and 0.861 (95% CI, 0.721-0.947) in postpubertal adolescents; all P < 0.001. The optimal cutoff values of the HOMA-IR for detecting IR were > 3.22 (sensitivity, 85.7; 95% CI, 57.2-98.2; specificity, 82.6; 95% CI, 61.2-95.0) for pubertal and > 2.91 (sensitivity, 63.6; 95% CI, 30.8-89.1, specificity, 93.7; 95%CI, 79.2-99.2) for postpubertal adolescents. Conclusion: The threshold value of the HOMA-IR for identifying insulin resistance was > 3.22 for pubertal and > 2.91 for postpubertal adolescents.

Objective: Despite the fact that some evidence suggests that the administration of 17β-estradiol plus norethisterone acetate influences glucose and insulin metabolism in women, these findings are still contradictory. Thus, we aimed to examine the impact of the co-administration of 17β-estradiol and norethisterone acetate on glycated haemoglobin (HbA1c), fasting glucose, insulin and C-peptide concentrations in females by means of a systematic review and meta-analysis of randomized controlled trials (RCTs). Methods: We searched four databases (PubMed/MEDLINE, Scopus, Embase, and Web of Science) using specific keywords and word combinations. The random-effects model (DerSimonian and Laird model) was employed to compute the weighted mean difference (WMD) and 95% confidence intervals (CIs) for the variations from baseline of HbA1c, fasting glucose, insulin, and C-peptide concentrations. Results: In total, 14 RCTs were entered into the quantitative synthesis. The combined administration of 17β-estradiol and norethisterone acetate decreased HbA1c (WMD: -0.65%, 95% CI: -1.15 to -0.15; P=0.011), fasting glucose (WMD: -11.05 mg/dL, 95% CI: -16.6 to -5.5; P<0.001) and insulin (WMD: -1.35 mIU/L, 95% CI: -2.20 to -0.50; P=0.001) levels. C-peptide concentrations' declined only in females diagnosed with overweight/obesity or diabetes. Conclusion: Evidence to date points out that the administration of 17β-estradiol and norethisterone acetate has a positive impact on glucose metabolism in women by reducing fasting glucose, HbA1c, and insulin values. Future studies need to confirm the potential benefits of this drug combination in the prevention and/or management of cardiometabolic disorders. [ABSTRACT FROM AUTHOR]

Introduction: The prevalence of obesity constantly increases worldwide and definitely increases the risk of premature death in early adulthood. While there is no treatment yet with proven efficacy for the metabolic clamp such as arterial hypertension, dyslipidemia, insulin resistance, diabetes type 2, and fatty liver disease, it is imperative to find a way to decrease cardiometabolic complications. Early prevention strategies beginning in childhood are the most logical step to reduce future cardiovascular morbidity and mortality. Therefore, the aim of the current study is to determine the most sensitive and specific predictive markers of the metabolically unhealthy phenotype with high cardiometabolic risk in overweight/obese adolescent boys. Methods: This study was carried out at the Ternopil Regional Children's hospital (Western Ukraine) and involved 254 randomly chosen adolescent overweight or obese boys [median age was 16.0 (15.0,16.1) years]. A control group of 30 healthy children with proportional body weight comparable in gender and age to the main group was presented. A list of anthropometrical markers with biochemical values of carbohydrate and lipid metabolism with hepatic enzymes was determined. All overweight/obese boys were divided into three groups: 51.2% of the boys with metabolic syndrome (MetS) based on the IDF criteria; 19.7% of the boys were metabolically healthy obese (MHO) without hypertension, dyslipidemia, and hyperglycemia; and the rest of the boys (29.1%) were classified as metabolically unhealthy obese (MUO) with only one criterion (hypertension, dyslipidemia, or hyperglycemia). Results: Based on multiple logistic regression analysis that included all anthropometric and biochemical values and calculated indexes in boys from the MHO group and MetS, it was revealed that the maximum likelihood in the prediction of MetS makes the combination of triglyceride glucose index, pediatric nonalcoholic fatty liver disease fibrosis index (PNFI), and triglyceride-to-high-density lipoprotein cholesterol ratio (R² =0.713, p<0.000). By tracing the receiver operating characteristic curve, the model is confirmed as a good predictor of MetS (AUC=0.898, odds ratio=27.111 percentage correct=86.03%) in overweight and obese boys. Conclusion: Triglyceride glucose index, pediatric NAFLD fibrosis index, and triglyceride-to-high-density lipoprotein cholesterol ratio are a valuable combination of predictive markers of the metabolically unhealthy phenotype in Ukrainian overweight/obese boys. [ABSTRACT FROM AUTHOR]

Background: Insulin resistance (IR) and nonalcoholic fatty liver disease (NAFLD) are closely related. The triglyceride-glucose index (TyG index) has been proposed as a new indicator of IR. It remains unclear whether the triglycerideglucose (TyG) index is prospectively associated with incident nonalcoholic fatty liver disease (NAFLD). Methods: This large-scale study comprised 1 prospective cohort totaling 22,758 subjects without NAFLD at baseline who underwent repeated health examinations and 1 subcohort totaling 7,722 subjects with more than three visits. The TyG index was ascertained mathematically by ln (fasting triglycerides [mg/dL] × fasting glucose [mg/dL]/2). NAFLD was diagnosed by ultrasound without other concomitant liver diseases. A combinatorial Cox proportional hazard model and latent class growth mixturemodelingmethodwere used to identify the association of the TyGindex and its transition trajectories with NAFLD risk. Results: During 53,481 person-years of follow-up, there were 5319 incident cases with NAFLD. Compared with those in the lowest quartile of the baseline TyG index, participants in the highest quartile had 2.52-fold (95% confidence interval, 2.21-2.86) higher odds of incident NAFLD. Similarly, restricted cubic spline analysis showed a dose-response relationship (p nonlinearity<0.001). Subgroup analyses showed a more significant association in the female and normal body size populations (p for interaction<0.001). Three distinct trajectories of changes in the TyG index were identified. Compared with the continued low group, the moderately increasing and highly increasing groups conferred 1.91-fold (1.65-2.21) and 2.19-fold (1.73-2.77) higher NAFLD risk, respectively. Conclusions: Participants with a higher baseline TyG index or a higher excessive TyG exposure were associated with an increased NAFLD risk. The findings imply that lifestyle interventions and modulation of IR might be considered to both reduce TyG index levels and prevent NAFLD development. [ABSTRACT FROM AUTHOR]

The growing amount of evidence suggests the existence of a bidirectional relation between coronavirus disease 2019 (COVID-19) and type 2 diabetes mellitus (T2DM), as these two conditions exacerbate each other, causing a significant healthcare and socioeconomic burden. The alterations in innate and adaptive cellular immunity, adipose tissue, alveolar and endothelial dysfunction, hypercoagulation, the propensity to an increased viral load, and chronic diabetic complications are all associated with glucometabolic perturbations of T2DM patients that predispose them to severe forms of COVID-19 and mortality. Severe acute respiratory syndrome coronavirus 2 infection negatively impacts glucose homeostasis due to its effects on insulin sensitivity and β-cell function, further aggravating the preexisting glucometabolic perturbations in individuals with T2DM. Thus, the most effective ways are urgently needed for countering these glucometabolic disturbances occurring during acute COVID-19 illness in T2DM patients. The novel classes of antidiabetic medications (dipeptidyl peptidase 4 inhibitors (DPP-4is), glucagon-like peptide-1 receptor agonists (GLP-1 RAs), and sodium-glucose co-transporter-2 inhibitors (SGLT-2is) are considered candidate drugs for this purpose. This review article summarizes current knowledge regarding glucometabolic disturbances during acute COVID-19 illness in T2DM patients and the potential ways to tackle them using novel antidiabetic medications. Recent observational data suggest that preadmission use of GLP-1 RAs and SGLT-2is are associated with decreased patient mortality, while DPP-4is is associated with increased in-hospital mortality of T2DM patients with COVID-19. Although these results provide further evidence for the widespread use of these two classes of medications in this COVID-19 era, dedicated randomized controlled trials analyzing the effects of in-hospital use of novel antidiabetic agents in T2DM patients with COVID-19 are needed. [ABSTRACT FROM AUTHOR]

Background: High-Intensity Interval Training (HIIT) involves bursts of high-intensity exercise interspersed with lower-intensity exercise recovery. HIIT may benefit cardiometabolic health in people with nonalcoholic steatohepatitis (NASH). Aims: We aimed to examine the safety, feasibility, and efficacy of 12-weeks of supervised HIIT compared with a sham-exercise control (CON) for improving aerobic fitness and peripheral insulin sensitivity in biopsy-proven NASH. Methods: Participants based in the community [(n = 14, 56 ± 10 years, BMI 39.2 ± 6.7 kg/m2, 64% male), NAFLD Activity Score 5 (range 3–7)] were randomized to 12-weeks of supervised HIIT (n = 8, 4 × 4 min at 85–95% maximal heart rate, interspersed with 3 min active recovery; 3 days/week) or CON (n = 6, stretching; 3 days/week). Safety (adverse events) and feasibility determined as ≥ 70% program completion and ≥ 70% global adherence (including session attendance, interval intensity adherence, and duration adherence) were assessed. Changes in cardiorespiratory fitness (V̇O2peak), exercise capacity (time-on-test) and peripheral insulin sensitivity (euglycemic hyperinsulinemic clamp) were assessed. Data were analysed using ANCOVA with baseline value as the covariate. Results: There were no HIIT-related adverse events and HIIT was globally feasible [program completion 75%, global adherence 100% (including adherence to session 95.4 ± 7.3%, interval intensity 95.3 ± 6.0% and duration 96.8 ± 2.4%)]. A large between-group effect was observed for exercise capacity [mean difference 134.2 s (95% CI 19.8, 248.6 s), ƞ2 0.44, p = 0.03], improving in HIIT (106.2 ± 97.5 s) but not CON (− 33.4 ± 43.3 s), and for peripheral insulin sensitivity [mean difference 3.4 mg/KgLegFFM/min (95% CI 0.9,6.8 mg/KgLegFFM/min), ƞ2 0.32, p = 0.046], improving in HIIT (1.0 ± 0.8 mg/KgLegFFM/min) but not CON (− 3.1 ± 1.2 mg/KgLegFFM/min). Conclusions: HIIT is safe, feasible and efficacious for improving exercise capacity and peripheral insulin sensitivity in people with NASH. Clinical Trial Registration Number: Australian New Zealand Clinical Trial Registry (anzctr.org.au) identifier ACTRN12616000305426 (09/03/2016). [ABSTRACT FROM AUTHOR]

Objective: This study aimed to explore the factors affecting the bioequivalence of test and reference insulin preparations so as to provide a scientific basis for the consistency evaluation of the quality and efficacy of insulin biosimilars. Methods: A randomized, open, two-sequence, single-dose, crossover design was used in this study. Subjects were randomly divided into TR or RT groups in equal proportion. The glucose infusion rate and blood glucose were measured by a 24-h glucose clamp test to evaluate the pharmacodynamic parameters of the preparation. The plasma insulin concentration was determined by liquid chromatography-mass spectrometry (LC-MS/MS) to evaluate pharmacokinetic parameters. WinNonlin 8.1 and SPSS 23.0 were applied for PK/PD parameter calculation and statistical analysis. The structural equation model (SEM) was constructed to analyze the influencing factors of bioequivalence by using Amos 24.0. Results: A total of 177 healthy male subjects aged 18-45 years were analyzed. Subjects were assigned to the equivalent group (N = 55) and the non-equivalent group (N = 122) by bioequivalence results, according to the EMA guideline. Univariate analysis showed statistical differences in albumin, creatinine, Tmax, bioactive substance content, and adverse events between the two groups. In the structural equation model, adverse events (β = 0.342; p < 0.001) and bioactive substance content (β = -0.189; p = 0.007) had significant impacts on the bioequivalence of two preparations, and the bioactive substance content significantly affected adverse events (β = 0.200; p = 0.007). Conclusion: A multivariate statistical model was used to explore the influencing factors for the bioequivalence of two preparations. According to the result of the structural equation model, we proposed that adverse events and bioactive substance content should be optimized for consistency evaluation of the quality and efficacy of insulin biosimilars. Furthermore, bioequivalence trials of insulin biosimilars should strictly obey inclusion and exclusion criteria to ensure the consistency of subjects and avoid confounding factors affecting the equivalence evaluation. [ABSTRACT FROM AUTHOR]

We aimed to investigate the effects of maternal obesity on brain structure and metabolism in frail women, and their reversibility in response to exercise. We recruited 37 frail elderly women (20 offspring of lean/normal-weight mothers (OLM) and 17 offspring of obese/overweight mothers (OOM)) and nine non-frail controls to undergo magnetic resonance and diffusion tensor imaging (DTI), positron emission tomography with Fluorine-18-fluorodeoxyglucose (PET), and cognitive function tests (CERAD). Frail women were studied before and after a 4-month resistance training, and controls were studied once. White matter (WM) density (voxel-based morphometry) was higher in OLM than in OOM subjects. Exercise increased WM density in both OLM and OOM in the cerebellum in superior parietal regions in OLM and in cuneal and precuneal regions in OOM. OLM gained more WM density than OOM in response to intervention. No significant results were found from the Freesurfer analysis, nor from PET or DTI images. Exercise has an impact on brain morphology and cognition in elderly frail women. [ABSTRACT FROM AUTHOR]

BACKGROUND: Sacha inchi meal (SIM) is a by‐product of oil processing. Our previous studies showed that SIM hydrolysates exhibited dipeptidyl peptidase‐IV (DPP‐IV) inhibition activity. The objective of the present work was to identify and characterize the bioactive peptides from protein hydrolysates of SIM; enzyme kinetics and peptide–enzyme interaction were also investigated. RESULTS: From SIM hydrolysates, ten peptides responsible for the activity were identified: GPSRGF (GF‐6), FPILSPDPA (FA‐9), APYRRGGKI (AI‐9), WPYH (WH‐4), DPATWLALPT (DT‐10), NPEDEFRQQ (NQ‐9), APESKPVGV (AV‐9), LEWRDR (LR‐6), APVYWVQ (AQ‐7) and LLMWPY (LY‐6). The IC50 values of five peptides (GF‐6, WH‐4, AQ‐7, AV‐9 and LY‐6) with better inhibitory activity on DPP‐IV were within the range of 23.43–128.40 μmol L−1. AQ‐7 had the best activity, with an IC50 value of 23.43 μmol L−1. Enzyme kinetics indicated the presence of various inhibition types (mixed, non‐competitive and competitive). Isothermal titration microcalorimetry showed that the main forces of the binding sites between peptide (GF‐6 or AQ‐7) and DPP‐IV were hydrogen bond, hydrophobic interaction and van der Waals force. The key residues involved in peptide–enzyme interaction were determined by molecular docking. Furthermore, at a concentration of 800 μmol L−1, GF‐6 was found to significantly increase the glucose consumption in insulin‐resistant HepG2 cells (P < 0.05) compared with the model group. CONCLUSION: Sacha inchi meal‐derived peptides displayed potent DPP‐IV inhibition activity and could be used in the health food industry and as lead compounds for diabetes therapy. © 2023 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Insulin resistance is a critical cause of metabolic dysfunctions. Metabolic dysfunction is common in patients with cancer and is associated with higher cancer recurrence rates and reduced overall survival. Yet, insulin resistance is rarely considered in the clinic and thus it is uncertain how frequently this condition occurs in patients with cancer. To address this knowledge gap, we performed a systematic review and a meta-analysis guided by the Preferred Items for Systematic Review and Meta-Analyses (PRISMA) statement. We included studies assessing insulin resistance in patients with various cancer diagnoses, using the gold-standard hyperinsulinemic–euglycemic clamp method. Studies eligible for inclusion were as follows: (1) included cancer patients older than 18 years of age; (2) included an age-matched control group consisting of individuals without cancer or other types of neoplasms; (3) measured insulin sensitivity using the hyperinsulinemic–euglycemic clamp method. We searched the databases MEDLINE, Embase, and Cochrane Central Register of Controlled Trials for articles published from database inception through March 2023 with no language restriction, supplemented by backward and forward citation searching. Bias was assessed using funnel plot. Fifteen studies satisfied the criteria. The mean insulin-stimulated rate of glucose disposal (Rd) was 7.5 mg/kg/min in control subjects (n = 154), and 4.7 mg/kg/min in patients with a cancer diagnosis (n = 187). Thus, the Rd mean difference was −2.61 mg/kg/min [95% confidence interval, −3.04; −2.19], p<.01). Heterogeneity among the included studies was insignificant (p=.24). These findings suggest that patients with a cancer diagnosis are markedly insulin resistant. As metabolic dysfunction in patients with cancer associates with increased recurrence and reduced overall survival, future studies should address if ameliorating insulin resistance in this population can improve these outcomes thereby improving patient care. Metabolic dysfunction increases cancer recurrence rates and reduces survival for patients with cancer. Insulin resistance is a critical cause of metabolic dysfunctions. To date, no comprehensive compilation of research investigating insulin resistance in cancer patients has been produced. In this meta-analysis, we found that patients with various cancers were markedly insulin-resistant. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to investigate whether a reduction in daily sedentary behavior (SB) improves insulin sensitivity in adults with metabolic syndrome in 6 months, without adding intentional exercise training. Methods: Sixty-four sedentary inactive middle-age adults with overweight and metabolic syndrome (mean (SD) age, 58 (7) yr; mean (SD) body mass index, 31.6 (4.3) kg·m−2; 27 men) were randomized into intervention and control groups. The 6-month individualized behavioral intervention supported by an interactive accelerometer and a mobile application aimed at reducing daily SB by 1 h compared with baseline. Insulin sensitivity by hyperinsulinemic euglycemic clamp, body composition by air displacement plethysmography, and fasting blood samples were analyzed before and after the intervention. SB and physical activity were measured with hip-worn accelerometers throughout the intervention. Results: SB decreased by 40 (95% confidence interval, 17–65) min·d−1, and moderate-to-vigorous physical activity increased by 20 (95% confidence interval, 11–28) min·d−1 on average in the intervention group with no significant changes in these outcomes in the control group. After 6 months, fasting plasma insulin decreased (~1 mU·L−1) in the intervention group compared with the control group (time–group, P = 0.0081), but insulin sensitivity did not change in either group. The changes in body mass or adiposity did not differ between groups. Among all participants, the changes in SB and body mass correlated inversely with the change in insulin sensitivity (r = −0.31, −0.44; P = 0.025, 0.0005, respectively). Conclusions: An intervention aimed at reducing daily SB resulted in slightly decreased fasting insulin, but had no effects on insulin sensitivity or body adiposity. However, as the change in insulin sensitivity associated with the changes in SB and body mass, multifaceted interventions targeting to weight loss are likely to be beneficial in improving whole-body insulin sensitivity. [ABSTRACT FROM AUTHOR]

Obesity is a health problem that occurs due to the wrong lifestyle, such as lack of physical activity and the wrong diet. Accumulation of adipose tissue in obesity may increases pro-inflammatory cytokines, particularly in pancreatic beta cells leading to type 2 diabetes mellitus (T2DM). Sleeve gastrectomy (SG) is an alternative therapy for T2DM in obese patients by losing about 40-60% of body weight and increasing GLP-1 secretion which stimulates increased insulin secretion. However, the SG procedure cannot reduce pro-inflammatory cytokines which promote damaged pancreatic cells. Pancreatic omentoplasty can suppress pro-inflammatory cytokines and promote the regeneration of damaged pancreatic cells. The goal of this study is to investigate HOMA-IR in obese rats with diabetes mellitus who underwent SG and pancreatic omentoplasty procedures. An experimental using pre and post-test control group design were done in this study. Eighteen Diabetes Mellitus rats were divided into 3 groups: K1 (SG), K2 (SG + Omentoplasty), and K3 (control). Blood glucose and insulin level were measured using a glucoDR Glucometer Bio-sensor kit and ELISA, respectively before and 10 days after the procedure. HOMA-IR measurement was calculated based on insulin and blood glucose level. A significant decrease of fasting blood gluocese levels were shown in all treatment groups of this study after day 10th. There was a significant increase in the insulin levels after day 10th. Highest decrease of the blood glucose levels and increase of the insulin levels were shown in group K2. Furthermore, a significant decrease of HOMA-IR was shown in the K2 on day 10th. From this study, we may conclude that SG and Pancreas Omentoplasty may significantly reduce the HOMA-IR value in obese rats with T2DM. [ABSTRACT FROM AUTHOR]

Purpose: This study evaluated the effect of body mass index (BMI) on pharmacokinetic (PK) and pharmacodynamic (PD) parameters of insulin degludec in healthy Chinese males, depending on an euglycemic glucose clamp study. Methods: Sixty-five healthy male subjects were divided into four groups according to quartile of BMI value. Group A: BMI ≤ 20.7 kg/m2; group B: 20.7 < BMI ≤ 22.5 kg/m2; group C: 22.5 < BMI ≤ 23.6 kg/m2; group D: BMI > 23.6 kg/m2. Each volunteer received a single subcutaneous dose (0.4 U/kg) of insulin degludec and accepted a 24-h euglycemic glucose clamp study. The primary PK parameters were maximum observed drug concentration (Cmax) and the area under the curve (AUCINS) for the specified time intervals. The primary PD parameters were the time to the start of glucose infusion (Tonset), maximal glucose infusion rate (GIRmax) and area under the curve (AUCGIR) for the specified time intervals. The differences of these PK/PD parameters were compared among groups. Results: Cmax and the AUC of insulin (0–6 h, 6–12 h and 0–24 h) were more than onefold higher in group A than those in groups B, C, D, and the concentration-time curve of group A was significantly shifted to the left compared with the other three groups. The GIRmax, total AUCGIR, and AUCGIR for each time interval were significantly higher in group A than those in other three groups. The proportion of AUCGIR in group A was the lowest proportion among four groups seen in the late stage. Multiple linear regression analysis showed that BMI was negatively correlated with AUCGIR,0-24 h. Conclusions: Insulin degludec in healthy Chinese male subjects with BMI ≤ 20.7 kg/m2 had a faster absorption, clearance, and a stronger glucose-lowering effect, but a steeper decrease of insulin action in the late stage after dosing. [ABSTRACT FROM AUTHOR]

Impaired insulin sensitivity (IS) and β-cell dysfunction result in hyperglycaemia in patients of acromegaly. However, alterations in incretins and their impact on glucose-insulin homeostasis in these patients still remain elusive. Twenty patients of active acromegaly (10 each, with and without diabetes) underwent hyperinsulinemic euglycaemic clamp and mixed meal test, before and after surgery, to measure indices of IS, β-cell function, GIP, GLP-1 and glucagon response. Immunohistochemistry (IHC) for GIP and GLP-1 was also done on intestinal biopsies of all acromegalics and healthy controls. Patients of acromegaly, irrespective of presence or absence of hyperglycaemia, had similar degree of insulin resistance, however patients with diabetes exhibited hyperglucagonemia, and compromised β-cell function despite significantly higher GIP levels. After surgery, indices of IS improved, GIP and glucagon levels decreased significantly in both the groups, while there was no significant change in indices of β-cell function in those with hyperglycaemia. IHC positivity for GIP, but not GLP-1, staining cells in duodenum and colon was significantly lower in acromegalics with diabetes as compared to healthy controls possibly because of high K-cell turnover. Chronic GH excess induces an equipoise insulin resistance in patients of acromegaly irrespective of their glycaemic status. Dysglycaemia in these patients is an outcome of β-cell dysfunction consequent to GIP resistance and hyperglucagonemia.